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1、Introduction to antimicrobial agents,Definition: Use of drugs to combat infectious diseases and cancer. Antimicrobial drug (抗微生物药) Antiparasitic drug( 抗寄生虫药) Anticancer drug (抗癌药),1. Chemotherapy,化学治疗,Antimicrobial drug,Antimicrobial drugs either kill microbes (microbicidal) or prevent the growth of
2、 microbes (microbistatic). Antibacterial(抗菌药） Antiviral（抗病毒药） Antifungal（抗真菌药）,Antimicrobial Chemotherapy,Differential toxicity: based on the concept that the drug is more toxic to the infecting organism than to the host Majority of antibiotics are based on naturally occurring compounds ( antibiotic
3、s) or may be semi-synthetic or synthetic,Definitions,Spectrum of Activity（抗菌谱） Narrow spectrum - drug is effective against a limited number of species Broad spectrum - drug is effective against a wide variety of species Gram negative (G+) agent Gram positive (G-) agent Anti-anaerobic activity,Defini
4、tions,Minimum Inhibitory Concentration (MIC) - minimum concentration of antibiotic required to inhibit the growth of the test organism Minimum Bactericidal Concentration (MBC) - minimum concentration of antibiotic required to kill the test organism,Definitions,Bacteriostatic（抑菌药） Bactericidal（杀菌药） C
5、hemotherapeutic Index ( 化疗指数，CI ): LD50/ED50 or LD5/ED95,Definitions,Post antibiotic effect (抗生素后效应，PAE) the continued suppression of antibacterial growth after the administration of antibiotic has ceased and serum concentrations have fallen below the MIC Unit: hour PAE is longer in vivo,Clinical si
6、gnificance of PAE,Design therapeutic regimen Increase dose: carbapenems (concentration dependent PAE) Determination of dosing interval： Antibiotics without PAE: serum concentration higher than MIC Antibiotics with PAE: serum concentration higher than MIC+PAE Evaluation of combined medication,What is
7、 the ideal antibiotic,Have the appropriate spectrum of activity for the clinical setting Have no toxicity to the host, be well tolerated Low propensity for development of resistance Not induce hypersensitivies in the host,What is the ideal antibiotic,Have rapid and extensive tissue distribution Have
8、 a relatively long half-life Be free of interactions with other drugs Be convenient for administration Be relatively inexpensive,pathogenic microorganism,Antimicrobial drugs,antibacterial action,resistance,Disease Resistance,pathogenicity,adverse reaction,intracorporal process,body,The glycan backbo
9、ne,Peptidoglycan cross-bridges,Tetrapeptide side chain,Peptidoglycan,Five modes of antimicrobial action,(i) Inhibition of cell wall synthesis (ii) Disruption of cell membrane function (iii) Inhibition of protein synthesis (iv) Inhibition of nucleic acid synthesis (v) Inhibition of folic acid synthes
10、is,Targets of antimicrobial drugs,Disruption of cell membrane function,Polymyxin,Cationic and alters cytoplasmic membrane permeability by binding to a negatively charged site in the lipopolysaccharide layer,Amphotericin B,Associates with ergosterol, the main component of fungal cell membranes,Drugs
11、that disrupt cell membrane function,Inhibition of protein synthesis,Generally work at different stages of prokaryotic mRNA translation into proteins, like initiation, elongation (including aminoacyl tRNA entry, proofreading, peptidyl transfer and ribosomal translocation) and termination.) The antibi
12、otic only affects 70S ribosomes in the bacteria and does nothing for the 80S ribosomes in human.,Inhibition of protein synthesis,Macrolides Lincomycin Chloromycetin Tetracyclines Aminoglycosides,bind to 50s,bind to 30s,Quinolones Inhibit the DNA gyrase Interfer with DNA replication Rifampicin Inhibi
13、ts DNA-dependent RNA polymerase mRNA, Inhibitors of nucleic acid synthesis,Inhibition of folic acid synthesis,Antibiotics that mimic the structure of the specific substrate that the normal substrate is replaced and dont have contact with the enzyme which acts on a substrate to produce a certain meta
14、bolically important metabolite inside the cell.,Action of sulfanilamide,Antimicrobial resistance,Resistance: the inability to kill or inhibit the organism with clinically achievable drug concentrations,Antimicrobial resistance,Resistance may be innate (naturally resistant) Resistance may be acquired
15、 - mutation - acquisition of foreign DNA,Antimicrobial resistance,Factors which may accelerate the development of resistance - overuse / misuse of antibiotics inadequate levels of antibiotics at the site of infection duration of treatment too short overwhelming numbers of organisms,General mechanism
16、s of resistance,Inactivation / destruction of antibiotic: production of -lactamases Altered binding site: PBP Altered permeability: OprD Efflux (pumps) mechanisms,Acquired resistance,Mutation Transduction(转导）: phage Transformation（转化） Conjugation: plasmid,Resistance gene transmission,Resistance,MDR: Multi-drug resistance（多重耐药） MRSA(甲氧西林耐药金黄色葡萄球菌）; MRCNS（凝固酶阴性，耐甲氧西林表皮葡萄球菌和溶血葡萄球菌） PRSP：青霉素耐药肺炎链球菌 VRE：万古霉素耐药肠球菌,Resistance,-lactmase ：ESBL, Am
