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Antimicrobial Pharmacodynamics: Concepts for Rational Selection and Dosing of Antibiotics

Antimicrobial Pharmacodynamics: Concepts for Rational Selection and Dosing of Antibiotics. Effect of Adequate Antimicrobial Therapy For Bloodstream Infections on Mortality. P<0.001. Ibrahim E, et al. Chest 2000; 118: 146-155.

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Antimicrobial Pharmacodynamics: Concepts for Rational Selection and Dosing of Antibiotics

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  1. Antimicrobial Pharmacodynamics: Concepts for Rational Selection and Dosing of Antibiotics

  2. Effect of Adequate Antimicrobial Therapy For Bloodstream Infections on Mortality P<0.001 Ibrahim E, et al. Chest 2000; 118: 146-155.

  3. Effect of Adequate Antimicrobial Therapy For Bloodstream Infections on Mortality OSSA=oxacillin-susceptible S. aureus; CNS=coagulase-negative staphylococci; VRE=vancomycin resistant enterococci Ibrahim E, et al. Chest 2000; 118: 146-155.

  4. What does “S” Mean? • Susceptible - Isolates are inhibited by the usually achievable concentrations of antimicrobial agent when the recommended dose is used for the site of infection. • Intermediate – Implies clinical efficacy in the areas where drugs are physiologically concentrated or when higher than normal dosages of drugs can be used • Resistant – Isolates are not inhibited by the usually achievable concentrations of the agent with normal dosage schedules CLSI. M-100-S16. January 2006

  5. Pharmacokinetics • Absorption • Distribution • Metabolism • Elimination “PK is what the body does to the drug”

  6. Pharmacokinetics Serum/Tissue Concentrations Half-Life Pathogen Susceptibility MIC/MBC Pharmacodynamics Peak/MIC AUC/MIC Time > MIC Eradication/Cure

  7. Pharmacodynamic Interactions Peak/MIC AUC/MIC Concentration MIC Time>MIC Time

  8. Concentration Dependent vs. Concentration Independent Bacterial Killing Tobramycin Ciprofloxacin Ticarcillin Time (hours) Craig WA, et al. Scand J Infect Dis, 1991; Suppl (74)

  9. Optimizing Antimicrobial Therapy Concentration at Infection Site Host Factors PK PD Bacterial Killing Pathogen MIC/MBC Antibiotic Outcome

  10. Pharmacokinetic-Pharmacodynamic Indices Correlating with Efficacy

  11. In-vitro Pharmacodynamic Models

  12. Murine Thigh Infection Pharmacodynamic Model Antimicrobial Cyclophosphamide Organism 107 CFU CFU determination Bacteriostatic dose Pharmacokinetic parameters 2 hours Vesga A, et al. 37th ICAAC. 1997.

  13. b-lactams

  14. Correlation of PK/PD Parameters With Effect of Cefotaxime Against K. pneumoniae in Lungs of Neutropenic Mice Peak/MIC 24-Hr AUC/MIC T>MIC Craig WA. Diagn Microbiol Infect Dis 1995: 22:89-96

  15. Relationship Between Time Serum Levels Exceed the MIC and Mortality for B-Lactams Against S. pneumoniae Penicillins Cephalosporins Craig WA. Diagn Microbiol Infect Dis 1996:25:213-7

  16. Craig WA. Diagn Microbiol Infect Dis 1996:25:213-7

  17. Relation Between PD Parameters and Efficacy for Ticarcillin against P. aeruginosa 24-Hr AUC/MIC Peak/MIC T>MIC Vogelman B., et al. J Infect Dis 1988. 158(4).

  18. What %T>MIC is our target for β-lactams? “Static” dose 1 log 2 log 3 log 24-Hr AUC/MIC Peak/MIC T>MIC Vogelman B., et al. J Infect Dis 1988. 158(4).

  19. b-lactam Pharmacodynamics Gunderson BW, et al. Pharmacotherapy. 2001 Nov;21(11 Pt 2):302S-318S

  20. Concentration Time Profile: Antibiotic Y MIC=2 %T>MIC >90% DI

  21. Concentration Time Profile: Antibiotic Y (q12h) MIC=8 %T>MIC=50% DI

  22. Concentration Time Profile: Antibiotic Y (q8h) MIC=8 %T>MIC>90% DI

  23. Continuous Infusion Beta-lactams Beta-lactam Serum Concentrations Intermittent Continuous MIC MIC Time (h)

  24. Cefamandole: Continuous vs. Intermittent infusion p=NS Bodey, GP, et al. Am J Med 1979. 67.

  25. Cure Rate of Infections in Persistently Febrile Neutropenic Patients p=0.03 Bodey, GP, et al. Am J Med 1979. 67.

  26. Fluoroquinolones

  27. Correlation of PK/PD Parameters With Effect of Levofloxacin Against S. pneumoniae in Thighs of Neutropenic Mice 24-Hr AUC/MIC Peak/MIC T>MIC Handbook of Experimental Pharmacology. Vol 127: Quinolone Antibacterials. 1998

  28. Pharmacodynamic Interactions Peak/MIC AUC/MIC Concentration MIC Time>MIC Time

  29. Relationship Between 24-Hour AUC/MIC and Mortality for Fluoroquinolones AgainstS. pneumoniae Craig, WA 37th IDSA, 1999 Clin Infect Dis. (in press)

  30. Relationship Between 24-Hour AUC/MIC and Mortality for Fluoroquinolones Against Gram-Negative Bacilli in a Murine Model Craig, WA 37th IDSA, 1999 Clin Infect Dis. (in press)

  31. Relationship Between AUC24/MIC and Efficacy of Ciprofloxacin in Patients with Serious Bacterial Infections Forrest A, et al. AAC, 1993; 37: 1073-1081

  32. Fluoroquinolone Pharmacodynamics: S. pneumoniae Gunderson BW, et al. Pharmacotherapy. 2001 Nov;21(11 Pt 2):302S-318S

  33. Fluoroquinolone Pharmacodynamics: Gram Negative Bacilli Gunderson BW, et al. Pharmacotherapy. 2001 Nov;21(11 Pt 2):302S-318S

  34. Aminoglycosides

  35. Max Peak/MIC Ratio and Clinical Response with Aminoglycosides Moore,et al. J Inf Disease, 1987; 155(1): 93-98

  36. Pharmacodynamic Interactions Peak/MIC AUC/MIC Concentration MIC Time>MIC Time

  37. Aminoglycoside Pharmacodynamics: Human Studies Moore,et al. J Inf Disease, 1987; 155(1): 93-98 Deziel-Evans LM, et al. Clin Pharm 1986; 5:319-324 Nicolau DP, et al. Antimicrob Agents Chemother 1995; 39:650-5

  38. Methods for AG Dosing

  39. Single Daily Dosing Aminoglycosides: Efficacy Bailey TC, et al. Clin Infect Dis 1997; 24: 786-95. Zaki M, Goetz MB. Clin Infect Dis 1997; 24: 796-809

  40. Single Daily Dosing Aminoglycosides: Toxicity Bailey TC, et al. Clin Infect Dis 1997; 24: 786-95. Zaki M, Goetz MB. Clin Infect Dis 1997; 24: 796-809

  41. Extended Interval Dosing of Aminoglycosides Clin Infect Dis 2000 Mar;30(3):433-9 National survey of extended-interval aminoglycoside dosing (EIAD). Chuck SK, Raber SR, Rodvold KA, Areff D. • 500 acute care hospitals in the United States • EIAD adopted in 3 of every 4 acute care hospitals • 4-fold increase since 1993 • written guidelines for EIAD in 64% of all hospitals • rationale • 87.1% : equal or less toxicity, • 76.9% : equal efficacy • 65.6% :cost-savings • dose: > 5 mg/Kg • 47% used extended interval in case of decline in renal function (38% with Hartford nomogram)

  42. Optimal Pharmacodynamic Indices Craig WA. Infect Dis Clin N Am 2003. 17:479-501 Gunderson BW, et al. Pharmacotherapy 2001. 21: 302S-318S

  43. Conclusions • There are associations between antibiotic concentrations and microbiologic effects. • “WHAT CONCENTRATION AM I GOING TO ACHIEVE WITH A GIVEN DOSE AND HOW DOES THIS CONCENTRATION RELATE TO THE CONCENTRATION NEEDED TO INHIBIT/KILL IN VITRO” • These associations are dependent on the organisms and the antibiotic class. • GN vs GP • CEPHALOSPORINS/PENICILLINS/CARBAPENEMS • Investigations have led to new knowledge and application of these principles to optimizing antibiotic doses. • NEW DRUGS COMING TO MARKET • WHAT ABOUT OLDER DRUGS?? • AMINOGLYCOSIDES • CONTINUOUS INFUSION B-LACTAMS • Organisms can be susceptible (by MIC) to an antibiotic that can not kill the organism. • P. AERUGINOSA • FLUOROQUINOLONES & PIPERACILLIN/TAZOBACTAM • Additional studies evaluating the outcome of patients are needed to refine these principles.

  44. Selection of Antimicrobial Therapy I think your patient needs Imipenem 1gmq6h

  45. Impact of PD on Outcomes Examples of Drug-Bug Combinations with Low Conc:MIC Ratios Staphylococcus sp. cephalosporins, FQ, vancomycin Streptococcus sp. FQ, oral beta-lactams Enterobacter sp. 3rd Generation cephalosporins Pseudomonas sp. Beta-lactams, FQ, aminoglycosides Acinetobacter sp. Beta-lactams, FQ * May be unlikely to achieve optimal PD targets

  46. Dose t1/2 100 %T>MIC = ln ----------- * ------ * ------- Vd * MIC 0.693 DI Dose t1/2 24 AUC24/MIC = ----------- * ------ * ------- Vd * MIC 0.693 DI Mathematical Expression of Pharmacodynamic Indices Dose (mg) DI = Dosing Interval (q6h, DI=6) t1/2 = Half life of the Drug (hr) Vd = Apparent Volume of Distribution (Liters/kg) MIC = Minimum Inhibitory Concentration (mg/L)

  47. Pharmacokinetic Changes in Critically Ill

  48. 13 patients with CrCl>50 Received Cefepime 2gm x 1 dose Vd Mean: 21.8 + 5.1 L Range: 16.2 L – 31.4 L t1/2 Mean: 3 + 1.2 hours Range: 1.5 – 5.6 hrs Cefepime Pharmacokinetics in Critically Ill Adults with Sepsis

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