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)
Dapsone
Structurally related to sulfonamides
Bacteriostatic
Inhibits folate synthesis (via dihydropterate synthetase inhibition)
Also used in tx. of pneumonia (P. jiroveci) in HIV +ve patients.
PK: well absorbed and distributed (highlevels in skin)
Acedapsone = repository form of dapsone
Dapsone - AE
- Hemolysis (esp. G6PD def.)
- Erythema nodosum leprosum (treated w/ corticosteroides or thalidomide)
- Other effects - GI irritation, fever, hepatitis methemoglobinemia
- CYP P450 inhibitor
Clofazimine
MOA
Phenazine dye
Binds to DNA and inhibits replication
Redox properties may generate cytotoxic oxygen radicals
Bactericidals to M. leprae (some activity against M. avium-intracellulare complex)
Clofazimine AE
what doesn’t develop with clofazimine
Red-brown discoloration of skin
GI irritation
Eosinophilic enteritis
Erythema nodosum does not develop (drug has anti-inflammatory action.)
WHO tx. recommendations for leprosy types:
Pauci-bacillary (PB): 1-5 skin lesions:
Multi-bacillary: >5 skin lesions
PB:
- regimen of 2 drugs: Rifampin + dapsone (6 months)
Multi-bacillary:
- regimen of 3 drugs: Rifampin, clofazimine + dapsone (12 months)
Tx options for infections w/ atypical mycobacterium
- M. Kansaii
- M. marinum
- M. avium complex
- M. chelonae
- M. fortuitum
- resembles TB: Isoniazid + rifampin + ethambutol
- Granulomatous cutaneous disease: 2 drug combo (rifampin, etahmbutol, clarithromycin, minocycline, doxycycline, sulfonamides)
- Pulmonary disease (clarithromycin + ethambutol +/- rifabutin)
- Abscess, sinus tract, ulcer; bone, joint, tendon infection (clarithromycin - monotherapy usually adequate )
- Abscess, sinus tract, ulcer; bone, joint, tendon (Amikacin, cefoxitin, levofloxacin, sulfonamides, impenem)
