Vancomycin AUC ₂₄ /MIC Ratio in Patients with Complicated Bacteremia and Infective Endocarditis Due to Methicillin-Resistant Staphylococcus aureus and Its Association with Attributable Mortality during Hospitalization

Abstract

Methicillin-resistant Staphylococcus aureus (MRSA) is a common cause of complicated bacteremia (CB) and infective endocarditis (IE).The gold standard treatment for these infections is vancomycin. A vancomycin area under the concentration-time curve from 0 to 24 h (AUC 24 )/MIC ratio of >400 has been suggested as a target to achieve clinical effectiveness, and yet to date no study has quantitatively investigated the AUC 24 /MIC ratio and its association with attributable mortality (AM). We performed a review of patients treated for MRSA CB and IE from 1 July 2006 to 30 June 2008. AM was defined as deaths where CB or IE was documented as the main cause or was mentioned as the main diagnosis. Classification and regression tree analysis (CART) was used to identify the AUC 24 /MIC ratio associated with AM. Mann-Whitney and Fisher exact tests were used for univariate analysis, and logistic regression was used for multivariate modeling. The MICs were determined by Etest, and the AUC 24 was determined using a maximum a posteriori probability-Bayesian estimator. A total of 32 CB and 18 IE patients were enrolled. The overall crude mortality and AM were 24 and 16%, respectively. The CART-derived partition for the AUC 24 /MIC ratio and AM was <211. Patients with an AUC 24 /MIC ratio of <211 had a >4-fold increase in AM than patients who received vancomycin doses that achieved an AUC 24 /MIC ratio of >211 (38 and 8%, respectively; P ‫؍‬ 0.02). In bivariate analysis the APACHE-II score and an AUC 24 /MIC ratio of <211 were significantly associated with AM. In the multivariate model, the APACHE-II score (odds ratio, 1.24; P ‫؍‬ 0.04) and a vancomycin AUC/MIC ratio of <211 (odds ratio, 10.4; P ‫؍‬ 0.01) were independent predictors of AM. In our analysis, independent predictors of AM were the APACHE-II score and an AUC 24 /MIC ratio of <211. We believe further investigations are warranted.

Are Vancomycin Trough Concentrations Adequate for Optimal Dosing?

“…First, on the basis of our simulations, even in an ideal population of adults with normal renal function who get the same dosing regimen, vancomycin AUC values can vary as much as 30-fold between patients, with associated variability in peak and trough concentrations. This interpatient variability, in light of substantial evidence of concentration-response relationships (6)(7)(8)14), is strong justification for ongoing vancomycin TDM, especially since exposure among patients with various degrees of renal function will be even more unpredictable from a dose.…”

“…Specifically, a total drug steady-state AUC/MIC ratio that is 400 times the MIC for the organism is the suggested target (5)(6)(7)(8). To reconcile a trough concentration-only monitoring approach with an AUC-dependent mode of action, the committee made the assertions that vancomycin trough concentrations are a good surrogate for the AUC and that in most adult patients with normal renal function (creatinine clearance [CL CR ] of Ն100 ml/min), a steady-state trough concentration of 15 to 20 mg/liter would correlate with an AUC/MIC ratio of Ն400 for an organism for which the MIC is Յ1 mg/liter.…”

Guidelines for Therapeutic Drug Monitoring of Cardiovascular Drugs Clinical Use of Blood Drug Concentration Monitoring (JCS 2015) ― Digest Version ―

“…71 As vegetation may reduce penetration of vancomycin into MRSA, 72,73 it is considered that higher trough concentrations should be maintained in the treatment of infective endocarditis. 73 The guidelines for the diagnosis and treatment of infective endocarditis published in the United Kingdom, 74 and those in the United States 75 recommend that trough serum vancomycin concentrations be maintained at 15-20 μg/mL.On the other hand, an initial trough concentration of ≥15 μg/mL is reported as a risk factor for nephrotoxicity.…”

Immunocytochemistry for Vancomycin Using a Monoclonal Antibody That Reveals Accumulation of the Drug in Rat Kidney and Liver

“…VM sometimes produces several side effects, the most serious of which is nephrotoxicity (3,39). However, there are few data about its renal uptake and subcellular distribution.…”