Pharmacodynamics of antibiotics

Antibiotics, Pharmacology

1. Pharmacodynamics of antibiotics Capt. Htet Wai Moe Resident Pharmacology

2. The time course of drug concentration is closely related to the antibiotic effect at the site of infection and to any toxic effects Pharmacodynamic factors include pathogen susceptibility testing, drug bactericidal versus bacteriostatic activity, drug synergism, antagonism and post-antibiotic effects Pharmacodynamic information is important for selection of optimal antibiotic dosage regimens

3. Pharmacodynamics “ W hat the drug does to the body ” Includes physiological and biochemical effects of the drug & MOA Integrates : organism susceptibility + patient pharmacokinetics

4. Antibiotic activity Bactericidal Kills the organism Examples : B lactams , Vancomycin, Fluroquinolones, Aminoglycosides, Daptomycin, metronidazole Bacteriostatic Inhibits the growth Requires aid of host defenses Relapses can occur after discontinuation of drug Examples: Macrolides, Clindamycin, Sulfonamides, Linezolid, chloramphenicol

5. Bacteriostatic vs Bactericidal activity Bacteriostatic and bactericidal agents are equivalent for treatment of most infectious disease in immunocompetent hosts Bactericidal agents should be selected over bacteriostatic ones in circumstances of impaired local or systemic host defenses

6. Bactericidal agents Concentration-dependent killing Killing action is concentration-dependent Rate and extent of killing increase with increasing drug concentration E.g. Aminoglycosides, Fluroquinolones

7. Bactericidal agents Time-dependent killing Bactericidal activity continues as long as serum concentrations are greater than the MBC Minimal serum conc of free drug present for 40 - 50 % of dosing interval is called pharmacodynamic breakpoint If MIC is below this breakpoint, then the drug is clinically effective (sensitive ) If MIC is above this breakpoint, the organism is resistant E.g. β lactams, Vancomycin

8. Site and Mechanism of Action of Antibiotics Inhibition of cell wall synthesis Alteration of cell membrane integrity Inhibition of ribosomal protein synthesis Suppression of DNA synthesis

9. Post-antibiotic effect Bactericidal drugs B acterial count reduces till conc above MBC When concentration falls below MBC, but remains above MIC – bacterial count remains stable or continues to decline 2 . Bacteriostatic drugs Levels above MIC – bacterial counts decline due to host factors ( immunity ) Below MIC – persistent antibacterial effects act

10. Post-antibiotic effect (PAE) A persistent antibacterial effect after a brief antibiotic exposure that occurs even in the absence of host defenses is termed PAE The organism may become more susceptible to phagocytes – post antibiotic leucocyte enhancement Concentration below MIC can alter bacterial morphology, slows bacterial growth rate and prolongs PAE

11. Mechanism of PAE Slow recovery after reversible nonlethal damage to cell structures Persistence of the drug at a binding site or within the periplasmic space The need to synthesize new enzymes before growth can resume

12. PAE (cont.) Most antibiotic possess significant in vitro PAE against susceptible gram-positive cocci Antibiotics with significant PAEs against susceptible gram-negative bacilli are limited to carbapenems and the agents that inhibit protein or DNA synthesis

13. PAE (cont.) In vivo PAEs usually much longer than in vitro PAEs Due to post-antibiotic leukocyte enhancement (PALE) and exposure of bacteria to subinhibitory antibiotic concentrations Efficacy of once-daily dosing regimens is in-part due to PAE

14. Concepts of MIC & MBC MIC (minimum inhibitory concentration) Defined as the minimal concentration of antibiotic that prevents the clear suspension of 10 5 CFU/ ml from becoming turbid after overnight incubation Turbidity signifies at least 10 times increase in bacterial density MBC (minimal bactericidal concentration) For Bactericidal drugs : same as MIC or upto 4 times MIC For Bacteriostatic drugs : many fold higher than MIC

15. Pharmacokinetic principles The PK parameters define only the serum level time course of an antibiotic They do not quantify the killing effect PK parameters : C max – the peak antibiotic concentration C min – the trough AUC – the area under serum concentration time curve

16. The PD parameters integrate organism susceptibility (MIC ) and PK parameters Define the killing effect PD parameters C max / MIC ratio T > MIC AUC 24 / MIC Post antibiotic effect Pharmacodynamic principles

17. AUC The area under concentration – time curve at a steady state over 24 hr period It is used as a reference value, if not stated, assumed to be of 24 hours T > MIC The cumulative percentage of a 24 hr. period that the drug concentration exceeds the MIC at a steady state

18. Patterns of antibiotic action Pattern of activity PK/PD parameter Goal of therapy Examples Type I Concentration dependent prolonged PAE AUC/MIC C max /MIC Maximize concentration Aminoglycoside Fluroquinolones Daptomycin Ketolides Type II Time dependent minimal PAE T>MIC Maximize duration of exposure Penicillins Carbapenems Cephalosporins Linezolids E.mycin Type III Time dependent prolonged PAE AUC/MIC Maximize amount of drug Azithromycin Clindamycin Tetracycline Vancomycin

19. Antimicrobial drug combinations Rationale for combination antibiotic therapy To provide broad-spectrum empiric therapy in seriously ill patients To treat polymicrobial infections To decrease the emergence of resistant strains To decrease dose-related toxicity To obtain enhanced inhibition or killing

20. Synergism and Antagonism Synergism > A + B Greater bactericidal activity with the combination than activity of either agents alone

21. Mechanism of Synergistic Action Blockade of sequential steps in a metabolic sequences E.g. Trimethoprim- sulfamethoxazole Inhibition of enzymatic inactivation E.g. β lactamase inhibitor drugs ( Sulbactam ) Enhancement of antimicrobial agent uptake E.g. Penicillin can increase the uptake of aminoglycosides by a number of bacteria

22. Mechanism of Antagonistic Action Inhibition of cidal activity by static agents Bacteriostatic agents can antagonize the action of bactericidal cell wall-active agents as cell wall-active agents require that the bacteria be actively growing and dividing Induction of enzymatic inactivation Some gram-negative bacilli possess inducible β lactamase β lactam antibiotics are potent inducers of β lactamase production If an inducing agent is combined with an intrinsically active but hydrolysable β lactam such as piperacillin , antagonism may result

23. Inoculum effect Significant increase in the MIC of an antibiotic when the number of organisms inoculated is increased Occurs with beta-lactam antibiotics in relation to beta-lactamase-producing bacteria Although certain antibiotics exhibit an IE, they are still capable of eradicating infections when administered appropriately Thus , the clinical significance of this laboratory phenomenon has yet to be elucidated

24. Pharmacodynamic differences in Antibiotic classes Penicillin & Beta lactams Primarily time dependent killing T > MIC is the most important determinant for beta lactam killing effect Longer exposure resulted in better killing effect as seen in E. coli

25. Aminoglycosides Concentration dependent killing effect Peak/MIC of > 8:1 is associated with treatment success They demonstrate 2-10 hr , cocentration dependent PAE for many GN organisms Pharmacodynamics differences in Antibiotic classes

26. Fluroquinolones C oncentration dependent killing Both peak/MIC & AUC/MIC : linked to efficacy Estimated AUC/MIC of 350-450 – linked with maximal killing for ciprofloxacin AUC/MIC of 125 -250 demonstrated optimal killing levofloxacin in UTI, demonstrated optimal efficacy with peak/MIC of 12.2 Pharmacodynamics differences in Antibiotic classes

27. Miscellaneous nomenclature Pharmacodynamic indices and related AUBC Area under bactericidal curve Calculated over 24 hrs at steady state AUIC Area under inhibitory curve Reserved for those cases where actual inhibitory titers have been measured

28. Post E xposure E ffects In vitro PAE Period of suppression of bacterial growth after short exposure of organisms to antibiotic Sub MIC effect Any effect of antibiotic with concentration below MIC Post antibiotic sub-MIC effect Effect of sub MIC drug concentration on bacterial growth following serial exposure to drug concentration exceeding MIC Post MIC effect The difference in time for number of antibiotic exposed bacteria vs controls to increase 1 log values after drug concentration falls below the MIC

29. Terms under consideration Mutation prevention concentration Concentration preventing growth at a high inoculum (>10 9 ) using agar dilution technology Due to higher inoculum, higher chances of selecting mutants Mutant selection window Difference between MIC and MPC for a given organism Mutant prevention index Ration between MPC and MIC

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