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

2. Concepts Pharmacokinetics Pharmacodynamics
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 hrs incubation.
Minimum Bacteriocidal Concentrations.
The lowest concentration of an antibiotic required to kill 99.9% bacterial growth after 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. Static versus Cidal
CFU
Time
Control
Static
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.

9. In vitro offers some help
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?
Time
Conc
MIC

10. 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

11. 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)

12. 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.

13. 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.

14. 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.

15. 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.

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

17. Tobramycin
Hours
Log 10 CFU/ml
Ticarcillin
Ciprofloxacin

18. Ceftazidime effect on K. pneumoniae thigh infection in neutropenic mice
Log 10 CFU/thigh
24hr AUC/MIC
Peak/MIC
Time above MIC

19. Temafloxacin effect on S
Temafloxacin effect on S. pneumoniae thigh infection in neutropenic mice
Log 10 CFU/thigh
24hr AUC/MIC
Peak/MIC
Time above MIC

20. Ceftazidime Temafloxacin Log 10 CFU/thigh 24hr AUC/MIC Peak/MIC
24hr AUC/MIC
Peak/MIC
Time above MIC
Ceftazidime
Log 10 CFU/thigh
24hr AUC/MIC
Peak/MIC
Time above MIC
Temafloxacin

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

22. Survival of Animals infected with GN bacilli treated with Fluoroquinolones
Mortality%
24hr AUC/MIC 60 40 80 20
100

23. 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.

24. Beta lactams
MIC
Time

25. Aminoglycosides
MIC
Time
C-p

26. Fluoroquinolones
MIC
Time
C-p
AUC

27. Glycopeptides
MIC
Time
C-p
AUC

28. Effects of PD on breakpoints Recommended for many antibiotics for S
Effects of PD on breakpoints Recommended for many antibiotics for S. pneumoniae
Drug
Old NCCLS Breakpoint
PD (T>MIC>40%)
New NCCLS Breakpoints
Amoxicillin
0.5 2
Cefaclor -
0.5-1 1
Cefprozil
1-2
Cefpodoxime
Cefuroxime