ANTI-TUBERCULOSIS
DRUGS
• An Antitubercular drug should satisfy the following criteria
(a) Highly effective
(b) Free from side-effects
(c) Easy to administer
(d) Reasonably cheap
• The currently used drugs may be classified into two groups
• Bactericidal - kill the bacilli in vivo
• Bacteriostatic - inhibit the multiplication of the bacilli and lead to their
destruction by the immune mechanism of the host
THE FIRST LINE DRUGS
Bactericidal Bacteriostatic
• Rifampicin • Ethambutol
• Isoniazid
• Streptomycin
• Pyrazinamide
Rifampicin (RMP)
• Powerful bactericidal drug better sterilizing than INH.
• Permeates all tissue membranes including the blood-brain and placental barriers.
• Equally effective against intracellular as well as extracellular bacilli.
• Only bactericidal drug active against the "persisters" or dormant bacilli
MOA: Inhibits DNA-dependent RNA-polymerase which in turn inhibits bacterial protein synthesis leading to cell death
Elimination: Billiary
Adverse effects:
• Red-orange discolouration of body fluids (eg. urine, tears)
• Cytochrome P450 induction causing minor drug interactions (Rifabutin is preferred in HIV patients)
Contraindications:
• Breastfeeding women
• Hepatic Dysfunction
Mechanism of Resistance:
RNA polymerase mutations (Resistance develop rapidly if used as monotherapy)
Isoniazid (INH)
Prodrug that needs to be converted into its active metabolite by bacterial catalase-peroxidase (encoded by KatG)
Only drug that can be used as monoprophylaxis agianst TB
MOA: Prevents cell wall synthesis by inhibiting the synthesis of Mycolic acid
Metabolization: Primarily hepatic by N-Acetyltransferase(NAT), individuals with low NAT levels have higher half-life of
active drug, likewise one with high hepatic NAT have lower half-life of the drug.
• Dose adjustments are needed for these patients
• Rate of NAT acetylation is genitically determined
Route of elimination: Renal elimination after hepatic metabolization.
Adverse effects:
• Hepatotoxicity (drug-induced hepatitis)
• Pheripheral neuropathy
• Vitamin B6 difficiency (administered with pyridoxine)
Mechanism of resistance:
Mutations causing decreased KatG leading to decreased expression of catalase-peroxidase causing less/no biologically
active INH
Streptomycin
It acts entirely on rapidly multiplying bacilli and less active agianst slow multipliers.
CNS penetration is also poor.
MOA: Binds 30S subunit of bacterial ribosomes -> Irreversible inhibition of initiation complex -> Inhibition of bacterial protein
synthesis -> Cell death (Bactericidal)
Elimination: Renal (via glomerular filtration)
Adverse effects:
• Nephrotoxicity (should be avoided with other nephrotoxic agents)
• Ototoxicity and vestibulartoxicity (risk increases with concurrent use of loop dieuretics)
• Neuromuscular blockade (risk increases in hypomagnesemia, myasthenia gravis and with use of calcium channel blockes)
• Teratogenecity
Contraindications:
• Myasthenia gravis
• Botulism
• Pregnancy
Mechanism of resistance: Inactivation via acetylation, phosphorylation and/or adenylation by secreated bacterial
transferase enzymes.
Pyrazinamide
Particularly active agianst the slow-multiplying intracellular bacilli.
Increase the sterilizing ability of rifampicin.
MOA: Prodrug converted into active form pyrazinoic acid. Most effective in acidic pH (eg. in acidic
phagolysosomes)
CNS penetration: Only when meninges are inflamed.
Elimination: Renal elimination after hepatic metabolization.
Adverse effects:
• Hyperurecemia
• Hepatotoxicity
Contraindications:
• Acute Gout
• Hepatic Failure
Mechanism of resistance: mutations in RpsA gene coding for ribosomal protein S1
Ethambutol
Bacteriostatic and is used in combination to prevent the emergence of resistance to other drugs.
Resistance develop rapidly if used as monotherapy.
MOA: inhibits arabinosyltransferase -> Decreased carbohydrate polymerization -> prevention of mycobacterial cell wall
synthesis (Bacteriostatic)
CNS penetration: Only when meninges are inflamed.
Elimination: Primarily renal.
Adverse effects:
• Optic neuropathy with decreased visual acuity and red-green color blindness, which may lead to irreversible blindness.
• Hyperurecemia.
Contraindications:
• Contraindicated in patients with optic neuritis & who are unable to report visual changes.
• Children < 13 years of age (safety not yet sufficiently established)
Mechanism of resistance: mutations of EmbCAB gene coding for arabinosyltransferase.
THE SECOND-LINE DRUGS
Fluoroquinolones
• Ciprofloxacin, ofloxacin, levofloxacin, moxifloxacin and gatifloxacin are active against M. tuberculosis, even those resistant
to other drugs.
• Given orally or IV.
• Useful in treating infections resistant to standard drugs and in cases with relapse.
Ethionamide
• Structurally related to INH and acts by inhibiting the mycolic acid synthesis.
• Effective against bacilli resistant to other drugs and has proved effective in infections due to atypical mycobacteria.
• Effective against intracellular as well as extracellular organisms.
Capreomycin
It is bactericidal. Its mechanism of action, pharmaco_x0002_kinetics and adverse reactions are similar to those of
streptomycin. It should be administered with caution in
presence of renal impairment.
Kanamycin and Amikacin
They are bactericidal and are active against bacilli resistant to streptomycin, INH and cycloserine.
Cycloserine
• Mainly bacteriostatic, effective against bacilli resistant to INH or streptomycin and against atypical mycobacteria, although
antitubercular activity is less than that of these two drugs.
• Acts by inhibiting the synthesis of the bacterial cell wall.
Thioacetazone
• Bacteriostatic drug rapidly diffuses into various body tissues and also crosses the placenta barrier.
• It is also secreted in milk.
• Never used in HIV patients as it can cause severe and fatal skin reactions.
Adverse effects:
• Blurring of vision,
• Haemolytic anaemia
• Urticaria.
Macrolides
Newer macrolides azithromycin and clarithromycin also have action against tubercular bacilli. They are used to treat atypical
mycobacterial infection and cases with relapse.
Newer anti-tuberculous drugs
Bedaquiline (BDQ)
• Bedaquiline (BDQ) is a new class of drug diarylquinoline, that specifically targets mycobacterial ATP synthase, an enzyme
essential to supply of energy to mycobacterium.
• It is a bactericidal drug with high volume of tissue distribution, highly bound to plasma proteins and hepatically
metabolized. The drug has extended half-life, which means that it is still present in the plasma up to 5.5 months post
stopping BDQ.
• Shown significant benefits in improving the time to culture convertion in MDR-TB
The basic criteria for patient selection is :
(1) Age of the patient should be above/= 18 years having MDR- TB;
(2) Pregnancy is a contraindication for BDQ therapy and the patient should be using non-hormonal based birth control
measure throughout the treatment period or have been post_x0002_menopausal for past 2 years.
(3) Cardiac arrythmia is a contraindication for BDQ treatment
The following group of patients are eligible for BDQ therapy:
1. MDR/RR TB with resistance to any/all fluoroquinolones (FQ) or to any/all second-line injectable agents (SU)
2. XDR-TB
3. Mixed pattern resistant TB (XDR-TB + additional first line / second line resistant TB)
4. Treatment failure of MOR- TB + FQ/SLJ resistance or XDR-TB
Delamanid (OLM)
Delamanid is a recently approved drug for the treatment of TB conditional use under programmatic setting
only.
Phase III clinical trial results for safety and effectiveness of the drug is yet to be published.
The Drug Controller General of India has issued permission to use Delamanid (50 mg) as part of an
appropriate combination regimen for pulmonary MDR-TB in adult patients when an effective treatment
regimen cannot otherwise be composed for reasons of resistance or tolerability.
Adverse Reactions
Reaction Drug Responsible
Severe rash. agranulocytosis Thioacetazone
Hearing loss or disturbed balance Streptomycin
Hearing loss or disturbed balance Ethambutol
Renal failure. shock or Rifampicin
thrombocytopenia
