Exported on: 25/04/2023

Tuberculosis
Practical guide for clinicians, nurses, laboratory technicians and medical auxiliaries

© Médecins Sans Frontières

All rights reserved for all countries. No reproduction, translation and adaptation may be done without the prior permission of the
Copyright owner.

Médecins Sans Frontières and Partners in Health. Tuberculosis.

February 2023
ISBN 978-2-37585-208-8
Table of contents
Authors/Contributors

Introduction

Abbreviations and acronyms

Chapter 1: Introduction and epidemiology

1.1 Characteristics of Mycobacterium tuberculosis bacillus
1.2 Transmission
1.3 Evolution of tuberculosis infection and disease in humans
1.4 Prognosis
1.5 Factors modifying tuberculosis epidemiology
1.6 Epidemiological indicators
1.7 Global burden of tuberculosis

Chapter 2: Clinical presentation

2.1 Pulmonary tuberculosis
2.2 Extrapulmonary tuberculosis
2.3 Disseminated or miliary tuberculosis
2.4 Clinical presentation in HIV-infected patients
2.5 Summary of clinical presentations of tuberculosis

Chapter 3: Diagnosis and follow-up investigations

3.1 Active tuberculosis
3.2 Latent tuberculosis infection
3.3 Other investigations

Chapter 4: Diagnostic algorithms for pulmonary tuberculosis (PT B) in adults and adolescents
4.1 Guiding principles for the use of the algorithms
4.2 Adult and adolescent algorithms

Chapter 5: Diagnosis of active tuberculosis in children

5.1 Introduction
5.2 Diagnostic approach
5.3 Paediatric diagnostic algorithms

Chapter 6: Intensive case finding in HIV-infected individuals

6.1 Routine screening
6.2 Purposes of screening

Chapter 7: Case definitions for registration

7.1 Definition of a tuberculosis case
7.2 History of prior anti-T B treatment
7.3 Anatomical site of the disease
7.4 Bacteriological status
7.5 HIV status
7.6 Other co-morbidities
7.7 Summary of patient registration
Chapter 8: Tuberculosis drugs and treatment regimens
8.1 Introduction
8.2 Standard code for treatment regimens
8.3 Drugs for drug-susceptible tuberculosis
8.4 Drugs for drug-resistant tuberculosis
8.5 Tuberculosis drug formulations

Chapter 9: Treatment of drug-susceptible tuberculosis

9.1 Introduction
9.2 Conventional treatment regimens
9.3 Alternative treatment regimens
9.4 Special situations
9.5 Adjunctive therapy
9.6 Patient monitoring
9.7 Adverse effects
9.8 Treatment adaptation and change of treatment
9.9 Treatment interruptions

Chapter 10: Treatment of multidrug-resistant and rifampicin-resistant tuberculosis

10.1 Introduction
10.2 Treatment regimens in programmatic conditions
10.3 Treatment regimens in operational research conditions
10.4 Special situations
10.5 Adjunctive therapy
10.6 Patient monitoring
10.7 Adverse effects
10.8 Treatment adaptation and change of treatment
10.9 Treatment interruptions
10.10 Surgery
10.11 Treatment failure and palliative care

Chapter 11: Treatment of mono- and poly-drug resistant tuberculosis (PDR-T B)

11.1 Treatment schemes
11.2 Treatment algorithms for PDR-T B

Chapter 12: Tuberculosis and HIV co-infection

12.1 HIV counselling and testing
12.2 Concomitant treatment of tuberculosis and HIV co-infection
12.3 Interactions and overlapping toxicities between tuberculosis drugs and antiretrovirals
12.4 Prevention of opportunistic infections
12.5 Immune reconstitution inflammatory syndrome
12.6 Patient monitoring

Chapter 13: Adherence to tuberculosis treatment

13.1 Introduction
13.2 Treatment delivery model
13.3 Factors that influence adherence
 13.4 Patient education and support

Chapter 14: Tuberculosis infection control

14.1 Introduction
14.2 Implementation of T B IC strategies
14.3 Administrative controls
14.4 Environmental controls
14.5 Personal protective measures
14.6 Hospital hygiene
14.7 Patients’ homes

Chapter 15: Follow-up of staff exposed to tuberculosis

15.1 Introduction
15.2 Baseline assessment
15.3 BCG vaccination
15.4 Follow-up

Chapter 16: Treatment of latent tuberculosis infection

16.1 Introduction
16.2 Target populations
16.3 Latent tuberculosis infection treatment regimens
16.4 Latent tuberculosis infection in HIV-infected patients
16.5 Latent tuberculosis infection in household contacts
16.6 Latent tuberculosis infection in other individuals at risk
16.7 Latent tuberculosis infection and multidrug-resistant tuberculosis
16.8 Follow-up for patients treated for latent tuberculosis infection

Chapter 17: Monitoring and evaluation

17.1 Introduction
17.2 Definitions of treatment outcomes
17.3 Recording tools
17.4 Reporting
17.5 Programme assessment

Appendices
Appendix 1. Xpert assays
Appendix 2. Interpretation of Xpert assay results
Appendix 3. Sputum specimen: collection, storage and shipment
Appendix 4. Sputum smear microscopy
Appendix 5. T ime required for diagnostic test results
Appendix 6. Ventilated work station (VWS) and bio-safety cabinet (BSC)
Appendix 7. Lymph node fine needle aspiration
Appendix 8. Protein estimation
Appendix 9. Tuberculin skin test
Appendix 10. Drug information sheets and patient instructions for the treatment of tuberculosis
Tuberculosis drug information sheets

Amikacin (Am)
Amoxicillin/clavulanic acid ratio 4:1 (Amx/Clv)

Bedaquiline (Bdq)

Clofazimine (Cfz)

Cycloserine (Cs) or terizidone (Trd)

Delamanid (Dlm)

Ethambutol (E)

Ethionamide (Eto) or prothionamide (Pto)

Imipenem/cilastatin (Ipm/Cln)

Isoniazid - Standard dose (H)

Isoniazid - High dose (Hh)

Levofloxacin (Lfx)

Linezolid (Lzd)

Meropenem (Mpm)

Moxifloxacin (Mfx)

Para-aminosalicylate sodium (PAS)

Pretomanid (Pa)

Pyrazinamide (Z)

Rifabutin (Rfb)

Rifampicin (R)

Rifapentine (P)

Streptomycin (S)
Patient instructions

Patients on drug-susceptible T B treatment

Patients on drug-resistant T B treatment

Appendix 11. Use of tuberculosis drugs in pregnant or breastfeeding women
Appendix 12. Dose adjustments in renal insufficiency
Appendix 13. Daily dose of tuberculosis drugs using fixed-dose combinations
Appendix 14. Monitoring of patients on drug-susceptible tuberculosis treatment
Appendix 15. Monitoring of patients on drug-resistant tuberculosis treatment
Appendix 16. Additional investigations in drug-resistant tuberculosis
Appendix 16. Basic T B infection control risk assessment tool
Appendix 17. Management of adverse effects
Gastrointestinal disorders

Abdominal pain

Diarrhoea

Epigastric pain

Hepatotoxicity

Metallic taste
Nausea and vomiting
Neurotoxicity

Depression

Headache

Optic neuritis

Ototoxicity

Peripheral neuropathy

Psychosis

Seizures
Endocrine disorders

Gynecomastia

Hypothyroidism
Dermatological disorders

Alopecia

Fungal infection

Photosensitivity

Skin reactions
Musculoskeletal disorders

Arthralgias

Tendinitis/tendon rupture
Miscellaneous

Electrolyte disorders

Haematologic disorders

Lactic acidosis

Nephrotoxicity

QT prolongation
Appendix 17. Air change per hour (ACH) measurement recommendations
Appendix 18. Compassionate use
Appendix 18. Advantages and disadvantages of ventilation techniques
Appendix 19. Drug interactions and overlapping toxicities
Appendix 19. Upper room ultraviolet germicidal irradiation (UVGI) system
Appendix 20. Treatment supporters
Appendix 21. Patient therapeutic education
Appendix 23. Treatment card for patients on first-line anti-T B therapy
Appendix 24. Tuberculosis register for patients on first-line anti-T B therapy
Appendix 25. Treatment card for patients on second-line anti-T B therapy
Appendix 26. Tuberculosis register for patients on second-line anti-T B therapy
Appendix 27. Respirators
Appendix 28. Surgical masks
Appendix 28. Request form for sputum culture, LPA and DST
Appendix 29. BCG vaccine
Appendix 29. Sputum smear microscopy register
Appendix 30. Xpert MT B/RIF register
Appendix 31. Drug-o-gram
Appendix 32. Quaterly report
Appendix 33. Report on detection and enrolment of T B cases with rifampicin and multidrug-resistance
Appendix 34. Request form for smear microscopy and Xpert assays
Appendix 34. Report of final outcomes of drug-resistant tuberculosis
Appendix 35. Check-list for the evaluation of a T B service
Authors/Contributors
Chief Authors
Francis Varaine, M.D.
Michael L. Rich, M.D., M.P.H.

Technical Editor
Véronique Grouzard

Contributing Authors
PIH
Amy Elizabeth Barrera-Cancedda, Salmaan Keshavjee, Carole Mitnick, Joia Mukherjee, Anne Peruski, Kwonjune Seung
MSF
Elisa Ardizzoni, Saar Baert, Suna Balkan, Karen Day, Philipp Ducros, Gabriella Ferlazzo, Cecilia Ferreyra, Marianne Gale, Pamela
Hepple, Myriam Henkens, Cathy Hewison, Northan Hurtado, Frauke Jochims, Jean Rigal, Joannie Roy, Peter Saranchuk, Clara Van
Gulik, Carole Zen Ruffinen

Published by
Médecins Sans Frontières
Partners In Health
Introduction
Tuberculosis is an infectious disease caused by Mycobacterium tuberculosis. Tuberculosis typically attacks the lungs, but can also
affect other parts of the body. T he disease has become rare in high income countries, but is still a major public health problem in
low- and middle-income countries.

It is estimated that between the years 2000 and 2010, eight to nine million new cases emerged each year. Approximately 1.5 million
people die from the disease each year. In adults, tuberculosis is the second leading cause of death due to an infectious disease
(after AIDS), with 95% of deaths occurring in low-income countries. Tuberculosis is a major problem of children in poor countries
where it kills over 100,000 children each year.

T he treatment of tuberculosis remains a constraint for patients and a heavy burden for the healthcare system. Drug-susceptible
tuberculosis requires at least six months of therapy under close supervision. A treatment for multidrug-resistant tuberculosis
requires nearly two years of treatment with poorly tolerated and less effective drugs. In most places the diagnosis still relies mainly
on direct microscopy that is unable to detect a large proportion of patients. T he BCG vaccine, developed almost a century ago,
confers only partial protection.

After 40 years of minimal progress in the tools to fight tuberculosis there are some reasons for hope. A few new drugs are reaching
the final phase of development; a new molecular test that can be decentralized to some extent and allows the rapid diagnosis of
tuberculosis and of resistance to rifampicin has been introduced. T hough this is undeniable progress, much will be needed to bring
the new tools and drugs to the patients in need. Furthermore, a true “point of care” diagnostic test still does not exist and little
progress has been made in research for a more effective vaccine.

Case management of patients does not necessarily have to involve a major, vertical programme. It should be incorporated into the
framework of other medical activities in order to offer comprehensive and integrated treatment even if the number of patients
being treated is relatively small.

T his guide has been developed jointly by Médecins Sans Frontières and Partners In Health. It aims at providing useful information to
the clinicians and health staff for the comprehensive management of tuberculosis. Forms of susceptible and resistant tuberculosis,
tuberculosis in children, and HIV co-infection are all fully addressed.

As treatment protocols are constantly changing, medical staff are encouraged to check this website for updates.
Abbreviations and acronyms
ACH Air change per hour

AFB Acid-fast bacilli

AIDS Acquired immunodeficiency syndrome

Amk Amikacin

Amx/Clv Amoxicillin/clavulanic acid

ARI Annual risk of infection

ART Antiretroviral therapy

ARV Antiretroviral

BCG Bacillus Calmette-Guérin

Bdq Bedaquiline

CDC United States Centers for Disease Control and Prevention

Cfz Clofazimine

Cm Capreomycin

CMX Cotrimoxazole

CPC Cetylpyridinum chloride

CPT Cotrimoxazole preventive therapy

Cs Cycloserine

CXR Chest X-ray

DOT Directly observed therapy

DR Drug resistance

DR-T B Drug-resistant tuberculosis

DST Drug susceptibility test(ing)

E Ethambutol

ECG Electrocardiogram

EPT B Extrapulmonary tuberculosis

Eto Ethionamide

FDC Fixed-dose combination

FNAC Fine needle aspiration cytology

FQ Fluoroquinolone

GFR Glomerular filtration rate

H Isoniazid

HCW Health care worker

HIV Human immunodeficiency virus

HPF High-power field

IC Infection control

IM Intramuscular

Imp/Cln Imipenem/cilastatin

IPT Isoniazid preventive therapy

IRIS Immune reconstitution inflammatory syndrome

IUAT LD International Union against Tuberculosis and Lung Disease

Km Kanamycin

LFT Liver function test

Lfx Levofloxacin

LPA Line probe assay

Lzd Linezolid

MDR Multidrug resistance

MDR-T B Multidrug-resistant tuberculosis

Mfx Moxifloxacin

MGIT Mycobacteria growth indicator tube

MODS Microscopic observation of drug susceptibility

Mpm Meropenem

NNRT I Non-nucleoside reverse transcriptase inhibitor

NRT I Nucleoside reverse transcriptase inhibitor

NT M Non tuberculous mycobacteria

Ofx Ofloxacin

PAS Para-aminosalicylic acid

PCP Pneumocystosis

PCR Polymerase chain reaction

PI Protease inhibitor

PO Orally (per os)

Pto Prothionamide

R Rifampicin

Rfb Rifabutin

RR Rifampicin resistance

S Streptomycin

TAT Turn around time

TB Tuberculosis

T hz T hioacetazone

T LA T hin-layer agar

T SH T hyroid-stimulating hormone

T ST Tuberculin skin test

UVGI Ultraviolet germicidal irradiation

WHO World Health Organization

XDR Extensive drug resistance

XDR-T B Extensively drug-resistant tuberculosis

Z Pyrazinamide
Chapter 1: Introduction and epidemiology
1.1 Characteristics of Mycobacterium tuberculosis bacillus

1.2 Transmission

1.3 Evolution of tuberculosis infection and disease in humans

1.4 Prognosis

1.5 Factors modifying tuberculosis epidemiology

1.6 Epidemiological indicators

1.7 Global burden of tuberculosis

Update: January 2022

1.1 Characteristics of Mycobacterium tuberculosis
bacillus
Mycobacterium tuberculosis, along with M. bovis, M. africanum, M. microti and others, make up the Mycobacterium
tuberculosis complex, a group of bacteria that cause clinical tuberculosis (T B) in humans.
Most T B cases are caused by M. tuberculosis. Cases due to other species are far less prevalent.

M. tuberculosis is a small, rod-shaped, strictly aerobic, acid-fast bacillus a . Like other mycobacteria, it is slow growing, resulting in
more gradual development of disease when compared with other bacterial infections.

Footnotes
(a) Acid-f ast bacilli are bacilli, which once st ained, resist discolorat ion by acid and alcohol.
1.2 Transmission
M. tuberculosis is transmitted from human-to-human and spread is mainly airborne. T he source of infection is usually a patient with
pulmonary or laryngeal T B. During coughing, speaking, or sneezing, the patient produces tiny infectious droplets. T hese particles,
called droplet nuclei, are about 1 to 5 microns in diameter. Depending on the environment, they can remain suspended in the air for
several hours.

Transmission may occur when these infectious droplets are inhaled. UV light (sunshine or artificial sources) and ventilation reduce
the probability of transmission (Chapter 14).

Other modes of transmission are far less common. Inoculation of cutaneous or mucous membranes rarely occurs, although such
cases have been observed in laboratory personnel. Congenital infection (by transplacental transmission or via aspiration or
swallowing of infected amniotic fluid at birth) has been reported, but is very rare. Transmission through breast milk does not occur.

T he infectiousness of a patient is associated with the quantity of bacilli contained in their sputum. Patients with smear-positive
sputum on microscopy are by far the most infectious. T hose with smear-negative/culture-positive results are less infectious, but
still contribute to T B transmission due to more frequent delays in diagnosis.

Patients infected with M. tuberculosis, but who have not developed active T B (latent tuberculosis infection), are not infectious.
Patients with extrapulmonary T B (EPT B) are only infectious in exceptional circumstances.

Children are generally much less infectious than adults. T his may be due to weaker cough mechanics, less sputum production and
lower bacillary load.

Not everyone who is exposed to an infectious T B patient becomes infected with M. tuberculosis. T he probability that T B will be
transmitted depends on several factors:

Infectiousness of the source (the most important factor)

• Bacteriological status: smear-positive patients are the most infectious.
• Virulence of the bacilli: some strains are highly transmissible (and/or more likely to cause active T B).

Environment where the exposure occurred

• Outdoor environments or those with good ventilation and sunlight are less likely to lead to transmission. Small rooms or rooms
with no ventilation are conditions most likely to lead to transmission.
• T he proximity of the person to the patient is also important (e.g. the risk is higher if the person sleeps next to the patient than if
they sleep 20 metres away from the patient).

Duration of exposure
People in close and prolonged contact with T B patients are at highest risk of becoming infected with M. tuberculosis. T hey may be
family members, roommates, friends, co-workers or other people who spend several hours a day with the infectious patient.

T he best way to stop transmission is to start effective T B treatment as soon as possible. It is estimated that a person with
untreated smear-positive T B transmits the bacillus to 10 to 20 people a year (with variations according to living conditions and
environment).
1.3 Evolution of tuberculosis infection and disease in
humans
When a person inhales infectious droplets containing M. tuberculosis, most of the larger droplets become lodged in the upper
respiratory tract (nose and throat) where infection is unlikely to develop. However, smaller droplet nuclei may reach the small air
sacs of the lung (the alveoli) where infection can occur.

1.3.1 Primary infection and latent tuberculosis infection

After transmission, M. tuberculosis multiplies slowly, in most cases in the terminal alveoli of the lungs (primary focus) and in the
lymph nodes of corresponding drainage areas: this is the primary infection. T he primary focus and related hilar lymphadenopathy
form the primary complex.

In one to two months, due to the action of lymphocytes and macrophages (cellular immunity), the primary focus is contained and
encapsulated, with a central zone of parenchymal necrosis (caseous lesions). It is not usually detectable on chest x-ray, unless it
calcifies or grows substantially. Primary infection is usually asymptomatic. In most cases (90 to 95% of non-HIV infected patients),
the pulmonary lesions gradually heal.

During the primary infection, specific immunity develops and a positive skin reaction to tuberculin is observed [1] . T his immune
response may persist without clinical signs of T B. T he patient is infected by M. tuberculosis, but does not develop the disease.
T his is referred to as latent tuberculosis infection (LT BI).

In 5 to 10% of infected people, primary infection and/or LT BI progresses to active T B over their lifetime. For HIV co-infected
patients, this risk is much higher.

1.3.2 Active tuberculosis

Before immunity is established, bacilli from the primary infectious focus or from a near-by lymph node can be transported and
disseminated throughout the body via the lymph system or the bloodstream.
Secondary foci can develop this way, particularly in the lungs, lymph nodes, serous membranes, meninges, bones and kidneys. As
soon as an immune response is mounted, most of these foci resolve spontaneously. However, some bacilli may remain dormant in
the secondary foci for months and sometimes years.
Different factors can reduce the immune response (e.g. HIV infection) and lead to reactivation of the bacilli and their multiplication
in one or more of these foci. T his reactivation or progression of the primary or secondary foci results in active T B [2] .
An active T B lesion contains actively, slowly or sporadically multiplying bacilli as well as dormant bacilli.
While active T B may occur months or years following primary infection, half of T B cases appear in the year following infection.

1.3.3 Risk factors for developing active tuberculosis

Certain factors increase the risk of developing active T B within the first two years of being infected. T hese factors include any
factor that results in a weakened immune system, damaged lungs and the intensity and duration of exposure.

Host immune response factors:

HIV infection
Children under 5 years [3] [4]
Malnutrition
Persons over 60 years
Diabetes mellitus
Other risk factors: prolonged corticosteroid therapy (g. prednisolone) and other immunosuppressive therapies, severe kidney
disease, alcoholism, substance abuse, certain types of cancer (e.g. leukaemia, Hodgkin's lymphoma, cancer of the head and
neck); pregnancy

Conditions that damage the lung:

Tobacco smoking
 Silicosis
Chronic obstructive pulmonary disease (COPD)

Intensity of exposure (high number of inhaled bacilli):

Highly infectious source
Poorly ventilated environment
Proximity with infectious source, including residents and employees of institutions such as prisons, boarding schools and
residential care facilities
Long duration of exposure

References
1. Ahmad, S. Pathogenesis, immunology, and diagnosis of latent Mycobacterium tuberculosis infection. Clin Dev Immunol. 2011: p. 814943.
ht t p://downloads.hindawi.com/journals/jir/2011/814943.pdf

2. Ai, JW, et al. Updates on the risk factors for latent tuberculosis reactivation and their managements. Emerging Microbes & Inf ect ions, 2016. 5:
p. e10.
ht t ps://www.ncbi.nlm.nih.gov/pmc/art icles/PMC4777925/pdf /emi201610a.pdf

3. Marais, BG, et al. The natural history of childhood intra-thoracic tuberculosis: A critical review of literature from the pre-chemotherapy era . The
int ernat ional journal of t uberculosis and lung disease: t he of ficial journal of t he Int ernat ional Union against Tuberculosis and Lung
Disease. 2004. 8(4) p. 392-402.
ht t ps://www.ingent aconnect .com/cont ent /iuat ld/ijt ld/2004/00000008/00000004/art 00002;jsessionid=11hrh2bb6hf pv.x-ic-live-03#

4. Erkens, CG., et al. Risk of developing tuberculosis disease among persons diagnosed with latent tuberculosis infection in the Netherlands. Eur
Respir J, 2016. 48(5): p. 1420-1428.
ht t ps://erj.ersjournals.com/cont ent /erj/48/5/1420.f ull.pdf
1.4 Prognosis
Without treatment, T B is a severe and potentially fatal disease. After 5 years without treatment, the outcome of smear-positive
pulmonary T B (PT B) in non-HIV-infected patients is as follows [1] :
50 to 60% die (case fatality ratio (CFR) for untreated T B);
20 to 25% are cured (spontaneous cure);
20 to 25% continue to have symptoms.

In non-HIV infected patients, the CFR is estimated at 3% [2] . Untreated T B in HIV-infected patients (not on effective antiretroviral
therapy) is almost always fatal. Even on antiretroviral therapy, the CFR is higher than in non-HIV infected patients [3] [4] .

Risk factors for poor outcomes of T B treatment (death and relapse) include co-morbidities (e.g. HIV infection, diabetes, COPD),
cavities on chest x-ray, high bacillary load and resistance to T B drugs.

References
1. Tiemersma EW, van der Werf MJ, Borgdorf f MW, Williams BG, Nagelkerke NJ. Natural history of tuberculosis: duration and fatality of untreated
pulmonary tuberculosis in HIV negative patients: a systematic review. PLoS One. 2011;6(4):e17601. Published 2011 Apr 4.
ht t ps://www.ncbi.nlm.nih.gov/pmc/art icles/PMC3070694/pdf /pone.0017601.pdf

2. St raet emans M, Glaziou P, Bierrenbach AL, Sismanidis C, van der Werf MJ (2011). Assessing Tuberculosis Case Fatality Ratio: A Meta-
Analysis. PLoS ONE 6(6): e20755.
ht t ps://doi.org/10.1371/journal.pone.0020755
ht t ps://journals.plos.org/plosone/art icle?id=10.1371/journal.pone.0020755

3. World Healt h Organizat ion. Global Tuberculosis Report 2021. Geneva: World Healt h Organizat ion; 2021.
ht t ps://apps.who.int /iris/rest /bit st reams/1379788/ret rieve

4. Manosut hi, W., et al. Survival rate and risk factors of mortality among HIV/tuberculosis-coinfected patients with and without antiretroviral
therapy. J Acquir Immune Defic Syndr, 2006. 43(1): p. 42-6.
ht t ps://journals.lww.com/jaids/f ullt ext /2006/09000/Survival_Rat e_and_Risk_Fact ors_of _Mort alit y_Among.7.aspx
1.5 Factors modifying tuberculosis epidemiology
Five major factors influence T B epidemiology: (1) socioeconomic conditions, (2) T B treatment, (3) HIV infection, (4) diabetes and
(5) BCG vaccination.

1.5.1 Socioeconomic conditions

T he principal factors leading to a reduction in T B cases are improved social and housing conditions. Most cases occur in low-
income countries. In industrialised countries, T B generally affects the most disadvantaged social groups.

1.5.2 Tuberculosis treatment

Diagnosing and initiating effective treatment in a patient early during their T B disease before they can infect multiple people is
considered the most effective preventive measure against T B. Once an effective T B treatment is started, there is a rapid
reduction in transmission[1] [2] .

Since the introduction of T B treatment, the risk of T B infection decreased by approximately 10% per year in industrialised
countries [3] . T his trend was observed in countries with a BCG vaccination programme as well as in those without one. Detection
programmes, diagnosis and treatment of T B contributed to this reduction in the risk of T B infection.

1.5.3 HIV infection

Immunodeficiency induced by HIV infection is a major risk factor for progression to active T B and has a considerable impact on the
epidemiology of T B. While the lifetime risk of developing active T B in the general population is 5 to 10% after infection with M.
tuberculosis, this risk is approximately 10% per year in patients co-infected with HIV and M. tuberculosis. Approximately 8% of
incident T B cases in the world are among HIV-infected patients (highest in the WHO African Region, more than 50% in parts of
southern Africa) [4] .

1.5.4 Diabetes
T he risk of T B among people with diabetes is higher than among those without diabetes. It is estimated that diabetes contributes
to 15% of T B cases worldwide [5] . Diabetes is also associated with poor absorption of T B drugs and therefore higher rates of
drug resistant tuberculosis (DR-T B).

1.5.5 BCG vaccination

Effectiveness of BCG at the individual level
BCG vaccination, if given at birth, is highly effective against the severe forms of T B (miliary and meningitis) in children[6] .

Epidemiological impact of vaccination

Despite some protection from the BCG vaccination, the impact of BCG vaccination on T B transmission and the T B epidemic is
considered negligible [7] .

1.5.6 Other factors

Other modifying factors include infection control measures (Chapter 14) and treatment of LT BI (Chapter 16). T he degree to which
in a given context the T B epidemiology is affected by these measures is not known.

References
1. Nardell, EA. Transmission and institutional infection control of tuberculosis. Cold Spring Harb Perspect Med. 2016;6(2):1-12.
ht t ps://www.ncbi.nlm.nih.gov/pmc/art icles/PMC4743075/pdf /cshperspect med-TUB-a018192.pdf
2. Giovanni Bat t ist a Migliori, Lia D'Ambrosio, Rosella Cent is, Mart in Van Den Boom, Soudeh Ehsani, Masoud Dara. Guiding Principles to
Reduce Tuberculosis Transmission in the WHO European Region. World Healt h Organizat ion, 2018.
ht t ps://www.euro.who.int /__dat a/asset s/pdf _file/0008/377954/ic-principles-eng.pdf

3. E Vynnycky and PEM Fine. Interpreting the decline of tuberculosis: the role of secular trends in effective contact. Int ernat ional Journal of
Epidemiology. 1999; 28:327-334

4. World Healt h Organizat ion. Global Tuberculosis Report 2021. Geneva: World Healt h Organizat ion; 2021.
ht t ps://apps.who.int /iris/rest /bit st reams/1379788/ret rieve

5. World Healt h Organizat ion & Int ernat ional Union against Tuberculosis and Lung Disease. (‎2011)‎. Collaborative framework for care and
control of tuberculosis and diabetes. World Healt h Organizat ion.
ht t ps://apps.who.int /iris/handle/10665/44698

6. World Healt h Organizat ion. (2018). BCG vaccines: WHO position paper – February 2018. Weekly Epidemiological Record, 93(‎08)‎,73-
96. World Healt h Organizat ion.
ht t ps://apps.who.int /iris/bit st ream/handle/10665/260307/WER9308-73-96.pdf ?sequence=1&isAllowed=y

7. Pai, M., Behr, M., Dowdy, D, et al. Tuberculosis. Nat Rev Dis Primers 2, 16076 (2016).
1.6 Epidemiological indicators
When a National T B Programme (NT P) functions well, indicators can be obtained from the local authorities and NT P.
T he WHO tuberculosis country profiles also provide an estimation of T B indicators by individual country a .

Box 1.1 - Most common indicators

Annual incidence rate of TB cases (a)

Numerator: number of new T B cases (all forms) that occur in a population over one year
Denominator: population at the start of the year

Annual incidence rate of smear-positive PTB cases (a)

Numerator: number of new smear-positive PT B cases that occur in a population over one year
Denominator: population at the start of the year

Prevalence of smear-positive PTB cases over a given period of time, usually one year (b)
Numerator: number of smear-positive PT B cases
Denominator: population at the start of the period of time

Proportion of multidrug- and rifampicin-resistant TB cases among TB cases over a given period of time (c)
Numerator: number of multidrug- and rifampicin-resistant T B cases
Denominators:
- Total number of T B cases
- Number of new T B cases
- Number of previously treated T B cases

Proportion of extensively drug-resistant TB cases among TB cases over a given period of time (c)
Numerator: number of extensively drug-resistant cases
Denominators: as for multidrug- and rifampicin-resistant T B cases

Proportion of HIV-infected patients among new TB cases over a given period of time (c)
Numerator: number of HIV-infected patients
Denominator: number of new T B cases

(a) The rat e is expressed as t he number of new TB cases (or new smear-posit ive PTB cases) per 100,000 populat ion.
(b) Prevalence is expressed as t he number of smear-posit ive PTB cases per 100,000 populat ion. It includes new and pre-exist ing cases.
Prevalence represent s approximat ely double t he incidence rat e.
(c) Proport ion is expressed in %.

Footnotes
(a) For more inf ormat ion:
ht t ps://worldhealt horg.shinyapps.io/t b_profiles/?_input s_&ent it y_t ype=%22group%22&lan=%22FR%22
1.7 Global burden of tuberculosis
1.7.1 Latent tuberculosis infection
T he global prevalence of LT BI is unknown due to difficulties in diagnosis. However, WHO estimates that one-quarter of the world
population has LT BI [1] .

1.7.2 Active tuberculosis

Globally, active T B remains a leading cause of death from infectious disease.

WHO estimates that each year there are approximately 10 million incident cases of T B and 1.5 million deaths due to T B, including
1.3 million among HIV-negative individuals and 214,000 among HIV-infected individuals [2] .
Children under 15 years account for 11% of all estimated T B cases [2] . However, T B cases in children are frequently undiagnosed
and unreported.

While the absolute number of global T B cases is stable, there are large individual country and regional differences in incidence and
prevalence.

Most T B cases are in Southeast Asia (43%), Africa (25%) and the Western Pacific (18%), with lower percentages in the Eastern
Mediterranean, the Americas and Europe [2] .

1.7.3 Drug-resistant tuberculosis

Drug-resistant T B (DR-T B) is a growing worldwide problem, and no region is spared.

WHO estimates that annually worldwide there are [3] :

• More than one million rifampicin-susceptible and isoniazid-resistant T B (Hr-T B) cases (11% of all incident T B cases).
• 3.3% of new cases and 18% of previously treated cases, with multidrug-resistant T B (MDR-T B) a and rifampicin-resistant T B
(RR-T B) b representing 465,000 cases and 182,000 deaths.

In Eastern Europe and Central Asia, T B incidence is lower than in Southeast Asia and Africa, but up to 30% of new and 65% of
retreatment cases exhibit rifampicin-resistance.

In China and India, there is a low proportion of rifampicin-resistant cases among all T B cases. However, because of their large
populations, these two countries represent 41% of global MDR/RR-T B cases.

Resources for detecting drug resistance are limited in many parts of Africa. However, available data suggest that the MDR-T B
burden is significant, especially in the south.

T he prevalence of extensively drug-resistant T B (XDR-T B) c , according to the new WHO definition, is currently unknown.

Footnotes
(a) Mult idrug-resist ant : resist ance t o at least rif ampicin and isoniazid.

(b) Rif ampicin-resist ant : resist ance t o rif ampicin, wit h or wit hout resist ance t o ot her TB drugs.

(c) Ext ensively drug-resist ant : rif ampicin-resist ance wit h resist ance t o any fluoroquinolone, and at least eit her bedaquiline or linezolid.

References
1. Houben RM, Dodd PJ. The Global Burden of Latent Tuberculosis Infection: A Re-estimation Using Mathematical Modelling. PLoS Med.
2016;13(10):e1002152. Published 2016 Oct 25.
ht t ps://www.ncbi.nlm.nih.gov/pmc/art icles/PMC5079585/pdf /pmed.1002152.pdf
2. World Healt h Organizat ion. Global Tuberculosis Report 2021. Geneva: World Healt h Organizat ion; 2021.
ht t ps://apps.who.int /iris/rest /bit st reams/1379788/ret rieve

3. World Healt h Organizat ion. Global Tuberculosis Report 2020. Geneva: World Healt h Organizat ion; 2020.
ht t ps://apps.who.int /iris/rest /bit st reams/1312164/ret rieve
Chapter 2: Clinical presentation
2.1 Pulmonary tuberculosis

2.2 Extrapulmonary tuberculosis

2.3 Disseminated or miliary tuberculosis

2.4 Clinical presentation in HIV-infected patients

2.5 Summary of clinical presentations of tuberculosis

Update: January 2022

2.1 Pulmonary tuberculosis
Prolonged cough (more than 2 weeks), with or without sputum production, is a common symptom in patients with pulmonary
tuberculosis (PT B).

Other frequent, less specific, signs and symptoms include weight loss, anorexia, fatigue, haemoptysis (blood in sputum), shortness
of breath, chest pain, moderate fever and night sweats.

Signs and symptoms may vary between individuals and generally evolve in a chronic, insidious manner. History-taking is therefore of
the utmost importance.

Advanced forms and complications are common:

Respiratory insufficiency due to extensive lesions and destroyed lungs;
Massive haemoptysis due to large cavities with hyper-vascularisation and erosion of vessels;
Pneumothorax due to the rupture of a cavity in the pleural space.

In endemic areas, the diagnosis of PT B should be considered in any patient consulting for respiratory symptoms lasting more than
2 weeks.

Table 2.1 provides a differential diagnosis of PT B for non-HIV infected patients.

Table 2.1 - Differential diagnosis for PT B (non-HIV infected patients)

 Diseases Remarks

Bacterial pneumonia Usually more acute and shorter in duration; high fever often present.
Response to antibiotics with no anti-T B activity suggests bacterial pneumonia.
Lobar consolidation is typical of bacterial pneumonia; however, CXR alone cannot differentiate PT B
from bacterial pneumonia.

Pulmonary abscess May arise from aspiration in individuals with impaired consciousness (coma, intoxication with
alcohol/drugs, etc.).
Foul-smelling, purulent sputum.
Cavities typically have a thick wall and air fluid levels.

Bronchiectasis Frequent complication of successive, poorly-treated bronchopulmonary infections in tropical

regions.
Characterised by chronic or repeated episodes of productive cough.
Hemoptysis, usually mild, can be present.

Lung cancer History of smoking or environmental exposure (working in a mine, etc.).

Haemoptysis in 20 to 50% of patients.

Paragonimiasis To be ruled out in presumed PT B cases in endemic areas (certain areas of Southeast Asia, West
(lung flukes) Africa and Latin America).

Pulmonary In Latin America, the Middle East, some Sub-Saharan African countries and China.
echinococcosis Lung involvement may cause chronic cough, with or without haemoptysis.
(hydatid disease) Cysts can mimic T B cavities.

Pneumocystosis Common in patients with advanced HIV disease and patients receiving long-term, even low dose,
corticosteroid therapy.

Less common Silicosis, sarcoidosis, melioidosis.

diseases Cryptococcosis, aspergillosis, histoplasmosis.

For differential diagnosis in HIV-infected patients see Section 2.4.

2.2 Extrapulmonary tuberculosis
Starting from a pulmonary localisation (primary infection), M. tuberculosis can spread to other organs during a silent phase, usually
soon after primary infection (Chapter 1). Active T B can develop in many other parts of the body, particularly in lymph nodes,
meninges, bones and joints, kidneys, genital organs and the abdominal cavity.

Extrapulmonary tuberculosis (EPT B) can develop at any age. Due to relative immunodeficiency, young children, HIV-infected and
malnourished patients are more at risk of developing EPT B.

Approximately 15% of global T B cases are classified as EPT B, although this figure varies according the local epidemiology [1] .

A patient with EPT B may also have pulmonary involvement, which should be searched for whenever EPT B is diagnosed or
suspected.

Table 2.3 at the end of this chapter summarises the characteristics of EPT B.

2.2.1 Lymph node tuberculosis

Lymph node T B is common, particularly in certain areas of Africa and Asia, and especially in children and HIV-infected patients.

T he presentation of lymph node T B is a non-inflammatory adenopathy. Nodes are cold and painless, multiple (usually bilateral) or
single, evolving in a chronic mode towards softening and fistulisation. Cervical localisation is most frequent. Axillary and mediastinal
localisations are also common. Other sites may be involved.
Diagnosis may be clinical, but whenever possible, fine needle aspiration should be performed (Chapter 3 and Appendix 7).
Adenopathy usually disappears within 3 months of treatment initiation. Paradoxical reactions may occur at the beginning of
treatment (appearance of abscesses, fistulas or other lymph nodes), but a change in the treatment is not required.

Differential diagnoses include malignancies (lymphoma, leukaemia, ear/nose/throat tumours, Kaposi sarcoma) and other infections
(bacterial, viral, non-tuberculosis mycobacteria, toxoplasmosis, HIV infection, syphilis, African trypanosomiasis).

2.2.2 Tuberculous meningitis

T B meningitis is a serious form of T B that affects the meninges. It is most common in children under 2 years and in HIV-infected
patients. It is a medical emergency. Any delay in diagnosis or treatment will result in irreversible neurological sequelae or death[2] .
T B meningitis typically has a subacute insidious course over days or weeks. Symptoms include headaches, irritability, fever,
vomiting and altered mental status, which worsen if treatment is delayed. T he meningeal syndrome (stiff neck, hypotonia in infants,
photophobia and headache) is present in most cases. T hird cranial nerve palsy (oculomotor paralysis) may occur.
Diagnosis is assisted by examination of cerebrospinal fluid (Chapter 3).

T he main differential diagnoses are other forms of meningitis.

2.2.3 Tuberculosis of bones and joints

Up to 40% of patients with T B of bones and joints have concurrent PT B [3] .

Spinal TB (spondylodiscitis or Pott's disease)

T B can affect vertebrae and intervertebral disks, causing destruction and deformation of the spine. T he thoracic spine is the most
frequently affected.
Localised back pain may precede by several months the appearance of the first radiological anomalies (destruction of an inter-
vertebral disk).
A spinal prominence (gibbus) due to destruction and deformity of the vertebral bodies may be felt.
Paravertebral cold abscesses and/or neurological complications can develop.
A missed diagnosis of thoracic or cervical spinal T B can result in paralysis.

Arthritis
T B most frequently causes a chronic mono-arthritis, starting insidiously, with little or no pain and accompanied by joint destruction.
T he joints most often affected are the hips, knees, elbows and wrists.
Osteitis
Osteitis is the least common presentation of T B of the bones. It may be a primary osteitis or an osteitis secondary to T B arthritis.
Typically, long bones are affected. Cold abscesses may occasionally occur. Like arthritis, it is distinguished from common bacterial
infections by the presence of mild symptoms, despite bone and joint destruction.

T he diagnosis is based on the patient’s history, clinical examination and radiography, as biopsy and culture are difficult to perform in
many settings. A history of prolonged and insidious osteitis or arthritis associated with a deterioration of the general physical
condition favours T B aetiology, as opposed to bacterial osteomyelitis or brucellosis. T he patient may have a history of non-
response to antibiotics.

2.2.4 Urogenital tuberculosis

Renal involvement is frequent and may be asymptomatic for a long period, with a slow development of signs and symptoms: painful
urination (dysuria), urinary urgency and frequency (pollakiuria), including during the night (nocturia); back/abdominal pain;
tenderness/swelling of the testes or epididymitis or haematuria. General physical condition is generally preserved.
Diagnosis is suspected in the presence of pyuria (white blood cells in the urine) and micro- or macroscopic haematuria, which does
not respond to antibiotics. Examination of the urine helps with diagnosis (Chapter 3).

In men, genital localisation is secondary to renal involvement. Signs are most often epididymitis with scrotal pain.

In women, genital tract infection can also occur by a hematogenous path. Signs are non-specific: pelvic pain, leucorrhoea and
abnormal vaginal bleeding. Infertility is often the reason leading women to seek medical attention.
Extension may be found in the peritoneum, with resulting ascites.

2.2.5 Abdominal tuberculosis

Abdominal T B commonly presents as ascites resulting from the peritoneal localisation of the infection.
Abdominal mass (often in the right lower quadrant), pain and diarrhoea may be present. T he frequency of chronic ascites in tropical
regions, with its many different causes, makes this relatively uncommon form of T B difficult to diagnose [4] .
Diagnosis is assisted by examination of the ascitic fluid via paracentesis (Chapter 3).
Constitutional symptoms (fever, night sweats, malaise and weight loss) may be present. Accumulation of ascites may mask weight
loss.

2.2.6 Tuberculous pleural effusion

Tuberculous pleural effusion is one of the most common forms of EPT B.
It is often asymptomatic, especially if less than 300 ml. Shortness of breath and chest pain (often unilateral) occur when the
effusion is large. Sputum production and cough are present in the case of concurrent PT B, which is common.
Constitutional symptoms such as fever, night sweats, malaise and weight loss may also be present.
Effusion can progress to tuberculous empyema, characterised by purulent fluid containing large numbers of bacilli. Tuberculous
empyema is often associated with thickened, scarred and calcified pleura.
Diagnosis is assisted by examination of the pleural fluid via paracentesis and chest x-ray (CXR). See Chapter 3.

2.2.7 Tuberculous pericardial effusion

Clinical signs of a tuberculous pericardial effusion include chest pain, shortness of breath, oedema of the lower limbs and
sometimes ascites.
Clinical examination may show pericardial friction rub, raised jugular pressure and tachycardia.
CXR and ultrasound are key elements for diagnosis (Chapter 3).
Pericardiocentesis may be necessary in the event of acute heart failure with haemodynamic compromise. It must be performed by
experienced personnel in well-equipped hospitals, and when possible, under direct visualisation with ultrasound.

2.2.8 Cutaneous tuberculosis

T he clinical presentation of cutaneous T B is chronic, painless, non-pathognomonic lesions, ranging from small papula and erythema
to large tuberculomas.
T he diagnosis is based on culture from a biopsy.

References
1. World Healt h Organizat ion. Global Tuberculosis Report 2020. Geneva: World Healt h Organizat ion; 2020.
ht t ps://apps.who.int /iris/rest /bit st reams/1312164/ret rieve

2. Wang, M.G., et al., Treatment outcomes of tuberculous meningitis in adults: a systematic review and meta-analysis. BMC Pulm Med, 2019.
19(1): p. 200. ht t ps://www.ncbi.nlm.nih.gov/pmc/art icles/PMC6833188/pdf /12890_2019_Art icle_966.pdf

3. Qian, Y., et al., Characteristics and management of bone and joint tuberculosis in native and migrant population in Shanghai during 2011 to
2015. BMC Inf ect Dis, 2018. 18(1): p. 543.
ht t ps://bmcinf ect dis.biomedcent ral.com/t rack/pdf /10.1186/s12879-018-3456-3

4. Sinkala, E., et al., Clinical and ultrasonographic features of abdominal tuberculosis in HIV positive adults in Zambia. BMC Inf ect Dis, 2009. 9: p.
44.
ht t ps://bmcinf ect dis.biomedcent ral.com/art icles/10.1186/1471-2334-9-44
2.3 Disseminated or miliary tuberculosis
Miliary T B is a generalised massive infection characterised by hematogenous diffusion of M. tuberculosis throughout the body. It is
a medical emergency.
T he disease may manifest as a miliary pattern, or very small nodulary elements (‘millet seeds’) in the lungs.

T he classic acute form is mostly found in children, young adults and HIV-infected patients. T he presentation can be either abrupt or
insidious, with progressive deterioration in the patient’s physical condition. T he clinical picture is often completed within one to two
weeks and is characterised by a profoundly altered physical condition, marked wasting, headache and constant high fever. Discrete
dyspnoea and coughing suggest a pulmonary focus; however, lungs can often be clear on auscultation. A moderate
hepatosplenomegaly is occasionally found. Certain forms of miliary T B evolve in a subacute manner over several months.
Given this non-specific clinical picture, typhoid fever and septicaemia should be considered in the differential diagnosis.

Diagnosis of miliary T B is confirmed by CXR (Chapter 3).

When feasible, fundoscopy may reveal choroidal tubercles.
Sputum smear examination is usually negative.
When there is no possibility of obtaining CXR, the lack of response to antibiotics is an argument in favour of miliary T B.
T he tuberculin skin test is more likely to be falsely negative than in any other form of T B.
In children, the risk of meningitis (20-40%) [1] is high. Lumbar puncture should be routinely performed if miliary T B is suspected.

References
1. Sharma, S.K., A. Mohan, and A. Sharma. Miliary tuberculosis: A new look at an old foe . J Clin Tuberc Ot her Mycobact Dis, 2016. 3: p. 13-27.
ht t ps://www.ncbi.nlm.nih.gov/pmc/art icles/PMC6850233/
2.4 Clinical presentation in HIV-infected patients
Among HIV-infected patients, T B is the most common opportunistic infection and the leading cause of morbidity and mortality [1]
. According to the WHO clinical staging system for HIV/AIDS, patients with PT B are in clinical stage 3 and patients with EPT B in
clinical stage 4 [2] .

In the early stages of HIV infection, when the immune system is functioning relatively normally, the clinical signs of T B are similar to
those in seronegative individuals.

As the immune system deteriorates in later stages of the disease, smear-negative PT B, disseminated T B and EPT B become more
common. T hese cases are more difficult to diagnose, and have a higher fatality rate than smear-positive PT B cases.
Patients may have difficulty expectorating, so more advanced sputum collection techniques may be necessary (Chapter 3 and
Appendix 3).

Algorithms presented in Chapter 4 use clinical criteria combined with laboratory and other investigations to help diagnose T B in
HIV-infected individuals.

Table 2.2 provides a differential diagnosis of PT B in HIV-infected patients.

Table 2.2 - Differential diagnosis for PT B in HIV-infected patients

Diseases Comments

Other pneumonia Bacterial pneumonia (most often S. pneumoniae, H. influenzae) is common at all stages of HIV
(bacterial, viral, infection.
atypical) Atypical pneumonia (M. pneumoniae, C. pneumoniae) and viral pneumonia are possible at any CD4
count, except in the case of cytomegalovirus, which occurs at CD4 < 50.

Pneumocystosis Pneumocystis has many characteristics in common with PT B (insidious onset, persistent cough,
(Pneumocystis fever) but tends to occur in the advanced stages of HIV infection (CD4 < 200).
jirovecii pneumonia Pneumocystosis is unlikely in patients taking co-trimoxazole prophylaxis.
or PCP or PJP) It imparts a greater degree of dyspnoea, rarely produces effusions, and is not usually accompanied by
haemoptysis.

Pulmonary KS can resemble PT B, with slow onset of cough, fever, haemoptysis, night sweats and weight loss. It
Kaposi's sarcoma is a disease of advanced stage HIV, and in most cases, is preceded or accompanied by lesions
(KS) involving the skin and mucus membranes.

Less common Pulmonary cryptococcosis, histoplasmosis and other fungal infections.

diseases Pulmonary nocardiosis: on direct smear, nocardia are weakly acid-fast, and similar in appearance to
mycobacteria (although they are branching filamentous bacilli, particularly on Gram staining).

T he most common EPT B in HIV-infected patients are miliary T B, T B meningitis and diffuse lymphadenopathy in children, and lymph
node T B, pleural effusion, pericarditis, T B meningitis and miliary T B in adults.

Immune reconstitution inflammatory syndrome (IRIS) is a clinical presentation of T B in patients starting antiretroviral therapy. See
Chapter 12 for clinical presentation and management of IRIS.

References
1. Ford, N., et al. TB as a cause of hospitalization and in-hospital mortality among people living with HIV worldwide: a systematic review and
meta-analysis. Journal of t he Int ernat ional AIDS Societ y 2016, 19:20714.
ht t ps://www.ncbi.nlm.nih.gov/pmc/art icles/PMC4712323/pdf /JIAS-19-20714.pdf

2. World Healt h Organizat ion. WHO Case definitions of HIV for Surveillance and Revised Clinical Staging and Immunological Classification of
HIV-related disease in adults and children. Geneva: World Healt h Organizat ion; 2007.
ht t ps://www.who.int /hiv/pub/guidelines/HIVst aging150307.pdf
2.5 Summary of clinical presentations of
tuberculosis
Table 2.3 - Clinical presentations and considerations for HIV-infected patients
 Sites Clinical presentations Considerations for HIV patients

Pulmonary TB Prolonged cough (> 2 weeks), with Fever and weight loss are more common and
or without sputum production. pronounced.
Weight loss, anorexia, fatigue, Cough and haemoptysis may be less
shortness of breath, chest pain, common (less inflammation and cavity
moderate fever, night sweats, formation).
haemoptysis. See algorithms, Chapter 4.

Disseminated miliary TB Non-specific symptoms: high fever, May be confused with severe wasting in
headache, weight loss. advanced HIV disease.
Deterioration over days or weeks. M. tuberculosis sometimes isolated
Simultaneous involvement from blood cultures.
of multiple organs.
High risk of meningitis in children.
Miliary findings CXR.

Lymph nodes TB Most often in cervical region. HIV infection can cause persistent
Non-inflammatory, painless node generalised lymphadenopathy (PGL). PGL
> 2 cm, chronic (> 4 weeks); lymph nodes are painless, and symmetrical.
fistulisation possible. Posterior cervical or epitrochlear nodes are
often involved.
Other common causes of lymphadenopathy
include lymphoma, carcinomatous
metastases, Kaposi sarcoma.

TB meningitis Subacute, insidious. Rule out cryptococcal meningitis: perform

Headaches, irritability, fever, antigen test on serum and CSF.
altered mental status.
Meningeal syndrome
usually present.

Bone and joint TB Monoarthitis with joint destruction Multifocal disease more common.
and little or no pain.
Deformity of the spine (Pott’s
disease).

Urogenital TB Renal: urinary symptoms, few

constitutional symptoms;
suspected when no response to
antibiotics for urinary infection.
Non-specific gynaecological
symptoms, infertility or epididymitis
with scrotal pain.

Abdominal TB Ascites (may mask weight loss). PT B is more frequently associated.

Abdominal mass, pain, diarrhoea.

Effusions Pleural: pleuritic chest Serious effusions are common.

pain, dyspnoea. T B is the most likely aetiology in high T B-HIV
Pericardial: chest pain, dyspnoea, prevalence settings.
lower limb oedema or ascites,
pericardial friction rub.
T B is considered as non-severe if the following criteria are met:
negative smear microscopy, and
uncomplicated PT B with a small infiltrate confined to one lobe and no cavities, or
uncomplicated extra-thoracic lymph node T B, or
uncomplicated intrathoracic lymph node T B.
Chapter 3: Diagnosis and follow-up investigations
3.1 Active tuberculosis

3.2 Latent tuberculosis infection

3.3 Other investigations

Update: October 2022

3.1 Active tuberculosis
3.1.1 Introduction
Active tuberculosis (T B) is bacteriologically confirmed by the detection of M. tuberculosis complex through different
bacteriological tests. T hese tests detect either the organism (smear microscopy and culture), or some of its genetic material
(genotypic tests, including rapid molecular tests and genome sequencing).

Specimens used for bacteriological testing include respiratory specimens (sputum, nasopharyngeal aspirate and, in children, gastric
aspirate) and extrapulmonary specimens (Table 3.6).

Drug susceptibility testing (DST ) is indicated for all patients with confirmed T B. It can be performed using genotypic or phenotypic
tests:
Genotypic DST (gDST ) can detect resistance to T B drugs by identifying specific gene mutations.
Phenotypic DST (pDST ) can detect resistance to T B drugs by measuring the growth of M. tuberculosis in the presence of the
drug.

To diagnose T B and determine the appropriate regimen at baseline:

All patients should be tested with a rapid molecular test (RMT ) to detect M. tuberculosis and rifampicin resistance a .
Whatever the result of the rifampicin susceptibility test (resistance detected or not), all patients, if possible, should be tested
with an RMT for isoniazid resistance and at least those with high risk of isoniazid resistance (for definition of high risk of
resistance, see below).
All patients with rifampicin resistance should be tested for resistance to fluoroquinolones and other T B drugs.
All patients with isoniazid resistance and rifampicin susceptibility should be tested for resistance to fluoroquinolones.
Culture, pDST and genome sequencing may be required.

In limited-resource settings, resistance to T B drugs should be investigated in priority in patients with:

High risk of mortality: e.g. HIV-infected patients or patients with extensive disease.
High risk of resistance: patients with previous T B treatment, or in contact with a T B case resistant to T B drug(s), or coming
from an area of high prevalence of resistance to T B drug(s).

Notes:
Negative bacteriological tests for M. tuberculosis does not rule out T B.
A negative DST does not necessarily rule out drug resistance.

Other investigations can assist T B diagnosis. T hese investigations include: lateral flow urine lipoarabinomannan assay (LF-LAM)
which detects an antigen of M. tuberculosis cell wall excreted in urine, medical imaging, and some biological tests.

3.1.2 Rapid molecular tests

RMTs are nucleic acid amplification tests (NAATs). T hey can detect M. tuberculosis and drug resistance by identifying resistance-
conferring mutations in certain genes (Table 3.1). Other drug resistance- conferring mutations may be present, but not detected by
RMTs. In areas where prevalence of these mutations is high, RMT sensitivity may be decreased [1] .

Table 3.1 – Rapid molecular tests and detection of drug resistance

 Tests TB drug resistance (targeted genes)

Low complexity NAATs Rifampicin (rpoB)

Xpert MT B/RIF
Xpert MT B/RIF Ultra
Truenat MT B-RIF Dx
Moderate complexity NAATs
High complexity NAATs
GenoType MT BDRplus (V2.0)
Genoscholar NT M+MDRT B II

Low complexity NAATs Isoniazid high-level resistance (katG)

Xpert MT B/XDR Isoniazid low-level resistance, thionamides (a) (inhA promoter)
Moderate complexity NAATs
High complexity NAATs
GenoType MT BDRplus (V2.0)
Genoscholar NT M+MDRT B II

Low complexity NAATs Fluoroquinolones (gyrA, gyrB) (b)

Xpert MT B/XDR Aminoglycosides (rrs, eis)
High complexity NAATs
GenoType MT BDRsl (V2.0)

High complexity NAATs Pyrazinamide (pncA)

Genoscholar PZA-T B II

(a) Mut at ions in ot her genes can result in resist ance t o t hionamides. Consequent ly, absence of inhA mut at ion does not rule out resist ance.
(b) Specific mut at ions in gyrA (e.g. mut at ions recognized by t he probes MUT3B, 3C, 3D) are associat ed wit h high-level fluoroquinolones
resist ance.
RMTs have a good specificit y, but are less sensit ive t han cult ure. Their various levels of complexit y det ermine t heir use at dif f erent levels
of healt h f acilit ies. Low complexit y RMTs are pref erred in rout ine pract ice.

RMTs have a good specificity, but are less sensitive than culture. T heir various levels of complexity determine their use at different
levels of health facilities. Low complexity RMTs are preferred in routine practice.

Low complexity nucleic acid amplification tests

1) Xpert assays

Xpert assays are almost fully automated. An uninterrupted power supply and a computer are required to perform and read assays.

Xpert assays can be performed on:

Respiratory specimens
Extrapulmonary (EP) specimens:
Lymph node biopsy or aspirate: suspicion of lymph node T B or detection of rifampicin resistance in clinically diagnosed
lymph node T B;
Cerebrospinal fluid (CSF): suspicion of T B meningitis;
Pleural fluid: suspicion of T B with pleural effusion;
Stool: suspicion of PT B in children;
Pericardial fluid: suspicion of T B with pericardial effusion (sampling to be performed only by experienced clinicians);
Urine: suspicion of genitourinary T B; suspicion of disseminated T B in HIV-infected patients;
Synovial fluid: suspicion of T B arthritis;
Peritoneal fluid: suspicion of abdominal T B;
Blood: suspicion of disseminated T B in HIV-infected patients.
Xpert MT B/RIF and Xpert MT B/RIF Ultra assays provide simultaneously results for M. tuberculosis detection and rifampicin
resistance.

Sensitivity of Xpert MT B/RIF Ultra assay is higher than that of Xpert MT B/RIF assay. It provides a result “trace” corresponding to
the lowest bacillary load for M. tuberculosis detection. It is preferred for HIV-infected patients, children, EP specimens, and sputum
smear-negative specimens. Its specificity is lower in patients with a history of T B, as a “trace” result may indicate that the
specimen contains fragments of dead bacilli.

WHO has validated their use on lymph node biopsy or aspirate, CSF, and pleural fluid, synovial fluid [2] . Xpert assays can be
performed on any biopsy specimens (lymph node, bone, skin, resection material, etc.) with good performance. Xpert assays have
shown acceptable performances in various studies on other specimens (peritoneal[3] and pericardial[4] fluids, stools [5] [6] [7] , and
urine [8] [9] ). Xpert assays on blood have a low sensitivity compared to culture and are not routinely recommended [10] .

Xpert MT B/XDR assay detects resistance to isoniazid (low- and high-level), fluoroquinolones (low- and high-level),
aminoglycosides, and thionamides. It does not detect resistance to rifampicin.

Xpert MT B/XDR assay employ the same platform as other Xpert assays, but require a 10-colour module instead of the 6-colour
module used for Xpert MT B/RIF and Xpert MT B/RIF Ultra assays. T he 10-colour module can also read Xpert MT B/RIF and Xpert
MT B/RIF Ultra assays.

Xpert MT B/XDR assay should be used:

When resistance to rifampicin has been detected by Xpert MT B/RIF or Xpert MT B/RIF Ultra, to detect resistance to other
drugs.
When M. tuberculosis has been detected by Xpert MT B/RIF or Xpert MT B/RIF Ultra or culture, to detect resistance to
isoniazid in all patients, if possible, and at least those with high risk of isoniazid resistance (Section 3.1.1).
Before using a fluoroquinolone containing regimen in isoniazid-resistant T B (Hr-T B), multidrug-resistant (MDR-T B), rifampicin-
resistant T B (RR-T B) or drug-susceptible T B treated with the regimen 2HPZ-Mfx/2HP-Mfx.
Before treating drug-susceptible T B meningitis with the regimen 6HRZ-Eto.
In patients with fluoroquinolone-susceptible T B, initially treated with a fluoroquinolone-containing regimen, and presenting a
smear-positive microscopy at Month 2 or later.

Table 3.2 – Main performances of Xpert assays

 Xpert
Performances
assays

Detection of M. tuberculosis (MTB) compared to culture:

Sensitivity in respiratory specimens [11] :
sputum-smear positive: 99%
sputum smear-negative: 68%
HIV-infected patients: 79%
MTB/RIF
children: see Appendix 1.
Sensitivity in EP specimen: see Appendix 1.
Specificity: very high in all specimens (99%), i.e. a positive result is unlikely to be a false positive.
Detection of rifampicin resistance compared to pDST [11] :
Sensitivity: 95%; specificity: 98%

Detection of MTB in respiratory and EP specimens [12] :

Sensitivity: + 5% compared to Xpert MT B/RIF
MTB/RIF Ultra
Specificity: - 3.2% compared to Xpert MT B/RIF; - 5.4% in patients with a history of T B
No result for rifampicin resistance if “trace” result.

Detection of MTB in respiratory and EP specimens (children and adults):

As Xpert MT B/RIF.
Detection of resistances compared to pDST [13] :
MTB/XDR To isoniazid (low- and high-level): sensitivity: 94.2%; specificity: 98%
To fluoroquinolones (low- and high-level): sensitivity: 93.1%; specificity: 98.3%
To aminoglycosides: sensitivity: 86.1%; specificity: 98.9%
To thionamides: sensitivity: 51.7%; specificity: 98.3%

For more information on specimen processing and Xpert instruments see Appendix 1.
For interpretation of Xpert assay results see Appendix 2.

2) Truenat assays

Truenat assays require:

Several manual steps (pipetting).
Sequential testing for M. tuberculosis detection (Truenat MT B Plus), then for rifampicin resistance detection (Truenat MT B-RIF
Dx).
Separate kits for specimen preparation, DNA extraction, DNA amplification, and detection of M. tuberculosis and rifampicin
resistance.

Truenat MT B Plus can only be performed on sputum specimens (positive or negative smear microscopy). It is not recommended
for other respiratory specimens or EP specimens [2] [7] .
Specificity is high, i.e. a positive result is unlikely to be a false positive [14] .
Tests can be run at room temperatures of up to 40 °C and humidity of up to 80%. Truenat instruments are battery-operated and
can be used in peripheral or mobile health facilities.
Interpretation of results is the same as for Xpert (Appendix 2).

Table 3.3 – Main performances of Truenat assays

 Truenat
Performances
assays

Detection of MTB in sputum specimens (children and adults) compared to culture:

Sensitivity:
MTB Plus sputum smear-positive: 80%
sputum smear-negative: 55%
Specificity: 96% [14]

Detection of rifampicin resistance compared to pDST:

Performed on the DNA isolated from sputum specimens with Truenat MT B Plus positive result.
MTB-RIF Dx
Sensitivity: 84%
Specificity: 97%

3) TB-LAMP

Although validated by WHO, this test has major limitations:

It does not detect rifampicin resistance.
Its sensitivity is lower than that of other low complexity NAATs in HIV-infected or smear-negative patients.
It cannot be used for the diagnosis of extrapulmonary T B (EPT B) [2] .

Box 3.1 – Choice of low complexity NAATs

Xpert: first line tests for the diagnosis of T B in children and adults.
Truenat: if no power supply or operating temperature between 31 and 40 °C.
TB-LAMP: not recommended.

Moderate complexity nucleic acid amplification tests

WHO recommends these tests for the simultaneous detection of M. tuberculosis and resistance to rifampicin and isoniazid, from
smear-positive and negative respiratory specimens, in children and adults, including HIV-infected patients.

Table 3.4 – Performances of moderate complexity NAATs

Tests Performances

Abbott Real T ime MT B and MT B Detection of MTB compared to culture:

RIF/INH BD MAX MDR-T B Sensitivity 93%
Hain FluoroType MT B and MT BDR Specificity 97.7%
Roche cobas MT B and MT B-INH/RIF Detection of rifampicin resistance compared to pDST:
Sensitivity 96.7%
Specificity 98.9%
Detection of isoniazid resistance compared to pDST:
Sensitivity 86.4%
Specificity 99.8%

NAATs of moderate complexity have several limitations:

Need for space, equipment, qualified staff; only feasible in regional laboratories.
T heir use does not eliminate the need for pDST, high complexity NAATs, or genome sequencing to:
test susceptibility to other T B drugs;
confirm a negative result in patients at high risk of drug resistance.
T heir use on EP specimens is not validated.
High complexity nucleic acid amplification tests
Line probe assays (LPA) can detect specific rifampicin, isoniazid, fluoroquinolones, aminoglycosides, and pyrazinamide resistance
encoding mutations in M. tuberculosis.

T hese tests can be performed on isolates of M. tuberculosis (indirect testing). Some can be performed on sputum specimens
(direct testing).

NAATs of high complexity have several limitations:

Need for space, equipment, highly qualified staff; only feasible in reference and national laboratories.
Risk of cross-contamination (tests are performed in an open system that can lead to the detection of DNA from sources other
than the specimen).
To benefit from the short turnaround time of these tests, efficient logistical support is required to ensure specimens are
transported to the laboratory and the results are delivered in a timely manner.
T heir use does not eliminate the need for pDST or genome sequencing to:
test sensitivity to other T B drugs;
confirm a negative result in patients at high risk of drug resistance.
Although direct test results can be obtained in 1 to 2 days, for indirect tests, it is necessary to wait the time required for
bacterial growth (Appendix 5).
T heir use on respiratory (non-sputum) or EP specimens is not validated.

Box 3.2 – WHO validated LPAs b

First-line LPAs
GenoType MT BDRplus version 2 (“Hain first line test”): initial test to detect resistance to rifampicin and isoniazid on smear-
positive sputum specimens and M. tuberculosis isolates. Compared to pDST, sensitivity is 98.2% for rifampicin, and 97.8%
for isoniazid; specificity is 95.4% for rifampicin, and 98.8% for isoniazid [15] . On smear-negative sputum specimens,
sensitivity is low (44.4%), and its use is not recommended [13] .
Genoscholar NT M+MDRT B II (“Nipro test”): performances comparable to GenoType MT BDRplus to detect resistance to
rifampicin and isoniazid on smear-positive sputum specimens and M. tuberculosis isolates. Not recommended on smear-
negative sputum specimens. Can differentiate M. avium, M. intracellulare and M. kansasii from other non-tuberculous
mycobacteria.
Genoscholar PZA-T B ll: to detect resistance to pyrazinamide on M. tuberculosis isolates. Compared to pDST, sensitivity is
81%, and specificity is 97% [13] .

Second-line LPA
GenoType MT BDRsl version 2 (“Hain second line test”): in patients with confirmed MDR/RR-T B, to detect resistance to
fluoroquinolones (high- and low-level) and aminoglycosides on smear-positive or smear-negative sputum specimens and M.
tuberculosis isolates. T he number of “indeterminate” results is higher for smear-negative than for smear-positive sputum
specimens. For smear-positive sputum specimens, sensitivity is 93% for fluoroquinolones, and 88.9% for aminoglycosides;
specificity is 98.3% for fluoroquinolones, and 91.7% for aminoglycosides [16] .

3.1.3 Genome sequencing

Genome sequencing can only be performed in highly specialized reference laboratories.
It can rapidly:
Detect mutations associated with T B drug resistance. When available, it is particularly useful to identify:
resistance to T B drugs for which pDST is unreliable, or no RMTs are available;
mutations missed by RMTs (+ 20% of drug resistance detection compared to RMTs has been described [17] ).
Detect mixed infection (infection with distinct M. tuberculosis strains).
Identify heteroresistance (same strain, with different resistance profiles).
Differentiate treatment relapse and reinfection with a different strain.

Genome sequencing methods include Sanger sequencing (reference method) and next generation sequencing (NGS). T he
advantage of NGS is that, unlike Sanger sequencing, it provides results for a large number of genes in a single reaction.
NGS results are interpreted by reference laboratories using specific software and mutation databases c .
Some mutations associated with resistance to recently introduced drugs (e.g. bedaquiline and delamanid) and their therapeutic
implications are still not well-known.

T he two main NGS techniques are targeted NGS (tNGS) and whole genome sequencing (WGS):
tNGS (on smear-positive sputum specimens or culture isolates): detection of resistance conferring mutations on 18 selected
genes: first-line T B drugs, fluoroquinolones, aminoglycosides, linezolid, bedaquiline, clofazimine, ethionamide (Deeplex®Myc-
T B). Used in routine.
WGS (on culture isolates): detection of resistance conferring mutations on whole genome (i.e. potentially all T B drugs). Used for
research.

3.1.4 Smear microscopy

T he purpose of smear microscopy is to detect acid-fast bacilli (AFB) in stained specimens.

Smear microscopy has several limitations:

It has a sensitivity lower than RMTs and culture in respiratory specimens (65% compared to culture [11] ) and EP specimens (48%
compared to culture [18] ).
It has a low sensitivity in patients with low bacillary load in sputum (paucibacillary T B), e.g. children and HIV-infected patients.
It cannot differentiate between M. tuberculosis and non-tuberculous mycobacteria. However, in areas with high T B prevalence,
AFB detected on smear microscopy are most likely M. tuberculosis.
It does not determine if bacilli are viable (alive) or non-viable (dead).
It does not determine susceptibility of the bacilli to T B drugs.

Sputum smear microscopy is no longer the recommended initial diagnostic test for PT B. However, it still plays a role:
When RMTs are not available.
For assessing the infectiousness of PT B patients.
For monitoring the response to T B treatment in patients with:
drug-susceptible PT B (Chapter 9)
drug-resistant PT B. However, culture is also required for monitoring treatment response in these patients (Chapter 10 and
Chapter 11).

For improving the sensitivity of smear microscopy:

1) Two sputum specimens should be examined. Approximately 86% of sputum smear-positive patients are identified during the first
examination, and an additional 12% during the second. It is not necessary to carry out more than 2 examinations [19] .
2) Light-emitting diode (LED) fluorescent microscopy to examine auramine-stained smears is preferred to Ziehl-Neelsen
microscopy, as it is more sensitive, and reading is more rapid.

Concentration techniques can also increase the sensitivity of smear microscopy [20] .

For sputum specimen collection, storage and shipment see Appendix 3.

For sputum smear preparation and staining techniques see Appendix 4.

3.1.5 Culture
Culture consists of growing M. tuberculosis in specific liquid or solid media.
Culture on liquid medium (automated or manual mycobacterial growth indicator tube, MGIT ) is the reference method for the
diagnosis of PT B and EPT B. Given the long turnaround time and equipment required, it is not used as initial diagnostic test.
Culture on solid medium (Lowenstein-Jensen) is cheaper, less prone to contaminations than cultures on liquid media, but its
turnaround time is longer.
Other culture techniques are less commonly used d .

Culture is necessary to:

Confirm treatment failure.
Assess treatment response in patients with drug-resistant PT B (Chapter 10 and Chapter 11).
Evaluate treatment outcome in patients with drug-resistant PT B (Chapter 17).
Provide isolates for the following tests:
First-line LPAs on sputum smear-negative and EP specimens
Genoscholar PZA-T B ll, regardless of sputum smear positivity
 First- or second-line LPA when an initial direct LPA gives an invalid result
WGS
tNGS on smear-negative sputum specimens
Differentiate between M. tuberculosis and non-tuberculosis mycobacteria. Differentiation between species within the M.
tuberculosis complex is not routinely performed.

Culture may help to diagnose T B when other bacteriological tests are negative or inconclusive:
In patients with signs and symptoms of T B and a negative RMT, particularly when resistance is suspected.
In adults with history of T B in the previous 5 years and showing a “trace” result by Xpert MT B/RIF Ultra.

Culture has several limitations:

Only specialized laboratories implementing systematic quality assurance procedures can be relied upon for culture (often
national reference laboratories or supranational).
M. tuberculosis is a slow-growing bacillus. Positive culture results are obtained after 2 to 4 weeks.

For sputum specimen collection, storage and shipment see Appendix 3.

For the time required to obtain the results see Appendix 5.

3.1.6 Phenotypic drug susceptibility testing

Phenotypic DST (pDST ) determines if a strain is resistant to a T B drug by evaluating the growth in the presence of the drug.
It can determine two levels of resistance (low and high) for isoniazid and fluoroquinolones.

T he pDST is essential to detect resistance to drugs for which there are no reliable RMTs, and when genome sequencing is not
available.
In addition, pDST may be necessary:
If an RMT indicates M. tuberculosis “detected” and drug resistance “indeterminate”.
If an RMT indicates drug susceptibility in a patient at high risk of resistance.
In areas with a high prevalence of mutations not detected by RMTs.

Phenotypic DST is performed on culture isolates by specialized laboratories (often national reference laboratories or
supranational).

T he pDST is not reliable for all drugs, even when performed by a highly qualified laboratory [21] .

Table 3.5 – Reliability of pDST for first- and second-line T B drugs

Reliability of pDST TB drugs

Highly reliable Isoniazid

Rifampicin
Fluoroquinolones
Aminoglycosides

Unreliable (should not be performed) Ethambutol

Ethionamide
Cycloserine or terizidone
Para-aminosalicylic acid (or sodium)
Delamanid

Reliable, but limited access outside of supranational laboratories Bedaquiline

Linezolid
Clofazimine

Reliable when performed in a high-quality laboratory (difficult to Pyrazinamide

perform)
3.1.7 Summary of bacteriological tests
T he tables below provide an overview of the specimens that can be used for each test, and of the tests that can detect resistance
to each T B drug.

Table 3.6 – Specimens for bacteriological tests

Tests Specimens

Xpert, microscopy, culture Respiratory or EP specimens

Truenat Sputum (smear-positive or negative)

Moderate complexity NAATs Respiratory specimens

GenoType MT BDRplus version 2 Sputum (smear-positive only)

Genoscholar NT M+MDRT B II M. tuberculosis isolate

Genoscholar PZA-T B ll M. tuberculosis isolate

Sputum (smear-positive or negative)

GenoType MT BDRsl version 2
M. tuberculosis isolate

Sputum (smear-positive only)

tNGS
M. tuberculosis isolate

WGS M. tuberculosis isolate

Table 3.7 - Tests to detect specific drug resistance

 TB drugs gDST pDST

Rifampicin Xpert MT B/RIF and Ultra, Truenat MT B-RIF Dx Yes

Moderate complexity NAATs
GenoType MT BDRplus, Genoscholar NT M+MDRT B II
Genome sequencing

Isoniazid (c) Xpert MT B/XDR Yes

Moderate complexity NAATs
GenoType MT BDRplus, Genoscholar NT M+MDRT B II
Genome sequencing

Pyrazinamide Genoscholar PZA-T B ll Yes

Genome sequencing

Ethambutol Genome sequencing Unreliable

Fluoroquinolones (c) Xpert MT B/XDR Yes

GenoType MT BDRsl
Genome sequencing

Amikacin Xpert MT B/XDR Yes

GenoType MT BDRsl
Genome sequencing

Streptomycin Genome sequencing Yes (d)

T hionamides (e) Xpert MT B/XDR Unreliable

GenoType MT BDRplus, Genoscholar NT M+MDRT B II
Genome sequencing

Cycloserine or terizidone Whole genome sequencing Unreliable

Para-aminosalicylic acid (or sodium)

Bedaquiline Genome sequencing Yes (d)

Linezolid
Clofazimine
Delamanid

(c) High- and low-level resist ance det ect ed by gDST and pDST.
(d) Rarely available in resource-limit ed set t ings.
(e) Most mut at ions conf erring resist ance t o t hionamides are not det ect ed by RMTs.

3.1.8 Lateral flow urine lipoarabinomannan assay

T B lipoarabinomannan (LF-LAM) is a urine-based point-of-care test that detects lipoarabinomannan (LAM) antigene , which is a
marker of active T B.

T his test is easy to perform by trained staff, including in peripheral heath facilities.

Advantages of LF-LAM over sputum-based tests include:

Urine specimens easier to collect.
No risk of staff contamination during specimen collection or processing.
 No specific storage requirements for the urine prior to testing.

T he urine is applied to the test strip, left at room temperature for 25 minutes, then read by the naked eye by comparing the band
for positivity to a grading scale provided by the manufacturer f .

T his rapid test should be used in the diagnosis of PT B and EPT B in HIV-infected children and adults. Its rapidly obtained result can
contribute to reducing T B mortality among these patients [7] .

Its performances depend on the individual level of immunodeficiency at the time of testing. Its sensitivity is low, but it has an
acceptable specificity (see below).

T he LF-LAM test is recommended for the following patient groups [22] :

HIV-infected patients with signs and symptoms of T B or seriously illg , irrespective of CD4 count (sensitivity: 35%; specificity:
95%).
Hospitalised patients with advanced HIV disease h (sensitivity: 64%; specificity: 82%).
HIV-infected outpatients with CD4 count < 100 cells/mm3 (sensitivity: 40%; specificity: 87%).

If LF-LAM test is positive: T B treatment should be initiated i .

Due to the low sensitivity of the LF-LAM test, a negative result does not rule out T B. T he test does not provide information on
drug susceptibility. T herefore, all above-mentioned patients should be tested with an RMT, regardless of whether the LF-LAM
result is positive or negative.

3.1.9 Medical imaging

Radiography

Chest x-ray (CXR) is used to:

Detect abnormalities suggestive of PT B and other intra-thoracic T B localisations (pleural, pericardial, miliary).
Evaluate the severity of intra-thoracic lesions.
It is particularly useful in the diagnosis of PT B in children (Chapter 5).

For PT B, CXR has a higher sensitivity than T B symptoms [23] : a patient with a normal CXR is unlikely to have PT B. For this reason,
it can also be used as a screening tool (Chapter 6) and a triaging tool to identify patients with respiratory symptoms eligible for an
RMT.

CXR is also used to:

Evaluate the response to T B treatment.
Look for possible complications in case of worsening respiratory symptoms (pneumothorax, tracheal stenosis, etc.).

CXR has several limitations:

Low specificity: except for cavities or miliary T B, which are specific to T B other abnormalities seen on CXR may be due to
other pulmonary diseases.
Variable quality, depending on several factors:
equipment and supply
positioning (obtaining quality CXR in children is challenging)
reader training and proficiency
Difficulty distinguishing active from healed lesions
Error rate of approximately 20% [24] (specialists’ under/over-reading of the film)

When available, digital CXR has advantages over x-ray films:

Consistent quality
Easier image archiving
No need for reagents and films
Rapid transmission for teleconsultation and specialist advice
Immediate results; possibility to screen large numbers of people within a short timeframe
Lower radiation exposure for staff and patients.

Interpretation of digital CXR can be assisted by computer-aided detection (CAD) software packages. CAD analyses CXR for the
presence of PT B-compatible abnormalities, and divides images into “normal” and “abnormal”, thereby reducing the number of CXR
that need to be read by a clinician. CAD is as sensitive as a radiologist [25] .
Computer-aided CXR interpretation assists clinicians when all CXR cannot be read by a radiologist.
However, a radiologist should be consulted locally or via telemedicine to interpret difficult CXR (e.g. in children).

Bone x-ray is used to diagnose and evaluate severity of bone and/or joint T B and assess treatment response.

Ultrasound

Ultrasound (including point-of-care ultrasound, POCUS) may be useful in:

PT B: pulmonary consolidation can support the diagnosis of PT B.
EPT B: if suspected pleural/pericardial effusion or abdominal T B in children and adults, particularly in immunocompromised
patients (e.g. HIV-infection, malnutrition).

Table 3.8 – Medical imaging findings suggestive of T B

Sites Findings

Pulmonary TB Children
See Chapter 5
Adolescents and adults
CXR can show:
Infiltrates typically located in apical and posterior segment of upper lobes and superior
segments of lower lobes.
Cavities (specific for T B), patchy, poorly defined consolidations.
Patients with TB/HIV
As above.
In advanced immunodeficiency, infiltrates tend to be more homogeneous, diffuse and located in
the lower lungs.
Less cavities than in non-HIV-infected patients.
Mediastinal and hilar lymphadenopathy may be observed.
Miliary pattern.

Miliary TB CXR can show miliary nodules (1-3 mm in diameter) disseminated in both fields and uniformly
distributed throughout the lung.

Pleural effusion CXR: effusion (even with minimal clinical signs):

Mostly unilateral.
Obliteration of costophrenic angle.
Opacity with curved upper margin.
Ultrasound: anechogenic fluid on the costophrenic angle (may be echogenic in empyema).

Pericardial effusion CXR: cardiac silhouette enlargement, “water bottle” silhouette (very large effusions).
Ultrasound: anechogenic fluid around the heart (may be echogenic if purulent).

Bone/joint TB X-ray can show:

Any bone/joint: osteopenia (demineralization), bone destruction with relative preservation of
cartilage space.
Spine: destruction of an inter-vertebral disk, osteopenia, irregularity of bone margin, bone
destruction, paravertebral abscesses.

Abdominal TB Ultrasound can show enlarged lymph nodes consistent with T B (and other diseases, especially in
HIV infection), bowel wall thickening (ileo-caecal region), hypoechogenic micro-abscesses of liver
and/or spleen, ascites.

Notes:
Radiographical and ultrasound findings of EPT B are non-specific. A differential diagnosis should always be considered.
 In HIV-infected patients in settings of high T B prevalence, pleural/pericardial effusion, enlarged abdominal lymph nodes, splenic
microabscesses, and ascites are highly suggestive of EPT B [26] .
Adolescents typically have CXR abnormalities similar to those found in adults, however, they may also have abnormalities
commonly seen in children, such as enlarged hilar lymph nodes.

3.1.10 Other laboratory tests on tissues and body fluids

T he diagnosis of T B can be supported by biological tests performed on tissues or body fluids.

Table 3.9 – Findings suggestive of T B in tissues or body fluids

Tissues/fluids Findings

Lymph node Cytology: granulomatous tissue, presence of giant Langhans cells, and/or caseous necrosis.
AFBs are not always found by microscopy.

CSF Clear, hyper-concentrated liquid.

High protein level > 0.40 g/l (see Pandy test, Appendix 8).
Low glucose < 60 mg/l.
Ratio CSF glucose/blood glucose < 0.5.
Between 100 and 1,000 white cells/mm3, of which over 80% are lymphocytes.
In HIV-infected patients, rule out cryptococcal meningitis.

Peritoneal fluid Translucent, yellow-coloured liquid.

Exudate rich in lymphocytes, usually > 300 white cells/mm3; Rivalta test positive (Appendix 8).
Serum-ascites albumin gradient (SAAG):
< 1.1 g/dl: consistent with T B (and many other conditions).
> 1.1 g/dl: peritoneal T B unlikely.
Adenosine deaminase (ADA) > 39 U/l, likely due to T B [27] .

Pleural fluid Straw-coloured fluid.

High protein level ≥ 30 g/l (Rivalta test, Appendix 8).
Rich in white cells (1,000-2,500/mm3), with predominant lymphocytes.
ADA typically > 50 U/l. Pleural effusion with an ADA < 40 U/l is much less likely due to T B. T he specificity is
increased when ADA is > 50 U/l and the lymphocyte-neutrophil ratio is > 0.75 [28] .

Notes:
ADA levels increase in T B. ADA is therefore a surrogate marker for T B in pleural and peritoneal fluids. Although not widely
available, kits can be purchased to perform the test if a spectrophotometer is available.
T he sensitivity of ADA in peritoneal fluid is lower in patients with cirrhosis.
HIV-infected patients may have lower levels of ADA.

Footnotes
(a) When microscopy is t he only diagnost ic t est available, specimens should be sent t o a f acilit y wit h capacit y t o perf orm RMTs.

(b) For more inf ormat ion, see: Global Laborat ory Init iat ive. Line probe assays f or drug resist ant t uberculosis det ect ion Int erpret at ion and
report ing guide f or laborat ory st af f and clinicians. ht t p://st opt b.org/wg/gli/asset s/document s/LPA_t est _web_ready.pdf

(c) For more inf ormat ion :

• WHO cat alogue of mut at ions in M. tuberculosis complex and t heir associat ion wit h drug
resist ance: ht t ps://www.who.int /publicat ions/i/it em/9789240028173
• Relat ional Sequencing TB (ReSeqTB) Dat a Plat f orm: ht t ps://c-pat h.org/programs/cpt r/cpt r-t ools/dat abases/relat ional-sequencing-t b-
dat a-plat f orm-reseqt b/

(d) Microscopic observat ion of drug suscept ibilit y (MODS), nit rat e reduct ase assay (NRA), t hin layer agar and colorimet ric redox indicat or
 (CRI).

(e) LAM ant igen is a component of t he mycobact erial cell walls released by M. tuberculosis t hen excret ed by t he kidneys.

(f ) Alere Det ermine® TB LAM Ag (Alere Inc, Walt ham, MA, USA).

(g) Seriously ill: respirat ory rat e > 30/minut e, t emperat ure > 39 °C, heart rat e > 120/minut e and unable t o walk unaided.

(h) For children > 5 years and adult s: CD4 count < 200 cells/mm3 or a WHO clinical st age 3 or 4. All children < 5 years are considered as
having advanced HIV disease.

(i) HIV-inf ect ed pat ient s diagnosed wit h TB using t he LF-LAM should be recorded as bact eriologically confirmed TB cases.

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ht t ps://apps.who.int /iris/bit st ream/handle/10665/112472/9789241506335_eng.pdf ?sequence=1

12. World Healt h Organizat ion. WHO meeting report of a technical expert consultation: non-inferiority analysis of Xpert MTF/RIF Ultra compared
to Xpert MTB/RIF. Geneva 2017.
ht t ps://apps.who.int /iris/bit st ream/handle/10665/254792/WHO-HTM-TB-2017.04-eng.pdf ?sequence=1

13. World Healt h Organizat ion. Update on the use of nucleic acid amplification tests to detect TB and drug-resistant TB: rapid communication.
Geneva: World Healt h Organizat ion; 2021.
ht t ps://apps.who.int /iris/rest /bit st reams/1332438/ret rieve

14. St opTB Part nership. Practical Guide to Implementation of Truenat Tests for the Detection of TB and Rifampicin Resistance. Geneva 2021.
ht t p://st opt b.org/asset s/document s/resources/publicat ions/sd/Truenat _Implement at ion_Guide.pdf
15. World Healt h Organizat ion. WHO Guideline: The use of molecular line probe assays for the detection of resistance to isoniazid and rifampicin.
21–23 (2016).
ht t ps://apps.who.int /iris/bit st ream/handle/10665/246131/9789241510561-eng.pdf ?sequence=1&isAllowed=y

16. Tagliani, E. et al. Diagnostic performance of the new version (v2.0) of GenoType MTBDRsl assay for detection of resistance to fluoroquinolones
and second-line injectable drugs: A multicenter study. J. Clin. Microbiol. 53, 2961–2969 (2015).
ht t ps://www.ncbi.nlm.nih.gov/pmc/art icles/PMC4540937/pdf /zjm2961.pdf

17. Connie Lam, Elena Mart inez, Taryn Cright on, Cat riona Furlong, Ellen Donnan, Ben J. Marais, Vit ali Sint chenko, Value of routine whole
genome sequencing for Mycobacterium tuberculosis drug resistance detection. Int ernat ional Journal of Inf ect ious Diseases, 2021.
ht t ps://www.ijidonline.com/art icle/S1201-9712(21)00251-4/f ullt ext

18. Enrico Tort oli, Crist ina Russo, Claudio Piersimoni, Est er Mazzola, Paola Dal mont e, Michela Pascarella, Emanuele Borroni, Alessandra
Mondo, Federica Piana, Claudio Scarparo, Luana Colt ella, Giulia Lombardi, Daniela M. Cirillo. Clinical validation of Xpert MTB/RIF for the
diagnosis of extrapulmonary tuberculosis. European Respiratory Journal 2012 40: 442-447.
ht t ps://erj.ersjournals.com/cont ent /40/2/442

19. Mase, S.R., et al. Yield of serial sputum specimen examinations in the diagnosis of pulmonary tuberculosis: a systematic review. Int J Tuberc
Lung Dis, 2007. 11(5): p. 485-95.
ht t p://docserver.ingent aconnect .com/deliver/connect /iuat ld/10273719/v11n5/s3.pdf ?
expires=1611823630&id=0000&t it leid=3764&checksum=39399CE1057042BD71BAC51B1470C1F8

20. Bonnet M, Ramsay A, Git hui W, Gagnidze L, Varaine F, Guerin PJ. Bleach Sedimentation: An Opportunity to Optimize Smear Microscopy for
Tuberculosis Diagnosis in Settings of High Prevalence of HIV . Clin Inf ect Dis. 2008 Jun.;46(11):1710–6.

21. Technical manual f or drug suscept ibilit y t est ing of medicines used in t he t reat ment of t uberculosis.
ht t ps://apps.who.int /iris/bit st ream/handle/10665/275469/9789241514842-eng.pdf ?ua=1

22. World Healt h Organizat ion. Lateral flow urine lipoarabinomannan assay (LF-LAM) for the diagnosis of active tuberculosis in people living with
HIV. Policy update 2019. Geneva: World Healt h Organizat ion; 2019.
ht t ps://apps.who.int /iris/bit st ream/handle/10665/329479/9789241550604-eng.pdf ?sequence=1&isAllowed=y&ua=1

23. World Healt h Organizat ion. Chest radiography in tuberculosis detection – summary of current WHO recommendations and guidance on
programmatic approaches. I. World Healt h Organizat ion, 2016.
ht t ps://apps.who.int /iris/bit st ream/handle/10665/252424/9789241511506-eng.pdf ;jsessionid=8552A4DE3F2B289132DA4342DBD962F9?
sequence=1

24. World Healt h Organizat ion. Koppaka R, Bock N. How reliable is chest radiography? In: Frieden T, edit or. Toman’s t uberculosis: case
det ect ion, t reat ment , and monit oring. Quest ions and answers, second edit ion. Geneva: World Healt h Organizat ion; 2004. p. 51-60.
ht t ps://apps.who.int /iris/bit st ream/handle/10665/42701/9241546034.pdf ?sequence=1

25. World Healt h Organizat ion. Rapid communication on systematic screening for tuberculosis. Geneva; 2020.
ht t ps://www.who.int /publicat ions/i/it em/rapid-communicat ion-on-t he-syst emat ic-screening-f or-t uberculosis

26. Heller T, Wallrauch C, Goblirsch S, Brunet t i E. Focused assessment with sonography for HIV-associated tuberculosis (FASH): a short protocol
and a pictorial review. Crit Ult rasound J. 2012 Nov 21;4(1):21.
ht t ps://www.ncbi.nlm.nih.gov/pmc/art icles/PMC3554543/pdf /2036-7902-4-21.pdf

27. Riquelme A, et al. Value of adenosine deaminase (ADA) in ascitic fluid for the diagnosis of tuberculous peritonitis: a meta-analysis. J Clin
Gast roent erol. 2006 Sep; 40(8):705-10.

28. Porcel JM. Tuberculous pleural effusion. Lung. 2009 Sep-Oct ;187(5):263-70.
3.2 Latent tuberculosis infection
Diagnosis is based on exclusion of active T B and demonstration of latent tuberculosis infection (LT BI).

For demonstrating LT BI, one of the following tests may be performed. However, these tests are not mandatory prior to initiating
LT BI treatment in:
Children under 5 years household contact of a T B case;
HIV-infected children and adults [1] .

3.2.1 Tuberculin skin test

A positive tuberculin skin test (T ST ) indicates that a mycobacterial infection has occurred.
For interpretation of T ST results, see Appendix 9.

T ST has several limitations:

It does not distinguish infection by M. tuberculosis from exposure to environmental mycobacteria.
It does not distinguish latent/active T B.
Prior BCG vaccination can result in a false positive T ST.
False negative T ST is common, particularly in HIV-infected patients and malnourished children.

After having ruled out active T B, a positive T ST is an indication for treatment of LT BI (Chapter 16).

Notes:
T ST is also used to check the absence of T B in neonates on isoniazid monotherapy (Chapter 16).
Other skin tests are available, but have not yet been evaluated by WHO.

3.2.2 Interferon gamma release assays

T he test is performed in vitro on blood to which M. tuberculosis antigens are added. T his results in the rapid stimulation of memory
T cells and release of interferon-gamma in patients previously exposed to the bacillus.

T he following tests measure:

QuantiFERON-T B Gold In-Tube: the amount of interferon-gamma released.
T-SPOT.T B test: the number of interferon-gamma producing T cells [2] .

T he advantage of IGRAs over T ST is the absence of cross-reaction with BCG vaccine and most environmental mycobacteria.

IGRAs have some limitations:

T hey do not distinguish latent/active T B.
T hey are more complex than T ST (equipment and trained laboratory technicians) and are not widely available.

A positive test indicates that LT BI is likely; a negative test indicates that it is unlikely.
After having ruled out active T B, a positive IGRA is an indication for treatment of LT BI (Chapter 16).

References
1. World Healt h Organizat ion. Latent tuberculosis infection: updated and consolidated guidelines for programmatic management. Geneva: World
Healt h Organizat ion; 2018.
ht t ps://apps.who.int /iris/bit st ream/handle/10665/260233/9789241550239-eng.pdf

2. Pai, M., et al., Gamma interferon release assays for detection of Mycobacterium tuberculosis infection. Clin Microbiol Rev, 2014. 27(1): p. 3-20.
ht t ps://cmr.asm.org/cont ent /27/1/3
3.3 Other investigations
In addition to T B diagnosis tests, the following investigations should be performed at baseline and during treatment. T he purpose is
to identify common comorbidities, contra-indications, as well as adverse effects of T B drugs.

Table 3.10 – Other investigations in T B treatment

Tests Indications

Electrocardiogram (ECG) Patients on QT prolonging drugs

Brief peripheral neuropathy screen (BPNS) (a) Patients on linezolid

Visual function tests Patients on MDR/RR-T B treatment including ethambutol, linezolid or

thionamides

Audiometry (b) Patients on aminoglycosides

Full blood count Patients on linezolid (or rifabutin)

Liver function tests Patients with pre-existing hepatic disease

Aspartate aminotransferase (AST ) Patients on MDR/RR-T B treatment
Alanine aminotransferase (ALT )

Creatinine Patients with pre-existing renal disease

Serum creatinine Patients on aminoglycosides
Creatinine clearance

Serum electrolytes (potassium) Patients on aminoglycosides

Glycated haemoglobin (HbA1c), or All patients

Blood glucose level (fasting or random)

HIV, hepatitis B and C testing Patients with undocumented HIV, hepatitis B and C status

CD4 count and viral load Patients with T B/HIV coinfection

Thyroid stimulating hormone (T SH) Patients on thionamides or PAS

Pregnancy test Patients of childbearing age with MDR/RR-T B

(a) BPNS is a clinical examinat ion f or det ect ing peripheral neuropat hy and grading t he severit y of sympt oms (Appendix 16).
(b) For children under 5 years, a specialized equipment and consult at ion are required.

For more information see Chapter 9, Chapter 10 and Chapter 11.

Chapter 4: Diagnostic algorithms for pulmonary
tuberculosis (PTB) in adults and adolescents
4.1 Guiding principles for the use of the algorithms

4.2 Adult and adolescent algorithms

4.1 Guiding principles for the use of the algorithms
T he aim of algorithms is to assist the diagnostic process and minimize incorrect diagnosis. T he following algorithms are for adults
and adolescents. For diagnostic algorithms for children < 10 years, see Chapter 5.

4.1.1 Clinical assessment [1]

– An assessment for danger signs is the first part of the clinical assessment. T he adult or adolescent is classified as seriously ill if
one or more of the following danger signs are present:
• Respiratory rate > 30/minute;
• Fever > 39°C;
• Pulse rate > 120/minute;
• Unable to walk unaided.

– In cases where there is no bacteriological confirmation of T B, the clinical (and radiological) assessment should determine if the
patient needs broad-spectrum antibiotics and/or anti-T B drugs.

– HIV testing should be routinely offered to all individuals suspected of having T B. If testing is refused or unavailable, it might be
assumed that a certain patient is likely to be HIVpositive (according to context and/or clinical presentation). In this event, follow the
algorithm for HIV-infected patients.

4.1.2 Clinical response

For patients who are treated empirically for bacterial pneumonia or pneumocystosis (PCP), a “non-response to antibiotics”
increases the likelihood of T B. T he converse is not necessarily true, such that a response to antibiotics does not automatically
exclude T B in a person suspected of having T B, particularly if respiratory symptoms persist after treatment. Pneumonia or PCP
may occur in patients with underlying T B.

Antibiotic treatment is appropriate for HIV-infected patients with cough because bacterial infections are common both with and
without T B. All seriously ill patients being started on anti-T B treatment should also be treated empirically, with broad-spectrum
antibiotics for bacterial pneumonia because benefits outweigh the risks [1] .

References
1. Improving t he diagnosis and t reat ment of smear-negat ive pulmonary and ext rapulmonary t uberculosis among adult s and adolescent s.
Recommendat ions f or HIV prevalent and resource-const rained set t ings. World Healt h Organizat ion, Geneva. (WHO/HTM/HIV/2007.01).
ht t p://www.who.int /hiv/pub/t b/pulmonary/en/index.ht ml.
4.2 Adult and adolescent algorithms
Diagnostic algorithm 1
PTB in HIV-negative patients with low risk of MDR-TB

a. When the patient’s serological status is unknown, this algorithm should be used in settings with HIV prevalence < 5%.
b.
Patients are considered to be at low risk of multidrug-resistant T B (MDR-T B) if they do not meet one of the following criteria: 1)
resident in areas with high MDR-T B prevalence; 2) all retreatment categories; 3) exposure to a known MDR-T B case; 4) patient
remaining smear + at 2 months; 5) exposure to institutions with high risk of MDR-T B (e.g. prisons).
c.
Danger signs: respiratory rate > 30/min and/or fever > 39°C and/or pulse rate > 120/min and/or unable to walk.
d.
Smear microscopy: two sputum examinations performed on the same day.
e.
Broad spectrum AT B:
 • If no danger signs: amoxicillin for 7 days (NO fluoroquinolones);
• If danger signs: parenteral AT B (e.g. ceftriaxone).
f. Clinical response to a broad spectrum antibiotic does not rule out T B. Patient should be informed to return for reassessment if
symptoms recur.
g.
According to setting:
• Xpert MT B/RIF available: two sputum smear microscopy on the same day and one Xpert MT B/RIF from one of the samples
collected for smear microscopy;
• Xpert MT B/RIF not available: two sputum smear microscopy on the same day.
h.
In groups of patients with high level of resistance to isoniazid (> 10%) it is recommended to perform a conventional DST at
baseline (and/or a line probe assay) in order to provide adequate treatment.
i.
According to setting:
• In groups of patients with prevalence of MDR-T B < 10%, patients seriously ill should immediately be initiated under empiric
MDR-T B treatment. H and R will be included in the regimen until confirmation of MDR-T B by conventional methods. If the
patient is stable, the clinician may choose to wait for confirmation before initiating a MDR treatment.
• In groups of patients with prevalence of MDR-T B ≥ 10%, patients should be initiated under empiric MDR-T B treatment.
Consider adding H in settings where mono-resistance to R is not uncommon.
j.
Clinical signs and chest X-ray (CXR) findings tend to be more typical in those who are HIV-negative having active T B:

TB Bacterial pneumonia

Clinical Weight loss, productive cough, purulent sputum, haemoptysis, • Acute onset
signs pleuritic chest pain • Fever

CXR • Infiltrates, nodules with or without cavitation in the upper lobes and • Lobar consolidation
in the superior segments of the lower lobes.
• Pleural effusions
• Adenopathy in the mediastinum or hila (rare in T B in adults and
adolescents)
• Miliary disease

When clinical signs AND CXR are strongly suggestive of active T B, treatment should be initiated without waiting for diagnosis
confirmation.

Diagnostic algorithm 2
PTB in HIV-positive patients
a. When the patient’s serological status is unknown, this algorithm should be used in settings with HIV prevalence > 5%.
b.
T B suspect is defined as: cough for more than 2 weeks or any cough with at least one of the following signs: loss of weight, night
sweats, fever, and suspicion based on clinical judgment.
c.
Danger signs: respiratory rate > 30/min and/or fever > 39°C and/or pulse rate > 120/min and/or unable to walk.
d.
According to setting:
• Xpert MT B/RIF available: two sputum smear microscopy on the same day AND one Xpert MT B/RIF from one of the samples
collected for smear microscopy;
• Xpert MT B/RIF not available: two sputum smear microscopy on the same day.
e. In patients groups with high level of resistance to isoniazid (> 10%) it is recommended to perform a conventional DST at baseline
(and/or a line probe assay) in order to provide adequate treatment.
f.
When possible a culture should be performed. A positive culture result at any point in time in the algorithm should lead to a full T B
treatment.
g.
T B treatment should be started when clinical signs AND chest X-ray (CXR) are suggestive of T B (Note k).
h.
Broad spectrum AT B/PCP:
• If no danger signs: amoxicillin for 7 days (or recommended oral agent for community-acquired pneumonia in the area). Do NOT
use fluoroquinolones;
• If danger signs: parenteral AT B (e.g. ceftriaxone) AND high dose cotrimoxazole.
i. If no danger signs: patient should be re-assessed after 7 days.
If danger signs: patient should be assessed daily and if no response, T B treatment should be considered after 3 to 5 days.
Clinical response to broad-spectrum AT B does not rule out T B. Patient should be informed to return for reassessment if
symptoms recur.
j. Differential diagnosis of a coughing HIV-infected adult/adolescent: bacterial (including atypical) pneumonia, PCP, fungal infection,
non-tuberculous mycobacteria, nocardiosis, Kaposi sarcoma and lymphoma.
k.
T he diagnosis should be based on clinical assessment, CXR and CD4 results, whether cotrimoxazole preventive therapy (CPT )
was used, and other treatment already used in the patient. If the index of suspicion for active T B is high, empiric T B treatment
should be initiated without waiting for diagnosis confirmation. Other treatments such as broad-spectrum AT B or therapy for PCP
may be needed in addition to T B treatment.

TB PCP (HIV+) Bacterial

pneumonia

Clinical • Current cough • Dry cough • Acute onset

signs • Weight loss • Dyspnoea ++ • High fever
• Purulent sputum and haemoptysis less likely if HIV- • Hypoxemia
positive with low CD4 count • Not on CPT
• Fever • More likely if low CD4 count
• Night sweats
• Pleuritic chest pain

CXR • Upper lobe infiltrates and cavitation only likely in HIV- • Bilateral interstitial infiltrate with • Lobar
positive adults with higher CD4 counts. Any lobe of the reticulonodular markings that are more consolidation
lung may be affected pronounced in the lower lobes
• In HIV-positive adults with lower CD4 counts, the • Findings lag behind symptoms and may be
following 4 patterns are suggestive of T B: normal early in the disease
1. miliary pattern
2. pleural effusion without airspace (with straw-
coloured liquid aspirate)
3. hilar and mediastinal adenopathy
4. large heart (especially if symmetrical and rounded)

l.
In the absence of any improvement of clinical signs (no weight gain, persistent cough, pain, etc.) AND no improvement on CXR
after 2 months of a well conducted T B treatment, diagnosis and treatment should be reconsidered. MDR-T B should also be
considered.
m. In addition to the differential diagnosis in Note k above, DR-T B should be considered.
n.
Immediately start empiric MDR treatment, even if positive predictive value of Xpert MT B/RIF for R resistance is low (this is done
to avoid the rapid and high mortality due to untreated MDR-T B in HIV patients). H and R should be included in the regimen until
confirmation of MDR-T B by conventional methods if the patient comes from a group with less than a prevalence of MDR-T B <
10%. In groups of patients with prevalence of MDR-T B ≥ 10%, patients should be initiated under an empiric MDR treatment
without H or R, although one can consider adding H in settings where mono-resistance to R is not uncommon.
Diagnostic algorithm 3 with Xpert MTB/RIF
PTB in patients with high risk of MDR-TB

a.
T he following patients are considered to be at high risk of MDR-T B: 1) resident in areas with high MDR-T B prevalence; 2) all
retreatment categories; 3) exposure to a known MDR-T B case; 4) patient remaining smear-positive at 2 months; 5) exposure to
institutions with high risk of MDR-T B (e.g. prisons).
b. Groups of patients at risk of MDR-T B are also at risk of other types of DR-T B as well. DST to the first-line should be performed
in order to provide adequate treatment for possible mono- or poly-drug resistance.
c.
In populations with a prevalence < 10% of MDR-T B, the resistance to R diagnosed by Xpert MT B/RIF must be confirmed by
conventional methods. Drug sensitivity testing (DST ) to both first-line drugs and secondline T B drugs should be performed if
possible.
d.
• In groups of patients with prevalence of MDR-T B < 10%, the decision to start the MDR-T B treatment will be made on clinical
presentation of the patient and immunological status. Patients seriously ill and/or HIV+ should be initiated immediately under empiric
MDR-T B treatment. H and R will be included in the regimen until confirmation by conventional methods.
• In groups of patients with prevalence of MDR-T B ≥ 10%, the patient should be initiated using an empiric MDR-T B treatment.
Consider adding H in settings where mono-resistance to R is not uncommon.
e.
Baseline sputum smear microscopy result on 1 specimen in order to: 1) allow patient follow-up with microscopy; 2) take
immediate decisions related to T B infection control.
Chapter 5: Diagnosis of active tuberculosis in
children
5.1 Introduction

5.2 Diagnostic approach

5.3 Paediatric diagnostic algorithms

Update: March 2023

5.1 Introduction
In children, defined in this chapter as patients under 10 years, tuberculosis (T B), pulmonary (PT B) and extrapulmonary (EPT B), is a
significant cause of morbidity and mortality.

Globally, WHO estimates that more than one million children develop active T B every year [1] and that 60% of T B cases in children
are not diagnosed or not reported [2] .

After exposure, the risk of T B infection and progression to active T B is high in children under 5 years [3] .
Progression to active T B is rapid (within 12 months) in children under 2 years [4] .
HIV infection is a significant risk factor for developing T B in children under 1 year [5] .

T he risk of miliary T B and EPT B, including severe forms such as T B meningitis, is higher in children under 5 years and in
immunocompromised children[3] . T he most common forms of EPT B are lymph node T B and T B pleural effusion. Osteoarticular
T B represents 1 to 2% of T B in children[4] .

T he risk of death from T B is higher in children under 2 years and children with HIV infection or severe acute malnutrition (SAM) [3] .
Almost all deaths due to T B in children occur in those not receiving T B treatment, and in the vast majority of cases, in children
under 5 years [6] .

T B treatment should not be delayed if investigations, or results of investigations, are not immediately available in children at high
risk of T B or death from T B.

Children often have the same resistance profile as the index case, i.e. the person who is the presumed source of the infection. If the
resistance profile is not available for the child, the resistance profile of the index case should be taken into account for the child’s
T B treatment.

Children are not considered infectious unless they have extensive lung involvement and/or cavitary PT B or positive smear
microscopy.

References
1. World Healt h Organizat ion. WHO consolidated guidelines on tuberculosis. Module 5: management of tuberculosis in children and adolescents.
Geneva: World Healt h Organizat ion; 2022.
ht t ps://apps.who.int /iris/rest /bit st reams/1414329/ret rieve

2. World Healt h Organizat ion. Global Tuberculosis Report 2021. Geneva: World Healt h Organizat ion; 2021.
ht t ps://apps.who.int /iris/rest /bit st reams/1379788/ret rieve

3. World Healt h Organizat ion. WHO operational handbook on tuberculosis. Module 5: management of tuberculosis in children and adolescents.
Geneva: World Healt h Organizat ion; 2022.
ht t ps://apps.who.int /iris/rest /bit st reams/1414333/ret rieve

4. Marais BJ, Gie RP, Schaaf HS, et al. The natural history of childhood intra-thoracic tuberculosis: a critical review of literature from the pre-
chemotherapy era . Int J Tuberc Lung Dis. 2004;8(4):392-402.
ht t ps://www.ingent aconnect .com/cont ent /iuat ld/ijt ld/2004/00000008/00000004/art 00002;jsessionid=6n3iklj7549s8.x-ic-live-03#

5. Hesseling AC, Cot t on MF, Jennings T, Whit elaw A, Johnson LF, Eley B, Roux P, Godf rey-Fausset t P, Schaaf HS. High incidence of
tuberculosis among HIV-infected infants: evidence from a South African population-based study highlights the need for improved tuberculosis
control strategies. Clin Inf ect Dis. 2009 Jan 1;48(1):108-14.
ht t ps://academic.oup.com/cid/art icle-pdf /48/1/108/815230/48-1-108.pdf

6. Dodd PJ, Yuen CM, Sismanidis C, Seddon JA, Jenkins HE. The global burden of tuberculosis mortality in children: a mathematical modelling
study. Lancet Glob Healt h. 2017 Sep;5(9):e898-e906.
ht t ps://www.t helancet .com/journals/langlo/art icle/PIIS2214-109X(17)30289-9/f ullt ext
5.2 Diagnostic approach
Children with T B usually have non-specific symptoms. Clinicians should therefore look for T B, particularly in children:
Under 2 years of age, or
With HIV infection or SAM, or
In contact with a person with T B, or
Not responding to antibacterial and/or nutritional treatment.

T he diagnosis of T B in children, particularly those under 5 years, is often based on a combination of history of exposure to a
person with T B, clinical assessment and investigations, such as radiology, when available.

In children at high risk of death from T B, treatment should be initiated as soon a T B diagnosis is considered likely.
In children not at high risk of death from T B, the diagnosis may not be made at the first consultation. A second consultation after
one to two weeks is often necessary to reassess the clinical status.

T he diagnosis is often made without bacteriological confirmation as:

Children under 5 years have low bacillary load and bacteriological tests are often negative.
Specimens for diagnosis of EPT B may be difficult to collect.
T B is bacteriologically confirmed in only 20 to 30% of children[1] .

To facilitate the diagnosis of PT B and enable rapid treatment in children, WHO has developed diagnostic algorithms (Section 5.3).
T he diagnosis of EPT B uses the same diagnostic approach. However, no evidence-based algorithms are currently available.

A trial of treatment with T B drugs is not recommended as a method to diagnose T B. Once a decision is made to treat T B in a
child, a full course of treatment should be given.

5.2.1 History of exposure to tuberculosis

Children are at risk of T B if they are exposed to a person with confirmed or presumed T B.
T hey are at higher risk of T B if:
T he index case is a household or close contact.
T he index case has PT B, sputum smear-positive or cavities on chest x-ray.
T he exposure to the index case has occurred in the past 12 months.

Note: conversely, when T B is diagnosed in children, it is important to detect the index case and any other undiagnosed household
member(s) or close contact(s).

5.2.2 Clinical assessment

Symptoms suggestive of tuberculosis

Ask if the child has symptoms commonly associated with T B:

Cough for more than 2 weeks.
Fever for more than 2 weeks.
Night sweats that soak the bed or clothes.
Weight loss or poor/no weight gain.
Fatigue, reduced playfulness, loss of appetite.
Haemoptysis (rare in children).
Non-painful, enlarged cervical, submandibular, or axillary lymph nodes.
Rapid breathing.

Physical examination and growth assessment

Look for signs suggestive of T B:

Fever, tachypnoea, tachycardia.
Weight loss, growth curve flattening, underweight or malnourished according to weight for height and/or mid-upper arm
circumference.
 Abnormal pulmonary auscultation.
Signs of respiratory distress and SpO2 < 90-92%.
Lethargy, altered mental status (may indicate T B meningitis).
Signs of EPT B:
Highly suggestive, e.g.:
Angular deformity of the spine, loss of ability to walk.
Cervical lymph node with fistula formation.
Requiring further investigation, e.g.:
Sub-acute meningitis not responding to antibiotic treatment.
Ascites.
Lymph node without fistula formation.
Non-painful enlarged joint.

HIV status should be assessed in all children with presumed or confirmed T B.

Clinical review

If diagnosis is not made at the first consultation, reassess the child (signs/symptoms suggestive of T B and growth) within one to
two weeks maximum.

T he following are suggestive of T B:

Persistent or worsening pneumonia despite non-T B antibiotic treatment.
No weight gain or weight loss despite nutritional support or treatment.
Persistent fever after other causes have been ruled out or treated (e.g. malaria).
Persistent or worsening fatigue, reduced playfulness, loss of appetite.

5.2.3 Baseline investigations

When PT B or EPT B is suspected, perform bacteriological tests, lateral flow urine lipoarabinomannan assay if indicated, and
radiography if available.

Bacteriological tests

Rapid molecular tests (RMTs) should be performed on respiratory, stool or extrapulmonary (EP) specimens as the initial diagnostic
test.
As the sensitivity of Xpert MT B/RIF Ultra is higher than that of Xpert MT B/RIF, preferably use MT B/RIF Ultra for the detection of
T B and rifampicin-resistance (Chapter 3).

Sputum specimens can be difficult to obtain in children. Explanation and encouragement are important. Chest clapping may help
expectoration.
If sputum cannot be obtained spontaneously, more invasive procedures, such as nasopharyngeal aspiration, sputum induction or
gastric aspiration (Appendix 3), can be performed, but only if the specimen is collected for rapid molecular tests, culture or genome
sequencing. T hese procedures should not be performed for smear microscopy.

Stool specimens (which may contain swallowed sputum) are an alternative to respiratory specimens for the diagnosis of PT B in
children. Respiratory specimens are more likely to give a positive result, but the use of stool specimens can avoid invasive
collection procedures.

For children at risk of DR-T B, i.e. contact with a person with DR-T B or coming from an area with high DR-T B prevalence:
Multiple specimens (respiratory, stool and EP) should be tested with RMTs. Multiple testing increases the likelihood of detecting
T B and obtaining the resistance profile.
Every effort should be made to perform culture and phenotypic drug susceptibility tests (Chapter 3).

For the diagnostic accuracy of Xpert MT B/RIF in specimens other than sputum, see Appendix 1.

Lateral flow urine lipoarabinomannan assay (LF-LAM)

LF-LAM should be performed in HIV-infected children:

With signs and symptoms of T B, or
Hospitalised with advanced HIV disease, or
Followed as outpatients with a low CD4 count.
Chest x-ray (CXR)

CXR is particularly useful when bacteriological tests are negative or not available. It is also useful to assess the severity of T B and
to determine eligibility for the 4-month drug-susceptible T B regimen.
Children with PT B usually have abnormalities on CXR, but a normal CXR does not rule out T B.

For young children unable to stand alone, perform anteroposterior and lateral CXRs if possible (lateral CXR can improve detection
of enlarged hilar/mediastinal lymph nodes).
For other children, perform a standard posteroanterior CXR.

CXR findings suggestive of T B in children include a : enlarged hilar/mediastinal lymph nodes, miliary pattern, and cavities. Although
generally less specific, consolidation and pleural/pericardial effusion in a child not acutely ill is also suggestive of T B.

Ultrasound

See Chapter 3.

Tuberculin skin test (TST)

In children, a positive T ST may be one element among many to establish the diagnosis of active T B. However, it has many
limitations (see Chapter 3 and Appendix 9).

5.2.4 Follow-up investigations

For children able to expectorate spontaneously, smear microscopy is used to monitor treatment progress (Chapter 3).
For children unable to expectorate spontaneously, monitoring of treatment progress is clinical. Invasive procedures should not be
performed to obtain respiratory specimens for smear microscopy.

Footnotes
(a) For more inf ormat ion see Diagnost ic CXR at las f or t uberculosis in children: A guide t o chest X-ray int erpret at ion. Int ernat ional Union
Against Tuberculosis and Lung Disease. Second edit ion, 2022.
ht t ps://t heunion.org/sit es/def ault /files/2022-03/The%20Union_Diagnost ic%20At las%20f or%20TB%20in%20Children_2022.pdf

References
1. Seddon JA, Jenkins HE, Liu L, Cohen T, Black RE, Vos T, Becerra MC, Graham SM, Sismanidis C, Dodd PJ. Counting children with
tuberculosis: why numbers matter. Int J Tuberc Lung Dis. 2015 Dec;19 Suppl 1(0 1):9-16.
ht t ps://www.ncbi.nlm.nih.gov/pmc/art icles/PMC4708268/pdf /nihms748754.pdf
5.3 Paediatric diagnostic algorithms
5.3.1 Diagnosis of PTB in symptomatic children with CXR

5.3.2 Diagnosis of PTB in symptomatic children without CXR

Chapter 6: Intensive case finding in HIV-infected
individuals
6.1 Routine screening

6.2 Purposes of screening

6.1 Routine screening
Intensive case-finding (ICF) should be in place in all projects providing care to HIV-infected patients. Screening can be performed at
multiple points in time by different levels of health care workers (e.g. counsellors during HIV testing, health care providers during
clinical consultations).

All children and adults should be regularly screened for T B using the following criteria:

Table 6.1 - Screening criteria/symptoms in children and adults [1]

Children Adults

Current cough(a) Current cough(a)

Fever Fever
(b) Weight loss
Poor weight gain
Contact with a contagious person Night sweats

(a) Asking about “current cough”, rat her t han cough f or 2 weeks, is more sensit ive f or TB disease in HIV-inf ect ed individuals
(b) Poor weight gain is defined as report ed weight loss or underweight or confirmed weight loss > 5% since last visit , or growt h curve
flat t ening.

References
1. World Healt h Organizat ion. Guidelines for intensified tuberculosis case finding and isoniazid preventive therapy for people living with HIV in
resource constrained settings. World Healt h Organizat ion, Geneva, 2011.
ht t p://whqlibdoc.who.int /publicat ions/2011/9789241500708_eng.pdf
6.2 Purposes of screening
6.2.1 Early detection and treatment of active TB
Children and adults found to have one or more of the above symptoms/criteria during screening may have active T B, and they
should be evaluated with an appropriate T B diagnostic algorithm in order to rapidly diagnose those who do have T B (see
Diagnostic algorithms, Chapter 4 and Chapter 5).

6.2.2 Identification of patients eligible for isoniazid preventive therapy (IPT)

T he significant proportion of asymptomatic active T B described in patients eligible for ART (15 to 20%) [1] [2] leads to use this
screening method with caution. It should only be used for ruling out T B in patients not yet eligible for antiretroviral therapy (CD4
greater than 350 and no WHO stage 3 or 4 illnesses) or after three months of treatment in patients started under antiretroviral
therapy in order to allow for possible unmasking of T B.

For IPT, see Chapter 16.

References
1. Get ahun H, Kit t ikraisak W, Heilig CM, Corbet t EL, Ayles H, et al. Development of a Standardized Screening Rule for Tuberculosis in People
Living with HIV in Resource- Constrained Settings: Individual Participant Data Meta-analysis of Observational Studies. PLoS Med 8(1):
e1000391. doi:10.1371/journal.pmed.1000391. 2011.
ht t p://www.plosmedicine.org/art icle/inf o%3Adoi%2F10.1371%2Fjournal.pmed.1000391

2. Basset t IV, Wang B, Chet t y S, Giddy J, Losina E, Mazibuko M, Bearnot B, Allen J, Walensky RP, Freedberg KA. Intensive tuberculosis
screening for HIV-infected patients starting antiretroviral therapy in Durban, South Africa . Clin Inf ect Dis. 2010 Oct 1;51(7):823-9.
Chapter 7: Case definitions for registration
7.1 Definition of a tuberculosis case

7.2 History of prior anti-T B treatment

7.3 Anatomical site of the disease

7.4 Bacteriological status

7.5 HIV status

7.6 Other co-morbidities

7.7 Summary of patient registration

7.1 Definition of a tuberculosis case
A tuberculosis (T B) case is a patient that has been diagnosed as such by a clinician, regardless if the diagnosis has been confirmed
bacteriologically or not.

T he elements necessary for defining a T B case are: the T B treatment history, the bacteriological status, the anatomical site of the
disease and the patient’s HIV status.

Note: any person receiving treatment for T B should be recorded as a T B case.

7.2 History of prior anti-TB treatment
Patients who have interrupted or failed a previous anti-T B treatment have a higher risk of developing drug-resistance (DR).
T herefore, it is important to question patients about their previous treatment prior to treatment initiation.

Case registration distinguishes between[1] :

New patients: patients who have never been treated for T B or have taken anti-T B drugs for less than 1 month.

Previously treated patients: patients who have received 1 month or more of anti-T B drugs in the past.
Previously treated patients are further sub-classified into relapse, failure and return after treatment interruption:
Relapse: patients who were cured or completed treatment on their last T B treatment;
Failure: patients who have failed their most recent treatment (see Chapter 17 for outcome definitions for failure);
Treatment interruption: patients who interrupted (see Chapter 17 for outcome definition of treatment interruption) their last
treatment should be classified as “Return after treatment interruption”.

Others: patients who cannot be included in one of the above categories (e.g. patients who have previously been treated via an
erratic or unknown T B regimen).

References
1. World Healt h Organizat ion. Implementing the WHO STOP TB strategy: A handbook for national tubercuslosis control programmes. World
Healt h Organizat ion, Geneva. (WHO/HTM/TB/2008.401. 2008).
ht t p://www.who.int /t b/st rat egy/en/
7.3 Anatomical site of the disease

Pulmonary TB (PTB)
Refers to a case of T B presenting with involvement of the lung parenchyma.

Notes:
Miliary T B is also classified as PT B because there are lesions in the lungs.
Any patient presenting with PT B and an EPT B form at the same time is classified as a PT B case for recording purposes.

Extrapulmonary TB (EPTB)
Refers to a case of T B involving organs other then the lungs. Diagnosis is based on clinical signs corresponding to extrapulmonary
active T B and a decision by a clinician to treat with a full course of anti-T B drugs a .

Notes:
Sputum smear microscopy should always be done, and if possible culture and/or molecular test.
Patients presenting with tuberculous pleural effusion, or mediastinal lymphadenopathy without evidence of parenchymal
localization are classified in this category.

Footnotes
(a) If possible, obt ain hist ological or bact eriological evidence (microscopy, cult ure or molecular t est ).
7.4 Bacteriological status
Bacteriological status refers to the detection of M. tuberculosis by smear, culture or molecular methods. T he bacteriological
status can be further sub-classified on the basis of drug sensitive and drug resistant cases.

7.4.1 Detection of M. tuberculosis

Every T B case should be classified into one of two categories:
Confirmed TB case: a case with a positive bacteriological result (microscopy, culture or molecular method).
Non-confirmed TB case: a case where investigations are negative (microscopy, culture or molecular method) and for whom a
clinician prescribes anti-T B treatment.

Confirmed T B cases are further sub-classified as:

1. smear positive/negative/not done
2. culture positive/negative/not done
3. molecular test positive/negative/not done

7.4.2 Strain sensitivity/resistance

When possible, culture and DST should be done to determine if the strain presents resistance to some drugs:
Susceptible TB: the strain is not resistant to any first-line anti-T B drugs.

Drug-resistant TB:
Monodrug-resistant TB: resistance to one first-line anti-T B drug only;
Polydrug-resistant TB (PDR-T B): resistance to more than one first-line anti-T B drug, other than isoniazid and rifampicin;
Multidrug-resistant TB (MDR-T B): resistance to at least isoniazid and rifampicin;
Extensively drug-resistant TB (XDR-T B): MDR-T B resistant to at least one fluoroquinolone and at least one second-line
injectable drug (Km, Amk, Cm).

Patients with DR-T B should be classified in the following manner:

Confirmed isoniazid resistance and rifampicin susceptible: resistance to isoniazid but not rifampicin. Resistance to first and
second-line anti-T B drugs may be present.
Confirmed rifampicin resistant TB (RR-T B): resistance to rifampicin confirmed by phenotypic drug susceptibility test or line
probe assay or Xpert MT B/RIF (isoniazid susceptible or unknown).
Confirmed MDR-TB: resistance to isoniazid and rifampicin, with or without resistance to first and second-line anti-T B drugs.
Confirmed XDR-TB: resistance to isoniazid and rifampicin, and to at least one fluoroquinolone, and one second-line injectable
drug (Km, Amk, Cm).
Unconfirmed DR-TB: patients treated as DR-T B but without DST results (e.g. children who are contacts of a known case,
patients with clinical failure and for whom no DST was available for some reason).
7.5 HIV status
Determining and recording the patient’s HIV status is critical for treatment decisions, as well as for assessing programme
performances. T he T B treatment card and T B register, which should be treated as confidential documents, should include: dates
and results of HIV tests, starting date of cotrimoxazole and antiretroviral therapy.
7.6 Other co-morbidities
Any other significant diseases, such as diabetes, hepatitis B or C, cancer and malnutrition, should be noted at registration.
7.7 Summary of patient registration
Table 7.1 summarizes the elements necessary for defining a T B case.

Table 7.1 - Patient registration by outcome of most recent T B treatment [1]

Registration groups based on

Further classification
treatment history

New 1. PTB or EPTB? If EPT B, indicate site.

2. Bacteriologically confirmed or non-confirmed TB case?
3. Sub-category of bacteriological status:
Relapse Smear positive/negative/not done
Culture positive/negative/not done
Molecular test positive/negative/not done
Failure
Previously 4. If previously treated:
treated Document last regimen received
Treatment History of second-line drug use
interruption 5. DST pattern: susceptible to H and R, confirmed H resistance and R susceptible,
RR-T B, MDR-T B or XDR-T B
6. HIV status (negative/positive/not done)
Other 7. Other co-morbidities?

References
1. World Healt h Organizat ion. Treatment of Tuberculosis Guidelines 4th edition. World Healt h Organizat ion, Geneva. 2009.
(WHO/HTM/TB/2009.420).
ht t p://whqlibdoc.who.int /publicat ions/2010/9789241547833_eng.pdf
Chapter 8: Tuberculosis drugs and treatment
regimens
8.1 Introduction

8.2 Standard code for treatment regimens

8.3 Drugs for drug-susceptible tuberculosis

8.4 Drugs for drug-resistant tuberculosis

8.5 Tuberculosis drug formulations

Update: October 2022

8.1 Introduction
A combination of several antituberculosis drugs is needed to treat tuberculosis (T B) and prevent the emergence of resistance.
Each T B drug has a specific action on one or more bacillary populations, but none on dormant bacilli.

T B drugs are classified into two categories:

Drugs for drug-susceptible T B (DS-T B), also referred to as “first-line T B drugs”.
Drugs for drug-resistant T B (DR-T B), also referred to as “second-line T B drugs”. WHO has further classified DR-T B drugs in
groups based on their effectiveness and safety profile.

Treatment regimens define the T B drug combinations used and the intended duration of T B treatment.

For more information on the T B drugs, see Appendix 10.

8.2 Standard code for treatment regimens
8.2.1 Tuberculosis drugs
Each T B drug has an abbreviation.

Table 8.1 - Categories and abbreviations of T B drugs

Categories TB drugs Abbreviations

Drug-susceptible TB (first-line drugs)

Isoniazid (standard dose) H

Rifampicin R
Pyrazinamide Z
Ethambutol E
Rifabutin Rfb
Rifapentine P

Drug-resistant TB (second-line drugs)

Group A Levofloxacin or moxifloxacin Lfx or Mfx

Bedaquiline Bdq
Linezolid Lzd

Group B Clofazimine Cfz

Cycloserine or terizidone Cs or Trd

Group C Delamanid Dlm

Ethambutol E
Pyrazinamide Z
Imipenem/cilastatin or meropenem Ipm/Cln or Mpm
Amikacin or streptomycin Am or S
Ethionamide or prothionamide Eto or Pto
Para-aminosalicylate sodium or para-aminosalicylic acid PAS
Isoniazid (high-dose) Hh

Ungrouped Pretomanid Pa

Notes:
High-dose isoniazid, although not a Group C drug according to the WHO classification, is considered in this guide as a Group C
drug as it is used as such when building a treatment regimen for DR-T B.
Pretomanid is not categorized in the WHO classification and is only used in standard treatment regimens for DR-T B (Chapter
10).

8.2.2 Treatment regimens

T B treatment regimens are expressed as follows:
Drugs are designated by their abbreviation.
For some regimens, the treatment is divided into two phases: initial (or intensive) phase, and continuation phase. T he phases are
separated by a slash /.
Letters in brackets ( ) indicate fixed-dose combinations (FDCs).
 Letters that are not in brackets indicate individual drugs.
Second-line drugs are separated by a hyphen.
Letters in square brackets [ ] indicate that drugs are used, but not considered as likely effective (Chapter 10).
A superscript h (h) indicates that the drug is administered in a high dose.
Numbers before letters indicate the duration (in months) of the treatment or of each phase.
Numbers in subscript and angle brackets < > after a drug indicate the duration (in months) of the treatment with this drug.

Box 8.1 – Examples

2(HRZE)/4(HR): the initial phase lasts 2 months with an FDC containing 4 drugs; the continuation phase lasts 4 months, with an
FDC containing 2 drugs.

18Bdq-Lzd-Cfz-Cs-Dlm-[Z]: the treatment lasts 18 months with 6 individual drugs; Z is used, but not considered as a likely
effective drug.

4Bdq<6>-Lfx-Cfz-Z-E-Hh-Lzd<2>/5Lfx-Cfz-Z-E: the initial phase lasts 4 months but bedaquiline is given for 6 months and
linezolid for 2 months only; the continuation phase lasts 5 months.
8.3 Drugs for drug-susceptible tuberculosis
All drugs used for DS-T B treatment are taken 7 days a week.

8.3.1 First-line drugs

Table 8.2 – Main characteristics of first-line T B drugs

TB drugs Activity Resistance

Isoniazid Bactericidal High level of resistance in some regions.

Cross-resistance with thionamides.

Rifampicin Bactericidal High level of resistance to rifampicin in some regions.

Rifabutin High level of cross-resistance between rifamycins.
Rifapentine

Ethambutol Bacteriostatic Unknown (no reliable drug susceptibility test for ethambutol).

Pyrazinamide Weakly bactericidal High level of resistance in regions where rifampicin resistance is
frequent.

Isoniazid

Isoniazid is usually well tolerated at recommended doses.

It may cause peripheral neuropathy, hepatotoxicity, and hypersensitivity reactions.
Peripheral neuropathy can be prevented by administration of pyridoxine (vitamin B 6). See Appendix 17.

Rifamycins (rifampicin, rifabutin, rifapentine)

Rifamycins are usually well tolerated at recommended doses.

T hey may cause hypersensitivity reactions, hepatotoxicity, and thrombocytopenia.
T hey are strong inducers of cytochrome P450 and can affect the plasma concentrations of many drugs (Appendix 19).
Rifampicin is the most used rifamycin in the treatment of DS-T B.
Rifabutin is used instead of rifampicin in patients taking certain antiretrovirals (Appendix 19).
Rifapentine is only used in the 4-month regimen 2HPZ-Mfx/2HP-Mfx.

Note: rifampicin and rifapentine are also used to treat latent T B infection (Chapter 16).

Ethambutol

Ethambutol is usually well tolerated, including in children, particularly with respect to ocular toxicity [1] . Ocular toxicity is dose- and
duration-dependent. It is uncommon when ethambutol is used at the recommended dose for 2 months.

Pyrazinamide

Pyrazinamide is usually well tolerated however, it may cause hepatotoxicity, gout, arthralgias and photosensitivity.

8.3.2 Other drugs

Two second-line drugs are also used in the treatment of DS-T B: moxifloxacin (Section 8.4.1) and ethionamide (Section 8.4.3).
References
1. World Healt h Organizat ion. Guidance for national tuberculosis programmes on the management of tuberculosis in children. Geneva: World
Healt h Organizat ion; 2014.
ht t ps://apps.who.int /iris/bit st ream/handle/10665/112360/9789241548748_eng.pdf ?sequence=1
8.4 Drugs for drug-resistant tuberculosis
Drugs used for DR-T B treatment (except bedaquiline) are taken 7 days a week.

8.4.1 Group A drugs

Table 8.3 – Main characteristics of T B drugs Group A

TB drugs Classes Activity Resistance

Levofloxacin Fluoroquinolones Bactericidal Resistance common in some regions.

Moxifloxacin (FQs) Cross-resistance between FQs.

Bedaquiline Diarylquinolines Bactericidal Partial cross-resistance with Cfz.

Growing resistance as use increases.

Linezolid Oxazolidinones Bactericidal Resistance assumed to be rare due to its limited

use.

Fluoroquinolones (levofloxacin, moxifloxacin)

FQs are usually well tolerated.

T hey may cause tendinopathy and QT prolongation.
Moxifloxacin is sometimes used at high dose (Mfxh) in the presence of low-level resistance to FQs.

Bedaquiline

Bedaquiline is usually well tolerated. It may cause hepatotoxicity and QT prolongation.

Bedaquiline has a long half-life (5.5 months). T herefore, adverse effects can persist after the drug is stopped, and if T B is still
active, resistance can develop.
Bedaquiline is metabolized in the liver by the cytochrome P450 (CYP450) system enzymes. Drugs, which induce or inhibit CYP450,
can affect bedaquiline plasma concentrations and should be avoided (Appendix 19).
T he extent of cross-resistance bedaquiline/clofazimine and the clinical implications are not fully understood [1] [2] [3] .

Linezolid

Linezolid may cause myelosuppression, dose- and duration-dependent neuropathy and lactic acidosis.
Pyridoxine supplementation (vitamin B 6) is recommended for all patients on linezolid, although there is no evidence that pyridoxine
can prevent linezolid-induced neuropathy.
Adverse effects frequently lead to reducing the dose or discontinuing linezolid. T he optimal dose and duration of treatment are not
established.
Linezolid has many interactions and overlapping toxicities with other drugs (e.g. risk of serotonin syndrome when administered with
serotonergic drugs [4] ). However, it is not always possible to avoid concomitant use of these drugs (e.g. even on linezolid, a patient
with depression may require an antidepressant).

8.4.2 Group B drugs

Table 8.4 – Main characteristics of T B drugs Group B
 TB drugs Classes Activity Resistance

Clofazimine Riminophenazine (anti- Probably bacteriostatic Partial cross-resistance with Bdq.

leprosy drug) Growing resistance as use increases.

Cycloserine Analogue of D-alanine Bacteriostatic Resistance common in areas where it has

Terizidone been used extensively.
Full cross-resistance between the 2 drugs.

Clofazimine

Clofazimine is a QT-prolonging drug.

Orange-pink to brownish-black discolouration of the skin and body fluids occur in almost all patients. T hese changes are reversible
and not harmful.
Clofazimine has a long half-life (approximately 70 days). Consequently, its adverse effects can persist for several weeks or months
after the drug is stopped.

Cycloserine or terizidone

Cycloserine and terizidone are structural analogues used at the same dose.
Both drugs may cause neurotoxicity including psychiatric adverse events.
To prevent neurotoxicity, pyridoxine (vitamin B 6) should be administered along with these drugs throughout the course of treatment
(Appendix 17).

8.4.3 Group C drugs

Table 8.5 – Main characteristics of T B drugs Group C
 TB drugs Classes Activity Resistance

Delamanid Nitroimidazooxazines Bactericidal Potential cross-resistance with pretomanid.

Resistance assumed to be rare due to its limited use.

Ethambutol Bacteriostatic High prevalence of resistance among MDR/RR-T B

patients (> 49% in some settings [5] [6] ).

Pyrazinamide Bactericidal High prevalence among MDR/RR-T B patients (> 80% in

some areas [7] [8] ).

Imipenem/cilastatin Carbapenems Full cross-resistance between carbapenems.

Meropenem

Amikacin Streptomycin Aminoglycosides Bactericidal Partial cross-resistance between the 2 drugs.

Ethionamide T hionamides Weak Full cross-resistance between thionamides.

Prothionamide bacteriostatic Cross-resistance with isoniazid if inhA mutation present.
High prevalence of resistance among MDR-T B patients
in some areas [9] .

Para-aminosalicylate Weak Common in some regions.

sodium bacteriostatic
Para-­aminosalicylic
acid

Isoniazid high-dose Cross-resistance with thionamides if inhA mutation present.

Delamanid

Delamanid is usually well tolerated.

It may cause QT prolongation[10] .
It is particularly useful in patients with pre-existing hepatic disease (no reported hepatotoxicity) or HIV infection (no significant drug
interactions or overlapping toxicities with antiretrovirals).
It is also useful for replacing a Group A or B drug causing toxicity.

Ethambutol

See Section 8.3.1. Vision monitoring is required when ethambutol is administered for more than 2 months (risk of optic neuritis).

Pyrazinamide

See Section 8.3.1.

Carbapenems (imipenem/cilastatin, meropenem)

Imipenem is always combined with cilastatin. Cilastatin has no antibacterial activity, its role is to inhibit a renal enzyme that
inactivates imipenem.
Meropenem does not need to be combined with cilastatin, as it is metabolised through a different pathway.
High cost and difficulty with administration limits the use of carbapenems.
Carbapenems may cause gastrointestinal disturbances, neurotoxicity and hypersensitivity reactions.
Meropenem should be used in children and adolescents under 15 years, and if possible, in epileptic patients and patients with T B
meningitis (risk of seizures lower than with imipenem/cilastatin).
T he first dose is always administered in a health facility so that an eventual hypersensitivity reaction can be managed. If conditions
permit, carbapenems can be continued as an outpatient.
Amoxicillin/clavulanic acid is routinely administered prior to carbapenems, as clavulanic acid prevents the development of
carbapenem resistance.

Aminoglycosides (amikacin, streptomycin)

Aminoglycosides should only be used when no alternative is available. Most DR-T B patients can be treated without
aminoglycosides, including some cases of extensively drug-resistant T B (XDR-T B).
Aminoglycosides are nephrotoxic and ototoxic drugs. Streptomycin is less nephrotoxic than other aminoglycosides, but causes
vestibular toxicity [11] more frequently. If an aminoglycoside is used, close monitoring is essential (audiometry, electrolytes and renal
function). If close monitoring cannot be ensured, aminoglycosides should not be used.

Note: kanamycin and capreomycin are no longer recommended, as their use is associated with higher rates of treatment failure and
death[12] .

Thionamides (ethionamide, prothionamide)

Ethionamide and prothionamide are used at the same dose.

T hey may cause gastrointestinal disturbances, hypothyroidism (especially if co-administered with para­aminosalicylic acid),
neuropathy and hepatotoxicity.
In diabetic patients, the dose of antidiabetics may need to be adjusted.

Para-aminosalicylate sodium or para-aminosalicylic acid

PAS often causes gastrointestinal disturbances and can decrease the absorption of other T B drugs.
It may also cause hypothyroidism, especially when co-administered with a thionamide.

High-dose isoniazid

See Section 8.3.1. T here is limited evidence to support the use of high-dose isoniazid.
High-dose isoniazid may cause more adverse effects than the standard dose.
It has overlapping toxicity with linezolid (neuropathy) and hepatotoxic drugs.
To prevent peripheral neuropathy, pyridoxine (vitamin B 6) should be administered to all patients throughout the course of treatment
(Appendix 17).

8.4.4 Ungrouped drugs

Pretomanid

Pretomanid belongs to the same class as delamanid and has bactericidal activity.
It is used only as part of standard regimens for DR-T B in the following combinations: BPaLM, BPaL (and BPaLC in operational
research conditions only), see Chapter 10.
Regimens that include bedaquiline, pretomanid and linezolid may cause hepatotoxicity, lactic acidosis, myelosuppression,
neuropathy and QT prolongation.
Pretomanid/delamanid cross-resistance is likely.

8.4.5 Other drugs

Amoxicillin/clavulanic acid

Amoxicillin/clavulanic acid is administered before each dose of carbapenem.

T he clavulanic acid component prevents the development of carbapenem resistance.
Only formulations with a ratio of 4:1 (e.g. 500/125 mg) or 2:1 (e.g. 250/125 mg) are suitable for this indication. Do not use
formulations with a ratio of 8:1 or 7:1.

References
1. Camus Nimmo, James Millard, Lucy van Dorp, et al. Population-level emergence of bedaquiline and clofazimine resistance-associated variants
 among patients with drug-resistant tuberculosis in southern Africa: a phenotypic and phylogenetic analysis. Lancet Microbe 2020; 1: e165–74.
ht t ps://www.t helancet .com/act ion/showPdf ?pii=S2666-5247%2820%2930031-8

2. Thi Van Anh Nguyen, Richard M Ant hony, et al. Bedaquiline Resistance: Its Emergence, Mechanism, and Prevention. Clinical Inf ect ious
Diseases, Volume 66, Issue 10, 15 May 2018, Pages 1625–1630.
ht t ps://academic.oup.com/cid/art icle/66/10/1625/4602986

3. Ghodousi A, Rizvi AH, Baloch AQ,et al. Acquisition of Cross-Resistance to Bedaquiline and Clofazimine following Treatment for Tuberculosis in
Pakistan. Ant imicrob Agent s Chemot her. 2019 Aug 23;63(9):e00915-19.
ht t ps://www.ncbi.nlm.nih.gov/pmc/art icles/PMC6709449/

4. Quinn DK, St ern TA. Linezolid and serot onin syndrome. Prim Care Companion J Clin Psychiat ry. 2009;11(6):353-356.
ht t ps://www.ncbi.nlm.nih.gov/pmc/art icles/PMC2805572/

5. Hoek K G P, Schaaf H S, Gey van Pit t ius N C, van Helden P D, Warren R M. Resistance to pyrazinamide and ethambutol compromises
MDR/XDR-TB treatment. SAMJ, S. Af r. med. j. 2009 Nov; 99(11): 785-787.
ht t p://www.scielo.org.za/scielo.php?script =sci_art t ext &pid=S0256-95742009001100011&lng=en.

6. Arshad Javaid, Naf ees Ahmad, Amer Hayat Khan, Z ubair Shaheen. Applicability of the World Health Organization recommended new shorter
regimen in a multidrug-resistant tuberculosis high burden country. European Respirat ory Journal Jan 2017, 49 (1) 1601967.

7. Mat t eo Z ignol, Anna S Dean, Nat avan Alikhanova, et al. Population-based resistance of Mycobacterium tuberculosis isolates to pyrazinamide
and fluoroquinolones: results from a multicountry surveillance project. Lancet Inf ect Dis 2016; 16: 1185–92.
ht t ps://www.t helancet .com/journals/laninf /art icle/PIIS1473-3099(16)30190-6/f ullt ext

8. Kwok Chiu Chang, Wing Wai Yew, Ying Z hang. Pyrazinamide Susceptibility Testing in Mycobacterium tuberculosis: a Systematic Review with
Meta-Analyses. Ant imicrobial Agent s and Chemot herapy Sep 2011, 55 (10) 4499-4505.

9. Lange C, Duart e R, Fréchet -Jachym M, Guent her G, Guglielmet t i L, Olaru ID, Oliveira O, Rumet shof er R, Veziris N, van Let h F; European
MDR-TB dat abase collaborat ion. Limited Benefit of the New Shorter Multidrug-Resistant Tuberculosis Regimen in Europe . Am J Respir Crit
Care Med. 2016 Oct 15;194(8):1029-1031.

10. Dooley KE, Rosencrant z SL, Conradie F, et al. QT effects of bedaquiline, delamanid or both in patients with rifampicin-resistant-tuberculosis: a
phase 2, open-label, randomised, controlled trial. Lancet Inf ect Dis. 2021.

11. Brit ish Thoracic Societ y. Guidelines for the prevention and management of Mycobacterium tuberculosis infection and disease in adult patients
with chronic kidney disease Prepared by members of the Guideline Group on behalf of the British Thoracic Society. St andards of Care
Commit t ee and Joint Tuberculosis Commit t ee, Thorax 2010;65:559e570.
ht t ps://t horax.bmj.com/cont ent /t horaxjnl/65/6/559.f ull.pdf

12. World Healt h Organizat ion. WHO consolidated guidelines on drug resistant tuberculosis treatment. Geneva: World Healt h Organizat ion; 2019.
ht t ps://apps.who.int /iris/bit st ream/handle/10665/311389/9789241550529-eng.pdf ?ua=1, accessed 20 March 2020
8.5 Tuberculosis drug formulations
Only quality-assured drugs should be used. Several internationally recognized mechanisms ensure the quality of T B drugs a , b .

8.5.1 Fixed-dose combinations

FDC formulations combine several T B drugs (2, 3 or 4) in the same tablet. FDCs are only available for first-line T B drugs.
FDCs improve adherence (decreased pill burden, decreased risk of omission of one or more drugs).

Table 8.6 – Quality-assured FDC formulations

FDCs Available formulations

Children

HZR H50 mg/Z150 mg/R75 mg

HR H50 mg/R75 mg

Adults

EHZR E275 mg/H75 mg/Z400 mg/R150 mg

EHR E275 mg/H75 mg/R150 mg

HR H75 mg/R150 mg

Note: when needed in children, ethambutol is given as a single formulation, in addition to the paediatric FDCs.

8.5.2 Individual drugs

Quality-assured single drug formulations are available for all first-line T B drugs. It may be necessary to use them when FDCs
cannot be used due to adverse effects or drug interactions.
T here are no quality-assured FDCs for second-line T B drugs. T he treatment of DR-T B is based on a combination of individual
drugs.

8.5.3 Paediatric formulations

Paediatric formulations should be used whenever possible.

However, they are not available for all T B drugs. When the only option is to manipulate the adult formulations:
Preferably use scored tablets.
Ensure that tablets/capsules can be split, crushed or opened (e.g. active ingredients may be protected from gastric acidity by
an enteric coating).
If tablets must be crushed (or capsules opened), a fraction of the powder corresponding to the required dose is mixed with food
or liquids. Such manipulations should be done immediately before administering the drug. Any remaining powder should be
discarded.
T he preparation of extemporaneous formulations using adult formulations is an alternative, however, this can only be
considered if there are qualified personnel to ensure preparation in compliance with the appropriate compounding procedures.
Footnotes
(a) Qualit y assurance:
• WHO Prequalificat ion Scheme: ht t p://apps.who.int /prequal/
• St ringent Regulat ory Aut horit ies (SRA): ht t ps://www.who.int /init iat ives/who-list ed-aut horit y-reg-aut horit ies/SRAs

(b) Supply:
Global Drug Facilit y: ht t ps://www.st opt b.org/f acilit at e-access-t o-t b-drugs-diagnost ics/global-drug-f acilit y-gdf
Chapter 9: Treatment of drug-susceptible
tuberculosis
9.1 Introduction

9.2 Conventional treatment regimens

9.3 Alternative treatment regimens

9.4 Special situations

9.5 Adjunctive therapy

9.6 Patient monitoring

9.7 Adverse effects

9.8 Treatment adaptation and change of treatment

9.9 Treatment interruptions

Update: October 2022

9.1 Introduction
Drug-susceptible tuberculosis (DS-T B) treatment is indicated:
When susceptibility to rifampicin and isoniazid is confirmed by drug susceptibility testing (DST ), or
If the probability of resistance to rifampicin and isoniazid is low:
while waiting for DST results for rifampicin and/or isoniazid,
when susceptibility to rifampicin is confirmed and susceptibility to isoniazid cannot be tested.

T he probability of resistance is considered low in the following situations:

No previous T B treatment;
No contact with a drug-resistant T B (DR-T B) patient;
T he patient comes from an area of low prevalence of resistance according to drug resistance surveys.

Patients with DS-T B should start a conventional regimen based on first-line drugs (Table 9.1) or, if eligible, an alternative regimen
(Table 9.2).
All regimens for DS-T B are standard regimens.

For dosages of fixed-dose combinations see Appendix 13.

For dosages of individual drugs see Appendix 10.
9.2 Conventional treatment regimens
T able 9.1 – Conventional DS-T B regimens according to the infection site

Regimens
Eligibility
Duration

2(HRZE)/2(HR) Children > 3 months and adolescents < 16 years with[1] :

4 months Pulmonary TB (PTB)
microscopy smear-negative or Xpert result “negative”, “trace”, “very low” and “low”
or
clinically diagnosed with T B lesions confined to one lobe and no cavities on chest x-ray (CXR)

Extrapulmonary TB (EPTB) non severe, i.e.:

pleural effusion without complications (e.g. no empyema, pneumothorax or fistula)
extra- or intra-thoracic lymph node T B with no airway obstruction

2(HRZE)/4(HR) PTB and EPTB (except miliary TB, TB meningitis and bone and joint TB) [2]
6 months Adolescents ≥ 16 years and adults
Children and adolescents < 16 years not eligible for the 4-month regimen or when the national protocol
does not include the 4-month regimen.

2(HRZE)/10(HR) Miliary TB and TB meningitis [3]

12 months All children, adolescents and adults.

2(HRZE)/7‑10(HR) Bone and joint TB [4]

9-12 months All children, adolescents and adults.

If bacteriological testing and/or CXR are not available, children meeting the following criteria are eligible for the 4-month regimen
2(HRZE)/2(HR):
Signs and symptoms not requiring hospitalisationa .
Extra-thoracic lymph node T B without involvement of other EP sites.
If after one month of treatment symptoms have completely resolved, continue treatment until the end. If symptoms have not
completely resolved, further investigations are needed.
If after 4 months of treatment symptoms have not completely resolved and/or there is no weight gain, further investigation is
needed. T he treatment can be extended to 6 months if causes of non-response to treatment (including DR-T B, non-adherence
and non-T B disease) are ruled out or unlikely.

Ethambutol can be removed from the 4- and 6-month regimens in non-HIV-infected children living in areas where the prevalence of
HIV and/or isoniazid resistance is low with:
PT B microscopy smear-negative, or
Extra- or intra-thoracic lymph node T B​​[5] .

For spinal T B, rest and back support bracing are indicated in addition to drug therapy. For patients with neurological deficit or
unstable spine lesion, surgery can also be considered.

Footnotes
(a) Sympt oms requiring hospit alisat ion: signs of severe respirat ory disease or dist ress, severe acut e malnut rit ion, f ever > 39 °C, severe pallor,
rest lessness, irrit abilit y or let hargy, et c.
References
1. World Healt h Organizat ion. WHO operational handbook on tuberculosis. Module 5: management of tuberculosis in children and adolescents.
Geneva: World Healt h Organizat ion; 2022.
ht t ps://apps.who.int /iris/rest /bit st reams/1414333/ret rieve

2. World Healt h Organizat ion. Guidelines for treatment of drug-susceptible tuberculosis and patient care . 2017 updat e.
ht t ps://apps.who.int /iris/bit st ream/handle/10665/255052/9789241550000-eng.pdf ?sequence=1

3. World Healt h Organizat ion. Rapid advice: treatment of tuberculosis in children. Geneva, Swit zerland 2010. WHO/HTM/TB/2010.13.
ht t p://whqlibdoc.who.int /publicat ions/2010/9789241500449_eng.pdf

4. S. Ramachandran, I. J. Clif t on, T. A. Collyns, J. P. Wat son, S. B. Pearson. The treatment of spinal tuberculosis: a retrospective study. INT J
TUBERC LUNG DIS 9(5):541–544 © 2005 The Union.
ht t ps://www.ingent aconnect .com/cont ent /iuat ld/ijt ld/2005/00000009/00000005/art 00013?crawler=t rue

5. World Healt h Organizat ion. Guidance for national tuberculosis programmes on the management of tuberculosis in children. Geneva: WHO;
2014.
ht t ps://www.who.int /publicat ions/i/it em/9789241548748
9.3 Alternative treatment regimens
Table 9.2 – Alternative DS-T B regimens according to the infection site

Regimens
Eligibility
Duration

2HPZ-Mfx/2HP- PTB and non-severe EPTB [1] [2]

Mfx Adolescents ≥ 12 years and adults meeting all the following criteria:
4 months Weight ≥ 40 kg
CD4 ≥ 100 if HIV-infected
No resistance to fluoroquinolones (FQs) or living in areas where the prevalence of FQs resistance is
low.

6HRZ-Eto TB meningitis [3]

6 months Non-HIV infected children and adolescents under 20 years without inhA mutation detected.

Regimen 2HPZ-Mfx/2HP-Mfx

T his regimen is an alternative to the conventional regimens for PT B and EPT B in eligible patients.
Implementation requires DST to FQs and supply of rifapentine.
T here are no fixed-dose combinations (FDC) for this regimen which makes treatment adherence more difficult.

Regimen 6HRZ-Eto

Small studies have shown lower mortality, but more neurological sequelae with the 6HRZ-Eto regimen compared to the 12-
month conventional regimen. However, no clinical trials have been conducted to compare the two regimens [3] .
T he advantages of this regimen are short duration and better central nervous system penetration of ethionamide compared to
ethambutol.
Implementation requires supply of ethionamide.
T here are no FDC for this regimen which makes treatment adherence more difficult.
T he daily doses of T B drugs in this regimen are higher than those of other regimens:
isoniazid 20 mg/kg daily (max. 400 mg)
rifampicin 20 mg/kg daily (max. 600 mg)
pyrazinamide 40 mg/kg daily (max. 2 g)
ethionamide 20 mg/kg daily (max. 750 mg)

References
1. World Healt h Organizat ion. WHO operational handbook on tuberculosis Module 4: Treatment – drug-susceptible tuberculosis treatment.
Geneva: World Healt h Organizat ion; 2022.
ht t ps://www.who.int /publicat ions/i/it em/9789240050761

2. Dorman SE, Nahid P, Kurbat ova EV, et al; AIDS Clinical Trials Group; Tuberculosis Trials Consortium. Four-month rifapentine regimens with or
without moxifloxacin for tuberculosis. N Engl J Med. 2021;384(18):1705-1718.
ht t ps://www.nejm.org/doi/pdf /10.1056/NEJMoa2033400?art icleTools=t rue

3. World Healt h Organizat ion. WHO operational handbook on tuberculosis. Module 5: management of tuberculosis in children and adolescents.
Geneva: World Healt h Organizat ion; 2022.
ht t ps://apps.who.int /iris/rest /bit st reams/1414333/ret rieve
9.4 Special situations
9.4.1 Women (pregnant or breastfeeding or of childbearing age)
Pregnant or breastfeeding women

All first-line T B drugs, except rifabutin and rifapentine, can be used during pregnancy and breastfeeding [1] .
Isoniazid may cause peripheral neuropathy due to vitamin B 6 (pyridoxine) deficiency:
Pregnant and breastfeeding women should receive pyridoxine PO (10 mg once daily) throughout the course of T B
treatment.
Breast-fed neonates or infants should receive pyridoxine PO (5 mg once daily).
Rifampicin may cause clotting disorders due to increased vitamin K (phytomenadione) metabolism:
Women in late pregnancy on rifampicin (or rifabutin) should receive phytomenadione PO (10 mg once daily) for 2 weeks prior
to expected date of delivery.
Neonates should also receive phytomenadione IM at birth (1 mg single dose) to prevent haemorrhagic disease of the
newborn.
Regimens containing rifapentine, moxifloxacin[2] and ethionamide cannot be used to treat DS-T B in pregnant and
breastfeeding women.

Women of childbearing age

Women on contraception should use an intra-uterine device or a progestogen-only injectable throughout the courses of T B
treatment, as rifamycins reduce the effectiveness of implants and oral contraceptives.

9.4.2 Malnutrition or risk of malnutrition

For patients with malnutrition, therapeutic feeding should be initiated.
For children with severe acute malnutrition, a 6-month regimen is preferred over a 4-month regimen until more data on the
efficacy of the 4-month regimen in these patients become available.
For at-risk populations, such as children, pregnant and breastfeeding women and the elderly, nutritional supplementation with a
standard food package or ready-to-use food may be considered during the first 2 months of treatment.

9.4.3 Diabetes
T B can impair glycaemic control in patients with diabetes​​[3] . It is necessary to increase blood glucose monitoring in these patients.

T B drugs can exacerbate complications of diabetes (e.g. peripheral neuropathy). Avoid prescribing ethambutol in patients with pre-
existing diabetic retinopathy.
Rifampicin can reduce the effect of sulfonylureas (e.g. glibenclamide, gliclazide). In contrast, first-line T B drugs have no interactions
with metformin.

If diabetes is diagnosed, treat and monitor according to standard protocols.

At the end of T B treatment, it is recommended to schedule a specialist consultation for a complete evaluation and, if necessary,
adjust antidiabetic treatment.

9.4.4 Renal insufficiency

In patients with renal insufficiency, creatinine clearance should be calculated. If it is less than 30 ml/minute, doses of certain T B
drugs should be adjusted.
For the formula to estimate the creatinine clearance and dose adjustments in renal insufficiency see Appendix 12.

References
1. World Healt h Organizat ion. Guidelines for treatment of drug-susceptible tuberculosis and patient care – Annex 6: Essential first line
antituberculosis drugs. 2017 updat e.
ht t ps://apps.who.int /iris/bit st ream/handle/10665/255052/9789241550000-eng.pdf

2. Wendy Carr, Ekat erina Kurbat ova, et al. Interim Guidance: 4-Month Rifapentine-Moxifloxacin Regimen for the Treatment of Drug-Susceptible
Pulmonary Tuberculosis. Morbidit y and Mort alit y Weekly Report Weekly. Vol. 71 / No. 8 February 25, 2022.
ht t ps://www.cdc.gov/mmwr/volumes/71/wr/pdf s/mm7108a1-H.pdf

3. World Healt h Organizat ion & Int ernat ional Union against Tuberculosis and Lung Disease. (‎2011)‎. Collaborative framework for care and
control of tuberculosis and diabetes. World Healt h Organizat ion.
ht t ps://apps.who.int /iris/bit st ream/handle/10665/44698/9789241502252_eng.pdf ?sequence=1&isAllowed=y
9.5 Adjunctive therapy
9.5.1 Pyridoxine prophylaxis
Pyridoxine (vitamin B 6) prophylaxis is indicated for all patients at risk of peripheral neuropathy, i.e. pregnant or breastfeeding women
and patients with HIV infection, chronic alcohol use, malnutrition, diabetes, chronic hepatic disease or renal impairment (see
Appendix 17).

9.5.2 Corticosteroid therapy

Corticosteroid therapy is indicated for:
T B meningitis [1] and pericarditis [2] ;
Treatment and prevention of T B-associated immune reconstitution inflammatory syndrome (T B-IRIS). See Chapter 12.

T here is insufficient evidence regarding the use of corticosteroids in other indications [3] [4] .

Table 9.3 – Corticosteroid treatment

Indications Dosage and duration

TB meningitis [5] dexamethasone IV/PO

Child: 0.6 mg/kg once daily for 4 weeks, tapered off over 4 weeks
Adult: 0.4 mg/kg once daily for 7 days, tapered off over 6 to 8 weeks

TB pericarditis prednisolone PO
Child: 1.5 mg/kg once daily for 4 weeks, tapered off over 6 weeks
Adult: 60 mg once daily for 4 weeks, tapered off over 6 weeks

References
1. Burch Jane, Eisenhut Michael. What effect do adjunctive corticosteroids have on mortality and disability in people with tuberculous meningitis?
Cochrane Clinical Answers 2016.
ht t ps://www.cochranelibrary.com/cca/doi/10.1002/cca.1303/f ull#0

2. Wiysonge CS, Nt sekhe M, Thabane L, Volmink J, Majombozi D, Gumedze F, Pandie S, Mayosi BM. Interventions for treating tuberculous
pericarditis. Cochrane Dat abase Syst Rev. 2017 Sep 13;9(9):CD000526.
ht t ps://www.ncbi.nlm.nih.gov/pmc/art icles/PMC5618454/pdf /CD000526.pdf

3. Schut z C, Davis AG, Sossen B, et al. Corticosteroids as an adjunct to tuberculosis therapy. Expert Rev Respir Med. 2018;12(10):881-891.
ht t ps://www.ncbi.nlm.nih.gov/pmc/art icles/PMC6293474/pdf /nihms-1514618.pdf

4. Kadhiravan T, Deepanjali S. Role of corticosteroids in the treatment of tuberculosis: an evidence-based update . Indian J Chest Dis Allied Sci.
2010 Jul-Sep;52(3):153-8. PMID: 20949734.

5. BMJ Best Pract ice. Ext rapulmonary t uberculosis [Accessed 01 March 2023]
9.6 Patient monitoring
Patients should be assessed at baseline, then, regardless of the regimen prescribed, monitored throughout the course of
treatment.

Monitoring includes:
Assessment of treatment response
Detection of adverse effects and adherence issues.
For the schedule of follow-up examinations see Appendix 14.

Baseline and follow-up findings should be noted in the patient file to enable the detection and interpretation of potential changes.

9.6.1 Clinical visits

Baseline assessment

Assessment includes:
Symptoms of T B and their severity (cough, fever, night sweats, weight loss, shortness of breath, ability to perform daily
activities).
Vital signs and weight.
Comorbidities and other risk factors for adverse effects requiring monitoring adaptation.
Psychological assessment.

Other investigations may be needed depending on the drugs used in the regimen prescribed (Section 9.6.3).
Clinical assessment should be performed by a clinician. Psychological assessment should be performed whenever possible by
personnel with appropriate training.
All patients starting treatment should be given the information they need to understand the disease and its treatment (Appendix 21).

Follow-up visits

Each follow-up visit, assessment includes:

Clinical progress, vital signs and weight. Dosages should be adjusted to the weight if necessary.
Occurrence of adverse effects.
Adherence to treatment (Appendix 22).
Psychological condition.

Frequency of visits depends on the patient’s clinical condition and evolution:

A visit every other week for the first month, then once a month if there is no particular problem.
Additional visits may be required in case of comorbidities, severe or multiple adverse effects, pregnancy, etc.

Visits should coincide with bacteriological examinations and other investigations when possible.

T he clinician should take into account any information and concerns regarding treatment tolerance and adherence reported by the
patient or the team responsible for the patient’s follow-up and support.

9.6.2 Bacteriological tests

To assess treatment response in patients with:
PT B: bacteriological tests are essential.
EPT B: evaluation is based on clinical evolution. However, bacteriological tests are required if patients also develop PT B.

Baseline tests

Baseline tests are those performed on specimens collected just prior to treatment initiation. T hey include:
Rapid molecular tests (RMTs) for detection of M. tuberculosis and rifampicin and isoniazid resistance.
Smear microscopy to monitor treatment progress.
Culture and phenotypic DST (pDST ) when indicated.
For more information see Chapter 3.
Follow-up tests

Smear microscopy
Microscopy should be performed every 2 months until treatment completion.
If treatment is effective, microscopy at Month 2, 4 and 6 should be negative.
Notes:
Patients with high bacillary load at baseline may have dead bacilli in their sputum for several months.
As microscopy cannot distinguish dead from live bacilli, a positive result does not necessarily indicate that the treatment has
failed.

Rapid molecular tests

RMTs cannot be used to monitor treatment progress. However, if microscopy or culture is positive at Month 2 or later, RMTs
should be performed to detect the emergence of new drug resistance not present at baseline (Chapter 3).

Culture and pDST

Culture and pDST should be performed:
at Month 2 or later, if RMTs show a new resistance to rifampicin or isoniazid;
at Month 4, if microscopy is positive.
Full pDST (for first- and second-line drugs) should be performed on any positive culture.
Note: bacteriological tests are performed at the end of the month (e.g. Month 2 means the end of the 2nd month of treatment).

Regardless of the above schedule, RMTs, culture and pDST should be performed if the patient's clinical condition deteriorates.

End of treatment test

Microscopy should be performed at end of treatment to confirm the end of treatment outcome (Chapter 17).

9.6.3 Other investigations

Radiography

CXR: for children with presumptive PT B, patients with non-bacteriologically confirmed PT B, suspicion of other intra-thoracic
T B at baseline, then if indicated (e.g. worsening respiratory symptoms, non-response to T B treatment).
Bone x-ray: for patients with osteoarticular and spinal T B at baseline, then every 6 months.

Biological tests

Table 9.4 – Blood tests at baseline and during treatment

Tests Indications

Full blood count (a) HIV-infected patients on rifabutin or zidovudine (AZT ), at baseline, then once a month for the first
2 months, then if indicated.

Liver function tests (b) Patients with pre-existing hepatic disease, at baseline, then once a month.

Serum creatinine (c) Patients with renal insufficiency at baseline, then if indicated.

HbA1C and/or blood All patients, at baseline, to detect diabetes. If diabetes is detected, monitor according to standard
glucose level protocols.

HIV, hepatitis B and C For patients with undocumented HIV, hepatitis B and C status; HIV test every 6 months in high HIV
prevalence areas. Tests can be repeated in case of recent exposure.

CD4 count and viral load HIV-infected patients: at baseline, then every 6 months.

(a) Haemoglobin, red and whit e blood cells, plat elet s.

(b) Aspart at e aminot ransf erase (AST) and alanine aminot ransf erase (ALT). Bilirubin if elevat ed liver enzymes.
(c) For est imat ion of creat inine clearance see Appendix 12.
9.7 Adverse effects
Rapid management of adverse effects is essential to increase tolerance and improve outcomes.
In the event of minor adverse effects, drugs should not be stopped. Providing support and using ancillary medicines is all that is
necessary.
In the event of major adverse effects, the regimen may need to be adapted.

Table 9.5 – Main adverse effects and likely responsible drugs

Adverse effects Drug(s) likely responsible Management

Minor

Nausea, vomiting Eto, Z Appendix 17

Arthralgia Z Appendix 17

Peripheral neuropathy H, Eto Appendix 17

Orange/red urine, tears, etc. R, P Patients should be told that this is normal before
starting treatment.

Major

Skin reactions E, Z, R, H, P, Mfx, Eto Appendix 17

Hepatotoxicity Z, H, R, P, Eto Appendix 17

Optic neuritis E Appendix 17

Haematologic disorders R, P, H, E Appendix 17

For more information on individual drugs see Appendix 10.

9.8 Treatment adaptation and change of treatment
9.8.1 Treatment adaptation
T he whole treatment or individual drug(s) may be temporarily interrupted by the clinician in case of severe adverse effects (Appendix
17).
T his is considered as treatment adaptation, as long as it does not meet the definition of “treatment failure” (Chapter 17).

9.8.2 Change of treatment

T he clinician should replace the DS-T B treatment with:

A treatment for isoniazid-resistant T B when RMT or pDST show:

the development of isoniazid resistance (Chapter 11) after treatment initiation, or
undetected isoniazid resistance at baseline, for any reason.

A treatment for multidrug-resistant or rifampicin-resistant T B (MDR/RR-T B, see Chapter 10) in the following circumstances [1] :
Development of rifampicin resistance after treatment initiation.
Rifampicin resistance not detected at baseline, for any reason.
No bacteriological conversion or bacteriological reversion (Chapter 17).
Insufficient clinical response to treatment in patients:
with non-bacteriologically confirmed T B (e.g. miliary T B, some forms of EPT B, T B in children).
with bacteriologically confirmed T B, when the bacteriological response cannot be assessed, or the result is inconclusive.

T he above treatment changes meet the outcome definition of “treatment failure” except when the reason for change is a
resistance undetected at baseline [1] (Chapter 17).

References
1. World Healt h Organizat ion. Meeting report of the WHO expert consultation on drug-resistant tuberculosis treatment outcome definitions, 17-
19 November 2020. Geneva: World Healt h Organizat ion; 2021.
ht t ps://www.who.int /publicat ions/i/it em/9789240022195
9.9 Treatment interruptions
Treatment interruptions can lead to the emergence of new resistances.
Problems of treatment interruption by the patient (e.g. discontinuation of certain drugs, recurrent treatment interruptions) should be
detected and addressed (management of adverse effects if necessary and reinforcement of patient support measures).
Interruption of the entire treatment for two consecutive months or more meet the definition of “lost to follow-up” (Chapter 17).

Table 9.6 – ­Management of patients who interrupt treatment

Length of treatment Length of

Management
before interruption interruption

Continue treatment at the point it was stopped. Doses missed during interruption
< 2 weeks
must be made up to complete the treatment.

Re­start treatment or perform RMTs (see below) depending on patient’s clinical

2-­7 weeks
< 1 month evolution.

Perform RMTs:
≥ 8 weeks if no resistance, restart treatment.
if resistance, start DR-T B treatment.

Continue treatment at the point it was stopped. Doses missed during interruption
< 2 weeks
must be made up to complete treatment.

≥ 1 month
Perform RMTs:
≥ 4 weeks if no resistance, restart treatment.
if resistance, start DR-T B treatment.

For patients on 6-month regimen who have received adequate treatment for 4 months or more, who return smear ­negative, are in
good clinical condition and with no resistance detected, the decision to re-start a treatment is considered on a case-by-case
basis.

When a DST is not feasible (e.g. miliary T B, some forms of EPT B, T B in children), clinical and radiological evaluation should guide
the decision to either restart DS-T B treatment or switch to an DR-T B treatment.
Chapter 10: Treatment of multidrug-resistant and
rifampicin-resistant tuberculosis
10.1 Introduction

10.2 Treatment regimens in programmatic conditions

10.3 Treatment regimens in operational research conditions

10.4 Special situations

10.5 Adjunctive therapy

10.6 Patient monitoring

10.7 Adverse effects

10.8 Treatment adaptation and change of treatment

10.9 Treatment interruptions

10.10 Surgery

10.11 Treatment failure and palliative care

Update: February 2023

10.1 Introduction
When selecting or building a treatment regimen for multidrug-resistant tuberculosis (MDR-T B) and rifampicin-resistant tuberculosis
(RR-T B), the following should be considered:

10.1.1 Standard short regimens and individualized long regimens

Patients should receive a standard short treatment regimen (ST R) except if they do not meet the eligibility criteria for ST Rs, or do
not tolerate ST Rs. In such cases, patients require an individualized long treatment regimen (LT R).

It may be necessary to switch from an ST R to an LT R, based on the latest drug-susceptibility test (DST ) results and/or clinical
evolution during treatment course (e.g. drug intolerance, persistence of a positive culture).

10.1.2 Likely effective drugs

Treatment is based on a combination of “likely effective” T B drugs.

Table 10.1 - Definition of likely effective drugs (adapted from WHO [1] )

DST Definition of a likely effective TB drug

Available and reliable DST indicates susceptibility to the drug.

Unavailable, unreliable, T he following criteria should be met:

or result pending No resistance detected by DST to a drug with cross-resistance.
No resistance to the drug or to a drug with a cross-resistance to it detected by DST in the
presumed source case.
No previous exposure (> 1 month) to the drug or to a drug with a cross-resistance.
T he drug has not been widely used in the treatment of T B or drug resistance surveys indicate
that drug resistance is rare in the area the patient comes from.

When the criteria of a likely effective drug are not met:

If the strain of the patient (or the presumed source case) is resistant to clofazimine, bedaquiline can be used but not counted as
a likely effective drug until DST demonstrates susceptibility to bedaquiline. T he same applies to all drugs with known or
potential cross-resistance (e.g. delamanid/pretomanid). For more information on drug resistance and cross-resistance see
Chapter 8.
If a drug has been widely used and there is no reliable DST for this drug (e.g. ethambutol, cycloserine, para-aminosalicylate
sodium): it can be used but never counted as a likely effective drug.
If a drug has been widely used and there is a reliable DST for this drug (e.g. pyrazinamide): it can be used but not counted as a
likely effective drug until DST demonstrates susceptibility.

10.1.3 Other considerations

T he following should also be considered when choosing or building a treatment regimen:
Interactions and overlapping toxicities between T B drugs or other drugs the patient may take (see Appendix 10 for individual
drugs and Appendix 19 for co-administration of T B drugs and antiretrovirals);
Comorbidities that can result in increased drug toxicity;
Absolute contraindications to any drug included in a regimen;
Pregnancy and breastfeeding (Appendix 11).

References
1. World Healt h Organizat ion. Companion handbook to the WHO guidelines for the programmatic management of drug-resistant tuberculosis.
Geneva. 2014.
ht t ps://www.ncbi.nlm.nih.gov/books/NBK247420/pdf /Bookshelf _NBK247420.pdf
10.2 Treatment regimens in programmatic conditions
10.2.1 Short treatment regimens
A. 6-month BPaLM regimen
Eligibility

(adapted from WHO [1] )

BPaLM is the preferred treatment regimen for all MDR/RR-T B patients meeting the following criteria:
1 - Bedaquiline, pretomanid, linezolid and moxifloxacin are likely effective.
2 - Age ≥ 14 years.
3 - No miliary T B, osteoarticular T B or T B of the central nervous system (CNS), i.e. brain, spinal cord or meninges.

Regimen composition

Box 10.1 - 6-month BPaLM regimen

6Bdq-Pa-Lzd-Mfx

In the BPaLM regimen, the starting dose of linezolid (600 mg once daily) is reduced after 16 weeks to 300 mg once daily.

Note:
In the event of resistance to fluoroquinolones (FQs), this guide recommends a short four-drug regimen under operational research
conditions where possible (Section 10.3). An LT R or BPaL (6-9Bdq-Pa-Lzd with linezolid given at 600 mg for 6 months) can be
used in settings where an ST R under operational research conditions is not feasible. Note that linezolid causes frequent toxicity.
Management of linezolid adverse effects include temporary or early permanent interruption of the drug. If interruptions are
recurrent or linezolid is stopped permanently early in the treatment, patients on BPaL would receive a two-drug regimen for a
significant period of time, which is not optimal[1] .

B. 9-month bedaquiline-containing regimens [1]

Eligibility

If pretomanid is not available or for patients not eligible for the BPaLM regimen, a 9-month ST R should be used in MDR/RR-T B
patients meeting the following criteria [2] :
1 - Susceptibility to FQs is confirmed by a rapid molecular test (RMT ).
2 - Other drugs used in the regimen, except isoniazid, are likely effective (Section 10.1.2). High treatment failure rates and
amplification of FQ resistance have been observed in some countries [3] in patients with strains presenting resistance to other
drugs in the ST R.
3 - No extensive pulmonary T B (PT B):
no bilateral lung cavities or extensive lung damage,
no cavities or bilateral disease in patients < 15 years.
4 - No severe extrapulmonary T B (EPT B):
no miliary T B, osteoarticular T B, T B of the CNS, or pericardial T B,
no EPT B other than lymph node T B (peripheral nodes or isolated mediastinal mass without compression) in patients < 15
years.
5 - No pregnancy or breastfeeding for the ethionamide-containing regimen.

Regimen composition

Box 10.2 - 9-month bedaquiline-containing regimens

 4 to 6Bdq<6>-Lfx-Cfz-Z-E-Hh-Lzd<2>/5Lfx-Cfz-Z-E
or
4 to 6Bdq<6>-Lfx-Cfz-Z-E-Hh-Eto/5Lfx-Cfz-Z-E

T his guide recommends the regimen that includes linezolid (a drug from Group A), rather than the regimen that includes ethionamide.

Regimen 4 to 6Bdq<6>-Lfx-Cfz-Z-E-Hh-Lzd<2>/5Lfx-Cfz-Z-E

Bdq<6> means that bedaquiline is administered for 6 months (not for 4 months). However, it should be extended to 9 months if
the sputum microscopy is positive at Month 4.
Lzd<2> means that linezolid is administered for 2 months (not for 4 months).
Hh is administered for 4 months or extended to 6 months if the sputum microscopy is positive at Month 4.
Lfx-Cfz-Z-E is administered for 9 months or extended to 11 months if the sputum microscopy is positive at Month 4.
Moxifloxacin (Mfx) at standard dose can be used instead of levofloxacin.

In practice the patient receives:

A 9-month regimen if microscopy negative at Month 4:

TB drugs Intensive phase Continuation phase

Months M1 M2 M3 M4 M5 M6 M7 M8 M9

Bdq

Lfx-Cfz-Z-E

Hh

Lzd

An 11-month regimen if microscopy positive at Month 4:

TB drugs Intensive phase Continuation phase

Months M1 M2 M3 M4 M5 M6 M7 M8 M9 M10 M11

Bdq

Lfx-Cfz-Z-E

Hh

Lzd

Regimen 4 to 6Bdq<6>-Lfx-Cfz-Z-E-Hh-Eto/5Lfx-Cfz-Z-E

Bdq<6> means that bedaquiline is administered for 6 months (not for 4 months). However, it should be extended to 9 months if
the sputum microscopy is positive at Month 4.
Hh-Eto are administered for 4 months or extended to 6 months if the sputum microscopy is positive at Month 4.
Lfx-Cfz-Z-E are administered for 9 months or extended to 11 months if the sputum microscopy is positive at Month 4.
Mfx at standard dose can be used instead of Lfx.

In practice the patient receives:

A 9-month regimen if microscopy negative at Month 4:

 TB drugs Intensive phase Continuation phase

Months M1 M2 M3 M4 M5 M6 M7 M8 M9

Bdq

Lfx-Cfz-Z-E

Hh-Eto

An 11-month regimen if microscopy positive at Month 4:

TB drugs Intensive phase Continuation phase

Months M1 M2 M3 M4 M5 M6 M7 M8 M9 M10 M11

Bdq

Lfx-Cfz-Z-E

Hh-Eto

10.2.2 Long treatment regimens

Eligibility

All MDR/RR-T B patients not eligible for ST Rs (programmatically or under operational research).

Regimen composition

T he regimen should include a minimum number of likely effective drugs.

Box 10.3 - Number of likely effective drugs required in LT Rs

At least 4 likely effective T B drugs, including:

3 from Group A
1 from Group B

If this optimal combination is not feasible:

At least 5 likely effective T B drugs, prioritizing Group A and B drugs and adding Group C drug(s) to bring the total to at least 5 T B
drugs.

LT Rs may contain more than 5 T B drugs if there is uncertainty of effectiveness in some of the drugs used.

While waiting for full DST results, patients can be treated with:
An individualized LT R, or
An empiricala LT R according to the known resistance profile.
It may be necessary to switch from an empirical LT R to an individualized LT R, based on the latest DST results and/or clinical
evolution during treatment course (e.g. drug intolerance, persistence of a positive culture).

Individualized long regimens

To build an individualized LT R, a stepwise process is recommended.

Table 10.3 - Steps to build an LT R

 Use all 3 Group A drugs, unless confirmed resistance or contra-indication.

1.1 - Levofloxacin (Lfx) or moxifloxacin (Mfx)

Use Lfx (rather than Mfx) if the patient takes other QT-prolonging drugs.
High dose moxifloxacin (Mfxh) can be used:
Step 1
if low-level resistance to FQs is detected, but not counted as a likely effective drug [1] .
with other QT-prolonging drugs, but only if options are very limited (weigh benefits/risks and discuss with
the patient).
1.2 - Bedaquiline (Bdq)
1.3 - Linezolid (Lzd)

Add 1 or 2 Group B drug(s), unless confirmed or suspected resistance or contra-indication.

2.1 - Clofazimine (Cfz)

Step 2
Use Cfz rather than Cs or Trd if possible (better safety profile).
2.2 - Cycloserine (Cs) or terizidone (Trd)
Interchangeable and used at the same dose.

Add Group C drugs when the combination of 3 Group A drugs and at least 1 Group B drug is not feasible, to bring
the regimen to 5 likely effective drugs.

3.1 - Delamanid (Dlm)

First choice (good safety profile and still limited drug resistance).
3.2 - First-line drugs: ethambutol (E), pyrazinamide (Z)
3.3 - Imipenem/cilastatin (Ipm/Cln) or meropenem (Mpm)
If no other option (high cost and difficult to administer).
Always administered with amoxicillin/clavulanic acid (Amx/Clv).
Step 3
Use Mpm in patients < 15 years or with a history of epilepsy.
3.4 - Amikacin (Am) or streptomycin (S)
If no other option and confirmed susceptibility.
Use Am rather than S. Use S if Am is unavailable or the strain is resistant to Am.
3.5 - Ethionamide (Eto) or prothionamide (Pto)
Interchangeable and used at the same dose.
3.6 - Para-aminosalicylic acid or sodium (PAS)
3.7 - High-dose isoniazid (Hh)
Can be used if low-level resistance to H, but not counted as a likely effective drug.

Note: isoniazid standard dose can be administered to patients with RR-T B when isoniazid susceptibility is documented. When
isoniazid is used in this manner it can be counted as a likely effective drug.

Empirical long regimens

Table 10.4 - Examples of empirical long regimens at treatment initiation

Resistance profiles Examples

18Lfx-Bdq-Lzd-Cfz
Group A and B drugs likely effective If Bdq is contra-indicated: 18Lfx-Lzd-Cfz-Cs-Dlm
If Lzd is contra-indicated: 18Lfx-Bdq-Cfz-Cs-Dlm

FQs not likely effective 18Bdq-Lzd-Cfz-Cs-Dlm-[Mfxh] (a)

Other Group A and B drugs likely effective If Bdq is contra-indicated: 18Lzd-Cfz-Cs-Dlm-Ipm/Cln
(a) Moxifloxacin high dose can be used, but not count ed if low-level FQ resist ance is suspect ed or f ound on DST.

Duration of treatment

At least for 18 months, with at least 15 months after culture conversion (for definition see Chapter 17). If well tolerated, all drugs
should be taken for the full treatment duration[4] [5] .

Preliminary evidence suggests that stopping bedaquiline at 6 months is associated with high rates of culture reversion (for definition
see Chapter 17) in patients with resistance to several drugs or extensive lung damage [6] . No safety issues have been reported with
bedaquiline treatment longer than 6 months [2] [4] [7] .

Carbapenems are commonly used for a minimum of 2 months after culture conversion. When the number of likely effective drugs
included in the regimen is limited, a carbapenem may be required for the entire duration of treatment.

Footnotes
(a) An empirical regimen is a regimen designed t o t reat most pat ient s in a region whilst wait ing t he f ull DST result s.

References
1. World Healt h Organizat ion. WHO operational handbook on tuberculosis. Module 4: treatment - drug-resistant tuberculosis treatment, 2022
update .
ht t ps://www.who.int /publicat ions/i/it em/9789240065116

2. World Healt h Organizat ion. WHO operational handbook on tuberculosis. Module 4: treatment - drug-resistant tuberculosis treatment. Geneva
2020.
​ht t ps://www.who.int /publicat ions/i/it em/9789240006997

3. du Cros P, Khamraev A, Tigay Z , et al. Outcomes with a shorter multidrugresistant tuberculosis regimen from Karakalpakstan, Uzbekistan. ERJ
Open Res 2021; 7: 00537-2020.
ht t ps://www.ncbi.nlm.nih.gov/pmc/art icles/PMC7869592/pdf /00537-2020.pdf

4. endTB. Bedaquiline and delamanid containing regimens achieve excellent interim treatment response without safety concerns: endTB interim
analysis. 2018 Jul 13.
ht t p://www.endt b.org/sit es/def ault /files/2018-07/endTB%20int erim%20analysis%20%2813%20July%202018%29.pdf

5. Guglielmet t i L, Jaspard M, Le Dû D, et al. French MDR-TB Management Group. Long-term outcome and safety of prolonged bedaquiline
treatment for multidrug-resistant tuberculosis. Eur Respir J. 2017 Mar 22;49(3):1601799.
ht t ps://erj.ersjournals.com/cont ent /erj/49/3/1601799.f ull.pdf

6. Hewison C, et al. Is 6 months of bedaquiline enough? Results from the compassionate use of bedaquiline in Armenia and Georgia . Int J
Tuberc Lung Dis. 2018 Jul 1;22(7):766-772.
ht t ps://www.ingent aconnect .com/cont ent one/iuat ld/ijt ld/2018/00000022/00000007/art 00011?crawler=t rue&mimet ype=applicat ion/pdf

7. endTB. Bedaquiline- and delamanid-containing regimens achieve excellent interim treatment response without safety concerns: endTB interim
analysis. 2018. Bost on, MA.
10.3 Treatment regimens in operational research
conditions
MDR/RR-T B patients can be treated under operational research conditions with short regimens other than the standard ST Rs.
Whatever the rationale or results of operational research, they should be communicated as they may complement those of clinical
trials.

10.3.1 Operational research conditions

T he requirements for conducting operational research include:
A study protocol including 12-month post-end-of-treatment follow-up.
A clinical treatment guide.
A patient consent process.
Approval by an ethics review board and Ministry of Health.
A pharmacovigilance system (core aDSM a ).

Study protocol templates are available from the Global Drug-resistant T B Initiative (GDI) b and WHO c .

10.3.2 Treatment regimens under investigation

T he following regimens are examples of standardized regimens that can be used under operational research conditions. T hese
regimens have been reviewed by scientific committees and have been tested, or are currently being tested, in clinical trials.

For FQ-susceptible MDR/RR-TB patients

T he five endT B trial experimental regimens [1] :
9Bdq-Lzd-Mfx-Z
9Bdq-Cfz-Lzd-Lfx-Z
9Bdq-Dlm-Lzd-Lfx-Z
9Dlm-Cfz-Lzd-Lfx-Z
9Dlm-Cfz-Mfx-Z
T he T B-PRACT ECAL regimen that includes clofazimine [2] : 6Bdq-Pa-Lzd-Cfz (BPaLC regimen)

For FQ-resistant MDR/RR-TB patients

T he endT B-Q trial regimen: 6 or 9Bdq-Dlm-Lzd-Cfz [3]
T he T B-PRACT ECAL regimen that includes clofazimine: 6Bdq-Pa-Lzd-Cfz (BPaLC regimen)

Footnotes
(a) World Healt h Organizat ion. Act ive t uberculosis drug-saf et y monit oring and management (aDSM). Framework f or implement at ion. WHO,
Geneva, 2015.
ht t ps://apps.who.int /iris/bit st ream/handle/10665/204465/WHO_HTM_TB_2015.28_eng.pdf ;jsessionid=97A194C2FA7D78CF2E18BD60C8C6
E3F7?sequence=1

(b) Global Drug Init iat ive-St opTB Part nership: The Evaluat ion of Ef f ect iveness and Saf et y of Novel Short er Treat ment Regimens f or
Mult idrug-Resist ant Tuberculosis Operat ional Research Prot ocol Templat e, May 2018.
ht t p://www.st opt b.org/wg/mdrt b/asset s/document s/GDI%20OR%20generic%20prot ocol%20final.pdf

(c) World Healt h Organizat ion. ShORRT. Short , all-Oral Regimens f or Rif ampicin-resist ant Tuberculosis) Research Package. Version 4 June
2020.
ht t ps://www.who.int /t dr/research/t b_hiv/shorrt /en/

References
1. ht t ps://clinicalt rials.gov/ct 2/show/NCT02754765
2. ht t ps://clinicalt rials.gov/ct 2/show/NCT02589782

3. ht t ps://clinicalt rials.gov/ct 2/show/NCT03896685

10.4 Special situations
10.4.1 Women (pregnant or breastfeeding or of childbearing age)
Pregnant women

Early treatment initiation after diagnosis is recommended. For choosing or building a regimen, see Appendix 11.
Pregnancy outcome and any congenital anomalies in the neonate should be documented.

Breastfeeding women

Use of infant formula is recommended as many second-line drugs should be avoided in breastfeeding women (Appendix 11).
Mothers must be informed of its benefits and risks and provided with infant formula, clean water, fuel for boiling water and a heating
device (stove, saucepan and bottles). T hey must also receive training on how to prepare and use the formula. When infant formula
cannot be used safely, infants must be breastfed.

If the mother is smear-positive, mother-infant contact should be maintained, but kept to a minimum. Appropriate infection
prevention and control measures should be taken during contact. Care of the infant should be largely entrusted to family members
until the mother becomes smear-negative.

Women of childbearing age

A pregnancy test should be performed before starting treatment and, if necessary, repeated during treatment. A highly effective
contraception method (e.g. intra-uterine device or implantable hormonal contraceptive) should be offered prior to starting
treatment.

10.4.2 Children and adolescents

Given the severity of MDR/RR-T B, no T B drugs are contra-indicated (except pretomanid while waiting data on appropriate
dosing) [1] . Children and adolescents generally tolerate second-line T B drugs well. T hey should be treated without delay based on
the index case resistance profile when DST is not available (e.g. clinically diagnosed T B, EPT B).

Children and adolescents should receive an ST R when eligible, however BPaLM and BPaL regimens are not recommended in
patients under 14 years.

Children with non-severe T B receiving an LT R can usually be treated for less than 18 months [1] . Some experts suggest that even
severe T B could be treated for less than 18 months [2] .

10.4.3 Patients with malnutrition or risk of malnutrition

See Chapter 9.

10.4.4 Extrapulmonary tuberculosis

Patients with some forms of EPT B are not eligible for ST Rs (Section 10.2.1) and should be treated with an LT R as described in
Section 10.2.2.

For patients with T B of the CNS, drug penetration into the CNS should be taken into account.

Table 10.5 - Choice of T B drugs for T B of the CNS [3] [4] [5]
 Drugs CNS penetration

Fluoroquinolones and linezolid: good CNS penetration.

Group A
Bedaquiline: limited data; can be used, but not counted.

Cycloserine: good CNS penetration.

Group B
Clofazimine: limited data; can be used, but not counted.

Pyrazinamide, carbapenems, thionamides and isoniazid high dose: good CNS penetration.
Delamanid: limited data; can be used, but not counted.
Group C
Ethambutol and PAS: poor CNS penetration.
Aminoglycosides: better CNS penetration if meningeal inflammation.

Other Pretomanid: no data.

If the regimen contains a carbapenem, use preferably meropenem in patients with T B meningitis (less risk of seizures than with
imipenem/cilastatin).

10.4.5 Diabetes
T B can impair glycaemic control in patients with diabetes [6] . It is therefore necessary to increase blood glucose monitoring in
these patients.

T B drugs may exacerbate complications of diabetes (e.g. peripheral neuropathy). Avoid prescribing ethambutol or linezolid for
patients with pre-existing diabetic retinopathy.

If diabetes is diagnosed, treat and monitor according to standard protocols. At the end of T B treatment, it is recommended to
schedule a specialist consultation for a complete evaluation and, if necessary, adjustment of antidiabetic treatment.

10.4.6 Renal insufficiency

In patients with renal insufficiency, creatinine clearance should be calculated. If it is less than 30 ml/minute, doses of certain T B
drugs should be adjusted.
For the formula to estimate creatinine clearance and dose adjustments in renal insufficiency see Appendix 12.

References
1. World Healt h Organizat ion. WHO consolidated guidelines on tuberculosis. Module 5: management of tuberculosis in children and
adolescents. Geneva: World Healt h Organizat ion; 2022.
ht t ps://apps.who.int /iris/rest /bit st reams/1414329/ret rieve

2. The Sent inel Project f or Pediat ric Drug-Resist ant Tuberculosis. Management of Drug-Resistant Tuberculosis in Children: A Field Guide .
Bost on, USA. November 2021, Fif t h edit ion.
ht t p://sent inel-project .org/wp-cont ent /uploads/2022/04/DRTB-Field-Guide-2021_v5.1.pdf

3. World Healt h Organizat ion. WHO operational handbook on tuberculosis. Module 4: treatment - drug-resistant tuberculosis treatment, 2022
update .
ht t ps://www.who.int /publicat ions/i/it em/9789240065116

4. Sun F, Ruan Q, Wang J, Chen S, Jin J, Shao L, et al. Linezolid manifests a rapid and dramatic therapeutic effect for patients with life-
threatening tuberculous meningitis. Ant imicrob Agent s Chemot her. 2014;58(10):6297–301.
ht t ps://journals.asm.org/doi/pdf /10.1128/AAC.02784-14

5. Thwait es GE, Bhavnani SM, Chau TTH, Hammel JP, Torok ME, Van Wart SA, et al. Randomized pharmacokinetic and pharmacodynamic
comparison of fluoroquinolones for tuberculous meningitis. Ant imicrob Agent s Chemot her. 2011;55(7):3244–53.
ht t ps://www.ncbi.nlm.nih.gov/pmc/art icles/PMC3122453/

6. World Healt h Organizat ion & Int ernat ional Union against Tuberculosis and Lung Disease. (‎2011)‎. Collaborative framework for care and
control of tuberculosis and diabetes. World Healt h Organizat ion.
ht t ps://apps.who.int /iris/bit st ream/handle/10665/44698/9789241502252_eng.pdf ?sequence=1&isAllowed=y
10.5 Adjunctive therapy
10.5.1 Pyridoxine prophylaxis
Pyridoxine (vitamin B 6) is routinely administered to all patients receiving linezolid, cycloserine or teridizone, thionamides or isoniazid
high dose to prevent neurotoxic effects (Appendix 17).

10.5.2 Corticosteroid therapy

See Chapter 9.
10.6 Patient monitoring
Patients should be assessed at baseline, then, regardless of the regimen prescribed, monitored throughout the course of
treatment.

Monitoring includes:
Assessment of treatment response.
Detection of adverse effects and adherence issues.
For the schedule of follow-up examinations see Appendix 15.

Baseline and follow-up findings should be noted in the patient file to enable the detection and interpretation of potential changes.

10.6.1 Clinical visits

Baseline assessment

Assessment includes:
Signs and symptoms of T B and severity (cough, fever, night sweats, weight loss, shortness of breath, ability to perform daily
activities).
Vital signs and weight.
Comorbidities and other risk factors for adverse effects requiring monitoring schedule adaptation.
Psychological assessment.
Other investigations may be needed depending on the drugs used in the regimen prescribed (Section 10.6.3).

Clinical assessment should be performed by a clinician. Psychological assessment should be performed whenever possible by
personnel with appropriate training.

All patients starting treatment should be given the information they need to understand the disease and its treatment (Appendix 21).

Follow-up visits

Each follow-up visit includes assessing:

Clinical progress, vital signs and weight. Dosages should be adjusted to the weight if necessary.
Occurrence of adverse effects.
Adherence to treatment (Appendix 22).
Psychological condition.

Frequency depends on the patient’s clinical condition and evolution:

A visit every week for the first month, every other week for the second month, then once a month if there is no particular
problem.
Additional visits may be required in case of comorbidities, severe or multiple adverse effects, pregnancy, etc.

Visits should coincide with bacteriological examinations and other investigations when possible.

T he clinician should take into account any information and concerns regarding treatment tolerance and adherence reported by the
patient or the team responsible for the patient’s follow-up and support.

10.6.2 Bacteriological tests

To assess treatment response in patients with:
PT B: bacteriological tests are essential.
EPT B: evaluation is based on clinical evolution. However, bacteriological tests are required if patients also develop PT B.

Baseline tests

Baseline tests are those performed on specimens collected just prior to treatment initiation. Baseline tests include:
RMTs for detection of M. tuberculosis and rifampicin, isoniazid and fluoroquinolone resistance.
Sputum smear microscopy.
 Culture and full phenotypic DST (pDST ) or genome sequencing.
For more information see Chapter 3.

If DST results are obtained on a specimen collected more than 2 to 3 weeks prior to treatment initiation, a new specimen should be
collected just prior to treatment initiation. T he new results are considered as baseline results.

Follow-up tests

Microscopy: once a month until treatment completion. Although less reliable than culture, it provides immediate results which
contribute to the assessment of treatment response.
Culture: once a month until treatment completion. Culture conversion and reversion are useful markers of whether the treatment
is effective or not.
Full pDST (or genome sequencing): if positive culture at Month 4 or later.
RMTs: Xpert MT B/XDR (or GenoType MT BDRsl if Xpert MT B/XDR is not available) if positive microscopy at Month 4 or later,
as it can detect resistance-conferring mutations not present at baseline (Chapter 3).

End of treatment tests and post-treatment tests

Culture and microscopy should be performed:

At end of treatment, to confirm the end of treatment outcome.
6 and 12-month post-treatment completion, to detect any relapse.

10.6.3 Other investigations

Radiography

At baseline, then every 6 months:

chest x-ray for patients with PT B,
bone x-ray for patients with osteoarticular and spinal T B.

Electrocardiogram

Some T B drugs cause prolongation of the QT interval, which increases the risk of a potentially life-threatening ventricular
arrhythmia, including torsade de pointes (T dP) [1] .

To monitor the QT interval, electrocardiogram (ECG) should be performed:

At baseline in all patients taking QT-prolonging T B drugs
T hen:
Once a month in patients:
taking < 2 moderate or strong QT-prolonging T B drugs,
taking < 3 QT-prolonging drugs (T B and non-T B).
Once a week for one month, then once a month in patients:
taking ≥ 2 moderate or strong QT-prolonging T B drugs,
taking ≥ 3 QT-prolonging drugs (T B and non-T B),
with other risk factors for QT prolongation or T dP:
a history of syncopal episodes, T dP or congenital long QT syndrome;
uncompensated heart failure, severe coronary disease, bradycardia;
untreated hypothyroidism.

Increased ECG monitoring is required in patients in whom a QT prolongation is detected.

For ECG reading see Appendix 16.

For the management of QT prolongation see Appendix 17.
For the list of QT prolonging drugs see Appendix 19.

Brief peripheral neuropathy screen

For patients on linezolid: brief peripheral neuropathy screen (BPNS) at baseline, then once a month to detect peripheral neuropathy
(Appendix 16).

Visual function tests

For patients on drugs with ocular toxicity: visual acuity and colour vision tests (Ishihara test) at baseline, then once a month to
detect the first signs of optic neuritis.

Audiometry

For patients on aminoglycosides: at baseline, then once a month to detect hearing loss. Monitoring is particularly important in
children, as hearing loss in childhood has negative effects on development.

Full blood count

For all patients: haemoglobin, red and white blood cells, and platelets at baseline, then if indicated.
For patients on linezolid: every 2 weeks for the first 2 months, then once a month.
For patients on zidovudine (AZT ): once a month for the first 2 months, then if indicated.

Liver function tests

For all patients: serum levels of aspartate aminotransferase (AST ) and alanine aminotransferase (ALT ) at baseline, then once a
month.
Bilirubin, if AST and ALT are elevated, or if indicated.
Monitor liver function more frequently in case of increase in AST /ALT or other signs of hepatic disorder or risk factors, such as
hepatitis B or C.

Serum creatinine and potassium level

For all patients: at baseline, then if indicated (e.g. patients with renal insufficiency).
For patients on aminoglycoside: once a month, or more frequently if indicated.

Creatinine clearance

For patients with renal insufficiency: at baseline. If < 30 ml/minute, the dose of certain T B drugs should be adjusted (Appendix 12).

Glycated haemoglobin (HbA1c) and/or blood glucose level (BGL)

For all patients: at baseline to detect diabetes. If diabetes is diagnosed, monitor according to standard protocols.

HIV, hepatitis B and C

For all patients with undocumented HIV hepatitis B and C status: at baseline; HIV test every 6 months in high HIV prevalence areas.
Tests can be repeated in case of recent exposure.

CD4 and viral load

For HIV-infected patients: at baseline, then every 6 months.

Thyroid-stimulating hormone (TSH)

For patients on thionamides or PAS: at baseline, then every 3 months.
If hypothyroidism is diagnosed: 4 to 12 weeks after levothyroxine initiation and after each levothyroxine dose adjustment until
stable, then every 6 months until the end of T B treatment, or for as long as the patient takes levothyroxine.

Pregnancy test
For all adolescents and women of childbearing age: at baseline, then if indicated.

References
1. Roden DM. Drug-induced prolongation of the QT interval. New Engl J Med . 2004; 350: 1013-1022.
ht t ps://www.nejm.org/doi/10.1056/NEJMra032426?url_ver=Z 39.88-2003&rf r_id=ori:rid:crossref .org&rf r_dat =cr_pub%20%200pubmed
10.7 Adverse effects
Rapid and aggressive treatment of adverse effects is essential to improve tolerance and treatment outcomes.
Some adverse effects should be routinely prevented (e.g. peripheral neuropathy).
Most adverse effects cannot be prevented, but can be managed with symptomatic treatment (e.g. arthralgia due to pyrazinamide).
Some adverse effects cannot be eliminated, but are not serious (e.g. skin discoloration due to clofazimine). Patients need
reassurance and support to be able to tolerate them until they subside spontaneously.
Some adverse effects can be serious (e.g. optic neuritis due to linezolid), which can lead to dose reduction or temporary or
permanent interruption of the drug.

Ascertaining which drug is responsible for a particular adverse effect can be challenging. Temporarily stopping a drug, or reducing
the dose, can help identify the responsible drug.

Adverse effects can appear at any time during treatment. Patients should be informed that they are likely to experience adverse
effects and should report them immediately to health staff. Treatment supporters and nurses should rapidly report adverse effects
to the clinician. Only the managing clinician can modify or stop a T B treatment.

For the management of adverse effects see Appendix 17.

10.8 Treatment adaptation and change of treatment
10.8.1 Treatment adaptation
Treatment adaptation may be done by the clinician in case of severe adverse effects (Appendix 17). T he following are considered
treatment adaptations:
For BPaLM and BPaL:
permanent interruption of linezolid after Month 4, or
interruption < 2 consecutive weeks or < 4 nonconsecutive weeks of individual drug(s) or the whole treatment.
For 9-month bedaquiline-containing regimens:
temporary interruption of individual drug(s) or the whole treatment, or
permanent interruption of ethambutol or pyrazinamide during the continuation phase.
For LT Rs:
temporary interruption of individual drug(s) or the whole treatment, or
change of one drug class in the regimen (no more than one).

In an LT R, at least 4-5 likely effective drugs are needed (Box 10.3). If any of these drugs must be permanently stopped:
during the first 6 months, the regimen should be modified while maintaining the required number of likely effective drugs.
after the first 6 months, if the patient clinical status has improved and bacteriological tests are negative, the clinician can decide
to continue the treatment if it still includes at least 3 drugs from Group A and/or B.

T hese modifications are considered as treatment adaptations (not treatment changes, see Section 10.8.2) as they do not meet
the definition of “treatment failure” (Chapter 17).

10.8.2 Change of treatment

Treatment change is defined as the switch from an ST R to an LT R or from an LT R to a newly designed LT R.

Treatment should be changed by the clinician in the following circumstances [1] :

Emergence of a new resistance after treatment initiation.
Resistance not detected at baseline for any reason.
No bacteriological conversion or bacteriological reversion (Chapter 17).
Insufficient clinical response to treatment in patients:
with no bacteriologically confirmed T B (e.g. miliary T B, some forms of EPT B, children);
with bacteriologically confirmed T B when bacteriological response cannot be assessed, or the result is inconclusive.
Drug interruption due to severe adverse effects [2] :
For BPaLM and BPaL:
permanent interruption of bedaquiline or pretomanid, or
permanent interruption of linezolid before the end of Month 4, or
interruption ≥ 2 consecutive weeks or ≥ 4 nonconsecutive weeks of the whole treatment.
For 9-month bedaquiline-containing regimens:
permanent interruption of bedaquiline, levofloxacin/moxifloxacin, linezolid, ethionamide or clofazimine, or
permanent interruption of both ethambutol and pyrazinamide.
For LT Rs: change of at least 2 drug classes in the regimen.

Note: for BPaLM regimen, if moxifloxacin must be interrupted, see the note in Section 10.2.1.

Treatment changes meet the outcome definition of “treatment failure” (Chapter 17) except when the reason for change is a
resistance not detected at baseline [1] .

References
1. World Healt h Organizat ion. Meeting report of the WHO expert consultation on drug-resistant tuberculosis treatment outcome definitions, 17-
19 November 2020. Geneva: World Healt h Organizat ion; 2021.
 ht t ps://www.who.int /publicat ions/i/it em/9789240022195

2. World Healt h Organizat ion. WHO operational handbook on tuberculosis. Module 4: treatment - drug-resistant tuberculosis treatment, 2022
update .
ht t ps://www.who.int /publicat ions/i/it em/9789240065116
10.9 Treatment interruptions
Problems of treatment interruption by the patient (e.g. discontinuation of certain drugs, recurrent treatment interruptions) should be
detected and addressed (management of adverse effects if necessary and reinforcement of patient support measures).

Interruptions of individual drug(s) or of the whole treatment may lead to the emergence of new resistances.
Moreover, in case of treatment interruption, drugs with a long half-life such as bedaquiline or clofazimine remain in the blood for
several months. In practice, it is as if the patient is receiving bedaquiline and/or clofazimine alone, which increases the risk of
developing resistance to these drugs.

Patients who have interrupted the whole treatment for 2 months or more meet the definition of patients “lost to follow-up”
(Chapter 17). If the patient returns, repeat bacteriological tests (RMTs, culture and full pDST or genome sequencing) to detect
potential new resistance; start a new individualized regimen.

For patients who have interrupted the whole treatment for 4 weeks or more but less than 2 months, perform new bacteriological
tests as above. Further treatment depends on the results of the RMTs (pending full bacteriological tests results) and the patient's
clinical status: new individualized regimen or continuation of the same regimen with catch-up of doses missed during interruptions
to complete treatment.

For patients on BPaLM/BPaL who have interrupted the whole treatment for 2 weeks or more, perform new bacteriological tests
as above and start a new individualized regimen.
10.10 Surgery
Surgery is an adjunct to the pharmacological treatment of MDR/RR-T B patients.
It can be performed only by trained thoracic surgeons, in specialized surgical units with excellent postoperative care. T hese units
must implement strict infection prevention and control measures because thoracic surgery, mechanical ventilation and post-
operative physiotherapy generate large quantities of aerosols.

When access to surgery is limited, it should be considered in priority for patients with resistance to a large number of drugs and
localized lung damage.

Surgery can be performed early, when the disease is still localized (e.g. to a lobe). Partial lung resection (lobectomy or wedge
resection) can be effective and safe if performed under appropriate conditions [1] [2] [3] .

At the beginning of treatment, there is a window of opportunity during which the bacillary load decreases transiently under the
pressure of T B drugs (decrease in mycobacteria in smears and/or culture). T his window is the optimal time for surgery. T he
prognosis is better when resection is performed after culture conversion[1] [2] .

It is recommended to perform culture and DST of the resection material. Depending on the results, modification of treatment may
be required.

References
1. Fox GJ, Mit nick CD, Benedet t i A, Chan ED, Becerra M, Chiang C-Y, et al. Surgery as an adjunctive treatment for multidrug-resistant
tuberculosis: An individual patient data meta-analysis. Clin Inf ect Dis. 2016; 62(7):887–95.
ht t ps://academic.oup.com/cid/art icle/62/7/887/2462976?login=f alse

2. Harris RC, Khan MS, Mart in LJ, Allen V, Moore DAJ, Fielding K, et al. The effect of surgery on the outcome of treatment for multidrug-resistant
tuberculosis: a systematic review and meta-analysis. BMC Inf ect Dis. 2016; 16(1).
ht t ps://bmcinf ect dis.biomedcent ral.com/art icles/10.1186/s12879-016-1585-0

3. World Healt h Organizat ion. WHO treatment guidelines for drug-resistant tuberculosis, 2016 update. October 2016 revision. Geneva. 2016.
ht t ps://apps.who.int /iris/bit st ream/handle/10665/250125/9789241549639-eng.pdf
10.11 Treatment failure and palliative care
When a treatment is failing, treatment outcome should be recorded as “failure” (Chapter 17).

A new baseline specimen should be collected, and a new individualized regimen designed according to the principles described in
Section 10.2.2.
When the minimum number of likely effective drugs cannot be reached, the use of T B drugs under development available for
compassionate use is encouraged (Appendix 18).

When no therapeutic option or new regimen is possible, the patient can continue a T B regimen that is reasonably tolerated, or the
regimen can be stopped. T he decision to stop treatment should be made after careful evaluation and consultation with the patient,
family, and T B treatment team. Palliative and supportive care should be continued.

Palliative and supportive care is an integral part of patient care throughout their illness [1] [2] . Some care should be continued after
cure if the patient remains with significant respiratory damage.
Palliative and supportive include [3] :
Relief of respiratory symptoms: oxygen for shortness of breath; corticosteroids (prednisolone) for severe respiratory failure;
codeine to help control cough.
Identification, assessment and treatment of pain: non-opioids/mild opioids/strong opioids depending on the intensity of pain.
Use of all necessary ancillary drugs.
Nutritional support for undernourished patients.
Care to improve comfort and prevent complications in debilitated patients; regular position changes in bedridden patients to
prevent bedsores; bathing and oral hygiene to improve patient comfort and prevent skin infections
Management of anxiety or depression (due to prolonged illness, separation from family, difficult living conditions, etc.); support
to family as needed.

Offer home care to families who need help. Reserve inpatient rooms for end-of-life patients if they cannot be cared for at home.

References
1. World Healt h Organizat ion. Planning and implementing palliative care services: a guide for programme managers. Geneva. 2016.
ht t ps://apps.who.int /iris/bit st ream/handle/10665/250584/9789241565417-eng.pdf ?sequence=1&isAllowed=y

2. Hughes, J. Snyman, L. Palliative care for drug-resistant tuberculosis: when new drugs are not enough. The Lancet Respiratory Medicine .
Volume 6, Issue 4, P251-252, April 01, 2018.
ht t ps://www.t helancet .com/journals/lanres/art icle/PIIS2213-2600(18)30066-3/f ullt ext

3. World Healt h Organizat ion. Companion handbook to the WHO guidelines for the programmatic management of drug-resistant tuberculosis.
Geneva. 2014.
ht t ps://www.ncbi.nlm.nih.gov/books/NBK247420/pdf /Bookshelf _NBK247420.pdf
Chapter 11: Treatment of mono- and poly-drug
resistant tuberculosis (PDR-TB)
11.1 Treatment schemes

11.2 Treatment algorithms for PDR-T B

Update: January 2014
11.1 Treatment schemes
11.1.1 Choice of the treatment scheme
Mono- and poly-drug resistant tuberculosis (PDR-T B) management is based on the PDR treatment schemes presented in Table
11.1.

Table 11.1 - Resistance pattern and recommended treatment schemes

Sus. = susceptible; Res. = resistant.

Resistance category H R E S Treatment scheme

Sus. Sus. Sus. Sus. New case regimen

Sus. Sus. Sus. Res. New case regimen

H-R susceptible
Sus. Sus. Res. Sus. New case regimen

Sus. Sus. Res. Res. New case regimen

Res. Sus. Sus. Sus. PDR Scheme A (a)

Res. Sus. Sus. Res. PDR Scheme A (a)

H-resistance
Res. Sus. Res. Sus. PDR Scheme B

Res. Sus. Res. Res. PDR Scheme B

Sus. Res. Sus. Sus. PDR Scheme C

Sus. Res. Sus. Res. PDR Scheme C

R-resistance
Sus. Res. Res. Sus. PDR Scheme C

Sus. Res. Res. Res. PDR Scheme C

(a) Except previously t reat ed pat ient s, f or whom PDR Scheme B + et hambut ol is pref erred.

T he treatment schemes of mono/PDR-T B are based on the assumption that a full baseline drug susceptibility testing (DST ) is
performed before or at the start of treatment with first line anti-T B drugs.

T here is little published evidence to determine the best treatment for mono/PDR-T B. T he treatment schemes are therefore based
on the principles of T B treatment and expert opinion[1] [2] [3] .

At least 3, ideally 4, likely effective drugs are included in the regimen. DST results at baseline and previous treatment history are
used to choose the appropriate scheme.

T he use of Xpert MT B/RIF can greatly aid in getting patients on the proper regimens when isoniazid resistance is present and
amplification of resistance to rifampicin is a possibility.

Perform second-line DST if patients come from a region of high second-line resistance and if there is a history of second-line anti-
T B drug use. Resistance to second-line anti-T B drugs will impact the choice of regimen.
11.1.2 PDR Scheme A for cases with H or HS resistance
For new patients, the treatment regimen is 9 RZE. However, the combination HRZE can be used if more convenient since it can be
given as fixed-dose combination.

At Month 2, perform smear, Xpert MT B/RIF, and culture:

Xpert Xpert RIF+: switch to empiric MDR regimen while waiting for full DST results then, adapt treatment
available accordingly.
Xpert RIF−: continue PDR Scheme A.

Xpert Culture+: switch to empiric MDR regimen with the inclusion of R while waiting for full DST results.
not available DST is unchanged (H or HS resistance only): stop the MDR regimen, and resume PDR Scheme A;
DST has changed: adapt treatment accordingly.
Culture−: continue PDR Scheme A.

Perform smear and culture every other month. If cultures or smears are positive, switch to MDR regimen while waiting for full DST
results then, adapt treatment accordingly.

For previously treated patients, it is safer to use Scheme B plus ethambutol, as DST to this drug should not be relied upon if the
patient has already received it.

11.1.3 PDR Scheme B for cases with HE or HES resistance

Start patients on 3 Cm (or Km)-Lfx-RZ/7 Lfx-RZ regardless of smear status at the time of diagnosis.

At Month 2, perform smear, Xpert MT B/RIF and culture:

Xpert Xpert RIF+: switch to empiric MDR regimen while waiting for full DST results then, adapt treatment
available accordingly.
Xpert RIF−: continue PDR Scheme B.

Xpert Culture+: switch to empiric MDR regimen with the inclusion of R while waiting for full DST results.
not available DST is unchanged (HE or HES resistance only): stop the MDR regimen, and resume PDR Scheme B;
DST has changed: adapt treatment accordingly.
Culture−: continue PDR Scheme B.

At Month 3, perform smear, Xpert MT B/RIF, and culture. If Xpert shows RIF+ or if the culture is still positive, this regimen is declared
“failure”. Switch to MDR treatment.

Even if found susceptible, streptomycin should not be used given the high rates of resistance to this drug in patients with DR-T B
and the poor reliability of the DST.

11.1.4 PDR Scheme C for cases with R or RS or RE or RES resistance

Start patient on MDR regimen until confirmation that the strain is susceptible to fluoroquinolones and injectable agents.
When DST results confirm resistance to R, RS, RE or RES and susceptibility to H, fluoroquinones and an injectable agent, there are
two options:
1 - Continue the full course of MDR-T B treatment plus isoniazid. T his is a reasonable consideration given that DST reliability is not
100%. T his is recommended if the suspicion for MDR-T B is high (i.e. a contact of an MDR-T B patient or failure of a first-line
regimen).
2 - Start PDR Scheme C: 3 Cm (or Km)-Lfx-HZ (+/-E)/12 Lfx-HZ (+/- E). Ethambutol is added if it is likely to be effective.

Even if found susceptible, streptomycin should not be used given the high rates of resistance to this drug in patients with DR-T B
and the poor reliability of the DST.

At Month 2, perform smear and culture:

Culture+: start empiric MDR regimen and repeat DST.
DST is unchanged: resume PDR Scheme C;
DST has changed: adapt treatment accordingly.
Culture−: complete PDR Scheme C.

At Month 3, perform smear and culture. If the culture is still positive, this regimen is declared “failure.” Switch to MDR treatment.

Note: if the baseline DST is performed by LPA (Hain® test), only DST for R and H are available. In order to avoid possible
resistance amplification, the worst scenario should be assumed:
If only resistance to H is detected, treat with Scheme B, even new patients while waiting for full DST.
If only resistance to R is detected, treat as MDR-T B as sensitivity of Hain® test for H resistance is low.

References
1. World Healt h Organizat ion. Guidelines f or t he Programmat ic Management of Drug-Resist ant Tuberculosis. Emergency Updat e 2008.
(WHO/HTM/TB/2008.402).
ht t p://whqlibdoc.who.int /publicat ions/2011/9789241501583_eng.pdf

2. Francis J. Curry Nat ional Tuberculosis Cent er and Calif ornia Depart ment of Public Healt h, 2008: Drug-Resist ant Tuberculosis: A Survival
Guide f or Clinicians, Second Edit ion.
ht t p://www.curryt bcent er.ucsf .edu/drt b/

3. American Thoracic Societ y/Cent ers f or Disease Cont rol and Prevent ion/Inf ect ious Diseases Societ y of America: Treat ment of
Tuberculosis, Am J Respir Crit Care Med Vol 167. pp 603–662, 2003.
11.2 Treatment algorithms for PDR-TB
PDR scheme A

PDR scheme B
PDR scheme C
Chapter 12: Tuberculosis and HIV co-infection
12.1 HIV counselling and testing

12.2 Concomitant treatment of tuberculosis and HIV co-infection

12.3 Interactions and overlapping toxicities between tuberculosis drugs and antiretrovirals

12.4 Prevention of opportunistic infections

12.5 Immune reconstitution inflammatory syndrome

12.6 Patient monitoring

Update: March 2023

12.1 HIV counselling and testing
When HIV status is unknown, HIV counselling and testing is recommended for patients with latent tuberculosis infection (LT BI) and
patients with presumed or confirmed active tuberculosis (T B).

T he HIV test is performed after counselling, unless the person explicitly declines to be tested.
12.2 Concomitant treatment of tuberculosis and HIV
co-infection
12.2.1 Active tuberculosis
For all HIV-infected patients, treatment of active T B should be started first.
T hen, antiretroviral therapy (ART ) should be initiated within 2 weeks of starting treatment of active T B, except for patients with T B
meningitis.
For patients with T B meningitis, early initiation of ART is associated with an increased risk of serious adverse events. It is therefore
recommended to start ART 4 to 8 weeks after the start of T B treatment [1] .

Table 12.1 - First-line ART for patients with active T B and HIV co-infection[2]

ABC: abacavir; AZT: zidovudine; DT G: dolutegravir; EFV: efavirenz; FT C: emtricitabine; LPV/r: lopinavir/ritonavir; RAL: raltegravir;
T DF: tenofovir disoproxil fumarate; 3T C: lamivudine.

Patients First choice Main alternatives

Neonates AZT + 3T C + RAL (a) AZT + 3T C + LPV/r (b) (c)

Children ABC + 3T C + DT G (a) If paediatric DT G not available:

ABC + 3T C + LPV/r (c)
ABC + 3T C + RAL (d)

Adolescents and adults T DF + 3T C (or FT C) + DT G T DF + 3T C (or FT C) + EFV

Childbearing-aged and pregnant women ABC + 3T C + DT G
AZT + 3T C + EFV

(a) Doses of DTG and RAL should be doubled in pat ient s t aking rif ampicin.
(b) LPV/r paediat ric f ormulat ion can be administ ered t o children as of t he age of 2 weeks.
(c) LPV/r should not be used in children t aking bedaquiline. The dose of LPV/r should be adjust ed in neonat es and children t aking rif ampicin.
(d) RAL should be used only if LPV/r paediat ric f ormulat ion is not available.

12.2.2 Latent tuberculosis infection

For patients with LT BI not yet on ART, the initiation of ART should take priority over the initiation of LT BI treatment. See Chapter
16.

References
1. World Healt h Organizat ion. Updated recommendations on HIV prevention, infant diagnosis, antiretroviral initiation and monitoring: March
2021. Geneva: World Healt h Organizat ion; 2021.
ht t ps://apps.who.int /iris/rest /bit st reams/1336192/ret rieve

2. World Healt h Organizat ion. Update of recommendations on first- and second-line antiretroviral regimens. Geneva: World Healt h Organizat ion;
2019.
ht t ps://apps.who.int /iris/rest /bit st reams/1238289/ret rieve
12.3 Interactions and overlapping toxicities between
tuberculosis drugs and antiretrovirals
Certain combinations of T B drugs and ARVs are contraindicated or should be avoided or require dose adjustments of T B drugs or
ARVs. For more information see Appendix 19.

Note: drug interactions and overlapping toxicities between T B drugs and drugs other than ARVs are common. For example,
rifampicin reduces plasma concentrations of fluconazole by 25%. It may be necessary to increase the dose of fluconazole.
Conversely, fluconazole increases plasma concentrations of rifabutin. It is necessary to monitor for signs of rifabutin toxicity [1] . If
patients are taking drugs other than ARVs, clinicians should be aware of potential interactions and overlapping toxicities.

References
1. European Medical Agency. Fluconazole: Summary of Product Characteristics. 2012.
ht t ps://www.ema.europa.eu/en/document s/ref erral/diflucan-art icle-30-ref erral-annex-iii_en.pdf
12.4 Prevention of opportunistic infections
During T B treatment, co-trimoxazole preventive therapy should be started or continued in order to prevent common and
opportunistic infections.
12.5 Immune reconstitution inflammatory syndrome
T B-associated immune reconstitution inflammatory syndrome (T B-IRIS) can occur in a patient on antiretroviral and/or T B
treatment. It is characterised by the onset of new or worsening (after initial improvement) signs and symptoms of T B resulting from
the restoration of the immune system by ART.
Most common signs and symptoms of T B-IRIS are fever, lymphadenopathy, pulmonary infiltrates, pleural effusion, respiratory
distress, neurological signs [1] .

T B-IRIS occurs in two circumstances:

Paradoxical T B-IRIS: the diagnosis of active T B is made, the patient starts T B treatment, followed by ART and then signs and
symptoms of T B worsen.
Unmasking T B-IRIS: T B is not detected, the patient starts ART and then develops signs and symptoms of T B.

T B-IRIS is more common in patients with low CD4 count. It usually occurs within 3 months of starting ART, most often within the
first month[2] .

T he following differential diagnoses should be considered before making the diagnosis of T B-IRIS:
New onset of opportunistic infection.
Other infections unmasked after immune reconstitution due to ART.
Failure of T B treatment due to drug resistance.

T B-IRIS is considered severe in patients with neurological signs, respiratory distress, or if their condition requires hospitalisation or
frequent ambulatory care.
Treatment of severe T B-IRIS is based on corticosteroids, except in the case of Kaposi's sarcoma or cryptococcal meningitis, for
which corticosteroids are contraindicated.
Patients on corticosteroids should be monitored to detect any other opportunistic infections.

In patients with non severe T B-IRIS, treatment is based on non-steroidal anti-inflammatory drugs.

In case of unmasking T B-IRIS, T B treatment should be started immediately.

ART should not be interrupted, except in case of life-threatening IRIS.

Table 12.2 - Symptomatic treatment of T B-IRIS

TB-IRIS Treatment

Severe prednisolone PO
Child and adult: 1.5 mg/kg once daily (2 weeks) then 0.75 mg/kg once daily (2 weeks) [3]

Non-severe ibuprofen PO for the shortest possible duration

Child over 3 months: 5 to 10 mg/kg 3 to 4 times daily (max. 30 mg/kg daily)
Child 12 years and over and adult: 200 to 400 mg 3 to 4 times daily (max. 1200 mg daily)

References
1. M. Lanzaf ame, S. Vent o. Tuberculosis-immune reconstitution inflammatory syndrome. Journal of Clinical Tuberculosis and Ot her
Mycobact erial Diseases, Volume 3, 2016.
ht t ps://doi.org/10.1016/j.jct ube.2016.03.002

2. World Healt h Organizat ion. Operat ional handbook on t uberculosis. Module 5: management of t uberculosis in children and adolescent s.
Geneva: World Healt h Organizat ion; 2022.
ht t ps://apps.who.int /iris/bit st ream/handle/10665/352523/9789240046832-eng.pdf
3. Meint jes G, Wilkinson RJ, Morroni C et al. Randomized placebo-controlled trial of prednisone for paradoxical tuberculosis-associated immune
reconstitution inflammatory syndrome . Aids, 24(15), 2381–2390 (2010). [PubMed: 20808204].
12.6 Patient monitoring
For patients on drug susceptible T B treatment see Chapter 9.
For patients on multidrug-resistant or rifampicin-resistant T B treatment see Chapter 10.
For patients on isoniazid-resistant T B treatment see Chapter 11.
Chapter 13: Adherence to tuberculosis treatment
13.1 Introduction

13.2 Treatment delivery model

13.3 Factors that influence adherence

13.4 Patient education and support

Update: January 2022

13.1 Introduction
Good adherence is when the patient follows the treatment as prescribed. Patient understanding, acceptance and motivation to
start and complete T B treatment are essential to maximise chances of cure. Good knowledge of drug dosing, length of treatment,
required clinical follow-up and common adverse effects help patients to follow the prescribed therapy.

Failure to take tuberculosis (T B) drugs consistently, or in an inappropriate manner, or stopping the treatment too soon, can lead to
treatment failure or relapse. It may also contribute to the development of resistance, which can complicate subsequent treatment,
thereby decreasing the chances of a successful outcome.
13.2 Treatment delivery model
13.2.1 Self-administered treatment
Self-administered treatment (SAT ) is taken autonomously by the patient without daily supervision. T he patient is seen at a health
facility at regular intervals (e.g. monthly) to receive drugs, support and treatment education. SMS telephone reminders may be
considered to reinforce adherence.

13.2.2 Directly observed therapy

Drugs are sometimes provided daily to the patient and the treatment is taken under direct observation (DOT ) by a third party.

DOT may be provided:

In health facilities (facility-based DOT ): in this model, DOT is implemented in a centralised setting and treatment is administered
by healthcare workers.
Outside of health facilities (community or home-based DOT ): in this model, DOT is implemented in a decentralised setting and is
usually provided by supervised, trained and remunerated treatment supporters.
For the roles and responsibilities of treatment supporters see Appendix 20.
Remotely (video-observed therapy or VOT ): VOT uses secure Internet connections via a smart phone or computer application
to remotely supervise patients taking their treatment.

DOT is labour-intensive to implement and can be inconvenient for patients. Community and home-based DOT and VOT require
fewer resources (personnel and transport) than facility-based DOT and may be more convenient for patients.

Box 13.1 – Recommended treatment delivery models

Drug-susceptible TB (DS-TB)
DOT has not been proven to improve treatment outcomes for DS-T B when compared to SAT in controlled trials [1] .
When there is no factor to complicate adherence, and provided the patient receives appropriate support, treatment should
be self-administered.
T here are some situations in which DOT may be preferred:
Patients with mental health issues or serious socioeconomic problems (e.g. the homeless) and all patients incapable of
taking drugs on their own.
Prisoners (risk of drugs being sold or stolen).

Drug-resistant TB (DR-TB)
Due to the lack of fixed-dose combinations (FDC), length of treatment, adverse effects of T B drugs and lack of therapeutic
alternatives if treatment fails, patients usually require reinforced support.
If DOT is considered useful, home-based DOT [2] or VOT are preferred to facility-based DOT. A combination of approaches
may be required for some patients.

Latent TB infection (LTBI)

LT BI treatments can be self-administered.
DOT may be preferred with the 3HP regimen, as it may cause serious hypersensitivity reactions. However, SAT can be
considered if the patient well informed and is able to seek rapid medical attention if adverse effects develop.

References
1. Karumbi, J. and P. Garner. Directly observed therapy for treating tuberculosis. Cochrane Dat abase Syst Rev, 2015(5): p. CD003343.
ht t ps://www.cochranelibrary.com/cdsr/doi/10.1002/14651858.CD003343.pub4/f ull

2. Williams et al. Community-based management versus traditional hospitalization in treatment of drug-resistant tuberculosis: a systematic review
and meta-analysis. Global Healt h Research and Policy (2016) 1:10
ht t ps://www.ncbi.nlm.nih.gov/pmc/art icles/PMC5693550/pdf /41256_2016_Art icle_10.pdf
13.3 Factors that influence adherence
Several factors can influence adherence, including barriers related to the patient, the treatment or the therapeutic environment.
While it is not always feasible to address all these factors, at the very least it is possible to control the treatment and therapeutic
environment-related factors.

13.3.1 Patient-related factors

A discussion should be held with the patient prior to treatment initiation and then during every contact they have with the healthcare
team. T he objective is to identify and anticipate barriers to treatment adherence. Barriers may include:
Socioeconomic factors (work and home responsibilities, treatment-related costs, decreased income, etc.).
Psychological factors (feelings of shame, fear of stigma or marginalisation, uncertainty about the future, conceptions about the
disease and its treatment, etc.).
Physical or mental disability.
Lack of knowledge about the disease and treatment.
Perception of the disease and treatment (a patient might abandon treatment due to improvement or absence of improvement,
a negative experience with a previous treatment, etc.).

Solutions depend on the context and the patient’s problem, and therefore should be identified on a case-by-case basis.

13.3.2 Treatment-related factors

Simplicity of treatment improves adherence. T he use of FDC simplifies the treatment by reducing the number of tablets. In
addition, FDC prevents omission of one or more prescribed T B drugs.
Adverse effects may lead patients to interrupt their treatment, so these should be detected and managed promptly.

13.3.3 Factors related to the therapeutic environment

To ensure the widest possible access to treatment, T B diagnosis, monitoring and treatment (including T B drugs and drugs for
adverse effects and co-morbidities) should be provided free of charge.
T he relationship between patients and healthcare workers influences If patients have confidence in healthcare workers, they are
more likely to follow recommendations and engage with the treatment process. Patients are also more likely to bring questions
and concerns to the attention of healthcare workers. T he same applies to the relationship with treatment supporters.
In health facilities, the way in which patients are received is Waiting times for diagnosis or follow-up visits should be reasonable.
Drug supply management must be rigorous. Shortages can lead to treatment interruption and negatively impact adherence
(patients waste time in unnecessary travel and lose confidence in the health facility, ).
T he proximity of drug distribution sites limits the number of patients who abandon due to transportation problems. To anticipate
potential problems, give the patients a few extra days of treatment in case they are unable to come to get their drugs on the
scheduled
For the co-management of T B and HIV infection, patients should receive T B and HIV treatment at the same time and in the
same place (“one-stop service”). T his reduces the number of visits and decreases waiting times, which results in greater patient
satisfaction and improved treatment outcomes. Co-management of other co-morbidities (e.g. diabetes, hypertension) should,
when possible, use the same approach.
Hospitalisation should be limited to patients with clinical conditions requiring hospital level care. If hospitalisation is necessary,
accommodation (comfort, food, heating, etc.) should be adequate. T he duration of stay should be as short as possible and
patients should be discharged as soon as their clinical condition allows.
13.4 Patient education and support
Patient education and support require the involvement of the entire healthcare team (clinicians, nurses, treatment supporters, social
workers, etc.). In large-scale programmes, the healthcare team sometimes includes trained counsellors who provide information
and support.

Treatment education and support may be provided through various channels: organising educational sessions during in-facility or
home visits, video and telephone contacts.

Patient education and support are required throughout treatment, as adherence may vary over time and patients may experience
phases of treatment acceptance and rejection.

Due to the toxicity and long duration of treatment, patients on DR-T B treatment usually require substantial support.

13.4.1 Patient education

Patient education consists of:
Helping patients to understand the disease and treatment.
Enabling patients to acquire and maintain skills that allow them to manage their treatment and disease in their everyday lives.
Answering patients’ questions throughout the treatment.

For more information see Appendix 21.

13.4.2 Emotional support

Listen to patients and give them encouragement, so that they feel comfortable saying they have forgotten or have made a mistake
with their treatment. T his is common, and it is important to know so that solutions can be found.

Psychological problems, such as depression and anxiety are frequent, and may have a negative impact on adherence. T he
healthcare team should be sensitised to their early detection and management.

13.4.3 Social support

Implement social support measures for patients with limited resources. Depending on the situation and specific needs of patients:
Social workers can help to obtain disability allowances, housing assistance, shelter for the homeless, etc.
T he programme can provide meals or food, vouchers or money for transportation or reimburse the cost, etc.
Chapter 14: Tuberculosis infection control
14.1 Introduction

14.2 Implementation of T B IC strategies

14.3 Administrative controls

14.4 Environmental controls

14.5 Personal protective measures

14.6 Hospital hygiene

14.7 Patients’ homes

14.1 Introduction
T he largest source of M. tuberculosis transmission is the contagious patients with respiratory tuberculosis not yet diagnosed and
put on treatment. T herefore, tuberculosis infection control (T B IC) relies, above all, on:
Early diagnosis (including in clinics and any non-tuberculosis medical wards, whereby active case finding through cough
surveillance of all admissions should avoid days or weeks of transmission from unsuspected T B cases);
AND
Prompt implementation of effective treatment. With effective treatment, contagiousness decreases even after a few days and
may be considered nil after 2 to 3 weeks of treatment [1] [2] [3] [4] . It is essential the treatment is “effective,” as multidrug-resistant
T B (MDR-T B) patients that are placed on first-line anti-T B drugs are likely to remain contagious.

However, in health care facilities where T B patients or persons suspected of having T B congregate, additional measures are
needed to reduce the risk of transmission between patients, to health care staff and to vulnerable (particularly
immunocompromised) patients/visitors [5] .

T B infection control (IC) a consists in different strategies for preventing transmission of T B in health care facilities.

Footnotes
(a) This chapt er reviews t he basic TB IC st rat egies. More in dept h inf ormat ion can be f ound f rom t he Tuberculosis Coalit ion f or Technical
Assist ance which has published a f ramework and developed a websit e (ht t p://www.t bct a.org/Library ) t hat provides a comprehensive set
of examples.

References
1. Clinical diagnosis and management of tuberculosis and measures for its prevention and control. London, UK: Nat ional Inst it ut e f or Healt h
and Clinical Excellence, 2006.

2. Rouillon A, Perdrizet S, Parrot R. Transmission of tubercle bacilli: the effects of chemotherapy. Tubercle 1976; 57:275–299.

3. Long, R et al. Relative versus absolute non contagiousness of respiratory tuberculosis on treatment. Inf ect Cont rol Hosp Epidemiol
2003;24:831-838.

4. Migliori, GB et al. Review of multi-drug resistant and extensively drug-resistant TB: global perspectives with a focus on sub-Saharan Africa .
TMIH 2010; vol. 15, N° 09 PP 1052 – 1066.

5. World Healt h Organizat ion. WHO policy on TB infection control in health-care facilities, congregate settings and households. World Healt h
Organizat ion, Geneva. 2009.
ht t ps://apps.who.int /iris/bit st ream/handle/10665/44148/9789241598323_eng.pdf ?sequence=1
14.2 Implementation of TB IC strategies
T here is a trio of infection control levels, which include (1) administrative, (2) environmental and (3) personal protective controls [1] .
T he implementation of these measures requires a dedicated staff and an IC plan.

14.2.1 Infection control practitioner

A person should be clearly identified and designated as responsible for T B IC. T his person should have the support and authority to
conduct, apply and evaluate T B IC policies. T his person in some settings is also known as IC officer.

14.2.2 Infection control committee

T he IC practitioner would evaluate the need to create an infection control committee (ICC). T he ICC might include doctors, nurses,
laboratory technicians, logisticians and administration staff (including representation from the maintenance and housekeeping
services). According to the context and degree of risk, experts in IC may be needed.

14.2.3 Infection control plan

All facilities should have a detailed written IC plan that is at least annually updated and distributed to healthcare staff.
A simplified version of the plan must be accessible to all healthcare workers including staff not directly involved in T B patients’
management, such as cleaners, kitchen staff, etc.

T he first step in developing an IC plan is assessing the health care facility’s risk for T B transmission[2] . T his should be performed by
the IC practitioner. T he plan must be specific to each facility.
An example of risk assessment tool is given in Appendix 16.

T he IC plan should include the different types of measures—administrative, environmental and personal. Information on specific
precautions and procedures for high-risk areas should be detailed.

It is recommended to draw a floor plan of the facility with the different areas, including the patient flow and identifying areas of high
risk.

Listed below from highest to lowest level of risk:

Highest risk
Smear-positive inpatient unit
Diagnosis department
Culture/drug susceptibility test (DST ) and sputum smear preparation area (laboratory)
Sputum collection area
Radiology department
Waiting area

Limited risk
Children inpatient ward
Extrapulmonary T B (EPT B) and smear-negative unit
Sputum reception and smear reading area (laboratory)
Waste management area

Lowest risk (non-TB zone)

Kitchen area
Administration
References
1. World Healt h Organizat ion. WHO policy on TB infection control in health-care facilities, congregate settings and households.World Healt h
Organizat ion, Geneva. 2009.
ht t ps://apps.who.int /iris/bit st ream/handle/10665/44148/9789241598323_eng.pdf ?sequence=1

2. Implementing the WHO policy on TB infection control. Tuberculosis Coalition for Technical Assistance .
ht t p://st opt b.org/wg/t b_hiv/asset s/document s/TBICImplement at ionFramework1288971813.pdf
14.3 Administrative controls
T he administrative controls aim at preventing the exposure to infectious droplet nuclei.

14.3.1 Patients triage

Upon entry into the health facility, a member of the medical staff should identify patients with a cough as soon as possible.
Patients with a cough over two weeks should be sent to a separate waiting room if possible.

All patients with cough (including patients with less than two weeks of cough) should receive tissues or face masks, and they should
be requested to cover their mouth and nose when they cough.

14.3.2 Patient, visitors and attendants' flow

Inside the T B department, circulation of patients and attendants is controlled:
Encourage patients/attendants to spend as much time as possible outdoors if weather permits or in areas that are open on
three or four sides.
Have visible signage on entry doors to T B wards that forbid visitors to enter.
Limit visitation duration, particularly for contagious patients.
Encourage visits outside the building, especially for contagious patients.
Have visiting areas well identified with signage.
Before any visit, the nurse should provide information on transmission risk, including the usage of respirators if carers need to go
in high risk areas, such as smear-positive, drug-resistant T B (DR-T B), re-treatment smear-positive inpatient units and areas or
clinics were diagnosis of T B is being undertaken.
Avoid that known or suspect T B patients go through areas where they may infect other patients, and vice versa, that patients
without T B go through areas where they are unnecessarily exposed to the bacillus.

14.3.3 Segregation of hospitalized patients

Patients should preferably be treated in ambulatory care. Hospitalisation should be limited and reserved for clinically unwell
patients.
T B wards must be separated from the others wards in the health structure compound.
Ideally, within the T B department, patients should be placed in single rooms. If this is not possible, cohort isolation must be
implemented and different sections should be labelled according to the degree of contagiousness (smear/culture status) and risk of
resistance.

T he following is one scheme of separation. It does involve the use of some single isolation rooms (all T B inpatient facilities should
have some isolation rooms. If none exist, a very high priority is to add some).
Smear-positive patients with proven or suspected DR-T B, including chronic cases and retreatment cases that are likely to have
MDR-T B. MDR-T B cases should have single isolation rooms (place in 2 to 4 person rooms with other MDR-T B patients if
there are no single rooms and try to match DST patterns). It is particularly important not to mix MDRT B patients with
extensively drug-resistant T B (XDR-T B) patients.
Smear-positive patients with fully susceptible T B.
Smear-negative patients (or patients who have converted), with proven or suspected DRT B (once patients are on effective
treatment, they rapidly become non-contagious).
Less or non-contagious T B: patients with smear-negative pulmonary T B (PT B), EPT B, patients having converted their
sputum/culture and most children.
Patients who are undergoing diagnosis as suspected cases: when possible do not hospitalize patients for diagnosis. If
hospitalization is necessary, these patients need isolation rooms. Never put a patient who is not receiving T B medications in a
T B ward.

If women and men are to be separated, this scheme requires at least 8 different wards and enough single rooms for suspect cases
and MDR-T B patients.
14.3.4 TB IC training
All healthcare personnel should receive initial training on T B transmission, information on high-risk areas in the facility and on
protective measures. Continuing education should be offered annually.

T he training should also include how staff can teach patients, visitors and attendants about the risk of T B transmission and how to
avoid it (cough etiquette, use of masks and respirators).
14.4 Environmental controls
T he environmental measures aim at reducing the concentration of infectious droplet nuclei in the air.

14.4.1 Ventilation
Ventilation (replacement of inside air with outside air) is the most effective means for reducing the concentration of M. tuberculosis
in the air, and as a result, the risk of transmission.
T he WHO recommends that in areas where T B transmission might occur, a minimum ventilation rate of 12 air changes per hour
(ACH) [1] should be achieved. See Appendix 17 for recommendations on ACH measurement.
Effective ventilation can be obtained by natural (assisted or not) or mechanical means.

Natural ventilation
Natural ventilation, especially cross-ventilation (windows/doors in opposite sides of the room), has the best cost-effective ratio. It
should be done with the windows and outside doors open (as much as weather conditions permit). Inside doors should be closed so
that the flow of air is directed outside and not toward the corridors.
Create shady spaces so that patients, attendants and visitors can stay outside during the day.
Wind-driven roof turbines (whirly birds) or chimneys can also be used to improve natural ventilation, in that they can keep the
principle of directing room air towards the exterior. In addition, fans can be used when the natural ventilation flow rate is too low
(assisted natural ventilation).

Mechanical ventilation
When natural ventilation cannot reach adequate rates, centralised mechanical ventilation should be considered in some settings,
such as within cold climates. Centralised mechanical ventilation relies on the use of mechanical equipment to maintain an air
pressure difference between two areas in order to draw air into a room and vent it to the outside. It requires continuous and
meticulous maintenance, which renders it costly and difficult to implement and operate.

Advantages and disadvantages of each ventilation technique are presented in Appendix 18.

14.4.2 Architectural considerations

Airborne infection control should be always considered during the planning/construction stages of new health facilities and those
being modified. It is important to achieve the following:
Building layout and design with maximised natural ventilation (assisted or not) and sunlight. Waiting areas should be open on
three sides. Design of T B wards should avoid internal hallways with doors from the rooms and wards opening into them.
Instead, doors should open to outside hallways that are open to air (this may not be feasible in cold climates).
Specific areas (open air, sputum collection booth, etc.) should be reserved for procedures with a high risk of M. tuberculosis
transmission (e.g. sputum collection, sputum induction, etc.).
Allow patient flow that reduces exposure of patients at risk to patients that are infectious (e.g. separate waiting rooms for
different cohorts, one patient per room in a hospital). If designing a new T B ward, incorporate plenty of single rooms or at least
small rooms with 2 to 4 beds for easier separation of the different cohorts of patients.
General hospitals should also have isolation rooms available for T B suspects and contagious patients.

Rehabilitation of existing structures in order to maximise natural ventilation could be a viable economical option instead of building
expensive systems, like centralised mechanical ventilation.

14.4.3 Ultra-violet germicidal irradiation

Ultra-violet germicidal irradiation (UVGI) lamps a may be used when adequate ventilation cannot be achieved in high-risk areas. When
properly installed, designed, maintained and operated, an UVGI system, in addition to 6-12 ACH ventilation, could be the equivalent
of 10-25 ACH [2] .
For technical information on upper room UVGI, see Appendix 19.
 Main requirements and constraints in UV lamps usage include:
Expertise in installation and testing;
Rigorous monitoring and maintenance;
Electricity, relative humidity less than 70%, good air mixing.

Potential hazards include: Transient eye and skin injuries from overexposure, mercury poisoning (broken or mishandled lamp).

14.4.4 Areas requiring specific measures

Sputum collection areas
T hese areas must be settled, wherever possible, outside in open air where bacilli will naturally be dispersed by wind rather than in a
closed room where the concentration of bacilli will be high.
In cold regions, sputum collection should be performed in very well ventilated indoor rooms (at least 20 ACH) or in well ventilated
rooms (at least 12 ACH) equipped with a UVGI system.
Another option for sputum collection areas in cold climate regions is to assign a specific room of small size (1 m2) with one single
glass door opening outside. Keep the door largely open for 5 minutes between each patient. T he small volume of air in this room
facilitates rapid ventilation.

Laboratory
All laboratories should undergo a risk assessment, and IC measures should be adapted accordingly. In any case, limit the access to
all T B laboratories.
T he use of ventilated workstation (Appendix 7) is strongly recommended for smear preparation (microscopy and test Xpert). In
laboratories where culture are carried out, biological safety cabinets type II must be used.
Laboratories must have easy to clean working surfaces (avoid wood) to allow proper disinfection. T hey should also have large
windows to let in sunlight and allow natural ventilation if the laboratory has no mechanical ventilation.
Water-filters should be used to avoid contamination by saprophyte mycobacteria that are sometimes present in the water.

Footnotes
(a) UVGI inact ivat e bacilli. Nat ural light dries t he droplet but does not inact ivat e bacilli.

References
1. Implementing the WHO policy on TB infection control. Tuberculosis Coalition for Technical Assistance .
ht t p://st opt b.org/wg/t b_hiv/asset s/document s/TBICImplement at ionFramework1288971813.pdf

2. Riley RL, Knight M, Middlebrook G. Ultraviolet susceptibility of BCG and virulent tubercle bacilli. Am Rev Respir Dis 1976;113:413–8.
14.5 Personal protective measures
Personal protective measures aim at minimising the risk of bacillus transmission by providing barriers to inhaling or exhaling
infectious droplet nuclei.

14.5.1 Respirators (or high-filtration masks or anti-inhalation masks)

A respirator is personal protective equipment that prevents inhalation of infectious droplet nuclei by the person who wears it.

Exposed staff
Staff must wear a respirator, regardless if they are the caregiver or not. Respirators should be worn:
When in contact with contagious patients (suspect or confirmed T B case);
When collecting sputum samples;
When collecting and disposing of sputum containers;
In areas where droplet nuclei could be present (i.e. a room that has been occupied by a T B case, prior to the time required for
air cleaning).
Using respirators needs proper training, fit testing and continuous supervision. T his also applies to home-based DOT supervisors.

Visitors/attendants
Visitors and attendants must wear a respirator when entering a contagious T B patient’s room.

For more information on respirators, see Appendix 27.

14.5.2 Face or surgical masks

Face masks are medical devices that prevent patients from spreading infectious droplets when talking, coughing or sneezing. T hey
should be worn by contagious patients (suspect or confirmed) when they leave their rooms to go to another department or any
other enclosed area. T hey should not be worn when the patient is alone in his/her room and outdoors.

For more information on surgical masks, see Appendix 28.

Using a mask in public areas could be stigmatizing. Patients can use a cloth scarf to achieve the same purpose.
14.6 Hospital hygiene
14.6.1 Hygiene and disinfection
Sputum containers
Patients with pulmonary T B produce sputum that may contain tubercle bacilli.
In the wards, patients’ sputum containers should be large (about 200-ml), non-sterile, and sealable. T hey are to be replaced daily
and cannot be re-used.
In the laboratories, containers for sample collection are smaller (25-35 ml), with hermetic screw cap, non-sterile and for single
use.

Environmental cleaning
Sterilization or the use of disinfecting chemicals in a T B patient’s room is not necessary. Ordinary cleaning of rooms and objects
(linens, dishes, etc.) used by T B patients is sufficient. After the patient is discharged, air the empty room well according to the
calculated ACH.

Reusable medical items

Standard operating procedures for reprocessing items should be followed. T here are no specific measures for T B services.

Standard precautions
Standard precautions (hand hygiene, gowns, etc.) apply in T B wards, as they do in any other hospital department.

14.6.2 Waste management

Standard operating procedures for handling and the disposal of healthcare waste (including soft, sharp, etc.) should be followed.
T here are no specific measures for T B services.

Note: used sputum containers should be collected in a leak proof trash bag and incinerated without filling the containers with
chlorine solution before incineration (this can produce toxic gases).
14.7 Patients’ homes
In settings where DR-T B (and HIV) is highly prevalent, systematic T B IC evaluations on patients’ homes are recommended.

T B IC at patients’ homes follows the same principles and measures as in healthcare facilities. Administrative, environmental and
personal measures should be followed at least until patient’s smear is negative, ideally until culture conversion.

Administrative measures
Assess the risk of T B transmission: gather information on the number of people that live in the house, number of rooms, etc.
Screen contacts for T B.
Children under 5 should spend as little time as possible in the same spaces as culture-positive patient (although the risk to the
child is greatly reduced once a patient starts an effective regimen). T he mother should use a surgical mask while taking care of
the child until she becomes smear-negative.
Offer education on T B transmission, airborne precautions (cough etiquette, masks), clinical symptoms and waste management
of sputum containers or tissues (do not empty the container; throw it in the latrines or enclose it hermetically in plastic bags and
discard in the normal waste).

Environmental measures
Ideally, the patient should sleep in a separated room, with door closed off to the rest of the house.
Common spaces should be well ventilated (often done by keeping windows open at all times).
T he patient should be encouraged to spend time outside in a shaded area if weather permits.

Personal protective measures

If smear-positive or not responding to the regimen, the patient should wear surgical masks when in contact with persons in
areas poorly ventilated. Once smear-negative, the patient can be considered non-infectious and no longer needs to wear
masks.
Any person attending to the patient in enclosed spaces should wear a respirator. A fit test should be performed, and the person
should be educated on the proper use of respirators. Once the patient is smear-negative, respirators are no longer necessary.
Chapter 15: Follow-up of staff exposed to
tuberculosis
15.1 Introduction

15.2 Baseline assessment

15.3 BCG vaccination

15.4 Follow-up

Update: October 2022

15.1 Introduction
T he following recommendations apply to staff who work in health facilities and are in contact with tuberculosis (T B) patients and/or
infectious laboratory specimens.

T hey provide general guidance, but should be adapted to the context and regulations of each country.
15.2 Baseline assessment
New staff should undergo a baseline assessment. T his includes:
BCG status (BCG scar check)
Tuberculin skin test (T ST ) or interferon gamma release assay (IGRA)
Chest x-ray (CXR)
HIV test

In addition, the following information should be provided:

Risk of occupational transmission of M. tuberculosis
Infection prevention and control (IPC) measures to reduce the risk of transmission
Higher risk of active T B in immunocompromised individuals (e.g. HIV-infected, diabetics) and in pregnant women
Vigilance required for, and self-reporting of, signs and symptoms suggestive of T B

Immunocompromised staff and pregnant women should not work in T B departments or areas where the risk of exposure to M.
tuberculosis is high (Chapter 14).
15.3 BCG vaccination
Recommendations vary between countries, with some requiring staff to be BCG vaccinated if never vaccinated and T ST negative.

T here is limited evidence regarding the benefits of BCG vaccination in adults who have not previously had BCG vaccination[1] .
Vaccination should be considered on a case-by-case basis in the following situations [2] :
Significant exposure to multidrug-resistant T B (MDR-T B): facilities treating MDR-T B, prisons, or areas with high MDR-T B
prevalence.
While corrective actions are implemented:
when transmission of MDR-T B to staff has occurred;
when IPC measures are inadequate or poorly applied.

T he following information should be provided to staff considered for BCG vaccination:

Benefits and risks of BCG vaccination.
Impact of BCG on the interpretation of T ST results in diagnosing a potential latent T B infection (LT BI).
No complete protection conferred by the vaccine: T B may still occur if other IPC measures are not used.

BCG vaccine should only be administered if the person:

Is HIV-negative.
Is not pregnant.
Has never had a BCG vaccination.
Has never had active T B.
Has a T ST negative result.

For more information on BCG vaccine see Appendix 29.

References
1. Punam Mangt ani, Ibrahim Abubakar, Cono Arit i, Rebecca Beynon, Laura Pimpin, Paul E. M. Fine, Laura C. Rodrigues, Pet er G. Smit h, Marc
Lipman, Penny F. Whit ing, Jonat han A. St erne. Protection by BCG Vaccine Against Tuberculosis: A Systematic Review of Randomized
Controlled Trials. Clinical Inf ect ious Diseases, Volume 58, Issue 4, 15 February 2014, Pages 470–480.
ht t ps://doi.org/10.1093/cid/cit 790

2. Cent ers f or Disease Cont rol and Prevent ion Fact Sheet s on BCG Vaccine.
ht t ps://www.cdc.gov/t b/publicat ions/f act sheet s/prevent ion/bcg.ht m
15.4 Follow-up
Follow-up of routinely exposed staff includes:
An annual clinical evaluation.
Assessment for T B (including CXR) and HIV, if symptomatic.

For staff who were T ST or IGRA negative at baseline, T ST may be performed once a year.

Staff working in a T B department and presenting with a recent immunodepression (e.g. HIV infection, immunosuppressive
treatment) or a pregnancy, should be transferred to another department or to an area within the T B department where the risk of
exposure to M. tuberculosis is low (Chapter 14).

LT BI treatment (Chapter 16) should be offered, after exclusion of active T B:

Once to staff who become T ST or IGRA-positive.
To all HIV-infected staff.
Chapter 16: Treatment of latent tuberculosis
infection
16.1 Introduction

16.2 Target populations

16.3 Latent tuberculosis infection treatment regimens

16.4 Latent tuberculosis infection in HIV-infected patients

16.5 Latent tuberculosis infection in household contacts

16.6 Latent tuberculosis infection in other individuals at risk

16.7 Latent tuberculosis infection and multidrug-resistant tuberculosis

16.8 Follow-up for patients treated for latent tuberculosis infection

Update: January 2022

16.1 Introduction
Exposure to M. tuberculosis may result in latent tuberculosis infection (LT BI). WHO defines LT BI as a state of persistent immune
response to stimulation by M. tuberculosis antigens with no evidence of clinically manifest active tuberculosis (T B) [1] . T his is also
referred to as “tuberculosis infection”.

Identification and treatment of LT BI can reduce T B morbidity and mortality, as well as T B transmission.

Tuberculin skin test (T ST ) or interferon-gamma release assay (IGRA) can be used to detect LT BI (Chapter 3).

T he goal of LT BI treatment is to reduce the risk of progression to active T B. It must be initiated only once active T B has been
ruled out by appropriate evaluation.

If a patient develops signs and symptoms of active T B while on LT BI treatment, a specimen should be taken for diagnosis and
detection of drug resistance (Xpert MT B/RIF, Xpert MT B/XDR, culture and drug susceptibility test, DST ) and according to the
results, T B treatment should be initiated.

References
1. World Healt h Organizat ion. WHO consolidated guidelines on tuberculosis: module 1: prevention: tuberculosis preventive treatment. Geneva:
World Healt h Organizat ion. 2020.
ht t ps://www.who.int /publicat ions/i/it em/who-consolidat ed-guidelines-on-t uberculosis-module-1-prevent ion-t uberculosis-prevent ive-
t reat ment
16.2 Target populations
T ST or IGRA cannot predict which patients with LT BI are likely to develop active T B. T herefore, widespread LT BI testing and
treatment are not recommended.

However, in certain populations, the risk of progression to active T B significantly exceeds that of the general population. For these
at-risk populations, the benefits of LT BI treatment of preventing active T B and T B transmission outweigh the potential risks.

Populations who benefit most from LT BI treatment include:

HIV-infected individuals.
Household contacts of patients with bacteriologically confirmed pulmonary T B (PT B), in particular children under 5 years.
Other individuals or populations at risk (e.g. health staff, prisoners).
16.3 Latent tuberculosis infection treatment
regimens
T here are 3 recommended LT BI treatment regimens and 2 alternative treatment regimens [1] . T he decision to prescribe one
regimen rather than the other should take into consideration:
Drug-susceptibility of the strain of the presumed source patient, if known.
Co-morbidities (e.g. HIV infection, pre-existing hepatic disease or neuropathy).
Risk of drug interactions (especially with antiretrovirals), tolerability, length of treatment and likelihood of adherence.
Individual characteristics (e.g. age, pregnancy, living conditions, individual preference).
Epidemiological and programmatic aspects (e.g. HIV prevalence, available drugs, national recommendations).

Table 16.1 - LT BI treatment regimens

Recommended regimens

Isoniazid daily for 6 months (6H) isoniazid PO once daily:

or 36 months (36H) < 30 kg: 10 mg/kg (7 to 15 mg/kg)
≥ 30 kg: 5 mg/kg (4 to 6 mg/kg)
(max. dose 300 mg daily)

OR isoniazid PO once weekly:

Isoniazid + rifapentine weekly < 30 kg and ≥ 2 years: 20 to 30 mg/kg
for 3 months (3HP) ≥ 30 kg: 900 mg
+
rifapentine PO once weekly [2] :
10 to 14 kg and ≥ 2 years: 300 mg
14.1 to 25 kg and ≥ 2 years: 450 mg
25.1 to 32 kg: 600 mg
32.1 to 49.9 kg: 750 mg
≥ 50 kg: 900 mg max.

OR isoniazid PO once daily:

Isoniazid + rifampicin daily < 30 kg: 10 mg/kg (7 to 15 mg/kg)
for 3 months (3HR) ≥ 30 kg: 5 mg/kg (4 to 6 mg/kg)
(max. dose 300 mg daily)
+
rifampicin PO once daily:
< 30 kg: 15 mg/kg
≥ 30 kg: 10 mg/kg
(max. dose 600 mg daily)
 Alternative regimens

Isoniazid + rifapentine daily isoniazid PO once daily:

for 1 month (1HP) ≥ 13 years: 300 mg
+
rifapentine PO once daily:
≥ 13 years: 600 mg

OR rifampicin PO once daily:

Rifampicin daily for 4 months (4R) < 30 kg: 15 mg/kg
≥ 30 kg: 10 mg/kg
(max. dose 600 mg daily)

16.3.1 Isoniazid monotherapy

Isoniazid monotherapy (or isoniazid preventive therapy, IPT ) is the treatment currently most often used for LT BI. T his treatment
has proven to be effective in preventing active T B in both HIV-infected and non-HIV-infected patients [3] [4] .
WHO recommends this treatment in all patients regardless of their HIV status, including children of any age and pregnant women.
T he main disadvantage of isoniazid monotherapy is the length of treatment. Patients are usually healthy and may not be motivated
to complete a 6-month therapy.
Adverse effects (e.g. peripheral neuropathy, hepatotoxicity) can also lead to treatment interruption.
All patients at risk of peripheral neuropathy should receive pyridoxine (vitamin B 6) for the entire duration of treatment to prevent this
risk (for doses see Appendix 17).
In HIV-infected patients, the treatment may be difficult due to additive adverse effects of antiretrovirals and isoniazid, the
extending of the duration of treatment to 36 months in some adolescents and adults (Section 16.4.2) and the high number of
tablets to be taken daily. T he number of tablets can be reduced using a fixed-dose combination (FDC) of
isoniazid/cotrimoxazole/pyridoxine.

16.3.2 Rifapentine-containing regimens

Combination isoniazid-rifapentine once weekly for 3 months (3HP)
T his treatment has proven to be effective in preventing active T B in both HIV-infected and non-HIV- infected patients. WHO
recommends this treatment in children 2 years and over, adolescents and adults, regardless of their HIV status.
It is short, requires few doses, has a high completion rate and the risk of hepatoxicity is low [5] [6] .
T he disadvantages of this regimen are the lack of FDC and the development of hypersensitivity reaction in almost 4% of
patients [4] (Section 16.8.3).

Combination isoniazid-rifapentine once daily for 1 month (1HP)

T his treatment has proven to be effective in preventing active T B in HIV-infected patients. WHO recommends this treatment as an
alternative regimen in patients 13 years and over, regardless of their weight and HIV status.
T he treatment is short, has a high completion rate and the risk of hepatoxicity is low [7] . However, cutaneous reactions (rash,
itching) are common.

Rifapentine containing regimens are not currently recommended for pregnant women. Despite some reassuring data [8] , safety is
not definitively established.

16.3.3 Rifampicin-containing regimens

Combination isoniazid-rifampicin once daily for 3 months (3HR)
T his treatment has proven to be effective in preventing active T B in both HIV-infected and non-HIV- infected patients. WHO
recommends this treatment in all patients regardless of their HIV status, including children of any age and pregnant women.
It is short, safe, has a good completion rate [3] and FDC are available for children and adults. Hypersensitivity reaction may occur in
approximately 2% of patients [9] .

Rifampicin monotherapy once daily for 4 months (4R)

T his treatment has proven to be effective in preventing active T B in non-HIV-infected patients of all ages. WHO recommends this
regimen as an alternative regimen in all patients regardless of their HIV status, including children of any age and pregnant women.
T he advantages of this regimen (better safety profile and completion rate compared to 6H) [10] should be weighed against the risk
associated with use of rifampicin in monotherapy (development of resistance to rifampicin in patients with undiagnosed active T B).

Notes on rifamycin-containing regimens:

Rifapentine and rifampicin have interactions with many drugs, particularly antiretrovirals (Appendix 19) and contraceptives
(Chapter 9).
For pregnant women taking rifampicin, administer phytomenadione (vitamin K) in the last few weeks of pregnancy (Chapter 9).
Rifapentine and rifampicin are not interchangeable.
Rifabutin can replace rifampicin if rifampicin cannot be used due to drug interactions [2] .

References
1. World Healt h Organizat ion. WHO consolidated guidelines on tuberculosis: Module 1: prevention: tuberculosis preventive treatment. Geneva:
World Healt h Organizat ion. 2020.
ht t ps://www.who.int /publicat ions/i/it em/who-consolidat ed-guidelines-on-t uberculosis-module-1-prevent ion-t uberculosis-prevent ive-
t reat ment

2. St erling TR, Njie G, Z enner D, et al. Guidelines for the Treatment of Latent Tuberculosis Infection: Recommendations from the National
Tuberculosis Controllers Association and CDC. 2020. MMWR Recomm Rep 2020;69(No. RR-1):1–11.
ht t p://dx.doi.org/10.15585/mmwr.rr6901a1

3. Z enner D, Beer N, Harris RJ, Lipman MC, St agg HR, van der Werf MJ. Treatment of latent tuberculosis infection: an updated network meta-
analysis. Ann Int ern Med. 2017 Aug 15; 167(4):248.
ht t ps://www.acpjournals.org/doi/10.7326/M17-0609?url_ver=Z 39.88-2003&rf r_id=ori:rid:crossref .org&rf r_dat =cr_pub%20%200pubmed

4. Badje et al. Effect of isoniazid preventive therapy on risk of death in west African, HIV-infected adults with high CD4 cell counts: long-term
follow-up of the Temprano ANRS 12136 trial. Lancet Glob Healt h 2017; 5: e1080–89.
ht t ps://www.t helancet .com/journals/langlo/art icle/PIIS2214-109X(17)30372-8/f ullt ext

5. St erling TR, Villarino ME, Borisov AS, Shang N, Gordin F, Bliven-Sizemore E, et al. Three Months of Rifapentine and Isoniazid for Latent
Tuberculosis Infection. New England Journal of Medicine. 2011;365(23):2155–66.
ht t ps://www.nejm.org/doi/10.1056/NEJMoa1104875?url_ver=Z 39.88-2003&rf r_id=ori:rid:crossref .org&rf r_dat =cr_pub%20%200pubmed

6. Villarino ME, Scot t NA, Weis SE, Weiner M, Conde MB, Jones B, et al. Treatment for preventing tuberculosis in children and adolescents: a
randomized clinical trial of a 3-month, 12-dose regimen of a combination of rifapentine and isoniazid. JAMA Pediat r. 2015;169(3):247–55.
ht t ps://www.ncbi.nlm.nih.gov/pmc/art icles/PMC6624831/

7. BRIEF TB/A5279 St udy Team. One month of Rifapentine plus Isoniazid to prevent HIV-related Tuberculosis. n engl j med 2019; 380: 1001.
ht t ps://www.nejm.org/doi/f ull/10.1056/NEJMoa1806808

8. Moro RN, Scot t NA, Vernon A, Tepper NK, Goldberg SV, Schwart zmann K, et al. Exposure to latent tuberculosis treatment during pregnancy.
The Prevent TB and the iAdhere Trials. Annals ATS. 2018 May; 15 (5): 570.
ht t ps://www.ncbi.nlm.nih.gov/pmc/art icles/PMC6624829

9. World Healt h Organizat ion. WHO operational handbook on tuberculosis. Module 1: prevention - tuberculosis preventive treatment. Geneva:
World Healt h Organizat ion. 2020.
ht t ps://apps.who.int /iris/rest /bit st reams/1272664/ret rieve

10. Menzies D, Adjobimey M, Ruslami R, Trajman A, Sow O, Kim H, et al. Four Months of Rifampin or Nine Months of Isoniazid for Latent
Tuberculosis in Adults. New Eng J Med. 2018 Aug 2;379(5):440.
ht t ps://www.nejm.org/doi/f ull/10.1056/NEJMoa1714283
16.4 Latent tuberculosis infection in HIV-infected
patients
Treatment of LT BI reduces the risk of active T B by 33-64% [1] .

For patients not yet on antiretroviral treatment (ART ), ART initiation should take priority over initiation of LT BI treatment.
Among these patients, there is a high proportion of undiagnosed, asymptomatic T B cases and it is important to use all existing
diagnostic means to rule out active T B.

Note: a treatment programme for LT BI should be combined with a screening programme for active T B in HIV-infected patients
(Chapter 6).

16.4.1 Children
HIV-exposed childrena and HIV-infected children and who do not have active T B (for evaluation, see Chapter 5) should receive
LT BI treatment:
After contact with a T B case, including smear-positive, smear-negative and extrapulmonary T B (EPT B), regardless of their age;
In high T B transmission areas: if aged 12 months and over, regardless of their contact history.

In addition, for children treated for active T B and living in high T B transmission areas, LT BI treatment may also be prescribed
immediately after the successful completion of T B treatment to reduce the risk of reinfection.

16.4.2 Adolescents and adults

HIV-infected adolescents and adults who do not have active T B should receive LT BI treatment, regardless of contact history and
T B prevalence in the area.
In areas with high T B transmission, HIV-infected adolescents and adults with a LT BI test positive or unknown and who are unlikely
to have active T B (no cough, no fever, no weight loss, no night sweats) should receive the treatment for at least 36 months (long-
term regimen).
T his regimen is more effective in preventing T B in HIV-infected adults with a positive T ST than those with a negative T ST [2] .

If T ST is not feasible, or where the national guidelines do not recommend long-term isoniazid monotherapy, HIV-infected
adolescents and adults without any T B symptoms should receive another LT BI treatment (6H or a rifapentine- or rifampicin-
containing regimen).

Table 16.2 – LT BI treatments for HIV-infected patients

Age Recommended regimens Alternative regimens

Child < 2 years 6H or 3RH 4R

Child ≥ 2 years 6H or 3HP or 3RH 4R

Adolescent and adult 6H or 3HP or 3RH or 36H 1HP (if ≥ 13 years) or 4R

Footnotes
(a) HIV-exposed children are children born t o HIV-inf ect ed women whose HIV st at us has not been est ablished and/or are st ill at risk of
inf ect ion (e.g. st ill breast f ed).
References
1. Akolo C, Adet if a I, Shepperd S, Volmink J. Treatment of latent tuberculosis infection in HIV infected persons. Cochrane Dat abase Syst Rev.
2010;1.
ht t ps://www.ncbi.nlm.nih.gov/pmc/art icles/PMC7043303/

2. Den Boon S, Mat t eelli A, Ford N, Get ahun H. Continuous isoniazid for the treatment of latent tuberculosis infection in people living with HIV:
AIDS. 2016 Mar;30(5):797.
ht t ps://pubmed.ncbi.nlm.nih.gov/26730567/
16.5 Latent tuberculosis infection in household
contacts
A household contact is a person who has shared the same enclosed living space as the index case for one or more nights or for
frequent or extended daytime periods during 3 months before the start of the current treatment [1] .

16.5.1 Neonates of mothers with active pulmonary tuberculosis

All neonates born to mothers with active PT B should receive treatment for LT BI, after exclusion of active T B, if the mother:
Has been treated for PT B less than 2 weeks at the time of birth, or
Has a positive smear microscopy result on a sputum sample collected at birth or close to the time of birth[2] .

A test Xpert MT B/RIF and Xpert MT B/XDR should be performed to rule out resistance to rifampicin and isoniazid before starting
LT BI treatment.

T he recommended regimens are 3HR or 6H. For HIV-exposed neonates receiving nevirapine, only 6H is recommended.

BCG vaccine should be administered just after LT BI treatment completion (not during the treatment).

If a T ST is feasible and the regimen chosen is 6H:

Administer isoniazid for 3 months, then perform a T ST.
If the T ST is positive, complete isoniazid monotherapy.
If the T ST is negative, stop isoniazid and administer the BCG vaccine.

Notes:
A neonate should not be separated from its mother unless severely ill.
Breastfeeding should continue, and breastfed neonates should receive pyridoxine (vitamin B 6).

16.5.2 Other household contacts

Children under 5 years
It is not mandatory to perform T ST or IGRA prior to LT BI treatment.
All children < 5 years in contact with a confirmed PT B case and who do not have active T B (for evaluation, see Chapter 5) should
receive LT BI treatment, regardless of their HIV and BCG vaccination status.
If LT BI treatment is contra-indicated or in case of parental refusal, monitor the child closely for one year to enable the early
detection of active T B.

Children 5 years and older, adolescents and adults

A T ST or IGRA should be performed prior to LT BI treatment. If this is not feasible, LT BI treatment may be considered, weighing
benefits and risks.
Children 5 years and over in contact with a confirmed PT B case and who do not have active T B (for evaluation, see Chapter 5)
may receive LT BI treatment, regardless of their HIV status.
Adolescents and adults in contact with a confirmed PT B case and who do not have active T B (no T B symptoms and no
abnormality on CXR) may receive LT BI treatment, regardless of their HIV status.

Table 16.3 - LT BI regimens for household contacts

 Age Recommended regimens Alternative regimens

Child < 2 years 6H or 3RH 4R

Child ≥ 2 years and < 5 years 6H or 3HP or 3RH 4R

Child ≥ 5 years, adolescent, adult 6H or 3HP or 3RH 1HP (if ≥ 13 years) or 4R

References
1. World Healt h Organizat ion. WHO consolidated guidelines on tuberculosis: Module 1: prevention: tuberculosis preventive treatment. Geneva:
World Healt h Organizat ion. 2020.
ht t ps://www.who.int /publicat ions/i/it em/who-consolidat ed-guidelines-on-t uberculosis-module-1-prevent ion-t uberculosis-prevent ive-
t reat ment

2. Mit t al H, Das S, Faridi MM. Management of newborn infant born to mother suffering from tuberculosis: current recommendations & gaps in
knowledge . Indian J Med Res. 2014;140(1):32-39.
ht t ps://www.ncbi.nlm.nih.gov/pmc/art icles/PMC4181157/
16.6 Latent tuberculosis infection in other individuals
at risk
Routine LT BI testing (T ST or IGRA) and treatment after exclusion of active T B:
Are recommended for patients with silicosis, on dialysis or taking long-term immunosuppressive therapy.
Can be considered for health staff, populations in congregate living settings (e.g. prisoners, refugees), migrants from countries
with a high T B prevalence, homeless people and drug users.

LT BI testing should be performed periodically (e.g. once a year).

Routine LT BI testing and treatment is not recommended for diabetic, malnourished or alcoholic patients, unless they belong to the
above-mentioned risk groups.
16.7 Latent tuberculosis infection and multidrug-
resistant tuberculosis
Due to limited evidence, routine LT BI treatment for all household contacts of multidrug-resistant T B (MDR-T B) patients cannot be
recommended at this time.

However, treatment of LT BI should be considered in certain high-risk household contacts based on an individual risk-benefit
assessment.
Individual assessment includes:
High risk of progression to active T B: children under 5 years, individuals with HIV infection or on immunosuppressive therapy.
Resistance pattern of the source case: the LT BI treatment regimen must be individually tailored as contacts of MDR-T B
patients are often infected with the same strain[1] .
Intensity of exposure.
Contra-indication or risk of adverse drug reactions.

A T ST or IGRA should be performed prior to LT BI treatment. If not feasible, LT BI treatment may be considered, weighing benefits
and risks.

16.7.1 Household contacts of multidrug-resistant tuberculosis cases eligible for

treatment
Evidence is lacking on the choice of treatment to prevent disease in MDR-T B contacts. Few observational studies, primarily using
a fluoroquinolone (FQ) for 6 months, reported promising results [2] [3] . Randomized clinical trials are ongoing [4] [5] .

For contacts of FQ-susceptible MDR-T B patients, levofloxacin PO for 6 months can be proposed at the following doses:

Weight 5 to 9 kg 10 to 15 kg 16 to 23 kg 24 to 34 kg 35 to 45 kg > 45 kg

Daily dose 150 mg 200 to 300 mg 300 to 400 mg 500 to 750 mg 750 mg 1g

If active T B develops during LT BI treatment, DST including resistance to FQs is necessary due to the potential risk associated
with use of FQs in monotherapy (development of resistance to FQs in patients with undiagnosed active T B).
Independent of LT BI treatment, monitor these patients for 2 years for the development of active T B.

16.7.2 Household contacts of multidrug-resistant tuberculosis cases not eligible

for treatment
If the contact is not eligible for LT BI treatment, closely monitor for signs and symptoms of active T B every 3 months for the next 2
years.

If active T B develops, initiate T B treatment promptly with a regimen designed according to the DST. If DST is not feasible, a
regimen can be designed according to the resistance profile of the source case.

References
1. Verver S et al. Proportion of tuberculosis transmission that takes place in households in a high-incidence area . Lancet , 2004, 363(9404):212.

2. Trieu L, Proops DC, Ahuja SD. Moxifloxacin Prophylaxis against MDR TB. New York, New York, USA. Emerg Inf ect Dis. 2015;21(3):500–3.
ht t ps://www.ncbi.nlm.nih.gov/pmc/art icles/PMC4344279/

3. Bamrah S, Brost rom R, Dorina F, Set ik L, Song R, Kawamura LM, et al. T reatment for LTBI in contacts of MDR-TB patients, Federated States of
 Micronesia, 2009–2012. Int J Tuberc Lung Dis. 2014;18(8):912–8.
ht t ps://www.ncbi.nlm.nih.gov/pmc/art icles/PMC4730114/

4. Protecting Households On Exposure to Newly Diagnosed Index Multidrug-Resistant Tuberculosis Patients (PHOENIx MDR-TB).
ht t ps://clinicalt rials.gov/ct 2/show/NCT03568383

5. Tuberculosis child multidrug-resistant preventive therapy: TB CHAMP trial.

ht t ps://doi.org/10.1186/ISRCTN92634082
16.8 Follow-up for patients treated for latent
tuberculosis infection
For the modality of administration of LT BI treatments see Chapter 13.

16.8.1 Baseline assessment of liver function

Before initiating LT BI treatment, look for clinical signs of hepatic disease and specific risks of hepatotoxicity.

For patients with hepatic disease, baseline liver function tests (LFTs), i.e. aspartate aminotransferase (AST ), alanine
aminotransferase (ALT ) and bilirubin should be performed.
T he benefit of LT BI treatment should be weighed against the potential risk of aggravation of existing hepatic disease. LT BI
treatment is contra-indicated in patients with end-stage hepatic disease or LFTs > 5 times the upper limit of normal (ULN) and
should be used with caution in patients with LFTs > 3 times ULN [1] .

Depending on available resources, baseline LFTs can be performed in groups at risk for hepatotoxicity (e.g. patients with HIV
infection, women during pregnancy and post-partum period, chronic alcohol consumption, age > 35 years, concomitant use of
hepatotoxic drugs, history of hepatic disease).

16.8.2 Follow-up
All patients should be evaluated monthly for signs and symptoms of active T B, adverse effects and adherence.

T ST or IGRA should not be repeated.

In patients with pre-existing hepatic disease:

Baseline LFT S are normal: monitor LFTs monthly.
Baseline LFTs are elevated or LFTs increase during LT BI treatment: monitor LFTs once a week [2] .

Other patients should be tested if they develop symptoms of hepatotoxicity.

Any problems with adherence should be addressed with the patient.

If signs and symptoms of active T B develop, the patient should undergo full evaluation (Chapter 3, Chapter 4 and Chapter 5).

16.8.3 Management of adverse effects

Hepatotoxicity
Clinical features resemble that of viral hepatitis. Early symptoms include malaise, fatigue, loss of appetite, muscle and joint pain.
Nausea, vomiting and abdominal pain are common in severe disease. Jaundice, scleral icterus, dark (tea-coloured) urine and
discoloured stool are signs of clinical worsening.
Clinical hepatitis can be fatal, so action should be taken immediately.

Patient with symptoms of hepatitis:

Stop all T B drugs and perform LFTs:
a) AST or ALT or bilirubin ≥ 3 times ULN or severe symptoms: do not re-initiate LT BI treatment.
b) AST, ALT, and bilirubin < 3 times ULN and mild symptoms (no jaundice): after discussion with the patient on benefits and risk,
treatment may be re-initiated. Closely monitor the patient and perform LFTs once a week. Continue treatment as long as LFTs
levels remain < 3 ULN and there are no signs of worsening hepatitis.
c) If LFTs are not available, do not re-initiate LT BI treatment.

Patient without symptoms of hepatitis, but elevated LFTs:

a) AST or ALT ≥ 5 times ULN or bilirubin ≥ 3 ULN: stop and do not re-initiate LT BI treatment.
b) AST and ALT < 5 times ULN and bilirubin < 3 ULN: stop LT BI treatment. Perform LFTs once a week. If LFTs return to normal,
 after discussion with the patient on benefits and risk, treatment may be re-initiated. Closely monitor the patient and perform
LFTs once a week.

Note: 10-20% of patients taking isoniazid alone may have a mild, transient, asymptomatic elevation of LFTs (AST and/or ALT ). In
most cases, this does not require treatment interruption.

Hypersensitivity reaction
Approximately 2% of patients on 3HR regimen and 4% of patients on 3HP regimen have hypersensitivity reaction, typically after
the first 3 to 4 doses [3] .
Symptoms may include fever, headache, dizziness, nausea and vomiting, muscle and bone pain, rash, itching, red eyes,
angioedema, shortness of breath and, more rarely, hypotension and altered consciousness.
In case of hypersensitivity reaction, treatment should be stopped immediately. Symptoms usually resolve within 24 hours after T B
drug withdrawal. In case of mild reaction (fever, rash, itching), consider re-initiating the treatment. In this case, the patient should be
observed at least 4 hours after each dose is administered to detect first signs of hypersensitivity reaction.

Other adverse effects

See Appendix 17.

References
1. World Healt h Organizat ion. WHO operational handbook on tuberculosis. Module 1: prevention - tuberculosis preventive treatment. Geneva:
World Healt h Organizat ion. 2020.
ht t ps://apps.who.int /iris/rest /bit st reams/1272664/ret rieveWorld Healt h

2. Saukkonen JJ, Cohn DL, Jasmer RM, Schenker S, Jereb JA, Nolan CM, Peloquin CA, Gordin FM, Nunes D, St rader DB, Bernardo J,
Venkat aramanan R, St erling TR; ATS (American Thoracic Societ y) Hepatotoxicity of Antituberculosis Therapy Subcommittee. An official ATS
statement: hepatotoxicity of antituberculosis therapy. Am J Respir Crit Care Med. 2006 Oct 15;174(8):935-52.
ht t ps://www.at sjournals.org/doi/pdf /10.1164/rccm.200510-1666ST

3. St erling TR, Moro RN, Borisov AS, Phillips E, Shepherd G, Adkinson NF, Weis S, Ho C, Villarino ME; Tuberculosis Trials Consort ium. Flu-like
and Other Systemic Drug Reactions Among Persons Receiving Weekly Rifapentine Plus Isoniazid or Daily Isoniazid for Treatment of Latent
Tuberculosis Infection in the PREVENT Tuberculosis Study. Clin Inf ect Dis. 2015 Aug 15;61(4):527-35. doi: 10.1093/cid/civ323. Epub 2015 Apr
22. PMID: 25904367; PMCID: PMC4560029.
ht t ps://www.ncbi.nlm.nih.gov/pmc/art icles/PMC4560029/pdf /civ323.pdf
Chapter 17: Monitoring and evaluation
17.1 Introduction

17.2 Definitions of treatment outcomes

17.3 Recording tools

17.4 Reporting

17.5 Programme assessment

17.1 Introduction
Monitoring and evaluation rely on both quantitative and qualitative information in order to provide information on the following:
Programme performance (e.g. number of patients started on anti-T B treatment, treatment results, number of patients tested
for MDR-T B, etc.);
Planning for human resources, patient support, diagnostic tests and drug orders, etc.;
Evaluation of the functioning of the programme (quality of drugs, diagnostics, patient support, etc.).

Recording and reporting are based on a set of standard case and outcome definitions.

Case definitions are presented in Chapter 7.

17.2 Definitions of treatment outcomes
For all forms of T B, outcome definitions have many similarities. T hese are:
Outcome assignment is standardized, as to permit comparisons across clinicians, time and sites.
Outcome assignment relies heavily, but not exclusively, on bacteriologic endpoints (smear or culture a ).
Outcomes are mutually exclusive and exhaustive.

For all forms of T B, definitions exist for:

Interim outcomes (intended to have an indication on how the programme is functioning before final outcomes are available);
Final outcomes (cure, completion, failure, treatment interruption, death or not evaluated).

17.2.1 Interim outcomes for drug-susceptible TB and MDR-TB

Given that T B treatment is long (6 to 18 months or more), interim outcomes provide early indicators of programme results. Table
17.1 provides a summary on interim outcomes.

Table 17.1 - Interim outcomes

TB Interim outcomes

Drug-susceptible At 2-3 and 4-5 months:

TB Bacteriological status (smear negative/positive/no information)
Final outcomes in patient who had already interrupted or died

MDR-TB At 6 months:
Bacteriological status (negative/positive/no information) based on smear and culture
Final outcomes in patient who had already interrupted or died

17.2.2 Final outcomes for drug-susceptible TB and DR-TB

Table 17.2 provides definitions for the final outcomes.

Table 17.2 - Summary table of final outcome definitions [1] [2]

 Outcomes TB Definitions

Patient initially bacteriologically confirmed (microscopy, culture or molecular test) who

completed treatment
AND shows no signs of continued active disease
DS T B
AND has at least 2 negative smears or cultures: one at 4-5 months and the other at the
end of treatment
AND does not meet the definition of failure.

Patient initially bacteriologically confirmed (culture or molecular test), who completed

treatment
PDR-T B AND has been consistently culture-negative with at least 3 results on sputum tested at
Cured least one month apart for the final 6 months of treatment
AND does not meet the definition of failure.

Patient initially bacteriologically confirmed (culture or molecular test), who completed

treatment
AND with at least 3 negative cultures in the last 8 months of treatment
AND does not meet the definition of failure.
MDR-T B
If there is a lone positive culture or smear reported during that time, and no concomitant
clinical evidence of deterioration, a patient may still be considered cured, provided that this
positive culture is followed by a minimum of 3 consecutive negative cultures taken at least
30 days apart.

Patient who completed treatment

Completed All AND has no signs of continued active disease
AND does not meet the bacteriological criteria for cure.

Patient with signs of continued active disease or deterioration requiring a treatment

change:
DS T B • Any patient with positive smear or culture at 4-5 months of treatment or thereafter.
• Any patient with no significant clinical improvement, no significant gain of weight after 4-5
months of treatment and for whom the diagnosis of failure is established by a clinician.

Treatment terminated or need for permanent treatment change of at least 2 classes of

anti-T B drugs because of one or more of the following:
Failure
• Lack of monitoring cultures converting to negative by 6 months for MDR-T B (3 months
for PDR-T B), and/or
DR-T B (a) (b) • Resistance amplification to rifampicin or isoniazid (PDR-T B) or to Group 2 or Group 3
(c) drugs (MDR-T B), and/or
• Bacteriological reversion (at least two positive smears or cultures at least 7 days apart
after monitoring smears or cultures have become negative), or
• A clinical decision has been made to terminate treatment early due to poor response or
adverse events. T hese latter failures can be indicated separately in order to do sub-
analysis.

Interrupted All Patient who interrupted treatment for 2 months or more.

Patient who died on T B treatment or while awaiting T B treatment, irrespective of the

Death All
cause of death. T he cause of death should be recorded.

Treatment Patient initially treated with a standard regimen and for whom the treatment is secondarily
DS T B
adapted (d) (e) adapted according to the results of DST (and not because of a treatment failure).
 Not evaluated All Patient whose treatment outcome is unknown (including patients “transferred out” to
another treatment centre, for whom the outcome is unknown).

(a) A pat ient regist ered as “f ailure” can be re-regist ered as DR-TB “previously t reat ed 2n d line” and st art ed again on a new regimen if
possible.
(b) This cat egory does not include t he changing of one drug due t o an adverse ef f ect or a t emporary cessat ion of drugs in order t o manage
severe adverse event .
(c) If a pat ient was defined as a “f ailure”, and no appropriat e t reat ment was possible, but t he t reat ment was cont inued and t he pat ient
subsequent ly int errupt ed t he t reat ment or died, t he out come is “f ailure” (t he first out come is recorded).
(d) For programmes t hat report using t he WHO’s mut ually exclusive six out comes, t he “t reat ment adapt ed” out come can be added t o
f ailures f or report ing purposes, but should also be kept t rack of separat ely f or good programmat ic monit oring and evaluat ion.
(e) Not applicable f or DR-TB.

If treatment is continuing at the time of a cohort analysis, an outcome of “still on treatment” may be provisionally assigned

Footnotes
(a) Molecular t echniques are not used t o monit or t reat ment response or t o declare f ailure. These t est s may ident if y dead bacilli f or a long
t ime and can even be posit ive af t er a pat ient is t ruly cured.

References
1. Laserson KF, Thorpe LE, Leimane V, Weyer K, Mit nick CD, Riekst ina V, et al. Speaking the same language: treatment outcome definitions for
multidrug-resistant tuberculosis. Int . J. Tuberc. Lung Dis. 2005:9(6):640–5.

2. World Healt h Organizat ion. Definitions and reporting framework for tuberculosis - 2013 revision (WHO/HTM/TB/2013.2). WHO Geneva. 2013.
ht t p://apps.who.int /iris/bit st ream/10665/79199/1/9789241505345_eng.pdf
17.3 Recording tools
Forms used in recording and reporting can be found in the appendices. T hey are intended to be examples that programmes or
country can use to produce their own forms.

17.3.1 Drug-susceptible TB treatment card and drug-susceptible TB register

Drug-susceptible T B treatment card and drug-susceptible T B register (Appendix 23 and Appendix 24) are used for all new patients
or previously treated patients treated by standard first-line regimens (with or without confirmation of the drug susceptibility by a
DST ).

17.3.2 DR-TB treatment card and DR-TB register

DR-T B treatment card (Appendix 25) tracks, in particular, each dose of each drug taken during the full course of treatment. T he
number of actually observed doses and the number of expected observed doses are reported each month. In addition to the
treatment card, it is recommended to keep a medical chart with a full admission note at the time of enrolment and a progress note
at each medical encounter.

DR-T B register (Appendix 26) includes data on case definition, bacteriological exams (indicate date of specimen collection and not
the date of result), type of treatment and treatment outcome. It is a separate register from the drug-susceptible T B register.

Each DR-T B patient detected should be registered, including patients who refuse treatment.

Transfer of patients from the drug-susceptible T B register to the DR-T B register is done usually while on treatment when DST
results are available. Patient’s outcome is reported as ‘treatment adapted’ in the comment row of the drug-susceptible T B register
(Appendix 24).

17.3.3 Laboratory request form(s) and register(s)

Request form for smear microscopy and Xpert assays (Appendix 34);
Request form for sputum culture, LPA and DST (Appendix 28);
Sputum smear microscopy register (Appendix 29);
Xpert MT B/RIF register (Appendix 30).

17.3.4 Drug-O-Gram
T he Drug-O-Gram is a summary of the patient’s treatment history. It includes consecutive DST and treatment changes presented
in a chronological order and gives a short summary of the patient status (Appendix 31).
17.4 Reporting
T he key evaluation tool for all forms of T B is the periodic report. It must be presented in a standardized manner in two parts: case
enrolment and treatment outcomes. T he data presented in the report comes from the T B register. It is generally completed by
quarter for drug-susceptible T B and by semester for DR-T B.

Evaluation of interim and final treatment outcomes is a fundamental stage in the evaluation. T his evaluation is done through a
cohort analysis. A "cohort" is a group of individuals presenting certain common characteristics and undergoing the same events. In
respect to the evaluation of T B patients, a cohort is represented by patients all put under treatment within a given period of time
(usually a quarter for drug-susceptible T B and a semester for DR-T B). At the end of treatment, a final outcome is assigned to each
patient (Table 17.1).

Notes:
T he number of patients in each group should, in principle, be identical to those registered for the same interval in the case
enrolment part of the corresponding periodic report. If it is different, an explanation should be given (e.g., patients “interrupting
before treatment” can be excluded from the outcome analysis).
T he outcomes of patients "transferred in" should not be included in the outcomes of the facility to which they were transferred.
T heir outcome results should be recorded in the facility that initially enrolled the patient in T B treatment.

17.4.1 Case detection and enrolment report for TB

T he elements necessary for defining a T B case (treatment history, bacteriological status, anatomical site of the disease, and HIV
status) are defined in Chapter 7.

See Quarterly report for case enrolment, Appendix 32.

Main indicators
Proportion of confirmed pulmonary TB (PTB)
= Number of PTB cases confirmed enrolled/Total number of TB cases enrolled for the period
With the introduction of automated molecular tests and rapid cultures, it is expected that the proportion of confirmed PT B
cases will increase as compared to programmes where only smear microscopy is available.

Proportion of smear-negative PTB

= Number of smear-negative PTB cases enrolled/Total number of TB cases enrolled for the period
T his indicator essentially depends on the following: the quality of microscopy, the number of children under treatment (children
are rarely smear-positive), the prevalence of HIV infection within the population (these patients present more smear-negative
PT B), and the other diagnostics used (culture, Xpert MT B/RIF, etc).
T he proportion of smear-negative PT B is about 20% when HIV prevalence is low. It is 40 to 60% when HIV prevalence is high.
Proportions that differ significantly from these should make one consider the possibility of under- or over-diagnosis of smear-
negative forms.

Proportion of smear-positive PTB

= Number of smear-positive PTB cases enrolled/Total number of TB cases enrolled for the period
In practice, the proportion of smear-positive PT B should correspond to roughly half of all patients. T his proportion is lower,
however, in areas where HIV prevalence is high. Proportion of smear-positive PT B is around 60% where HIV prevalence is low,
and it is 30 to 40% where HIV prevalence is high. Proportions that differ significantly from these should make one consider the
possibility of under- or over-diagnosis of smear-negative pulmonary T B and extra-pulmonary B forms.

Proportion of new cases

= Number of new TB cases enrolled/Total number of cases enrolled for the period
T his indicator indirectly reflects the relapse and failure rates and possible parallel treatments outside the programme.

Proportion of children
= Number of TB patients less than 15 years enrolled/Total number of TB cases enrolled for the period
Children should represent approximately 10 to 15% of the total number of patients. Proportions that differ significantly from
these should make one consider the possibility of under- or over-diagnosis of T B in children.
 Proportion of detected cases enrolled under treatment
= Number of cases enrolled under treatment/Total number of cases detected for the period
Patients enrolled are counted from the T B register. Patients detected are counted from the laboratory register and include
patients who “interrupted before treatment”.

Case detection rate

= Number of new smear-positive PTB cases detected/Expected number of smear-positive PTB cases for the period
A rough estimate of the expected number of new smear-positive cases can be obtained using the estimated T B incidence given
by the WHO in the country profile, which allows an estimate of detection efficacy.

Note: even the best programmes often do not detect more than 60 to 70% of expected new smear-positive cases within a
population. In addition, patients might come from outside the target area.

17.4.2 Case detection and enrolment report for DR-TB

See standard DR-T B case detection and enrolment reports in Appendix 33.

Early detection of resistance is intended to ensure that an appropriate treatment is initiated from the start. DST is usually
performed for patients at risk of DR-T B. Target groups vary according to local situation, but should at a minimum always include
patients who have been previously treated and contacts of confirmed MDR-T B patients.

T he indicators for detection aim at measuring the access of T B patients to DST. T he frequency of MDR-T B among individuals in
different risk groups is also evaluated.

All patients in whom DR-T B is highly suspected or detected should be started on appropriate treatment in the shortest time
possible.

A comparison of enrolled patients under treatment to detected DR-T B cases gives an indication of access to care, though some
patients started on treatment may have been detected prior to the period of assessment.

T he period of assessment is six calendar months. T his is usually counted from January to the end of June and July to the end of
December. Indicators are measured three months after the end of the six-month period. All data can be extracted from the DR-T B
register (Appendix 26), the laboratory register for culture and DST and the Xpert register (Appendix 30).

Each indicator should be calculated for all patients and for each risk group of patients, including: all cases, previously treated
cases, failures, household contacts and other local risk groups according to the strategy.

Case detection indicators

Proportion of TB patients detected with DST result for isoniazid and rifampicin (for each risk group during the period)
= Number of TB cases detected with DST result for both isoniazid and rifampicin/Total number of TB cases detected

Proportion of TB patients detected with Xpert MTB/RIF result (for each risk group during the period)
= Number of TB cases detected with Xpert MTB/RIF result/Total number of TB cases detected

Proportion of confirmed MDR-TB cases detected among TB patients tested for isoniazid and rifampicin DST (for each risk
group during the period)
= Number of TB cases with confirmed resistance to isoniazid and rifampicin/Total number of TB cases tested for these 2 drugs

Proportion of Xpert RIF resistant cases detected among patients tested by Xpert MTB/RIF (for each risk group during the
period)
= Number of Xpert RIF resistant cases/Total number of TB cases with Xpert MTB/RIF result

Enrolment indicators
Proportion of confirmed MDR-TB cases enrolled on MDR-TB treatment
= Number of confirmed MDR-TB cases registered and started on MDR-TB treatment/Total number of confirmed MDR-TB cases
detected
T his can also be calculated for rifampicin resistant T B cases.

Proportion of confirmed PDR-TB cases enrolled on PDR-TB treatment

= Number of confirmed PDR-TB cases registered and started on PDR-TB treatment/Total number of confirmed PDR-TB cases
 detected
T his calculation does not include rifampicin resistance and unknown isoniazid resistance.

17.4.3 Interim treatment outcomes for drug-susceptible TB and DR-TB

Interim analysis should be completed approximately 3 months after all patients who were registered during a particular interval
completed the intensive phase of treatment (three months should allow culture results for all those patients).

Interim treatment outcomes for drug-susceptible TB

Interim results at Month 2 or 3 should be evaluated for all patients treated as new or previously treated patients by standard first-
line regimens (with or without confirmation of the drug susceptibility by a DST ). T hese results may be disaggregated by treatment
history (new, previously treated, and by type of previous treatment).

At the beginning of a programme, when it is not yet possible to do cohort analysis, the conversion rate at Month 2-3 is a proxy
indicator of the effectiveness of treatment, and it allows early detection of potential problems. T he smear conversion rate of new
smearpositive patients is the proportion of new smear-positive patients who are smear-negative at Month 2. T he smear
conversion rate of previously treated smear-positive patients is the proportion of previously treated smear-positive patients who
are smear-negative at Month 3.

Interim treatment outcomes for DR-TB

T he period of assessment is six calendar months, usually counted from January to end June, July to end December. All patients
registered and starting treatment during the period of assessment are included in the calculation. T he interim report form should be
completed 9 months after the closing day of the cohort. T his allows culture information at 6 months of treatment to be included
for all patients in the cohort. For instance, interim results of T B patients who started treatment during the first semester of a year
(1 January to 30 June), should be calculated at the beginning of April of the following year.

Culture conversion (for confirmed DR-T B cases) and death by six months are used as proxies for final outcomes. Information on
treatment interruption by six months is helpful. It is also useful to know how many patients started on second-line drugs for MDR-
T B turned out not to be MDR.

All data can be extracted from the DR-T B register (Appendix 26).

At six months:

Proportion of death
= Number of confirmed MDR-TB cases registered and started on MDR-TB treatment who died of any cause by the end of
Month 6/Total number of confirmed MDR-TB cases started on treatment for MDR-TB during the period
Proportion of treatment interrupted
= Number of confirmed MDR-TB cases started on MDR-TB treatment who interrupted by the end of Month 6/Total number of
confirmed MDR-TB cases started on treatment for MDR-TB during the period
Proportion with negative culture
= Number of bacteriologically confirmed pulmonary MDR-TB cases registered and started on MDR-TB treatment with negative
culture at Month 6/Total number of bacteriologically confirmed pulmonary MDR-TB cases registered and started on treatment
for MDR-TB during the period
Proportion with positive culture
= Number of bacteriologically confirmed pulmonary MDR-TB cases registered and started on MDR-TB treatment with positive
culture at Month 6/Total number of bacteriologically confirmed pulmonary MDR-TB cases registered and started on treatment
for MDR-TB during the period
Proportion found not to have MDR-TB
= Number of patients started on MDR-TB treatment during the period and later found not to be MDR/Total number of patients
started on MDR-TB treatment during the period

17.4.4 Final treatment outcomes for TB

See standard T B treatment outcomes reports (Appendix 32 and Appendix 33).
T he final outcome is the most important direct measurement of the effectiveness of a T B programme in terms of patient care. All
patients entered on the T B register should be assigned one of six mutually exclusive outcomes at the end of their therapy. All
patients should be assigned the first outcome they experience for the treatment being evaluated [1] .

Final treatment outcome cohort analysis could be carried out when all patients admitted in a given period of time had a chance to
complete their treatment. In practice:
For drug-susceptible T B (and all patients treated by standard first-line regimens) cohort results are analysed quarterly, one year
after inclusion of the last patient of the cohort (e.g. cohort of patients admitted during the first quarter 2014 will be evaluated at
the end of the first quarter 2015).
For DR-T B, evaluation occurs 27 months after inclusion of the last patient in the cohort in order to have the results of cultures
performed at 24 months. T he period of assessment is six calendar months, usually counted from January to the end of June and
July to the end of December. All patients starting treatment during this period are included in the calculation. Indicators are
measured 24 months after the end of the semester of assessment. All data can be extracted from the DR-T B register.

Although the timing of the analysis is different for drug-susceptible T B and DR-T B, the indicators are the same.

Indicators should be calculated for patients treated by standard first-line regimens (with or without confirmation of drug-
susceptible T B by a DST ), and for patients with PDR-T B and MDR-T B.
T he most important indicators are:

Proportion of cured
= Number of confirmed TB cases declared “cured”/Total number of confirmed TB cases put under treatment during the period
​T his indicator is calculated for all confirmed drug-susceptible T B cases and DR-T B cases. It is the best indicator of the
success of a programme for confirmed T B patients. T hough the effectiveness of the treatment for drug-susceptible T B is
theoretically above 90%, the proportion of cure is rarely above 70%. For MDR-T B this indicator rarely exceeds 50%.

Proportion of treatment completed

= Number of patients registered as “treatment completed”/Total number of patients put under treatment for the period
​A high proportion of patients completing treatment is a positive sign for not confirmed PT B and EPT B. For confirmed T B, it
indicates insufficient bacteriological verification at the end of treatment, thus, suggesting that a step should therefore be
reinforced.

Proportion with successful outcome

= Number of patients registered as “cured” or “treatment completed”/Total number of patients put under treatment during the
period
​T his is the best indicator to measure the efficacy of a programme for all forms of T B (confirmed and not confirmed, PT B and
EPT B). T his indicator rarely exceeds 80% for drug-susceptible T B and 60% for MDR-T B.

Proportion of treatment interrupted

= Number of patients registered as “treatment interrupted”/Total number of patients put under treatment during the period
​P atients who interrupted treatment are at risk of not being cured or of relapsing. Treatment interruption indicates a failure of the
programme in supporting the patient to be able to successfully complete treatment.

Proportion of death
= Number of patients registered as “death”/Total number of patients put under treatment during the period
​T his ratio usually does not exceed 5% for drug-susceptible T B. Over-mortality may be related to the poor functioning of a
programme. It may also be due to a high prevalence of HIV infection among cases or late referrals.

Proportion of failure
= Number of patients registered as “failures”/Total number of patients put under treatment during the period
​A high failure rate in new cases can be related to poor treatment adherence, high rate of primary resistance or poor quality of
anti-T B drugs. T he failure rate should not be over 2% in new cases under treatment.

Proportion of patients for whom HIV status is known

= Number of patients for whom HIV status is known by the end of treatment/Total number of patients put under treatment
during the period
​T his is one of the indicators that help evaluate the integration of T B and HIV services.

TB-HIV co-infection rate

= Number of HIV-infected TB patients/Total number of TB patients put under treatment during the period and for whom HIV
status is known at the end of treatment
 In high HIV-prevalence regions, co-infection rate may exceed 80%. T his information is important in assessing other indicators,
in particular the proportion of death.

References
1. Mult idrug-resist ant t uberculosis (MDR-TB) indicat ors. A minimum set of indicat ors f or t he programmat ic management of MDR-TB in
nat ional t uberculosis cont rol program. World Healt h Organizat ion, Geneva. 2010.
ht t p://apps.who.int /iris/bit st ream/10665/70484/1/WHO_HTM_TB_2010.11_eng.pdf
17.5 Programme assessment
To be complete, evaluation should look at how well the programme functions, particularly with respect to three aspects:
organization of care, established procedures and human resources. A set of quality criteria is evaluated for each of these aspects.
T he criteria may be either qualitative (description) or quantitative (indicators). T he following tables can be used as a rough guide.

17.5.1 Organization
 Criteria Indicators Goals

Access to care Accessibility of treatment facilities, decentralization, etc. Easy access to care during the
Home-based treatment available when appropriate. intensive/continuation phases

Patient comfort Patient welcome According to needs

Condition of the facility, heating (or cooling), overall Bed occupancy rate ≤ 100%
organization and cleanliness.
Food during hospitalization and/or for outpatients
(supplemental rations, quantities, organization in charge).
Bed occupancy rate of the T B ward.

Information and Patient interviews conducted. Patient understanding of treatment

therapeutic education

Hospital hygiene Equipment (respirators, masks, gloves, gowns, All necessary equipment is available
autoclaves, cleaning supplies, etc.) and used.
Waste management (sorting, incinerator, etc.)

Constant supply of lab Supplied by (government, agency or facility, other) 3-month buffer stock
materials Buffer stock No shortages
Number and duration of shortages

Constant supply of Stock card maintenance Stock cards up-to-dated

quality-assured Order frequency, delivery time, buffer stock One person in charge of the
anti-TB drugs Shortage(s) pharmacy
Drug sources All adequate
Institution in charge of supply No shortages
Use of FDCs first-line drugs WHO-prequalified sources (or
Storage conditions equivalent)
Organization of supply for peripheral facilities Use of FDCs
Appropriate storage conditions
Regular supply

Case detection Type of case detection (active or passive) Know the type, in order to interpret
Contacts screening the quantitative results of case
Detection rate of new smear-positive cases detection
Percentage of smear-positive patients out of the total 100%
number of patients who had a sputum smear. Depends on the context
Detection rate of MDR-T B < 20%
Depends on the context

Diagnosis of smear- Automated molecular test Yes

negative PTB and EP Culture or molecular techniques Yes
forms X-rays Yes
Others (e.g. ADA, Pandy, Rivalta, FNAC) Yes
Algorithms used Yes

DST DST possible (methods, quality control) Detection of DR-T B

Treatment support Number of patients receiving treatment support/month 100% of those eligible for support

Identification of non- System for identifying and looking for non- adherent Yes
 adherent patients patients > 90%
Percentage of patients who resumed treatment among
those missing for less than 2 months who had to be
looked for

Integrated TB/HIV care Access to voluntary counselling and testing (VCT ) Yes
Access to ART Yes
Access to cotrimoxazole prophylaxis Yes
HIV treatment integrated in the T B service (or T B Yes
treatment in the HIV service)

17.5.2 Procedures
 Criteria Indicators Goals

Registers/records Description of the documents Records reliable

Consistency between T B registers and 100%
treatment cards 100%
Consistency between T B register and lab
registers

Standard case definitions Percentage of patients with exact case 100%

definition out of a randomized sample of
patients

Adequate standard treatment regimens and Percentage of new cases correctly > 95%
follow-up treated (combinations, dosage, duration) < 10%
out of a randomized sample of patients < 10%
Percentage of patients who did not have
bacteriological follow-up according to
schedule out of a randomized sample of
patients
Percentage of MDR-T B patients who did
not have biochemistry tests according to
schedule out of a randomized sample of
patients

HIV testing Percentage of new cases tested for HIV 100%

ART Percentage of HIV-positive T B cases started 100%

on ART
ART started within:
< 2 weeks; 2 weeks-< 2 months; ≥ 2 months

Criteria for cure Percentage of confirmed cases declared > 90%

cured who actually met the definition of cure
out of a randomized sample of patients

Regular monitoring of drug-susceptible TB Quarterly report and cohort analysis for Quantitative data on
and DR-TB drug-susceptible T B inclusions and results
Bi-annual report and cohort analysis for collected
DR-T B Rapid detection of
potential problems

Adherence monitoring Percentage of patients coming in for their > 90% in both the
appointment out of number of patients intensive and
expected continuation phases
Percentage of doses given under DOT for 100%
DR-T B treatment in a randomized sample
of patients

Prevention of M. tuberculosis airborne Isolation Isolation of smear

transmission in TB facilities Building ventilation, lights, UV lamps positive patients
(hospital wards, outpatient clinics, Isolation of DR smear
laboratory); respirators for staff and positive patients
visitors in contact with contagious
 patients; masks for contagious patients (if Appropriate use of
they move about) means
Written prevention plan? Yes
Person in charge identified? Yes

Standard precautions Description Standard precautions

followed

Laboratory quality control Regular evaluation of laboratory Ensure the quality of

functioning laboratory analyses for
Quarterly EQA of smear microscopy bacteriological diagnosis
Annual EQA of DST Results according to
standards
Results according to
standards

17.5.3 Human resources

Criteria Indicators Goals

Staff Job descriptions (doctors, nurses, lab technicians, On average:

cleaning staff, etc.) One nurse for 10-15
Medical staff-to-patient ratio patients
One doctor for 40-50
patients

Training Refer to training programme evaluation criteria Competent staff

Other contributors Description: other NGOs, local associations, etc.

A grid for evaluating T B clinic operations can be found in Appendix 35. Each criterion is rated either “satisfactory” or
“unsatisfactory”.
Appendices
Appendix 1. Xpert assays

Appendix 2. Interpretation of Xpert assay results

Appendix 3. Sputum specimen: collection, storage and shipment

Appendix 4. Sputum smear microscopy

Appendix 5. T ime required for diagnostic test results

Appendix 6. Ventilated work station (VWS) and bio-safety cabinet (BSC)

Appendix 7. Lymph node fine needle aspiration

Appendix 8. Protein estimation

Appendix 9. Tuberculin skin test

Appendix 10. Drug information sheets and patient instructions for the treatment of tuberculosis
Tuberculosis drug information sheets

Amikacin (Am)

Amoxicillin/clavulanic acid ratio 4:1 (Amx/Clv)

Bedaquiline (Bdq)

Clofazimine (Cfz)

Cycloserine (Cs) or terizidone (Trd)

Delamanid (Dlm)

Ethambutol (E)

Ethionamide (Eto) or prothionamide (Pto)

Imipenem/cilastatin (Ipm/Cln)

Isoniazid - Standard dose (H)

Isoniazid - High dose (Hh)

Levofloxacin (Lfx)

Linezolid (Lzd)

Meropenem (Mpm)

Moxifloxacin (Mfx)

Para-aminosalicylate sodium (PAS)

Pretomanid (Pa)

Pyrazinamide (Z)

Rifabutin (Rfb)

Rifampicin (R)

Rifapentine (P)

Streptomycin (S)
Patient instructions
Patients on drug-susceptible T B treatment

Patients on drug-resistant T B treatment

Appendix 11. Use of tuberculosis drugs in pregnant or breastfeeding women

Appendix 12. Dose adjustments in renal insufficiency

Appendix 13. Daily dose of tuberculosis drugs using fixed-dose combinations

Appendix 14. Monitoring of patients on drug-susceptible tuberculosis treatment

Appendix 15. Monitoring of patients on drug-resistant tuberculosis treatment

Appendix 16. Additional investigations in drug-resistant tuberculosis

Appendix 16. Basic T B infection control risk assessment tool

Appendix 17. Management of adverse effects

Gastrointestinal disorders

Abdominal pain

Diarrhoea

Epigastric pain

Hepatotoxicity

Metallic taste

Nausea and vomiting

Neurotoxicity

Depression

Headache

Optic neuritis

Ototoxicity

Peripheral neuropathy

Psychosis

Seizures
Endocrine disorders

Gynecomastia

Hypothyroidism
Dermatological disorders

Alopecia

Fungal infection

Photosensitivity

Skin reactions
Musculoskeletal disorders

Arthralgias

Tendinitis/tendon rupture
Miscellaneous
Electrolyte disorders

Haematologic disorders

Lactic acidosis

Nephrotoxicity

QT prolongation

Appendix 17. Air change per hour (ACH) measurement recommendations

Appendix 18. Compassionate use

Appendix 18. Advantages and disadvantages of ventilation techniques

Appendix 19. Drug interactions and overlapping toxicities

Appendix 19. Upper room ultraviolet germicidal irradiation (UVGI) system

Appendix 20. Treatment supporters

Appendix 21. Patient therapeutic education

Appendix 23. Treatment card for patients on first-line anti-T B therapy

Appendix 24. Tuberculosis register for patients on first-line anti-T B therapy

Appendix 25. Treatment card for patients on second-line anti-T B therapy

Appendix 26. Tuberculosis register for patients on second-line anti-T B therapy

Appendix 27. Respirators

Appendix 28. Surgical masks

Appendix 28. Request form for sputum culture, LPA and DST

Appendix 29. BCG vaccine

Appendix 29. Sputum smear microscopy register

Appendix 30. Xpert MT B/RIF register

Appendix 31. Drug-o-gram

Appendix 32. Quaterly report

Appendix 33. Report on detection and enrolment of T B cases with rifampicin and multidrug-resistance

Appendix 34. Request form for smear microscopy and Xpert assays

Appendix 34. Report of final outcomes of drug-resistant tuberculosis

Appendix 35. Check-list for the evaluation of a T B service

Appendix 1. Xpert assays
Update: October 2022

1.1 Specimen processing

Staff members present during specimen preparation should wear a respirator (FFP2 or N95) to prevent the inhalation of bacilli.
A biosafety cabinet (Appendix 6) should be used to protect staff from aerosols when the specimen is to be centrifuged or
cut/ground.

1.1.1 Sputum specimens

See Xpert MT B/RIF package insert:
https://www.cepheid.com/Package%20Insert%20Files/Xpert-MT B-RIF-ENGLISH-Package-Insert-301-1404-Rev-G.pdf

See Xpert MT B/XDR package insert:

https://www.cepheid.com/Package%20Insert%20Files/Xpert%20MT B-XDR%20ENGLISH%20Package%20Insert%20302-
3514%20Rev%20C.pdf

1.1.2 Lymph node and other tissue specimens

If the Xpert assay is performed on a biopsy (adapted from WHO) [1] :

Cut the tissue specimen in small pieces in a sterile mortar (or grinder).
Add 2 ml of sterile phosphate buffer saline (PBS).
Grind solution of tissue and PBS to obtain a homogeneous mixture.
Transfer 0.7 ml of mixture into a centrifuge tube using a transfer pipette. Avoid transferring clumps that are not well
homogenized.
Add 1.4 ml of Xpert Sample Reagent (XSR) using a transfer pipette.
Shake vigorously 10 to 20 times or vortex for at least 10 seconds.
Keep at room temperature for 10 minutes.
Shake vigorously 10 to 20 times or vortex for at least 10 seconds.
Keep at room temperature for 5 minutes.
Transfer 2 ml of the mixture to the Xpert cartridge using a transfer pipette.
Load the cartridge into the Xpert instrument as per the manufacturer’s instructions.

If the Xpert assay is performed on a lymph node specimen obtained by fine needle aspiration (FNA):

Flush the needle and syringe into a sterile container containing 1 ml of sterile 0.9% sodium chloride or sterile PBS.
Transfer 0.7 ml of mixture into a centrifuge tube using a transfer pipette.
Add 1.4 ml of XSR using a transfer pipette.
For the next steps, continue as above.

For lymph node fine needle aspiration technique see Appendix 7.

1.1.3 Cerebrospinal fluid specimens

Adapted from WHO [1]

T he processing method for cerebrospinal fluid (CSF) depends on the volume available for testing.
 Volume of
Procedure
CSF

0.1 to 1 ml Add XSR to the CSF to obtain a final volume of 2 ml.

Transfer 2 ml of the mixture into the Xpert cartridge.
Load the cartridge into the Xpert instrument as per the manufacturer’s instructions.

1 to 5 ml Add an equal volume of XSR to the CSF.

Add 2 ml of the mixture directly into the Xpert cartridge.
Load the cartridge into the Xpert instrument as per the manufacturer’s instructions.

> 5 ml Centrifuge the CSF at 3,000g for 15 minutes.

Pour the supernatant and add XSR to the sediment to obtain a final volume of 2 ml.
Transfer 2 ml of the mixture into the Xpert cartridge.
Load the cartridge into the Xpert instrument as per the manufacturer’s instructions.

Note: a volume of CSF less than 0.1 ml is insufficient for testing.

1.1.4 Stool specimens [2]

Stool specimens can be used within 3 hours if kept at room temperature.
Add 0.8 to 1 g of stool into the 8 ml XSR bottle.
Shake vigorously for 30 seconds.
Keep at room temperature for 10 minutes.
Shake vigorously for 30 seconds.
Sediment at room temperature for 10 minutes.
Without disturbing the sediment, transfer 2 ml of the supernatant into the Xpert cartridge.
Load the cartridge into the Xpert instrument as per the manufacturer’s instructions.

1.1.5 Urine specimens [3]

Urine specimens can be used within 3 hours if kept at room temperature.
Centrifuge 4 ml of urine at 3,000g for 5 minutes.
Pour the supernatant and add 2 ml of XSR to the sediment.
Shake vigorously.
Transfer 2 ml of the mixture into the Xpert cartridge.
Load the cartridge into the Xpert instrument as per the manufacturer’s instructions.

1.2 Diagnostic accuracy of Xpert in specimens other than sputum

 Performances of Xpert MTB/RIF
Specimens
compared to culture [4]

Lymph node biopsy or aspirate Biopsy: sensitivity: 82%; specificity: 79%

Aspirate: sensitivity: 89%; specificity: 86%

CSF Sensitivity: 70%; specificity: 97%

Pleural fluid Sensitivity: 50%; specificity: 99%

Pericardial fluid Sensitivity: 67.6%; specificity: 99.4%

Nasopharyngeal aspirate (children with suspected PT B) Sensitivity: 46%; specificity: 100%

Gastric aspirate (children with suspected PT B) Sensitivity: 73%; specificity: 98%

Stool (children with suspected PT B) Compared to respiratory specimens' culture:

No HIV infection: sensitivity: 61%; specificity: 98%
HIV infection: sensitivity: 70%; specificity: 98%

Urine (suspected genitourinary T B) Sensitivity: 85%; specificity: 97%

Urine (HIV patients with suspected disseminated T B) Sensitivity: 40%; specificity: 98% [5]

Synovial fluid Sensitivity: 97%; specificity: 94%

Peritoneal fluid Sensitivity: 59%; specificity: 97%

Blood (HIV patients with suspected disseminated T B) Child: sensitivity: 7%; specificity: 99% [6]
Adult: sensitivity: 56%; specificity: 94%

Note: the performances of Xpert MT B/XDR in non-sputum specimens are considered similar to those of Xpert MT B/RIF as the
tests are based on similar technologies. [4]

1.3 Logistic requirements

All Xpert assays are performed with the same instrument.
T he 10-colour module can read all Xpert cartridges.
T he 6-colour module can read Xpert MT B/RIF and Xpert MT B/RIF Ultra cartridges.

1.3.1 Power supply

T he instrument requires a constant and stable power supply.
If power cuts are short (less than 10 minutes), use a 1500VA "on line" UPS.
If power cuts are long, the system must be able to sustain a full cycle (approximately 45 minutes). Use a battery charger, a
stationary battery, and a voltage stabilizer.

1.3.2 Storage and operating temperatures

Storage of cartridges and reagents: between 2 and 28 °C for 12 months from date of manufacture.

Operating temperature for the Xpert instrument: between 15 and 30 °C. According to climate conditions, air conditioning may be
required.
1.3.3 Calibration
T he Xpert modules require annual calibration performed by an authorized service provider or carried out by swapping out the
modules. A detailed contract with the supplier should guarantee regular maintenance, calibration, repair, and replacement as and
when needed.

1.3.4 Required space

T he dimensions of the Xpert IV instrument (4 modules enabling the processing of 4 specimens at the same time) are:
Width: 29.8 cm; height 35.6 cm; depth 31.1 cm; weight: 12 kg.

T he instrument is designed for indoor use only. Provide at least 5 cm of clearance on each side to ensure adequate ventilation. Do
not place the instrument close to the vents of other instruments or air-handling units.

T he dimensions of the kits containing cartridges and reagents are:

Xpert MT B/RIF kit 50 tests: 31 cm x 28 cm x 20 cm
Xpert MT B/XDR kit 10 tests: 24 cm x 16 cm x 7 cm

1.3.5 Waste disposal

Same procedure as for sputum containers.
Xpert assays generate large volumes of waste.

References
1. World Healt h Organizat ion. Xpert MTB/RIF implementation manual: technical and operational ‘how-to’; practical considerations. Geneva;
2014. ht t ps://apps.who.int /iris/bit st ream/handle/10665/112469/9789241506700;jsessionid=44788E3067C3F9DBF836E8BB6BB0F253?
sequence=1

2. de Haas P, Yenew B, et al. The Simple One-Step (SOS) Stool Processing Method for Use with the Xpert MTB/RIF Assay for a Child-Friendly
Diagnosis of Tuberculosis Closer to the Point of Care . J Clin Microbiol. 2021 Jul 19;59(8).
ht t ps://www.ncbi.nlm.nih.gov/pmc/art icles/PMC8373220/

3. MSF Sout h Af rica Medical Unit . SOP: Urine GeneXpert MTB/Rif Assay.
ht t ps://samumsf .org/sit es/def ault /files/2018-01/2.%20Urine%20GeneXpert %20MTB-Rif %20Test ing%20SOP_0.pdf

4. World Healt h Organizat ion. WHO consolidated guidelines on tuberculosis. Module 3: diagnosis - rapid diagnostics for tuberculosis detection.
2021 updat e. Geneva; 2021.
ht t ps://www.who.int /publicat ions/i/it em/9789240029415

5. World Healt h Organizat ion. Rapid communication on updated guidance on the management of tuberculosis in children and adolescents.
Geneva: World Healt h Organizat ion; 2021.
ht t ps://apps.who.int /iris/rest /bit st reams/1365106/ret rieve

6. Pohl C, Rut aihwa LK, Haraka F, Nsubuga M, Aloi F, Nt inginya NE, Mapamba D, Heinrich N, Hoelscher M, Marais BJ, Jugheli L, Reit her K.
Limited value of whole blood Xpert(®) MTB/RIF for diagnosing tuberculosis in children. J Inf ect . 2016 Oct ;73(4):326-35.
ht t ps://www.journalofinf ect ion.com/art icle/S0163-4453(16)30161-X/f ullt ext
Appendix 2. Interpretation of Xpert assay results
Update: October 2022

2.1 Xpert MTB/RIF and Xpert MTB/RIF Ultra

MT B: M. tuberculosis; RIF: rifampicin
 Results Interpretation and decisions

Invalid/Error/No result Perform a 2nd test on a new specimen.

MT B not detected Child with suspected PT B: perform a 2nd test on a new (respiratory or stool) specimen.
Adult: re-evaluate clinically, perform x-ray if indicated, perform a 2nd test and/or a
culture on a new specimen.

MT B detected Treat for DS-T B.

No RIF resistance detected Perform Xpert MT B/XDR, LPA or pDST to detect H resistance (a) ; adjust treatment
according to DST.

MT B detected Evaluate risk factors for rifampicin resistance (RR):

RIF resistance detected High risk of RR (b) : treat for MDR/RR-T B.
Low risk of RR (c) : perform a 2nd test on a new specimen(d) . If 2nd test shows:
R susceptibility: treat for DS-T B.
R resistance: treat for MDR/RR-T B.

For patients with MDR/RR-T B, perform:

Xpert MT B/XDR or LPA and pDST or genome sequencing for resistance to other T B
drugs.
Culture and pDST for treatment monitoring.
If discordant results with pDST (R resistance with Xpert, R susceptibility with pDST ):
treat for MDR/RR-T B [1] .

MT B detected Xpert MT B/RIF:

RIF resistance indeterminate Perform a 2nd test on a new specimen. If still “indeterminate”, treat for DS-T B
while investigating RR.
Perform pDST or other gDST to confirm or rule out RR.
Perform Xpert MT B/XDR, LPA or pDST to detect H resistance (a) .
Xpert MT B/RIF Ultra:
Send an extraction of the raw results (gxx file) to a reference laboratory for
identification of possible mutations (interpretation of melting curves).
If not feasible or still “indeterminate”: proceed as for Xpert MT B/RIF.

MT B detected “trace” HIV-infected patients, children and EP specimens: a “trace” result should be
RIF resistance indeterminate considered as positive.
(Xpert Ultra) Adults with history of T B in the previous 5 years: a “trace” result cannot be interpreted,
culture should be performed.
No interpretation of RR is possible.
If suspected resistance to R or other T B drugs: perform pDST or other gDST. Adjust
treatment according to DST.
Do not test the specimen with Xpert MT B/XDR as the Xpert MT B/XDR has a higher
detection limit than Ultra.

(a) For all pat ient s if possible, and at least t hose wit h high risk of H resist ance (pat ient s wit h previous TB t reat ment wit h H, or cont act wit h
a TB case resist ant t o H, or f rom an area wit h a prevalence of resist ance t o H ≥ 3%).
(b) Pat ient s wit h previous TB t reat ment wit h R, or cont act wit h a TB case resist ant t o R, or f rom an area of high prevalence of resist ance t o
R.
(c) Pat ient s wit h no previous TB t reat ment wit h R, or cont act wit h a TB case resist ant t o R, and f rom an area of low prevalence of
resist ance t o R.
(d) A 2n d t est is necessary because in a populat ion wit h a prevalence of resist ance t o rif ampicin < 5%, t he posit ive predict ive value of one
t est is < 80%, i.e. > 20% of rif ampicin resist ant result s are f alse posit ive.
2.2 Xpert MTB/XDR
MT B: M. tuberculosis; RIF: rifampicin; INH: isoniazid; FLQ: fluoroquinolones; ET H: ethionamide; AMK: amikacin; KAN: kanamycin;
CAP: capreomycin

Results Interpretation and decisions

Invalid/Error/No result Perform a 2nd test on a new specimen.

MT B detected After a positive Xpert MT B/RIF, an “MT B detected” result is expected because Xpert
MT B/XDR and Xpert MT B/RIF have similar detection limit.

MT B not detected After a positive Xpert MT B/RIF: perform a 2nd test on a new specimen. If the 2nd test
No resistance detected is negative, it can be performed on culture isolates.
After a “trace” result with Ultra, a negative result is expected because the Xpert
MT B/XDR has a higher detection limit than Ultra.

MT B detected Treat according to the result of Xpert MT B/RIF or Ultra.

No resistance detected Resistance cannot be ruled out because other resistance-conferring mutations are
not detected by Xpert MT B/XDR (e.g. only 30% of Eto resistance conferring
mutations are detected).
Perform pDST for resistance to other T B drugs and monitor treatment.

MT B detected Evaluate risk factors of resistance for each drug:

Low INH resistance detected High risk of resistance (e) : consider as resistant to the drug.
INH resistance detected If low-level H resistance detected (inhA mutation and no katG mutation): Hh can be
Low FLQ resistance detected used, but not counted as a likely effective drug.
FLQ resistance detected If low-level resistance to FQs detected: Mfxh can be used, but not counted as a
ET H resistance detected likely effective drug [2] .
AMK, KAN and/or CAP Resistance to Eto can be detected (inhA mutation). However, a negative result
resistance detected does not rule out resistance.
Perform pDST for resistance to other T B drugs and monitor treatment.
Low risk of resistance (f) : perform a 2nd test on a new specimen(g) . If the 2nd test
shows:
Drug susceptibility: treat with the drug.
Drug resistance: consider as resistant (see above for “High risk of resistance to the
drug).

MT B detected Perform a 2nd test on a new specimen. If still “indeterminate”: treat with likely effective
Drug resistance indeterminate (h) drug(s) while investigating resistance with pDST or other gDST (second-line LPA, genome
sequencing).

(e) Pat ient s wit h previous TB t reat ment wit h t he drug or cont act wit h a TB case resist ant t o t he drug, or f rom an area of high prevalence of
resist ance t o t he drug.
(f ) Pat ient s wit h no previous TB t reat ment wit h t he drug or cont act wit h a TB case resist ant t o t he drug, and f rom an area of low
prevalence of resist ance t o t he drug.
(g) A 2n d t est is necessary because in a populat ion wit h a prevalence of resist ance < 5%, t he posit ive predict ive value of one t est is < 80%
(i.e. > 20% of resist ant result s are f alse posit ive).
(h) No “indet erminat e” result is given f or Et o.

References
1. World Healt h Organizat ion. Xpert MTB/RIF implementation manual: technical and operational ‘how-to’; practical considerations. Geneva
 2014. ht t ps://apps.who.int /iris/bit st ream/handle/10665/112469/9789241506700;jsessionid=44788E3067C3F9DBF836E8BB6BB0F253?
sequence=1

2. World Healt h Organizat ion. WHO operational handbook on tuberculosis. Module 4: treatment - drug-resistant tuberculosis treatment. Geneva
2020.
ht t ps://www.who.int /publicat ions/i/it em/9789240006997
Appendix 3. Sputum specimen: collection, storage
and shipment
3.1 Sputum collection techniques
Regardless the collection technique used, staff member present during sputum collection should wear a respirator to prevent
bacilli inhalation.

3.1.1 Sputum obtained spontaneously

Two specimens are to be collected. When possible, specimens should be collected outside in the open air and far away from other
people.
T he first sample is collected on the spot, at the consultation, when the patient is identified as suspected T B case. If the patient
has recently eaten, ask him/her to rinse his/her mouth with water in order to avoid the presence of food in the sample.
T he second sample is collected the day after, in the early morning, right after the patient wakes up and before eating. T he second
sample may be collected at home then the patient brings it to the health facility.
Alternatively, two sputum specimens can be collected one hour apart (frontloaded microscopy).

Collection technique:
T he patient must be given a labelled sputum container (or a Falcon® tube, if the sample is to be shipped by air).
Have the patient take a deep breath, hold for a few seconds, exhale, repeat two or three times, then cough: sputum is material
brought up from the lungs after a productive cough. One or two minutes of chest clapping are of benefit.
Collect at least 3 ml and close the container hermetically.

T he quality of sample determines the reliability of the result. Always check that the sample contains solid or purulent material and
not only saliva. Take a new sample if unsatisfactory.

If the sample is collected at home, make sure that the patient has understood the technique, including closing the container
hermetically after collecting the sputum.

3.1.2 Sputum induction

Sputum induction is sometimes used in children when sputa cannot be spontaneously expectorated, and only in order to perform
cultures or Xpert MT B/RIF.
Sputum induction must be performed under close medical supervision. T he child should be observed for respiratory distress during,
and for 15 minutes after, the procedure. Bronchospasm may occur. Salbutamol spray and oxygen must be ready at hand.

Equipment
Gloves and respirator
Suction catheter (6, 7, 8F)
Sputum container
50 ml syringe, needle
Mask and tubing for nebulizer
Holding chamber with child’s mask (to be sterilized between each patient)
Sterile hypertonic solution of 5% sodium chloride (to be kept refrigerated)
Sterile solution of 0.9% sodium chloride (for the specimen)
Salbutamol spray
Oxygen

Procedure
T he child should fast for at least 2 hours before the procedure.
 Prior to nebulization:
Explain the procedure to the child and/or the person accompanying him/her (this person must wear a respirator).
Place the child in a sitting position in the adult’s arms.
Administer 2 puffs of salbutamol via a holding chamber, 10 minutes before nebulization.
Prepare a sputum container.
Nebulization:
Fill the nebulizer with 5 ml of 5% hypertonic saline solution (sputum inducer).
Place the nebulizer mask over the child’s mouth.
Leave the child to inhale until the reservoir is empty.
Nasopharyngeal suction:
Do 1 to 2 minutes of clapping.
Clean out the nasal cavity.
During suction, the child is laid on his /her side, back to the operator, who is behind him/her.
Fit a suction catheter to a 50 ml syringe. Lubricate the end of the catheter.
Measure the distance from the tip of the nose to the angle of the jaw. Insert the suction catheter to that depth.
When inserting and withdrawing the tube, pull on the plunger of the syringe to create suction.
Once the syringe is filled with air and mucus, disconnect it from the suction catheter and purge the air (tip facing upward), so
that only mucus is left in the syringe.
To collect the mucus: draw 2 ml of 0.9% sodium chloride into the syringe to rinse, then empty contents into the sample
container.

3.1.3 Gastric aspiration

Gastric aspiration is sometimes used in children when sputa cannot be spontaneously expectorated nor induced using hypertonic
saline, and only in order to perform cultures or Xpert MT B/RIF.

Equipment
Gloves and respirator
Suction catheter (6, 7, 8F)
Sputum container
50 ml syringe
Sterile water

Procedure
Prior to inserting the suction catheter:
Explain the procedure to the child and/or the person accompanying him/her (this person must wear a respirator);
Place the child in a half-sitting or sitting position in the adult’s arms.
Insert a nasogastric tube and check that it is correctly placed.
First suction to collect the gastric fluid and place it in the sputum container, then rinse the stomach with 30 ml of sterile water
and suction again. Add the suctioned fluid to the first sample.
Start culture within 4 hours of collecting the sample. If there will be more than four hours’ delay, neutralize with 100 mg of
sodium bicarbonate.

3.2 Sputum specimen storage

When examinations are not performed on the site of collection:

Specimen for smear microscopy

Smears should be performed within three-four days of collection and in the meanwhile stored refrigerated (2 to 8 °C) and protected
from light.
Contamination does not affect microscopy but heat make specimen liquefy, with selection of mucopurulent part of the sample
more difficult.

Specimen for culture in liquid medium

Keep the specimen refrigerated (2 to 8 °C), protected from light. Do not use cethylpyrodinium chloride (CPC) as it is not compatible
with MGIT.
T he specimen should be processed as soon as possible.

Specimen for culture on Lowenstein-Jensen medium (LJ)

Specimens that can be cultured in less than 3 days after collection:
Keep refrigerated (2 to 8 °C) and protected from light until transport OR immediately transport to the laboratory for processing.

Specimens that will be cultured more than 3 days after collection:

Use Falcon tubes and add 1% CPC to preserve the specimen for up to 2 weeks. Specimens with CPC should not be
refrigerated, as the CPC will crystallize and be ineffective.
Samples with CPC can be inoculated on LJ. For inoculation on agar, they require prior neutralization by neutralizing buffer
(Difco®).
CPC can be used for specimens tested by Xpert MT B/RIF.

3.3 Sputum specimen shipment

To a local laboratory
Without CPC transport medium: between 2 and 8 °C and protected from light;
With CPC transport medium: should not be refrigerated because at low temperatures the CPC will crystallize and ruin the
sample. Specimens should be kept at room temperature, protected from heat and light.

By air to a reference laboratory for culture

Samples are collected and shipped in 50 ml Falcon® conical tubes with screw caps. T he tubes are labelled UN 3373,
corresponding to Category B infectious substances. If transport times are less than 12 hours, even specimens without CPC can be
transported at room temperature.

Samples are triple-packaged, in accordance with IATA packing instruction 650:

1. Primary container holding the sputum sample: tube tightly closed and placed into a latex glove;
2. Secondary container intended to protect the primary container: leak-proof box with enough absorbent material to absorb the
entire sample, should the primary container break;
3. Outer packaging intended to protect the secondary container, with UN 3373 labelling.

Information to be provided:
Primary container: label with the patient’s name or identification number and the sample collection date and location;
Outer package: indicate the name of the receiving laboratory, the complete address (name, street, postal code, locality,
country), and telephone number.
All samples must be accompanied by the corresponding laboratory test request form (including clinical information).

Notes:
Procedures for shipping bacterial strains obtained after culture are different, more complicated, and rarely feasible in practice.
Cultures are classified as Category A infectious substances (UN 2814).
For a detailed description of the shipment procedures, see MSF Medical catalogue, volume 4.
Appendix 4. Sputum smear microscopy
Update: January 2022

4.1 Sputum smear preparation

Staff members present during sputum smear preparation should wear a respirator to prevent the inhalation of bacilli.
Sputum smears should be prepared promptly after sputum collection.

Equipment
Gloves
Respirator (FFF2 or N95)
New, clean glass slides (never re-use sputum smear slides)
Wooden applicator sticks

Technique
Label one end of the slide with the date of sputum collection and laboratory serial number.
Select a mucopurulent or blood-stained portion of the sputum specimen.
Use an applicator stick to transfer to the slide.
Smear the specimen over an area of 1.5 to 2 cm x 2 to 3 cm. Make it thin enough to be able to read through it.
Allow the smear to air dry for 15 minutes. Do not dry the smear in direct sunlight or over a flame.
Fix the smear by passing the underside of the slide through a flame for 2 to 3 seconds. Repeat 3 or 4 times.
Allow to cool before staining.

4.2 Ziehl-Neelsen staining

Equipment
Gloves
Distilled or filtered water
0.3% carbol fuchsin
3% acid-alcohol
0.3% methylene blue
Binocular microscope with oil immersion objective (100x magnification)

Technique
Flood the slide with 0.3% carbol fuchsin (after filtering the carbol fuchsin).
Gently heat the underside of the slide. Begin timing as soon as steam appears. Let it steam for 5 minutes. Do not let the stain
boil or dry.
Gently rinse the slide until the water runs clear, then drain off excess water.
Flood the slide with 3% acid-alcohol for 2 to 3 minutes, then drain. Repeat this operation if the slide is not
completely decolourised.
Gently rinse the slide, then drain off excess water.
Flood the slide with 0.3% methylene blue for one minute, then drain.
Gently rinse the slide until the water runs clear, then drain off excess water.
Allow to air dry. Do not wipe or blot.

Reading
T he slides should be examined by an experienced technician. Technicians must be given sufficient time to accurately read slides.
Before reading the slide, apply a drop of immersion oil to the left edge of the stained smear. Do not touch the slide with the
immersion oil applicator (risk of AFB transfer into the oil bottle and onto another slide).
 Examine at least one length (100 high power fields, HPF) before giving a negative result (this should take at least 5 minutes).
AFB are red, straight or slightly curved rods. T hey may be found singly or in small groups. T he background stains blue.

Reporting
Table 4.1 - Grading AFB scale (WHO-IUAT LD) [1]

Number of AFB
Reporting
(1000x magnification: one length = 100 HPF)

Zero AFB/one length No AFB

1-9 AFB/one length or 100 HPF Report exact number of AFB

10-99 AFB/one length or 100 HPF 1+

1-10 AFB/one HPF in at least 50 fields 2+

> 10 AFB/one HPF in at least 20 fields 3+

Note: 1-9 AFB in 100 HPF is a positive result. Note that 1-9 AFB in 100 HPF is reported as “scanty” followed by the exact number
of AFB seen in 100 HPF (e.g. “scanty 3” means there are 3 AFB in 100 HPF). Do not confuse "scanty 3" (3 AFB in 100 HPF) with
AFB 3+ (more than 10 AFB per HPF).

4.3 Auramine O or auramine/rhodamine staining

Equipment
Gloves
Distilled or filtered (not chlorinated) water
0.1% auramine O or auramine/rhodamine solution
0.5% acid alcohol
0.5% potassium permanganate or 0.3% methylene blue
Fluorescence microscope (or a LED device that can be attached to a standard light microscope)

Technique
Flood the slide with auramine O or auramine/rhodamine solution for 15 minutes. Ensure that the staining solution remains on the
smear.
Gently rinse, then drain off excess water. Do not use chlorinated water to avoid disturbing the fluorescence reading.
Flood the slide with 0.5% acid-alcohol for one minute, then drain.
Gently rinse, then drain off excess water.
Flood the slide with 0.5% potassium permanganate solution or 0.3% methylene blue for one minute, then drain.
Gently rinse, then drain off excess water.
Allow to air dry. Do not wipe or blot.

Note: to control the quality of the colouration include at least one known positive smear in the batch.

Reading
T he slides should be examined by an experienced technician (artefacts are frequent). Technicians must be given sufficient time
to read slides.
Use a 20x objective to screen the smear.
Examine one length before giving a negative result.
Always read the positive control smear first. If the positive control is not positive do not continue with the patient smears, but
re-stain the batch.
 AFB are bright yellow, straight or slightly curved rods. T hey may be found singly or in small groups. T he background is dark. Non-
specific debris stains pale yellow.

Reporting
Table 4.2 - Grading AFB scale (WHO-IUAT LD) [1]

Number of AFB
Reporting
(200-250x magnification: one length = 300 HPF)

Zero AFB/one length No AFB

1-29 AFB/one length Report exact number of AFB

30-299 AFB/one length 1+

10-100 AFB/one field on average 2+

> 100 AFB/one field on average 3+

Notes:

1-29 AFB per length is a positive result. Note that 1-29 AFB per length is reported as “scanty” followed by the exact number of
AFB seen per length (e.g. “scanty 3” means there are 3 AFB per length). Do not confuse "scanty 3" (3 AFB per length) with AFB
3+ (more than 100 AFB per field).

T he fluorescence stain remains stable when sheltered from light for only 3 days. Quality control should be done within this time.

References
1. European Cent re f or Disease Prevent ion and Cont rol. Handbook on tuberculosis laboratory diagnostic methods in the European Union –
Updated 2018. St ockholm: ECDC; 2018.
ht t ps://www.ecdc.europa.eu/sit es/port al/files/document s/TB-handbook-updat ed-2018.pdf
Appendix 5. Time required for diagnostic test results

Update: October 2022

Estimated time for results Additional time for DST

Xpert MTB/RIF 110 minutes –

Xpert MTB/RIF Ultra < 80 minutes –

Xpert MTB/XDR < 90 minutes –

Truenat 35 minutes (Truenat MT B) 1 hour (Truenat MT B-RIF Dx)

Culture liquid medium 8 days (smear+) 2 weeks

(MGIT ) 16 days (smear−)

Culture solid medium 16 days (smear+) 6 weeks

LJ standard medium 29 days (smear–)

Culture microcolonies 14 days –

(T LA, MODS)

Smear microscopy 2 hours –

LPA 1 to 2 days (direct testing on smear+) –

GenoType MT BDRplus (V2.0) 21 days (indirect testing)

LPA 1 to 2 days (direct testing) –

GenoTypeMT BDRsl (V2.0) 21 days (indirect testing)

LF-LAM 25 minutes –

tNGS 1 to 3 days (direct testing on smear+) –

21 days (indirect testing)

WGS 21 days (indirect testing) –

Note: to provide negative results, cultures need to be incubated for 6 to 7 weeks on liquid media and 8 weeks on solid media.
Appendix 6. Ventilated work station (VWS) and bio-
safety cabinet (BSC)
6.1 Ventilated workstation (VWS)
T he VWS provides a safe work environment while preparing sputum smears for AFB staining and Xpert MTB/RIF. It is used when
adequate natural ventilation cannot be achieved. Designed to be placed over a bench, it is constituted by a rectangular box ducted
to the outside, where the duct is connected to an extraction fan.
VWS are used without filter and do not provide product protection. T hey should never be used for preparing cultures.

6.2 Class II BSC

A Class II BSC protects not only the operator and the environment, but also the material being manipulated inside the cabinet.
T he room air and the air circulating within the cabinet are drawn by a downward flowing current through a grate then, through a
HEPA filter, which protects both the operator and the product. T he air exiting the cabinet is filtered through a HEPA filter to protect
the environment.
Class II BSCs are required for performing cultures.

Notes:
Class I BSCs cannot be used for performing cultures and VWS are sufficient for preparing samples for microscopy and tests
Xpert MT B/RIF. T herefore, their use is not recommended in this manual.
Class III BSCs are generally not used for T B.
Appendix 7. Lymph node fine needle aspiration
FNAC is used to obtain material from lymph nodes. T he material is expressed onto slides and prepared for examination.
Two smears will be prepared with Giemsa staina to look for caseum, granuloma, giants cells, and epithelioid cells or histocytes and
1 or 2 will be prepared with Ziehl-Neelsen (ZN) stain to look for acid-fast bacilli (AFB).

Equipment
Needle 23G (in very few cases, it would be possible to use 19G)
10 ml syringe
2 slides for Giemsa + one or 2 slides for ZN stain
10% povidone iodine, sterile gauze, gloves

Technique
Disinfect the area.
With the needle attached to the syringe, insert the needle deep into the lymph node.
After the needle has entered the mass, pull back on the syringe plunger to create a vacuum.
Rapidly move the needle in a to-and-fro fashion to allow material entering the needle.
When blood or material appears in the needle hub the aspiration should be stopped. Try to aspirate as much as possible of
materials, the amount of materials that has been aspirated would have effect on the specificity and sensitivity of diagnosis.
Release the negative pressure before to take out the needle from the lymph node. Do not continue sucking while taking out the
needle, this will avoid aspiration of materiel into the barrel of the syringe and avoid mixing the sample with the possible peripheral
blood in the skin.

Slide preparation
Slide should be identified prior to the aspiration and prepared immediately after the aspiration.
Detach the needle from the syringe immediately after the aspiration.
Fill the syringe with air (needle is still detached).

Prepare the smear as follow:

Giemsa
Reattach the needle to the syringe and carefully release one small drop of sample onto one end of the slide by pushing down
the plunger of the syringe (if the drop is placed in the middle of slide it would be difficult to make smear afterwards).
Put another slide over the sample.
Slide the two slides against each other, in opposite directions, to spread the sample out completely between them. Do not
press the slides together forcefully, to avoid crushing the cells.
Allow to air dry.
Fix the smears by methanol when they are completely dry.
Proceed to Giemsa staining.
Ziehl-Neelsen
Place a small drop of ganglion aspirate on the slide.
Make a smear that is neither to thin or too thick.
Allow to air dry.
Fix the smear by flame when it is completely dry.
Proceed to ZN staining.

Reading after Giemsa staining

On each slide, one or several of the following aspects can be found:
Caseation necrosis (caseum): a uniform, acellular, pinkish substance.
Granuloma: cluster of epithelioid cells and lymphocytes scattered through out smear with or without caseous necrosis.
Epithelioid cells: elongated, often semi-lunar cells with a fine granular nuclear chromatin surrounded by pink cytoplasm.
 Giant cells: huge multinuclear cells.

Notes:
It would be better to look for granuloma and necrosis with the 10x and 40x power of microscope then to look for epithelioid
cells and giant cells with 100x power.
Observation of smear requires a competent reader with skills in cytology. Slides have to be sent to a referral cytopathology
laboratory for quality control or confirmation.
T he quality of the specimen and the preparation are essential. T he smear is to be done by skilled technicians.

Footnotes
(a) The golden st andard of diagnosis f or TB on t issue samples is hemat oxylin-eosin st ain, but Giemsa st ain can be used as an alt ernat ive in
remot e areas wit h limit ed equipment .
Appendix 8. Protein estimation
Update: January 2022

8.1 Pandy test

Pandy test is used to detect an increase of protein in the cerebrospinal fluid (CSF).
T he normal range of protein in CSF is 0.20 to 0.45 g/litre.
T he Pandy test is positive when protein is superior to 0.45 g/litre.

Equipment
Disposable gloves
Pandy reagent
Pasteur pipettes
Conical centrifuge glass tube or test tube
1 ml pipettes

Preparation of 500 ml of Pandy reagent

Pandy is a saturated phenol solution.
Weigh 30 g of phenol and transfer it into a 1000 ml bottle.
Add 500 ml of distilled water and shake vigorously.
Leave to stand for one 24 hours.
Check that some phenol remains undissolved:
If so, filter: the solution is ready.
If all the phenol has dissolved, add a further 10 g of phenol and wait another 24 hours before filtering.

Pandy reagent is a highly corrosive and toxic solution:

Label the bottle and mark it corrosive and poisonous.
Wash hands after preparation.

Technique
Place 1 ml of Pandy reagent in a centrifuge tube.
Add 3 drops of CSF, drop by drop.
After each drop, look for a white cloud in the tube.
To facilitate the reading, place a black surface behind the tube.

Results
Presence of a white precipitate: Pandy test
Absence of a white precipitate: Pandy test

8.2 Rivalta test

T he Rivalta test is used to detect an increase of protein in the body fluid (pleural fluid, ascites).
T he test is positive when the proteins are superior to 30 g/litre.

Equipment
Disposable gloves
Rivalta reagent
Pasteur pipettes
Conical centrifuge glass tube or test tube
5 ml pipette
Preparation of 100 ml of Rivalta reagent
Place 50 ml of distilled water in a 100 ml measuring cylinder.
With a 5 ml pipette, add 3 ml of glacial acetic acid and make up to the 100 ml mark with the remaining 50 ml of distilled water.
Transfer the solution into a bottle.

Technique
Place 2 ml of Rivalta reagent in a centrifuge tube.
Add 3 drops of pleural fluid/ascites, drop by drop.
After each drop, look for a white cloud in the tube.
To facilitate the reading, place a dark surface behind the tube.

Results
Presence of a white precipitate: Rivalta test positive.
Absence of a white precipitate: Rivalta test
Appendix 9. Tuberculin skin test
Update: January 2022

9.1 Introduction
A delayed hypersensitivity reaction occurs after an intradermal injection of tuberculin (tuberculin skin test, T ST ) in persons infected
by M. tuberculosis or vaccinated with BCG.

T he test is performed by injecting 5 international units of tuberculin (purified protein derivative, PPD) intradermally on the ventral
surface of the forearm (side of forearm exposed with palm facing up) a .

T he test, which should be performed by a trained healthcare worker, requires 2 visits. T he reading is done on the second visit, 48 to
72 hours after the tuberculin injection.
If the patient does not return within 72 hours, another T ST should be performed.

T he result is determined by the diameter of the reaction and individual characteristics of the person being tested (Table 9.1). It
should be recorded in millimetres, not as “positive” or “negative”.

T he reaction is the area of induration (swelling that can be felt) around the injection site.
Using a ruler, the diameter of induration is measured transversely. T he erythema (redness) around the indurated area is not the
reaction and should not be measured.
A reaction that appears several minutes, hours or even 24 hours after injection, but disappears on the day after its appearance, is
of no significance.

T here is no correlation between the diameter of the induration and:

likelihood of active T B,
risk of developing active T B,
protection against T B disease in vaccinated people.

9.2 Positive TST

A positive T ST signifies that a M. tuberculosis infection has occurred.
However, T ST cannot differentiate between active and latent infection.
A positive test supports the diagnosis of latent T B when other diagnostic tools have been used to rule out active T B.
In children, a positive T ST may be one element among many to establish the diagnosis of active T B.

Table 9.1 - Positive T ST results

 Diameter of
Individual characteristics
induration

HIV-infected persons
Severely malnourished children
≥ 5 mm
Patients taking corticosteroids (e.g. prednisolone ≥ 15 mg daily ≥ 1 month) or immunosuppressants
Recent contacts of T B patients
Persons with fibrotic changes on CXR consistent with prior T B

Persons from countries with high T B prevalence

Mycobacteriology laboratory personnel
Persons working and/or living in congregate settings, including healthcare facilities, prisons, homeless
shelters, etc. ≥ 10 mm
Children < 5 years
Children > 5 years and adolescents exposed to adults at risk of T B
Other at-risk categories (e.g. diabetes, injecting drug users, end-stage renal disease, leukemia, low
body mass index)

All other children and adults with no other risk factors or exposure to T B ≥ 15 mm

A highly positive (induration diameter > 20 mm) or phlyctenular reaction should be considered as an argument in favour of active T B
but is not enough to decide on treatment.

Some persons may have a positive T ST result even if they have not been infected with M. tuberculosis.
Causes of false positive results include:
Errors in tuberculin administration
Previous BCG vaccination
Infection with non-tuberculosis mycobacteria
Low specificity of T ST

BCG is given at birth so previous BCG vaccination has limited impact on the interpretation of T ST results, except in small children.
T he average diameter of the T ST reaction 1 year after BCG vaccination is 10 mm, with extremes ranging from 4 to 20 mm. T he
reaction becomes weaker over time and disappears 5 to 10 years post-vaccination.

9.3 Negative TST

Usually, a negative T ST result signifies that no M. tuberculosis infection has occurred. However, a negative T ST result does not
rule out T B infection.
Causes of false negative results include:
Errors in tuberculin administration
Recent viral illness or live virus vaccination (e.g. measles)
Severe T B disease (e.g. T B meningitis or miliary T B)
Recent (< 12 weeks) or very old (many years) T B infection
Immunodepression or a weak immune response (e.g. the very elderly, children < 5 years, malnutrition, patients taking
corticosteroids or immunosuppressants)
Persons with diseases that result in anergy (e.g. AIDS, haemopathy, sarcoidosis)
Natural extinction of post-vaccination reaction from the 5th year following BCG

Footnotes
(a) For more inf ormat ion on inject ion t echnique: WHO operat ional handbook on t uberculosis. Module 1: prevent ion - t uberculosis prevent ive
t reat ment . Geneva: World Healt h Organizat ion; 2020.
ht t ps://apps.who.int /iris/rest /bit st reams/1272664/ret rieve
Appendix 10. Drug information sheets and patient
instructions for the treatment of tuberculosis
Update: November 2022

Tuberculosis drug information sheets

Amikacin (Am)
Amoxicillin/clavulanic acid ratio 4:1 (Amx/Clv)
Bedaquiline (Bdq)
Clofazimine (Cfz)
Cycloserine (Cs) or terizidone (Trd)
Delamanid (Dlm)
Ethambutol (E)
Ethionamide (Eto) or prothionamide (Pto)
Imipenem/cilastatin (Ipm/Cln)
Isoniazid - Standard dose (H)
Isoniazid - High dose (Hh)
Levofloxacin (Lfx)
Linezolid (Lzd)
Meropenem (Mpm)
Moxifloxacin (Mfx)
Para-aminosalicylate sodium (PAS)
Pretomanid (Pa)
Pyrazinamide (Z)
Rifabutin (Rfb)
Rifampicin (R)
Rifapentine (P)
Streptomycin (S)
Patient instructions
Patients on drug-susceptible T B treatment
Patients on drug-resistant T B treatment
Tuberculosis drug information sheets
Update: November 2022

Amikacin (Am)
Amoxicillin/clavulanic acid ratio 4:1 (Amx/Clv)
Bedaquiline (Bdq)
Clofazimine (Cfz)
Cycloserine (Cs) or terizidone (Trd)
Delamanid (Dlm)
Ethambutol (E)
Ethionamide (Eto) or prothionamide (Pto)
Imipenem/cilastatin (Ipm/Cln)
Isoniazid - Standard dose (H)
Isoniazid - High dose (Hh)
Levofloxacin (Lfx)
Linezolid (Lzd)
Meropenem (Mpm)
Moxifloxacin (Mfx)
Para-aminosalicylate sodium (PAS)
Pretomanid (Pa)
Pyrazinamide (Z)
Rifabutin (Rfb)
Rifampicin (R)
Rifapentine (P)
Streptomycin (S)
Amikacin (Am)
Update: January 2022

Forms, strengths and route of administration

500 mg amikacin base in 2 ml ampoule (250 mg/ml), for IM injection

Dosage
Child and adult: 15 to 20 mg/kg once daily
Patient 60 years and over: 15 mg/kg 3 times a week
Maximum dose: 1000 mg daily
Renal insufficiency: 12 to 15 mg/kg 2 or 3 times a week
Weight Daily dose Daily dose (ml) - IM injection (a)
(kg) (mg) (500 mg in 2 ml = 250 mg/ml)

5 75-100 0.4 ml

6 90-120 0.4 ml

7 105-140 0.6 ml

8 120-160 0.6 ml

9 135-180 0.6 ml

10 150-200 0.8 ml

11 165-220 0.8 ml

12 180-240 0.8 ml

13 195-260 1 ml

14 210-280 1 ml

15 225-300 1 ml

16 240-320 1.2 ml

17 255-340 1.2 ml

18 270-360 1.2 ml

19 285-380 1.5 ml

20 300-400 1.5 ml

21 315-420 1.5 ml

22 330-440 1.5 ml

23 345-460 1.5 ml

24 360-480 1.5 ml

25 375-500 2 ml

26 390-520 2 ml

27 405-540 2 ml

28 420-560 2 ml

29 435-580 2 ml
 30-35 625 2.5 ml

36-45 750 3 ml

46-55 875 3.5 ml

56-70 1000 4 ml

> 70 1000 4 ml

(a) For doses less t han 1 ml, use a 1 ml syringe graduat ed in 0.01 ml.

Contra-indications, adverse effects, precautions

Do not administer to patients with hypersensitivity to aminoglycosides.
Administer with caution to patients 60 years and over or patients with pre-existing renal, vestibular, auditory or severe hepatic
impairment.
May cause:
nephrotoxicity, ototoxicity, electrolyte disturbances; rarely, hypersensitivity reactions;
local pain after injection.
For the management of adverse effects see Appendix 17.
Avoid or monitor combination with other ototoxic and/or nephrotoxic drugs (furosemide, amphotericin B, tenofovir, etc.).
Pregnancy: CONT RA-INDICAT ED
Breastfeeding: no contra-indication

Monitoring
Symptomatic monitoring.
Audiometry, serum creatinine and electrolytes (K, Ca, Mg).

Patient instructions
Maintain a good fluid intake to limit renal problems.

Remarks
Use a different site for each injection (absorption may be delayed if the same site is used repeatedly).

Storage
– Below 25 °C
Solution may darken from colourless to a pale yellow, but this does not indicate a loss of potency.
Amoxicillin/clavulanic acid ratio 4:1 (Amx/Clv)
Update: January 2022

Forms and strengths

500 mg amoxicillin/125 mg clavulanic acid tablet
250 mg amoxicillin/62.5 mg clavulanic acid per 5 ml, powder for oral suspension

Dosage (expressed in clavulanic acid)

Child under 30 kg: 3 mg (0.25 ml)/kg of clavulanic acid 3 times daily, 60 minutes before each dose of meropenem
Adolescent ≥ 15 years and ≥ 30 kg and adult: 125 mg of clavulanic acid 2 times daily, 60 minutes before each dose of
carbapenem
Maximum dose: 250 mg daily
Weight Daily dose 500 mg/125 mg 250 mg/62.5 mg per 5 ml
(kg) (mg) tablet oral suspension

5 50 − 1.3 ml x 3

6 60 − 1.5 ml x 3

7 70 − 2 ml x 3

8 80 − 2 ml x 3

9 90 − 2.5 ml x 3

10 100 − 2.5 ml x 3

11 110 − 3 ml x 3

12 120 − 3 ml x 3

13 130 − 3.5 ml x 3

14 140 − 3.5 ml x 3

15 150 − 4 ml x 3

16 160 − 4.5 ml x 3

17 170 − 4.5 ml x 3

18 180 − 5 ml x 3

19 190 − 5 ml x 3

20 200 − 5.5 ml x 3

21 210 − 5.5 ml x 3

22 220 − 6 ml x 3

23 230 − 6 ml x 3

24 240 − 6.5 ml x 3

25 250 − 6.5 ml x 3

26 250 − 6.5 ml x 3

27 250 − 6.5 ml x 3

28 250 − 6.5 ml x 3

29 250 − 6.5 ml x 3
 30-35 250 1 tab x 2 −

36-45 250 1 tab x 2 −

46-55 250 1 tab x 2 −

56-70 250 1 tab x 2 −

> 70 250 1 tab x 2 −

Contra-indications, adverse effects, precautions

Do not administer to penicillin-allergic patients and patients with history of hepatic disorders during a previous treatment with
amoxicillin/clavulanic acid.
Administer with caution to patients allergic to betalactams (cross-hypersensitivity may occur) and to patients with hepatic
impairment.
May cause: gastrointestinal disturbances (mainly diarrhoea), hypersensitivity reactions, hepatotoxicity.
For the management of adverse effects see Appendix 17.
Pregnancy: no contra-indication
Breastfeeding: no contra-indication

Monitoring
Symptomatic monitoring

Patient instructions
Take with food.

Storage
– – Below 25 °C
Powder for oral suspension: between 15 °C and 25 °C
Once reconstituted, the oral suspension must be kept refrigerated (between 2 °C and 8 °C) and may be used for up to 7 days.
Bedaquiline (Bdq)
Update: January 2023

Forms and strengths

100 mg tablet
20 mg dispersible tablet

Dosage
Child up to 15 kg: according to weight and age
Child 16 to 29 kg: 200 mg once daily for 2 weeks, then 100 mg 3 times a week
Child 30 kg and over and adult: 400 mg once daily for 2 weeks, then 200 mg 3 times a week
When administered 3 times a week, keep an interval of 48 hours between doses (Monday, Wednesday, Friday = M/W/F).

Weeks 1 and 2 Subsequent weeks

Once daily 3 times a week (M/W/F)
Weight
(kg)
Dose 100 mg 20 mg Dose 100 mg 20 mg
(mg) tablet dispersible tablet (mg) tablet dispersible tablet

< 3 months: 1½ tab < 3 months: ½ tab

5-6 30-60 – 10-20 –
≥ 3 months: 3 tab ≥ 3 months: 1 tab

< 3 months: 1½ tab < 3 months: ½ tab

7-9 30-80 – ≥ 3 months: 3 tab 10-40 – ≥ 3 months: 1 tab
≥ 6 months: 4 tab ≥ 6 months: 2 tab

< 6 months: 3 tab < 6 months: 1 tab

10-15 60-120 – 20-60 –
≥ 6 months: 6 tab ≥ 6 months: 3 tab

16-29 200 2 tab – 100 1 tab –

≥ 30 400 4 tab – 200 2 tab –

Alternatively, for children 16 to 29 kg: 10 dispersible tablets of 20 mg (200 mg) once daily on Weeks 1 and 2, then 5 dispersible
tablets of 20 mg (100 mg) 3 times a week.

If 20 mg dispersible tablets are not available, 100 mg tablets can be crushed and suspended in 10 ml of water or fruit juice to
obtain a solution containing 10 mg of bedaquiline per ml, then administered as follows:
 Weeks 1 and 2 Subsequent weeks
Once daily 3 times a week (M/W/F)

Weight (kg)
100 mg tablet 100 mg tablet
Dose (mg) in 10 ml Dose (mg) in 10 ml
(10 mg/ml) (10 mg/ml)

< 3 months: 3 ml < 3 months: 1 ml

5-6 30-60 10-20
≥ 3 months: 6 ml ≥ 3 months: 2 ml

< 3 months: 3 ml < 3 months: 1 ml

7-9 30-80 ≥ 3 months: 6 ml 10-40 ≥ 3 months: 2 ml
≥ 6 months: 8 ml ≥ 6 months: 4 ml

< 6 months: 6 ml < 6 months: 2 ml

10-15 60-120 20-60
≥ 6 months: 12 ml ≥ 6 months: 6 ml

Contra-indications, adverse effects, precautions

Do not administer (or discontinue) to patients with severe hepatic impairment, QTcF > 500 ms or clinically significant ventricular
arrhythmia.
Avoid or use with caution and under close monitoring in patients with:
history of syncopal episodes, torsades de pointes, congenital QT prolongation;
uncompensated heart failure, severe coronary artery disease, bradycardia;
electrolyte disturbances (correct first K, Ca, Mg), hypothyroidism (provide thyroxine);
severe renal impairment, end-stage renal disease (optimal dosing not established).
May cause:
hepatotoxicity, moderate QT prolongation;
nausea, vomiting, arthralgia, headache, increased amylase level.
For the management of adverse effects see Appendix 17.
Avoid or use with caution and under close monitoring in patients taking CYP450 inducers/inhibitors, some ARVs, or other QT
prolonging drugs (Appendix 19).
Pregnancy: use if benefits outweigh the risks (safety not established).
Breastfeeding: avoid breastfeeding during treatment (safety not established).

Monitoring
Symptomatic monitoring.
Liver function, ECG, electrolytes (K, Ca, Mg).

Patient instructions
Take with food.
100 mg tablets can be crushed and mixed with water or fruit juice.
20 mg tablets should be dispersed in water, juice, milk, yogurt, porridge, etc.
Avoid alcohol during treatment.

Remarks
For patients over 14 years who receive the regimen BPaL or BPaLM, bedaquiline can be given daily instead of 3 times a week:
200 mg once daily for the first 8 weeks then, 100 mg once daily.

Storage
– Below 25 °C
Clofazimine (Cfz)
Update: August 2022

Forms and strengths

50 mg and 100 mg soft capsules or tablets

Dosage
Child under 10 kg: doses are administered 3 times a week (Monday, Wednesday, Friday = M/W/F)
Child 10 to 29 kg: 2 to 5 mg/kg once daily
Child 30 kg and over and adult: 100 mg once daily
Weight Daily dose 100 mg 50 mg
(a)
(kg) (mg) capsule capsule (a)

5 − − 1 caps (M/W/F)

6 − − 1 caps (M/W/F)

7 − − 1 caps (M/W/F)

8 − − 1 caps (M/W/F)

9 − − 1 caps (M/W/F)

10 20-50 − 1 caps

11 22-55 − 1 caps

12 24-60 − 1 caps

13 26-65 − 1 caps

14 28-70 − 1 caps

15 30-75 − 1 caps

16 32-80 − 1 caps

17 34-85 − 1 caps

18 36-90 − 1 caps

19 38-95 − 1 caps

20 40-100 − 1 caps

21 42-105 − 1 caps

22 44-110 − 1 caps

23 46-115 − 1 caps

24 48-120 1 caps −

25 50-125 1 caps −

26 52-130 1 caps −

27 54-135 1 caps −

28 56-140 1 caps −

29 58-145 1 caps −
 30-35 100 1 caps −

36-45 100 1 caps −

46-55 100 1 caps −

56-70 100 1 caps −

> 70 100 1 caps −

(a) Capsule or t ablet

Contra-indications, adverse effects, precautions

Do not administer to patients with history of allergy to clofazimine.
Administer with caution to patients with severe hepatic impairment.
May cause:
orange-brown discolouration of skin and body fluids;
strong QT prolongation;
gastrointestinal intolerance (nausea, vomiting, abdominal pain);
severe abdomen pain, bowel obstruction, intestinal bleeding;
eye and skin dryness and irritation, hypersensitivity reactions, photosensitivity.
For the management of adverse effects see Appendix 17.
Avoid or use with caution and under close monitoring in patients taking other QT prolonging drugs (Appendix 19).
Pregnancy: use only if benefits outweigh the risks (safety is not established).
Breast-feeding: avoid breastfeeding during treatment (safety not established). If used, may cause breast milk discolouration
and reversible skin discolouration in breastfed infants.

Monitoring
Symptomatic monitoring.
ECG.

Patient instructions
Take with food to improve gastrointestinal tolerance.
Protect your skin from sun.
Harmless orange-brown discoloration of the skin and body fluids (urine, sweat, saliva, sputum, tears, breast milk, etc.). It is
reversible but may take months to disappear after stopping treatment.

Storage
– Below 25 °C
Cycloserine (Cs) or terizidone (Trd)
Update: January 2022

Forms and strengths

250 mg and 125 mg capsules

Dosage
Child under 30 kg: 7.5 to 10 mg/kg 2 times daily (or 15 to 20 mg/kg once daily if tolerated)
Child 30 kg and over and adult: 5 to 7.5 mg/kg 2 times daily (or 10 to 15 mg/kg once daily if tolerated)
Maximum dose: 1000 mg daily
Renal insufficiency: 250 mg once daily or 500 mg 3 times a week
Weight Daily dose 250 mg 125 mg
(kg) (mg) capsule capsule

5 75-100 − 1 caps

6 90-120 − 1 caps

7 105-140 − 1 caps

8 120-160 − 1 caps

9 135-180 − 1 caps

10 150-200 − 1 caps x 2

11 165-220 − 1 caps x 2

12 180-240 − 1 caps x 2

13 195-260 − 1 caps x 2

14 210-280 − 1 caps x 2

15 225-300 − 1 caps x 2

16 240-320 − 1 caps (morning) + 2 caps (evening)

17 255-340 − 1 caps (morning) + 2 caps (evening)

18 270-360 − 1 caps (morning) + 2 caps (evening)

19 285-380 − 1 caps (morning) + 2 caps (evening)

20 300-400 − 1 caps (morning) + 2 caps (evening)

21 315-420 − 1 caps (morning) + 2 caps (evening)

22 330-440 − 1 caps (morning) + 2 caps (evening)

23 345-460 − 1 caps (morning) + 2 caps (evening)

24 360-480 1 caps x 2 −

25 375-500 1 caps x 2 −

26 390-520 1 caps x 2 −

27 405-540 1 caps x 2 −

28 420-560 1 caps x 2 −

29 435-580 1 caps x 2 −
 30-35 500 1 caps x 2 −

36-45 500 1 caps x 2 −

46-55 750 1 caps (morning) + 2 caps (evening) −

56-70 750 1 caps (morning) + 2 caps (evening) −

> 70 750 1 caps (morning) + 2 caps (evening) −

Contra-indications, adverse effects, precautions

Avoid in patients with epilepsy, depression, psychosis, severe anxiety, history of neurological or psychiatric disorders, chronic
alcohol use. However, if essential to the regimen, it can be administered under close monitoring.
May cause:
neurotoxicity: seizure, headache, lethargy, confusion, mood change, drowsiness, anxiety, psychosis, depression, suicidal
ideation, peripheral neuropathy; rarely, vestibular toxicity;
hypersensitivity reactions.
For the management of adverse effects see Appendix 17.
Avoid or monitor combination with isoniazid and thionamides (increased risk of neurotoxicity).
Administer concomitantly pyridoxine (vitamin B 6); child: 1 to 2 mg/kg (usual range: 10 to 50 mg) once daily; adult: 100 mg once
daily.
Pregnancy: use if the benefits outweigh the risks. Administer pyridoxine to the mother (as above).
Breastfeeding: no contra-indication. Administer pyridoxine to the mother (as above) and the breast-fed neonate or infant (1 to
2 mg/kg once daily).

Monitoring
Symptomatic monitoring.

Patient instructions
Take capsules with water before or after meals.
Avoid alcohol during treatment.

Remarks
To increase tolerance, start with a low dose (e.g. 250 mg daily in adults), then increase over 1 to 2 weeks to achieve the
requested dose.

Storage
– Below 25 °C
Delamanid (Dlm)
Update: September 2022

Forms and strengths

50 mg tablet
25 mg dispersible tablet

Dosage
Child under 10 kg: according to weight and age
Child 10 to 15 kg: 25 mg 2 times daily
Child 16 to 29 kg: 50 mg morning and 25 mg evening
Child 30 to 45 kg and under 15 years: 50 mg 2 times daily
Child 46 kg and over and adult: 100 mg 2 times daily

Weight 25 mg
Daily dose (mg) 50 mg tablet
(kg) dispersible tablet

< 3 months: 1 tab

5-9 25-50 –
≥ 3 months: 1 tab x 2

10-15 50 – 1 tab x 2

16-29 75 – 2 tab (morning) + 1 tab (evening)

< 15 years: 1 tab x 2

30-45 100-200 –
≥ 15 years: 2 tab x 2

If 25 mg dispersible tablets are not available, 50 mg tablets can be crushed and suspended in 10 ml of water or fruit juice to
obtain a solution of 5 mg of delamanid per ml, administered as follows:

Weight Daily dose 50 mg tablet in 10 ml

(kg) (mg) (5 mg/ml)

< 3 months: 5 ml
5-9 25-50
≥ 3 months: 5 ml x 2

10-15 50 5 ml x 2

16-29 75 10 ml (morning) + 5 ml (evening)

Contra-indications, adverse effects, precautions

Do not administer (or discontinue) to patients with QTcF > 500 ms or albumin level < 2.8 g/dl.
Avoid or use with caution and under close monitoring in patients with:
history of syncopal episodes or torsades de pointes, congenital QT prolongation, cardiac disease;
electrolyte disturbances (correct first K, Ca, Mg);
severe renal or hepatic impairment.
 Use with caution and under close monitoring in patients taking QT-prolonging drugs (Appendix 19).
May cause: nausea, vomiting, dizziness, insomnia, mild QT prolongation.
For the management of adverse effects see Appendix 17.
Pregnancy: use if benefits outweigh the risks (safety not established).
Breastfeeding: avoid breastfeeding during treatment (safety not established).

Monitoring
Symptomatic monitoring.
ECG.

Patient instructions
Take with food.
50 mg tablets should be swallowed whole if possible.
25 mg tablets should be dispersed in water or fruit juice.

Storage
– Below 25 °C
Ethambutol (E)
Update: January 2022

Forms and strengths

100 mg and 400 mg tablets
100 mg dispersible tablet, to be dispersed in 10 ml water

Dosage
Child and adult: 15 to 25 mg/kg once daily
Maximum dose: 1200 mg daily
Renal insufficiency: 15 to 25 mg/kg 3 times a week
Weight Daily dose 400 mg 100 mg
(kg) (mg) tablet tablet

5 75-125 − 1 tab

6 90-150 − 1 tab

7 105-175 − 1 tab

8 120-200 − 2 tab

9 135-225 − 2 tab

10 150-250 − 2 tab

11 165-275 − 2 tab

12 180-300 − 2 tab

13 195-325 − 2 tab

14 210-350 − 3 tab

15 225-375 − 3 tab

16 240-400 − 3 tab

17 255-425 − 3 tab

18 270-450 1 tab −

19 285-475 1 tab −

20 300-500 1 tab −

21 315-525 1 tab −

22 330-550 1 tab −

23 345-575 1 tab −

24 360-600 1 tab −

25 375-625 1 tab −

26 390-650 1 tab −

27 405-675 1½ tab −

28 420-700 1½ tab −

29 435-725 1½ tab −
 30-35 800 2 tab −

36-45 800 2 tab −

46-55 1200 3 tab −

56-70 1200 3 tab −

> 70 1200 3 tab −

Contra-indications, adverse effects, precautions

Do not administer to patients with severe renal impairment or pre-existing optic neuritis (e.g. diabetic retinopathy).
May cause: dose-related retrobulbar optic neuritis, exarcerbated in renal impairment.
T he dosage must be carefully adjusted to the weight, especially for children under 5 years, as it is more difficult to detect visual
changes at this age.
For the management of adverse effects see Appendix 17.
Pregnancy: no contra-indication
Breastfeeding: no contra-indication

Monitoring
Symptomatic monitoring.

Patient instructions
Take with or without food.
100 mg dispersible tablets should be dispersed in 10 ml water.

Remarks
For adults on drug-susceptible T B treatment, ethambutol is given as part of a fixed-dose combination.
Ethambutol is also used in the treatment of drug-resistant T B treatment for longer duration. For treatment > 2 months, daily
doses should be closer to 15 mg/kg and visual acuity and colour discrimination should be monitored.

Storage
– – Below 25 °C
Ethionamide (Eto) or prothionamide (Pto)
Update: January 2022

Forms and strengths

250 mg tablet (ethionamide or prothionamide)
125 mg dispersible tablet (ethionamide), to be dispersed in 10 ml water

Dosage
Child and adult: 15 to 20 mg/kg once daily
Maximum dose: 1000 mg daily
Weight Daily dose 250 mg 125 mg
(kg) (mg) tablet dispersible tablet

5 75-100 − 1 tab

6 90-120 − 1 tab

7 105-140 − 1 tab

8 120-160 − 1 tab

9 135-180 − 1½ tab

10 150-200 − 1½ tab

11 165-220 − 2 tab

12 180-240 − 2 tab

13 195-260 − 2 tab

14 210-280 − 2½ tab

15 225-300 − 2½ tab

16 240-320 − 2½ tab

17 255-340 − 2½ tab

18 270-360 − 2½ tab

19 285-380 − 3 tab

20 300-400 − 3 tab

21 315-420 − 3 tab

22 330-440 − 3 tab

23 345-460 − 3 tab

24 360-480 − 3 tab

25 375-500 2 tab −

26 390-520 2 tab −

27 405-540 2 tab −

28 420-560 2 tab −

29 435-580 2 tab −
 30-35 500 2 tab −

36-45 500 2 tab −

46-55 750 3 tab −

56-70 750 3 tab −

> 70 1000 4 tab −

Contra-indications, adverse effects, precautions

Do not administer to patients with severe hepatic impairment.
Administer with caution to patients with hepatic disease, diabetes or depression.
May cause:
frequently: gastrointestinal disturbances (abdominal or epigastric pain, diarrhoea, metallic taste, nausea and vomiting,
stomatitis, etc.);
occasionally: endocrine disorders (gynecomastia, hypothyroidism), alopecia, depression, anxiety, psychosis, hypoglycaemia,
vestibular disorders, hepatotoxicity, peripheral neuropathy, optic neuritis, hypersensitivity reactions, seizures
For the management of adverse effects see Appendix 17.
Monitor combination with: cycloserine or terizidone (increased risk of seizures) and para-aminosalicylic acid (increased risk of
gastrointestinal disturbances and hypothyroidism).
Administer concomitantly pyridoxine (vitamin B 6); child: 1 to 2 mg/kg (usual range: 10 to 50 mg) once daily; adult: 100 mg once
daily.
Pregnancy: CONT RA-INDICAT ED
Breastfeeding: administer pyridoxine to the mother (as above). Observe the breast-fed neonate or infant for adverse effects
and supplement it with pyridoxine (1 to 2 mg/kg once daily).

Monitoring
Symptomatic monitoring.
Liver function and thyroid function.

Patient instructions
Take with food and/or at bedtime to limit gastrointestinal disturbances.
125 mg tablets should be dispersed in 10 ml water.
Avoid alcohol during treatment.

Remarks
To improve tolerance, start with a low dose (e.g. 250 mg daily in adults), then increase over 1 to 2 weeks to achieve the
requested dose.
For the 6HRZEto regimen for drug-susceptible T B meningitis, the dose is 20 mg/kg once daily (max. 750 mg daily).

Storage
– Below 25 °C
Imipenem/cilastatin (Ipm/Cln)
Update: January 2022

Forms, strengths and route of administration

Powder for injection, in vial of 500 mg imipenem monohydrate/500 mg cilastatin sodium, to be reconstituted with 20 ml of 0.9%
sodium chloride (25 mg imipenem/ml).
Each dose is to be diluted in 100 ml of 0.9% sodium chloride and to be administered by IV infusion:
over 30 minutes for doses ≤ 500 mg/500 mg
over 60 minutes for doses > 500 mg/500 mg
Use a deep line, preferably an implantable venous access device (Port-a-Cath).

Dosage (expressed in imipenem)

Adolescent 15 years and over (and ≥ 30 kg) and adult: 1000 mg (2 vials) 2 times daily with 10 hours minimum between infusions
Maximum dose: 2000 mg daily
Renal insufficiency: 750 mg every 12 hours for CrCl 20-40 ml/minute; 500 mg every 12 hours for CrCl < 20 ml/minute

Weight Daily dose Daily dose (ml) - IV infusion

(kg) (mg) (500 mg/500 mg per vial)

5-29 Do not used in patients < 15 years and < 30 kg

30-33 2000 2 vials (40 ml) in 100 ml of 0.9% NaCl x 2

34-40 2000 2 vials (40 ml) in 100 ml of 0.9% NaCl x 2

41-45 2000 2 vials (40 ml) in 100 ml of 0.9% NaCl x 2

46-50 2000 2 vials (40 ml) in 100 ml of 0.9% NaCl x 2

51-70 2000 2 vials (40 ml) in 100 ml of 0.9% NaCl x 2

> 70 2000 2 vials (40 ml) in 100 ml of 0.9% NaCl x 2

Contra-indications, adverse effects, precautions

Do not administer to patients with hypersensitivity to carbapenems.
Administer with caution to patients allergic to other betalactams (cross-hypersensitivity may occur).
May cause:
nausea, vomiting (the infusion rate may be slowed down in case of nausea), diarrhoea;
neurotoxicity: confusional state, seizures (most frequently in patients with history of seizures or renal impairment);
hypersensitivity reactions;
local reactions (phlebitis/thrombophlebitis).
For the management of adverse effects see Appendix 17.
Avoid or monitor combination with: valproic acid (decreased plasma concentration of valproic acid and risk of seizures), oral or
injectable ganciclovir (risk of seizures).
 Pregnancy and breastfeeding: avoid unless the benefits outweigh the risks

Monitoring
Symptomatic monitoring.

Remarks
Administer clavulanic acid 60 minutes before each dose of imipenem/cilastatin.
Do not mix with Ringer lactate (incompatibility) but may be administered via Y-site.
Do not mix with other drugs in the infusion bag.

Storage
– Below 25 °C
Once reconstituted, solution:
remains stable 4 hours at room temperature or 24 hours between 2 to 8 °C;
may darken from colourless to yellow (this does not indicate a loss of potency);
should be discarded if it becomes brown.
Isoniazid - Standard dose (H)
Update: January 2022

Forms and strengths

300 mg and 100 mg tablets
100 mg and 50 mg dispersible tablets, to be dispersed in 10 ml water

Dosage
Child under 30 kg: 10 mg/kg (7 to 15 mg/kg) once daily
Child 30 kg and over and adult: 5 mg/kg (4 to 6 mg/kg) once daily
Maximum dose: 300 mg daily
Weight Daily dose 300 mg 100 mg
(kg) (mg) tablet tablet

5 35-75 − ½ tab

6 42-90 − 1 tab

7 49-105 − 1 tab

8 56-120 − 1 tab

9 63-135 − 1 tab

10 70-150 − 1½ tab

11 77-165 − 1½ tab

12 84-180 − 1½ tab

13 91-195 − 2 tab

14 98-210 − 2 tab

15 105-225 − 2 tab

16 112-240 − 2 tab

17 119-255 − 2 tab

18 126-270 − 2 tab

19 133-285 − 2 tab

20 140-300 − 2 tab

21 147-300 1 tab −

22 154-300 1 tab −

23 161-300 1 tab −

24 168-300 1 tab −

25 175-300 1 tab −

26 182-300 1 tab −

27 189-300 1 tab −

28 196-300 1 tab −

29 203-300 1 tab −
 30-35 150 ½ tab −

36-45 300 1 tab −

46-55 300 1 tab −

56-70 300 1 tab −

> 70 300 1 tab −

Alternatively, 50 mg dispersible tablets may be used instead of ½ tablets of 100 mg.

Contra-indications, adverse effects, precaution

Do not administer to patients with severe hepatic impairment.
May cause:
peripheral neuropathy;
hepatotoxicity;
hypersensitivity reactions, arthragias, optic neuritis, psychotic reactions, seizures and depression.
Monitor closely:
pregnant and breastfeeding women, patients with renal impairment or diabetes; malnourished or HIV-infected patients
(increased risk of neuropathy);
alcoholic patients (increased risk of neuropathy and hepatotoxicity);
patients with chronic hepatic disease or taking rifampicin or ≥ 35 years (increased risk of hepatotoxicity);
patients taking anticonvulsants, benzodiazepines (risk of toxicity), warfarin (risk of bleeding). Dose adjustment may be
required.
For the management of adverse effects see Appendix 17.
Administer concomitantly pyridoxine (vitamin B 6) to patients at risk of peripheral neuropathy (child: 5 to 10 mg once daily; adult:
10 mg once daily).
Pregnancy and breastfeeding: no contra-indication. Administer pyridoxine to the mother (as above) and the breast-fed
neonate or infant (5 mg once daily).

Monitoring
Symptomatic monitoring.
Liver function in patients with hepatic disease.

Patient instructions
Take without food.
100 mg dispersible tablet should be dispersed in 10 ml water.
Avoid alcohol during treatment.

Remarks
For patients on drug-susceptible T B treatment, isoniazid is given as part of a fixed-dose combination.
For the 6HRZ-Eto regimen for drug-susceptible T B meningitis, the dose of isoniazid is 20 mg/kg once daily (max. 400 mg daily).
Isoniazid is also used in the treatment of latent T B infection and multidrug-resistant T B treatment (at high dose - Hh).

Storage
– – Below 25 °C
Isoniazid - High dose (Hh)
Update: November 2022

Forms and strengths

300 mg and 100 mg tablets
100 mg and 50 mg dispersible tablets, to be dispersed in 10 ml water

Dosage
Child under 30 kg: 15 to 20 mg/kg once daily
Child 30 kg and over and adult: 10 to 15 mg/kg once daily
Maximum dose: 600 mg daily
Weight Daily dose 300 mg 100 mg
(kg) (mg) tablet tablet

5 75-100 − 1 tab

6 90-120 − 1 tab

7 105-140 − 1½ tab

8 120-160 − 1½ tab

9 135-180 − 1½ tab

10 150-200 − 2 tab

11 165-220 − 2 tab

12 180-240 − 2 tab

13 195-260 − 2 tab

14 210-280 − 2 tab

15 225-300 − 3 tab

16 240-320 − 3 tab

17 255-340 − 3 tab

18 270-360 − 3 tab

19 285-380 − 3 tab

20 300-400 − 3 tab

21 315-420 − 4 tab

22 330-440 − 4 tab

23 345-460 − 4 tab

24 360-480 − 4 tab

25 375-500 − 4 tab

26 390-520 − 4 tab

27 405-540 − 4 tab

28 420-560 − 4½ tab

29 435-580 − 4½ tab
 30-35 450 1½ tab −

36-45 450 1½ tab −

46-55 600 2 tab −

56-70 600 2 tab −

> 70 600 2 tab −

Alternatively, 50 mg dispersible tablets may be used instead of ½ tablets of 100 mg.

Contra-indications, adverse effects, precautions

Do not administer to patients with severe hepatic impairment.
May cause:
peripheral neuropathy;
hepatotoxicity;
hypersensitivity reactions, arthragias, optic neuritis, psychotic reactions, seizures and depression.
Monitor closely:
pregnant and breastfeeding women, patients with renal impairment or diabetes; malnourished or HIV-infected patients
(increased risk of neuropathy);
alcoholic patients (increased risk of neuropathy and hepatotoxicity);
patients with chronic hepatic disease or taking rifampicin or ≥ 35 years (increased risk of hepatotoxicity);
patients taking anticonvulsants, benzodiazepines (risk of toxicity), warfarin (risk of bleeding). Dose adjustment may be
required.
For the management of adverse effects see Appendix 17.
Administer concomitantly pyridoxine (vitamin B 6): child: 1 to 2 mg/kg (usual range: 10 to 50 mg) once daily; adult: 100 mg once
daily.
Pregnancy and breastfeeding: no contra-indication. Administer pyridoxine to the mother (as above). Observe the breast-fed
neonate or infant for adverse effects and supplement it with pyridoxine (1 to 2 mg/kg once daily).

Monitoring
Symptomatic monitoring.
Liver function.

Patient instructions
Take without food.
Dispersible tablets should be dispersed in 10 ml water.
Avoid alcohol during treatment.

Storage
– – Below 25 °C
Levofloxacin (Lfx)
Update: September 2022

Forms and strenghts

250 mg and 500 mg tablets
100 mg dispersible tablet, to be dispersed in 10 ml water

Dosage
Child under 30 kg: 15 to 20 mg/kg once daily
Child 30 kg and over and adult: 750 to 1000 mg once daily
Maximum dose: 1500 mg daily
Renal insufficiency: 750 to 1000 mg 3 times a week
Weight Daily dose 500 mg 250 mg 100 mg dispersible tablet
(kg) (mg) tablet tablet

5 75-100 − − 1 tab

6 90-120 − − 1 tab

7 105-140 − − 1½ tab

8 120-160 − − 1½ tab

9 135-180 − − 1½ tab

10 150-200 − − 2 tab

11 165-220 − − 2 tab

12 180-240 − − 2 tab

13 195-260 − − 2 tab

14 210-280 − − 2 tab

15 225-300 − − 2 tab

16 240-320 − − 3 tab

17 255-340 − − 3 tab

18 270-360 − − 3 tab

19 285-380 − − 3 tab

20 300-400 − 3 tab

21 315-420 − − 4 tab

22 330-440 − − 4 tab

23 345-460 − − 4 tab

24 360-480 − − 4 tab

25 375-500 − 2 tab −

26 390-520 − 2 tab −

27 405-540 − 2 tab −

28 420-560 − 2 tab −

29 435-580 − 2 tab −
 30-35 750 − 3 tab −

36-45 750 − 3 tab −

46-55 1000 2 tab − −

56-70 1000 2 tab − −

> 70 1000 2 tab − −

Contra-indications, adverse effects, precautions

Do not administer to patients with hypersensitivity or tendon damage during a previous treatment with a fluoroquinolone.
Administer with caution to patients:
over 60 years or on corticosteroid treatment (increased risk of tendon damage);
with diabetes or history of mental disorders or seizures.
May cause:
tendinitis, tendon rupture, mild QT prolongation;
gastrointestinal disturbances (abdominal or epigastric pain, diarrhoea);
neurological disorders (headache, psychosis, seizures, etc.);
photosensitivity;
hypersensitvity reactions, hypo/hyperglycaemia;
rarely: crystalluria, peripheral neuropathy, ototoxicity.
For the management of adverse effects see Appendix 17.
Avoid or use with caution and under close monitoring in patients taking other QT prolonging drugs (Appendix 19) or warfarin.
Do not administer simultaneously with: antacids containing magnesium/aluminium, calcium, iron and zinc salts (administer 2 hours
apart).
Pregnancy: use if benefits outweigh the risks (safety not established).
Breastfeeding: avoid breastfeeding during treatment (no absolute contra-indication).

Monitoring
Symptomatic monitoring.

Patient instructions
Take 2 hours apart from milk-based product, antacids, calcium, iron and zinc salts.
100 mg tablets should be dispersed in 10 ml water.
Maintain a good fluid intake.
Protect your skin from sun.

Storage
– – Below 25 °C
Linezolid (Lzd)
Update: October 2022

Forms and strengths

600 mg tablet (breakable and non-breakable)
150 mg dispersible tablet
100 mg/5 ml, granules for oral suspension

Dosage
Child under 15 kg: 15 mg/kg once daily
Child 15 to 45 kg: 10 to 12 mg/kg once daily
Patient 46 kg and over: 600 mg once daily
Maximum dose: 600 mg daily

Note: in the BPaLM therapeutic regimen for patients 15 years and over, the dose of linezolid is 600 mg once daily for 16 weeks
then 300 mg once daily up to the end of treatment.

Weight Daily dose 600 mg 150 mg 100 mg per 5 ml

(kg) (mg) tablet dispersible tablet oral suspension

5 75 – – 3 ml

6 90 – – 4 ml

7 105 – – 5 ml

8-9 120-135 – – 6 ml

10-15 150-180 – 1 tab –

16-23 160-276 – 1½ tab –

24-29 240-348 – 2 tab –

30-35 300 – 2 tab –

36-45 450 – 3 tab –

46-55 600 1 tab – –

56-70 600 1 tab – –

> 70 600 1 tab – –

Alternatively, for children 5 to 6 kg, if oral suspension is not available: one half of a 150 mg dispersible tablet (75 mg) once daily.
If 150 mg dispersible tablets are not available, 600 mg tablets can be crushed and suspended in 10 ml of water or fruit juice to
obtain a solution of 60 mg of linezolid per ml, administered as follows:
 Weight Daily dose 600 mg tablet in 10 ml
(mg) (mg) (60 mg/ml)

5 75 1.25 ml

6 90 1.5 ml

7-9 105-135 2 ml

10-15 150-180 2.5 ml

Contra-indications, adverse effects, precautions

Administer with caution to patients with haematological disorders or hypertension.
May cause:
anaemia, neutropenia and/or thrombocytopenia;
lactic acidosis;
peripheral neuropathy (can be irreversible); rarely, optic neuritis;
abdominal pain, diarrhoea, nausea.
For the management of adverse effects see Appendix 17.
Avoid or monitor combination with serotonergic drugs such as tricyclic antidepressants (e.g. amitriptyline) or selective serotonin
reuptake inhibitors (e.g. fluoxetine, paroxetine): risk of serotonin syndrome.
Administer concomitantly pyridoxine (vitamin B 6); child: 1 to 2 mg/kg (usual range: 10 to 50 mg) once daily; adult: 100 mg once
daily.
Pregnancy: use if the benefits outweigh the risks. Administer pyridoxine to the mother (as above).
Breastfeeding: avoid breastfeeding during treatment (safety not established).

Monitoring
Symptomatic monitoring.
Full blood count.
Visual acuity and colour discrimination.

Patient instructions
Take with or without food.

Storage
– – Below 25 °C
Once reconstituted, the oral suspension may be kept at room temperature for 21 days, protected from light.
Meropenem (Mpm)
Update: January 2022

Forms, strengths and route of administration

Powder for injection, in 500 mg vial, to be reconstituted with 10 ml of water for injection (50 mg meropenem/ml).
Each dose is to be diluted in 5 ml/kg of 0.9% sodium chloride in children under 20 kg and in 100 ml of 0.9% sodium chloride in
children 20 kg and over and adults and to be administered by IV infusion over 15 to 30 minutes.
Use a deep line, preferably an implantable venous access device (Port-a-Cath).

Dosage
Child under 30 kg: 20 to 40 mg/kg every 8 hours
Child 30 kg and over and adult: 1500 to 2000 mg 2 times daily with 10 hours minimum between infusions
Maximum dose: 6000 mg daily
Renal insufficiency: 750 mg every 12 hours for CrCl 20-40 ml/minute; 500 mg every 12 hours for CrCl < 20 ml/minute
Weight Daily dose Daily dose (ml) – IV infusion
(kg) (mg) (500 mg per vial)

5 300 2 ml in 25 ml of 0.9% NaCl x 3

6 300 2 ml in 30 ml of 0.9% NaCl x 3

7 600 4 ml in 35 ml of 0.9% NaCl x 3

8 600 4 ml in 40 ml of 0.9% NaCl x 3

9 600 4 ml in 45 ml of 0.9% NaCl x 3

10 900 6 ml in 50 ml of 0.9% NaCl x 3

11 900 6 ml in 55 ml of 0.9% NaCl x 3

12 900 6 ml in 60 ml of 0.9% NaCl x 3

13 900 6 ml in 65 ml of 0.9% NaCl x 3

14 900 6 ml in 70 ml of 0.9% NaCl x 3

15 900 6 ml in 75 ml of 0.9% NaCl x 3

16 1200 8 ml in 80 ml of 0.9% NaCl x 3

17 1200 8 ml in 85 ml of 0.9% NaCl x 3

18 1200 8 ml in 90 ml of 0.9% NaCl x 3

19 1200 8 ml in 95 ml of 0.9% NaCl x 3

20 1200 8 ml in 100 ml of 0.9% NaCl x 3

21 1200 8 ml in 100 ml of 0.9% NaCl x 3

22 1200 8 ml in 100 ml of 0.9% NaCl x 3

23 1200 8 ml in 100 ml of 0.9% NaCl x 3

24 1650 11 ml in 100 ml of 0.9% NaCl x 3

25 1650 11 ml in 100 ml of 0.9% NaCl x 3

26 1650 11 ml in 100 ml of 0.9% NaCl x 3

27 1650 11 ml in 100 ml of 0.9% NaCl x 3

28 1650 11 ml in 100 ml of 0.9% NaCl x 3

29 1650 11 ml in 100 ml of 0.9% NaCl x 3

 30-33 3000 3 vials (30 ml) in 100 ml of 0.9% NaCl x 2

34-40 3000 3 vials (30 ml) in 100 ml of 0.9% NaCl x 2

41-45 3000 3 vials (30 ml) in 100 ml of 0.9% NaCl x 2

46-50 3000 3 vials (30 ml) in 100 ml of 0.9% NaCl x 2

51-70 4000 4 vials (40 ml) in 100 ml of 0.9% NaCl x 2

> 70 4000 4 vials (40 ml) in 100 ml of 0.9% NaCl x 2

Contra-indications, adverse effects, precautions

Do not administer to patients with hypersensitivity to carbapenems.
Administer with caution to patients allergic to cephalosporins (cross-hypersensitivity may occur).
May cause:
nausea, vomiting (the infusion rate may be slowed down in case of nausea), diarrhoea;
neurotoxicity: confusional state, seizures (rarely compared to imipenem/cilastatin, most frequently in patients with history of
seizures or renal impairment);
hypersensitivity reactions;
local reactions (phlebitis/thrombophlebitis).
For the management of adverse effects see Appendix 17.
Avoid or monitor combination with valproic acid (decreased concentration of valproic acid and risk of seizures).
Pregnancy and breastfeeding: avoid unless the benefits outweigh the risks.

Monitoring
Symptomatic monitoring.

Remarks
Administer clavulanic acid 60 minutes before each dose of meropenem.
Do not mix with other drugs in the infusion bag.

Storage
– Below 25 °C
Once reconstituted, solution should be used immediately (within 1 hour of preparation)
Moxifloxacin (Mfx)
Update: September 2022

Forms and strengths

400 mg tablet
100 mg dispersible tablet, to be dispersed in 10 ml water

Dosage (standard dose)

Child under 30 kg: 10 to 15 mg/kg once daily
Child 30 kg and over and adult: 400 mg once daily
Maximum dose: 400 mg daily
Weight Daily dose 100 mg
400 mg tablet
(kg) (mg) dispersible tablet

5 50-75 − 7 ml

6 60-90 − 7 ml

7 70-105 − 1 tab

8 80-120 − 1 tab

9 90-135 − 1 tab

10 100-150 − 2 tab

11 110-165 − 2 tab

12 120-180 − 2 tab

13 130-195 − 2 tab

14 140-210 − 2 tab

15 150-225 − 2 tab

16 160-240 − 3 tab

17 170-255 − 3 tab

18 180-270 − 3 tab

19 190-285 − 3 tab

20 200-300 − 3 tab

21 210-315 − 3 tab

22 220-330 − 3 tab

23 230-345 − 3 tab

24 240-360 − 4 tab

25 250-375 − 4 tab

26 260-390 − 4 tab

27 270-405 − 4 tab

28 280-420 − 4 tab

29 290-435 − 4 tab
 30-35 400 1 tab −

36-45 400 1 tab −

46-55 400 1 tab −

56-70 400 1 tab −

> 70 400 1 tab −

Contra-indications, adverse effects, precautions

Do not administer to patients with hypersensitivity or tendon damage during a previous treatment with a fluoroquinolone.
Administer with caution to patients:
over 60 years or on corticosteroid treatment (increased risk of tendon damage);
with diabetes or history of mental disorders or seizures.
May cause:
tendinitis, tendon rupture, moderate QT prolongation;
gastrointestinal disturbances (abdominal or epigastric pain, diarrhoea);
neurological disorders (headache, psychosis, seizures, etc.);
photosensitivity;
hypersensitvity reactions, hypo/hyperglycaemia;
rarely: crystalluria, peripheral neuropathy, ototoxicity.
For the management of adverse effects see Appendix 17.
Avoid or use with caution and under close monitoring in patients taking other QT prolonging drugs (Appendix 19) or warfarin.
Do not administer simultaneously with: antacids containing magnesium/aluminium, calcium, iron and zinc salts (administer 2 hours
apart).
Pregnancy:
DR-T B: use if benefits outweigh the risks (safety not established).
DS-T B: do not use.
Breastfeeding:
DR-T B: avoid breastfeeding during treatment (no absolute contra-indication).
DS-T B: avoid breastfeeding during treatment.

Monitoring
Symptomatic monitoring

Patient instructions
Take 2 hours apart from milk-based product, antacids, calcium, iron and zinc salts.
100 mg tablets should be dispersed in 10 ml water.
Maintain a good fluid intake.
Protect your skin from sun.

Remarks
Higher dose moxifloxacin (Mfxh), i.e. 600 to 800 mg once daily in patients over 30 kg may be used in the presence of certain
mutations conferring low level fluoroquinolone resistance. Mfxh may cause strong QT prolongation.

Storage
– – Below 25 °C
Para-aminosalicylate sodium (PAS)
Update: October 2022

Forms and strengths

Powder for oral solution, 5.52 g sachet of para-aminosalicylate sodium (equivalent to 4 g PAS acid), to be dissolved in 100 ml
water

Dosage (expressed in PAS acid)

Child under 30 kg: 100 to 150 mg/kg 2 times daily
Child 30 kg and over and adult: 4 g 2 times daily (max. 12 g daily)
Weight Daily dose Oral solution or sachet
(kg) (mg) PAS sodium

5 1000-1500 19 ml x 2

6 1200-1800 19 ml x 2

7 1400-2100 25 ml x 2

8 1600-2400 25 ml x 2

9 1800-2700 25 ml x 2

10 2000-3000 50 ml x 2

11 2200-3300 50 ml x 2

12 2400-3600 50 ml x 2

13 2600-3900 50 ml x 2

14 2800-4200 50 ml x 2

15 3000-4500 50 ml x 2

16 3200-4800 75 ml x 2

17 3400-5100 75 ml x 2

18 3600-5400 75 ml x 2

19 3800-5700 75 ml x 2

20 4000-6000 75 ml x 2

21 4200-6300 75 ml x 2

22 4400-6600 75 ml x 2

23 4600-6900 75 ml x 2

24 4800-7200 80 ml x 2

25 5000-7500 80 ml x 2

26 5200-7800 80 ml x 2

27 5400-8000 80 ml x 2

28 5600-8000 80 ml x 2

29 5800-8000 80 ml x 2
 30-70 8g 1 sachet x 2

> 70 8-12 g 1 to 1½ sachet x 2

Contra-indications, adverse effects, precautions

Avoid in patients with severe renal disease.
Avoid or use with caution in patients with hepatic impairment or gastric ulcer.
May cause :
frequent gastrointestinal disturbances (nausea, vomiting, gastritis, diarrhoea);
hypothyroidism, hepatotoxicity, hypersensitivity reactions.
Monitor combination with ethionamide/prothionamide (increased risk of gastrointestinal disturbances and hypothyroidism).
For the management of adverse effects see Appendix 17.
Pregnancy: use only if benefits outweigh the risks (safety not established).
Breastfeeding: avoid breastfeeding during treatment (safety not established).

Monitoring
Symptomatic monitoring.
Liver and thyroid function.

Patient instructions
Mix the powder with 100 ml water.
Take with food to limit gastrointestinal disturbances.

Remarks
To increase gastrointestinal tolerance, start with a low dose, e. g. for an adult : 2 g 2 times daily for 1 to 2 weeks, then 4 g 2
times daily.

Storage
– – Below 25 °C
Pretomanid (Pa)
Update: October 2022

Forms and strengths

200 mg tablet

Dosage
Adolescent 15 years and over and adult: 200 mg once daily, in combination with :
bedaquiline, linezolid and moxifloxacin (BPaLM)
bedaquiline, linezolid and clofazimine (BPaLC)
bedaquiline and linezolid (BPaL)
Maximum dose: 200 mg daily

Age Daily dose (mg) 200 mg tablet

< 15 years Do not administer −

≥ 15 years 200 1

Contra-indications, adverse effects, precautions

Do not administer if one of the drugs included in the regimen is contraindicated.
T he contribution of pretomanid to the adverse effects of pretomanid-containing regimens is not determined.
For adverse effects of companion drugs see individual drug information sheets.
Pregnancy: use if benefits outweigh the risks (safety not established).
Breastfeeding: avoid breastfeeding during treatment (safety not established).

Monitoring
Symptomatic monitoring.
For monitoring of companion drugs see individual drug information sheets.

Patient instructions
Take with food.

Storage
– – Below 25 °C
Pyrazinamide (Z)
Update: January 2022

Forms and strengths

400 mg tablet
150 mg dispersible tablet, to be dispersed in 10 ml water

Dosage
Child under 30 kg: 35 mg/kg (30 to 40 mg/kg) once daily
Child 30 kg and over and adult: 25 mg/kg (20 to 30 mg/kg) once daily
Maximum dose: 2000 mg daily
Renal insufficiency: 25 mg/kg 3 times a week
Weight Daily dose 400 mg 150 mg
(kg) (mg) tablet dispersible tablet

5 150-200 – 1 tab

6 180-240 – 1 tab

7 210-280 – 2 tab

8 240-320 – 2 tab

9 270-360 – 2 tab

10 300-400 – 3 tab

11 330-440 – 3 tab

12 360-480 – 3 tab

13 390-520 – 3 tab

14 420-560 – 3 tab

15 450-600 – 3 tab

16 480-640 – 4 tab

17 510-680 – 4 tab

18 540-720 – 4 tab

19 570-760 – 4 tab

20 600-800 – 5 tab

21 630-840 – 5 tab

22 660-880 – 5 tab

23 690-920 – 5 tab

24 720-960 2½ tab –

25 750-1000 2½ tab –

26 780-1040 2½ tab –

27 810-1080 2½ tab –

28 840-1120 2½ tab –

29 870-1160 2½ tab –
 30-35 800 2 tab –

36-45 1000 2½ tab –

46-55 1200 3 tab –

56-70 1600 4 tab –

> 70 2000 5 tab –

Contra-indications, adverse effects, precautions

Do not administer to patients with hypersensitivity to pyrazinamide, severe hepatic impairment or severe gout.
May cause: gout and arthralgias, hepatotoxicity, gastrointestinal disturbances (epigastric pain, nausea and vomiting),
hypersensitivity reactions; rarely, photosensitivity.
For the management of adverse effects see Appendix 17.
Pregnancy: no contra-indication
Breastfeeding: no contra-indication

Monitoring
Symptomatic monitoring.
Liver function in patients with hepatic impairment or under drug-resistant T B treatment.

Patient instructions
Take with or without food.
150 mg tablets should be dispersed in 10 ml water.
Protect your skin from sun.

Remarks
For patients on drug-susceptible T B treatment, pyrazinamide is given as part of a fixed-dose combination.
For the 6HRZ-Eto regimen for drug-susceptible T B meningitis, the dose of pyrazinamide is 40 mg/kg once daily (max. 2000 mg
daily).

Storage
– – Below 25 °C
Rifabutin (Rfb)
Update: January 2022

Forms and strengths

150 mg capsule

Dosage
Child and adult: 5 to 10 mg/kg once daily
Maximum dose: 300 mg daily
Weight Daily dose 150 mg
(kg) (mg) capsule

5 25-50 −

6 30-60 −

7 35-70 −

8 40-80 −

9 45-90 −

10 50-100 −

11 55-110 −

12 60-120 −

13 65-130 −

14 70-140 −

15 75-150 1 caps

16 80-160 1 caps

17 85-170 1 caps

18 90-180 1 caps

19 95-190 1 caps

20 100-200 1 caps

21 105-210 1 caps

22 110-220 1 caps

23 115-230 1 caps

24 120-240 1 caps

25 125-250 1 caps

26 130-260 1 caps

27 135-270 1 caps

28 140-280 1 caps

29 145-290 1 caps
 30-35 300 2 caps

36-45 300 2 caps

46-55 300 2 caps

56-70 300 2 caps

> 70 300 2 caps

Contra-indications, adverse effects, precautions

Do not administer to patients with hypersensitivity to rifamycins or history of severe haematological disorders
(thrombocytopenia, purpura) during a previous treatment with a rifamycin.
Administer with caution to patients with severe renal impairment or hepatic or haematological disorders.
May cause:
gastrointestinal disturbances, hepatotoxicity;
haematological disorders (leukopenia, anaemia, thrombocytopenia), hypersensitivity reactions;
reversible uveitis.
For the management of adverse effects see Appendix 17.
Reduce the dose of rifabutin:
in patients taking boosted protease inhibitors (Appendix 19);
if rifabutin toxicity is suspected in patients taking clarithromycin, fluconazole or itraconazole.
Rifabutin reduces the effect of many drugs (macrolides, some antiretrovirals, some hormones, warfarin, etc.):
in patients taking antiretrovirals see Appendix 19;
in women using contraception, use injectable medroxyprogesterone or an intrauterine device;
for the other drugs, adjust dosage if necessary.
Pregnancy and breastfeeding: avoid (safety not established). If used in late pregnancy, administer phytomenadione (vitamin K1)
to the mother and the neonate.

Monitoring
Symptomatic monitoring.
Liver function in patients with hepatic disease.
Full blood count.

Patient instructions
Take with or without food.
Harmless orange-red discoloration of the urine, faeces, sweat, saliva, sputum, tears and other body fluids.

Storage
– – Below 25 °C
Rifampicin (R)
Update: January 2022

Forms and strengths

300 mg capsule and 150 mg tablet

Dosage
Child under 30 kg: 15 mg/kg (10 to 20 mg/kg) once daily
Child 30 kg and over and adult: 10 mg/kg (8 to 12 mg/kg) once daily
Maximum dose: 600 mg daily
Hepatic impairment: 8 mg/kg once daily max.
Weight Daily dose 300 mg 150 mg
(kg) (mg) capsule tablet

5 50-100 − ½ tab

6 60-120 − ½ tab

7 70-140 − ½ tab

8 80-160 − 1 tab

9 90-180 − 1 tab

10 100-200 − 1 tab

11 110-220 − 1 tab

12 120-240 − 1 tab

13 130-260 − 1½ tab

14 140-280 − 1½ tab

15 150-300 − 1½ tab

16 160-320 1 tab −

17 170-340 1 tab −

18 180-360 1 tab −

19 190-380 1 tab −

20 200-400 1 tab −

21 210-420 1 tab −

22 220-440 1 tab −

23 230-460 1 tab −

24 240-480 1 tab −

25 250-500 1 tab −

26 260-520 1 tab −

27 270-540 1 tab −

28 280-560 1 tab −

29 290-580 1 tab −
 30-35 300 1 tab −

36-45 450 1½ tab −

46-55 450 1½ tab −

56-70 600 2 tab −

> 70 600 2 tab −

Contra-indications, adverse effects, precautions

Do not administer to patients with hypersensitivity to rifamycins or history of severe haematological disorders
(thrombocytopenia, purpura) during a previous treatment with a rifamycin.
Avoid or administer with caution to patients with hepatic disorders.
May cause:
hepatotoxicity;
influenza-like symptoms, thrombocytopenia, hypersensitivity reactions.
For the management of adverse effects see Appendix 17.
Rifampicin reduces the effect of many drugs (antimicrobials, some antiretrovirals, some hormones, antidiabetics,
corticosteroids, phenytoin, direct-acting antivirals for chronic hepatitis C, warfarin, etc.):
in patients taking antiretrovirals see Appendix 19;
in women using contraception, use injectable medroxyprogesterone or an intrauterine device;
in the event of concomitant fluconazole administration, administer each drug 12 hours apart (rifampicin in the morning,
fluconazole in the evening);
for the other drugs, adjust dosage if necessary.
Pregnancy and breastfeeding: no contra-indication. If used in late pregnancy, administer phytomenadione (vitamin K1) to the
mother and the neonate.

Monitoring
Symptomatic monitoring.
Liver function in patients with hepatic disease.

Patient instructions
Take without food (or with a small amount of food to increase gastrointestinal tolerance).
Harmless orange-red discoloration of the urine, faeces, sweat, saliva, sputum, tears and other body fluids.

Remarks
For patients on drug-susceptible T B treatment, rifampicin is given as part of a fixed-dose combination.
For the 6HRZ-Eto regimen for drug-susceptible T B meningitis, the dose of rifampicin is 20 mg/kg once daily (max. 600 mg
daily).
Rifampicin is also used in the treatment of latent T B infection.

Storage
– – Below 25 °C
Rifapentine (P)
Update: October 2022

Forms and strengths

300 mg and 150 mg coated tablets

Dosage
Child 12 years and over and adult 40 kg and over: 1200 mg once daily

Age Daily dose (mg) 300 mg tablet

< 12 years Do not administer −

≥ 12 years 1200 4

Contra-indications, adverse effects, precautions

Do not administer to patients with hypersensitivity to rifamycins or history of severe haematological disorders
(thrombocytopenia, purpura) during a previous treatment with rifamycins.
Avoid or administer with caution to patients with hepatic disorders.
May cause:
hepatotoxicity;
influenza-like symptoms, thrombocytopenia, hypersensitivity reactions.
For the management of adverse effects see Appendix 17.
Rifapentine reduces the effect of many drugs (antimicrobials, some antiretrovirals, some hormones, antidiabetics,
corticosteroids, phenytoin, direct-acting antivirals for chronic hepatitis C, warfarin, etc.):
in patients taking antiretrovirals see Appendix 19.
in women using contraception, use injectable medroxyprogesterone or an intrauterine device;
in the event of concomitant fluconazole administration, administer each drug 12 hours apart (rifampicin in the morning,
fluconazole in the evening);
for the other drugs, adjust dosage if necessary.
Pregnancy and breastfeeding: not recommended (safety not established).

Monitoring
Symptomatic monitoring.
Liver function in patients with hepatic disease.

Patient instructions
Take with food.
Harmless orange-red discoloration of the urine, faeces, sweat, saliva, sputum, tears and other body fluids.

Remarks
While rifampicin should be taken on an empty stomach, rifapentine is better absorbed if taken with food.
Also comes in fixed dose combination containing 300 mg of rifapentine/300 mg of isoniazid which can be used in the treatment
regimen 2HPZ-Mfx/2HP-Mfx for drug-susceptible T B.
Rifapentine is also used in the treatment of latent T B infection in children, adolescents, and adults.
Storage
– – Below 25 °C
Streptomycin (S)
Update: January 2022

Forms, strengths and route of administration

Powder for injection, in vial of 1 g streptomycin base, to be dissolved in 4 ml of water for injection, for IM injection
DO NOT ADMINIST ER BY IV INJECT ION.

Dosage
Adolescent 30 kg and over and adult: 12 to 18 mg/kg once daily
Adult 60 years and over: 15 mg/kg 3 times a week
Maximum dose: 1000 mg daily
Renal insufficiency: 12 to 15 mg/kg 2 or 3 times a week

T he daily doses take into account the displacement volume (see note below).

Daily dose (ml) - IM injection

Weight Daily dose
(1 g in 4 ml of water for injection;
(kg) (mg)
final volume 4.83 ml; 207 mg/ml)

5-29 Not used in patients < 30 kg

30-33 500 2.4 ml

34-40 600 2.8 ml

41-45 700 3.4 ml

46-50 800 4 ml

51-70 900 4.4 ml

> 70 1000 Entire volume

Note: displacement volume

Powders for injection are usually formulated such that after reconstitution the final content of the vial corresponds to an adult
dose. Errors may occur when only part of the reconstituted solution is to be administered and no allowance is made for the
displacement volume. T he risk of error increases the greater the weight of the powder and the smaller the volume of solvent used.

Contra-indications, adverse effects, precautions

Do not administer to children or adolescents under 30 kg and patients with allergy to aminoglycosides.
Administer with caution to patients 60 years and over or patients with pre-existing renal, vestibular, auditory or severe hepatic
impairment.
May cause:
ototoxicity, nephrotoxicity, electrolyte disturbances; rarely, hypersensitivity reactions;
local pain after injection.
For the management of adverse effects see Appendix 17.
 Avoid or monitor combination with other ototoxic and/or nephrotoxic drugs (furosemide, amphotericin B, tenofovir, etc.)
Pregnancy: CONT RA-INDICAT ED
Breastfeeding: no contra-indication

Monitoring
Symptomatic monitoring.
Audiometry, serum creatinine and electrolytes (K, Ca, Mg).

Patient instructions
Maintain a good fluid intake to limit renal problems.

Remarks
Use a different site for each injection (absorption may be delayed if the same site is used repeatedly).

Storage
– Below 25 °C
Patient instructions
Update: January 2022

Patients on drug-susceptible T B treatment

Patients on drug-resistant T B treatment
Patients on drug-susceptible TB treatment
T B drugs are usually well tolerated. However, inform patients that they should immediately seek medical attention in the event of:

Skin rash
Yellowing of the skin or eyes or dark urine
Numbness or tingling of fingers or toes
Decreased urination
Palpitations
Blurred vision, reduced visual acuity, blind spot, green-red colour blindness, eye pain, sensitivity to light
Pain, burning, swelling of a tendon or muscle
Pain or swelling in the joints
Patients on drug-resistant TB treatment
Inform patients that they should immediately seek medical attention in the event of:

Skin rash
Yellowing of the skin or eyes or dark urine
Numbness or tingling of fingers or toes
Decreased urination
Palpitations
Dizziness or hearing loss
Blurred vision, reduced visual acuity, blind spot, green-red colour blindness, eye pain, sensitivity to light
Muscle cramps, spasms, or weakness
Pain, burning, swelling of a tendon or muscle
Pain or swelling in the joints
Personality changes (depression, aggressive behaviour, anxiety)
Severe abdominal upset or severe nausea, vomiting, black or bloody stools
Unusual bleeding
Appendix 11. Use of tuberculosis drugs in pregnant or
breastfeeding women
Update: October 2022
 TB Evidence and recommendations
drugs

FQs For DR-T B: commonly used in pregnant women despite limited data. Associated with low birth weight in one
observational study [1] . As FQs reduce mortality from DR-T B, the benefits often outweigh the risks.
Avoid breastfeeding if possible [2] (no absolute contra-indication).
For DS-T B: do not use the regimen 2HPZ-Mfx/2HP-Mfx in pregnant or breastfeeding women.

Bdq No evidence of fetal harm in animal studies. Associated with low birth weight in one observational study [1] . As Bdq
reduces mortality from DR-T B, the benefits often outweigh the risks.
Avoid breastfeeding if possible (high concentrations in human and animal breast milk) [3] [4] .

Lzd Few reported cases of use in pregnant women. Fetal harm in animal studies. As Lzd reduces mortality from DR-T B,
the benefits often outweigh the risks.
Avoid breastfeeding if possible (no data).

Cfz Despite common use for leprosy and MDR-T B in pregnant women, few data on pregnancy outcomes. Fetal harm in
animal studies.
Use during pregnancy only if the benefits outweigh the risks.
Avoid breastfeeding if possible (no data). If used, inform mother of possible (and reversible) skin discolouration of the
breastfed infant.

Cs, Trd Use during pregnancy only if the benefits outweigh the risks (no data).
No contra-indication during breastfeeding.

Dlm Use during pregnancy only if benefits outweigh the risks (limited human data, fetal harm in animal studies).
Avoid breastfeeding if possible (high concentrations in animal breast milk).

Ipm/Cln, Use during pregnancy and breastfeeding only if the benefits outweigh the risks (no data).
Mpm

Am, S Contra-indicated in pregnancy. No contra-indication during breastfeeding [2] .

Eto, Pto For DR-T B: contra-indicated in pregnancy (fetal harm in animal studies [5] ).
In breastfeeding women, use only if the benefits outweigh the risks (limited data).
For DS-T B: do not use the regimen 6HRZ-Eto in pregnant or breastfeeding women.

PAS Use in pregnancy only if the benefits outweigh the risks (limited human data, no fetal harm in animal studies).
Avoid breastfeeding if possible (no data).

R, Z, H, No contra-indication during pregnancy and breastfeeding.

E

Pa Use during pregnancy and breastfeeding only if the benefits outweigh the risks (no human data, no fetal harm in animal
studies [6] ).

P, Rfb Not recommended during pregnancy and breastfeeding.

For more specific recommendations for pregnant and breastfeeding women see Chapter 9, Chapter 10, and Appendix 10.
References
1. Loveday M, Hughes J, Sunkari B, et al. Maternal and Infant Outcomes Among Pregnant Women Treated for Multidrug/Rifampicin-Resistant
Tuberculosis in South Africa . Clin Inf ect Dis. 2021;72(7):1158-1168.
ht t ps://www.ncbi.nlm.nih.gov/pmc/art icles/PMC8028100/pdf /ciaa189.pdf

2. World Healt h Organizat ion. WHO consolidated guidelines on tuberculosis. Module 4: treatment - drug-resistant tuberculosis treatment.
Geneva: World Health Organization; 2020.
ht t ps://apps.who.int /iris/bit st ream/handle/10665/332397/9789240007048-eng.pdf ?sequence=1&isAllowed=y

3. Court et al. Bedaquiline exposure in pregnancy and breastfeeding in women with rifampicin-resistant tuberculosis; November 2021.
ht t ps://www.aut horea.com/doi/pdf /10.22541/au.163726220.09199594/v1

4. FDA product inf ormat ion Sit uro 2012 (bedaquiline).

ht t ps://www.accessdat a.f da.gov/drugsat f da_docs/label/2012/204384s000lbl.pdf

5. World Healt h Organizat ion. Companion handbook to the WHO guidelines for the programmatic management of drug-resistant tuberculosis.
Geneva. 2014.
ht t ps://apps.who.int /iris/bit st ream/handle/10665/130918/9789241548809_eng.pdf ;jsessionid=EFA574D0A45F34FAF833F58C2443130B?
sequence=1

6. TB Alliance product inf ormat ion pret omanid 2019.

ht t ps://www.t balliance.org/sit es/def ault /files/asset s/Pret omanid_Full-Prescribing-Inf ormat ion.pdf
Appendix 12. Dose adjustments in renal insufficiency
Update: January 2022

12.1 Normal values for creatinine clearance (CrCl)

Women: 88 to 128 ml/minute
Men: 97 to 137 ml/minute

12.2 Estimation of CrCl (Cockcroft-Gault method)

12.2.1 If serum creatinine is in µmol/litre
Weight (kg) x (140 – age) x (constant)
–––––––––––––––––––––––––––––––––––––
Serum creatinine (µmol/litre)

T he constant = 1.04 for women and 1.23 for men

12.2.2 If serum creatinine is in mg/dl

Weight (kg) x (140 – age)
–––––––––––––––––––––––––––––
72 x serum creatinine (mg/dl)

For women, the result must be multiplied by 0.85.

Example (calculation with serum creatinine in µmol/litre) a :

A woman on cycloserine (Cs), 50 kg, 46 years, serum creatinine = 212 µmol/litre
Step 1 - Calculate the CrCl:
50 x (140 – 46) x 1.04 = 4,888
4,888 ÷ 212 = 23.1
For this patient, the CrCl is 23.1 ml/minute
Step 2 - CrCl is < 30 ml/minute, administer 250 mg of Cs once daily or 500 mg 3 times a week.
Step 3 - Adjust each drug as required according to the table below.

12.2.3 Overweight and obese patients

For overweight (BMI > 25) or obese (BMI > 30) patients, use the ideal body weight (IBW) rather than the actual body weight to
avoid overestimation of the CrCl.

T he IBW is calculated using the patient’s height b :

IBW women (kg) = 45.4 + 0.89 (height in cm – 152.4)
IBW men (kg) = 49.9 + 0.89 (height in cm – 152.4)

Example:
A woman, weight 70 kg, height 160 cm (BMI = 27.3, i.e. overweight)
45.4 + 0.89 (160 – 152.4) = 45.4 + 0.89 (7.6) = 45.4 + 6.76 = 52.2
For this patient, the IBW is 52 kg.

12.3 Dosing of TB drugs in renal insufficiency

 Drugs Dose and frequency if Clcr < 30 ml/min

H No change

R No change

Z 25 mg/kg 3 times a week (not daily)

E 15-25 mg/kg 3 times a week (not daily)

Rfb No change

Mfx No change

Lfx 750-1000 mg 3 times a week (not daily)

Bdq (a) No change

Lzd No change

Cfz No change

Cs (b) 250 mg once daily or 500 mg 3 times a week

Dlm(a) No change

Ipm/Cln 750 mg every 12 hours for CrCl 20-40 ml/min

500 mg every 12 hours for CrCl < 20 ml/min

Mpm 750 mg every 12 hours for CrCl 20-40 ml/min

500 mg every 12 hours for CrCl < 20 ml/min

Am(c) 12-15 mg/kg 2 or 3 times a week (not daily)

S (c) 12-15 mg/kg 2 or 3 times a week (not daily)

Eto/Pto No change

PAS (d) 4 g 2 times daily

Hh No information

Amx/Clv (e) No change

P No change

Pa No information

(a) Use wit h caut ion in case of severe renal insuf ficiency or dialysis (limit ed dat a).
(b) Monit or caref ully f or signs of neurot oxicit y.
(c) Use wit h caut ion in case of severe renal insuf ficiency or dialysis (increased risk of nephrot oxicit y and ot ot oxicit y).
(d) Avoid sodium salt f ormulat ions of PAS in pat ient s wit h severe renal disease (risk of excessive sodium load).
(e) On a case-by-case basis, consider once daily dosing (e.g. 500/125 mg every 24 hours) f or pat ient s wit h CrCl < 10 ml/minut e.

Footnotes
(a) If possible use a calculat or t o avoid errors, e.g.:
ht t ps://www.mdcalc.com/creat inine-clearance-cockcrof t -gault -equat ion

(b) If possible use a calculat or t o avoid errors, e.g.:

ht t ps://www.mdcalc.com/ideal-body-weight -adjust ed-body-weight
Appendix 13. Daily dose of tuberculosis drugs using
fixed-dose combinations
Update: October 2022

13.1 Conventional regimens for drug-susceptible tuberculosis

Intensive phase

Paediatric formulations Adult formulations

Weight
(kg) HZR E E H EHZR
50/150/75 mg 100 mg 400 mg 100 mg 275/75/400/150 mg

4-7 1 tab 1 tab − − −

8-11 2 tab 2 tab − − −

12-13 3 tab 2 tab − − −

14-15 3 tab 3 tab − − −

16-17 4 tab 3 tab − − −

18-22 4 tab − 1 tab − −

23-29 − − − 1 tab 2 tab

30-34 − − − − 2 tab

35-39 − − − − 2½ tab

40-54 − − − − 3 tab

55-70 − − − − 4 tab

> 70 − − − − 4 tab

For example:
A child weighing 9 kg takes 2 tablets of HZR (50 mg/150 mg/75 mg) + 2 tablets of E (100 mg) once daily.
A child weighing 20 kg takes 4 tablets of HZR (50 mg/150 mg/75 mg) + 1 tablet of E (400 mg) once daily.

Note: ethambutol is not routinely given to all children: see Chapter 9.

Continuation phase
 Weight Paediatric formulation Adult formulation
(kg) HR 50/75 mg HR 75/150 mg

4-7 1 tab −

8-11 2 tab −

12-14 3 tab −

15-21 − 2 tab

22-29 − 3 tab

30-34 − 2 tab

35-39 − 3 tab

40-54 − 3 tab

55-70 − 4 tab

> 70 − 4 tab

TB drugs Daily dosing in patients < 30 kg Daily dosing in patients ≥ 30 kg

E 15 to 25 mg/kg 15 to 25 mg/kg

H 7 to 15 mg/kg 4 to 6 mg/kg

Z 30 to 40 mg/kg 20 to 30 mg/kg

R 10 to 20 mg/kg 8 to 12 mg/kg

13.2 2HPZ-Mfx/2HP-Mfx regimen for drug-susceptible tuberculosis

Weight HP P Z Mfx
(kg) 300/300 mg 300 mg 400 mg 400 mg

40-49 1 tab 3 tab 4 tab 1 tab

50-64 1 tab 3 tab 4 tab 1 tab

≥ 65 1 tab 3 tab 5 tab 1 tab

TB drugs Daily dosing in patients < 40 kg Daily dosing in patients ≥ 40 kg

H – 300 mg

Z – 1600 to 2000 mg

P – 1200 mg

Mfx – 400 mg
Appendix 14. Monitoring of patients on drug-
susceptible tuberculosis treatment
Update: October 2022

A cross "X" with no brackets indicates that the exam should be performed in all patients.
A cross between brackets "(X)” indicates that the exam should only be performed in certain patients.
 Treatment
End of
Baseline
Until end of treatment
W2 M1 M2 M3 M4 M5 M6
treatment (a)

Clinical visits

Vital signs, weight, etc. X X X X X X X X At each visit X

Adverse events X X X X X X X At each visit X

Bacteriological tests

Rapid molecular
X (X)
tests (b)

Smear microscopy X X X X X

Culture and pDST (c) (X) (X) (X)

Other investigations

If
Radiography (d) (X) (X) If indicated
indicated

If
Full blood count (e) (X) (X) (X)
indicated

If
Liver function(f) (X) (X) (X) (X) (X) (X) (X)
indicated

If
Serum creatinine (g) (X)
indicated

HbA1c, blood If
X
glucose (h) indicated

If
HIV, HBV, HCV (i) X (X)
indicated

CD4 and viral load (j) (X) (X) (X)

(a) For t reat ment s longer t han 6 mont hs.

(b) Rapid molecular t est s:
• Xpert MTB/RIF (or Ult ra) and Xpert MTB/XDR (or GenoType MTBDRsl if Xpert MTB/XDR not available).
• Repeat RMTs if microscopy or cult ure is posit ive at Mont h 2 or lat er.
(c) Cult ure and pDST t o first - and second-line drugs:
• At baseline if RMTs are not available, t o det ect rif ampicin and isoniazid resist ance or rif ampicin resist ance mut at ions not det ect ed by
RMTs.
• At Mont h 2 or lat er, if RMTs show a new resist ance.
• At Mont h 4, if microscopy is st ill posit ive.
(d) Radiography:
• Chest : at baseline f or children wit h presumpt ive PTB, pat ient s wit h non-bact eriologically confirmed PTB, suspicion of ot her int ra-
t horacic TB, t hen if indicat ed (e.g. worsening respirat ory sympt oms, non-response t o TB t reat ment ).
• Bone: at baseline t hen every 6 mont hs f or pat ient s wit h bone and joint TB.
(e) For pat ient s on AZ T or rif abut in.
(f ) For pat ient s wit h pre-exist ing hepat ic disease: AST and ALT (and bilirubin if AST or ALT are elevat ed).
(g) For pat ient s wit h renal insuf ficiency.
(h) For all pat ient s t o det ect diabet es. If diabet es is det ect ed, monit or according t o st andard prot ocols.
(i) For all pat ient s, unless document ed HIV, hepat it is B and C st at us; HIV t est every 6 mont hs in high HIV prevalence areas.
(j) For HIV-inf ect ed pat ient s.
Appendix 15. Monitoring of patients on drug-resistant
tuberculosis treatment
Update: October 2022

A cross "X" with no brackets indicates that the exam should be performed in all patients.
A cross between brackets "(X)” indicates that the exam should only be performed in certain patients.
 Post end
Treatment of
treatment
End of
Baseline
treatment
Until end
W1 W2 W3 W4 W5 W6 W7 M2 M3 of M6 M12
treatment

Clinical visits

Vital signs, At each

X X X X X X X X X X X
weight, etc. visit

Adverse At each
X X X X X X X X X X
events visit

(a)
BPNS (X) (X) (X) (X) (Monthly) (X) (X)

Visual function
(b) (X) (X) (X) (X) (Monthly) (X) (X)
tests

(c)
Audiometry (X) (X) (X) (X) (Monthly) (X) (X)

(d)
ECG (X) (X) (X) (X) (X) (X) (X) (Monthly)

Bacteriological tests

Smear
X X X X Monthly X X X
microscopy

Culture X X X X Monthly X X X

Rapid
If culture or microscopy positive at M4
molecular X
(e) or later
tests

(f)
Full pDST X If culture positive at M4 or later

Other investigations

(g)
Radiography X X

Full blood
(h) X (X) (X) (X) (X) (Monthly) (X)
count

Liver
(i) X (X) (X) (X) (Monthly)
function

Serum
creatinine and X (X) (X) (X) (Monthly)
(j)
potassium

HbA1c, blood X
(k)
 (k)
glucose

HIV, HBV,
(l) X If indicated
HCV

CD4 and viral (Every

(m) (X)
load 6 months)

(n) (Every
T SH (X) (X)
3 months)

Pregnancy
(o) X If indicated
test

(a) For pat ient s on Lzd.

(b) For pat ient s on E, Lzd or t hionamides: visual acuit y and colour vision deficiency.
(c) For pat ient s on Am or S.
(d) Elect rocardiogram, f or pat ient s t aking:
• < 2 moderat e or severe QT-prolonging TB drugs or < 3 QT-prolonging drugs (TB and non-TB): at baseline t hen mont hly.
• ≥ 2 moderat e or severe QT-prolonging TB drugs or ≥ 3 QT-prolonging drugs (TB and non-TB) or wit h ot her risk f act ors f or QT
prolongat ion or TdP: once a week f or t he first mont h, t hen once a mont h.
(e) Rapid molecular t est s:
• Xpert MTB/RIF (or Ult ra) and Xpert MTB/XDR (or GenoType MTBDRsl if Xpert MTB/XDR not available).
• Repeat Xpert MTB/XDR (or GenoType MTBDRsl) if cult ure or microscopy is posit ive at Mont h 4 or lat er.
(f ) For first - and second-line drugs. Repeat if cult ure is posit ive at Mont h 4 or lat er.
(g) At baseline, t hen every 6 mont hs:
• Chest x-ray f or pat ient s wit h PTB,
• Bone x-ray f or pat ient s wit h ost eoart icular and spinal TB.
(h) For all pat ient s at baseline, t hen:
• Pat ient s on Lzd: every 2 weeks f or t he first 2 mont hs, t hen once a mont h.
• Pat ient s on AZ T: once a mont h f or t he first 2 mont hs, t hen if indicat ed.
(i) For all pat ient s: AST and ALT (and bilirubin if AST or ALT are elevat ed).
(j) For all pat ient s at baseline. Repeat if indicat ed. For pat ient s on Am or S: once a mont h or more f requent ly if indicat ed.
(k) For all pat ient s t o det ect diabet es. If diabet es is det ect ed, monit or according t o st andard prot ocols.
(l) For all pat ient s, unless document ed HIV, hepat it is B and C st at us; HIV t est every 6 mont hs in high HIV prevalence areas.
(m) For HIV-inf ect ed pat ient s.
(n) For pat ient s on t hionamides or PAS.
(o) For adolescent s and women of childbearing age. Repeat if indicat ed.
Appendix 16. Additional investigations in drug-
resistant tuberculosis
Update: October 2022

16.1 Electrocardiogram (ECG)

T he QT interval is measured in milliseconds (ms) from the start of the QRS complex to the end of the T wave of the ECG. Its value
varies depending on the heart rate and should be corrected accordingly (QTc).

To calculate the QTc interval it is recommended to use the Fridericia formula (QTcF) a :
QTcF = QT interval divided by cube root of the interval between two waves R

Normal QTc values:

< 470 ms in women
< 450 ms in men

16.2 Brief peripheral neuropathy screen (BPNS)

Adapted from AIDS Clinical Trial Group (ACT G) [1] [2] .

Step 1. Grade subjective symptoms

Ask the patient to rate the severity of symptoms on a scale from 0 (no symptoms) to 10 (most severe symptoms) for right (R)
and left (L) feet and legs.
Enter the score for each symptom in the corresponding column.

Symptoms R L

a. Pain or burning sensation

b. Pins and needles sensation (tingling sensation)

c. Numbness (lack of feeling)

Symptoms may be unilateral or bilateral and of different intensity. Use the highest subjective sensory neuropathy score to obtain
the severity grade.

Subjective sensory neuropathy score Severity grade

0 0

1-3 1

4-6 2

7-10 3

Step 2. Evaluate vibration perception

Place the vibrating 128 Hz tuning fork on the top of the distal joint of the right and left big toes and begin counting the seconds.
Ask the patient to say when they no longer feel the vibration.

T here is a decrease in vibration perception if the patient feels the vibration for 10 seconds or less on both sides.

Vibration perception Result Grade

Felt > 10 seconds Normal 0

Felt 6-10 seconds Mild loss 1

Felt < 5 seconds Moderate loss 2

Not felt Severe loss 3

Step 3. Evaluate tendon reflexes

Using a reflex hammer, tap the Achilles tendon on each ankle.

Step 4. Make a diagnosis

Diagnosis of peripheral neuropathy is based on the combination of:
subjective symptoms of grade 1, 2 or 3, and
at least one bilateral objective finding:
reduced vibration perception (grade 1, 2 or 3), or
decreased reflexes (absent or hypoactive reflexes)

16.3 Ishihara test

T he patient is asked to look at a set of plates with circles made of dots of different sizes and colours.

Some circles contain dots that form a number or a shape clearly visible to patients with normal colour vision. Patients who cannot
see or have difficulty distinguishing numbers or shapes have a red-green colour vision defect.
Some circles contain dots that form a number or a shape visible to patients with red-green colour vision defect, but invisible to
patients with normal colour vision.

T he test should be performed as per the manufacturer’s instructions.

Footnotes
(a) When possible, use a calculat or t o avoid errors, e.g. ht t ps://www.mdcalc.com/correct ed-qt -int erval-qt c

References
1. Cat herine L. Cherry, St even L. Wesselingh, Luxshimi Lal, Just in C. McArt hur. Evaluation of a clinical screening tool for HIV-associated sensory
neuropathies. Neurology Dec 2005, 65 (11) 1778-1781.
ht t ps://n.neurology.org/cont ent /65/11/1778.long

2. Mawunt u, Art hur H.P. Mahama, Corry N. et al. Early detection of peripheral neuropathy using stimulated skin wrinkling test in human
immunodeficiency virus infected patients; A cross-sectional study. Medicine: July 2018 - Volume 97 - Issue 30.
ht t ps://journals.lww.com/md-journal/Fullt ext /2018/07270/Early_det ect ion_of _peripheral_neuropat hy_using.28.aspx
Appendix 16. Basic TB infection control risk
assessment tool
Control risk assessment tool.pdf
Appendix 17. Management of adverse effects
Update: January 2022

Gastrointestinal disorders
Abdominal pain
Diarrhoea
Epigastric pain
Hepatotoxicity
Metallic taste
Nausea and vomiting
Neurotoxicity
Depression
Headache
Optic neuritis
Ototoxicity
Peripheral neuropathy
Psychosis
Seizures
Endocrine disorders
Gynecomastia
Hypothyroidism
Dermatological disorders
Alopecia
Fungal infection
Photosensitivity
Skin reactions
Musculoskeletal disorders
Arthralgias
Tendinitis/tendon rupture
Miscellaneous
Electrolyte disorders
Haematologic disorders
Lactic acidosis
Nephrotoxicity
QT prolongation
Gastrointestinal disorders
Abdominal pain
Diarrhoea
Epigastric pain
Hepatotoxicity
Metallic taste
Nausea and vomiting
Abdominal pain
Eto or Pto, PAS, Cfz, Lzd, FQs, H, Z

Abdominal pain is common with MDR/RR-T B treatment. It can be the early sign of severe adverse effects such as hepatitis,
pancreatitis, or lactic acidosis.

Deposition of Cfz crystals may cause severe abdominal pain (presentation of acute abdomen). In this case, stop Cfz until
symptoms resolve.
Diarrhoea
PAS, FQs, Eto or Pto, Amx/Clv, Ipm/Cln or Mpm

Diarrhoea, along with cramping, can cause significant difficulty and lead to discontinuation of treatment.

PAS often causes diarrhoea at treatment initiation. It usually resolves or improves substantially after some weeks.

For diarrhoea with no blood in stools and no fever, loperamide PO (adult: 4 mg followed by 2 mg after each loose stool to a
maximum of 10 mg daily) may be used intermittently, especially when the patient needs to attend social functions or return to work,
but not on a daily basis.
Encourage the patient to tolerate some degree of diarrhoea. Prevent (encourage fluid intake including oral rehydration solution) or
treat dehydration.

In the event of severe diarrhoea, particularly if associated with blood in stools, severe abdominal pain, or fever > 38.5 °C, consider
other causes such as acute bacterial enteritis, or pseudo-membranous colitis (C. difficile) due to FQs. Do not use loperamide in
bloody diarrhoea or diarrhoea associated with fever.

Monitor serum electrolytes in patients with severe diarrhoea on QT prolonging drugs.

Epigastric pain
PAS, Eto or Pto, FQs, E, Z

Gastritis (epigastric burning or cramp relieved by eating) or dyspepsia (epigastric pain or discomfort following meals, often
accompanied by bloating, sensation of fullness and nausea) are frequent with PAS, Eto or Pto.

For gastritis:
omeprazole PO: 20 mg once daily in the morning for 7 to 10 days. In severe or recurrent cases, dose may be increased to 40
mg once daily and the treatment may be prolonged for up to 8 weeks.
Histamine H2-antagonists (e.g., ranitidine) may be an alternative.

For dyspepsia:
omeprazole PO: 10 mg once daily in the morning for 4 weeks

Haematemesis (vomiting of blood) and melena (black stools) are symptoms of a bleeding gastric ulcer and require urgent
intervention.
Hepatotoxicity
Z, H, R, P, Eto or Pto, PAS, Bdq, Amx/Clv

All T B drugs may cause hepatotoxicity. However, certain drugs are likely more responsible than others for this adverse effect.

T he liver function tests (LFTs) used for the diagnosis and monitoring of hepatotoxicity are serum levels of alanine aminotransferase
(ALT ), aspartate aminotransferase (AST ) and bilirubin.

A mild, transient elevation of ALT and AST may be observed during treatment and usually remains asymptomatic. Significant
hepatotoxicity is usually symptomatic.

Clinical features resemble that of viral hepatitis. Early symptoms include malaise, fatigue, loss of appetite, muscle and joint pain.
Nausea, vomiting and abdominal pain are common in severe toxicity. Jaundice, scleral icterus, dark (tea-coloured) urine and
discoloured stool are signs of clinical worsening.
Differential diagnosis includes infections (e.g. viral hepatitis, cytomegalovirus, leptospirosis, yellow fever, rubella), chronic alcohol
use and hepatotoxicity due to other drugs (e.g. anti-epileptics, paracetamol, sulfa drugs, erythromycin).

Clinical hepatitis can be fatal and action should be taken immediately.

1) General management
Patient with symptoms of hepatitis:
Stop all T B drugs and perform LFTs:
a) AST or ALT or bilirubin ≥ 3 times upper limit of normal (ULN): wait for resolution of symptoms, perform LFTs weekly and
restart T B treatment when LFTs are < 3 times ULN.
b) AST, ALT and bilirubin < 3 times ULN and mild symptoms (no jaundice): restart T B treatment, closely monitor the patient and
perform LFTs weekly. Continue T B treatment as long as LFTs levels remain < 3 ULN and there are no signs of worsening
hepatitis.

Patient without symptoms of hepatitis, but elevated LFTs:

a) AST or ALT ≥ 5 times ULN or bilirubin ≥ 3 ULN: stop all T B drugs and perform LFTs weekly. Restart T B treatment when LFTs
return < 3 times ULN.
b) AST and ALT < 5 times ULN and bilirubin < 3 ULN: continue T B treatment and perform LFTs weekly.
If LFTs continue to increase after stopping T B treatment, then ongoing progressive drug-induced hepatitis or an unrelated cause
of hepatitis should be suspected.

2) Patient on DS-TB treatment

In most cases, the same treatment can be resumed without incident. T he objective is to resume the initial regimen or an alternative
regimen as rapidly as possible.

If symptoms reappear or LFTs re-increase, try to reintroduce the T B drugs one by one. Start with E and R and reintroduce H three
to 7 days later. If E, R and H have been introduced and the LFT abnormalities have not recurred, do not introduce Z as it is most
likely the causative agent.

T he alternative regimen depends on the drug causing hepatotoxicity:

Z is involved: 2 (HR)E/7 (HR)
H is involved: 6RZE-Lfx
R is involved: treat as MDR/RR-T B

3) Patient on DR-TB treatment

When restarting T B treatment, start with the drugs least hepatotoxic (E, Lfx or Mfx, Cs or Trd, Dlm, Am or S, Ipm/Cln or Mpm), then
drugs moderately hepatotoxic (Bdq, Cfz, Amx/Clav), then give the most hepatotoxic (Z, H, R, Eto or Pto, PAS). Add drugs one at a
time every 5 to 7 days, and check LFTs.
T he causative agent can generally be identified in this manner. It can be discontinued if not essential and replaced with another less
hepatotoxic T B drug.

Note: hepatotoxicity may occur in patients receiving regimens containing pretomanid (Pa-Mfx-Z and Bdq-Pa-Lzd). However, the
responsible drug has not been determined.
Metallic taste
Eto or Pto, FQs

Encourage the patient to tolerate this adverse effect. Normal taste returns when T B treatment is stopped.
Nausea and vomiting
Eto or Pto, PAS, Z, Amx/Clv, Cfz, Lzd, Ipm/Cln or Mpm, Bdq

Nausea and vomiting are frequent, especially with Eto or Pto and PAS during the first few weeks of treatment. To avoid nausea
and vomiting, these drugs can be initiated at low dose with gradual increase over one to 2 weeks.
Always look for:
Signs of dehydration (thirst, dry mouth, sunken eyes)
Serum electrolytes disorders if vomiting
Signs of hepatitis
Haematemesis and melena
Dehydration and electrolyte disorders should be corrected as necessary.
Treat nausea and vomiting aggressively, using a stepwise approach:

First phase - Adjust administration of the responsible drug

Try to identify the drug(s) causing nausea and vomiting. Stop it/them for 2 or 3 days, then gradually reintroduce.
Administer the drug(s) causing nausea at bedtime.
Patient on PAS:
Take one hour after taking other T B drugs.
If PAS is taken once daily, take in 2 divided doses.
Encourage the patient: nausea and vomiting often improve over the first weeks and may resolve entirely with time.

Second phase - Administer an antiemetic

ondansetron PO 30 minutes before T B drugs:
Child 6 months to < 2 years: 2 mg once daily
Child 2 to < 4 years: 2 mg 2 times daily
Child 4 to < 12 years: 4 mg 2 times daily
Child ≥ 12 years and adult: 4 to 8 mg 2 times daily
Ondansetron is a QT prolonging drug and should be avoided in patients on Cfz, Bdq, Mfx, Dlm, Lfx.

In adults, when ondansetron is not available or is to be avoided:

metoclopramide PO:
Adult < 60 kg: 5 mg 3 times daily
Adult ≥ 60 kg: 10 mg 3 times daily
T he interval between each dose should be at least 6 hours (even in the event of vomiting). Do not use metoclopramide if
neurological problems develop.
or
promethazine PO 30 minutes before T B drugs:
Adult: 25 mg

Third phase - Reduce the dose or temporarily stop the responsible drug
Patient on Eto or Pto: consider reducing dose by one weight class (e.g. if taking 1000 mg daily, reduce to 750 mg). Avoid giving
an adult weighing more than 33 kg less than 500 mg daily of Eto or Pto.
Patient on Cfz: reduce the dose by half.
In the event of intractable nausea and vomiting, stop all T B drugs until symptoms resolve.

Note: if there is excessive anxiety over the nausea caused by T B drugs, consider adding diazepam PO (adult: 5 mg 30 minutes
before T B drugs). T his can help to avoid “anticipation nausea”. T he treatment must be short as benzodiazepines may cause
dependence and tolerance. Do not exceed 10 days of treatment.
Neurotoxicity
Depression
Headache
Optic neuritis
Ototoxicity
Peripheral neuropathy
Psychosis
Seizures
Depression
Cs or Trd, Eto or Pto

T he treatment of MDR/RR-T B may contribute to depression. Depressive symptoms may fluctuate during T B treatment. History of
depression may increase the risk of developing depression during treatment, but is not a contra-indication to use of any of the
above T B drugs.

Consider lowering the dose or discontinuing a suspected T B drug, provided this does not compromise the effectiveness of T B
treatment.

Other interventions include psychological support to patient (and family if needed) and, when necessary antidepressant treatment.
Avoid selective serotonin reuptake inhibitors and tricyclic antidepressants with Lzd (risk of serotonin syndrome).

Suicidal ideation is more commonly associated with Cs or Trd. Evidence of suicidal ideation should prompt immediate action:
Keep the patient in the hospital for surveillance.
Stop Cs or Trd.
Lower the dose of Eto or Pto to 500 mg daily until the patient is stable.
Refer to mental health consultation.
Headache
Cs or Trd, Bdq, Dlm, FQs

Headache is common during the first months of treatment. It can be treated with analgesics.
Headache due to Cs or Trd can be prevented by starting at low dose (250 to 500 mg daily), with gradual increase over 1 to 2
weeks.
Optic neuritis
Lzd, E; rarely H, Eto or Pto

T his adverse effect is typically due to Lzd and E.

Symptoms include loss of red-green colour distinction, reduced visual acuity and central scotoma. Loss of red-green colour
distinction is the first sign. In this case, stop the suspect drug immediately and permanently.

Symptoms are usually reversible after discontinuation of the drug, but optic neuritis due to Lzd may be irreversible.
Ototoxicity
Aminoglycosides; rarely: Cs or Trd, FQs, Eto or Pto, Lzd

Hearing loss, tinnitus and/or vestibular disorders (vertigo, dizziness, imbalance) are signs of ototoxicity.
Ototoxicity is most commonly observed in patients receiving large cumulative doses of aminoglycosides. Concomitant use of loop
diuretics (furosemide), particularly in patients with renal insufficiency, may exacerbate ototoxicity.

Baseline and follow-up audiometry is required to detect early hearing loss. Hearing loss in high frequencies (> 4000 Hz) is often the
first sign of auditory toxicity due to aminoglycosides and can be unnoticed by the patient.

In case of hearing loss, tinnitus or vestibular disorders, discontinue the suspected drug if this does not compromise the
effectiveness of T B treatment.
If no alternative is available, reduce the dose of aminoglycoside (3 times weekly rather than daily, e.g. on Monday, Wednesday and
Friday). Continuation of aminoglycoside therapy despite hearing loss almost always results in deafness.

T innitus and vestibular disorders can rarely be due to the following drugs: Cs or Trd, FQs, Eto or Pto and Lzd. If stopping the
aminoglycoside does not improve symptoms, other drugs can be discontinued to see if the symptoms improve, then reintroduced
one by one to see if symptoms return.
Drug-induced tinnitus and vestibular disorders can be irreversible.
Peripheral neuropathy
Lzd, Cs or Trd, H, Eto or Pto; rarely E, FQs

Peripheral neuropathy refers to damage to the nerves located outside of the central nervous system. T his adverse effect is
associated to several T B drugs but is commonly due to Lzd, Cs or Trd and H.

Peripheral neuropathy occurs most commonly in the lower extremities. Signs and symptoms include sensory disturbances (e.g.
numbness, tingling, burning, pain, loss of temperature sensation), difficulty walking, weakness and decreased or absent deep tendon
reflexes. At times, sensory changes may occur in upper extremities.
Linezolid-induced neuropathy is extremely painful and may be non-reversible.

1) Patient on DS-TB treatment

To prevent isoniazid-induced peripheral neuropathy:
Administer pyridoxine PO to patients at risk (pregnant and breastfeeding women, neonates and breastfed infants, and patients
with HIV infection, alcohol dependency, malnutrition, diabetes, chronic hepatic disease, and renal impairment) along with their T B
treatment:
Neonate, infant and child < 5 kg: 5 mg once daily
Child ≥ 5 kg and adult: 10 mg once daily

If peripheral neuropathy develops:

Administer pyridoxine PO
Child < 12 years: 10 to 20 mg 2 times daily
Child ≥ 12 years: 50 mg 2 times daily
Adult: 50 mg 3 times daily
For pain management: ibuprofen or paracetamol.

2) Patient on DR-TB treatment

To prevent peripheral neuropathy:
Administer pyridoxine PO:
Patient on H: all patients at risk, as for DS-T B.
Patient on Cs or Trd, Lzd, Hh and Eto or Pto:
Neonate, infant, child: 1 to 2 mg/kg (usual range in child: 10 to 50 mg) once daily
Adult: 100 mg once daily

If peripheral neuropathy develops:

Patient on Lzd: stop Lzd immediately. For mild symptoms not requiring analgesics, Lzd can be restarted at a lower dose
once symptoms subside. For moderate or severe symptoms, stop Lzd permanently. Consider additional T B drugs to
reinforce the therapeutic regimen.
Patient on Cs or Trd or Hh: stop these drugs. If they are essential to the regimen, they may be re-introduced once symptoms
subside.
Other contributing causes should be addressed (e.g., diabetes or malnutrition).
Administer pyridoxine PO: 100 mg daily in adults until symptoms resolve.
For pain management: ibuprofen or paracetamol.
Physiotherapy may be of benefit.
If these measures are insufficient, treat as chronic neuropathic pain, but avoid tricyclic antidepressants in patients on Lzd (risk
of serotonin syndrome).
Do not use carbamazepine (strong CYP450 inducer) in patients on Bdq or Dlm.
Psychosis
Cs or Trd, FQs, H, Eto or Pto

Visual or auditory hallucinations, delusions, paranoia and bizarre behaviour are hallmarks of psychosis. Health personnel should be
familiar with these symptoms to allow early detection.

T he most likely T B drug involved is Cs or Trd, but psychotic symptoms may occur with FQs, H, Eto or Pto.

History of psychosis is not a contra-indication to the use of the above-mentioned drugs, though psychiatric symptoms are more
likely to occur in such circumstances.

Some patients may need antipsychotic treatment throughout the duration of T B treatment.
Psychosis is generally reversible upon discontinuation of T B treatment.

For acute psychosis:

If patients are at risk of harming themselves or others: urgent hospitalisation.
Stop Cs or Trd.
Treat the acute psychosis.

Once psychotic symptoms have resolved, antipsychotic treatment can be tapered most of the time. Cs or Trd can be resumed,
generally at lower dose.
Antipsychotic treatment should be continued until the end of Cs or Trd treatment and then can usually be stopped gradually (do not
stop it abruptly).

If the patient does not tolerate the reintroduction of Cs or Trd, another T B drug should be considered.
Whenever psychosis occurs in a patient on Cs or Trd, check the serum creatinine. Cs or Trd is 100% renally excreted and a
decrease in renal function can result in toxic levels of Cs or Trd. In this case, a temporary suspension of Cs or Trd and re-
introduction at an adjusted dose may be needed (Appendix 12).
Seizures
Cs or Trd, H, FQs, Eto or Pto, Ipm/Cln or Mpm

All the above-mentioned drugs may cause seizures. However, rule out or treat other possible causes (e.g., epilepsy, meningitis,
encephalitis, alcohol withdrawal, hypoglycaemia, stroke, cancer, or toxoplasmosis in HIV-infected patients).

In the event of seizures, measure blood glucose level and blood electrolytes. Measure also serum creatinine. With impaired renal
function, T B drugs can reach toxic levels, causing seizures. Dosage adjustment may be necessary (Appendix 12).
A history of seizures is not an absolute contra-indication to the use of the above-mentioned drugs. However, do not use Cs or Trd
if there is an alternative. In patients with epilepsy, seizures should be controlled with anti-epileptic therapy before starting T B
treatment.

T he use of T B drugs (especially H and R) in patients on antiepileptics may lead to decreased blood levels of antiepileptics and
seizures.

In patients without history of seizures, a first episode of seizures on T B treatment is likely due to the T B drugs. However, none of
the above drugs leave permanent damage.

If a patient has a seizure for the first time:

Stop suspected T B drugs for a short period.
Start antiepileptic treatment, especially in the event of repeated seizures after stopping suspected drugs. Do not use
carbamazepine or phenytoin in patients receiving Bdq or Dlm (strong CYP450 inducers).
Reintroduce T B drugs that are essential to T B treatment. Usually, they can be resumed at a lower dose, but the effective dose
should be reached as soon as possible.

Antiepileptic treatment may be necessary until the end of the T B treatment.

Endocrine disorders
Gynecomastia
Hypothyroidism
Gynecomastia
Eto or Pto

Eto or Pto may cause breast enlargement in men and women. Galactorrhoea has been reported. Encourage the patient to tolerate
this adverse effect. Symptoms resolve when Eto or Pto is stopped.
Hypothyroidism
Eto or Pto, PAS

Symptoms appear slowly, are nonspecific and may include fatigue, muscle weakness, daytime sleepiness, excessive sensitivity to
cold, dry skin, coarse hair, constipation, facial puffiness, and depression.
T hyroid enlargement and delayed deep tendon reflexes may be seen on examination.

T he diagnosis is confirmed by a serum level of thyroid-stimulating hormone (T SH) ≥ 10 mIU/litre.

Eto or Pto and PAS may cause hypothyroidism, even more frequently when used together. If possible the responsible T B drugs
should be replaced but may be continued if there is no alternative.

In both cases, replacement hormone therapy is required:

levothyroxine PO
Adult < 60 years: initially 75 to 100 micrograms once daily then, adjust in 25 microgram increments every 4 to 12 weeks according
to response. Usual maintenance dose is 100 to 200 micrograms daily.
Adult ≥ 60 years and/or with significant cardiovascular disease: initially 25 micrograms once daily then, adjust in 25 microgram
increments every 4 to 12 weeks according to response. Usual maintenance dose is 100 to 125 micrograms daily.

T he daily dose should be taken at the same time each day, 30 to 60 minutes before a meal or a caffeine-containing drink (e.g.
coffee, tea) or other drugs to improve absorption.
Monitor T SH until it normalizes below 5 mIU/litre.
T hyroid dysfunction resolves upon discontinuation of T B treatment. Hormone replacement may be discontinued several months
after T B treatment completion.
Dermatological disorders
Alopecia
Fungal infection
Photosensitivity
Skin reactions
Alopecia
H, Eto or Pto

Temporary and mild hair loss may (rarely) occur in the first months of treatment. Encourage the patient to tolerate this adverse
effect. Symptoms resolve when T B treatment is stopped.
Fungal infection
FQs

Vaginal, penile, skin fold and oral candidiasis may occur in patients taking FQs.
Topical antifungals or short-course oral antifungals are usually effective.
Photosensitivity
Cfz, FQs; rarely Z

Advise patient to avoid direct exposure to the sun, wear protecting clothes (e.g. long sleeves) and use sunscreen.
Skin reactions
All TB drugs

Skin reactions such as itch and skin rash may be hypersensitivity reactions due to any T B drug. General signs of hypersensitivity
such as fever, dizziness, vomiting and headache may also occur.
Skin reactions usually appear early during treatment, often in the first month, but rarely during the first week. Most skin reactions are
mild or moderate. Severe – even lethal – exfoliative dermatitis (Stevens­Johnson's syndrome) may occasionally occur, particularly
if administration of the T B drug continues after first signs of hypersensitivity appear.

Minor skin reactions

Simple itching: symptomatic treatment (e.g. antihistamine) without interrupting or modifying the T B treatment.
Localised, mild skin rash, with or without itching:
Rule out other possible causes unrelated to T B drugs (i.e. scabies, contact dermatitis).
If no obvious other cause, stop all T B drugs.
Give symptomatic treatment (an antihistamine, no corticosteroids except in emergencies) and wait for disappearance of
symptoms.
Once the reaction has resolved, try to determine which drug caused the reaction (see re- challenge of T B drugs below).

Major skin reactions

Stop all T B drugs.
In the event of anaphylaxis, manage according to standard emergency protocol (epinephrine, etc.).
For severe generalised rash, a parenteral corticosteroid may be needed.
Once the reaction has resolved, try to determine which T B drug caused the reaction (see re- challenge of T B drugs below).
Never re-introduce any drug resulting in Stevens-Johnson syndrome or anaphylaxis.

Rechallenge of TB drugs
Each T B drug can be reinstated as a “challenge” (a test-dose). Introduce one drug at a time, starting with the drugs least likely to
have caused the reaction.
Give the drugs in a setting where a health care provider can respond to any severe allergic reaction.

If a test-dose of any drug causes a reaction, discontinue this drug, unless it is deemed essential to the regimen (in this case,
desensitisation can be considered).

First-­line T B drugs
Start with isoniazid over 3 days then add rifampicin over 3 days, etc.

Drug Likelihood Trial dose 1 Trial dose 2 Trial dose 3

H Least likely 50 mg Full dose Full dose

R Least likely 75 mg 300 mg Full dose

Z Likely 250 mg 1000 mg Full dose

E Likely 100 mg 500 mg Full dose

Note: if the initial reaction to treatment is severe, a weaker trial dose should be used (approximately 1/10th of the dose
indicated for trial dose 1).
Second-­line T B drugs
Start with the most important drug in a regimen unless there is suspicion that it is the cause of the reaction. Restart each T B
drug one after the other, starting at about 1/10 of the dose on Day 1, half-dose on Day 2 and full dose on Day 3.
Musculoskeletal disorders
Arthralgias
Tendinitis/tendon rupture
Arthralgias
Z, Rfb, H, Bdq, FQs

Arthralgias generally diminish over time. Serum uric acid levels are frequently elevated, but this is of little clinical relevance. Anti-
hyperuricaemic therapy is of no proven benefit in these patients.

Begin therapy with an anti-inflammatory agent, e.g. ibuprofen PO (adult: 400 to 800 mg 3 times daily). Paracetamol PO (adult: 500
to 1000 mg 3 times daily) may also help bring relief when given together with an anti-inflammatory drug.
If symptoms fail to resolve, consider lowering the dose of the suspected agent (most often Z), if this does not compromise the
effectiveness of T B treatment.
Tendinitis/tendon rupture
FQs

In the acute phase, the main symptom of tendinitis is pain when moving the affected joint or palpating the tendon.
In later phase, continuous pain and tendon thickening or nodularity may be present.
T he Achilles tendon is involved in most cases, but other joints may be affected (shoulder, hand, etc.).
New and intense physical activities are not recommended during a treatment with a FQ.
Tendinitis is more common in older patients, patients with renal insufficiency or under corticosteroids.

Tendon rupture is a complication of tendinitis. Signs and symptoms include a snap or pop sound at the time of rupture, bruising,
inability to move the joint and a lack of continuity of the tendon on palpation.

Early detection of tendinitis, symptomatic treatment, and discontinuation of FQ can prevent tendon rupture. If the T B treatment is
likely to fail without the FQ, try to continue the FQ. Inform the patient that tendon rupture may occur, but that FQ is essential to
prevent T B treatment failure.

Symptomatic treatment:
Rest the joint involved.
Pain management: application of ice, and ibuprofen PO:
Adult: 400 to 600 mg every 4 to 6 hours when required, maximum dose: 2400 mg daily.
Miscellaneous
Electrolyte disorders
Haematologic disorders
Lactic acidosis
Nephrotoxicity
QT prolongation
Electrolyte disorders
Aminoglycosides

Electrolyte disorders can occur with the aminoglycosides and are typically reversible with discontinuation of therapy.

Other potential causes (vomiting and diarrhoea) should be treated if present.

If clinical signs of mild to moderate hypokalaemia develop (i.e. muscle cramps, spasms or weakness) or if serum potassium level is
between 2.5-3.4 mmol/litre, potassium replacement is required:
potassium chloride PO:
Child under 45 kg: 2 mmol/kg (2 ml/kg) daily in divided doses
Child 45 kg and over and adult: 30 mmol (30 ml) 3 times daily

If clinical signs of severe hypokalaemia develop (i.e. marked muscle weakness, cardiac arrhythmias) or if serum potassium level is <
2.5 mmol/litre, hospitalise and urgently administer potassium chloride by slow IV infusion.

For a patient with hypokalaemia:

Monitor serum potassium levels and QT interval until they return to normal.
Consider magnesium PO if serum magnesium cannot be measured. Untreated hypomagnesaemia may lead to "resistance" to
correction of hypokalaemia. Magnesium should be taken at least 2 hours before or 4 to 6 hours after the FQs.
Haematologic disorders
Lzd, R, P, Rfb, E

Most T B drugs can cause hematological disorders that may involve any blood cells (red cells, white cells, platelets). However, the
T B drugs most involved are Lzd and rifamycins.

Severity grade
Anaemia Neutropenia Thrombocytopenia
in adults (a)

Mild 10.5 - 9.5 g/dl 1500 - 1000/mm³ 100,000 - 75,000/mm³

Moderate < 9.5 - 8.0 g/dl < 1000 - 750/mm³ < 75,000 - 50,000/mm³

Severe < 8.0 - 6.5 g/dl < 750 - 500/mm³ < 50,000 - 20,000/mm³

Life-threatening < 6.5 g/dl < 500/mm³ < 20,000/mm³

(a) Adapt ed f rom NIAID Division of Microbiology and Inf ect ious Diseases, severit y scale, Nov-2007.

1) Patient on DS-TB treatment

Rifamycins can cause potentially life-threatening thrombocytopenia. T his is more common when used intermittently.
Clinical features may include minor haemorrhage (e.g. epistaxis) or severe haemorrhage and thrombocytopenic purpura.

Measure platelets when thrombocytopenia is suspected:

Moderate thrombocytopenia: stop the rifamycin and monitor platelets weekly until > 75,000/mm3.
Severe thrombocytopenia: stop all T B drugs. Hospitalise. Treat shock or severe haemorrhage.

In any event rifamycins should not be reintroduced.

2) Patient on DR-TB treatment

Lzd may cause anemia, neutropenia and/or thrombocytopenia.
 Toxicity Management

Mild to moderate In all cases:

Monitor carefully.
Consider reduction of dose of Lzd (e.g. 300 mg once daily or 600 mg 3 times weekly in
adults).
For moderate anemia: consider adding erythropoietin (EPO).
For moderate neutropenia:
Stop Lzd.
Restart at reduced dose once toxicity has decreased to ‘mild’.

Severe In all cases:

Stop Lzd and monitor carefully.
If Lzd is essential to the regimen, restart at reduced dose once toxicity has decreased to
‘mild’.
For severe anemia: consider adding EPO.

Life-threatening Stop Lzd and monitor carefully.

Hospitalise.
Perform blood transfusion
If Lzd is essential to the regimen consider restarting at reduced dose once toxicity has
decreased to ‘mild’.
Lactic acidosis
Lzd

Lactic acidosis is a rare but potentially life-threatening increase of lactic acid in the bloodstream, that can be due to mitochondrial
toxicity of certain T B drugs, usually Lzd.
Signs and symptoms include nausea and vomiting, abdominal pain, extreme fatigue, muscle cramps and increased respiratory rate.

If lactic acidosis is suspected, measure blood lactate and pH. Blood lactate ≥ 4 mmol/litre and pH < 7.35 confirm the diagnosis.
Stop Lzd and hospitalise for adequate management.

Note that lactic acidosis may also be due to ART (NRT Is).
Nephrotoxicity
Aminoglycosides

Nephrotoxicity is diagnosed by a rise in serum creatinine above baseline. In its early form it is usually asymptomatic, which means it
is very important to monitor serum creatinine while on aminoglycosides.

Symptomatic cases may present with decreased urine output, evidence of volume overload (edema, anasarca or shortness of
breath) or uremic symptoms such as mental status changes (confusion, somnolence).

Comorbidities such as diabetes or chronic renal failure are not a contra-indication to treatment with aminoglycosides, though
caution must be exercised in such circumstances.
If renal failure occurs:
Stop the aminoglycoside.
Rule out other causes of renal failure (e.g. diabetes, dehydration, other drugs, congestive heart failure, urinary obstruction,
urinary tract infection, prostate hypertrophy).
Adjust doses of other T B drugs to creatinine clearance (Appendix 12).
Monitor serum creatinine and electrolytes every 1 to 2 weeks until stable.
If renal function stabilises or improves and if the drug is essential, resume the aminoglycoside adjusted to creatinine clearance
(Appendix 12).
QT prolongation
Cfz, Mfxh, Bdq, Mfx, Dlm, Lfx

Some T B drugs may cause QT prolongation and predispose to torsades de pointes, arrhythmias, and sudden death.
ECG should be performed before starting T B treatment then monitored throughout the course of treatment in patients taking
these drugs.
Possible other causes include other QT prolonging drugs (Appendix 19), hypothyroidism and genetic causes such as long QT
syndrome.

Mild or moderate QT prolongation (QTcF > 470 in women and > 450 ms in men and ≤ 500 ms) is common. Severe QT prolongation
(QTcF > 500 ms or increase > 60 ms from baseline) is relatively rare.

In all cases:
Measure serum electrolytes and correct electrolyte disorders if necessary.
Measure thyroid stimulating hormone (T SH) and, if necessary, treat hypothyroidism.
For mild and moderate QT prolongation: monitor ECG at least weekly.
For severe QT prolongation: stop QT prolonging drugs, hospitalise, perform continuous ECG monitoring until QT returns to
normal. Once the patient is stable (normal QT CF and no electrolyte disorders), critical QT prolonging T B drugs can be
reintroduced:
Patient on Bdq: consider resuming while suspending all other QT prolonging drugs.
Patient on Mfx: use Lfx instead.
Patient on Cfz or Dlm: consider stopping if alternatives are available.
Patient on QT prolonging non-T B drug: consider stopping it.
Appendix 17. Air change per hour (ACH) measurement
recommendations
T he ACH in a mechanically ventilated room should remain more or less constant, whereas natural ventilation will vary according to:
Whether the doors/windows/vents in that room are open or not;
Wind speed and direction;
Temperature and humidity differential between inside and outside.

T he ACH rate is one tool among others to assess if:

T he efficiency of the system in delivering the outdoor air and in removing the pollutants to each location in the room;
T he overall airflow direction is from clean to dirty zones.

To calculate the ACH in a given room:

Start by drawing a sketch of the room;
Measure the dimensions of the room and calculate the volume (in m3);
Measure the surface (in m2) of all the openings/vents in the room and air direction across the openings/vents;
Measure the air speed (in meters per second) using an anemometer.

ACH = 0.65 x air speed (m/s) x opening area (m2) x 3600

–––––––––––––––––––––––––––––––––––––––––––––––––––––––––
Room volume (m3)

Summary of proposed specifications:

Surface Height Opening window

ACH
(m²) (m) surface area (m²)

Single rooms > 7.5 (2.5 x 3) >3 > 12 > 25%

Wards 4.5 m²/patient > 3.5 > 12 > 15%

Waiting rooms
3 m²/patient > 3.5 > 12 > 15%
(preferably outside)

Sputum collection areas

> 1.5 > 2.5 > 20 > 50%
(preferably outside)

Toilets > 1.2 > 2.5 > 12 > 25%

Consultation rooms > 7.5 (2.5 x 3) >3 > 12 > 25%

Central corridors
>2 >3 > 12 > 25%
(avoid in new buildings)

T here are two main techniques to measure the ventilation. T he most commonly used is the anemometer that measures the velocity
(speed) of air (see manufacturer’s recommendations for various types of anemometers). T he technique using the gas analyser is
difficult and should only be used by trained staff.
Appendix 18. Compassionate use
18.1 Definitions
T he term “compassionate use” refers to the use of potentially life-saving experimental treatments to patients suffering from a
disease for which no satisfactory authorised therapy exists and/or who cannot enter a clinical trial. For many patients, these
treatments represent their last hope.
Experimental treatment is below referred to as investigational new drug (IND).

18.2 Indications
Both MDR-T B and XDR-T B can be life-threatening diseases for which approved drugs alone may be ineffective. In some cases,
experimental T B drugs, used in combination with approved drugs, could potentially be effective or life-saving.

Compassionate use may be considered for patients presenting with a life-threatening condition (e.g. deteriorating clinical condition
due to T B and/or severe immune depression) when:
Available treatments have failed or are very likely to fail (e.g. regimen comprises less than 3 highly likely effective drugs and/or
clinical evolution shows that the treatment is not effective).
No medical or surgical options are appropriate.
At least one highly likely effective drug is available (based in the DST result and previous use by the patient). T he IND should
never be used in monotherapy. It should always be used in conjunction with other drug(s) with proven or probable efficacy in
order to prevent emergence of resistance to the IND. In that respect, will be taken into consideration on a case by case basis:
the number of remaining drug(s) and their bactericidal or bacteriostatic activity: at least one bactericidal or 2 bacteriostatic
drugs could be considered as a minimum;
the reliability of the DST to the remaining drug(s), treatment history prior to the last DST result;
the vulnerability to resistance amplification of the IND if known;
the use of the IND does not result in the discontinuation of an essential effective drug. Special attention will be paid if the
use of the IND imposes the replacement of an anti- T B drug by a less effective one.

Compassionate use might be considered for a single patient or a group of patients presenting similar characteristics.

T he use of two INDs would basically follow the same indications and conditions. Possible interactions and overlapping toxicity
between the INDs have to be taken into consideration.

18.3 Minimal requirements

Compassionate use should only be considered if conditions for an adequate management of DR-T B patients are in place: optimal
treatment regimen; clinical, biological and bacteriological monitoring; adherence support and follow-up. Results of DST by a
validated laboratory are critical to decision making.

In addition to the basic components of regular DR-T B case management a specific monitoring might be required for the use of an
IND.

It is essential that a reporting system is in place in order to diligently report any adverse events.

18.4 National regulations

In most countries, only drugs for which a marketing authorization has been granted by the national regulatory agency can be used in
humans. Some national regulatory agencies have developed mechanisms to facilitate the access to new drugs at different stages
of development, but before market approval. In this case, a party can apply for approval of an IND and then seek the proper
permission to import the drug to a country. T he use of an IND requires permission from the proper national regulatory authorities
and/or country ethic boards.
Appendix 18. Advantages and disadvantages of
ventilation techniques

Climate Technical considerations

Installation/
Cost Comments
equipment Cold Hot Assessment/ Installation/
calculation maintenance

Wind depending. No guarantee

Windows and
no yes simple very simple low on direction intensity and
doors
frequency.

Wind depending (no electricity

Natural
needed).
ventilation Whirly birds no yes very simple very simple low
No guarantee on intensity and
frequency.

Climate and wind depending.

Chimney no yes very simple simple medium
No guarantee on intensity.

Ceiling, wall and Improve dilution. Needs small

no yes simple simple low
Assisted desk fans energy power.
natural
ventilation Extractors/ Small energy power needed.
no yes simple very simple low
exhaust fans Could be solar power (R&D).

Relative pressure between

Heating
rooms. High consumption of
Mechanical ventilation and yes ideal difficult difficult high
energy. Could need filter, HEPA
air conditioning
filter and heat exchange.
Appendix 19. Drug interactions and overlapping
toxicities
Update: October 2022

19.1 Interactions between cytochrome P450 inducers/inhibitors and bedaquiline

Drugs interfering with the cytochrome P450 (CYP450) enzyme system should be avoided with bedaquiline.

Strong CYP450 inducers Moderate CYP450 inducers Effect

Rifampicin Efavirenz Decrease bedaquiline plasma

Phenytoin Rifapentine concentrations
Carbamazepine Rifabutin
Phenobarbital

Strong CYP450 inhibitors Moderate CYP450 inhibitors Effect

Atazanavir Erythromycin Increase bedaquiline plasma

Itraconazole Fluconazole concentrations
Clarithromycin Verapamil
Lopinavir
Nelfinavir
Ritonavir

Drugs metabolized by CYP Effect

Emtricitabine Can increase bedaquiline plasma

concentrations

T his list is not exhaustive. Clinicians should be informed of any cytochrome P450 inducers and inhibitors their patients may be
taking.

19.2 Overlapping toxicity of QT-prolonging drugs

TB drugs (mean QT interval prolongation)
Mild QT prolongation: delamanid (8.6 ms) [1] , levofloxacin (4.6 ms) [2] ,
Moderate QT prolongation: bedaquiline (12.3 ms) [2] , moxifloxacin (12.3 ms) [3] .
Strong QT prolongation: clofazimine (28.5 ms) [4] , moxifloxacin high dose (23.14 ms) [3] .

Non-TB drugs [5]

Antimalarials: artemisinine derivatives (high risk), quinine
Antipsychotics: haloperidol (high risk), chlorpromazine, fluphenazine, olanzapine, risperidone
Cardiac drugs: amiodarone (high risk), beta-blockers, digoxin
Oral azole antifungals: fluconazole, itraconazole
Macrolides: azithromycin, clarithromycin, erythromycin
Anti-nausea drugs: ondansetron
Antiretrovirals: boosted protease inhibitors, efavirenz

T his list is not exhaustive. Clinicians should be informed of any QT-prolonging drugs their patients may be taking.
19.3 Interactions between TB and antiretroviral drugs
AZT: zidovudine; AT V: atazanavir; 3T C: lamivudine; RAL: raltegravir; ABC: abacavir; DT G: dolutegravir; FT C: emtricitabine; T DF:
tenofovir disoproxil fumarate; LPV/r: lopinavir/ritonavir; EFV: efavirenz; RT V or r: ritonavir.
R: rifampicin; Rfb: rifabutin; P: rifapentine; Bdq: bedaquiline.

TB NRTI INI NNRTI Boosted PI

drugs (ABC, 3TC, TDF, AZT) (DTG, RAL) (NVP, EFV) (LPV/r, ATV/r, DRV/r)

R [6] [7] All NRTI DTG NVP ATV/r or DRV/r

Can be combined. Can be combined. Do not combine. Do not combine.
No dose adjustment. Double the dose of Replace NVP with Replace R with Rfb.
DT G (a) . DT G or EFV. LPV/r
RAL If not possible, Replace R with Rfb.
Can be combined. replace R with Rfb. If not possible and a PI is
Double the dose of EFV essential, dose adjustment is
RAL (b)
. Can be combined. required (c) .
No dose adjustment.

Rfb [7] All NRTI All INI NVP All boosted PI

Can be combined. Can be combined. Can be combined. Can be combined.
No dose adjustment. No dose adjustment. No dose adjustment. Reduce the dose of Rfb by half
Monitor Rfb toxicity. Monitor Rfb toxicity.
EFV
Do not combine.

P [6] [7] All NRTI All INI NVP All boosted PI

Can be combined. Can be combined. Do not combine. Do not combine.
No dose adjustment. No dose adjustment. Replace NVP with
DT G or EFV.
EFV
Can be combined.
No dose adjustment.

Bdq [7] Can be combined. All INI NVP All boosted PI

[8] No dose adjustment. Can be combined. Can be combined. Do not combine.
No dose adjustment. No dose adjustment. Replace boosted PI with DT G.
EFV If no alternative, closely
Do not combine. monitor ECG.
Replace EFV with
DT G or NVP.

(a) DTG: administ er 50 mg 2 t imes daily, rat her t han t he usual dose of 50 mg once daily.
(b) RAL: e.g. administ er 12 mg/kg 2 t imes daily, rat her t han t he usual dose of 6 mg/kg 2 t imes daily.
(c) LPV/r:
• Child: increase t he dose of RTV t o obt ain a one-t o-one (1:1) LPV/r rat io
• Adult : double t he dose (e.g. 800/200 mg 2 t imes daily, rat her t han t he usual dose of 400/100 mg 2 t imes daily)

For more information, see University of Liverpool HIV Drug Interaction Checker: https://www.hiv-druginteractions.org/checker.

19.4 Overlapping toxicities of antiretrovirals and TB drugs

Drugs strongly associated with the listed toxicities appear in bold lettering.
 Toxicity ARVs TB drugs Comments

Abdominal pain All ARVs Eto or Pto, Common. Often benign, but can be an early symptom of severe adverse effects (
PAS, Cfz, Appendix 17).
Lzd, FQs, H,
Z

Depression EFV, Cs or Trd, EFV: consider replacing EFV in the event of severe depression.
DTG FQs, Eto or DT G: can cause depression, but less frequently [9] .
Pto, H

Diarrhoea All PI, Eto or Pto, Common. Also consider opportunistic infections as a cause of diarrhoea or
DT G PAS, FQs, Clostridium difficile infection (pseudomembranous colitis).
Amx/Clv,
Ipm/Cln

Electrolyte TDF Am, S See Nephrotoxicity.

disorders (rare)

Haematological AZT Lzd Monitor blood count.

disorders Replace AZT in the event of bone marrow suppression.
For Lzd, see Appendix 17.
If the patient takes CMX, also consider CMX as a cause of haematological
disorders.

Headache AZT, Cs or Trd, Rule out bacterial or cryptococcal meningitis, toxoplasmosis, etc. Headache
EFV, Bdq, Dlm secondary to AZT, EFV, DT G and Cs or Trd are usually transient.
DTG

Hepatotoxicity NVP, Z, H, R, E, If severe, stop ART and T B drugs. When treatment is resumed, start the T B
EFV, PAS, drugs first (Appendix 17).
boosted Eto or Pto, If the patient takes CMX, also consider CMX as a cause of hepatotoxicity.
PIs, Bdq,
DT G Amx/Clav

Nausea and RTV, Eto or Pto, Persistent vomiting can be a result of more severe conditions, such as lactic
vomiting NVP, PAS, Z, acidosis and/or drug-induced hepatitis.
and Amx/Clv,
most Cfz, Lzd,
other Ipm/Cln,
ARVs Bdq

Nephrotoxicity TDF Am, S Avoid T DF in patients on aminoglycosides.

If an aminoglycoside is essential:
For patients already on ART, replace T DF with ABC
For new patients, start with AZT or ABC.
If T DF and aminoglycoside cannot be avoided, monitor serum creatinine,
creatinine clearance and electrolytes at least every 2 weeks.

Neurotoxicity EFV, Cs or Trd, EFV: numerous transient effects on the central nervous system during first 2-3
DTG H, Eto or weeks of treatment. If they do not resolve, consider replacing EFV. T here is
Pto, FQs limited data on the use of EFV with Cs or Trd; concomitant use is accepted
practice provided the patient is closely monitored for neurotoxicity.
 DT G: can cause insomnia and dizziness. Administer in the morning or consider
replacing with EFV, a boosted PI or RAL.

QT Boosted Cfz, Mfxh, For monitoring see Appendix 15.

prolongation PIs, EFV Bdq, Mfx,
Dlm, Lfx

Skin reactions ABC, All TB Do not re-introduce ABC (risk of anaphylaxis).

NVP, drugs Do not re-introduce any agent that may have caused Stevens-Johnson
EFV, syndrome.
and all If the patient takes CMX, also consider CMX as a cause of skin reactions.
other
ARVs

References
1. Dooley KE, Rosencrant z SL, Conradie F, et al. QT effects of bedaquiline, delamanid or both in patients with rifampicin-resistant-tuberculosis: a
phase 2, open-label, randomised, controlled trial. Lancet Inf ect Dis. 2021.

2. Et han Rubinst ein, John Camm. Cardiotoxicity of fluoroquinolones. Journal of Antimicrobial Chemotherapy, Volume 49, Issue 4, April 2002,
Pages 593–596.
ht t ps://academic.oup.com/jac/art icle/49/4/593/718753

3. Moon SJ, Lee J, An H, et al. The effects of moxifloxacin on QTc interval in healthy Korean male subjects. Drugs R D. 2014;14(2):63-71.
ht t ps://www.ncbi.nlm.nih.gov/pmc/art icles/PMC4070463/

4. Abdelwahab MT, Court R, Everit t D, Diacon AH, Dawson R, Svensson EM, Maart ens G, Dent i P. 2021. Effect of clofazimine concentration on
QT prolongation in patients treated for tuberculosis. Ant imicrob Agent s Chemot her 65:e02687-20.
ht t ps://doi.org/10.1128/AAC.02687-20

5. Khat ib R, Sabir FRN, Omari C, et al. Managing drug-induced QT prolongation in clinical practice. Post graduat e Medical Journal 2021;97:452-
458.
ht t ps://pmj.bmj.com/cont ent /97/1149/452.cit at ion-t ools

6. World Healt h Organizat ion. WHO Consolidated guidelines on tuberculosis. Module 1: Prevention. Geneva: World Healt h Organizat ion; 2020.
ht t ps://www.who.int /publicat ions/i/it em/9789240001503

7. Universit y of Liverpool HIV Drug Int eract ion Checker.

ht t ps://www.hiv-drugint eract ions.org/checker

8. World Healt h Organizat ion. WHO consolidated guidelines on tuberculosis. Module 4: treatment - drug-resistant tuberculosis treatment.
Geneva: World Healt h Organizat ion; 2020.
ht t ps://apps.who.int /iris/rest /bit st reams/1280998/ret rieve

9. Fet t iplace A, St ainsby C, Winst on A, et al. Psychiatric symptoms in patients receiving dolutegravir. J Acquir Immune Defic Syndr, 2017 Apr 1,
74 (4): 423.
ht t ps://www.ncbi.nlm.nih.gov/pmc/art icles/PMC5321108/
Appendix 19. Upper room ultraviolet germicidal
irradiation (UVGI) system
T he use of UVGI in the upper part of rooms may be effective in killing or inactivating M. tuberculosis generated by infected
persons.

19.1 Mechanism of action

UV lamps are installed into fixtures suspended from a ceiling or mounted on a wall. Fixtures are shielded with louvers or bafflers in
order to block radiation below the horizontal plane of the fixtures. UV lights create in the upper portion of the room a germicidal
zone where the bacilli are killed (Figure 1). Patients in the lower portion of the room are not exposed to UVGI lights. Good air mixing
is needed to transport the air (and thereby the bacilli) to the upper portion of the room. Disinfection is achieved through the rapid
dilution of contaminated lower room air with clean irradiated upper room air.

Figure 1

* 1 feet = 0.3048 m

From the WHO, Implementing the WHO Policy on TB Infection Control in Health-Care Facilities, Congregate Settings and
Households

T he lamps should irradiate the entire surface of the upper part of the room (Figure 2), in order to disinfect the largest possible
volume of air mixed at a low speed between the upper and lower part of the room.

UVGI Upper-room Irradiation

Figure 2
From Guidelines for the Utilization of Ultraviolet Germicidal Irradiation technology in controlling transmission of tuberculosis in
health care facilities in South Africa [1]

Several factors influence the efficiency of UVGI systems:

Ventilation rate: in controlled environment, at rates up to 6 air change per hour (ACH), UVGI systems increase the effect of air
cleaning to > 12 ACH [2] . But when ventilation rates are increased above 6 ACH, UVGI system effectiveness could be reduced
because the time for bacteria irradiation is shorter [3] [4] .
Effective mixing within the room may be provided by natural convection currents or fans, preferably, ceiling ones. Low velocity
ceiling fans boosted UVGI system’s effectiveness up to 33% when ACH was below 6 [5] [6] [7] .
Relative humidity: studies [8] [9] [10] have reported rapidly decreasing air cleaning effectiveness in UVGI systems when the relative
humidity goes above 70%.
Installation: the height of the room should be minimum 2.5 m and UVGI fixtures should be installed at the minimum height of 2.1
m. As a thumb rule, a 30W lamp should be sufficient for 18 m2 of surface [11] [12] , but room shape and type of fixture should be
taken into consideration when calculating the needs. For instance, wall-mounted lamps would have a smaller germicidal area
than ceiling-mounted ones. Lamps should be on whenever there is a risk of T B transmission. For example, in rooms with
hospitalized patients, the lamps should be turned on 24 hours a day.
Maintenance: see below.

19.2 Maintenance
Dust-covered and/or old UVGI lamps are less effective, hence the need for a careful maintenance, including regular cleaning:
Lamps and fixture surfaces should be wiped at least monthly (more often if necessary) with a cloth dampened with 70%
alcohol. Do not use water and soap or any detergent. T he cleaning should be performed when lamps and fixtures are cool.
Measurement of UVGI level must be done at installation and at least once a year. A UV light meter programmed to detect UV
light on a wavelength of 254 nm is needed. Measurements should be performed at eye level in the occupied zone (~ 1.6 m) and
in upper irradiated portion of the room, at a distance of 1.2 m from the fixture in all possible directions (imitating a circle with
measurements done while moving in circumference spaced of 1 m). Ideally, all upper room measurements should be around 30
μW/cm2 to 50 μW/cm2. Persons doing these measurements should wear protective equipment (UVprotective glasses, clothing
made of tightly woven fabric, soft cotton gloves) and cover exposed skin with opaque creams with solar-protection factors >
15.
UV lamps last between 5 000 and 10 000 hours of continue use (7 to 14 months). Check manufacturer’s information. After this
period, UV lamps rapidly lose effectiveness and need to be changed.

19.3 Disposal
UV lamps contain mercury and quartz and are considered as hazardous waste. Disposal is extremely difficult in many countries; this
should be considered before implementing them. If adequate disposal of the lamps by specialized enterprises is not possible in the
country, neither their repatriation; UV lamps should be disposed of by encapsulation (sealed in a metal 200 litre drum filled with
concrete and then buried away from water sources).

Safety considerations
Reflecting surfaces in the irradiation area of UV lamps must be avoided (i.e. oil painted ceilings, etc.).

At certain wavelengths (including UV-C) UV exposure may be harmful. Skin exposure can produce sunburn (erythema). Exposure of
the eyes can produce conjunctivitis (feeling of sand in the eyes, tearing) and/or keratitis (intense pain, sensitivity to light). T hese
symptoms typically commence 6 to 12 hours after exposure.

Despite the fact that these are reversible conditions, health care workers should immediately report them to the IC officer. T his
could mean that UV irradiation is higher than previously thought at lower room level (lamp poorly positioned? Reflecting surface?).

T he USA National Institute for Occupational Safety and Health (NIOSH) states that safe exposure limits are set below those found
to initiate eye irritation, the body surface most susceptible to UV. Next table shows the permissible exposure times for given
effective irradiances at 254 nm wavelength.
 Permissible exposure time (a)
Effective irradiance
(μW/cm 2)
(Units given) (Seconds)

8h 28,800 0.2

4h 14,400 0.4

2h 7,200 0.8

1h 3,600 1.7

30 min 1,800 3.3

15 min 900 6.7

10 min 600 10

5 min 300 20

1 min 60 100

30 s 30 200

10 s 10 600

1s 1 6,000

0.5 s 0.5 12,000

0.1 s 0.1 60,000

(a) The occupat ional exposure limit f or UV-C at 254 nm is 6,000 μJ/cm2. This can be also calculat ed wit h t he f ollowing f ormula: Dose (in
μJ/cm2) = Time (in seconds) * Irradiance (in μW/cm).

Exposures exceeding this limit would require the use of personal protection equipment to protect the skin and eyes.

In order to avoid overexposure of UVGI, education of health care workers should include basic information on UVGI systems and
their potential harmful effects of if overexposure occurs.

References
1. I Coker, E Nardell, B Fourie, P Brickner, S Parsons, N Bhagwandin and P Onyebujoh. Guidelines for the Utilisation of Ultraviolet Germicidal
Irradiation technology in controlling transmission of tuberculosis in health care facilities in South Africa . MRC.
ht t p://www.sahealt hinf o.org/t b/guidelines.pdf

2. Xu P. Ultraviolet germicidal irradiation for preventing infectious disease transmission. Boulder, CO: Universit y of Colorado, Depart ment of
Civil, Environment al, and Archit ect ural Engineering; 2001.

3. Collins FM. Relative susceptibility of acid-fast and non-acid-fast bacteria to ultraviolet light. Appl Microbiol 1971;21:411–3.

4. Ket hley TW, Branch K. Ultraviolet lamps for room air disinfection. Effect of sampling location and particle size of bacterial aerosol. Arc Environ
Healt h 1972;25:205–14.
5. Riley RL, Permut t S. Room air disinfection by ultraviolet irradiation of upper air. Air mixing and germicidal effectiveness. Arch Environ Healt h
1971;22:208–19.

6. Riley RL, Kauf man JE. Air disinfection in corridors by upper air irradiation with ultraviolet. Arch Environ Healt h 1971;22:551–3.

7. Ko G, First MW, Burge HA. The characterization of upper-room ultraviolet germicidal irradiation in inactivating airborne microorganisms.
Environmental Health Perspectives 2002;110:95–101.

8. Ko G, First MW, Burge HA. Influence of relative humidity on particle size and UV sensitivity of Serratia marcescens and Mycobacterium bovis
BCG aerosols. Tubercle Lung Dis 2000;80:217–28.

9. Peccia J, Wert h HM, Miller S, Hernandez M. Effects of relative humidity on the ultraviolet induced inactivation of airborne bacteria . Aerosol
Science and Technology 2001;35:728–40.

10. Riley RL, Kauf man JE. Effect of relative humidity on the inactivation of airborne Serratia marcescens by ultraviolet radiation. Appl Microbiol
1972;23:1113–20.

11. First MW, Nardell EA, Chaisson W, Riley R. Guidelines for the application of upper-room ultraviolet germicidal irradiation for preventing
transmission of airborne contagion—part I: basic principles. ASHRAE Trans 1999:105:869–876.

12. Riley RL, Nardell EA [1989]. Clearing the air: the theory and application of ultraviolet air disinfection. Am Rev Respir Dis 139(5):1286–1294.
Appendix 20. Treatment supporters
Update: January 2022

Treatment supporters need specific training to know and understand their role in order to provide the patient with adequate
treatment education and support.
T hey should be compensated for their time and services and reimbursed for expenses incurred.

20.1 Selecting a treatment supporter

T he treatment supporter a :
Is someone from the patient’s commmunity;
Is preferably a community health worker or a person with a background in health (e.g. pharmacist), but can also be a non health
worker (co-worker or neighbour);
Is chosen by, or is acceptable to, the patient and their family (e.g. supporter and patient of the same sex) ;
Is able to observe the patient’s confidentiality;
Has a stable living situation;
Has basic literacy skills (can read and write and has basic numeracy skills);
Is motivated to care for T B patients and committed to supporting them for the full duration of treatment;
Lives near enough to the patient to be able to make regular visits (daily or weekly) and go to their home immediately in the event
of an emergency;
Is in good physical condition and not immune­depressed b .

It is usually not recommended to have family members as treatment supporters. T he family relationship may interfere with the
ability to administer T B treatment, especially if the patient is a child.

20.2 Roles and responsibilities

Role and responsibilities of a treatment supporter may include:
Supervision of all drug intakes and keeping records on T B treatment card.
Detection of adverse effects and, when necessary, prompt referal of the patient to a health facility.
Accompanying the patient to medical consultations.
Collection and transport of sputum specimens for smear and culture.
Provision of health education to family members, including the risk of transmission and implementation of infection control
measures in the home.
Detection of signs and symptoms of T B in family members.
Participation in refresher trainings.

Footnotes
(a) From USAID TB CARE II (2017) Community-based Care for Drug-resistant Tuberculosis: A Guide for Implementers. Version 3. Updat ed in 2017.
ht t ps://t bcare2.org/wp-cont ent /uploads/2018/09/Communit y-Based-DR-TB-20180830-1.pdf

(b) The most common cause of immunosuppression is HIV inf ect ion, but chronic illnesses such as diabet es also alt er t he immune syst em and
are a risk f act or f or TB inf ect ion and act ive TB.
Appendix 21. Patient therapeutic education
Update: March 2023

T herapeutic education should be provided promptly after diagnosis, then at each clinical visit and whenever considered necessary
by the patient or the healthcare team, until the end of treatment.
Interviews are done either by the prescribing clinician alone, or with the help of a specially trained staff member or counsellor.
Patients may bring someone with them if they wish.

21.1 Initial therapeutic education

Two individual interviews should be organised:
T he first interview, before the start of treatment, aims to provide essential information to help the patient understand and
manage the disease and treatment.
T he second interview, one week later, aims to verify that the information given previously has been assimilated, and if necessary,
complete or clarify it.

21.1.1 First interview

Plan a 30 to 45 minute-session.
Adapt the information according to the:
Stage of disease (latent T B infection, active T B).
Site of T B (pulmonary, extrapulmonary).
Resistance pattern (drug-susceptible, drug-resistant).
Treatment regimen.
Comorbidities, especially HIV infection.
Explain:
T he disease and how it is transmitted.
T he treatment:
Total duration; duration of phases (intensive/continuation) if relevant.
Clinical and bacteriological monitoring.
Treatment administration (self-administered or directly observed).
T he T B drugs:
Where, when, and from whom to get them.
How to take them: number of tablets (or doses) per day; with or without food, etc.
Storage: e.g. not removed from blister pack ahead of time.
Main adverse effects and what to do if they occur.
Special precautions according to the situation (e.g. concomitant treatment, pregnancy).
Measures the patient and their household members should take to prevent the spread of T B or, if the patient is hospitalised,
the specific hospital infection control measures in place (Chapter 14).
T he importance of HIV testing if not already performed.
Stress the need to take the treatment regularly, without omission or interruption. Identify barriers to adherence and possible
solutions. Explain what enablers the patient is eligible for and how to access them (Chapter 13).
Answer any questions.
Give the date of the second interview.

21.1.2 Second interview

Plan a 30-minute session.
Review knowledge of disease, treatment and other information provided at the first interview.
Answer any questions.
Assess adherence (Appendix 22) and address problems (Chapter 13).
Remind the patient of the date of the next clinical visit.
21.2 Continuing therapeutic education
An individual interview should be organised at each clinical visit. For the schedule see Appendix 14 or Appendix 15.
T hese interviews aim to consolidate the patient's skills and update them if necessary, especially when there is a modification in the
treatment regimen, e.g. when moving from intensive to continuation phase; when replacing a treatment regimen with another; when
transitioning to outpatient treatment after hospitalisation.

Explain the changes in treatment if any (composition, duration, adverse effects, precautions, monitoring schedule, etc.).
Answer any questions.
Assess adherence (Appendix 22) and address problems (Chapter 13).
Remind the patient of the date of the next clinical visit.

Additional sessions should be scheduled as needed, e.g. if there are learning difficulties or significant changes in the patient's life.
Appendix 23. Treatment card for patients on first-
line anti-TB therapy
Treatment card for patients on first-line anti-T B therapy.pdf
Appendix 24. Tuberculosis register for patients on
first-line anti-TB therapy
Tuberculosis register for patients on first-line anti-T B therapy.pdf
Appendix 25. Treatment card for patients on second-
line anti-TB therapy
Treatment card for patients on second-line anti-T B therapy.pdf
Appendix 26. Tuberculosis register for patients on
second-line anti-TB therapy
Tuberculosis register for patients on second-line anti-T B therapy.pdf
Appendix 27. Respirators
Update: January 2022

27.1 Introduction
Respirators are masks designed to protect the wearer from inhaling bacilli.

Staff must wear a respirator when the risk of T B transmission is high (Chapter 14).

Visitors and attendants must wear a respirator when entering a ward or room of infectious T B patients.

Recommended respirators include:

T he CE-certified filtering facepiece EN 149 FFP2, filtering efficiency 94% if challenged with 0.4μm particles;
or
T he United States Centre for Disease Control and Prevention/National Institute for Occupational Safety and Health
(NIOSH) certified N95, filtering efficiency > 95% if challenged with 0.3µm particles.

27.2 Instructions for use

Respirators are for personal use. T he same respirator cannot be shared between staff members or between caregivers.

T he respirator should be put on before entering the room and removed after exiting the room.

Respirators must be worn covering the nose, mouth and chin and provide a tight seal around the edge. Every time that a respirator
is put on, a seal check has to be performed:
Fully open the respirator and slightly bend the nose wire to form a curve.
Separate the two elastic straps and position the respirator under the chin.
Stretch the two straps over the head, place the first strap at neck-height and the second strap across the top of the head.
Model the nose wire around the bridge of the nose and secure the edges until you achieve a perfect
Check for leaks by covering the respirator with both hands and forcefully inhaling and exhaling several times. T he respirator
should collapse when inhaling and expand when exhaling and no air leak between the face and the respirator should be
Otherwise, straps should be readjusted and/or the respirator repositioned until is sealed properly.

Different factors may not allow proper sealing of respirators to the face: respirator size and/or model; respirator wearer’s facial
features, including beard and facial hair; headscarves, etc.

T here is limited evidence on the acceptable length of time a respirator can be worn with maintained efficiency. T he filter materials
remain functional for weeks or months, but with frequent wearing the respirator will become less adjusted.
An extensively used respirator should be discarded after 7 days. However, if for example, it is only used a few hours 2 to 3 times a
week, it can be reused for several weeks [1] . During this period, staff can reuse their respirator provided it is not wet or damaged
and its straps are not loosened. Each staff member should keep their respirator in the pocket of their personal gown without
creasing it. If the filter material is damaged or the mask has loose straps, the respirator should be discarded immediately.

Note: T B bacillus is trapped in the filter of a mask and will not be released with shaking or other physical movements of the mask.

27.3 Storage
Store in a dry, well ventilated place. Respirators should not be crushed during storage.

27.4 Disposal
Respirators are disposed of as “soft waste” and do not need to be disinfected before being discarded.

27.5 Fit testing

Proper fit of a respirator is critical to ensure respiratory protection. T herefore, all staff members who could be exposed to M.
tuberculosis should before being required to wear a respirator perform a “fit testing” to determine if the respirators being used fit
them properly.

At least two models of respirators should be available. If a worker cannot be fitted with one model, the other one should be used.

Testing is performed using a fit testing kit. T he kit contains all the supplies and instructions needed to perform the test.

Fist testing kit

References
1. Roland Diel, Albert Nienhaus, Pet er Wit t e, Renat e Z iegler. Protection of healthcare workers against transmission of Mycobacterium
tuberculosis in hospitals: a review of the evidence. ERJ Open Research 2020 6: 00317-2019.
ht t ps://openres.ersjournals.com/cont ent /6/1/00317-2019
Appendix 28. Surgical masks
Update: January 2022

28.1 Introduction
T he purpose of surgical masks is to catch droplet nuclei that patients expel while talking, breathing or coughing.
Surgical masks should be worn by contagious or potentially contagious patients (confirmed or presumed cases) when they leave
their rooms to go to another department or any other enclosed area, or when they take care of young children.

T he terms “surgical”, “medical” or “procedure” are sometimes used interchangeably to qualify masks. Only masks that conform to
the norms EN 14683 or AST M F2100 should be used.

28.2 Instructions for use

Surgical masks are for personal use. T he same mask cannot be shared.
Open the mask.
Bend the nasal bar (if included).
Put the chin into the mask.
Attach the two straps behind the head or over the ears.

Surgical masks must be replaced at least once a day and when they become wet or damaged.

It is not recommended to wear masks for large portions of the day or while sleeping, as they restrict air movement and are not
comfortable.

28.3 Storage
Store in a dry, well ventilated place.

28.4 Disposal
Masks are disposed of as “soft waste” and do not need to be disinfected before being discarded.
Appendix 28. Request form for sputum culture, LPA
and DST
Request form for sputum culture, LPA and DST.pdf
Appendix 29. BCG vaccine
Update: January 2022

Composition, forms and route of administration

Live attenuated bacterial vaccine
Powder for injection, to be dissolved with the entire vial of the specific solvent supplied by the manufacturer, in multidose vial,
for intradermal injection

Dosage and vaccination schedule

Refer to national recommendations. In countries with a high incidence of T B (> 40 cases per 100,000), WHO recommends [1] :
Child under 12 months: 0.05 ml single dose as soon as possible after birth
Child 12 months and over a and adult: 0.1 ml single dose

Technique and site of administration

Clean the injection site with clean water. Do not use antiseptics as risk of inactivation of vaccine). Allow to dry.
Administer intradermally. If the injection is correctly performed, an “orange-skin” papule measuring 5-8 mm in diameter should
appear at the injection site.
T he vaccine is administered in the deltoid region of the arm, about one-third down the upper arm over the insertion of the
deltoid muscle.
T he vaccine should be injected in the same place for each child so that the BCG scar is easier to locate.

Contra-indications
Do not administer to patients with congenital or acquired immunodeficiency (e.g. HIV infection or serologic status unknown, but
symptoms consistent with HIV infection, immunosuppressive therapy, malignant haemopathy).
Postpone vaccination until recovery in the event of acute extensive dermatosis, acute complicated malnutrition or severe acute
febrile illness (minor infections are not contra-indications).

Adverse effects
Local reaction 2-4 weeks after injection: papule that ends up as an ulcer and usually heals spontaneously (dry dressing only)
after 2 to 5 months, leaving a permanent
Complications requiring no specific treatment and which almost always evolve favourably:
persistent ulcer with serous discharge for over 4 months after injection;
non-suppurated adenitis, most often axillary, sometimes cervical;
abscess at the injection site due to infection (red, hot and painful abscess) or inadvertent intradermal injection (cold and
painless abscess).
Uncommon complications:
suppurative lymphadenitis, mostly observed in neonates, usually due to inadvertent intradermal injection. T he lymph node,
which can have a diameter of over 3 cm, evolves toward softening and fistulisation with chronic osteomyelitis in exceptional
cases.
disseminated BCG disease b , most commonly in immunocompromised children under 2 years old (mortality rate > 70%) [2] .

Precautions
If administered simultaneously with other vaccines, use different syringes and injection sites. Do not mix with other vaccines in
the same syringe.
Pregnancy: CONT RA-INDICAT ED
Breastfeeding: no contra-indication
Storage

Reconstituted vaccine: between 2 °C and 8 °C for 6 hours max.

Powder: between 2 °C and 8 °C.
Solvent: a cold chain is not required for However, at least 24 hours before reconstitution of the vaccine, the solvent must be
refrigerated between 2 °C and 8 °C so that the solvent and lyophilised powder are at the same temperature: a temperature
difference during reconstitution may reduce vaccine efficacy. Do not freeze.

Footnotes
(a) BCG vaccine provides high prot ect ion f or neonat es, but only moderat e f or school age TST negat ive children.

(b) If disseminat ed BCG disease is diagnosed, a 6-mont h TB t reat ment should be administ ered.

References
1. World Healt h Organizat ion. BCG vaccines: WHO position paper – February 2018/Vaccins BCG: Note de synthèse de l’OMS – Février
2018. Weekly epidemiological record/Relevé épidémiologique hebdomadaire, 23 FEBRUARY 2018, 93th YEAR/23 FÉVRIER 2018, 93e ANNÉE,
No 8, 2018, 93, 73–96.
ht t ps://apps.who.int /iris/bit st ream/handle/10665/260306/WER9308.pdf ;jsessionid=872A2E82241BA438A3C9953650A92DF0?sequence=1

2. Hesseling AC, Rabie H, Marais BJ, Manders M, Lips M, Schaaf HS, et al. Bacille Calmette-Guérin vaccine-induced disease in HIV-infected and
HIV-uninfected children. Clin Inf ect Dis. 2006;42:548–58.
ht t ps://pubmed.ncbi.nlm.nih.gov/16421800/
Appendix 29. Sputum smear microscopy register
Sputum smear microscopy register.pdf
Appendix 30. Xpert MTB/RIF register
Xpert MT B/RIF register.pdf
Appendix 31. Drug-o-gram
Drug-o-gram.pdf
Appendix 32. Quaterly report
Quaterly report.pdf
Appendix 33. Report on detection and enrolment of
TB cases with rifampicin and multidrug-resistance
Report on detection and enrolment of T B cases with rifampicin and multidrug-resistance.pdf
Appendix 34. Request form for smear microscopy
and Xpert assays
Update: March 2023

Request form for smear microscopy and Xpert assays.pdf

Request form for smear microscopy and Xpert assays.docx

Appendix 34. Report of final outcomes of drug-
resistant tuberculosis
Report of final outcomes of drug-resistant tuberculosis.pdf
Appendix 35. Check-list for the evaluation of a TB
service
Check-list for the evaluation of a T B service.pdf