802. Optimal Vancomycin Dosing: How Much, How Often?
Session: Poster Abstract Session: Antimicrobial Agents: PK/PD Studies
Friday, October 9, 2015
Room: Poster Hall
Posters
  • 8887_Vancomycin_IDWeek_2015.pdf (1.2 MB)
  • Background: For Staphylococcus aureus, guidelines indicate vancomycin trough concentrations of 15-20 µg/mL should correspond to AUC24:MIC ratio of 400 for MIC = 1 µg/mL.  However, targets of 360 and 373 have also been proposed, and data are scarce linking trough concentrations to measured AUCs.  For q8h and q12h dosing, we modelled the association between vancomycin plasma AUCτ to troughs, predicted trough values at which AUC24:MIC optima would be met, and explored the impact of MIC and target ratio selection on the Probability of Target Attainment (PTA).

    Methods: Two cohorts with preserved renal function (eGFR 107.0±6.8 vs 122.2±36.2 mL/min/1.73 m2, P=0.38), dosed q8h (N=11) or q12h (N=6), were sampled after single steady-state doses (12.2±3.5 vs. 12.9±1.7 mg/kg, P=0.60).  Plasma concentrations at nominal sampling times of 0, 0.5, 2, 4, 8 and 12 hours (for q12h) after infusion were determined by HPLC.  AUC24 was extrapolated from AUCτ, determined by non-compartmental PK.  Linear regression modelled trough and AUC24.  Troughs satisfying AUC24:MIC targets (360, 373 and 400) were calculated.  PTA for targets were determined by 10,000-subject Monte Carlo simulation using cohort AUC24 values and EUCAST vancomycin MIC distributions for S. aureus (N=88,748).  Alternate dosing was simulated using population PK parameters.

    Results: Subjects were similar except for 24h dose (3.5±0.7 vs 2.2±0.3 g, P=0.0002).  For q8h and q12h dosing, AUC24 was modelled by [(21.1 * trough) + 173.8, R2=0.68] and [(32.1 * trough) + 52.5, R2=0.95] respectively.  For q8h/q12h dosing, troughs to achieve AUC24 of 400 µg•h/mL were 10.7/16.5 µg/mL.  In contrast to q12h dosing, 15-20 µg/mL troughs from q8h dosing met targets up to MIC 1.5 µg/mL.  For AUC24:MIC = 400, PTA from q8h/q12h dosing was 81.8%/72.1% (MIC 0.5 µg/mL), 56.6%/54.6% (MIC 1 µg/mL), and 8.2%/15.0% (MIC 2 µg/mL).  1.6 g q12h was the lowest q12h dose predicted to reach AUC24 ≥400. In contrast to the effect of MIC, the specific AUC24:MIC target had minimal impact on PTA.

    Conclusion: Trough-based prediction of AUC24 depends on the dose interval, which in part determines the total daily dose.  AUC24:MIC targets can be met with lower troughs using q8h dosing compared to q12h dosing, which allows for treatment of higher-MIC organisms.  In our patients, 1.6 g q12h is predicted to yield a similar AUC24 to 1 g q8h. The MIC has a greater impact on the Probability of Target Attainment than which target value is selected.

    Kevin S. Akers, MD, FIDSA1,2,3, Krista L. Niece, PhD1, Jason M. Cota, PharmD, MSc4, Kevin K. Chung, MD1,2 and Clinton K. Murray, MD, FIDSA2,3, (1)US Army Institute of Surgical Research, Fort Sam Houston, TX, (2)Dept. of Medicine, Uniformed Services University of the Health Sciences, Bethesda, MD, (3)Infectious Disease Service, Brooke Army Medical Center, Fort Sam Houston, TX, (4)University of the Incarnate Word, San Antonio, TX

    Disclosures:

    K. S. Akers, None

    K. L. Niece, None

    J. M. Cota, None

    K. K. Chung, None

    C. K. Murray, None

    Findings in the abstracts are embargoed until 12:01 a.m. PDT, Wednesday Oct. 7th with the exception of research findings presented at the IDWeek press conferences.