9/13/20101Anti-tubercular and Anti-leprosy agents MycobacteriaTuberculosisleprosy Mycobacterial avium complex disease Aerobic and like Gram (+/??)Characteristics:Grow slowly and remain dormantIncreased resistance to chemical damage and dehydration andrelatively resistant to antibiotics Unique cell wallThicker, waxy, hydrophobic and rich in mycolic acidMycobacterial Cell Wallcell wall skeleton1. outer lipids2. mycolic acid3. polysaccharides (arabinogalactan)4. peptidoglycan5. plasma membrane6. Lipoarabinomannan (LAM)7. phosphatidylinositol mannoside8. skeletonMycolic acidLong fatty acidsIn M tuberculosis: 3-types of fatty acids: alpha-, methoxy-, and ketoAlpha-mycolic acids ~ 70% and contain several cyclopropanerings. gMethoxy-mycolic acids, ~10-15% in the organism. Keto-mycolic acid ~ 10% to 15%.allow the bacterium to grow readily inside macrophages, effectively hiding it from the host's immune systemLung alveolar macrophage1. Pathogens2. Phagosome3. Lysosomes4. Waste material5. Cytoplasm6. Cell membraneM. Tuberculosis cell-wall prevent the fusion of the phagosome with a lysosome. UreC gene, which prevents acidification of the phagosome; bacteria can neutralize reactive nitrogen intermediates.•lungs (Pulmonary TB) primary•lymph nodes (tuberculous adenitis or scrofula)•Brain and CNS (Meningeal TB)•skin and the bones•skin and the bones•Liver•kidney.9/13/20102RLREMERGING as a plague globally2002-2010------- 1 billion persons will be newly colonzied•Mycobacteria agilein developing resistance to singleReasonsagilein developing resistance to single chemotherapy•Patient compliance•drug toxicity•drug interactions (HIV and TB)History• Before 1930’s • 1944 streptomycin• 1950’s Isoniazid• 1970’S Rifampin• 1990’s FluoroquinolonesTreatmentAtleast 2 different drugs to which organism is susceptibleTreat for sufficient duration to prevent relapseFirst lineSecond lineFirst LineIsoniazid (INH, Niconyl, Hyzyd)Rifampin (Rifadim, Rimactane)*Ethambutol (Myambutol) or StreptomicinPyrazinamideMoxifloxacin (gatifloxacin)CycloserineCapreromycinEthionamide (Trecator-sc)Aminosalicylic acid (PAS) (Panasol)AmikacinKanamycini lidSecond Line/Alternative agentsLinezolidClofazimineIsoniazid (INH)catalase-peroxidaseBacteriostatic---resting mycobac Bactericidal---growing mycobact prodrugp?? Active drugInhibits synthesis of mycolic acids (fatty acid transferases)I. Mechanism of action9/13/20103Mechanism of ResistanceMutation in Catalase/peroxidase (katg))Mutaion in inhA/kasMycolic acidMutaion in NADPH dehydrogenase (ndh)Conversion of prodrugAbsorption, Distribution, and Excretion•Well-absorbed by GI tract•Al+-antacids interfere with absorption•Diffuses all body fluids including CSF; (inflamed menings conc in tissue = plasma)Alantacids interfere with absorption•Eliminated as acetylated by products via renal system (24 hrs)Inactivation: bimodialCONHNH2Arylamine NAcetyltransferasesGenetic Slow (50% in US)Scandanavians, Jews, North african caucasians, CONHNHCOCH3N-AcetyltransferasesType 2 (NAT2)polymorphismfastInuit, japaneseUntoward Effects•Periphral neuropathypatients with predisposing conditions i.e. malnutritionalcoholics, diabetes, AIDS and uremiapyridoxine deficiency (competes with vit B6)•CNS toxicity (memory loss, psychosis, seizures)CNS toxicity (memory loss, psychosis, seizures)•Hepatotoxicity (high aminotranferases)•Hypersensitivity: fever, various skin eruptions, etc •Hematological reacns: eosinophilia, thrombocytopenia •Arthritic symptomsCONHNH2INHCONHNHCOCH3Acetyl INHHepatic Necrosis(>20 yrs old) CH3-C-N-NH2OAcetyl hydrazoneCYP-450Hepatic NecrosisDrug InteractionscoadministrationcycloserineCNS side effects such as dizziness or drowsinessDisulfiram HepatotoxicityRifampinor drowsinessCoordination difficultiesand psychotic episodesIncreases their conc in serum by inhibiting hepatic metabolismAnticonvulsantsi.e. carbamazepine9/13/20104Rifamycins (RIF) (bactericidal)(rifampin, rifabutin, rifapentine)Complex macrocyclic antibiotics)forms complex with b-subunit of Mechanism of actionpDNA-dependent RNA polymeraseBlocks initiation of chain formation in RNA synthesisDNARNADNA-dependent RNA polymeraserpoBMutation In polymeraseMechanism of ResistanceAbsorption, Distribution, and Excretion•absorbed by GI tract; decresaed by aminosalicylic acid Deacetylated via enterohepatic circulation after which it is eliminated by bile.•Diffuses all body fluids including CSF; Untoward Effects•Generally well-tolerated•Induces hepatitis in patients with: chronic liver disease, alchoholic or older patientsGatrointestinal disturbances•Flulike symptoms•By inducing CYP1A2, 2C9 decrease half life of HIV protease inhibitorsdigitoxin, verapamil etcRifapentine half life > rifampin, rifabutin;rifabutin preferred in HIV-infected patients Ethambutol (Myambutol)inhibits arabinosyltransferase and thereby prevent conversion of D-arabinose into arbinogalactan required for synthesis •Inhibit synthesis of outer coating of cell wallosy essResistance: single amino acid mutation in the embA gene •Well-absorbed•Less-toxic so replaced Aminosalicylic acid•Effective when given with INH•Excreated by tubular and glomerular secretionCrossesBBBAbsorption, Distribution, and ExcretionCrosses BBBaccumulates in renal failureUntoward EffectsOptic neuritisvisual acuity red:green color blindness; reversibleStreptomycinVery potent against mycobacteriaRecommended when less potentially hazardous therapeutic agents are ineffective or contraindicatedORAdded in patients with serious forms of TBi.e. Disseminated disease9/13/20105Pyrazinamide (Important for short term TB treatment)Pyrazinamide Pyrazinoic aciddeamidaseFatty acid synthase geneInhibits synthesis of mycolic acidsAbsorption, Distribution, and Excretion•Well-absorbed from GI •Diffuses all body fluids including CSF•Eliminated via glomerular filtration (half life > in older)No cross-resistence with other anti-TB drugsUntoward EffectsLiver injury, inhibits urate excretion, goutanorexia, vomiting etc(NOT recommended in pregnant woman in US) gCan be given along with INH and Rif in short regimns to prevent relapseQuinolonesGatifloxacin (Tequin)Moxifloxacin (Avelox)For multidrug-resistant (MDR) TBAminosalicylic acid (similar to sulphonamides)Inhibits DNA gyrase and topoisomeraseLinezoid (ZYVOX)Mechanism of action:binds P site of 50S and inhibits protein synthesisUntoward Effects•Myelosuppression
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