Antimicobacterial drugs Flashcards
Drugs for Tuberculosis
- Firstline?
- Second line?
- Tertatogenic
“RRIPE Tubercles for SALE”
First line: MOST are safe in prego
- Isoniazid (Bacteriostatic, Bacteriocidal)
- Rifampin (orange to red color)
- Rifabutin (1st line in HIV +ve patients)
- Ethambutol (Bacteriostatic)
- Pyrazinamide
Second line drugs: usually TERATOGENIC
- Streptomycin
- Ethionamide
- Levofloxacin
- Amikacin
When are Directly Observed Therapies (DOT) regimens recommended?
Recommended in noncompliant patients or resistant strains.
First line drug for TB?
Isoniazid - Narrow spectrum
- Sole drug in tx. of latent infection
- Part of combo therapy.
Isoniazid MOA
Pro-drug (activated by a mycobacterial catalase - peroxidase - KatG)
Targets enzymes involved in mycolic acid synthesis:
- enoyl acyl carrier protein reductase (InhA)
- B-ketoacyl-ACP synthase (KasA)
Note: bacteria can mutate these carriers–>resistance!
- cross resistance does NOT OCCUR
Isoniazid Antibacterial spectrum:
Resistance?
- Bacteriostatic effects against bacilli in stationary phase.
- Bactericidal against rapidly dividing bacilli
- Specific for M. tuberculosis
If used alone resistant organism usually emerge!
Isoniazid PK
AE?
Oral, IV, IM
- diffuses into all body fluids, cells and caseous material
AE: (INH - Injury to Nerve and Hepatocytes)
- Peripheral neuritis: corrected by pyridoxine (B6) supplementation
- Hepatotoxicity: clinical hepatitis and idiosyncratic
- CYP450 inibitor
- Lupus like syndrome: rare
Isoniazid effects on pregnancy?
Safe in pregnancy (increased risk of hepatitis, pyridoxine supplementation is recommended)
Rifamycins
Rifampin, Rifabutin
- First-line drugs for tx. of all susceptibe forms of TB*
- Part of combo therapy
Rifampin
MOA
Bactericidal
- Resistant strains rapidly emerge
- Usually Given In Combination
MOA: Blocks transcription by binding to B-subunit of bacterial DNA-dependent RNA polymerase
–> leading to inhibition of RNA synthesis
STRONG CYP 450 inducer more superior to Isoniazid Inhibitory effects !
Rifampin: Antimicrobial spectrum
Bactericidal for intracellular AND extracellular mycobacteria
- M. tuberculosis
- M. kansasii
Gram +ve and Gram -ve organisms
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
TB Latent TB in INH intolerant patients Leprosy Prophylaxis for individuals exposed to meningitis MRSA (with vancomycin)--> last option
Rifampin PK
Oral and parenteral well distributed (including CSF) excreted mainly into feces
Rifampin AE
- Light chain proteinuria
- GI distress
- Occasional effects: Thrombocytopenia, rashed, nephritis, liver dysfunction
- Imparts harmless orange/red colot to bodily fluids
- Strongly induces most CYP 450 isoforms
- SAFE IN PREGNANCY
Rifabutin
Preferred drug for use in HIV patients (due to lesser effects on CYP enzymes).- TB
Ethambutol
- First line treatment for susceptible forms of TB
- specific for most strains of M. tuberculosis and M. kansasii
- inhibits arabinosyl transferases
Ethambutol AE
- Dose-dependent visual disturbances (eg, red/green color blindness) - cannot be used in children too you to receive site tests
- Headache, confusion, hyperuricemia, peripheral neuritis (rare)
- safe in pregnancy
Pyrazinamide
PK?
First-line agent
- used in combo with isoniazid, rifampin and ethambutol
- must be enzymatically hydrolyzed to active pyrazonoic acid
PK: well absorbed orally and 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
- 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!!
Alternative Drugs (2nd line) for TB
Amikacin: used for streptomycin or multi drug resistant strains. Similar AE as strepto!
- TERATOGENIC
Levofloxacin: recommended for use against first line drug resistan strains. Should always be used in combination.
- Teratogenic
Ethionamide: Congener of INH (no cross resistance). Severe GI irritation and adverse neurologic effects. Also hepatotoxicity and endocrine effects.
- TERATOGENIC
Treatment of Latent TB regimens
Isoniazid: 6-9 months
Rifampin: 4 months
Anti drug regimens
Standard regimens for Empiric tx. of pulmonary TB:
Initiation
RIPE
- Rifampin, Isoniazid, Pyrazinamide, Ethambutol (4 drugs for 2 months)
RIE
- Rifampin, Isoniazid, Ethambutol ( 3 drugs for 2 months)
Continuation phase
- Isoniazid, Rifampin (2 drugs for 4 months- or 31 weeks)
Leprosy (Hansen’s disease)
“Leprosy killed in the DRC”
Dapsone
Cloffazimin
Rifampin (rifabutin)
