pk pd of antibiotics.pptx

While MIC is a good measure of antibiotic activity, it is static and reflects in vitro activity. PK and PD of the drug needs to be considered together with MIC if we wish to obtain an in vivo prediction of drug action and success.

1. Antibiotic Stewardship: Demystifyimg MIC, using PK PD aspects to improve patient care Prof. Ashok Rattan, MD, MAMS, INSA DFG, SEARO TA, WHO Lab Director (CAREC/PAHO) Adviser : PathKind Labs , Knowledge Forum, R & D, Quality

2. Discovery & Development of Anti- bacterials is one of the most important discovery of the 20 th Century                            

3. Power of antibiotics Disease Pre Antibiotic era deaths Deaths with antibiotics Change in deaths due to antibiotics CAP (1) 35% 10% - 25% HAP (2) 60% 30% - 30% Heart Infection (3) 100% 25% - 75% Brain Infections (4) > 80% < 20% - 60% Skin Infection (5) 11% < 0.5% -10% By comparison…. Treatment of heart attacks with aspirin or clot busting drugs (6) - 3% Ref.: (1) IDSA Position Paper. Clin Infect Dis 2008; 47 (S3): S 249 – 65 (2) IDSA/ACCP/ATS/SCCM position paper. CID 2010; 51 (S1): 51 – 3 (3) Kerr AJ. SABE Lancet 1935; 226: 383 – 4 (4) Waring et al. Am J Med 1948; 5: 402 – 18 (5) Spellberg et al CID 2009; 49: 383 – 91 (6) Lancet 1998; 351 : 233 – 41.

4. 1940 1950 1960 1970 1980 1990 2000 2002 2004 2006 2007 2008 2012 Introductions of New Antibiotic Classes Sulfas 1936 Penicillin 1940 Tetracycline 1949 Aminoglycosides 1950 Macrolides 1952 Glycopeptides 1958 Streptogramin 1962 Quinolones 1962 Oxazolidinone 2000 Daptomycin 2003 Tigecycline 2006 Telithromycin 2004 Doripenem 2007 Me too drugs Different Generations Ertapenem 2001 Ceftaroline 2010

5. “By the year 2000, nearly all experts agree that bacterial and viral diseases will have been virtually wiped out…” The futurists: looking toward year 2000 (Time magazine, february 25, 1966) US surgeon general William Stewart: “ The time has come to close the book on infectious diseases” (1969) Mankind has always had the benefit of “good” advice

6. 100 80 60 40 20 1980 1975 1985 1990 1995 2000 1997 VISA VRE PRSP MRSA MRSE Percentage of Pathogens Resistant to Antibiotics Increasing Incidence of Resistance in the US MRSE, MRSA, VRE, PRSP, GISA 1980-2006 VRSA 2006

7. We have a basic problem Resistance in important pathogens New and novel antibiotics New Antimicrobials

8. Problem of MDR Act of GOD Resistance arises as a mutation in the target gene Act of MAN Inappropriate use of antibiotic will provide selective pressure Inadequate Infection control practices also transfer of MDR from one to another

9. Consequences of antibiotic use Clinical cure Inhibition of non pathogenic bacteria Selection of resistant mutants Toxicity / side effects

10. PK / PD consideration & application Clinical cure Inhibition of non pathogenic bacteria Selection of resistant mutants Toxicity / side effects

11. The First Choice Diagnostic Laboratory

12. What the body does to the drug Dosage Regimen Time course of serum levels Time course of levels in tissues Time course of pharma & tox effect Time course of levels at site Time course of antimicrobial activity Absorption Distribution Metabolism Elimination Pharmacokinetics Pharmacodynamics What the drug does to the bacteria Pharmacology of Antimicrobial Therapy

13. PK/PD terminology & central role of MIC Serum Conc. (ug/ml) 16 8 4 2 1 0.5 0.25 0.12 0.06 32 C max MIC Time > MIC C max/ MIC AUC / MIC t > MIC

14. Patterns of antimicrobial activity In vitro activity Concentration dependent killing and prolonged persistent effect Seen with Aminoglycosides, Quinolones, daptomycin, ketolides, amphotericin B Goal of dosing: maximize concentration AUC/MIC and Cmax /MIC major parameters of efficacy

15. Patterns of antimicrobial activity Concentration independent killing Minimal to moderate persistent effects Seen with all b lactams, clindamycin, macrolides, oxazolidinones, Flucytosine Goal of dosing: Optimize duration t > MIC major parameter of efficacy

16. Experimental models to investigate PK/PD relationships: Overview Use neutropenic animals Evaluate 20 - 30 different dosing regimens (5 dose levels, 4-6 different intervals) Measure efficacy by change in Log 10 cfu per thigh or lung at end of 24 hours therapy Correlate efficacy with various PK/PD parameters (t > MIC, Cmax /MIC, 24 hours AUC/MIC)

17. The First Choice Diagnostic Laboratory

18. S. pneumoniae & Levofloxacin

19. PK/PD relationship is class dependent

20. Type of anti-microbial activity Time dependent or concentration independent killing T > MIC Penicillin Cephalosporins Carbapenems Monobactam Macrolides Clindamycin Oxazolidinones Glycylcyclines Flucytosine Concentration dependent killing AUC or Cmax /MIC Aminoglycosides Fluoroquinolones Metronidazole Daptomycin Ketolides Azithromycin Streptogramin Glycopeptides Amphotericin Fluconazole

21. Time serum conc. is above MIC (%) Mortality after 4 days of therapy (%) Craig W. Diagn Microbiol Infect Dis 1996; 25 :213–217. 20 40 60 80 100 20 40 60 80 100 Penicillins Cephalosporins Relationship between t ime > MIC and efficacy in animal infection models infected with S. pneumoniae

22. Levofloxacin PK/PD correlation

23. PK/PD Parameters & central role of MIC Serum Conc. (ug/ml) 16 8 4 2 1 0.5 0.25 0.12 0.06 32 C max MIC Time > MIC C max/ MIC AUC / MIC t > MIC

24. PK/PD parameters predictive of success Cmax / MIC > 10 AUC / MIC > 100 T > MIC > 40 % of dosing interval Variables affecting concentration : Volume of distribution (V d ) Clearance (Cl) T ½ = 0.693 x V d Cl

25. Maturity of Physiological Processes affecting Pharmacokinetics in Children Variable Neonates Age group reaching adult values Absorption 1. Gastric pH Increase child 2. Gastric emptying time Increase Child 3. Biliary function Decrease Infant 4. IM absorption Decrease Child 5. Skin permeability Increase child Distribution 1. Total body water Increase Late childhood 2. Total body fat & muscle mass Decrease Child 3. Total plasma binding proteins Decrease Early childhood

26. PK / PD Parameters of successful antimicrobial action Cmax /MIC or AUC /MIC >10 >100 Aminoglycosides Fluoroquinolones Metronidazole Daptomycin Ketolides Azithromycin Streptogramin Glycopeptides Amphotericin B Fluconazole T > MIC (>40%) Penicillin Cephalosporins Carbapenems Monobactam Macrolides Clindamycin Oxazolidinones Glycylcyclines Flucytosine

27. PK PD for new break points Epidemiological cut offs Probable Target Attainments PK of Imipenem Dosage 500 mgx4 1Gx4 Cmax (mg/L) 30 – 40 60 – 70 Cmin 0.25 – 0.5 0.5 – 1 Total body Clearance (L) 11 – 15 11 – 15 T ½ (hr) 1 1 Fraction Unbound 80 80 Volume of Distribution (L/kg) 14 – 15 14 – 15 PD of Imipenem GNB GPC % f T>MIC 25 – 40 15 – 20 (experimental) % f T>MIC 54 (clinical)

28. Potency of anti-TB drugs against M. tuberculosis Gatifloxacin

29. PK/PD correlation with efficacy T > MIC (>40%) Penicillin Cephalosporins Carbapenems Monobactam Macrolides Clindamycin Oxazolidinones Glycylcyclines Flucytosine AUC or Cmax /MIC >100 >10 Aminoglycosides Fluoroquinolones Metronidazole Daptomycin Ketolides Azithromycin Streptogramin Glycopeptides

30. Proof of the pudding is in the eating How to convert Good intention into reality ? Dr. Dharmendra Sharma Excel Program Will give free to Microbiologists interested in Using this

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32. It is not because things are difficult that we do not dare, It is because we do not dare that they are difficult Lucio Anneo Seneca (4 BC – 65 AD)