抗生素英文精品-ANTIBIOTICS课件.ppt
ANTIBIOTICS Presented by Dr.Pavan kumar.GP.G.STUDENTCONTENTS TERMINOLOGYHISTORY OF ANTIBIOTICSRATIONALE OF DRUG USEPATTERNS OF MISUSEDRUG LEGISLATIONSCLASSIFICATION OF AMASBACTERIAL GROWTH CURVEMODUS OPERANDI OF AMASPRINCIPLES OF ANTIBIOTIC DOSING DRUG RESISTANCESULFONAMIDESCOTRIMOXAZOLEFLOUROQUINOLONESCEPHALOSPORINSCHLORAMPHENICOLAMINOGLYCOSIDESMACROLIDESMISCELLANEOUS ANTIBIOTICSANTI FUNGALS&ANTI VIRAL DRUGSPENICILLINSTETRACYCLINESMETRONIDAZOLEANTIBIOTIC FAILURESNON-EFFECTIVE CONDITIONS IN DENTISTRYNEWER ANTI-MICROBIAL APPROACHESANTIBIOMABIBILOGRAPHYPHARMACOLOGY&THERAPEUTICS FOR DENTISTRY -Yagiela.Dowd.Neidle 5th editionESSENTIALS OF MEDICAL PHARMACOLOGY -K.D.Tripathi 5th editionTEXTBOOK OF MICROBIOLOGY -R.Ananthanarayan&C.K.J.PanikerORAL&MAXILLOFACIAL INFECTIONS -Topazian 4th editionMICROBIOLOGY AN INTRODUCTION -Tortora,Funke,Case 8th editionHISTORYPERIOD OF EMPIRICAL USE Use of mouldy curd by chinese on boilsChaulmoogra oil by hindus in leprosyChenopodium by aztecs for intestinal wormsMercury by paracelsus for syphilisCinchona bark for fevers EHRLICHS PHASE OF DYES&ORGANOMETALLICS(1890-1935)If dyes could selectively stain microbes,they could be selectively toxic also.Atoxyl for sleeping sickness.Arsphenamine&norarsphenamine for syphilisEHRLICH also coined the term“Chemotherapy”.THIS IS THE MOST DRUGGED GENERATION THE MYTH A PILL TO CURE EVERY ILL RATIONALE OF DRUG USENeedAimKnowledgeRoute&dosageAlternativesDurationObservationsEliminationUnwanted effectsPrecautionsContraindicationsPatients point if viewPatient*Overuse in situations in which pts are not at risk for metastatic infections.*Treatment of chronic adult periodontitis almost totally amenable to mechanical therapy.*Administration instead of mechanical therapy for periodontitis.*Long term administration in th management of periodontal disease.*Antibiotic therapy instead of incision&drainage.*Administrations to avoid claims of negligence.*Administrations in improper situations,dosage&duration of therapy.BACTERIAL GROWTH CURVEANTIBIOTIC MECHANISM OF ACTIONInhibition of cell wall synthesis.Alteration of cell membrane integrity.Inhibition of ribosomal protein synthesis.Suppression of DNA synthesis.Inhibition of folic acid synthesis.PRINCIPLES OF ANTIBIOTIC DOSINGM.I.CConc.Dependent v/s time dependent antibioticsPost antibiotic effects(PAE)Microbial persistence®rowthDosing&resistanceAntibiotic loading doseDuration&antibiotic dosingMICROBIAL DRUG RESISTANCEEnzymatic inactivationModification/protection of target sitesAltered cell membrane permeabilityActive drug effluxFailure to activate the drugUse of alternate growth requirementsOver production of target sitesq In addition drug resistance can also occur by MUTATION or GENE TRANSFERANTI BACTERIAL SPECTRUMPrimarily bacteriostatic agent against many gram+ve&gram_ve bacteria.Organisms still sensitive are St.pyogenes,H.influenzae,H.ducreyi,E.coli,V.cholera,Chalydiae,Actinomyces,Nocardia&Toxoplasma.PHARMACOKINETICSRapidly&completely absorbed from GIT.PPB ranges from 10-95%.Crosses placenta freely.Primarily metabolised in liver by ACETYLATION.Excreted by kidney through glomerular filtrationGood penetrability into brain&CSF.USESSuppressive therapy of chronic UTI.Streptococcal pharyngitis.Second drug of choice in LGV.In combination with Trimethoprim for many bacterial infections,p.carinii,etc.Sulfacetamide sol.(10-30%)for trachoma/inclusion conjunctivitis.Topical Silver sulfadiazine or Mafenide are used for preventing infections on burn surfaces.COTRIMOXAZOLECombination of TRIMETHOPRIM&SULFAMETHOAZOLE in the ratio of 1:20.Both are static but the combination is cidal in action.Combination is because of similar t1/2 of 10hrs.SPECTRUM:Active against S.typhi,Serratia,Klebsiella,Enterobacteria,P.carinii and many sulfonamide resistant strains.USES:UTI Specially valuable in chronic&recurrent cases&in prostitis.RTI like chronic bronchitis,facio maxillary infections&otitis media.Second DOC in typhoid.Bacterial diarrheas&dysentry.Chancroid (800mg+160mg BD/7 days)is one of the DOC.Granuloma inguinale alternative to doxycycline/erythromycin.P.carinii prophylactic as well as therapeutic.ADVERSE EFFECTS:Rarely folate deficiency.Contraindicated in pregnancy as trimethoprim being an antifolate has teratogenic risk.Neonatal hemolysis&Methemoglobinemia can occur.Uremia in patients with renal diseases.Bone marrow hypoplasia in AIDS pt.For P.carinii infection.Cotrimoxazole+Diuretics cause higher incidence of Thrombocytopenia.FLOUROQUINOLONESFIRST GENERATIONCinoxacinOxolinic acidNalidixic acidSECOND GENERATIONLomefloxacinCiprofloxcinNorfloxacinOfloxacinLevofloxacinFLOUROQUINOLONES3RD GENERATIONGatifloxacinSparfloxacinGrepafloxacinPazufloxacin4th GENERATIONClinafloxacinGemfloxacinMofifloxacinTrovafloxacinCIPROFLOXACINInhibits the enzyme bacterial DNA gyrase which nicks double stranded DNA introduces _ve supercoils&then reseals the nicked ends.FQ action is similar to Topoisomerase IV.This damaged DNA is phagocytosed by exonucleases.SPECTRUMMost susceptible are aerobic,gram_ve bacilli especially Enterobacteriaceac,Neisseria,E.coli,S.typhi,K.pneumoniae,H.influenzae,H.ducreyi,V.cholera,Staph.aureus,P.aeruginosa,B.anthracis,M.tuberculosis,etc.Remarkable microbiological features of ciprofloxacin&other FQs include Rapidly bactericidal&highly potent.Relatively long PAE.Low freq.Of mutational resistance Protective streptococci&anaerobes are spared Active against B-lactams&aminoglycoside resistant bacteria Less active against acidic pH.PHARMACOKINETICS:Rapidly absorbed orally but food delays absorption.First pass metabolism occurs.High tissue penetrability.Excreted primarily in urine.INTERACTIONS:Plasma conc.of Theophylline,caffiene,&warfarin are increased by C.floxacin.NSAIDs may enhance CNS toxicity.Antacids,Sucralfate,&Fe salts if given concurrently reduce absorption.USES:UTIsGonorrhoeasChacroid 500mg/BD/3 days.Excellent alt.To Cotrimoxazole.CONTDADVERSE EFFECTS:GIT symptoms like Nausea,Vomitting,Bad taste.CNS dizziness,headache,anxiety,insomnia,impairment of concentration and dextereit.(CAUTION WHILE DRIVING).FIRST CHOICE DRUGS IN Typhoid Bone,soft tissue,gynecological&wound infections Diabetic foot In combination therapy for T.BCEPHALOSPORINS1st generationCefazolinCephalexinCefadroxilCephradineCephalothin*2nd generationCefuroximeCefaclorCefoxitin*3rd generationCefotaximeCefoperaxoneCeftriaxoneCeftazidimeCefiximeCefdinir4th generationCefepimeCefpiromeCEPHALOSPORINS1st gen developed in 1960s have high activity against gram+ve bacteria.2nd gen more active against gram_VE with some active against anaerobes.3rd gen Introduced in 1980s,have highly augmented action against gram_ve enterobactericeac,B-lactamases,less active on gram+ve cocci.4th gen developed in 1990s spectrum of action similar to 3rd gen.Highly effective in nosocomial pneumonia,febrile neutropenia,bacterimia,septicemia,etc.EVOLUTION OF CEPHALOSPORINSUSES1ST gen are used as alterntives to penicillin G.UTI&RTIsPenicillinase producing staphylococcal infections.Cephalothin is the DOC.May be combined with aminoglycosides in septicemias.1st gen cephalosporins are used in surgical prophylaxis.Ceftazidime+Gentamicin for Pseudomonas meningitis.Ceftriaxone is the first DOC in gonorrhea caused by penicillinase producing m.oAs alternative to FQs in typhoid,especially in children.3rd gen cephalosporins are used in treatment of infections of neutropenic pts.ADVERSE EFECTS:Pain after i.m is very common.Hypersensitivity reactions similar to penicillins.Nephrotoxicity is highest with cephaloridine.A+ve coombs test occurs but hemolysis is rare.A disulfiram like reaction with alcohol has been reported with Cefoperaxone.CHLORAMPHENICOLInitially obtained from St.venezuelae in 1947.Has a nitrobenzene substitution.Inhibits bacterial protein synthesis by binding to 50s.SPECTRUMPrimarily static but cidal at high conc.&against H.influenzae.A broad spectrum AMA.PHARMACOKINETICSRapidly&completely absorbed orally.50-60%PPB&t1/2 of 3-5 hrs.Crosses placenta&secreted in bile&milk.Undergoes glucoronic acid conjugation in liver&excreted in urine.INTERACTIONSInhibits metabolism of Tolbutamide,Chlorpropamide,Warfarin,Phenytoin and Cyclophosphamide.Phenobarbitone,Phenytoin,Rifampin enhance the metabolism.USESSecond choice drug in enteric fever.H.influenzae meningitis 50-75mg/kg/day/2weeks.Prefferred drug for intraocular infections like endopthalmitis.Topically effective in conjunctivitis,external ear infections.AS SECOND CHOICE DRUG TO TETRACYCLINES in brucellosis,cholera,ricketssial&chlamydial infections in children below 6yrs&in pregnant women.TO ERYTHROMYCIN for whooping cough TO PENICILLIN for meningococal&pneumococcal meningitis TO COTRIMAZOLE for shigella,dysentry,enteritis.ADVERSE EFFECTSBone marrow depression causing aplastic anemia,agrnulocytosis,thrombocytopenia&pancytopenia.GRAYBABY SYNDROME:Occurred when high doses(100mg/kg)were given.Baby stopped feeding,vomited,became hypotonic,hypothermic,abdomen distended,irregular respiration,ashen gray cyanosis,CV collapse&death.Increase in blood lactic acid.At higher conc.It blocks e-transport in liver myocardium&skeletal muscle.Avoided in neonates.If given 25mg/kg/day.AMINOGLYCOSIDESBactericidal&effective against gram_ve bacteria.Streptomycin binds to 30s whereas others bind to 30s-50s interface.Various aminoglycosides include streptomycin,gentamicin,kanamycin,tobramycin,amikacin,etc.SHARED TOXICITY:OTOTOXICITY NEPHROTOXICITY NEURO MUSCULAR BLOCKADEPRECAUTIONS&INTERACTIONSAvoid during pregnancy risk of fetal ototoxicity.Avoid using with other ototoxic drugs like high ceiling diuretics&minocyclineAvoid concurrent use of other nephrotoxic drugs like AMB,vancomycin,cyclosporine,etc.Cautious use in renal pts.Cautious use of muscle relaxants.Do not mix aminoglycoside with any drug in same syringe/infusion bottle.STREPTOMYCINObtained from St.griseus.Narrow antibacterial spectrum.Practically restricte to use of T.B.PHARMACOKINETICSHighly ionised¬ metabolised.Neither absorbed nor destroyed in GIT.Absorption from site of inj.Is rapid.Only extracellular distribution with t1/2 of 2-4 hrs.Excreted unchanged in urine.USESTuberculosisMay be used with penicillin in SABE.In plague(tetracyclines in epidemics).Drug of first choice in tularemia.MACROLIDESBacteriostatic at low conc.But cidal at high conc.Various macrolides include erythromycin,roxithromycin,clarithromycin,and azithromycin.ERYTHROMYCINIsolated from St.erythreus.Acid labileWidely distributed,crosses serous membrane&placenta but not BBB.PPB is 70-80%with t1/2 of 1.5hrs.Excreted primarily in BILE.SPECTRUMNarrow spectrum.Mostly gram+ve organisms.Highly active against Str.pyogenes,Str.pneumoniae,gonococci,clostridia,C.diptheria,listeria,etc.INTERACTIONSInhibits hepatic oxidation&causes rise in plasma levels of drugs like theophylline,carbamazepine,valproate,ergotamine,warfarin,terfanadine,astemizole&cisapride.USESAs alternative to penicillins in streptococcal infections diptheria tetanus syphilisAs a first choice drug in atypical pneumonia caused by m.pneumoniae whooping cough chancroid(2gm/day/7days)As a second choice drug in campylobacter enteritis(next to FQ)legionnaires pneumonia chlamydia trachomitis(500/6hrs/7days)penicillin resistant staphylococcal infectionsADVERSE EFFECTSRemarkably safer drug.GIT symptoms include mild to severe epigastric pain&ocassional diarrhea.Very high doses have caused reversible hearing impairment.MISCELLANEOUS ANTIBIOTICSCLINDAMYCINLincosamide antibiotic with mechanism of action&spectrum of activity similar to erythromycin.Inhibits most gram+ve cocci including penicillinase producing staph.,C.diptheria,nocardia,Actinomyces&Toxoplasma.Highly active against anaerobes especially Bact.fragilis.Good oral absorption&does not cross BBB.Accumulates in neutrophils¯ophages.Metabolised in liver&excreted in urine and bile.T1/2 3hrsMajor adverse effect is diarrhea&pseudomembranous enterocolitis caused by C.difficle super infection.Employed for prophylaxis in colorectal/pelvic surgeries.In AIDS pt.,with pyrimethamine for toxoplasmosis,with primaquine for P.carinii pneumonia.Topically used for infected acne vulgaris.Clindamycin,Erythromycin&Chloramphenicol exhibit mutual antagonism.Potential neuromuscular blockers.VANCOMYCINGlycopeptide antibiotic discovered in 1956 as a penicillin substitute due to efficacy against MRSA,Str.viridans,Enterococcus,Cl.difficle.Bactericidal.Acts by inhibiting bacterial cell wall synthesis by binding to terminal D-ala-D-ala sequence.Not absorbed orally.After i.v,it is widely distributed,penetrates serous cavities,inflammed meninges&is excreted by urine.Toxicity cuses plasma conc.Dependent permanent deafness.kidney damage is also dose related.Rapid i.v injection causes chills,fever,urticaria,&intense flushing this is REDMAN SYNDROME.T1/2 of 6hrs.ANTI FUNGAL DRUGSUsed for superficial&deep fungal infections.Two important antifungals are AMB to deal with systemic mycosis GRISEOFULVIN to supplement attack on dermatophytesAdvancement of antifungals included development of imidazoles in 70s&triazoles in 80s.Imidazoles include clotrimazole,miconazole,etc.Triazoles are fluconazole,itraconazole.AMPHOTERICIN B(AMB)From St.nodosus.It is a polyene with a macrocyclic ring.One of the most toxic systemically used antibiotic&least toxic polyene.Antifungal spectrum include many yeasts&fungi like C.albicans,H.capsulatum,C.neoformans,B.dermatidis,Apergillosis,Sporothrix,etc.Fungicidal at high conc.Have high affinity for ergosterol present in fungal cell membrane.Resistance is rarely noted.Not effective against Dermatophytes.PHARMACOKINETICSNot absorbed&can be given orally for intestinal candidiasis.Widely distributed with poor CSF penetration.Metabolized in liver with t1/2 of 15days&excreted by urine&bile.USESGold standard of antifungal therapy.Used topically for oral,vaginal&cutaneous candidiasis&otomycosisMost effective for systemic mycoses.Reserve drug for resistant cases of kala azar.ADVERSE EFFECTSAcute reactions like chills,fever,aches,nausea,dyspnoea,etc.Thrombophlebitis of injected vein can occur.Nephrotoxicity is the most important long term effect.INTERACTIONS Flucytosine has supra-additive action with AMB.Rifampin&minocycline potentiate AMB.Aminoglycosides,vancomycin,cyclosporine enhance the renal impairment caused by AMB.GRISEOFULVINHeterocyclic Benzofuran from P.griseofulvam.Active against most most Dermatophytes but not candida.Interferes with mitosis causing multinucleated stunted fungal hyphae.Irregular absorption improved by taking it with fats.Gets deposited in keratin forming cells of skin,hair&nailsIneffective topically.Induces warfarin metabolism&reduces efficacy of OCP.Phenobarbitone reduces oral absorption&induces metabolism of the drug.ANTIVIRAL DRUGSTherapy has to be started in the incubation period,i.e,has to be prophylactic.Anti herpes include acyclovir,ganciclovir,idoxuridine etc.Anti-retroviral are NRTIs zidovudine,didanosine,etc;NNRTIs like nevirapine,efavire
