Evaluation of Once-Daily Vancomycin against Methicillin-Resistant Staphylococcus aureus in a Hollow-Fiber Infection Model

Abstract

For methicillin-resistant Staphylococcus aureus (MRSA) infections, data suggest that the clinical response is significantly better if the total vancomycin area under the concentration-time curve (AUC)/MIC ratio is >400. While the AUC/MIC ratio is the accepted pharmacokinetic/pharmacodynamic (PK/PD) index for vancomycin, this target has been achieved using multiple daily doses. We are unaware of a systematically designed dose fractionation study to compare the bactericidal activity of once-daily administration to that of traditional twice-daily administration. A dose fractionation study was performed with vancomycin in an in vitro hollow-fiber infection model against an MRSA USA300 strain (MIC of 0.75 g/ml) using an inoculum of ϳ10 6 CFU/ ml. The three vancomycin regimens evaluated for 168 h were 2 g every 24 h (q24h) as a 1-h infusion, 1 g q12h as a 1-h infusion, and 2 g q24h as a continuous infusion. Free steady-state concentrations (assuming 45% binding) for a total daily AUC/MIC ratio of >400 were simulated for all regimens. A validated liquid chromatography-tandem mass spectrometry method was used to determine vancomycin concentrations. Although once-daily and twice-daily dosage regimens exhibited total trough concentrations of <15 g/ml, all regimens achieved similar bactericidal activities between 24 and 168 h and suppressed the amplification of nonsusceptible subpopulations. No colonies were found on agar plates with 3؋ MIC for any of the treatment arms. Overall, the results suggest that once-daily vancomycin administration is feasible from a PK/PD perspective and merits further inquiry in the clinical arena. Given the dual threat of diminishing vancomycin efficacy against methicillin-resistant Staphylococcus aureus (MRSA) and recent reports of rising nephrotoxicity (10, 22) (albeit potentially due to concomitant dosing increases), new vancomycin dosing strategies are urgently needed. From a pharmacodynamic viewpoint, there is an opportunity to alter standard dosage regimens of vancomycin in clinical practice to optimize outcomes and minimize toxicity. Data suggest that killing by vancomycin is concentration dependent, and a near-maximal bactericidal effect is achieved against MRSA when the ratio of the area under the total vancomycin concentration-time curve (AUC) to the MIC exceeds 400 (22). While an AUC/MIC ratio of 400 is a well-recognized pharmacokinetic/pharmacodynamic (PK/PD) target for vancomycin, this target has been determined using multiple daily doses, which has resulted in the default stance of using multiple-daily-dosing regimens in clinical practice (4,5,7,9,12,13,20,21). The possibility of once-daily administration is appealing from a PK/PD perspective, as it affords the ability to achieve more robust AUCs in a defined interval (i.e., during the first 6 to 12 h) while minimizing trough concentrations, which predicts nephrotoxicity (10). However, we are unaware of a systematically designed dose fractionation study that compared the bactericidal activity of a once-daily administration of vanc...

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