Effect of cefepime dose on mortality of patients with Gram-negative bacterial bloodstream infections: a prospective cohort study

A new category of cefepime susceptibility, susceptible dose dependent (SDD), for Enterobacteriaceae, has been suggested to maximize its clinical use. However, clinical evidence supporting such a therapeutic strategy is limited. A retrospective study of 305 adults with monomicrobial Enterobacter cloacae bacteremia at a medical center from 2008 to 2012 was conducted. The patients definitively treated with in vitro active cefepime (cases) were compared with those treated with a carbapenem (controls) to assess therapeutic effectiveness. The 30-day crude mortality rate is the primary endpoint, and clinical prognostic factors are assessed. Of 144 patients receiving definitive cefepime or carbapenem therapy, there were no significant differences in terms of age, sex, comorbidity, source of bacteremia, disease severity, or 30-day mortality (26.4% versus 22.2%; P ‫؍‬ 0.7) among those treated with cefepime (n ‫؍‬ 72) or a carbapenem (n ‫؍‬ 72). In the multivariate analysis, the presence of critical illness, rapidly fatal underlying disease, extended-spectrum beta-lactamase (ESBL) producers, and cefepime-SDD (cefepime MIC, 4 to 8 g/ml) isolates was independently associated with 30-day mortality. Moreover, those infected by cefepime-SDD isolates with definitive cefepime therapy had a higher mortality rate than those treated with a carbapenem (5/7 [71.4%], versus 2/11 [18.2%]; P ‫؍‬ 0.045). Cefepime is one of the therapeutic alternatives for cefepime-susceptible E. cloacae bacteremia but is inefficient for cases of cefepime-SDD E. cloacae bacteremia compared with carbapenem therapy.

Section: Discussionsupporting

confidence: 73%

Section: Figsupporting

confidence: 65%

Cefepime Therapy for Monomicrobial Enterobacter cloacae Bacteremia: Unfavorable Outcomes in Patients Infected by Cefepime-Susceptible Dose-Dependent Isolates

Lee

et al. 2015

“…Several clinical studies have associated elevated cefepime MICs with an increased risk of treatment failure and mortality for cefepime-treated patients (1,3,8,9), while other investigations have shown improved clinical outcomes among patients receiving aggressive cefepime dosing for bloodstream infections (BSIs) (10,11). These previous studies lacked PK/PD data, which could be highly useful in interpreting observed outcomes.…”

mentioning

confidence: 99%

Defining Clinical Exposures of Cefepime for Gram-Negative Bloodstream Infections That Are Associated with Improved Survival

Rhodes

Kuti

Nicolau

et al. 2016

iThe percentage of time that free drug concentrations remain above the MIC (fT >MIC ) that is necessary to prevent mortality among cefepime-treated patients with Gram-negative bloodstream infections (GNBSI) is poorly defined. We conducted a retrospective study of adult patients with GNBSI. Eligible cases were frequency matched to ensure categorical representation from all MICs. Organism, MIC, infection source, gender, age, serum creatinine, weight, antibiotic history, and modified APACHE II score were collected from hospital records. Two population pharmacokinetic models (models 1 and 2) were used to impute exposures over the first 24 h in each patient from mean model parameters, covariates, and dosing history. From the imputed exposures, survival thresholds for fT >MIC were identified using classification and regression tree (CART) analysis and analyzed as nominal variables for univariate and multivariate regressions. A ntimicrobial resistance among contemporary Gram-negative (GN) isolates has eroded the efficacy of many first-line antibiotics. Increasing beta-lactam MICs have been correlated with increasing antimicrobial failures in the treatment of serious bacterial infections (1-4). Elevated beta-lactam MICs can be expected to reduce the probability of achieving pharmacokinetic-pharmacodynamic (PK/PD) targets for beta-lactams. As the percentage of time in 24 hours that free drug concentrations are above the MIC (fT ϾMIC ) is the PK/PD target predictive of microbiologic efficacy for beta-lactams (5), decreasing fT ϾMIC is expected to result in worse patient outcomes (6).Cefepime, a broad-spectrum fourth-generation cephalosporin, is widely prescribed as the primary therapy for serious Gramnegative infections, including bloodstream infections (termed GNBSIs) (7). Several clinical studies have associated elevated cefepime MICs with an increased risk of treatment failure and mortality for cefepime-treated patients (1,3,8,9), while other investigations have shown improved clinical outcomes among patients receiving aggressive cefepime dosing for bloodstream infections (BSIs) (10, 11). These previous studies lacked PK/PD data, which could be highly useful in interpreting observed outcomes. Very few studies have analyzed patient outcomes according to fT ϾMIC in cefepime-treated patients (12-14). As such, the necessary fT ϾMIC to prevent mortality for cefepime-treated patients with GNBSI is not well defined.We sought to analyze the cefepime fT ϾMIC to see if a threshold existed for improved survival among patients treated with cefepime for GNBSIs. Secondarily, we sought to examine if candidate clinical threshold values for cefepime fT ϾMIC were predictive of other outcomes, such as hospital and intensive care unit (ICU) lengths of stay (LOS) and 30-day readmission rates. MATERIALS AND METHODSThis retrospective cohort study was conducted at Northwestern Memorial Hospital (NMH) in Chicago, Illinois. Study methods were reviewed and approved by the Institutional Review Boards at Northwestern University and Midwestern Univ...

“…efepime is a broad-spectrum, fourth-generation cephalosporin commonly used to treat serious infections caused by Gram-negative bacteria (1). For organisms with high MICs, optimal pharmacodynamic targets (time Ͼ MIC) may not be achieved (1,2).…”

mentioning

confidence: 99%

“…For organisms with high MICs, optimal pharmacodynamic targets (time Ͼ MIC) may not be achieved (1,2). Given studies demonstrating cefepime treatment failure of Enterobacteriaceae with elevated MICs, the Clinical Laboratory and Standards Institute (CLSI) adopted a susceptible-dose-dependent (SDD) category in 2014 for cefepime MIC values of 4 and 8 g/ml (3,4).…”

mentioning

confidence: 99%

Impact of Cefepime Susceptible-Dose-Dependent MIC for Enterobacteriaceae on Reporting and Prescribing

Rivera

Narayanan

Patel

et al. 2016

The CLSI cefepime breakpoints were revised to include a susceptible-dose-dependent (SDD) category for Enterobacteriaceae, with the intention that higher cefepime doses be used for these isolates. In this study, 1.6% of Enterobacteriaceae isolates were reported as SDD, with Escherichia coli the most common SDD organism. Cefepime was prescribed in three cases (4.8%); the majority of SDD isolates were treated with a carbapenem. Enterobacteriaceae with cefepime SDD MICs were not commonly treated with cefepime at our institution.