Antimycobacterial Flashcards
Factors that
make mycobacterial therapy challenging ?
- Located intracellularly
- Intrinsically resistant to most antibiotics
- Quick to develop resistance
- Therapy can take months or even years
- Combination therapy required
TB overview
Mycobacterium tuberculosis
• Small aerobic non-motile bacillus
• Divides every 16-20 h
• 1/3 world’s population is thought to be infected
•New infections occur at rate of 1 per second (can be latent or active)
•Can lead to serious infections of the lungs, genitourinary tract, skeleton & meninges
list first line drugs of TB ?
- First line drugs
- Isoniazid
- Rifampin
- Rifabutin (1st line in HIV +ve patients)
- Ethambutol
- Pyrazinamide
List second line drugs of TB
- Second line drugs
- Streptomycin
- Ethionamide
- Levofloxacin
- Amikacin
Goals of TB therapy
• Kill tubercle bacilli
• Prevent emergence of drug resistance
•Eliminate persistent bacilli from host’s tissue to prevent relapse
To accomplish these goals, multiple drugs must be taken for a sufficiently long tim
TB therapy guidelines
- Antibiotic susceptibility testing of mycobacterial isolates required
- 3-4 drug combination regimen
- Directly Observed Therapy (DOT) regimens are recommended in noncompliant patients or resistant strains
two risk groups for TB therapy
Generally, persons at high risk for developing TB disease fall into two categories and will receive prophylaxis / treatment
- Persons who have been recently infected with TB bacteria, eg:
• Close contacts of a person with infectious TB •Persons who have immigrated from an area with a high rate of TB
• Children <5 who have a positive TB test
• Groups with high rates of TB transmission
2. Persons with medical conditions that weaken the immune system, eg: • HIV • Substance abuse • Diabetes mellitus • Organ transplants • Severe kidney disease
List the features of TB cell wall X7
Mycolic acid arabinogalactan peptidoglycan cell membrane lipoarabinomannan porin glycolipids
isoniazid overveiw
- Synthetic analog of pyridoxine
- First-line agent
- Most potent antitubercular drug
- Part of COMBINATION THERAPY for active infections
- Sole drug in treatment of latent infection
isoniazid MOA
- Pro-drug (activated by a mycobacterial catalaseperoxidase - KatG)
- Targets enzymes involved in mycolic acid synthesis:
- enoyl acyl carrier protein reductase (InhA)
- b-ketoacyl-ACP synthase (KasA)
isoniazid antibacterial spectrum
- Bacteriostatic effects against bacilli in stationary phase
- Bactericidal against rapidly dividing bacilli
- Specific for M.tuberculosis
- If used alone resistant organisms rapidly emerge
isoniazid resistance
- Chromosomal mutations resulting in:
- mutation of deletion of KatG
- mutations of acyl carrier proteins
- overexpression of inhA
•Cross-resistance between other anti-tuberculosis drugs DOES NOT OCCUR
isoniazid pk? AE ? pregnancy ?
- Oral, IV & IM
- Diffuses into all body fluids, cells & caseous material
AE--> •Peripheral neuritis: corrected by pyridoxine supplementation • Hepatotoxicity: clinical hepatitis & idiosyncratic • CYP P450 inhibitor • Lupus-like syndrome: rare
Safe in pregnancy (however, hepatitis risk is increased, pyridoxine supplementation is recommended
rifamycins overview
- 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 overview and MOA
- Antimicrobial and antimycobacterial
- Bactericidal
- Resistant strains rapidly emerge
- USUALLY GIVEN IN COMBINATION
•Blocks transcription by binding to b subunit of bacterial DNA-dependent RNA polymerase
→ leading to inhibition of RNA synthesis
rifampin antimicrobial spectrum
- Bactericidal for intracellular AND extracellular mycobacteria • M.tuberculosis • M.kansasii
- Active against Gram-positive & Gram-negative organisms
- Activity against MRSA
rifampin resistance
- Point mutations in rpoB, the gene for the b 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)
Rifampin PK ?
- Oral & parenteral
- Well distributed (including CSF)
- Excreted mainly into feces
- Strong CYP P450 inducer
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 overview and uses
- Preferred drug for use in HIV patients (due to less induction of CYP enzymes)
- Rifampin substitute to those that are intolerant
- Insufficient data to recommend use in pregnancy
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
- Resistance occurs rapidly if used alone (mutations in emb gene)
Ethambutol MOA ? AE
Inhibits arabinosyltransferase leading to decreased carbohydrate polymerization of cell wal
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 ? PK ?
- First-line agent
- Used in combination with isoniazid, rifampin & ethambutol
- Must be enzymatically hydrolysed to active pyrazinoic acid. Mechanism of action remains unclear
- Resistant strains lack pyrazinamidase or have increased efflux of drug
- Well absorbed orally & well distributed (including CSF)
- Renal or hepatic insufficiency may require dosage adjustment
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 (same MOA and adverse effects)
- Used for drug-resistant strains
- Used in drug combinations for treatment of life-threatening tuberculous disease: • meningitis • miliary dissemination • severe organ tuberculosis
- Increasing frequency of resistance to streptomycin limits use of drug
Amikacin
Used for streptomycin- or multi-drug-resistant strains. Similar adverse effects to streptomycin. Teratogenic
2nd line drug
Levofloxacin
Recommended for use against first-line drugresistant strains. Should always be used in combination. Teratogenic
2nd line drug
Ethionamide
Congener of INH (no cross-resistance). Severe GI irritation & adverse neurologic effects. Also hepatotoxicity & endocrine effects. Teratogenic
2nd line drug
drug regimen for treatment of latent TB
Drug and Duration of Treatment
1- Isoniazid 6-9 months
2- Rifampin 4 months
anti TB drug regimens for initial phase and continuation phase
initial phase
1- isoniazid, rifampin, pyrazinamide and thambutol for 8 weeks follwed by continuation phase with isoniazid and rifampin for 18 weeks
or
2- isoniazid, rifampin and ethambutol for 8 weeks intially followed by isoniazid and rifampin for 31 weeks
leprosy
- aka Hansen’s disease
- Caused by Mycobacterium leprae & Mycobacterium lepromatis
- Primarily granulomatous disease of peripheral nerves & mucosa of upper respiratory tract
- ~ 70 % cases are in India
drugs for leprosy
WHO recommends 3 drugs to be used in combination:
• Dapsone • Clofazimine • Rifampin
dapsone
- Structurally related to sulfonamides
- Bacteriostatic
- Inhibits folate synthesis (via dihydropteroate synthetase inhibition)
- Also used in treatment of pneumonia (P.jiroveci) in HIV +ve patients
dapsone PK and AE ?
- Well absorbed & distributed (high levels in skin)
- Acedapsone = repository form of 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. aviumintracellulare complex)
Clofazimine AE ?
• Red-brown discoloration of skin • GI irritation • Eosinophillic enteritis •Erythema nodosum DOES NOT develop (drug has antiinflammatory action
Pauci-bacillary (PB): 1-5 skin lesions
regimen
Regimen of 2 drugs: Rifampin + dapsone (6 months)
Multi-bacillary: > 5 skin lesions
regimen
Regimen of 3 drugs: Rifampin, clofazimine + dapsone (12 months)
Pattern of Drug Resistance (Isoniazid (+/Streptomycin)
Suggested Regimen
Rifampin, pyrazinamide, ethambutol (can add fluoroquinolone to strengthen treatment)
6 months
pattern of drug resistance - suggested regimen Isoniazid & rifampin (+/Streptomycin)
Fluoroquinolone, pyrazinamide, ethambutol + injectable agent +/- second-line agent
18-24 months
pattern of drug resistance - suggested regimen for –>Isoniazid, rifampin (+/streptomycin), + ethambutol or pyrazinamide
Fluoroquinolone (ethambutol or pyrazinamide if active) + injectable agent +/- two second-line agents
24 months
pattern of drug resistance - suggested regimen for –>Rifampin
Isoniazid, ethambutol, fluoroquinolone, supplemented with pyrazinamide for first 2 months
12-18 months
M kansaii clinical features and treatments
Resembles TB Isoniazid + rifampin + ethambutol
clinical features and treatments for for M marinum
Granulomatous cutaneous disease
2 drug combination (rifampin, ethambutol, clarithromycin, minocycline, doxycycline, sulfonamides)
clinical features and treatments for M avium complex
Pulmonary disease Clarithromycin + ethambutol +/- rifabutin
clinical features and treatments for M chelonae
Abscess, sinus tract, ulcer; bone, joint, tendon infection
Clarithromycin (monotherapy usually adequate)
clinical features and treatments for M fortuitum
Abscess, sinus tract, ulcer; bone, joint, tendon infection
Amikacin, cefoxitin, levofloxacin, sulfonamides, imipenem
