1. S. Balakrishnan Department of Pharmacology, Pondicherry Institute of Medical Sciences

2. Absorption zHow long it takes after absorption till drug is detectable? (lag time or t lag ). zHow long it takes before peak – serum or plasma concentration are achieved (t max ). zWhat is the peak serum concentration? (C max )

3. Absorption problems 1 zVomiting patient zKetoconazole needs acid yPatients on proton pump inhibitors (PPI), H 2 blockers yTake with Coca Cola

4. Absorption problems-2 zQuinolones (ciprofloxacin) yBind to antacids, sucralfate ySolution: PPI or H 2 blocker zDidanosine (ddI) unstable in acid; so: antacid in the tablet zDrugs taken with (out) food

5. Distribution

6. Changing V d zGentamicin distributes into space resembling extracellular fluid (ECF) zECF larger in shock, drops with recovery zGentamicin levels lower in shock, rise with recovery

7. Limited distribution-1 zMost antibiotics well distributed, but... zNot always intracellular zNot always to: Central nervous system EyeProstateBone Placenta Breast milk

8. Limited distribution-2 zMeningitis: Higher doses to get adequate CNS levels zProstatitis: Prefer trimethoprim- sulfamethoxazole, quinolones

9. Intracellular penetration zpH- only basic drugs penetrate zBeta lactams ansd AGs- NO zQuinolones and macrolides-YES

10. Distribution to placenta & breast milk zHard to predict zPractical matter: look up data on a drug

11. Plasma protein binding Unbound drug exerts effect. Unbound drug diffuses into extra vascular sites. Slows rate of elimination - & t ½ - longer dosing interval. Significant only if > 80%

12. Extensive protein binding z“Good”: Allows slow, steady release of heavily bound drug, e.g. ceftriaxone z“Bad”: since less “free” drug available for bacteria, e.g. Ceftriaxone zReality: Only one factor

13. Protein binding perinatal issue zSulfonamide displaces unconjugated bilirubin from serum protein zPerinatally, high unbound bilirubin causes kernicterus & brain damage zDon’t use sulfonamides in 3 rd trimester, neonate

14. Biotransformation zPhase I zPhase II

15. Biotransformation: CYP 450 zOften hepatic microsomal enzymes (CYP 450) zRates vary up to 6-fold from one person to the next zEnzymes genetically determined

16. Biotransformation: HIV & TB zRifampin (for TB) induces CYP450 3A4 & reduces levels of indinavir (for HIV) zIndinavir inhibits CYP450 3A4 & increases levels of rifampin zSolution: Low dose rifabutin, high dose indinavir

17. Biotransformation: ketoconazole, erythromycin zKetoconazole, erythomycin inhibit CYP450 3A4 zSlows metabolism of cisapride, levels rise, causes torsade de pointes, death zCisapride highly restricted

18. Bioavailability zIV to oral switch

19. Elimination Renal vs non renal clearance Elimination t 1/2

20. General concept: Elimination t 1/2 zHalf-life zTime for serum concentration to fall 50% zConstant if a person is stable zVaries from person to person

21. Concentration- time curve

22. Extravascularconcentration zExtracellular sites reached via diffusion from blood zIntracellular fluid zExtracellular sites with restrictive barriers zUrine

23. General concept: Clearance zQuantitative measure of body’s ability to eliminate the drug zIncludes various forms of excretion

24. Antimicrobial concept: MIC, MBC zMIC: Minimum inhibitory concentration (to inhibit growth in vitro) zMBC: Minimum bactericidal concentration (to kill in vitro) zMIC 90 : Inhibits 90% of strains

25. Break point zIs in part concentration which can be achieved at the site of infection zSusceptible: MIC < breakpoint zResistant: MIC > breakpoint

26. Post-antibiotic effect zPersistence of effect (inhibition of growth or killing) after drug removed (or level below MIC) z“PAE” + pharmacokinetics affects dosing strategy

27. Post-antibiotic effect zPost antibiotic sub – MIC effects zPost antibiotic – leukocyte effects

28. Important PK/PD Parameters Time above MIC Time Antibiotic concentration (ug/ml) 2 Drug A Drug B A B 4 6 8 0 Important PK/PD Parameters Drug A Drug B B Proportion of the dosing interval when the drug concentration exceeds the MIC Time above MIC:

29. Important PK/PD Parameters Antibiotic concentration Time Area under the curve over MIC PEAK AUC/MIC is the ratio of the AUC to MIC Peak/MIC is the ratio of the peak concentration to MIC

33. PK/PD and Antimicrobial Efficacy  2 main patterns of bacterial killing  Concentration dependent  Aminoglycosides, quinolones, macrolides, azalides, clindamycin, tetracyclines, glycopeptides, oxazolidinones  Correlated with AUC/MIC, Peak/MIC  Time dependent with no persistent effect  Beta lactams  Correlated with Time above MIC(T>MIC)

34. Goal of therapy based on PK/PD Pattern of Activity AntimicrobialsGoal of therapy and relevant PK/PD Parameter Concentration dependent killing AGs, Quinolones, Daptomycin, ketolides, Macrolides, azithro-mycin, clindamycin,streptogramines,tetracyclines, glycopeptides, oxazolidinones Maximise concentrations; AUC/MIC, peak/MIC Use high doses; daily dosing for some agents Time dependent killing with no persistent effects Beta lactamsMaximise duration of exposure; T>MIC Use more frequent dosing; longer infusion times including continuous infusion

35. Pattern of ActivityAntibiotics Goal of Therapy PK/PD Parameter Type I Concentration- dependent killing and Prolonged persistent effects Aminoglycosides Daptomycin Fluoroquinolones Ketolides Maximize concentratio ns 24h-AUC/MIC Peak/MIC Type II Time-dependent killing and Minimal persistent effects Carbapenems Cephalosporins Erythromycin Linezolid Penicillins Maximize duration of exposure T>MIC Type III Time-dependent killing and Moderate to prolonged persistent effects. Azithromycin Clindamycin Oxazolidinones Tetracyclines Vancomycin Maximize amount of drug 24h-AUC/MIC

37. Magnitude of PK/PD measures predictive of efficacy for select antibiotic classes versus some pathogens DrugPK/PD variableMagnitude of variable correlated with efficacy Beta lactamsTime > MIC>40-50% of dosing interval Quinolones vs Gram – ve bacteria 24- hour AUC:MIC>90-125 Quinolones vs S. pneumoniae 24-hour AUC:MIC>30-40

38. Aminoglycoside pharmacodynamics in vivo

39. Vancomycin Outcome vs 24h-AUC/ MIC ratio 24h- AUC/MIC ratio SatisfactoryUnsatisfactory < 1254 (50%)4 > 12571 (97%)2

40. 24h-AUC/MIC ratio Microbiological Response < 33.7(64%) > 33.7(100%) Fluoroquinolone PK/PD vs S. pneumoniae

41. PK/PD of beta-lactams and macrolides in otitis media

42. Concentration dependent killing….azithromycin 24 hour AUC/ 25-immunocompetent patients 24 hour AUC/ 125- immnocompromised patients 24 hour AUC mg.h/ L -3 mg.h/L Macrolide susceptible S.pneumoniae MIC 90 0.12 mg/L H. Influenzae MIC 90 1-2mg/L Macrolide resistant S. pneumoniae MIC 90 >8mg/L

43. PK/PD breakpoints of parenteral beta-lactams based on serum concentrations present for >40-50% of dosing regimens shown and MIC 90 values of isolates of S. pneumoniae DrugDosing regimenS.Pneumonia e MIC 90 mg/L PK/PD breakpoint mg/L Pen G2 X 10 6 U qid44 Ampicillin1 g qid42 Cefuroxime0.75 g tid84 Cefotaxime1 g tid22 Ceftriaxone1 g qd22 Cefepime1 g bid44 Ceftazidime1 g tid328 Meropenem0.5 g tid21

44. Dosage Adjustment Needed in Renal Impairment I Acyclovir ethambutol aminoglycosides,Penicillins (except antistaph) aztreonam,Quinolones cephalosporins (except cefaperazone & ceftriaxone) clarithromycin,Carbapenems

45. daptomycin,Vancomycin doripenem, emtricitabine, famiclovir, ertapenem, flucytosine, ganciclovir, imipenem, meropenem, lamivudine, foscarnet, fluconazole, Dosage Adjustment Needed in Renal Impairment II

46. C/I in renal failure Methanamine Nalidixic acid Nitrofurantoin Sulfonamides Tetracyclines except doxy & minocycline

47. Dosage adjust in hepatic impairment Chloramphenicol Clindamycin Erythromycin Metronidazole Tigecycline