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
Isoniazid pharmacokinetics
- Fast acetylators may require higher dosage than slow acetylators for equivalent therapeutic doses
- No therapeutic consequence when appropriate doses are administered daily, but subtherapeutic concentrations may occur if drug is administered as a once-weekly dose or if there is malabsorption
How to alleviate peripheral neuropathy from isoniazid ?
alleviated by giving pyridoxine (Vitamin B6)
Adverse effects of isoniazid
• Neurotoxicity like peripheral neuropathy, restlessness, muscle twitching, seizures, memory loss & insomnia which are more likely to be seen among slow acetylators
alleviated by giving pyridoxine (Vitamin B6)
• GI upset (anorexia, nausea, abdominal pain) and drowsiness
• Hepatotoxicity (INH-induced hepatitis) – MOST COMMON MAJOR TOXIC EFFECT
• Hemolysis in G6PD deficient patients
• Lupus-like syndrome – RARE
• SAFE IN PREGNANCY
PYRAZINAMIDE
MECHANISMS OF ACTION & RESISTANCE
MOA: must be enzymatically hydrolysed by mycobacterial pyrazinamidase (encoded by pncA) to active pyrazinoic acid
MOR: impaired uptake of pyrazinamide or mutations in pncA
PYRAZINAMIDE
PHARMACOKINETICS
Works best in acidic pH <6.0 (within phagolysosomes and granulomas)
Metabolized by the liver and excreted in the urine
Given orally
PYRAZINAMIDE
ADVERSE EFFECTS
• Non-gouty polyarthralgia- MOST COMMON
• Hyperuricemia- COMMON but usually ASYMPTOMATIC
- may precipitate acute gouty arthritis in predisposed patients
• Hepatotoxicity
• Myalgia, GI irritation, maculopapular rash, porphyria, photosensitivity- RARE
• Only given in pregnancy if benefits outweigh the risks, otherwise avoided
ETHAMBUTOL
- Part of combination therapy for active infections
- If used alone, resistance rapidly emerge
- Bacteriostatic agent which provides synergy with other drugs
- Least potent against MTB
ETHAMBUTOL
MECHANISMS OF ACTION & RESISTANCE
MOA: inhibits arabinosyltransferases (encoded by the emb gene) leading to decreased carbohydrate (arabinogalactan) polymerization of cell wall
MOR: mutations (usually overexpression) in the emb gene
ETHAMBUTOL
ADVERSE EFFECTS
• Visual disturbances (dose dependent)- MOST COMMON and REVERSIBLE
- decreased visual acuity
- red-green color blindness - optic neuritis
- retinal damage
- Headache, confusion, peripheral neuritis and hyperuricemia- RARE
- Safe in pregnancy
- NOT given in children too young to permit assessment of visual acuity and red- green color discrimination
STREPTOMYCIN
MOA & CLINICAL USE
• it’s an ______________
• Bactericidal against dividing mycobacteria
• MOA: ________________________________________
• Given parenterally
• Used principally in drug combinations for the treatment of life-threatening tuberculous disease including:
- _______
- _______
- _______
STREPTOMYCIN
MOA & CLINICAL USE
• Aminoglycoside
• Bactericidal against dividing mycobacteria
• MOA: inhibits protein synthesis by binding at 30s mycobacterial ribosome
• Given parenterally
• Used principally in drug combinations for the treatment of life-threatening tuberculous disease including:
- TB meningitis
- miliary dissemination
- severe organ TB
STREPTOMYCIN
ADVERSE EFFECTS
• Ototoxicity (vertigo and hearing loss)- MOST COMMON and may be permanent
• Nephrotoxicity (decreased urine output, elevated BUN & creatinine)
*Toxicities associated are dose-related and can be reduced by limiting therapy to no more than 6 months whenever possible
* Increasing frequency of resistance limits the use of this drug
• TERATOGENIC!
ETHIONAMIDE: MOA & ADVERSE EFFECTS
• Chemically related to __________
• MOA: _____________________
• Given orally
• AE: gastric irritation, neurotoxicity (can be alleviated by ____________ supplementation) and hepatotoxicity
• Resistance can develop rapidly if used alone
• NO cross-resistance with Isoniazid
ETHIONAMIDE: MOA & ADVERSE EFFECTS
• Chemically related to isoniazid
• MOA: blocks mycolic acid synthesis
• Given orally
• AE: gastric irritation, neurotoxicity (can be alleviated by pyridoxine supplementation) and hepatotoxicity
• Resistance can develop rapidly if used alone
• NO cross-resistance with Isoniazid
When is amikacin used
Mainly used for streptomycin-resistant or multidrug-resistant mycobacterial strains
AMIKACIN: MOA, CLINICAL USE & ADVERSE EFFECTS
• _______________ like streptomycin
• MOA: ___________________________
• Given parenterally
• AE: same as streptomycin (TERATOGENIC!)
• Resistance may still develop if used alone
• Prevalence of amikacin-resistant strains are low (<5%)
- Aminoglycoside like streptomycin
- MOA: inhibits protein synthesis by binding at 30s mycobacterial ribosome
- Given parenterally
- AE: same as streptomycin (TERATOGENIC!)
- Resistance may still develop if used alone
- Prevalence of amikacin-resistant strains are low (<5%)
Which drug is a fluoroquinolone
LEVOFLOXACIN
LEVOFLOXACIN MOA
interferes with DNA replication by inhibiting DNA gyrase (topoisomerase II)
LEVOFLOXACIN AE
AE: tendinopathy
• Resistance can rapidly develop if used alone
• TERATOGENIC!
LATENT TUBERCULOSIS TREATMENT
DRUGS FOR LEPROSY
Dapsone Rifampin Clofazimine
DR. Clof
Dapsone
- Structurally related to ____________
- Bacteriostatic
- Remains to be the most active drug against leprosy
- MOA:_________________________
- Given orally and topically
- Well absorbed and distributed in tissues (high levels in the skin)
- Also used in the treatment of pneumonia caused by Pneumocystis jirovecii in HIV-AIDS patients
• Structurally related to sulfonamides
• Bacteriostatic
• Remains to be the most active drug against leprosy
• MOA: inhibits folate synthesis via dihydropteroate synthase inhibition
• Given orally and topically
• Well absorbed and distributed in tissues (high levels in the skin)
• Also used in the treatment of pneumonia caused by Pneumocystis jirovecii in
HIV-AIDS patients
HOW TO TREAT ERYTHEMA NODOSUM LEPROSUM
Thalidomide
Dapsone AE
- Hemolysis in G6PD deficient patients
- Methemoglobinemia- COMMON but usually CLINICALLY INSIGNIFICANT
- GI upset, fever, pruritus and rash can occur
- Erythema nodosum leprosum often develops during the treatment of lepromatous leprosy which can be treated with Thalidomides
Leprosy caused by
Caused by Mycobacterium leprae andMycobacterium lepromatis
Disease of peripheral nerves and upper respiratory mucosa
_______ is used to treat multi bacillary leprosy
Clofazimine
CLOFAZIMINE MOA and PK
- MOA: inhibits replication by binding to DNA
- Given orally
- Variable absorption and distributed widely in reticuloendothelial tissues and skin
- Phenazine dye
- Bactericidal
CLOFAZIMINE
ADVERSE EFFECTS
- Discoloration of the skin and conjunctivae - MOST PROMINENT
- GI irritation- COMMON
- Does NOT cause erythema nodosum leprosum
Treat Pauci-bacillary: 1-5 skin lesions
Dapsone + Rifampin (6 months)
Treat Multi-bacillary:
> 5 skin lesions
Dapsone + Rifampin + Clofazimine (12 months)
Treat latent tuberculosis
Treat active pulmonary tuberculosis
Treat extra pulmonary tb
MANAGING DRUG ADVERSE EFFECTS TB
If patient has HIV. What drug not to give
Rifampin.
Use isoniazid instead
