Vancomycin AUC/MIC ratio and 30-day mortality in patients with Staphylococcus aureus bacteremia

Abstract

A ratio of the vancomycin area under the concentration-time curve to the MIC (AUC/MIC) of ≥ 400 has been associated with clinical success when treating Staphylococcus aureus pneumonia, and this target was recommended by recently published vancomycin therapeutic monitoring consensus guidelines for treating all serious S. aureus infections. Here, vancomycin serum trough levels and vancomycin AUC/MIC were evaluated in a "real-world" context by following a cohort of 182 patients with S. aureus bacteremia (SAB) and analyzing these parameters within the critical first 96 h of vancomycin therapy. The median vancomycin trough level at this time point was 19.5 mg/liter. There was a significant difference in vancomycin AUC/MIC when using broth microdilution (BMD) compared with Etest MIC (medians of 436.1 and 271.5, respectively; P < 0.001). Obtaining the recommended vancomycin target AUC/MIC of ≥ 400 using BMD was not associated with lower 30-day all-cause or attributable mortality from SAB (P = 0.132 and P = 0.273, respectively). However, an alternative vancomycin AUC/MIC of >373, derived using classification and regression tree analysis, was associated with reduced mortality (P = 0.043) and remained significant in a multivariable model. This study demonstrated that we obtained vancomycin trough levels in the target therapeutic range early during the course of therapy and that obtaining a higher vancomycin AUC/MIC (in this case, >373) within 96 h was associated with reduced mortality. The MIC test method has a significant impact on vancomycin AUC/MIC estimation. Clinicians should be aware that the current target AUC/MIC of ≥ 400 was derived using the reference BMD method, so adjustments to this target need to be made when calculating AUC/MIC ratio using other MIC testing methods.

Fig 1

Scattergram of vancomycin AUC/MIC using BMD versus Etest. The vertical dotted line represents an AUC/MIC of 400 using BMD. The horizontal dotted line represents an AUC/MIC of 226 using Etest. The line of best fit was obtained using linear regression. BMD, broth microdilution; AUC/MIC, ratio of area under the concentration-time curve (24 h) to vancomycin MIC.

Fig 2

Frequency distribution of vancomycin AUC/MIC according to the proportion of survivors, including line of best fit using linear regression. AUC/MIC, ratio of area under the concentration-time curve (24 hour) to vancomycin MIC; BMD, broth microdilution.

Fig 3

Thirty-day mortality in patients with SAB according to vancomycin AUC/MIC. (A) Vancomycin AUC/MIC according to survivors versus nonsurvivors for all-cause mortality. (B) Proportion of survivors according to target attainment using a vancomycin AUC/MIC of ≥400. (C) Kaplan-Meier curve for all-cause mortality according to target attainment using a vancomycin AUC/MIC of ≥400 (note that the P value derived using the log-rank test was slightly different to Fisher's exact test for the dichotomous variable). (D) Proportion of survivors according to target attainment using a vancomycin AUC/MIC of ≥373. (E) Kaplan-Meier curve for all-cause mortality according to target attainment using a vancomycin AUC/MIC of ≥373. The horizontal dotted line represents an AUC/MIC of 400 using BMD. Heavy black bars represent median and interquartile range. BMD, broth microdilution; AUC/MIC, ratio of area under the concentration-time curve (24 hour) to vancomycin MIC.

Fig 4

Vancomycin AUC/MIC according to groups with low versus elevated (defined as an Etest value of >1.5 mg/liter) vancomycin MIC. The horizontal dotted line represents an AUC/MIC of 400 using BMD. Heavy black bars represent median and interquartile range. BMD, broth microdilution; AUC/MIC, ratio of area under the concentration-time curve (24 hour) to vancomycin MIC.