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

Abstract

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...

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“…The nonparametric adaptive grid (NPAG) algorithm (29-31) with adaptive gamma implemented within the Pmetrics package (version 1.4.0; Laboratory of Applied Pharmacokinetics and Bioinformatics, Los Angeles, CA) for R (32) was used for all PK model-fitting procedures, as previously described (33)(34)(35)(36). There were 80,021 initial grid points.…”

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“…The parameter estimations we provided allow the practicing clinician to use population modeling to improve the chance that the patient will receive the most optimal therapy. It has been suggested that 100% f T>MIC should be a therapeutic goal in patients who are neutropenic . Among patients with neutropenic fever treated with cefepime, these targets appear possible if the pathogen MIC is 4 mg/L or less.…”

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“…41,146-152 For these agents, a broad range of f T >MIC values from >45-100% have been reported as necessary for achievement of favorable clinical or microbiological outcomes, a likely consequence of heterogeneous patient populations, infecting organisms, and study designs. However, the most robust evidence remains in line with in vitro and animal estimates, with cefepime f T >MIC values of >53-74% being associated with up to a 10-fold higher likelihood of favorable outcome.…”

“…However, the most robust evidence remains in line with in vitro and animal estimates, with cefepime f T >MIC values of >53-74% being associated with up to a 10-fold higher likelihood of favorable outcome. 149,151,152 Indeed, in a large study assessing the adequacy of contemporary beta-lactam dosing regimens in critically ill patients, the inability to attain a f T >MIC >50% was associated with a 32% decreased likelihood of a positive clinical outcome. 41 Extended infusion regimens of certain beta-lactams have become a widespread means of maximizing f T >MIC in specific clinical scenarios.…”