Drugs for tuberculosis

1. S. Parasuraman, M.Pharm., Ph.D.,
Associate Professor, Faculty of Pharmacy,
AIMST University
Drugs for tuberculosis

2. Data are as reported to WHO. Estimates of TB and MDR-TB burden are produced by
WHO in consultation with countries.
Generated: 2020-02-24

3. Learning Outcomes
• 1.3.1 First and second line antitubercular drugs with their
pharmacology
At the end of this session, the student would be able to discuss the:
– write the clinical utility of antitubercular drugs.
– describe the mechanism of action, pharmacological actions,
pharmacokinetic features, therapeutic uses, adverse effects, interaction
and contraindications of the first and second line antitubercular drugs
– describe the mechanism of resistance in mycobacteria
• 1.3.2 Drugs for mycobacterium avium complex
At the end of this session, the student would be able to discuss the:
– write the Runyon classification of nontuberculous mycobacteria
– describe the principles of therapy against Mycobacterium avium complex
– List the drugs active against atypical mycobacteria

4. Learning Outcomes
• 1.3.3 Management of tuberculosis
At the end of this session, the student would be able to
discuss the:
– describe the principles of antituberculosis chemotherapy
– describe the treatment of tuberculosis in adults, children,
pregnancy and lactation as per Malaysian clinical practice
guidelines
– describe management of Multidrug-Resistant Tuberculosis

5. Tuberculosis
Tuberculosis (TB)is a chronic
granulomatous disease and a
major health problem in
developing countries. About
1/3rd of the world’s
population is infected with
Mycobacterium tuberculosis.

6. Biology of tubercular infection
Ref: http://www.oxfordimmunotec.com/international/wp-content/uploads/sites/3/natural_history_TB.jpg

7. Development of anti-tubercular drug
1943: PAS (The first successful drug for treating TB)
1952: Isoniazid, Pyrazinamide
1957: Rifamycin
1961: Ethambutol
2000: Pretomanid; 2006: Bedaquiline

8. Tuberculosis
• Anti-TB drugs can be divided into
– First line: These drugs have high antitubercular efficacy
as well as low toxicity; are used routinely. Drugs:
Isoniazid (H), Rifampin (R), Pyrazinamide (Z),
Ethambutol (E), and Streptomycin (S)
– Second line: These drugs have either low antitubercular
efficacy or higher toxicity or both; and are used as
reserve drugs. Drugs: Thiacetazone (Tzn),
Paraaminosalicylic acid (PAS), Ethionamide (Etm),
Cycloserine (Cys), Kanamycin (Kmc), Amikacin (Am),
Capreomycin (Cpr), Bedaquiline and others.

9. First line-Antitubercular Drugs
• Isoniazid (H):
– Isoniazid (isonicotinic acid hydrazide; INH), also called INH.
– INH is an essential component of all antitubercular regimens.
– Active against M. tuberculosis, M. bovis, M. kansasii. INH has
poor activity against MAC.
– Mechanism of Action:
• Isoniazid enters bacilli by passive diffusion.
• Inhibition of synthesis of mycolic acids which are unique
fatty acid components of mycobacterial cell wall.
• Two gene products labelled ‘InhA’ and ‘KasA’, which
function in mycolic acid synthesis are the targets of INH
action.

10. First line-Antitubercular Drugs
• Isoniazid (H):
– Mechanisms of Resistance:
• Resistance to INH is associated with
– mutation in the kasA and katG genes
– deletion of KatG
– overexpression of the genes for InhA and ahpC
– Antibacterial Activity:
• Active against Mycobacterium tuberculosis.
• Moderately active against Mycobacterium bovis and
Mycobacterium kansasii
• Poor activity against MAC.

11. First line-Antitubercular Drugs
• Isoniazid (H):
– Pharmacokinetics:
• Well absorbed orally
• Orally bioavailability of isoniazid is about 100% for 300 mg
dose.
• Drug – plasma protein biding: 10%
• Excretion: 75-95% excreted through urine in 24 h.
• t1/2 = Fast acetylators: 1 hr ; Slow acetylators: 3hr.
• Isoniazid induced peripheral neuritis is more common in
slow acetylators.

12. First line-Antitubercular Drugs
• Isoniazid (H):
– Adverse effects:
• INH is well tolerated by most patients.
• Neurological manifestations (paresthesias, numbness,
mental disturbances, rarely convulsions)
• Peripheral neuritis.
• Hepatitis, a major adverse effect of INH, is rare in children,
but more common in older people and in alcoholics.
• Other side effects are lethargy, rashes, fever, acne and
arthralgia.
• INH neurotoxicity is treated by pyridoxine 100 mg/day.

13. First line-Antitubercular Drugs
• Rifamycins: Rifampin (R), Rifapentine, and Rifabutin
– Rifampin or rifampicin (macrocyclic antibiotics), is a
semisynthetic derivative of rifamycin B obtained from
Streptomyces mediterranei.
– Mechanism of Action:
• Rifampin interrupts RNA synthesis by binding to β subunit
of mycobacterial DNA-dependent RNA polymerase (rpoB).
– Mechanisms of Resistance:
• Mutations in rpoB gene
• Mutations in efflux pumps

14. First line-Antitubercular Drugs
• Rifampin (R):
– Antibacterial Activity:
• Rifampin is bactericidal to M. tuberculosis and many other
gram-positive and gram-negative bacteria.
• Rifampin is also bactericidal against Mycobacterium
leprae.
• Against TB bacilli, it is as efficacious as INH and better than
all other drugs.
• It has good sterilizing and resistance preventing actions.
– Use:
• Used for the treatment of leprosy; Prophylaxis of
Meningococcal and H. influenzae meningitis; Second/third
choice drug for MRSA, diphtheroids and Legionella
infections; Combination of doxycycline and rifampin is the
first line therapy of brucellosis.

15. First line-Antitubercular Drugs
• Rifampin (R):
– Pharmacokinetics:
• Well absorbed orally
• Orally bioavailability of rifampin is about ≈ 70%.
• Rifampin is to be taken in empty stomach (food decreases
absorption).
• It is widely distributed in the body: penetrates
intracellularly, enters tubercular cavities, caseous masses
and placenta. Also crosses meninges.
• Excreted mainly in bile, some in urine also.
• t1/2= 2-5 hr

16. First line-Antitubercular Drugs
• Rifampin (R):
– Adverse effects:
• Incidence of adverse effects is similar to INH.
• Serious but rare reactions:
– breathlessness which may be associated with shock
and collapse.
– Purpura, haemolysis, shock and renal failure.
Purpura

17. First line-Antitubercular Drugs
• Pyrazinamide (Z):
– It is weakly tuberculocidal and more active in acidic medium.
– Mechanism of Action:
• pyrazinamide passively diffuses into mycobacterial cells.
– Pharmacokinetics:
• Pyrazinamide is absorbed orally, widely distributed, has
good penetration in CSF, because of which it is highly
useful in meningeal TB; extensively metabolized in liver
and excreted in urine; plasma t1/2 is 6–10 hours.
– ADR: Hyperuricaemia, abdominal distress, arthralgia,
flushing, rashes, fever and loss of diabetes control.

18. First line-Antitubercular Drugs
• Ethambutol (E):
– It is selectively tuberculostatic and is active against MAC as
well as some other mycobacteria.
– Mechanism of Action:
• Inhibit arabinosyl transferases.
– Pharmacokinetics:
• About 3/4 of an oral dose of E is absorbed. It is distributed
widely, but penetrates meninges incompletely and is
temporarily stored in RBCs. It is excreted in urine.
• T1/2 is ≈ 4 hrs.
– ADR: visual impairment (largely reversible), nausea, rashes,
fever, rarely peripheral neuritis.

19. First line-Antitubercular Drugs
• Streptomycin (S):
– It was the first clinically useful antitubercular drug. It is
tuberculocidal, but less effective than INH or rifampin. It acts
only on extracellular bacilli. It penetrates tubercular cavities,
but does not cross to the CSF, and has poor action in acidic
medium.
Resistance developed
rapidly when streptomycin
was used alone in
tuberculosis
Lower margin of safety
(ototoxicity and
nephrotoxicity)

20. Second line-Antitubercular Drugs
• Thiacetazone (Tzn)
• Paraaminosalicylic acid (PAS)
• Ethionamide (Etm)
• Cycloserine (Cys)
• Kanamycin (Kmc)
• Amikacin (Am)
• Capreomycin (Cpr)
• Fluoroquinolones - well tolerated alternatives to 1st line
anti-TB drugs

21. Second line-Antitubercular Drugs
• Fluoroquinolones:
– Fluoroquinolones are active against MAC, M. fortuitum and
some other atypical mycobacteria.
– The revised TB control programme have included Ofx/ Lfx in
the standardized regimen for MDR-TB.
– Resistance development: Mycobacterial resistance to Ofx,
Lfx and Cfx develops rapidly by mutation of DNA gyrase gene.

22. Second line-Antitubercular Drugs
• Bedaquiline:
– Bedaquiline is an ATP synthase inhibitor
– Approved for the treatment of MDR-TB.
– Bedaquiline is administered orally.
– Bedaquiline is active against many types of mycobacteria.
– Bedaquiline may cause QT prolongation, and monitoring of
the electrocardiogram is recommended.

23. Management of tuberculosis

24. Goals of antitubercular chemotherapy
• Kill dividing bacilli: Drugs with early bactericidal action
rapidly reduce bacillary load in the patient and achieve
quick sputum negativity so that transmission of TB is
interrupted. This also affords quick symptom relief.
• Kill persisting bacilli: To effect cure and prevent
relapse. This depends on sterilizing capacity of the drug.
• Prevent emergence of resistance: The relative activity
of the first line drugs in achieving these goals.

25. Principles of antituberculosis chemotherapy
• Mycobacterium tuberculosis is not a single species, but
a complex of species with 99.9% similarity at the
nucleotide level. The complex includes M. tuberculosis
(typus humanus), M. canettii, M. africanum, M. bovis,
and M. microti.
• Antituberculosis Therapy:
– Traditionally, first-line anti-TB agents are used for the
treatment
– treating TB in less than 6 months
– Traditionally, first-line agents were more efficacious and better
tolerated
– relative to second-line agents. Second-line agents were used in
case of poor tolerance or resistance to first-line agents.

26. Types of Antituberculosis Therapy
• Prophylaxis
• Definitive therapy of drug-susceptible TB
• Definitive therapy of drug-resistant TB

27. Types of Antituberculosis Therapy
• Prophylaxis:
• After infection with M. tuberculosis, about 10% of people
will develop active disease over a lifetime. The highest risk
of reactivation TB is in patients with Mantoux tuberculin
skin test reaction 5 mm or greater who also fall into one of
the following categories
– recently exposed to TB
– have HIV coinfection
– have fibrotic changes on chest radiograms
– post-transplantation
– taking immunosuppressive medications
• Any person with a skin test greater than 15 mm is also at
high risk of disease.

28. Types of Antituberculosis Therapy
• Prophylaxis:
• In these patients at high risk of active TB, prophylaxis is
recommended to prevent active disease. Prophylaxis
consists of four regimens.
• Those who cannot take isoniazid should be given rifampin.

29. Types of Antituberculosis Therapy
• Definitive Therapy of Drug-Susceptible TB:
• All active TB cases should be confirmed by culture or rapid
diagnostic methods such as nucleic acid amplification tests.
• The duration of therapy of drug-susceptible pulmonary TB is
6 months. The first 2 months of the four-drug regimen is
termed the initial phase of therapy and the last 4 months
the continuation phase of therapy.
• A 9-month duration should be used for patients with
cavitary disease who are still sputum culture positive at 2
months.
• The treatment of TB pericarditis is a special case in which
the use of steroids has been advocated.

30. Types of Antituberculosis Therapy
• Definitive Therapy of Drug-Resistant TB:
• The XDR-TB is MDR-TB that is also resistant to fluoroquinolones
and at least one of three injectable second-line drugs (i.e.,
amikacin, kanamycin, or capreomycin).
• These diseases, virtually untreatable (bedaquiline and delaminid
in combination with optimized background regimens can be
used)
• Therapy should be based on evidence of susceptibility and
should include:
– at least three drugs with at least one of the injectable anti-TB agents
– MDR-TB, a prolonged course of 5 to 7 agents, except a
– shorter 9-12 month regimen if there is no resistance to fluoroquinolones
and second-line injectable agents

31. Treatment of tuberculosis in adults
• Fixed-Dose Combinations (FDCs)
• Directly Observed Therapy (DOT)

32. Treatment of tuberculosis in adults
• Fixed-Dose Combinations (FDCs)
• The following FDC preparations are registered in Malaysia
– Forecox-Trac Film Coated Tab: Isoniazid, Rifampicin, Ethambutol
and Pyrazinamide
– Rimactazid 300 Sugar Coated Tab: Isoniazid and Rifampicin
– Rimcure 3-FDC Film Coated Tab: Isoniazid, Rifampicin and
Pyrazinamide
– Akurit-Z Tab: Isoniazid, Rifampin (Rifampicin) and Pyrazinamide
– Akurit Tab:Isoniazid and Rifampin (Rifampicin)
– Akurit-Z Kid Dispersible Tab: Isoniazid, Rifampin (Rifampicin) and
Pyrazinamide
– Akurit-4: Ethambutol, Isoniazid, Rifampin (Rifampicin) and
Pyrazinamide

33. Treatment of tuberculosis in adults
• Directly Observed Therapy (DOT)
• WHO introduced 6–8 month multidrug ‘short course’ regimens in
1995 under the Direct Observed Therapy, Short Course (DOTS)
programme.
• Directly observed therapy (DOT) to ensure adherence and good
management practice.
• In this patients are divided into 4 categories.
– Category I: New case of sputum smear positive or severe
pulmonary TB.
– Category II: Defaulted, irregularly treated and relapse cases.
– Category III: New sputum smear negative pulmonary TB.
– Category IV: Chronic cases who remained or again became sputum
smear positive after receiving fully supervised category II
treatment.

34. Short Course Chemotherapy (DOTS)
Category wise treatment regimens for tuberculosis

35. Tuberculosis in children
• There is an increasing trend of TB cases among children in
Malaysia. AntiTB drug and management of children with TB
should be in line with the WHO Stop TB Strategy, taking into
consideration the epidemiology and clinical presentation of TB in
children.
Isoniazid (H), Rifampin (R), Pyrazinamide (Z), Ethambutol (E)
Tuberculosis in pregnant women
• The WHO and British Thoracic Society consider H, R, E and Z to
be safe to the foetus and recommend the standard 6 month
(2HRZE + 4HR) regimen for pregnant women with TB. S is
contraindicated because it is ototoxic to the foetus.

36. Tuberculosis in lactation
• Breastfeeding mothers with TB should receive a full course of
antiTB drugs. First-line antiTB drugs are safe in breast feeding.
• Mother and baby should stay together for continuation of
breastfeeding. Once active TB in the baby is ruled out, the baby
should be given six months isoniazid prophylaxis, followed by
BCG vaccination.
Isoniazid (H), Rifampin (R), Pyrazinamide (Z), Ethambutol (E)
Tuberculosis in AIDS patients
• The association of HIV and TB infection is a serious problem. HIV
positive cases have a higher incidence of extrapulmonary, more
severe, more lethal and more infectious TB.
• Initial intensive phase therapy with daily HRZE for 2 months is
started immediately on the diagnosis of TB, and is followed by a
continuation phase of HR for 4–7 months (total 6–9 months).

37. Multidrug-resistant (MDR) TB
• MDR-TB is defined as resistance to both H and R, and may be any
number of other (first line) drug(s). Its treatment requires
complex
• The general principles of treatment of MDR-TB are:
– The regimen should have at least 4 drugs certain to be
effective
– efficacy may be placed on survey of similar patients who have
been treated
– Avoid combining cross resistance drug. e.g. two FQs,
– Include drugs from group I to group IV (alternative
classification) in a hierarchial order

38. Multidrug-resistant (MDR) TB
Medicines recommended for the treatment of RR-TB and MDR-TB
Ref: WHO treatment
guidelines for drug- resistant
tuberculosis 2016

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