1. 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

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 ~10 7 to 10 8 CFU/mL –Vancomycin concentration: 16 μg/mL

4. Patient & Organism Characteristics Characteristic (N=34)Mean + SD (Median) Age (years)66 + 17 (70) Male sex, n (%)23 (68%) ICU, n (%)17 (50%) CrCL (mL/min)62 + 36 (58) Vancomycin MIC 0.5  g/mL, n (%) 13 (38%) 1.0  g/mL, n (%) 7 (21%) 2.0  g/mL, n (%) 14 (41%) Log 10 ↓ CFU/mL at 24 h 2.84 + 0.99 (2.81)

5. Outcomes by Bactericidal Activity Reduction in log 10 CFU/mL N Median DTE Eradication Rate by EOT <2.006---0/6 (0%) 2.00 – 2.74107.5 days5/10 (50%) 2.75 – 3.50126.5 days8/12 (67%) >3.5065.5 days5/6 (83%)

6. Time to Bacterial Eradication by Reduction in log 10 CFU/mL Time (Days) % Culture Positive 010203040 0 20 40 60 80 100 p=0.014 Reduction in log 10 CFU/mL: <2.5 (n=13) >2.5 (n=21) Grouped by Tree-based Modeling

7. Non-Linear Relationship: Sigmoid Emax Model P = Probability of coming to the event (eradication) P o = Probability of success as LogDec approaches 0 P max = Asymptotic maximum probability of success H = Hill’s constant (reflects steepness) LogDec = log 10 decrease at 24 hours LD m = LogDec giving ½ maximal effect

8. Non-Linear Regression P o = 0% P max = 86% LogDec = log 10 ↓ at 24 hr H=6 LD m =2.4 r 2 = 85%, p<0.001

9. 30-Day All Cause Mortality 30-day all cause mortality was higher in patients with MRSA isolates having <2.5 log 10 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 46 14 0 20 40 60 80 100 <2.5 LD (n=13) >2.5 LD (n=21) Mortality Rate (%)

10. MIC Values vs. Outcomes: What MIC is “Susceptible”? Vancomycin MIC Treatment Success Treatment Failure 0.5  g/mL, n (%) 8 (62%)5 (38%) 1.0  g/mL, n (%) 4 (57%)3 (43%) 2.0  g/mL, n (%) 2 (14%)12 (86%) 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 log 10 CFU/mL by 24 hr, in vitro.

12. 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; UOP; SUNY Buffalo School of Pharmacy