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Pamela A. Moise-Broder Alan Forrest Jerome J. Schentag

Relationship between Time to Eradication in vivo & Bactericidal Activity in vitro of Vancomycin for MRSA Infections. Pamela A. Moise-Broder Alan Forrest Jerome J. Schentag CPL Associates, LLC; University of the Pacific; SUNY Buffalo School of Pharmacy. Objective.

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Pamela A. Moise-Broder Alan Forrest Jerome J. Schentag

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  1. Relationship between Time to Eradication in vivo & BactericidalActivity in vitro of Vancomycin for MRSA Infections Pamela A. Moise-Broder Alan Forrest Jerome J. Schentag CPL Associates, LLC; University of the Pacific; SUNY Buffalo School of Pharmacy

  2. Objective • Relationship between time to MRSA eradication in vivo and the in vitro bactericidal activity of vancomycin • Activity of vancomycin in vitro • Probability of microbiologic success • All-cause mortality

  3. Methods • 34 patients with MRSA bacteremia • Free of endocarditis, osteomyelitis or CNS infection • Vancomycin monotherapy • Target 1hr “peak” concentrations, 28-32 g/mL • Target trough concentrations, 8-12 g/mL • 24-h time-kill curves performed • Initial inoculum ~107 to 108 CFU/mL • Vancomycin concentration: 16 μg/mL

  4. Patient & Organism Characteristics

  5. Outcomes by Bactericidal Activity

  6. Time to Bacterial Eradication by Reduction in log10 CFU/mL Grouped by Tree-based Modeling 100 Reduction in log10 CFU/mL: <2.5 (n=13) >2.5 (n=21) 80 60 % Culture Positive 40 20 0 0 10 20 30 40 p=0.014 Time (Days)

  7. Non-Linear Relationship:Sigmoid Emax Model • P = Probability of coming to the event (eradication) • Po = Probability of success as LogDec approaches 0 • Pmax = Asymptotic maximum probability of success • H = Hill’s constant (reflects steepness) • LogDec = log10 decrease at 24 hours • LDm = LogDec giving ½ maximal effect

  8. Non-Linear Regression Po= 0% Pmax= 86% LogDec = log10↓ at 24 hr H=6 LDm=2.4 r2 = 85%, p<0.001

  9. 100 80 60 46 Mortality Rate (%) 40 14 20 0 <2.5 LD >2.5 LD (n=13) (n=21) 30-Day All Cause Mortality • 30-day all cause mortality was higher in patients with MRSA isolates having <2.5 log10 reduction in CFU/mL at 24 hours (p=0.041) • 6/13 (46%) for <2.5 LD • 3/21 (14%) for >2.5 LD P=0.041

  10. MIC Values vs. Outcomes: What MIC is “Susceptible”? p=0.028

  11. Conclusions • In patients with MRSA bacteremia, in vitro activity was significantly related to: time to bacterial eradication, probability of microbiologic success and all-cause mortality. • Persistent bacteremia may occur despite vancomycin treatment, with “normal” plasma drug concentrations, against isolates with a “sensitive” MIC, but which had less than a 2.5 reduction in log10 CFU/mL by 24 hr, in vitro.

  12. Relationship between Time to Eradication in vivo & BactericidalActivity in vitro of Vancomycin for MRSA Infections Pamela A. Moise-Broder, Alan Forrest, Jerome J. Schentag CPL Associates, LLC; UOP; SUNY Buffalo School of Pharmacy

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