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.
K. S. Akers,
J. M. Cota, None
K. K. Chung, None
C. K. Murray, None