Cefepime vs Other Antibacterial Agents for the Treatment of Enterobacter Species Bacteremia

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.

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confidence: 99%

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.…”

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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...

“…Retrospective studies have shown that cefepime has an efficacy similar to that of carbapenems for treatment of Enterobacter spp. bacteremia (10,11). In these analyses, which included propensity score-matched pairwise comparisons, cefepime use resulted in no difference in duration of bacteremia (11), mortality, or length of stay compared to meropenem use (10).…”

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confidence: 98%

“…bacteremia (10,11). In these analyses, which included propensity score-matched pairwise comparisons, cefepime use resulted in no difference in duration of bacteremia (11), mortality, or length of stay compared to meropenem use (10). Based on these results, cefepime has become an important carbapenem-sparing option for the treatment of these organisms.…”

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confidence: 99%

Piperacillin-Tazobactam versus Other Antibacterial Agents for Treatment of Bloodstream Infections Due to AmpC β-Lactamase-Producing Enterobacteriaceae

Cheng

Nelson

Mehta

et al. 2017

In vivo induction of AmpC beta-lactamases produces high-level resistance to many beta-lactam antibiotics in Enterobacteriaceae, often resulting in the need to use carbapenems or cefepime (FEP). The clinical effectiveness of piperacillintazobactam (TZP), a weak inducer of AmpC beta-lactamases, is poorly understood. Here, we conducted a case-control study of adult inpatients with bloodstream infections (BSIs) due to Enterobacter, Serratia, or Citrobacter species from 2009 to 2015 to assess outcomes following treatment with TZP compared to FEP or meropenem (MEM). We collected clinical data and screened all isolates for the presence of ampC alleles by PCR. Primary study outcomes were 30-day mortality and persistent bacteremia at Ն72 h from the time of treatment initiation. Of 493 patients with bacteremia, 165 patients met the inclusion criteria, of which 88 were treated with TZP and 77 with FEP or MEM. To minimize differences between covariates, we carried out propensity score matching, which yielded 41 matched pairs. Groups only differed by age, with patients in the TZP group significantly older (P ϭ 0.012). There were no significant differences in 30-day mortality, persistent bacteremia, 7-day mortality, or treatment escalation between the two treatment groups, including in the propensity score-matched cohort. PCR amplification and sequencing of ampC genes revealed the presence of ampC in isolates with cefoxitin MICs below 16 g/ml, in particular in Serratia spp., and demonstrated that these alleles were highly genetically diverse. Taken together, TZP may be a valuable treatment option for BSIs due to AmpC betalactamase-producing Enterobacteriaceae, diminishing the need for broader-spectrum agents. Future studies are needed to validate these findings.