Anti-mycobacterials

Anti-mycobacterials

ANTI-TUBERCULAR DRUGS

Dr. J. R. Zaveri
Prof. & Head,
Pharmacology
 Competency achievement:
The student should be able to:
• Describe the first line antitubercular drugs,
their mechanisms of action, side effects and
doses. PH 1.44
• Describe the drugs used in MDR and XDR
(extensively drug – resistant) tuberculosis.
PH 1.45
 Topics
first-line drugs,
• isonicotinic acid hydrazide (INH),
• rifampicin,
• pyrazinamide,
• ethambutol,
second-line drugs

National Tuberculosis Elimination Programme,

MDR tuberculosis management,
glucocorticoids in tuberculosis,
chemoprophylaxis of tuberculosis,
BCG vaccine,
Learning Objectives :
This chapter will enable the reader:
1. To classify anti-TB drugs.
2. To discuss the mechanism of action, salient
pharmacokinetic features, ADR, drug interactions of
different classes of anti-TB drugs.
3. To state the rationale for combination therapy for TB.
4. To write the drug regimens as per National Tuberculosis
Elimination Programme (NTEP).
5. To state the response indicators for chemotherapy.
cont
Learning Objectives :
7. To outline the management of
multidrug-resistant TB.
8. To discuss the treatment of
extrapulmonary TB.
9. To enumerate the indications and C/I for
the use of glucocorticoids in treatment
of TB.
10. To state the chemoprophylaxis of TB.
Tuberculosis (TB)
• one of the oldest diseases
• is a major cause of death worldwide.
• Cause by bacteria of the Mycobacterium
tuberculosis complex,
• usually affects the lungs, although other
organs are involved in up to one-third of
cases.
• Tuberculosis (TB) is a chronic granulomatous
disease by Mycobacterium tuberculosis.
• In developing countries, it is a major public
health problem.
• India has the highest number of TB cases in
the world.
• Tuberculosis is also an enormous
socioeconomic burden to India with one-fifth
of global TB burden borne by India alone,
• accounting for ~1000 deaths every day.
• Though the disease burden in terms of
incidence, prevalence and mortality is
reduced,
• it is yet a major public health problem in
India.
• After the spread of AIDS, the problem has
become more complex,
• as tuberculosis and MAC (Mycobacterium
avium complex) infections are common and
rapidly progress in these patients.
• Tuberculosis is one of the most difficult infections
to cure. Why?
• Bcause of - slow division, development of
resistance, ability to remain as persisters for
years and intracellular location of the bacilli
have enhanced the problem.
• the caseous material makes it difficult for the
drugs to reach.
• long-term treatment, -- drug toxicity,
cost and thereby poor patient compliance have
all added to further complicate the problem.
• However, with the availability of effective
drugs, most patients can now be treated as
outpatients.
The aim of treatment
• is to kill the dividing bacilli thus making the
patient sputum negative (Intensive phase)
• and to destroy the persisters in order to
prevent relapse and ensure complete cure.
( Continuation phase )
 Tuberculosis:
• If properly treated, tuberculosis caused by
drug-susceptible strains is curable in virtually
all cases.
• If untreated, the disease may be fatal within
5 years in 50–65% of cases.
• Transmission - through the airborne spread
of droplet nuclei produced by patients with
infectious pulmonary tuberculosis.
 Clinical Manifestations
• Pulmonary Tuberculosis - lungs
• Extrapulmonary Tuberculosis
lymph nodes (Tuberculous Lymphadenitis), pleura,
genitourinary tract, bones and joints, meninges,
peritoneum, and pericardium.
 extrapulmonary tuberculosis is seen more
commonly today than in the past.
 For management of Tuberculosis
■ DESIRED
1. Rapid identification of a new TB case
2. Initiation of specific anti tuberculosis treatment
3. Prompt resolution of the signs and symptoms of
disease
4. Achievement of a noninfectious state in the patient,
thus ending isolation
5. Adherence to the treatment regimen by the patient
6. Cure of the patient as quickly as possible (generally
at least 6 months of treatment)
Drug therapy is given in two phases:

1. Intensive phase is the first phase of 1-3

months duration aimed at killing as many
bacilli as possible.

2. Continuation phase is second phase to

destroy the dormant or persisters-duration 4-9
months.
Classification of Anti-Tuberculosis Drugs
I. First-line drugs:
• Bactericidal:
Isonicotinic acid hydrazide (H),
rifampicin (R) and pyrazinamide (Z)
• Bacteriostatic: Ethambutol (E)
II. Second-line drugs:
Bactericidal:
• Fluoroquinolones (FQ) –Levofloxacin and
moxifloxacin;
• Injectables
e.g. amikacin (Am), streptomycin (S),
capreomycin (Cm) and kanamycin (K);
Bacteriostatic:
Ethionamide (Et), cycloserine (C), terizidone
(Trd), clofazimine (Cfz), linezolid (Lzd),
III. Third-line drugs:
• Bedaquiline (Bdq), delamanid(Dlm), imipenem
with cilastatin (Ipm-Cln), meropenem (Mpm),
thiacetazone (T), paraminosalicylic acid (PAS)

• The second- and third-line drugs are used for

multidrug resistant (MDR) and extensively
drug resistant (XDR) TB.
 Drugs
1. Rifampicin ® 2.INH (H)
3. Ethambutol 4. Pyrazinamide (Z)
5. Kanamycin (Km) 6. Capreomycin (Cm)
7.Amikacin (Am) 8. Levofloxacin (Lfx)
9.Moxifloxacin (Mfx) 10. Ethionamide (Eto)
11.Cycloserine (Cs) 12.PAS
13.Pyridoxine (Pdx) 14.Clofazimine (Cfz)
15.Linezolid (Lzd) 16.Amoxyclav (Amx/Clv)
17.Bedaquiline
 A single drug never be used to treat TB, as this
leads to the rapid development of drug-resistant
tubercle bacilli.

A combination of drugs is used in tuberculosis to:

1. Delay the development of resistance
2. Reduce toxicity
3. Shorten the course of treatment.
• Majority of cases are sensitive to first-line
drugs.
• Initial treatment should be intensive and
include drugs that have maximum effect.
• Good patient compliance and cost of therapy
should also be considered.
Common Adverse Effects of Anti-TB Drugs
 Isoniazid (H) –
Peripheral neuropathy, skin rash, hepatitis, sedation, lethargy
 Rampicin (R) --
Abdominal pain, nausea, vomiting, hepatitis, generalised
cutaneous reactions, thrombocytopenic purpura

 Pyrazinamide(Z)- Arthralgia, hepatitis, abdominal pain

 Ethambutol (E) - Retrobulbar neuritis

 strepto(S)/Kanamycin (K) /Capreomycin (Cm) --

Ototoxicity, nephrotoxicity, vertigo, electrolyte imbalance
 Common Adverse Effects of Anti-TB Drugs
 Fluoroquinolones (FQ)—
Diarrhoea, abdominal pain, dizziness, convulsions, phototoxicity,
tendinitis, rash, QT prolongation, arthralgia
 Ethionamide (Eto)–
Epigastric pain, anorexia, nausea, vomiting, metallic taste,
salivation, peripheral neuropathy, hallucination, depression,
hepatitis, hypothyroidism, gynaecomastia, menstrual
disturbances, impotence, acne
 Cycloserine (Cs)--
Dizziness, slurred speech, convulsions, headache, tremor,
insomnia, confusion, depression, suicidal tendency
 PAS- Anorexia, nausea, vomiting, abdominal pain, skin rash,
hepatitis, hypokalemia, hypothyroidism
INH:
• cheapest and one of the most effective AKT
• bactericidal and 'decimates' the population
of tubercle bacilli within a few days of
starting the treatment.
• Acts on the bacilli multiplying in the walls of
the cavities AND those inside macrophages
• Is more effective than other drugs in
preventing drug resistance to other drugs
 INH:
• Is well tolerated, cheap and safe even in
pregnancy
• Does not eliminate the persisters, which
rifampicin does
• effective both in acidic and alkaline medium.
• static for resting bacilli.
• If used alone, mycobacteria develop
resistance to it.
 INH

• MOA
• Tuberculocidal
• Inhibits mycolate synthetase
• Acts on both extra & intracellular organisms
• AMS
• Myco.tuberculosis, myco. kansasi.
 Isoniazid Drug Comments
• Isoniazid Daily for 9 months,
• In HIV patients, isoniazid may be
administered concurrently with NRTIs,
protease inhibitors, or NNRTIs
• Directly observed therapy (DOT) must be
used with twice-weekly dosing for 9 months
 Adverse drug reactions- INH
1. Peripheral neuropathy.
Due to Vit-B6 deficiency
2. Hepatotoxicity.
• Starts after 4-8wks, common in older individuals &
alcoholics.
• Due to its metabolite acetylhydrazine.
3.CNS.
• Confusion, psychosis, insomnia, suicidal tendency,
convulsions, restlessnes, giddiness, ataxia etc.
4. Hypersensitivity reactions.
• Rashes, urticaria, fever etc.
5. Others.
• Arthritis, epigastric distress, dryness of mouth etc
INH destroys:
i. Intracellular bacilli as it freely penetrates into
the cells, i.e. tubercle bacilli in macro phages,
and
ii. Bacilli multiplying in the walls of the cavities.

Thus it is effective against both intra- and

extracellular organisms
 RIFAMPIN

• Semisynthetic derivative of rifamycin-B

• Bactericidal.
• Inhibits DNA dependent RNA polymerase
• Suppression of initiation of chain
formation in RNA synthesis
 RIFAMPIN
• AMS-Extended spectrum.
• Myco. tuberculosis - acts best on slowly
dividing bacilli.
• Both extra & intra cellular organisms are
affected.
• Others
Myco.leprae,Myco.kansasii,Myco.scrofulaceu
m,Myco.avium,Myco.intracellulare,
• E.coli,proteus, Klebsiella, Pseudomonas,
Staph.,H.influenzae, Legionella, Meningococci.
 RIFAMPICIN ADRs
1.Hepatotoxicity; reversible,more common in
old age,alcoholics,chronic liver disease.

2.GIT ; Nasea , vomiting , abdominal pain,

epigastric distress.

3.A Flu like syndrome; fever,chills,myalgia,acute

tubular necrosis, thrombocytopenia etc

4.Orange red discoloration of various secretions.

 RIFAMPICIN ADRs
5.Cutaneous syndrome;
flushing,pruritus,redness & watering of
eyes.
6.Respiratory syndrome;
brethlessness,shock etc
7.CNS; headache, giddiness, ataxia,
confuion, drowsiness etc
It is a microsomal enzyme inducer.
 USES
1. Tuberculosis and atypical mycobacterial infections:
Rifampicin is given in combination with other
antitubercular drugs-in both .
also used for the prophylaxis as an alternative to INH.
2. Leprosy 600 mg once monthly supervised
3. Prophylaxis: H. influenzae and meningo coccal meningitis in
close contacts particularly children-20 mg/kg/day for 4 days.
4. Resistant staphylococcal infections: Rifampicin may
be given in combination with a beta lactam antibiotic
or vancomycin.

cont.
 USES

5. Brucellosis: Rifampicin 600-900 mg + doxycycline

200 mg daily for 6 weeks drug of choice.
6. Pneumococcal meningitis: If pneumococci are
resistant to penicillin, they can be treated with
rifampicin + ceftriaxone.
7. To eradicate carrier state: Rifampicin eradicates
the nasal carrier state of N.
meningitidis, H. influenzae and S. aureus 600
mg BD for 2 days.
 PYRAZINAMIDE
• Synthetic analogue of nicotinamide
MOA-Not known
AMS-Narrow spectrum
• Myco.tuberculosis
• More active in acidic medium-highly
lethal to intracellular bacilli as well as
those at inflammatory sites
• Highly effective during first two months
of therapy
 PYRAZINAMIDE- ADRs
1.Hepatotoxisity.
2.Hyperuricaemia-due to inhibition of uric
acid secretion in kidney.
3.Others-arthralgia, anorexia, nausea,
vomiting,dysuria, malaise, fever.

Preparation-Tab.500mg,750mg,1000mg.
Dose-15-30mg/kg/day.
 ETHAMBUTOL
MOA-Not exactly known.
• Bacteriostatic
• Inhibits the transfer of mycolic acid in to
mycobacterial cell wall
• Inhibits spermidine synthesis
• AMS-narrow spectrum
• Myco.tuberculosis-both extra & intra cellular
organisms are affected
• Myco. kansasii, Myco.avium.
 ETHAMBUTOL ADRs
1.Optic neuritis- retrobulbar,
Not indicated <5yrs of age –
@ reversible
• Peripheral neuritis

2.Hyperuricaemia

3.GIT-nausia,vomiting etc.

4.CNS- headache, giddiness, mental confusion,

disorientation, malaise.
 ETHAMBUTOL
• Preparation-Tab.200mg,400mg,600mg,800mg.

• Dose-15mg/kg/day.

USE
• Tuberculosis
NEWER DRUGS
BEDAQUILINE (BDQ):
• This diarylquinoline acts by inhibiting
mycobacterial ATP synthase, an enzyme essential
for energy production in tuberculous bacilli.

• It is bactericidal against sensitive and MDR

tuberculous bacilli.
• It also acts on dormant bacilli.
• It is metabolised by CYP3A4. It has long t1/2 and it
can be detected in plasma even after 5 months
after stopping treatment. It accumulates in tissues.
BEDAQUILINE (BDQ):
• indicated in adult patients with MDR TB who are
resistant to all FQ and/or second-line anti-TB drugs or
treatment failures of MDR TB.
• orally 400 mg o.d. for initial 2 weeks (in hospital setting)
followed by 200 mg three times a week for 22 weeks
along with at least four second-line drugs based on drug
sensitivity testing.
• After 6 months, BDQ is discontinued.
 BEDAQUILINE- ADR
• include nausea, anorexia, hepatic damage and
arthralgia.
• QT prolongation can occur resulting in fatal
arrhythmias.
• Therefore, ECG monitoring is recommended
daily in first 2 weeks and every 2 weeks for
next 3 months and then monthly.
 MANAGEMENT OF - TB

• Chemotherapy is the mainstay of the

treatment of TB and the rest like diet, climate
and bed rest are only of secondary
importance.
• Majority of the patients can now be treated
successfully as out-patients and
• up to 95% of drug-responsive new cases can
be cured by first line drugs
• Selection of Chemotherapeutic Regimen

• INH, rifampicin, ethambutol and

pyrazinamide are the four antituberculous
drugs preferred for initial therapy.(STREPT.)

• They are always administered in

combination as single dose (tablet) ,
• half an hour before breakfast.
 advantages of fixed dose drug combinations
are as follows:
• Reduction in the number of pills to be
swallowed
• Improvement in drug compliance Convenience
in mass-treatment of populations
• Delay the development of acquired resistance
and prolong the effective therapy.
• Eliminate persisters.
• Shorten the course of therapy.
• Reduce ADR.
 Revised National TB Control Programme - RNTCP
RNTCP (2016) has classified TB cases into:
I. Drug-sensitive TB:
patient's bacilli are susceptible to all first line anti-TB drugs (ATDs).
• All new TB patients who have never taken any ATD or have
taken them for less than one month are presumed to have drug-
sensitive TB.
2. Mullidrug resistant TB (MDR-TB):
The patient's bacilli are resistant to both R and H with or without
resistance to any number of other I st line drugs.
3. Rifampin resistant TB (RR-TB):
4. Mono-resistant TB:
5. Poly-drug resistanl TB (PDR-TB):
6. Extensive drug resistant TB (XDR-TB):
A MDR-TB case whose bacilli are additionally resistant to a FQ and one
2nd line injectable ATD.
 Drug-sensitive TB - This is treated by I st line ATDs

• Based on RNTCP guidelines 2016.

H,R,Z,E,S- Standard codes for lsoniazid, Rifampin , Pyrazinamide, Ethambutol,
Streptomycin.

Type of Intensive Continuation Total

patient phase phase Duration
months
New 2 HRZE 4 HRE 6
Previously 2 HRZES 5 HRE 8
treated +
1 HRZE
 Multidrug-resistant (MDR) TB-
• It is more rapid course with worse outcomes.
• requires complex multiple 2nd line drug
regimens ,
• longer in duration, and more expensive and more toxic.
• in India MDR-TB accounts for 3% of all new TB cases
and 12- 1 7% of retreatment cases in different states.
• The 'standard' RNTCP regimen for MDR-TB
consists of 6 drugs intensive phase lasting 6- 9
months and 4 drugs continuation phase of 18
months (see box).
This regimen is used in all confirmed or
suspect MDR-TB cases,
• The minimal 6 month intensive phase is extended
by I month each time till a maximum of 9 months,
if the sputum culture put up at the end of 4 th, 5th
and 6th month respectively are positive.
• Pyridoxine 100 mg/day is given to all patients
during the whole course of therapy to prevent
neurotoxicity o f the anti-TB drugs.
• This standard regimen has been found to be
highly successful.
 Extensive drug-resistant TB
• these are MDR-TB cases that are resistant to at
least 4 most effective cidal drugs,
• viz . H,R,FQ and one of Km/Am/Cm.
• The WHO estimated that 9.7% of MDR-TB
patients had XDR-TB in 2015.
• The exact incidence of XDR-TB in India is not
known. but with expanding laboratory facilities to
conduct sensitivity tests for 2nd line drugs, more
XDR-TB cases are likely to be confirmed.
• The XDR-TB is very difficult to treat,-

• to prevent further amplification of resistance, the

standard MDR regimen must be immediately stopped
when XDR-TB is detected or suspected.

• The RNTCP (2016) has recommended a treatment

regimen for XDR-TB consisting of 7 drugs in the
intensive phase (6-12 months) and 6 drugs in the
continuation phase ( 18 months)
The drugs and their adult daily doses (for 46-70 kg body
weight) are:
• Capreomycin 1000 mg
• Moxifloxacin 400 mg
• High dose isoniazid 900 mg
• PAS 12 g
• Clofazimine 200 mg
• Linezolid 600 mg
• Amoxicillin/clavulanate (875+125 mg tab) 2 tab
morning + one tab evening.
• In the continuation phase, injection capreomycin is
stopped and the remaining 6 drugs are continued for
another 18 months.
Causes of Failure of Drug Treatment of Tuberculosis
1.Failure of the patient to take the drugs
(noncompliance)
2.Incorrect prescribing of drugs
3. Primary drug resistance
4. Secondary drug resistance
5.Persisters which are dormant and therefore have not
been affected by the drugs
6.Poor general health due to malnutrition, diabetes or
chronic alcoholism
7.Associated disease such as diabetes mellitus or AIDS
Role of Glucocorticoids
• As glucocorticoids depress host defense
mechanisms,
• they should be used only in conditions like
tubercular meningitis, miliary tuberculosis, pleural
effusion, renal tuberculosis and rapidly progressing
pulmonary tuberculosis.
• In these conditions, steroids suppress
inflammatory reaction which can lead to extensive
fibrosis and damage.
Role of corticosteroids
• Corticosteroids should not be ordinarily used in tubercular
patients. :
• In seriously ill patients (miliary TB or severe pulmonary TB to
buy time for drugs to act.
• When hypersensitivity reactions occur to anti tubercular
drugs.
• ln meningeal/renal/pericardial TB or pleural effusion-to
reduce exudation, prevent its organisation and strictures, etc.
• In AIDS patients with severe manifestations of tuberculosis.
• Corticosteroids are contraindicated in intestinal tuberculosis
because silent perforation can occur.
• Corticosteroids, if given, should be gradually withdrawn
when the general condition of the patient improves.
 CHEMOPROPHYLAXIS
1.Neonate of TB mother.
2.Patients with old inactive disease.
3.Children with +ve montoux & a patient in the family.
4.Contacts of open cases who show recent montoux
test.
5.Leukemia, DM, Silicosis,AIDS.
INH-300mg/day for 6-12months,
• INH+R-300mg+600mg.
Chemoprophylaxis is given only in:
i. Contacts of open cases especially children.
INH is used daily (5 mg/kg) for 6-12 months.
Rifampicin can be used as an alternative to
INH.
ii. HIV-infected patients exposed to multi drug-
resistant tuberculosis-rifampicin and
pyrazinamide are given daily for 2 months.
Directly Observed Treatment,

ShortCourse (DOTS) Chemotherapy

• For regular intake of appropriate drugs by the patients.
• Directly Observed Treatment, Short Course (DOTS)
chemotherapy is a strategy that is found to be effective and is
recommended throughout the world.
• DOTS was launched in 1997 and is the fastest expanding
health programe in India.
• It involves providing most effective medicine and confirming
that it is taken-a DOTS provider ensures that the drug is taken
by the patient in his presence.
Tuberculosis in AIDS Patients

• Due to depressed immunity, AIDS patients

are at a higher risk (25-30 times) of
contracting tuberculosis.

• AIDS patients are likely to have more severe

and rapidly progressing tuberculosis.

• Moreover, adverse effects to antitubercular

drugs are more common in them.
 Tuberculosis in AIDS Patients
• They should be given more vigorous and
supervised chemotherapy as per the
guidelines.
• Antiretroviral therapy has to be started within
2-8 weeks of starting anti-TB treatment.
• If a TB patient who has been on treatment is
diagnosed to be having HIV infection
• 2 HRZES + 1 HRZE +5 HRE regimen is
recommended.
Drug resistance should be suspected in the following situations:
• Patients who have received prior therapy for TB
• Patients from areas with a high prevalence of resistance
(NewYork City, Mexico, Southeast Asia, the Baltic countries,
and the former Soviet states)
• Patients who are homeless, institutionalized, intravenous
drug abusers, or infected with HIV
• Patients who still have acid-fast bacilli-positive sputum
smears after 1 to 2 months of therapy
• Patients who still have positive cultures after 2 to 4 months
of therapy
• Patients who fail treatment or relapse after treatment
• Patients known to be exposed to MDR-TB cases
• Therapy of MAC infection Eradication of MAC has
not been achieved by any drug or regimen. Therapy is
di rec ted to suppress the disease and afford
symptomatic relief until immune status of the patient
improves by ART.
• A favoured regimen consists of 3 or 4 drug intensive
phase followed by 2 drug maintenance phase as
outlined in the box. The benefit of adding a FQ as the
4th drug is not clear.