Antimycobacterial Drugs Summary

Antimycobacterial Drugs

Drugs Used to Treat Tuberculosis

First-Line Drugs

  • Ethambutol
  • Isoniazid
  • Pyrazinamide
  • Rifabutin (alternative to Rifampin)
  • Rifampin
  • Rifapentine (alternative to Rifampin)
  • Aminoglycosides

Second-Line Drugs

  • Aminosalicylic acid
  • Bedaquiline
  • Capreomycin
  • Cycloserine
  • Ethionamide
  • Fluoroquinolones
  • Macrolides

Drugs Used to Treat Leprosy

  • Clofazimine
  • Dapsone
  • Rifampin (rifampicin)

Mycobacteria Overview

  • Characteristics:
    • Rod-shaped
    • Aerobic
    • Slow-growing (18-24 hours)
    • Acid-fast (due to mycolic acid in the cell wall)
    • Resistant to Gram staining and decolorization
  • Infections:
    • Cause granulomatous lesions, leading to tissue destruction.
    • M. tuberculosis → Latent TB (LTBI) & Active TB
    • M. leprae → Leprosy
    • Nontuberculous Mycobacteria (NTM) → Various infections
  • Treatment:
    • TB: Four first-line drugs; second-line for resistant cases.
    • NTM: No specific drugs, but macrolides, rifamycins, and aminoglycosides are used.

Chemotherapy for Tuberculosis

  • M. tuberculosis is slow-growing, requiring months to years of treatment.
  • Latent TB:
    • 9 months of isoniazid (INH) monotherapy
    • 12 once-weekly doses of INH and rifapentine
  • Active TB: Requires multiple drugs.
  • Drug-susceptible TB: At least 6 months of treatment.
  • Multidrug-resistant TB (MDR-TB): Typically lasts about 2 years.

Strategies for Addressing Drug Resistance

  • Drug Resistance & First-Line Treatments:
    • Naturally resistant organisms can emerge under drug pressure, especially from monotherapy.
    • Resistance develops rapidly with single-drug therapy (e.g., streptomycin).
    • Multidrug therapy is essential to suppress resistant organisms.
  • First-line drugs for TB:
    • Isoniazid (INH)
    • Rifampin
    • Ethambutol
    • Pyrazinamide
    • Rifabutin (alternative to Rifampin)
    • Rifapentine (alternative to Rifampin)
  • Standard TB treatment regimen:
    • Intensive phase (2 months): Isoniazid, Rifampin, Ethambutol, Pyrazinamide
    • Continuation phase (4 months): Isoniazid, Rifampin
    • Regimen should be tailored based on susceptibility data.

Second-Line Drugs, MDR-TB, and Treatment Strategies

  • Multidrug-resistant TB (MDR-TB): Resistance to at least Isoniazid and Rifampin.
  • Second-line drugs for MDR-TB:
    • Aminoglycosides (streptomycin, kanamycin, amikacin)
    • Capreomycin
    • Fluoroquinolones (levofloxacin, moxifloxacin)
    • Cycloserine
    • Ethionamide
    • p-Aminosalicylic acid
  • Extensively drug-resistant TB (XDR-TB): Requires drugs like Clofazimine, Linezolid.
  • Treatment adherence is challenging for long regimens (6 months or more).
  • Directly Observed Therapy (DOT):
    • Ensures medication adherence
    • Decreases drug resistance
    • Improves cure rates

Isoniazid (INH)

  • Mechanism of Action:
    • Prodrug activated by mycobacterial catalase-peroxidase (KatG).
    • Targets acyl carrier protein reductase (InhA) and β-ketoacyl-ACP synthase (KasA) for mycolic acid synthesis, disrupting the cell wall.
  • Antibacterial Spectrum:
    • Effective against M. tuberculosis.
    • M. kansasii may be susceptible at higher concentrations.
    • Most nontuberculous mycobacteria (NTM) are resistant.
  • Resistance:
    • Due to chromosomal mutations
    • Mutation/deletion of KatG (prevents prodrug activation).
    • Mutations in acyl carrier proteins.
    • Overexpression of InhA.
    • Cross-resistance with ethionamide.
  • Pharmacokinetics:
    • Readily absorbed orally; absorption impaired with food (especially high-fat meals).
    • Distributes into all body fluids, cells, and caseous material in tuberculous lesions.
    • Concentrations in cerebrospinal fluid (CSF) are similar to serum.
    • Undergoes N-acetylation and hydrolysis; acetylation rate is genetically regulated.
      • Fast acetylators: 90-min half-life
      • Slow acetylators: 3-4 hours
    • Excreted via glomerular filtration as metabolites; slow acetylators excrete more of the parent drug.
  • Adverse Effects:
    • Hepatitis: Most serious; can be fatal if untreated, risk increases with age, alcohol use, or rifampin co-administration.
    • Peripheral Neuropathy: Due to pyridoxine deficiency; avoidable with vitamin B6 supplementation.
    • CNS Effects: Convulsions in predisposed individuals.
    • Hypersensitivity: Includes rashes and fever.
  • Drug Interactions:
    • Inhibits metabolism of carbamazepine and phenytoin, potentiating adverse effects like nystagmus and ataxia.

Rifamycins: Rifampin, Rifabutin, and Rifapentine

Rifampin

  • Mechanism of Action:
    • Inhibits RNA transcription by binding to the β subunit of mycobacterial DNA-dependent RNA polymerase.
  • Antimicrobial Spectrum:
    • Bactericidal against both intracellular and extracellular mycobacteria, including M. tuberculosis and NTM (e.g., M. kansasii, M. avium complex).
    • Effective against gram-positive and gram-negative bacteria.
    • Used prophylactically for meningitis caused by Neisseria meningitidis and Haemophilus influenzae.
    • Highly active against M. leprae.
  • Resistance:
    • Occurs through mutations in the DNA-dependent RNA polymerase gene, reducing drug affinity.
  • Pharmacokinetics:
    • Absorbed well after oral administration.
    • Distributes to all body fluids and organs; CSF concentrations are 10-20% of blood levels.
    • Liver uptake with enterohepatic recycling.
    • Induces hepatic cytochrome P450 enzymes and transporters.
    • Autoinduction leads to a shortened elimination half-life after 1-2 weeks of dosing.
    • Eliminated primarily in bile and feces; small amounts excreted in urine.
    • Urine, feces, and secretions turn orange-red (including contact lenses).
  • Adverse Effects:
    • Common: Nausea, vomiting, rash.
    • Severe: Hepatitis (rare), liver failure (rare), flu-like syndrome (with intermittent dosing).
    • High-dose intermittent dosing may cause fever, chills, myalgia, acute renal failure, hemolytic anemia, and shock.
  • Drug Interactions:
    • Induces cytochrome P450 and phase II enzymes, decreasing the half-lives of coadministered drugs.
    • May require higher doses for affected drugs or a switch to rifabutin.

Rifabutin

  • Preferred for HIV coinfected TB patients on protease inhibitors or non-nucleoside reverse transcriptase inhibitors.
  • Less potent cytochrome P450 inducer (about 40% less than rifampin), reducing drug interactions.
  • Adverse effects: Similar to rifampin, including uveitis, skin hyperpigmentation, and neutropenia.

Rifapentine

  • Longer half-life than rifampin.
  • Used with isoniazid for once-weekly treatment of LTBI and in select HIV-negative patients with minimal pulmonary TB.

Pyrazinamide

  • Mechanism of action:
    • Enzymatically hydrolyzed by pyrazinamidase to pyrazinoic acid (active form).
    • Some resistant strains lack the pyrazinamidase enzyme.
    • Activity against tuberculosis bacilli in acidic lesions and macrophages.
  • Uses:
    • Part of the short-course combination for tuberculosis treatment (with isoniazid, rifampin, and ethambutol).
  • Pharmacokinetics:
    • Distributes throughout the body, including CSF.
    • Liver toxicity and uric acid retention (rarely causes gout).
  • Treatment regimen:
    • Clinical benefit is greatest early in treatment, so usually discontinued after 2 months of the 6-month regimen.

Ethambutol

  • Mechanism of action:
    • Bacteriostatic; inhibits arabinosyl transferase, essential for mycobacterial cell wall synthesis.
  • Uses:
    • Used in combination with pyrazinamide, isoniazid, and rifampin in tuberculosis treatment.
    • May be discontinued if isolate is susceptible to the other drugs.
  • Pharmacokinetics:
    • Distributes well throughout the body, with variable CNS penetration (adequate for tuberculous meningitis is questionable).
    • Excreted primarily in the urine.
  • Adverse effects:
    • Optic neuritis (diminished visual acuity and loss of color discrimination, especially red and green).
    • Risk increases with higher doses and renal impairment.
    • Decreased uric acid excretion, caution in gout patients.
    • Visual acuity and color discrimination should be tested regularly during treatment.

Alternate Second-Line Drugs

  • Streptomycin, para-aminosalicylic acid, capreomycin, cycloserine, ethionamide, bedaquiline, fluoroquinolones, and macrolides are second-line TB drugs.
  • In general, these agents are less effective and more toxic than the first-line agents.

Streptomycin

  • Aminoglycoside antibiotic; one of the first effective agents for TB.
  • Action appears to be greater against extracellular organisms.
  • Infections due to streptomycin-resistant organisms may be treated with kanamycin or amikacin.

Para-aminosalicylic acid (PAS)

  • Works via folic acid inhibition.
  • Largely replaced by ethambutol for drug-susceptible TB but remains important in MDR-TB regimens.

Capreomycin

  • Parenterally administered polypeptide that inhibits protein synthesis.
  • Primarily reserved for the treatment of MDR-TB.
  • Careful monitoring of renal function and hearing is necessary to minimize nephrotoxicity and ototoxicity.

Cycloserine

  • Orally effective, tuberculostatic drug that disrupts d-alanine incorporation into the bacterial cell wall.
  • Distributes well throughout body fluids, including the CSF.
  • Primarily excreted unchanged in urine.
  • Adverse effects: CNS disturbances (e.g., lethargy, difficulty concentrating, anxiety, and suicidal tendency) and seizures.

Ethionamide

  • Structural analog of isoniazid that also disrupts mycolic acid synthesis.
  • Mechanism of action is not identical to isoniazid, but there is some overlap in the resistance patterns.
  • Widely distributed throughout the body, including the CSF.
  • Adverse effects: Nausea, vomiting, and hepatotoxicity. Hypothyroidism, gynecomastia, alopecia, impotence, and CNS effects also reported.

Fluoroquinolones

  • Specifically, moxifloxacin and levofloxacin have an important place in the treatment of multidrug-resistant tuberculosis.

Macrolides

  • Azithromycin and clarithromycin are included in regimens for several NTM infections, including MAC.
  • Azithromycin may be preferred for patients at greater risk for drug interactions.
  • Clarithromycin is both a substrate and an inhibitor of cytochrome P450 enzymes.

Bedaquiline

  • A diarylquinoline; an ATP synthase inhibitor.
  • Approved for the treatment of MDR-TB.
  • Administered orally and is active against many types of mycobacteria.
  • Boxed warning for QT prolongation, and monitoring of the electrocardiogram is recommended.
  • Elevations in liver enzymes have also been reported, and liver function should be monitored during therapy.
  • Metabolized via CYP3A4, and administration with strong CYP3A4 inducers (e.g., rifampin) should be avoided.

Fixed-Dose Combinations (FDC)

  • FDC tablets are recommended over separate drug formulations for drug-susceptible TB.
  • Patient compliance and treatment satisfaction increase with FDCs.
  • Important for suppressing resistance development and improving clinical outcomes.

Multidrug-Resistant Tuberculosis

  • TB drug resistance can be isoniazid-resistant, rifampicin-resistant (RR-TB), multidrug-resistant (MDR-TB), or extensively drug-resistant (XDR-TB).
  • In 2016, China, India, and Russia accounted for 47% of global MDR and RR-TB cases; 6.2% were XDR-TB.
  • WHO recommends a shorter MDR-TB regimen of 9–12 months under specific conditions.
  • Longer regimens (18 months or more) are used for RR-TB and MDR-TB.
  • Linezolid and clofazimine are core second-line drugs for MDR-TB; para-aminosalicylic acid (PAS) is used as an add-on.
  • These drugs are now recommended for all RR-TB cases, even if isoniazid resistance isn’t confirmed.
  • Clarithromycin and other macrolides are no longer used for MDR and RR-TB.
  • Drugs are selected from WHO-defined groups, choosing 4–7 based on pathogen susceptibility.
  • HIV-negative status must be confirmed before starting thioacetazone.

Shorter MDR-TB Treatment Regimens

  • Split into two distinct phases based on the duration of treatment:
    • Intensive phase:
      • Duration: 4 months (extended up to 6 months if no sputum smear conversion).
      • Drugs: gatifloxacin (or moxifloxacin), kanamycin, prothionamide, clofazimine, high-dose isoniazid, pyrazinamide, and ethambutol.
    • Continuation phase:
      • Duration: 5 months.
      • Drugs: gatifloxacin (or moxifloxacin), clofazimine, pyrazinamide, and ethambutol.
  • Drug treatment needs continuous updating from the WHO Guideline.

Drugs For Leprosy

Dapsone

  • Structurally related to sulfonamides and inhibits dihydropteroate synthase in the folate synthesis pathway.
  • Bacteriostatic for M. leprae; resistant strains may be encountered.
  • Also used in the treatment of pneumonia caused by Pneumocystis jirovecii in immunosuppressed patients.
  • Well absorbed and distributed throughout the body, with high concentrations in the skin.
  • Undergoes hepatic acetylation.
  • Adverse reactions include hemolysis (especially in patients with glucose-6-phosphate dehydrogenase deficiency), methemoglobinemia, and peripheral neuropathy.

Clofazimine

  • A phenazine dye.
  • Mechanism of action may involve binding to DNA, or generating cytotoxic oxygen radicals.
  • Bactericidal to M. leprae, and has potentially useful activity against M. tuberculosis and NTM.
  • Recommended by the WHO as part of a shorter regimen (9 to 12 months) for MDR-TB.
  • Accumulates in tissues, allowing intermittent therapy, but does not enter the CNS.
  • Patients develop a pink to brownish-black discoloration of the skin.
  • Has some anti-inflammatory and anti-immune activities; erythema nodosum leprosum may not develop.