NR565_WEEK 6 STUDY GUIDE_ch24_COMPLETED

ANTIMYCOBACTERIALS  Mycobacteria- among the most difficult to cure (e.g. tuberculosis [TB]) o They grow slowly and are relatively resistant to drugs that are largely dependent on how rapidly cells are dividing o Hav ...

ANTIMYCOBACTERIALS  Mycobacteria- among the most difficult to cure (e.g. tuberculosis [TB]) o They grow slowly and are relatively resistant to drugs that are largely dependent on how rapidly cells are dividing o Have a lipid-rich cell wall relatively impermeable to many drugs o Are usually intracellular and inaccessible to drugs that does not have good intracellular penetration o Have the ability to go into a dormant state o Easily develop resistance to any single drugs o Pregnancy categories:  Isoniazid: Pregnancy category A  Streptomycin: Pregnancy category D  The rest: Pregnancy category C  Fetal death- d/t TB: isoniazid + rifampin + ethambutol for TB tx if pregnant and if drug resistance is a possibility.  Spectrum of coverage for various organisms/Pharmacodynamics o Isoniazid - most active drug for tx of TB  Bactericidal- against susceptible mycobacteria (intracellular and extracellular organisms)  Interferes with lipid and nucleic acid biosynthesis in growing organisms.  Isoniazid and ethambutol- inhibits synthesis of mycolic acid (important constituents for mycobacteria cell walls and are not found in mammalian cells). o Rifamycins – rifampicin, rifabutin, rifapentine  Bactericidal- against susceptible mycobacteria  Bind to the beta subunit of mycobacteria DNA-dependent RNA polymerase and inhibit RNA synthesis -> destruction of both multiplying and inactive bacilli.  Readily penetrate most tissues and can kill bacteria that are poorly accessible to many drugs.  Rifampin and rifabutin: N. gonorrhoeae, staphylococci, streptococci, Mycobacterium leprae, MAC, and H. influenzae type B.  Rifampin-resistance develop rapidly when used as monotherapy- should be combined with another active abx for tx of established infections. o Ethambutol  Bacteriostatic- against susceptible mycobacteria (M. tuberculosis, M. avium, M. kansasii)  Inhibits synthesis of arabinogalactan (an essential component of mycobacteria cells walls).  Arrests cell multiplication -> cell death  Enhances the activity of lipophilic drugs (rifampin and ofloxacin) that cross the mycobacteria cell wall primarily in lipid portions of this cell wall. o Pyrazinamide- an analogue of nicotinamide  Bactericidal – against M. tuberculosis in an acidic environment (pH <5.6).  Useful in tx of TB  Exhibits good activity within macrophages and plays a key role in killing intracellular organisms.  Shortening therapy and preventing relapses  Exact action is UNKNOWN. o Streptomycin – aminoglycoside, used now almost exclusively to treat M. tuberculosis infections.  Bactericidal in alkaline extracellular environment  Added as the 4th drug to the regimen for TB  Sensitive to M. avium and M. kansasii; resistant to all mycobacterium  Irreversible inhibitor of protein synthesis.  Penetrates cells poorly o Ethionamide- similar binding site and mechanism of action as isoniazid.  Ultimately blocks the synthesis of mycolic acids.  Bacteriostatic – M. tuberculosis  Can inhibit some other Mycobacterium species. o Capreomycin – peptide abx  Bactericidal to susceptible mycobacteria.  Inhibits RNA synthesis -> decreasing replication of M. tuberculosis.  Resistance easily develops when given as monotherapy (should be given as part of multidrug regimen) o Bedaquiline – unique antimycobacterial, approved by FDA in 2012  For tx of multidrug resistant TB  Inhibits mycobacterial adenosine triphosphate (ATP) synthesis  Active against replicating and dormant mycobacteria  Black-box warning: increased mortality as compared with a placebo tx group.  Only to be used when an effective tx regimen cannot otherwise be provided. o Para-aminosalicylic acid- structurally similar to PABA and sulfonamides  Folate synthesis antagonist  Active almost exclusive against M. tuberculosis.  Bacteriostatic  Not used frequently – primary resistance is common, and other drugs are better tolerated and less expensive.  Pharmacokinetics o Oral antimycobacterials are rapidly and well absorbed in GI tract after PO administration. o Isoniazid- 90% bioavailable but should be taken on an empty stomach  Readily diffuses into all body fluids including CSF (90% of serum levels), pleural, and ascitic fluids  Readily diffuses into tissues, organs, saliva, sputum, and feces  Crosses placenta and breastmilk  Metabolism is extensive and highly variable and dependent on acetylator status.  Primarily acetylated by the liver  50% of both blacks and whites are slow acetylators  Alaskan and Asians- majority are rapid acetylators  Rate of acetylator does not affect effectiveness but may increase risk for toxic reactions with slow acetylators.  Excreted in the urine- metabolites, and unchanged drug  Elimination is largely dependent on renal function o Rifamycins and ethambutol penetrate and concentrate in most body fluids.  Adequate CSF penetration occurs only in the presence of inflamed meninges.  Potent inducers of liver metabolism  Rifampin and rifapentine- metabolized in the liver by deacetylation.  Metabolites are active against M. tuberculosis.  t1/2 life decreases with repeated administration  excreted primarily in the bile -> enterohepatic recirculation -> feces, urine (small amount)  hepatic insufficiency and age slightly affect metabolism of rifabutin only.  Renal insufficiency- reduced drug distribution and faster drug elimination -> decreased drug concentrations.  Food slow the rate of absorption of rifamycins but not the extent of absorption (may be taken with or without food) o Pyrazinamide- widely distributed in body tissues and fluids including the liver and lung.  Reaches high concentrations in CSF  Crosses the placenta and enter breastmilk in small amounts  Poor CSF penetration (good penetration if meninges are inflamed)  70% excreted in urine by glomerular filtration  Hydrolyzed by the liver to as a metabolite  Prolonged t1/2 - significant on impaired hepatic and renal functions. o Ethionomide- widely distributed to body tissues and fluids- CSF and serum concentrations are equal  35% metabolized by the liver  Majority of the drug excreted in the urine as inactive metabolites o Ethambutol- mainly excreted as unchanged drug in the urine.  20% metabolized by the liver  Marked accumulation may occur in renal failure