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Pharmacodynamics of Antibiotics

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”. Concepts.

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Pharmacodynamics of Antibiotics

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  1. Pharmacodynamics of Antibiotics Hail M. Al-Abdely, MD

  2. Concepts • Pharmacokinetics • describe how drugs behave in the human host • Pharmacodynamics • the relationship between drug concentration and antimicrobial effect. “Time course of antimicrobial activity”

  3. Concepts • 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.

  4. 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.

  5. Control CFU Static Cidal Time Static versus Cidal

  6. 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?

  7. Can this antibiotic inhibit/kill these bacteria? • In vitro susceptibility testing Mixing bacteria with antibiotic at different concentrations and observing for bacterial growth.

  8. Conc MIC Time 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?

  9. 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

  10. 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)

  11. Persistent Effects • 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.

  12. 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.

  13. Patterns of Antimicrobial Activity • 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.

  14. 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.

  15. C-p C-p Concentration MIC AUC AUC Time PK/PD patterns

  16. Tobramycin Ticarcillin Log 10 CFU/ml Hours Ciprofloxacin

  17. Log 10 CFU/thigh 10 100 1000 1 10 100 1000 0 25 50 75 100 24hr AUC/MIC Peak/MIC Time above MIC Ceftazidime effect on K. pneumoniae thigh infection in neutropenic mice

  18. Log 10 CFU/thigh 10 100 1000 1 10 100 1000 0 25 50 75 100 24hr AUC/MIC Peak/MIC Time above MIC Temafloxacin effect on S. pneumoniae thigh infection in neutropenic mice

  19. Log 10 CFU/thigh Log 10 CFU/thigh 10 100 1000 10 100 1000 1 10 100 1000 1 10 100 1000 0 25 50 75 100 0 25 50 75 100 24hr AUC/MIC 24hr AUC/MIC Peak/MIC Peak/MIC Time above MIC Time above MIC Ceftazidime Temafloxacin

  20. 100 Penicillin Cephalosporins 80 60 40 Mortality% 20 0 0 20 40 60 80 100 Time above MIC% Survival of Animals infected with S. pneumoniae treated with cephalosporin and penicillin

  21. 100 80 60 40 Mortality% 20 0 1 10 100 1000 24hr AUC/MIC Survival of Animals infected with GN bacilli treated with Fluoroquinolones

  22. Human Data Percentage bacteriologic cure for ß-lactam agents against Streptococcus pneumoniae (black circle) and Haemophilus influenzae (white circle) in children with acute otitis media Craig WA, Andes W.. Pediatr Infect Dis J 1996;15:255-9.

  23. MIC Time Beta lactams

  24. C-p MIC Time Aminoglycosides

  25. C-p MIC Time Fluoroquinolones AUC

  26. C-p MIC Time Glycopeptides AUC

  27. Effects of PD on breakpoints Recommended for many antibiotics for S. pneumoniae

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