Cochrane Review: Anti‐pseudomonal beta‐lactams for the initial, empirical, treatment of febrile neutropenia: comparison of beta‐lactams

Abstract

BackgroundSeveral beta‐lactams are recommended as single agents for the treatment of febrile neutropenia.ObjectivesTo compare the effectiveness of different anti‐pseudomonal beta‐lactams as single agents in the treatment of febrile neutropenia. To compare the development of bacterial resistance, bacterial and fungal superinfections during or following treatment with the different beta‐lactams.Search strategyWe searched the Cochane Register of Controlled Trials (CENTRAL), Issue 3, 2010. MEDLINE, EMBASE, LILACS, FDA drug applications, conference proceedings and ongoing clinical trial databases up to August 2010. References of included studies were scanned.Selection criteriaRandomised controlled trials (RCTs) comparing an antipseudomonal beta‐lactam to another antipseudomonal beta‐lactam antibiotic, both given alone or with the addition of the same glycopeptide to both study arms, for the initial treatment of fever and neutropenia among cancer patients.Data collection and analysisTwo review authors applied inclusion criteria and extracted the data independently. Missing data were sought. Risk ratios (RR) were calculated with 95% confidence intervals (CI), and pooled using the fixed effect model. The primary outcome was all‐cause mortality. Risk of bias was assessed using a domain‐based evaluation and its effect of results was assessed through sensitivity analyses.Main resultsForty‐four trials were included. The antibiotics assessed were cefepime, ceftazidime, piperacillin‐tazobactam, imipenem and meropenem. Adequate allocation concealment and generation were reported in about half of the trials and only two trials were double‐blinded. The risk for all‐cause mortality was significantly higher with cefepime compared to other beta‐lactams (RR 1.39, 95% CI 1.04 to 1.86, 21 trials, 3471 participants), without heterogeneity and with higher RRs in trials at low risk for bias. There were no differences in secondary outcomes but for a non‐significantly higher rate of bacterial superinfections with cefepime. Mortality was significantly lower with piperacillin‐tazobactam compared to other antibiotics (RR 0.56, 95% CI 0.34 to 0.92, 8 trials, 1314 participants), without heterogeneity. Carbapenems resulted in similar all‐cause mortality and a lower rate of clinical failure and antibiotic modifications as compared to other antibiotics, but a higher rate of diarrhea caused by Clostridium difficile.Authors' conclusionsCurrent evidence supports the use of piperacillin‐tazobactam in locations where antibiotic resistance profiles do not mandate empirical use of carbapenems. Carbapenems result in a higher rate of antibiotic‐associated and Clostridium difficile‐associated diarrhea. There is a high level of evidence that all‐cause mortality is higher with cefepime compared to other beta‐lactams and it should not be used as monotherapy for patients with febrile neutropenia.Plain Language SummarySingle‐agent antibiotic treatment for cancer patients with fever and low white blood cell countsCancer patients develop neutropenia, a decrease in the neutrophil subset of the white blood cells, as a result of chemotherapy. Neutropenia exposes patients to infections, mainly bacterial. Without antibiotic treatment these infections may be fatal, therefore antibiotic treatment is administered when a patient with neutropenia develops fever. The objective of this review was to compare antibiotic treatments currently recommended in consensus guidelines for the initial treatment of cancer patients with fever and neutropenia.We identified 44 studies comparing different antibiotics. Cefepime resulted in significantly higher mortality compared to all other antibiotics combined, at the end of patients' hospital stay or 30 days after entry into the study. The risk was 39% higher with cefepime, ranging from 4 to 86% increased risk. We did not find an explanation for this when looking into other outcomes reported in the primary studies. Piperacillin‐tazobactam resulted in lower mortality than other antibiotics. The other antibiotics (ceftazidime, imipenem and meropenem) showed comparable efficacy, with a lower rate of antibiotic changes for imipenem or meropenem and a higher rate of severe diarrhea with these two antibiotics.We conclude that piperacillin‐tazobactam might be the preferred antibiotic for the treatment of cancer patients with fever and neutropenia and that cefepime should not be used. Antibiotic selection (other than cefepime) depends on the individual patient and the type of bacteria prevalent in the specific hospital.

Evidence-based approach to treatment of febrile neutropenia in hematologic malignancies

“…Regarding the choice of beta-lactam, no single agent is clearly superior, although piperacillintazobactam compares favorably in terms of equivalent efficacy and less toxicity (as long as the frequency of resistant bacteria is low). 10,49 Concerns regarding increased overall mortality with cefepime have been largely dismissed by the IDSA 13 and ASCO 17 after a reanalysis of the cefepime data by the FDA, although the authors of the original meta-analysis remain unconvinced. 49 A significant limitation of the evidence is that randomized trials of antibiotics in neutropenic patients have been performed since the 1980s.…”

“…10,49 Concerns regarding increased overall mortality with cefepime have been largely dismissed by the IDSA 13 and ASCO 17 after a reanalysis of the cefepime data by the FDA, although the authors of the original meta-analysis remain unconvinced. 49 A significant limitation of the evidence is that randomized trials of antibiotics in neutropenic patients have been performed since the 1980s. Some of the data are more than 20 years old and their applicability in the current microbiological milieu has been questioned.…”