ANTIMYCOBACTERIAL DRUGS Flashcards
MYCOBACTERIA
• Intrinsically resistant to most antibiotics
- Located intracellularly
- Quick to develop resistance
- Therapy can take months or even years
• Combination therapy required
TUBERCULOSIS
- 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
DRUGS FOR TB (1ST LINE, 2ND LINE)
• First line drugs
- 1) ISONIAZID
- 2) Rifampin
- 3) Rifabutin (1st line in HIV +ve patients)
- 4) Ethambutol
- 5) Pyrazinamide
• Second line drugs
- Streptomycin
- Ethionamide
- Levofloxacin
- Amikacin
GOALS OF THERAPY IN TB
- 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 time
TUBERCULOSIS THERAPY
• 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
LATENT TUBERCULOSIS
Generally, persons at high risk for developing TB disease fall into two categories and will receive prophylaxis / treatment:
1. Persons who have been recently infected withTB 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
NOTE: DRUG REGIMINS FOR TREATMENT
1) ISONIAZID USED FOR 6-9 MONTHS
2) RIFAMPIN USED FOR 4 MONTHS (better b/c shorter)
ISONIAZID:
• Synthetic analog of pyridoxine
• First-line agent
• Most potent antitubercular drug
• PART OF COMBINATION THERAPY
• Sole drug in treatment of latent infection
MOA:
- Pro-drug (activated by a mycobacterial catalase- peroxidase - KatG)
- Targets enzymes involved in _mycolic acid synthesis_:
1) • enoyl acyl carrier protein reductase (InhA)
2) • -ketoacyl-ACPsynthase(KasA)
PK:
- Oral, IV & IM
- Diffuses into all body fluids, cells & caseous material
ISONIAZID
ANTIBACTERIAL SPECTRUM +
RESISTANCE
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
RESISTANCE:
• Chromosomal mutations resulting in:
1) • mutation of deletion of KatG
2) • mutations of acyl carrier proteins
3) • overexpression of inhA
• Cross-resistance between other anti-tuberculosis drugs DOES NOT OCCUR
ISONIAZID
AE
PREGNANCY
- Peripheral neuritis: corrected by pyridoxine supplementation
- Hepatotoxicity: clinical hepatitis & idiosyncratic
• CYP P450 inhibitor
• Lupus-like syndrome: rare
PREGNANCY:
• Safe in pregnancy (however, hepatitis risk is increased, pyridoxine supplementation is recommended)
RIFAMPINS
RIFAMPIN, RIFABUTIN
First-line drugs for treatment of all susceptible forms of TB
• PART OF COMBINATION THERAPY
- Bactericidal
- Resistant strains rapidly emerge
- USUALLY GIVEN IN COMBINATION
MOA:
• Blocks transcription by binding to subunit of bacterial DNA-dependent RNA polymerase
–> leading to inhibition of RNA synthesis
PK:
- Oral & parenteral
- Well distributed (including CSF)
- Excreted mainly into feces
- Strong CYP P450 inducer
RIFAMPIN
ANTIMICROBIAL SPECTRUM
RESISTANCE
ANTIMICROBIAL SPECTRUM
- Bactericidal for intracellular AND extracellular mycobacteria
- M.tuberculosis
- M.kansasii
- Gram-positive & Gram-negative organisms
RESISTANCE
- Point mutations in rpoB, the gene for the subunit of RNA polymerase –> decreased affinity of bacterial DNA-dependent RNA polymerase for drug
- Decreased permeability
RIFAMPIN
CLINICAL APPLICATIONS
1) • TB
• Latent TB in INH intolerant patients
2) • Leprosy
3) • Prophylaxis for individuals exposed to meningitis (NOTE THAT CEFTRIAXONE IS USUALLY THE FIRST LINE IN US)
4) • MRSA (with vancomycin)
RIFAMPIN
AE
- Light chain proteinuria
- GI distress
- Occasional effects: thrombocytopenia, rashes, nephritis, liver dysfunction
- Imparts harmless orange/red color to bodily fluids
EG) PATIENT COMES BACK COMPLAINS OF RED/ORANGE URINE… AM I OKAY? YES YOU ARE!
–> don’t wear contacts or will dye the contacts!!!
• Strongly induces most CYP P450 isoforms
–> b/c it strongly induces CYP P450, and isoniazid is a weak inhibitor, RIFAMPIN WINS this induction
• SAFE IN PREGNANCY
RIFABUTIN
A RIFAMPIN SUBSTITUTE
• Preferred drug for use in HIV patients (due to lesser effects on CYP enzymes)
- Rifampin substitute to those that are intolerant
- Insufficient data to recommend use in pregnancy
ETHAMBUTOL
everythign + AE
- _*First-line agent* for treatment of all susceptible forms of TB_
- Specific for most strains of M.tuberculosis & M.kansasii
- _Inhibits arabinosyl transferases****_
Used in combination with pyrazinamide, izoniazid & rifampin
Resistance occurs rapidly if used alone (mutations in emb gene)
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
everything including AE
• First-line agent
- Used in combination with isoniazid, rifampin & ethambutol
- Must be enzymatically hydrolysed to active pyrazinoic acid
- Resistant strains lack pyrazinamidase or have increased efflux of drug
PK:
- Well absorbed orally & well distributed (including CSF)
- Renal or hepatic insufficiency may require dosage adjustment
AE:
- Nongouty polyarthralgia (~ 40%)
- Acute gouty arthritis (rare unless predisposed)
- Hyperuricemia
- Hepatotoxicity, myalgia, GI irritation, porphyria, rash, photosensitivity –> must ADJUST DOSE IN RENAL/HEPATIC INSUFFICIENCY!!
- Recommended for use in pregnancy when benefits outweigh risks
STREPTOMYCIN
2ND LINE DRUG
• 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
2ND LINE DRUG
Used for streptomycin- or multi-drug-resistant strains.
Similar adverse effects to streptomycin.
Teratogenic
LEVOFLOXACIN
2ND LINE AGENT
Recommended for use when first-line drug-resistant strains are present .
Should always be used in combination.
Teratogenic
ETHIONAMIDE
2ND LINE AGENT
Congener of INH (no cross-resistance).
Severe GI irritation & adverse neurologic effects.
Also hepatotoxicity & endocrine effects.
Teratogenic
ANTI-TB DRUG REGIMEN FOR EMPIRIC TREATMENT OF PULMONARY TB
4 DRUG REGIMEN = BETTER B/C SHORTER DURATION
“RIPE”
NO P IN THE 3 DRUG REGIMEN
ANTI-TB DRUG REGIMEN TO DRUG RESISTANT STRAINS
RESISTANT TO ISONIAZID (+/- STREPTOMYCIN)
RIPE W/O THE “I”
1) RIFAMPIN
2) PYRAZINAMIDE
3) ETHAMBUTAL
- can add fluoroquinolone to strengthen treatement
DURATION OF TREATMENT = 6 MONTHS
ANTI-TB DRUG REGIMEN FOR RESISTANT TB TO
ISONIAZID + RIFAMPIN (+/- STREPTOMYCIN)
1) FLUOROQUINOLONE
2) PYRAZINAMIDE
3) ETHAMBUTAL
4) + INJECTABLE AGENT (+/- 2ND LINE AGENT)
DURATION OF TREATMENT = 18-24 MONTHS
ANTI-TB DRUG REGIMEN WHEN RESISTANT TO:
1) ISONIAZID,
2) RIFAMPIN (+/- STREPTOMYCIN)
3) ETHAMBUTAL OR PYRAZINAMIDE
1) FLUOROQUINOLONE (ethambutol or pyrazinamide if active)
2) + INJECTABLE AGENT
3) + TWO 2ND-LINE AGENTS
DURATION OF TREATMENT = 24 MONTHS (2 years)
ANTI-TB DRUG REGIMENS RESISTANT TO
1) RIFAMPIN
1) ISONIAZID
2) ETHAMBUTOL
3) FLUOROQUINOLONE
4) SUPPLEMENTED with PYRAZINAMIDE for FIRST 2 MONTHS
LEPROSY
overview and drugs used
- 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 USED IN LEPROSY
1) • Dapsone
2) • Clofazimine
3) • Rifampin
DAPSONE
LEPROSY DRUG
- Structurally related to sulfonamides (SULFA RELATED)
- Bacteriostatic
- Inhibits folate synthesis (via dihydropteroate synthetase inhibition)
- Also _used in treatment of pneumonia ****(P.jiroveci) in HIV +ve patients_
PK:
• Well absorbed & distributed (high levels in skin)
• Acedapsone = repository form of dapsone
ADVERSE EFFECTS:
1) Hemolysis (esp. G6PD deficiency)
_*****2) Erythema nodosum leprosum_ (treated with corticosteroids or thalidomide) –> The dying mycobacterium basically cause this reaction (similar to what happens in syphillus)
• Other effects – GI irritation, fever, hepatitis, methemoglobinemia
• CYP P450 inhibitor (dapsone goes down ie inhibits)
CLOFAZIMINE
LEPROSY DRUG
- 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)
AE:
• ****Red-brown discoloration of skin
- GI irritation
- Eosinophillic enteritis
• ****Erythema nodosum DOES NOT develop (drug has anti- inflammatory action)
WHO TREATMENT RECOMMENDATIONS FOR LEPROSY
PAUCI-BACILLARY
VS.
MULTI-BACILLARY
PAUCI-BACILLARY: 1-5 SKIN LESIONS
TX: regimen of 2 drugs for 6 MONTHS
1) RIFAMPIN
2) DAPSONE
MULTI-BACILLARY: >5 SKIN LESIONS
TX: regimen of 3 drugs for 12 MONTHS
1) RIFAMPIN
2) DAPSONE
3) CLOFAZIMINE
TREATMENT OPTIONS FOR INFECTIONS WITH ATYPICAL MYCOBACTERIA
