Recent guidelines recommend vancomycin trough concentrations between 15 and 20 mg/liter. In response, some clinicians increased vancomycin dosing to >4 g/day. Scant data are available regarding toxicities associated with higher vancomycin doses. The purpose of this study was to examine vancomycin-associated nephrotoxicity at >4 g/day. To accomplish the study objective, a cohort study among a random selection of patients receiving vancomycin or linezolid between 2005 and 2006 was performed. Patients were included if they (i) were >18 years of age, (ii) were nonneutropenic, (iii) were on therapy for >48 h, (iv) had baseline serum creatinine levels of <2.0 mg/dl, (v) did not suffer from cystic fibrosis, and (vi) had no intravenous contrast dye within the previous 7 days. For drug exposure, three treatment strata were created: standard vancomycin dose (<4 g/day), high vancomycin dose (>4 g/day), and linezolid. Nephrotoxicity was defined as a serum creatinine increase of 0.5 mg/dl or 50%, whichever was greater, after therapy initiation. Stratified Kaplan-Meier analysis and Cox modeling were used to compare times to nephrotoxicity across groups. During the study, 246 patients on vancomycin (26 patients taking >4 g/day and 220 patients taking <4 g/day) and 45 patients on linezolid met the criteria. A significant difference in nephrotoxicity between patients receiving >4 g vancomycin/day, those receiving <4 g vancomycin/day, and those receiving linezolid was noted (34.6%, 10.9%, and 6.7%, respectively; P ‫؍‬ 0.001), and Kaplan-Meier analysis identified significant differences in time to nephrotoxicity for the high-vancomycin-dose cohort compared to those for groups taking the standard dose and linezolid. In the Cox model, patients taking >4 g vancomycin/day, a total body weight of >101.4 kg, estimated creatinine clearance of <86.6 ml/min, and intensive care unit residence were independently associated with time to nephrotoxicity. The data suggest that higher-dose vancomycin regimens are associated with a higher likelihood of vancomycinrelated nephrotoxicity.

There is growing concern that vancomycin has diminished activity for methicillin-resistant Staphylococcus aureus ( Despite its sustained in vitro microbiologic inhibitory activity, clinicians now question the continued utility of vancomycin for methicillin-resistant Staphylococcus aureus (MRSA) infections (18,23). Within the past 5 years, multiple reports have described MRSA strains with vancomycin MICs at the high end of the CLSI susceptibility range (MICs of 2 mg/liter) (6,18,22). Data suggest that vancomycin has reduced activity against MRSA infections, with vancomycin MICs at the high end of the CLSI susceptibility range (6,11,16,19,20).At the Albany Medical Center Hospital (AMCH), a large proportion of the MRSA bloodstream isolates have vancomycin MICs at the high end of the CLSI susceptibility range. The MIC 50 and MIC 90 for the 76 MRSA bloodstream isolates (59 patients) obtained by using the Etest method and recovered between

Although a growing number of studies have found a relationship between delayed appropriate antibiotic therapy and mortality, few have attempted to quantify the temporal association between delayed appropriate antibiotic therapy and mortality. This study was designed to measure the elapsed time associated with an increased risk of 30-day mortality among patients with Pseudomonas aeruginosa bacteremia. The retrospective cohort study was conducted among immunocompetent, adult patients with P. aeruginosa bacteremia onset at least 2 days after hospital admission between 1 January 2001 and 30 September 2006. Classification and regression tree analysis (CART) was used to identify the delay in appropriate antibiotic therapy that was associated with an increased risk of 30-day mortality. During the study period, 100 patients met the inclusion criteria. The CART-derived breakpoint between early and delayed treatment was 52 h. The delayed treatment group experienced a >2-fold significant increase in 30-day mortality compared to the early treatment group (44 and 19%, respectively, P ‫؍‬ 0.008). Delayed appropriate therapy of >52 h (odds ratio [OR] ‫؍‬ 4.1; 95% confidence interval [CI] 1.2 to 13.9, P ‫؍‬ 0.03) was independently associated with 30-day mortality in the multivariate analysis. Antibiotic resistance >3 classes (adjusted OR [AOR] ‫؍‬ 4.6; 95% CI ‫؍‬ 1.9 to 11.2, P ‫؍‬ 0.001) and chronic obstructive pulmonary disease (AOR ‫؍‬ 5.4; 95% CI ‫؍‬ 1.5 to 19.7, P ‫؍‬ 0.01) were independently associated with delayed appropriate therapy of >52 h. The data strongly suggest that delaying appropriate therapy for approximately 2 days significantly increases the risk of 30-day mortality in patients with P. aeruginosa bloodstream infections.

Patients with MRSA bloodstream infections in the ICU or with a history of vancomycin exposure should be considered at high risk of infection with strains for which vancomycin MICs are elevated. Appropriate and aggressive empirical therapy is required for these patients.

Despite the increasing prevalence of multiple-drug-resistant (MDR) Pseudomonas aeruginosa, the factors predictive of MDR have not been extensively explored. We sought to examine factors predictive of MDR among patients with P. aeruginosa respiratory tract infections and to develop a tool to estimate the probability of MDR among such high-risk patients. This was a single-site, case-control study of patients with P. aeruginosa respiratory tract infections. Multiple-drug resistance was defined as resistance to four or more antipseudomonal antimicrobial classes. Clinical data on demographics, antibiotic history, and microbiology were collected. Classification and regression tree analysis (CART) was used to identify the duration of antibiotic exposure associated with MDR P. aeruginosa. Log-binomial regression was used to model the probability of MDR P. aeruginosa. Among 351 P. aeruginosa-infected patients, the proportion of MDR P. aeruginosa was 35%. A significant relationship between prior antibiotic exposure and MDR P. aeruginosa was found for all of the antipseudomonal antibiotics studied, but the duration of prior exposure associated with MDR varied between antibiotic classes; the shortest prior exposure duration was observed for carbapenems and fluoroquinolones, and the longest duration was noted for cefepime and piperacillin-tazobactam. Within the final model, the predicted MDR P. aeruginosa likelihood was most dependent upon length of hospital stay, prior culture sample collection, and number of CART-derived prior antibiotic exposures. A history of a prolonged hospital stay and exposure to antipseudomonal antibiotics predicts multidrug resistance among patients with P. aeruginosa respiratory tract infections at our institution. Identifying these risk factors enabled us to develop a prediction tool to assess the risk of resistance and thus guide empirical antibiotic therapy.