Antimicrobials III Flashcards
Antitubercular agents
Isoniazid, Rifampin, Ethambutol, Pyrazinamide, Streptomyin
For active TB, what is drug regimen
4 drug therapy: Isoniazid, Rifampin, Ethambutol, and Pyrazinamide
-administered via directly observed therapy (DOT)
- if showing susceptibility, can get rid of pyrazinamide/ethambutol after 2 months and continue with isoniazid and rifampin for 6 months treatment
- sometimes can require other drugs if treatment resistant TB present
Why do we treat TB with multiple drugs for a long time
- Can evade host mechanisms/survive in macrophages, so many drugs don’t work
- treat with 4 to decrease development of more resistant strains
Isoniazid MOA
- most potent agent for treating TB
- Prodrug converted into active metabolite in bacterial cell to inhibit mycolic acid synthesis. Interats with catalase peroxidase enzyme, binds covalently to adenine nucleotide of nicotinamide in enoyl-acyl carrier protein reductase-InhA
(action analogous to penicillins) - tuberculoCIDAL for growing cells but tuberculoSTATIC for resting cells
- This is selectively toxic since other bacteria, fungi, humans don’t make mycolic acids
Isoniazid mechanism of resistance
- develops rapidly through alterations in drug uptake, mutations in KatG, and mutations in InhA target
- INH resistant strains seem to be less pathogenic
Isoniazid pharmacokinetics
- readily absorbed from GI, distributed through body water,
- penetrates brain & cells
- metabolized via acetylation to N-acetyl INH
- toxicity influenced by how fast it is acetylated (fast vs slow inactivators)
- Fast acetylators have poor therapeutic response; 50% of US are slow acetylators
- Most drug recovered in urine as metabolized drug
Isoniazid toxicity/adverse effects of isoniazid
- Peripheral neuritis, optic neuritis, convulsions, mental disturbances
- associated with increased excretion of pyridoxine, so prevent by administering pyridoxine
- Neuropathy more common in slow acetylators
- Sensitization reactions (fever, rash, blood dyscrasia)
- Hepatic damage (more common in rapid acetylators, older pts, Asian descent); worse with EtOH use
Isoniazid Spectrum/use
First line TB therapy for treatment and prophylaxis after exposure and testing
Rifampin MOA
- inhibit RNA synthesis initiation by binding beta subunit of DNA dependent RNA polymerase
- Bactericidal and synergistic with isoniazid/streptomycin
- selective for mycobacteria due to differences in mammalian vs bacterial RNA polymerase but can interact with human RNA polymerase and penetrate bacterial and mammalian cells
Rifampin mechanism of resistance
point mutations in RNA polymerase (rpoB)
- frequency of 10^(-7) - 10^(-8)
Rifampin pharmacokinetics
- orally active, widely distributed
- metabolized via deacetylation resulting in active product
- enterohepatic circulation and excreted mostly in feces (30% in urine)
Rifampin toxicity
- Immunologic reactions – flu-like syndrome maybe associated with renal/bone marrow toxicity
- rare hepatotoxicity
- Red-orange colored urine/feces and other secretions
- Induce microsomal enzyme oxidizing system (MEOS) –DDI. Decreases half life of other drugs (esp AIDS drugs, corticosteroids, theophylline)
Rifampin Spectrum/uses
- 1st line agent for TB and other mycobacteria (MAC and leprosy)
- Against Gram (+) and Gram (-) Cocci, Legionella for serious infections
- Prophylaxis against meningococcal infections in exposed individuals
Pyrazinamide MOA
unknown, possibly fatty acid synthesis but recent report suggests not
- prodrug hydrolyzed to pyrazinoic acid via pyrazinamidase (pncA)
- Active at low pH - effective tuberculocidal activity in caseous lesions at low pH
- Enters macrophages (controversial)
Pyrazinamide - resistance
- via mutations to pncA and alterations in drug uptake
- rapid development if used alone
Pyrazinamide Pharkacokinetics
- orally active, wide distribution (CNS, lungs, organs), quickly absorbed
- excrete in urine as hydrolyzed forms
Pyrazinamide toxicity/adverse effects
- hepatitoxic in 15%, some with jaundice, death rare–check hepatic function
- hyperuricemia since drug inhibits urate excretion
- arthralgias, anorexia, nausea, vomiting, dysuria, fever
Pyrizinamide spectrum/uses
1st line anti-TB agent. more potent than PAS or cycloserine but can be toxic. Used mainly in initial weeks of therapy
Ethambutol MOA
- inhibits mycobacterial cell wall biosynthesis via binding and inhibiting arabinosyltransferase (emb genes)
- Arabinosyltransferase polymerizes arabinan in arabino-galactan and lipoarabinomannan layers of cell wall
- Bactericida/static depending on environment of bacilli
- selective toxicity related to fact that other bacteria/fungi/human cells don’t make arabino-galactan
- CONCENTRATES IN LUNG-TB LESIONS. CONTROVERSY ON HOW WELL IT CAN ENTER MAMMALIAN CELLS
Ethambutol Resistance
- mutaiton in emb genes if used alone
- active against most isoniazid- and streptomycin-resistant strains
Ethambutol pharmacokinetics
- orally active, quickly absorbed, widely distributed to tissues/CSF
- Excreted in urine (10% metabolized)
Ethambutol toxicity/adverse events
- optic neuritis– reversible; rare with recommended doses and no impaired renal function
- Hyperuricemia
- Nausea/vomiting/dysuria/fever
Ethambutol Spectrum/use
active only against mycobacteria; 1st line TB agent
Route of TB drugs
all are oral except streptomycin (IV)
2nd Line Anti-TB drugs
1) cycloserine- inhibit alanine racemase and D-alanyl-D-alanine synthetase in cell wall synthesis. More toxic than isoniazid/PAS. Don’t combine with isoniazid
2) Aminosalicylic acid (PAS)
- slight tuberculostatic action but synergistic with other anti-TB drugs. GI toxicity common and not used much today due to poor pt acceptance
3) Capreomycin - similar to streptomycin but more toxic
4) Ethionamide
5) protein synthesis inhibitors (Amikacin, kanamycin)
5) fluoroquinolones (ofloxacin, cipro-, levo-, spar-)
6) Rifabutin - similar to rifampin
Treat mycobacterium avium complex (MAC)
Rifabutin Macrolides (calrithromycin/azithromycin) Fluoroquinolones Clofazamine (also in leprosy) Amikacin
Treat Leprosy
- use multidrug therapy
1) Sulfones (i.e. Dapsone) - bacteriostatic and thought to competitively antagonize PABA utilization
- relatively nontoxic but perhaps hemolytic anemia in G6PD deficiency.
- Have to give long time (1-5 years)
- Amithiozone = alternative agent
2) Rifampin- bactericidal for M. leprae. Used in multidrug therapy
3) Clofazimine - phenazine dye binding DNA.
- bactericidal and used for dapsone-resistant leprosy and skin ulcers.
- Orally available but slow activity (50 days)
TB drugs with good intracellular activity
INH, RIF, Pyrazinamide is variable
TB drugs with poor intracellular activity
Ethambutol, Streptomycin, Pyrazinamide is variable
Streptomycin
Protein synthesis inhibition at 30 S subunit (CIDAL)
- alternative 1st line treatment
- give IV/IM;
-accumulates in kidney, ear– high toxicity
- renal excretion
USE: Med. Spectrum Gram -ve aerobes, limited +
Use of TB drugs in pregnancy
- relatively safe
- Ethambutol/Rifampin = Pregnancy category C
- Benefits may outweigh risks with Rifampin
