Antimycobacterials Flashcards
Mycobacteria
Located intracellularly. Resistant to most antibiotics. Quick to develop resistance. Therapy can take months or years. Combination therapy is required.
1st Line drugs for TB
- Isoniazid
- Rifampin
- Rifabutin (1st line in HIV +ve patients)
- Ethambutol
- Pyrazinamide
2nd Line drugs for TB
- Streptomycin
- Ethionamide
- Levofloxacin
- Amikacin
TB Therapy
3-4 drug combination therapy
Latent TB Prophylaxis
- Persons who have been recently infected with TB bacteria
2. Persons with medical conditions that weaken the immune system
Isoniazid MOA
Targets enzymes involved in mycolic acid synthesis:
- enoyl acyl carrier protein reductase (InhA)
- b-ketoacyl-ACP synthase (KasA)
Isoniazid is activated by
KatG- a mycobacterial catalase peroxidase.
Isoniazid is what kind of drug
Prodrug
Isoniazid Antibacterial Spectrum
Bacteriostatic effects against bacilli in stationary phase. Bactericidal against rapidly dividing bacilli. Specific for M.tuberculosis
Isoniazid Resistance
Chromosomal mutations resulting in:
• mutation of deletion of KatG
• mutations of acyl carrier proteins
• overexpression of inhA
Isoniazid AE
- Peripheral neuritis: corrected by pyridoxine supplementation
- Hepatotoxicity: clinical hepatitis & idiosyncratic
- CYP P450 inhibitor
- Lupus-like syndrome: rare
Isoniazid in Pregnancy
Safe in pregnancy (however, hepatitis risk is increased, pyridoxine supplementation is recommended)
Rifamycins
Rifampin & rifabutin. First-line drugs for treatment of all susceptible forms of
TB. Part of COMBINATION THERAPY for active infections. Sole drug in treatment of latent infection (2nd line).
Rifampin
USUALLY GIVEN IN COMBINATION
Rifampin MOA
Blocks transcription by binding to beta subunit of bacterial DNA-dependent RNA polymerase leading to inhibition of RNA synthesis.
Rifampin Antimicrobial Spectrum
Bactericidal for intracellular AND extracellular mycobacteria: M.tuberculosis and M.kansasii. Active against Gram-positive & Gram-negative organisms. Activity against MRSA.
Rifampin Resistance
Point mutations in rpoB, the gene for the beta subunit of RNA polymerase: decreased affinity of bacterial DNA-dependent RNA polymerase for drug. Decreased permeability.
Rifampin Clinical Applications
• Active TB infections
• Latent TB in isoniazid intolerant patients
• Leprosy (delays resistance to dapsone)
• Prophylaxis for individuals exposed to meningitis
• Prophylaxis in contacts of children with H.influenzae type B
• MRSA (with vancomycin)
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Rifampin AE
- Light chain proteinuria
- GI distress
- Occasional effects: thrombocytopenia, rashes, nephritis, liver dysfunction
- Imparts harmless orange/red color to bodily fluids
- Strongly induces most CYP P450 isoforms
- SAFE IN PREGNANCY
Rifabutin
Preferred drug for use in HIV patients (due to less induction of CYP enzymes)
Ethambutol
First-line agent for treatment of all susceptible forms of TB. Specific for most strains of M.tuberculosis & M.kansasii. Used in combination with pyrazinamide, izoniazid &
rifampin.
Ethambutol MOA
Inhibits arabinosyltransferase leading to decreased carbohydrate polymerization of cell wall.
Ethambutol AE
- Dose-dependent visual disturbances (eg, red/green color blindness) – cannot be used in children too young to receive sight tests
- Headache, confusion, hyperuricemia, peripheral neuritis (rare)
- Safe in pregnancy
Pyrazinamide
- First-line agent
- Used in combination with isoniazid, rifampin & ethambutol
- Must be enzymatically hydrolysed to active pyrazinoic acid.
Pyrazinamide AE
- Nongouty polyarthralgia (~ 40%)
- Acute gouty arthritis (rare unless predisposed)
- Hyperuricemia
- Hepatotoxicity, myalgia, GI irritation, porphyria, rash, photosensitivity
- Recommended for use in pregnancy when benefits outweigh risks
Streptomycin
Aminoglycoside. Used for drug resistant strains. Used in drug combinations for treatment of life-threatening tuberculous disease:
• meningitis
• miliary dissemination
• severe organ tuberculosis
Amikacin
Used for streptomycin- or multi-drug-resistant strains. Similar adverse effects to streptomycin. Teratogenic
Levofloxacin
Recommended for use against first-line drug- resistant strains. Should always be used in combination. Teratogenic
Ethionamide
Congener of INH (no cross-resistance). Severe GI irritation & adverse neurologic effects. Also hepatotoxicity & endocrine effects. Teratogenic
Leprosy alternative name
Hansen’s disease
Leprosy Caused by
Mycobacterium Leprae and Mycobacterium Lepromatis.
Leprosy Definition
Granulomatous disease of peripheral nerves and mucosa of URT.
Drugs for leprosy
• Dapsone
• Clofazimine
• Rifampin
(used in combination)
Dapsone
Structurally related to sulfonamides. Inhibits folate synthesis (via dihydropteroate synthetase inhibition). Also used in treatment of pneumonia (P.jiroveci) in HIV +ve patients.
Acedapsone
Respiratory form of Dapsone
Dapsone AE
• Hemolysis (esp. G6PD deficiency)
• Erythema nodosum leprosum (treated with
corticosteroids or thalidomide)
• Other effects – GI irritation, fever, hepatitis, methemoglobinemia
• CYP P450 inhibitor
Clofazimine
- Phenazine dye
- Binds to DNA & inhibits replication
- Redox properties may generate cytotoxic oxygen radicals
- Bactericidal to M.leprae (some activity against M. avium- intracellulare complex)
Clofazimine AE
- Red-brown discoloration of skin
- GI irritation
- Eosinophillic enteritis
- Erythema nodosum DOES NOT develop (drug has anti- inflammatory action)
