Antimycobacterial Drugs Flashcards
Monoresistant TB
Resistance to only one first-line drug
Polydrug-resistant TB
Resistance to more than one first-line drug (other than BOTH rifampin and isoniazid)
Multidrug-resistant TB (MDR-TB)
Resistance to AT LEAST BOTH rifampin and isoniazid
Extensively drug-resistant TB (XDR-TB)
Resistance to any fluoroquinolone AND to at least one of the other 2nd-line drugs
Latent vs active tb
Active TB has sign, symptoms, radiologic and laboratory evidence. Positive TST/PPD test
Latent TB does not have sign, symptoms, radiologic and laboratory evidence. Positive TST/PPD test
Latent tb treatment depends on measurement and underlying conditions of patient
Principles of TB therapy
- Most sites of disease require ___ months treatment
- CNS and bone disease require ___ months treatment
- Standard is a treatment is ___________
- Dose is dictated by patient ________
- Most sites of disease require 6 months treatment
- CNS and bone disease require 12 months treatment
- Standard is a quadruple therapy (RIPE regimen)
- Dose is dictated by patient weight
Direct Observed Therapy (DOT)
ensure adherence and safety and to prevent emergence of drug resistance
First line drugs for TB
RIPE
Rifamycins Isoniazid Pyrazinamide Ethambutol
Second line drugs for TB
SEAL
Streptomycin, ethionamide, amikacin, levofloxacin
Rifamycins
- Rifampin a.k.a. Rifampicin
- Rifabutin (mainly used in HIV patients)
- If used alone, resistance rapidly emerge—> combination therapy
- Used in the treatment of latent infection
Rifampin MOA and MOR
MOA: binds to 𝜷 subunit of bacterial DNA-dependent RNA polymerase leading to inhibition of RNA synthesis
MOR: point mutations in rpoB (gene for the 𝛽 subunit of RNA polymerase)—> Reduced binding to RNA polymerase
Rifampin is
- administered ________
- Well distributed (including CSF) in body fluids and tissues
- Excreted mainly into _______
- Rifampin is a strong __________________, while Rifabutin is NOT
- Oral & parenteral
- Well distributed (including CSF) in body fluids and tissues
- Excreted mainly into feces, small amount in the urine
- Rifampin is a strong CYP P450 inducer, while Rifabutin is NOT
Rifampin anti microbial spectrum
- Bactericidal against both intracellular and extracellular mycobacteria
- Bactericidal against both dividing and non-dividing mycobacteria
- Active against Gram-positive & Gram-negative organisms
- Activity against MRSA!
Rifampin clinical applications
*remember SMALL P
- Serious staphylococcal infections (osteomyelitis, prosthetic joint infections and prosthetic valve endocarditis)
- MRSA (with vancomycin)
- Active TB infections
- Latent TB in isoniazid intolerant patients
- Leprosy (delays resistance to dapsone)
- Prophylaxis for meningitis and H.influenzae type B in exposed individuals
Rifampin adverse effects
- Hepatotoxicity (elevated LFTs)
- SAFE IN PREGNANCY
- Red-orange body fluids (urine, sweat and tears) - MOST COMMON & HARMLESS
- GI upset (anorexia, nausea, abdominal pain)
- Renal (light-chain proteinuria, nephritis, acute tubular necrosis) - RARE
- Rashes, anemia, thrombocytopenia are OCCASIONAL
- Flu-like symptoms
- Preferred drug for use in HIV patients due to less induction of CYP enzymes
- Can be a substitute to those patients who are intolerant to rifampin
- INSUFFICIENT DATA TO RECOMMEND USE IN PREGNANCY
Rifabutin
Isoniazid
- Synthetic analog of pyridoxine
- Abbreviated as INH
- Most potent anti-TB drug
- Part of combination therapy for active infections
- If used alone, resistance rapidly emerge
- Used in the treatment of latent infection
ISONIAZID
ANTIMICROBIAL SPECTRUM
- Bactericidal against both intracellular and extracellular mycobacteria
- Bactericidal against actively dividing mycobacteria
- Bacteriostatic against slowly dividing mycobacteria
ISONIAZID
MECHANISMS OF ACTION
Inhibits synthesis of mycolic acid by inhibiting inhA and KasA
ISONIAZID
MECHANISMS OF RESISTANCE
- High level of resistance due to deletion of KatG
* Low level of resistance due to overexpression of inhA and mutations of KasA
Isoniazid is a
- CYP P450 ____________
- Metabolized by the ______________ via acetylation (genetically determined)
- Oral & parenteral
- Diffuses readily in body fluids, tissues and caseous material
- Excreted in the urine
- CYP P450 inhibitor
- Metabolized by the liver N-acetyltransferase via acetylation (genetically determined)
- Oral & parenteral
- Diffuses readily in body fluids, tissues and caseous material
- Excreted in the urine