Antimycobacterials

• Antimycobacterial drugs


  Drugs used to treat infections caused by mycobacteria
• Mycobacteria


  • Rod-shaped, aerobic bacteria
  • Cell wall with peptidoglycolipids, fatty acids, waxes, and mycolic acid
  • Slow growth, acid fast, resistant to detergents/antibiotics
• Mycobacteria infecting humans

  • M. tuberculosis (pulmonary tuberculosis, extrapulmonary TB)
  • M. leprae (leprosy)
  • M. bovis (tuberculosis-like illness)
  • Mycobacterium avium complex (disseminated infection, pulmonary infections, common in immunocompromised states/HIV)
• Mycobacteria properties

  • Intrinsically resistant to most antibiotics
  • Slow growing
  • Cell wall is impermeable to many agents
  • Intracellular pathogens, inaccessible to drugs that penetrate these cells poorly
  • Can also be dormant, resistant to many drugs or killed very slowly
• Use of drug combinations

  • To delay emergence of resistance
  • To enhance antimycobacterial efficacy
• Complications of antimycobacterial chemotherapy

  • Limited information about the mechanism of action
  • Development of resistance
  • Intracellular location of mycobacteria
  • Chronic nature of the disease (protracted therapy and drug toxicities)
  • Patient compliance
• Tuberculosis commonly involves the lungs but can also infect other organs (liver, CNS, bone, GI, kidneys)
• Tuberculosis is the 6th leading cause of mortality in the Philippines, and the Philippines is the 4th in worldwide rank of TB (WHO, 2020)
• First-line drugs for M. tuberculosis

  • Isoniazid (H)
  • Rifampicin (R)
  • Pyrazinamide (Z)
  • Ethambutol (E)
• Second-line drugs for M. tuberculosis

  • Levofloxacin
  • Moxifloxacin
  • Bedaquiline
  • Linezolid
  • Clofazimine
  • Cycloserine
  • Ethambutol
  • Delamanid
  • Pyrazinamide
  • Imipenem-Cilastatin
  • Meropenem
  • Amikacin
  • Streptomycin
  • Prothionamide
  • P-amino salicyclic acid
• Isoniazid mechanism of action

  • Structural congener of pyridoxine
  • Inhibition of enzymes required for the synthesis of mycolic acid
  • Bactericidal
  • Resistance can emerge rapidly if used alone
• Isoniazid resistance mechanisms

  • katG gene - catalase peroxidase bioactivation of INH
  • inhA gene - enzyme acyl carrier reductase
• Isoniazid pharmacokinetics


  • Well absorbed orally
  • Metabolized by acetylation in the liver (affected by genetic control of acetylation - "fast" or "slow")
• Isoniazid clinical use


  • Single most important drug used for TB (component of drug combination regimen)
  • For latent TB infection (LTBI); close contacts (sole drug)
• Isoniazid toxicity


  • Peripheral neuritis, restlessness, muscle twitches, insomnia (pyridoxine 25-50mg/d)
  • Hepatotoxic
  • CYP 450 enzyme inhibitor
  • Hemolysis in G6PD deficient patients
• Rifampin/Rifampicin mechanism of action


  • Bactericidal
  • Inhibits DNA-dependent RNA polymerase
  • Resistance from changes in drug sensitivity of polymerase
• Rifampin/Rifampicin pharmacokinetics


  • Well-absorbed orally
  • Distributed to most body tissues, including CNS
  • Undergoes enterohepatic cycling, partially metabolized in the liver
  • Free drug and metabolites are excreted mainly in feces (orange body fluids)
• Rifampin/Rifampicin clinical uses


  • Used in combination with drugs
  • Can be used as sole drug in LTBI or close contacts with INH-resistant strains
  • In leprosy - it delays resistance to dapsone
  • Used for MRSA, PRSP
• Rifampin/Rifampicin toxicities and interactions


  • Can impair antibody responses
  • Skin rashes, thrombocytopenia, nephritis, liver dysfunction
  • Flu-like symptoms, anemia
  • Induces liver drug-metabolizing enzymes
• Rifabutin


  • Equally effective as antimycobacterial agent; less drug interactions
  • Preferred over rifampin in AIDS patients taking some antiretrovirals
• Rifaximin


  Not absorbed from GI tract, used in traveler's diarrhea
• Ethambutol mechanism of action


  • Inhibits arabinosyltransferase enzyme needed for cell wall synthesis
  • Resistance due to mutation in emb gene if drug is used alone
• Ethambutol pharmacokinetics


  • Well absorbed orally, distributed to most tissues including CNS
  • Majority is excreted unchanged in urine (dose reduction in renal impairment)
• Ethambutol clinical use


  Mainly for TB, in combination with other drugs
• Ethambutol toxicity


  • Dose-dependent visual disturbances (decrease in acuity, color blindness, optic neuritis, retinal damage)
  • Headache, confusion, hyperuricemia, peripheral neuritis
• Pyrazinamide mechanism of action


  • Not well known mechanism
  • Bacteriostatic action - through pyrazinamidases
  • Resistance due to mutations in genes that encode enzymes; drug-efflux systems esp. when used alone
• Pyrazinamide pharmacokinetics


  • Well-absorbed orally
  • Penetrates most body tissues, including CNS
  • Partly metabolized to Pyrazinoic acid
  • Half-life prolonged in liver or kidney failure
• Pyrazinamide clinical use


  In combination with other drugs for M. tuberculosis
• Pyrazinamide toxicity


  • Joint pains
  • Asymptomatic hyperuricemia
  • Myalgia, GI irritation, rash, hepatic dysfunction
  • Should be avoided in pregnancy
• Second-line drugs for M. tuberculosis


  • Streptomycin (used in combination for life-threatening TB)
  • Amikacin (for TB caused by streptomycin-resistant or MDR-TB)
  • Ciprofloxacin and ofloxacin (active against strains of MTB resistant to first-line agents; used in combination)
  • Ethionamide (congener of INH; major effect - severe GI irritation & neurologic toxicity)
• Tuberculosis treatment


  • Intensive phase: 2 months
  • Continuation or maintenance phase: >4 months
• Multidrug-resistant TB (MDR-TB) refers to M. tuberculosis strains in which resistance to both isoniazid and rifampicin has been confirmed in vitro
• Fixed-dose combination - anti TB pills containing 2 or more drugs
• TB-DOTS


  • Diagnostic and therapeutic unit that caters patients diagnosed with TB or suspected of having TB
  • The Directly Observed Treatment Strategy (DOTS) is the most effective approach in the diagnosis, treatment, and control of TB
• Dapsone mechanism of action


  • Most active drug against M. leprae
  • Inhibition of folic acid synthesis
  • Resistance can develop if low doses are given - usually in combination with Rifampin and/or Clofazimine
• Dapsone pharmacokinetics

  • Given orally, penetrates tissues well
  • Eliminated in the urine
• Dapsone toxicity


  • GI irritation
  • Fever
  • Skin rashes
  • Methemoglobinemia
  • Hemolysis in patients with G-6PD
• Acedapsone


  • Repository form of dapsone
  • Provides inhibitory plasma concentrations for several months
  • Alternative drug for P. carinii pneumonia in HIV patients
• Clofazimine


  • Phenazine dye used for multibacillary leprosy
  • Mechanism of action not clearly established
  • Stored widely in reticuloendothelial tissues and skin
  • T1/2 can be as long as 2 months
  • Most prominent adverse effect - discoloration of skin and conjunctivae
• Drugs for nontuberculous mycobacteria (NTM)

  • NTM's are less susceptible to anti-TB drugs
  • Tetracyclines, macrolides, sulfonamides - active for NTM
  • M. avium complex: M. avium and M. intracellulare (common among AIDS patients, treated with Azithromycin/Clarithromycin + Ethambutol, or Rifabutin)
  • Prophylaxis - Azithromycin/Clarithromycin