Predictor factors of inadequate concentrations of continuous infusion of vancomycin in septic patients

INTRODUCTION. Continuous infusion (CI) of vancomycin is frequently used in critically ill patients to treat severe infections caused by Gram-positive bacteria. However, sepsis can alter drug pharmacokinetics (PKs), resulting in insufficient drug concentrations. Inadequate antimicrobial concentrations, especially during the first days of treatment, may have potential deleterious effects on morbidity and mortality of septic patients. Recent recommendations suggest a loading dose of 15 mg/kg followed by a CI of 30 mg/kg of vancomycin, but data on the efficacy of this strategy in sepsis are scarce.OBJECTIVES. The aim of this study was to identify the predictor factors of inadequate vancomycin concentrations in septic patients.METHODS. Retrospective analysis of all patients admitted in the ICU from January 2008 to December 2009 in whom a vancomycin was given as a CI. Patients were included if they (a) were > 18 years old, (b) had sepsis according to standard criteria, (c) received at least 28mg/kg daily for the first 48 h. Demographics, microbiological and treatment data were collected. Creatinine clearance (CrCl) was calculated from 24-hr urine collection and normalized to body surface area (BSA). Concentrations below 20 mcg/mL were considered as inadequate. Multivariate logistic regression analysis was performed using all variables showing a significant association (p < 0.2) with inadequate vancomycin concentrations at day 1 or day 2 of therapy in univariate analysis.RESULTS. During the study period, 114 patients met the inclusion criteria. 57 (50%) and 40 (35%) patients had inadequate vancomycin concentrations at day 1 and 2 of therapy, respectively. Univariate analysis showed that male sex (p=0.13), vasopressor therapy (p=0.08), high body weight (p=0.13), low loading vancomycin dose (p=0.12) and daily vancomycin dose (p=0.1), high CrCl (p< 0.001) were associated with inadequate vancomycin concentrations at day 1 of therapy; male sex (p=0.01), vasopressor therapy (p=0.16), inadequate concentrations at day 1 (p< 0.001), SOFA score at day 2 (p=0.31), low daily vancomycin dose (p=0.09) and high CrCl (p< 0.001) were associated with inadequate vancomycin concentrations at day 2 of therapy. Multivariate regression analysis showed that high CrCl was the only variable that indipendently predicted inadequate vancomycin concentrations at day 1 and 2 of therapy. Hence, CrCl > 120 ml/min.m2 had a sensitivity of 91%, a specificity of 40%, a positive predictive value of 82% and a negative predictive value of 60% for inadequate vancomycin concentrations at day 1. Receiver operating characteristic curve analysis for CrCl showed an area under the curve of 0.76 (95% CI: 0.67-0.85).CONCLUSIONS. In ICU septic patients treated with a CI of vancomycin, drug concentrations were found insufficient in nearly half of cases, even when standard recommended regimen was applied. CrCl was the strongest variable to predict inadequate drug concentrations.