MINIREVIEW

Extensively drug-resistant tuberculosis: current challenges

and threats
Amita Jain & Rajesh Mondal
Department of Microbiology, C.S.M. Medical University, Lucknow, India

Correspondence: Amita Jain, Department of Abstract

Microbiology, C.S.M. Medical University
(former K.G. Medical University), Lucknow
Extensively drug-resistant tuberculosis (XDR-TB) is defined as tuberculosis caused
226003, Uttar Pradesh, India. Tel.: 191 by a Mycobacterium tuberculosis strain that is resistant to at least rifampicin and
9415023928; fax: 191 522 4007400; isoniazid among the first-line antitubercular drugs (multidrug-resistant tubercu-
e-mail: [email protected] losis; MDR-TB) in addition to resistance to any fluroquinolones and at least one of
three injectable second-line drugs, namely amikacin, kanamycin and/or capreo-
Received 11 September 2007; revised 10 mycin. Recent studies have described XDR-TB strains from all continents. World-
February 2008; accepted 11 February 2008. wide prevalence of XDR-TB is estimated to be c. 6.6% in all the studied countries
First published online 8 May 2008.
among multidrug-resistant M. tuberculosis strains. The emergence of XDR-TB
strains is a reflection of poor tuberculosis management, and controlling its
DOI:10.1111/j.1574-695X.2008.00400.x
emergence constitutes an urgent global health reality and a challenge to tubercu-
Editor: Willem van Leeuwen
losis control activities in all parts of the world, especially in developing countries
and those lacking resources and as well as in countries with increasing prevalence
Keywords of HIV/AIDS.
Mycobacterium tuberculosis ; extensively
drug-resistant tuberculosis.

isoniazid and rifampicin, is defined as MDR-TB. Treatment of

Introduction MDR-TB is resource-intensive, and the therapeutic strategies
Mycobacterium tuberculosis infects one-third of the global recommended for high-prevalence areas comprise combina-
population. More than eight million people develop active tions of second-line drugs that are more expensive, more toxic
tuberculosis (TB) every year, and the disease claims two and less effective than the drugs used in standard therapy
million lives annually (Dye et al., 1999). The emergence of (Iseman, 1993; Rajbhandary et al., 2004; Ward et al., 2005;
drug resistance in recent years has made an effective control Nathanson et al., 2006). A Green Light Committee of the Stop
strategy for tuberculosis indispensable. The rapid spread of Tuberculosis partnership was established to facilitate treat-
drug resistance, especially multidrug-resistant tuberculosis ment of MDR-TB in resource-limited countries, where most
(MDR-TB) and currently extensively drug-resistant tuber- tuberculosis cases occur (Gupta et al., 2002). While ensuring
culosis (XDR-TB), both in new and in previously treated the proper use of second-line drugs in these countries to
cases, adds urgency to the need for decisive action to develop prevent drug resistance, this committee encountered strains
control measures (WHO, 2006). Efforts to report on XDR- resistant to virtually all second-line drugs, and this has led to
TB status worldwide form an important part of tuberculosis the emergence of new terminology in relation to drug-
control and management. Here we review the global epide- resistant tuberculosis, known as XDR-TB. The worldwide
miology and challenges to the management of XDR-TB emergence of XDR-TB and a provisional definition for this
worldwide. form of tuberculosis were first reported in November 2005
(Holtz et al., 2005; Shah et al., 2005) and the term XDR-TB
was used for the first time in March 2006, in a report jointly
XDR-TB published by US Centers for Disease Control and Prevention
(CDC) and World Health Organization (WHO) (CDC,
Definition
2006). According to this report, XDR-TB was defined as
Infection with an M. tuberculosis strain that is resistant to the M. tuberculosis that was resistant not only to isoniazid and
two most commonly used front-line antitubercular drugs, rifampicin (MDR-TB) but also to at least three of the six

FEMS Immunol Med Microbiol 53 (2008) 145–150

c 2008 Federation of European Microbiological Societies
Published by Blackwell Publishing Ltd. All rights reserved
146 A. Jain & R. Mondal

classes of second-line antituberculosis drugs (aminoglyco- XDR-TB is 6.6% among all MDR-TB isolates; reported
sides, polypeptides, fluoroquinolones, thioamides, cyclo- XDR-TB prevalence in industrialized countries (e.g. USA,
serine and para-aminosalycilic acid). As the definition is UK, Ireland, Germany, France, Belgium, Spain, Japan and
dependent on difficult-to-perform drug susceptibility test- Australia) is 6.5%; and reported XDR-TB prevalence in Russia
ing and as some forms of drug resistance are less treatable and Eastern Europe (e.g. Republic of Georgia, Czech Repub-
than others, it was eventually modified at a meeting of the lic, Armenia and Azerbaijan) is around 13.6%. Prevalence of
WHO XDR-TB Task Force, held at Geneva (Switzerland) on XDR-TB from the Asiatic region (e.g. Bangladesh, Indonesia,
10–11 October 2006. The committee gave a widely accepted Thailand, Papua New Guinea and East Timor), Africa and the
definition of XDR-TB: ‘resistance to at least RIF and INH Middle East was not well defined in the report owing to a
among the first line-anti tubercular drugs (MDR-TB) in small number of tuberculosis cases taken in the study in
addition to resistance to any fluroquinolones i.e. ofloxacin, comparison with other studied nations. However, reported
ciprofloxacin and levofloxacin, and at least one of three XDR prevalence is around 1.5% in Asia and only 0.6% in
injectable second line anti tubercular drugs i.e. amikacin, Africa and the Middle East. The Republic of Korea has
kanamycin and capreomycin’ (CDC, 2006). reported the highest number of XDR-TB cases, these repre-
senting 15.4% of all MDR-TB patients (Shah et al., 2007).
A detailed description of XDR-TB findings and prelimin-
Epidemiology
ary data from the US National TB Surveillance System was
MDR-TB strains constitute 1–3% of global tuberculosis published in 2006 (CDC, 2006). These data indicated that 74
(Farmer et al., 1999). According to the WHO, 425 000 new tuberculosis cases reported during 1993–2004 met the case
MDR-TB cases occur every year with the highest rates in the definition for XDR-TB. A recent report from Germany and
former Soviet Union and China, where up to 14% of all new Italy reported 10.3% and 14.3% XDR-TB isolates, respec-
cases are not responding to standard drug treatment (Zignol tively, among 83 and 43 MDR-TB strains. These patients had
et al., 2006). MDR-TB has been identified as a significant a fivefold higher risk for death and longer hospitalization
problem in every regime under WHO surveillance (WHO, with longer treatment durations, revealing a highly signifi-
2004). Mismanagement of such cases paves the way for cant association between XDR-TB status and mortality risk
emergence of XDR-TB cases. (Migliori et al., 2007a, b). A recent study reported that
The CDC and WHO undertook surveillance to estimate prevalence of XDR-TB in France was 4% of tested multi-
worldwide XDR-TB prevalence during 2000–2004, based on drug-resistant strains (Bouvet, 2007). A recent study from
data from 25 supranational reference laboratories (SRLs) on Iran reported 12 (10.9%) XDR strains from 113 MDR-TB
six continents that collaborate with national reference strains (Masjedi et al., 2006). In Hong Kong, nine out of the
laboratories (NRLs) to increase culture and drug suscept- 75 MDR-TB strains (12%) had extensive drug resistance
ibility testing (DST) capacity and provide quality control for with simultaneous resistance to ethionamide, amikacin,
global surveys to assess antituberculosis drug resistance. ofloxacin and cycloserine (Kam & Yip, 2004). From India,
They used a standardized reporting form, and requested 7.4% of XDR-TB cases were recognized from 68 MDR-TB
anonymous, individual-level data from all reference labora- strains during a preliminary study made by us recently
tories on all isolates tested for susceptibility to at least three (Mondal & Jain, 2007). Although this figure was based upon
second-line drug (SLD) classes, during 2000–2004. SRLs a small number of MDR-TB from a North Indian setting,
receive varying proportions of isolates from countries for this clearly indicates that the problem of XDR-TB exists, and
surveillance, diagnosis and quality assurance. Hence, to the true extent may be much higher than the reported figure,
complement the SRL survey, additional population-based given that the annual risk of tuberculosis and prevalence of
data were analysed from the United States National Tuber- acquired MDR-TB and tuberculosis with HIV is increasing
culosis Surveillance System, which contains data on all in India (Narain & Lo, 2004). The emergence of XDR-TB in
reported tuberculosis cases during 1993–2004, and Latvia’s settings such as India, South Africa, China, South Korea,
national MDR-TB registry from the 2000–2002 cohort of Ethopia and Estonia, where tuberculosis control pro-
MDR-TB patients. Limitations to this surveillance were: (1) grammes have been unable to monitor treatment regimens
not all SRLs tested for susceptibility to SLDs, (2) certain for MDR-TB adequately due to huge population sizes and
laboratories test for only one or two SLDs, (3) laboratories high annual tuberculosis cases, is a cause of great concern.
used different (but generally accepted) media and methods Comorbidity with tuberculosis and HIV/AIDS affects
to test for SLD susceptibility and (4) SLD-susceptibility data around 11 million people and resulted in the death of nearly
from SRLs are based on a convenience sample and are not 200 000 in 2005. Yet, o0.5% of HIV-positive people were
population-based, with one exception: South Korea. Based screened for tuberculosis in that year. A recent study from
on the surveillance data, worldwide occurrence of XDR-TB India by Singh et al. (2008) of 54 full-blown AIDS patients
was reported. Reported overall worldwide prevalence of suspected of having HIV–TB coinfection reported a high

c 2008 Federation of European Microbiological Societies FEMS Immunol Med Microbiol 53 (2008) 145–150
Published by Blackwell Publishing Ltd. All rights reserved
XDR-TB challenges and threats 147

mortality rate among those with XDR-TB. Of the 54 patients Treatment of MDR-TB cases is difficult, complicated, very
studied, 12 (22.2%) were MDR-TB cases, among which were costly, challenging and requires experienced skills, together
four (33.3%) XDR-TB cases. All four patients in whom with good quality of second line antituberculosis drugs, a
XDR-TB was isolated died within 2.6 months of diagnosis. high standard of microbiology laboratories as well as proper
The first report of XDR-TB with HIV came from Kwazulu management of patient care with standardized, empirical
Natal (KZN), South Africa (Gandhi et al., 2006). Of 536 and individual approaches (Iseman, 1993; Farmer et al.,
tuberculosis patients at the Church of Scotland Hospital, 1999; Gupta et al., 2001). Treating MDR-TB with SLDs may
KZN, which serves a rural area with high HIV infection cure 4 65% of patients and prevent ongoing transmission
rates, 221 were found to have MDR; of these, 53 were (Mukherjee et al., 2004; Van Deum et al., 2004; Leimane
diagnosed with XDR-TB. Fifty-two of these patients died, et al., 2005). However, most of the evidence relating to the
most within 25 days. Of the 53 patients, 44 were tested for successful management of MDR-TB has been generated
HIV and all 44 were HIV-positive. In KZN, two healthcare from high-income countries where treatment is provided
workers died from XDR-TB with HIV. Spoligotyping results in referral hospitals (Espinal & Dye, 2005).
of 46 XDR-TB isolates demonstrated that 85% of the strains Most XDR-TB cases seem to have appeared among HIV-
belonged to the KZN family and 15% to the Beijing family. positive individuals, and the epidemic of XDR-TB among
A number of cases in KZN resulted from in-hospital those living with HIV/AIDS in all parts of world is increas-
infection. Acquisition of extensive drug resistance appears ing rapidly and represents a serious challenge to researchers,
to be the primary mechanism for the XDR-TB epidemic in epidemiologists, clinicians and policy-makers. Confirmed
South Africa, and an estimated 63–75% of cases developed cases of XDR-TB from KZN, South Africa, are of particular
XDR-TB through acquisition (Mlambo et al., 2008). A large significance given the high mortality rate in those who
number of XDR-TB patients in KZN were infected with the are HIV-positive. Dr Mario Raviglione, WHO Stop TB
same strain of M. tuberculosis (F15/LAM4/KZN) (Pillay & Department Director, said ‘this is a wake-up call’. There are
Sturm, 2007). problems in the management of tuberculosis. HIV
fuels XDR-TB. Once someone is infected with the bacterium
there is a 5–10% lifetime risk of developing tuberculosis; the
Challenges and threats in management
risk is 5–15% annually with those who are HIV-positive. The
Mismanagement of tuberculosis cases has played a major incidence of tuberculosis is decreasing or stable in all regions
role in the emergence of drug-resistant tuberculosis, mainly of the world except for Africa, where it is on the increase,
owing to poor treatment methodologies (Uplekar & She- with HIV fuelling tuberculosis. Coordination of tuberculo-
pard, 1991; Prasad et al., 2002; Nathanson et al., 2006). The sis and HIV programmes and interventions will be needed.
erratic use of SLDs (and their poor quality; Prasad & Garg, Dr Karin Weyer, tuberculosis Research Director at the South
2007) and factors linked to poor control practices, e.g. lack African Medical Research Council, warns: ‘We are afraid that
of measures to ensure adherence to treatment protocols and this outbreak of XDR-TB might be the tip of the iceberg, as
the treatment of tuberculosis in unmonitored private-sector we haven’t really looked properly elsewhere. There are
hospitals, have played a major role in the appearance of higher prevalence rates in pockets of eastern Europe
XDR-TB cases in developing countries. Uplekar (2003) and South-East Asia but we are particularly worried in
reported on the low quality of some tuberculosis manage- South Africa given our HIV problem, because of the
ment in the private sector in some parts of world. It is vital rapid spread of XDR-TB amongst HIV patients and their
that clinicians caring for tuberculosis patients are aware of rapid death’ (Wise, 2006). This threat is also worrisome in
the possibility of drug resistance and have access to labora- eastern European countries where 53% of the projected
tories that can provide early and accurate diagnosis so that number of MDR-TB cases will be treated and where HIV
effective treatment is provided as soon as possible. Effective infection is spreading rapidly (Stop TB, 2006). The appear-
treatment of tuberculosis cases requires good quality front- ance of XDR-TB among HIV-infected individuals is
line drugs and all six classes of SLDs available to clinicians very concerning, as rapid progression of infection towards
who have expertise in treating drug-resistant cases, espe- disease and the high potential of spread among immuno-
cially MDR-TB. A report from South Korea revealed that suppressed individuals greatly accelerate the consequences
XDR-TB was significantly associated with the cumulative of poor control practices and management of drug-resistant
duration of previous treatment received with second-line tuberculosis. However, the presence of XDR-TB is indepen-
tuberculosis among patients in a tertiary-care tuberculosis dent of poor prognostic factors in non-HIV-infected
hospital (Jeon et al., 2008). The inexorable rise of drug- patients with MDR-TB (Kim et al., 2007). These epidemio-
resistant strains (one in ten new infections is resistant to at logical trends have resulted in a change to our global
least one antituberculosis drug) and the worrying spread of strategy to call for ‘universal access to high-quality
XDR-TB threaten to undermine tuberculosis control efforts. diagnosis and patient-centred treatment’, including

FEMS Immunol Med Microbiol 53 (2008) 145–150

c2008 Federation of European Microbiological Societies
Published by Blackwell Publishing Ltd. All rights reserved
148 A. Jain & R. Mondal

specialized treatment for MDR-TB and for tuberculosis/HIV drug-resistant tuberculosis have been reported worldwide.
coinfection. However, recent outbreaks of XDR-TB have differed con-
Controlling community- and hospital-acquired infec- siderably from previous outbreaks of drug-resistant tuber-
tions among patients (e.g. tuberculosis and TB-HIV) and culosis and even MDR-TB outbreaks. The global threat of
healthcare workers is of importance (Migliori et al., XDR-TB has great significance for public health. Its very
2007a, b). Strengthening basic tuberculosis programmes existence is a reflection of weaknesses in tuberculosis
and infection control measures is crucial for preventing the management. Controlling the tuberculosis epidemic and
selective pressure and environments in which resistant preventing XDR-TB necessitate that healthcare providers
strains are transmitted from person to person. Additionally, diagnose tuberculosis early and initiate effective therapy
MDR-TB programmes that rely on quality assured and promptly. Tuberculosis patients should then successfully
internationally recommended treatment regimens according complete the therapy with high-quality antitubercular drugs
to WHO guidelines must be scaled up and strengthened to for the appropriate duration. Specifically, directly observed
prevent further SLD resistance and spread of XDR-TB. therapy should be used more widely. Initial treatment regi-
The Green Light Committee of the Stop Tuberculosis mens should be used that prevent the development of drug-
partnership provides a global mechanism to help affected resistant tuberculosis, and treatment activities should be
countries to achieve these steps. The main priority interven- coordinated between public health departments and other
tions that will be needed for XDR management is the hospitals that provide facilities and care for patients with
strengthening of tuberculosis control (through sound im- tuberculosis. XDR-TB will prove to be far more serious due
plementation of the Stop tuberculosis strategy and systema- to its virulence. All evidence suggests that XDR-TB reflects a
tic application of treatment in both the public and the failure to implement the measures recommended in the
private sectors, with a focus on laboratory capacities and WHO’s Stop Tuberculosis Strategy. This strategy emphasizes
infection control), improvement of SLD management based expanding high-quality DOTS programmes, surveillance of
on the new WHO guidelines (Mukherjee et al., 2004), and drug-resistant tuberculosis and HIV associated with tuber-
promotion of research and development of new diagnostics, culosis, strengthening healthcare systems and primary care
vaccines and drugs against tuberculosis (Hopewell et al., services, good clinical practices, empowering patients and
2006; Matteelli et al., 2007). communities to improve health, and enabling and promot-
A study by Huong et al. (2006) from Vietnam suggested ing research (newer drugs and vaccines for tuberculosis)
that, from a public health perspective, treatment of patients with advanced microbiology laboratories for early and
with MDR-TB with SLDs might not be necessary to prevent accurate diagnosis, as well drug susceptibility testing for
its spread and that directly observed therapy short course first- and second-line antitubercular drugs.
(DOTS), the internationally recommended standardized ‘The WHO emphasizes that good tuberculosis control
management strategy for tuberculosis, alone may suffice in prevents the emergence of drug resistance in the first place
some settings (DeRiemer et al., 2005). In the absence of a and that the proper treatment of multi-drug resistant
specific public health treatment programme, there was no tuberculosis prevents the emergence of XDR-TB.’
apparent increase in the prevalence of MDR-TB among
untreated patients between surveys conducted in 1996 and
2001 in Vietnam. However, a good DOTS programme
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c 2008 Federation of European Microbiological Societies FEMS Immunol Med Microbiol 53 (2008) 145–150
Published by Blackwell Publishing Ltd. All rights reserved