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ANTI – MYCO BACTERIAL DRUGS

BIETE LUNDAU LUKE

DipPharm, Bpharm, Mclinpharm
OVERVIEW
 Mycobacteria are acid fast bacilli that cause a variety of diseases including 2
1. Tuberculosis (TB)
2. Leprosy
3. Mycobacteium avium intracellular infections (localized or disseminated )

 T.B is caused by Mycobaterium tuberculosis of which about one third of the world
population is latently infected with T.B courtesy of the competent host immunity

 This latent infection is likely to develop into an active infection in 10% lifetime of
individuals having an intact immunity

 Mycobacterium avium infections are most frequently seen in immunocompromised

patients e.g. HIV/AIDS patients mostly presenting as a form of pulmonary disease,
lymphadenitis or bacteremia

 Leprosy or Hansen’s disease is caused by Mycobacterium leprae which infects the

skin and peripheral nervous system
Overview Cont’d
 The respiratory tract is the principal route of infection through inhalation of
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infected air droplet nuclei

Type of T.B
i. Pulmonary T.B – localised within the airway
Ii. Extrapulmonary T.B – affecting other parts away from the airway

Classical symptoms of T.B

 Prolonged coughing of more than 2 weeks which is productive in nature
with or without hemoptysis
 Fever
 Drenching night sweats
 Loss of appetite
 Loss of weight
 Fatigue
 ANTI – TB DRUGS 4

 In terms of treatment or sensitivity of the mycobacteria to drugs, T.B is

further classified as either susceptible TB or Multi drug resistant (MDR) T.B

 Based on the category of T.B being treated, anti – TB drugs are referred to
as either first or second line drugs

 Multi drug therapy for a period of at least 6 months is required to

eradicate the pathogen and also prevent the emergence of resistance
by the mycobacterium and thus monotherapy is not promoted

 Compliance and adherence to treatment are key and because of this

direct observed therapy (DOT) has been found effective where a health
care provider observes each drug administered
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Goals of TB treatment
Treatment of TB is focused as achieving both the public health and the
therapeutic desired outcome and to achieve this below is the
treatment goal of TB;
 To kill tubercle bacilli rapidly leading to elimination of persistent
bacilli
 Prevent relapse of TB infection
 Prevent disease transmission
 Enhance adherence to TB treatment course
First line drugs
These are the initially used drugs to treat most TB patients 6
 Isoniazid
 Ethambutol
 Rifampicin
 Pyrazinamide

Second line drugs

These are reserved to treat patients infected with organisms that are resistant to first line
drugs
 Fluoroquinolones – levofloxacin, moxifloxacin
 Cycloserine
 Ethionamide
 Aminosalicylic acid
 Aminoglycosides – Kanamycin, amikacin, capreomycin
 Delamanid
 Bedaqaline
 Linezolide
 etc
ISONIAZID
 Isoniazid is a nicotinic acid derivative also called isonicotinic acid hydrazine (INH) and
it has remained the mainstay of most TB regimens
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 Isoniazid is widely distributed to all tissues with sufficient concentrations likely to be

effective against organisms inside cells and caseous

 It is extensively metabolised with both the parent drug and its metabolized being
excreted in urine

 The primary metabolite acetylisoniazid is formed by conjugation of acetate with

isoniazid in a process catalyzed by the enzyme called acetyltransferase

 The enzyme acetyl transferase is genetically determined where slow acetylators tend
to have increased plasma concentration compared to the fast acetylators

 Small amount of isoniazid is converted to isonicotinic acid and acetylhydrazine

 Acetylhydrazine is believed to be the causer of hepatic toxicity and peripheral

neuropathy
Mechanism of action of Isoniazid
Isoniazid inhibits the synthesis of mycolic acid, a fatty acid which is component of the
mycobacteria cell wall and is responsible for acid fast staining properties
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Indications
 Isoniazid is bactericidal against sensitive strains of M.tuberculosis and some strains of
M.kansaii, has little activity against M.avium intracellure while it has no active against
M.leprae

 Isoniazid is part of the standard four drug regimen for TB in persons without known or
suspected resistance to isoniazid which are believed to kill different populations of TB
bacilli

 Isoniazid together with rifampicin, pyrazinamide eradicate the rapidly growing

organisms during the first two months of treatment

 In the next four months of treatment, isoniazid and rifampicin act against persistent
bacteria that slowly revert to actively growing forms

 Isoniazid is also given in latent TB as prophylaxis in persons who are at high risk of
contracting TB e.g. HIV patients, recently infected patients with positive tuberculin
skin test in the past 2 years
Adverse effects of Isoniazid
 Isoniazid causes drug induced hepatitis and so patients taking it should 9
have their serum transaminase levels be regularly monitored

 Peripheral neuropathy – this usually occurs due to pyridoxine

deficiencies due to its direct inactivation by isoniazid

 Administering of pyridoxine supplements in patients taking isoniazid helps

in preventing of peripheral neuropathy

 In rare cases, isoniazid causes CNS effects like toxic encephalopathy or

seizures

 Haematologic abnormalities like granulocytosis, anemia or

thrombocytopenia can occur
 ETHAMBUTOL
 Ethambutol is a butanol derivative that has bacteriostatic activity
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against mycobacterial organisms
 Administered orally, undergoes hepatic biotransformation and
excreted in urine and stool

Indications
 Used in combination with other drugs to treat TB or M.avium
intracellulare infections

Adverse effects
 Optic neuritis
 Visual acquity which inlvolves impaired red-green color discrimination
and hence it should not be used in children who are not able to tell the
changes is colour differentiation
 Hyperuricemia and gout
 Thrombocytopenia
PYRAZINAMIDE 11
 Pyrazinamide is nicotinamide derivative

 It is an important drug in TB therapy because of its more rapid

bactericidal and sterilizing effect

Mechanism of action
 As nicotinamide derivative, pyrazinamide is converted to pyrazinoic
acid by susceptible mycobacteria

 This pyrazinoic acid inhibits mycobacterium growth by inhibiting fatty

acid synthesis
Indication 12
 Administered in combination with rifampicin, isoniazid and ethambutol
in treatment of TB

 Its inclusion in the TB regimen made it possible to reduce the duration of

treatment to 6 months from the earlier 9 to 12 months

Adverse effects for pyrazinamide

 Athralgia
 Hyperuricemia and gout
 Drug induced hepatitis
 Hematologic toxicity
 Increase in serum iron concentration
RIFAMPICIN
 Rifampicin is a derivative of the antibiotic rifamycin which has
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improved pharmacokinetic properties than its parent drug

 It is rapidly absorbed after oral administration and converted to

desacetyl rifampin

 Rifampicin and its metabolite are widely distributed to tissues and fluids
including lung tissue, saliva and peritoneal and pleural fluids

Mechanism of action
 Rifampicin binds to β subunit of DNA dependent RNA polymerase
enzyme

 This prevents the enzyme from binding to DNA and therefore, inhibits
DNA transcription and RNA synthesis
Indications of rifampicin
 Rifampicin is a broad spectrum antibiotic that has significant activity against many gram 14
negative, gram positive and acid fast bacilli like M.tuberculosis, M.kansaii, M.avium
intracellulare, M.leprae

 Administered in combination with isoniazid, pyrazinamide and ethambutol to treat TB

 Given as an alternative to isoniazid in latent TB when resistance to isoniazid is known or

suspected while it is given in combination with dapson or clofazimine to treat leprosy

 Given to individuals exposed to Haemophillus influenza type b and likely to transmit the
disease to unvaccinated children aged 4 years and younger

 Prevention of meningococcal disease in individuals who would have come in contact with
patients infected with Neisseria meningitidis though ciprofloxacin and ceftriaxone are
mostly preferred

 Rifampicin penetrates inflamed meninges and hence can be used to treat tubercular
meningitis

 Administered in combination with vancomycin and gentamycin in the treatment of

staphylococcal endocarditis
Adverse effects
 Drug induced hepatotoxity – liver function tests should be done regularly 15
and like the other hepatotoxic drugs, rifampicin should be discontinued if
signs of hepatic dysfunction become evident

 Consumption of alcohol by individuals taking rifampicin appears to

increase of liver toxicity or drug induced hepatitis

 Hypersensitive reaction – manifesting as a flu like illness with chills, fever,

fatigue and headache, this reaction being common in those on
intermittent treatment who take large doses 2 to 3 times a week

 Reddish-orange or reddish-brown discoloration of saliva, tears and urine

and can also cause permanent staining of soft contact lenses

 Rifampicin induces cytochrome P450 isozymes CYP1A2, CYP2C9 and

CYP3A4 and hence can accelerate the metabolism of drugs like
benzodiazepines, calcium channel blockers, digoxin, oestrogen based
contraceptives, theophylline, warfarin thereby reducing their serum
concentration and their subsequent effectiveness
 Modality of susceptible TB treatment course
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 Susceptible TB treatment is done for a period of 6 months which is
divided into two phases namely;
1. Intensive phase
 This involves the administration of a combination of four drugs i.e.
rifampicin, isoniazid, pyrazinamide and ethambutol
 This is done for a period of 2 months and it is meant to eradicate the
rapidly growing organisms

2. Extensive phase
 This involves the administration of rifampicin and isoniazid
 It is done for the next 4 months and it is meant to act against persistent
bacteria which if not attacked can slowly revert to actively growing
forms
MULTI DRUG RESISTANT TUBERCULOSIS (MDR TB)
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 Multi drug resistant TB is the type of TB which become resistant to
rifampicin and isoniazid

 Pre XDR TB is MDR TB that has also become resistant to either

fluoroquinolones or aminoglycosides

 XDR TB is MDR TB that has also become resistant to both

fluoroquinolones and aminoglycosides

 Previously the treatment for MDR was 18 months to 24 months but

currently a shorter regimen can only go on up to 9 to 12 months

 A shorter regimen requires at least a minimum of 6 drugs

 For Pre – XDR and XDR TB, individualized treatment regimens are used
according to the drugs to which the mycobacteria is still sensitive to
Drugs used in MDR TB
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Group A – Fluoroquinoles like levofloxacin, moxifloxacin, gatifloxacin

Group B – Aminoglycosides (second line injectables) like amikacin,

capreomycin, kanamycin

Group C – Also referred to as second line core drugs and these include
cycloserine, ethionamide, linezolide, clofazamine

Group D –
D1 – High dose isoniazid, pyrazinamide
D2 – Bedaquiline, delamanid
D3 – p- aminosalicylic acid, imipenem-cilastatin, meropenem,
amoxicillin-clavulanic acid
DRUGS USED IN MYCOBACTERIUM AVIUM-
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INTRACELLULARE INFECTIONS
 Drugs that are active against M.avium intracellulare (Mycobacterium avium
complex [MAC]) infections are the following;

 Ethambutol, rifampicin, rifabutin, azithromycin and clarithromycin,

ciprofloxacin, streptomycin and amikacin

 Azithromycin, clarithromycin or rifabutin are used alone to prevent MAC

infection in HIV infected and other immunocompromised patients

 A combination of azithromycin, ethambutol and rifampicin or rifabutin is

used to treat MAC with rifampicin preferred in HIV patients while rifabutin is
preferred in immuno competent patients

 Clofazimine, streptomycin or amikacin is an alternative drug for treating MAC

infections in immunocompromised patients when other drugs are ineffective
or not tolerated
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END