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1、1 13/29/20233/29/2023AntibioticsHugh B.Fackrell:antibiot.ppt2 23/29/20233/29/2023OutlineHistoryIdeal propertiesSources“Sulfas”Antimetabolitesantibiotic synergismMajor Groups of antibioticsMechanisms of action3 33/29/20233/29/2023HistorySalvarsan 606ProntosilPenicillin4 43/29/20233/29/2023Salvarsan 6
2、06Paul Ehrlichearly 1900ssyphilisarsenic+organic compoundAniline dyes-wasnt able to find the magic bullet”5 53/29/20233/29/20236 63/29/20233/29/2023Penicillin1928,Alexander Flemingantibacterial activity in Penicillium mold (called it Penicillin)1938,Howard Florey and Ernst Chaindeveloped Penicillin
3、as an effective antibiotic7 73/29/20233/29/2023Antimicrobial TherapyAntimicrobicssubstances produced by microbes that inhibit other microbes Semi-synthetic antibiotics naturally produced but alteredSynthetic antibiotics:derived from chemicals8 83/29/20233/29/2023Ideal Properties of an AntibioticLow
4、toxicity for patientkills the invading microorganism without damaging the hostno adverse side reactionsnon allergenicHigh toxicity for microbebactericidal not bacteriostaticbroad spectrumLow risk of other infections9 93/29/20233/29/202310103/29/20233/29/2023Still More CharacteristicsLow probability
5、of resistanceMicrobial drug resistance develops slowlymicrobicidal rather than microbistaticNot inactivated by organic materialAssists the host in eliminating the infecting microbeNot a powerful allergen11113/29/20233/29/2023Sources of AntibioticsMost spore-forming microorganismsFungiPenicillium pen
6、icillin,Cephalosporium griseofulvinBacteriaBacillus bacitracin,polymyxin,tyrothricin,colimycin,gramicidinStreptomycetes Aminoglycosides,nystatin,chloramphenicol,erythromycin,tetracylcine.12123/29/20233/29/2023Sulfa Drugs14143/29/20233/29/202315153/29/20233/29/2023Structure of Sulfa DrugsProntosilPro
7、ntosilSulfisoxazoleSulfisoxazoleSulfanilamideSulfanilamide16163/29/20233/29/2023Folic Acid MetabolismPABA+pteridinePABA+pteridineThymidineThymidineDNADNAPurinesPurinesDNA,RNADNA,RNAMethionineMethioninetRNa,ProteinstRNa,ProteinsPteridine Pteridine synthetasesynthetaseDihydropteroic acidDihydropteroic
8、 acidGTPGTPDihydrofolic AcidDihydrofolic AcidDihydrofolate Dihydrofolate SynthetaseSynthetaseL-GlutamineL-GlutamineTetrahydrofolic AcidTetrahydrofolic AcidDihydrofolate Dihydrofolate synthetasesynthetase2 NADPH2 NADPH2 NADP+2 NADP+SulfonamideSulfonamideTrimethoprimTrimethoprim17173/29/20233/29/20231
9、8183/29/20233/29/2023Antibiotic SynergismSulfisoxazoleSulfisoxazoleTrimethoprimTrimethoprim19193/29/20233/29/2023Antibiotic SynergismSulfonamide+trimethoprimEffective dosage 10%of two separatelyBroader spectrum of actionReduce emergence of resistant strainsMajor Groups of Antibiotics21213/29/20233/2
10、9/2023Major Groups of AntibioticsAminoglycosidesstreptomycin,kanamycin,neomycin,gentamicin,spectinomycin,tobramycin,amikacinBeta lactamsPenicillins,cephalosporinsLincomycinslincomycin clindamycin22223/29/20233/29/2023Major Groups of AntibioticsMacrolideserythromycin,carbomycinPolypeptidespolymyxin,c
11、olimycin,bacitracin,tyrothricinPolyenesamphotericin B,nystatinRifamycinsRifampin23233/29/20233/29/202324243/29/20233/29/2023PENEMSCarbapenems“Ideal”antibioticsnon toxicbroad spectrumgood“Shelf”lifeeffective at very low concAttach to Penicillin Binding Proteins found in cell membraneGm+ve lysis throu
12、gh loss of cell wall integrityGm-ve filamentous bacteria loss of septum formation25253/29/20233/29/2023Adverse Effects of AntibioticsAminoglycosidesOtotoxic-destroys cochlear hair cellsrenal toxicChloramphenicoldepresses bone marrowaplastic anemiafatal“Grey baby”syndromePenicillinsallergy anaphylaxi
13、sVancomycinthrombophlebitisototoxicrenal toxicPolymyxin,bacitracin colimycinrenal toxicSulfasskin allergyanemiarenal toxichepato toxic26263/29/20233/29/2023Adverse Effects of AntibioticsBroad spectrumSuper infections Candida albicansClostridium difficleStaphylococcus Gram-vel lTetraclycineDepress bo
14、ne marrowDepress bone marrow“Yellow teeth”“Yellow teeth”l lPregnant womenPregnant womenl lchildren 7 yearschildren RNA58583/29/20233/29/2023Acylovir vs Deoxyguanosine59593/29/20233/29/2023Inhibition of Transcription60603/29/20233/29/2023AntimetabolitesSulfonamidesDonald D.WoodsSulfanilamide blocks f
15、olic acid folic acid is essential to the synthesis of DNA and RNAPara amino benzoic acid(PABA)not incorporated into folic acidReversible inhibitionHigh PABA competitively inhibit sulfanilamide 61613/29/20233/29/2023Inhibited metabolites,Synthesis62623/29/20233/29/2023Drug Resistancesynthesis of enzy
16、mes that inactivate the drugdecrease in cell permeability and uptake of the drugchange in the number or affinity of drug receptor sitesmodification of an essential metabolic pathway63633/29/20233/29/2023Development of Drug Resistanceintrinsicchromosomal mutations-low probabilityacquiredtransfer of e
17、xtra chromosomal DNA from a resistant species to a sensitive onePlasmidsTransposons64643/29/20233/29/2023Plasmidsresistance factors or R factors transfered by conjugation,transformation or transduction65653/29/20233/29/2023Transposonssequences that can move from plasmid chromosome plasmid plasmid666
18、63/29/20233/29/2023Clinical Trialspatient-has a diagnosed infection-two possibilities:a)the new drug is the drug of choice by testingb)the patient has not responded to other drugs and the new drug is testing well in the labsamples of blood etc.taken to determine all the possible parameters:level of
19、antimicrobial and presence of agentcultures of infecting agent taken 2 times per daydisappearance of the bacteria and patient recovery conclude a successful trial67673/29/20233/29/2023Reference:lab manual p.270Minimum Inhibitory Concentration1.test for antimicrobial activity2.dilute antibiotic(pictu
20、res of tubes)3.range selected obtained from therapeutic index4.add to medium5.add pure culture of isolated bacteria6.incubate-tubes that are clear after 16 hours incubation at 35 C are subcultured0.1 ml removed and plated on suitably rich medium-usually the agar version of the liquid growth medium68
21、683/29/20233/29/2023Reference:lab manual p.270Kirby-Bauer Plate Sensitivitydisks impregnated with various concentrations of appropriate antibiotics are placed aseptically on innoculated platesmeasurement of drug concentrations in the blood preclinical trialssubjects receive varying dose levels and i
22、ntervals of dosagepretrials usually determine the route of entry-oral or parenteral(injected subcutaneously,intramuscularly,etc.)pretrials determine the carrier substance69693/29/20233/29/2023Subjects Tested for Antimicrobial Levelsblood,lymph,urine,feces tested for effective levels depending on diseasealso of concern is rapid metabolism(catabolism)of the drug and also rapid excretion70703/29/20233/29/2023Disk Diffusion Testsdiffusion of antibiotic from disk controlled by agar concentrationZone of Inhibitioncontrolled by diffusion ratelevel of sensitivityeach antibiotic is unique