Vancomycin exposure in patients with methicillin-resistant Staphylococcus aureus bloodstream infections: how much is enough?

BACKGROUND: Contemporary vancomycin dosing schemes are designed to achieve an area under the curve (AUC) to minimum inhibitory concentration (MIC) ratio of ≥400. However, scant clinical data exist to support this target and available data relied on pharmacokinetic formulas based on daily vancomycin dose and estimated renal function (demographic pharmacokinetic model) to estimate AUCs. METHODS: A cohort study of hospitalized, adult, nondialysis patients with methicillin-resistant Staphylococcus aureus bloodstream infections treated with vancomycin was performed to quantitatively evaluate the relationship between vancomycin exposure and outcomes. Bayesian techniques were used to estimate vancomycin exposure profile for day 1 and 2 of therapy for each patient based on their dosing schedule and collected concentrations. Classification and Regression Tree (CART) analysis was used to identify day 1 and 2 exposure thresholds associated with an increased risk of failure. Failure was defined as 30-day mortality, bacteremia was ≥7 days, or recurrence. RESULTS: During the study period, 123 cases met criteria. Failure was uniformly less pronounced (approximately 20% less in absolute value) in patients who achieved the CART-derived day 1 and 2 thresholds for AUC/MIC by broth microdilution and AUC/MIC by Etest. In the multivariate analyses, all risk ratios were approximately 0.5 for all CART-derived AUC/MIC exposure thresholds, indicating that achievement of CART-derived AUC/MIC exposure thresholds was associated with a 2-fold decrease in failure. CONCLUSIONS: These findings establish the critical importance of daily AUC/MIC ratios during the first 2 days of therapy. As with all observational studies, these findings should be interpreted cautiously and validated in a multicenter randomized trial before adoption into practice.

A comparative evaluation of adverse platelet outcomes among Veterans' Affairs patients receiving linezolid or vancomycin.

OBJECTIVES: The primary objectives were to compare the incidences of severe thrombocytopenia, critical thrombocytopenia and a relative decline in platelets from baseline (≥50% decline) between patients receiving linezolid and those receiving vancomycin. The secondary objective was to assess the relationship between vancomycin trough concentration and adverse platelet outcomes. METHODS: A matched cohort study was performed at the Upstate New York Veterans' Affairs Healthcare Network from January 2005 until February 2008. Eligibility criteria were: (i) receipt of linezolid or vancomycin therapy for ≥48 h; (ii) initiation of therapy as an inpatient; and (iii) baseline platelets available for evaluation. Patients who received linezolid were matched 1:1 to patients who received vancomycin. Cumulative incidences and times to event for (i) platelet count ≤50,000 cells/mm(3), (ii) platelet count ≤20,000 cells/mm(3) and (iii) ≥50% decline in platelets from baseline were evaluated. Multivariate analyses were performed. RESULTS: The study included 502 patients (251 matched pairs). The occurrences of platelet counts ≤50,000 cells/mm(3) and ≤20,000 cells/mm(3) did not differ significantly between linezolid and vancomycin patients. A ≥50% decline in platelets from baseline was observed in 78 (31.1%) patients receiving vancomycin and 43 (17.1%) patients receiving linezolid (risk ratio 0.55; 95% CI 0.40-0.77). A clear exposure-response relationship was observed between vancomycin trough concentration and ≥50% decline in platelets from baseline. CONCLUSIONS: The incidence of thrombocytopenia was low and did not differ significantly among vancomycin and linezolid patients.

Clinical epidemiology of carbapenem-intermediate or -resistant Enterobacteriaceae.

OBJECTIVES: Despite the increasing incidence of carbapenem-intermediate or -resistant Enterobacteriaceae (CIRE), risk factors associated with CIRE infections have not been well defined. This study characterizes factors associated with CIRE among two different source populations. METHODS: A case-control study was performed at a tertiary care medical centre between January 2005 and December 2009. Cases were adults with a culture-confirmed Enterobacteriaceae infection with reduced susceptibility to meropenem or ertapenem. The CIRE cases were matched 1:1 to patients from two different control series: (i) those with carbapenem-susceptible Enterobacteriaceae (CSE) infections; and (ii) inpatients residing on the same ward within 30 days of CIRE culture date. Logistic regression was used to identify variables independently associated with CIRE among each source population. Restricted multivariate analyses were performed to determine if covariates predictive of CIRE varied by infecting organism or presence of the bla(KPC) gene. RESULTS: There were 102 cases of CIRE during the study period. The only covariate independently associated with CIRE in all multivariate analyses was the cumulative number of prior antibiotic exposures. Compared with CSE controls, the odds ratios (95% confidence interval) were 1.43 (1.19-1.72), 2.05 (1.70-2.47) and 2.93 (2.43-3.53) for 1, 2 and ≥ 3 antibiotic exposures, respectively. The strength of this association was comparable for the hospitalized control group and analyses stratified by organism and presence of the bla(KPC) gene. CONCLUSIONS: A patient's cumulative antibiotic exposure history is likely to be more important than any one specific exposure when determining the likelihood of developing a CIRE infection.