抗生素的药效动力学pharmacodynamicsofantibiotics课件

Pharmacodynamics of Antibiotics,Hail M. Al-Abdely, MD,Concepts,Pharmacokinetics describe how drugs behave in the human host Pharmacodynamics the relationship between drug concentration and antimicrobial effect. “Time course of antimicrobial activity”,Minimum Inhibitory Concentration (MIC) The lowest concentration of an antibiotic that inhibits bacterial growth after 16-20 hrs incubation. Minimum Bacteriocidal Concentrations. The lowest concentration of an antibiotic required to kill 99.9% bacterial growth after 16-20 hrs exposure. C-p Peak antibiotic concentration Area under the curve (AUC) Amount of antibiotic delivered over a specific time.,Concepts,Antimicrobial-micro-organism interaction,Antibiotic must reach the binding site of the microbe to interfere with the life cycle. Antibiotic must occupy “sufficient” number of active sites. Antibiotic must reside on the active site for “sufficient” time. Antibiotics are not contact poisons.,Static versus Cidal,Questions,Can this antibiotic inhibit/kill these bacteria? Can this antibiotic reach the site of bacterial replication? What concentration of this antibiotic is needed to inhibit/kill bacteria? Will the antibiotic kill better or faster if we increase its concentration? Do we need to keep the antibiotic concentration always high throughout the day?,Can this antibiotic inhibit/kill these bacteria?,In vitro susceptibility testing Mixing bacteria with antibiotic at different concentrations and observing for bacterial growth.,What concentration of this antibiotic is needed to inhibit/kill bacteria?,In vitro offers some help Concentrations have to be above the MIC. How much above the MIC? How long above the MIC?,Patterns of Microbial Killing,Concentration dependent Higher concentration greater killing Aminoglycosides, Flouroquinolones, Ketolides, metronidazole, Ampho B. Time-dependent killing Minimal concentration-dependent killing (4x MIC) More exposure more killing Beta lactams, glycopeptides, clindamycin, macrolides, tetracyclines, bactrim,Persistent Effects,Persistent suppression of bacterial growth following antimicrobial exposure. Moderate to prolonged against all GM positives (In vitro) Moderate to prolonged against GM negatives for protein and nucleic acid synthesis inhibitors. Minimal or non against GM negatives for beta lactams (except carabapenems against P. aeruginosa),Post-antibiotic sub-MIC effect. Prolonged drug level at sub-MIC augment the post-antibiotic effect. Post-antibiotic leukocyte killing enhancement. Augmentation of intracellular killing by leukocytes. The longest PAE with antibiotics exhibiting this characteristic.,Persistent Effects,Patterns of Antimicrobial Activity,Concentration dependent with moderate to prolonged persistent effects Goal of dosing Maximize concentrations PK parameter determining efficacy Peak level and AUC Examples Aminoglycosides, Flouroquinolones, Ketolides, metronidazole, Ampho B.,Time-dependent killing and minimal to moderate persistent effects Goal of dosing Maximize duration of exposure PK parameter determining efficacy Time above the MIC Examples Beta lactam, macrolides, clindamycin, flucytosine, linezolid.,Patterns of Antimicrobial Activity,Patterns of Antimicrobial Activity,Time-dependent killing and prolonged persistent effects Goal of dosing Optimize amount of drug PK parameter determining efficacy AUC Examples Azithromycin, vancomycin, tetracyclines, fluconazole.,PK/PD patterns,Tobramycin,Ciprofloxacin,Ceftazidime effect on K. pneumoniae thigh infection in neutropenic mice,Temafloxacin effect on S. pneumoniae thigh infection in neutropenic mice,Ceftazidime,Temafloxacin,Survival of Animals infected with S. pneumoniae treated with cephalosporin and penicillin,Survival of Animals infected with GN bacilli treated with Fluoroquinolones,Percentage bacteriologic cure for -lactam agents against Streptococcus pneumoniae (black circle) and Haemophilus influenzae (white circle) in children with acute otitis media,Crai