Anti-pseudomonal beta-lactams for the initial, empirical, treatment of febrile neutropenia: comparison of beta-lactams.
BACKGROUND
Several beta-lactams are recommended as single agents for the treatment of febrile neutropenia.


OBJECTIVE
To 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.


METHODS
We 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.


METHODS
Randomised 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.


METHODS
Two 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.


RESULTS
Forty-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.


CONCLUSIONS
Current 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.
Infectious Diseases Unit, Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel, 49100.
Mical
M
Paul
Dafna
D
Yahav
Assaf
A
Bivas
Abigail
A
Fraser
Leonard
L
Leibovici
D000900:Anti-Bacterial Agents / Q000627:therapeutic use*; D000077723:Cefepime; D002442:Ceftazidime / Q000627:therapeutic use; D002511:Cephalosporins / Q000627:therapeutic use; D005334:Fever / Q000188:drug therapy*; D006801:Humans; D015378:Imipenem / Q000627:therapeutic use; D000077731:Meropenem; D009503:Neutropenia / Q000188:drug therapy*; D010397:Penicillanic Acid / Q000031:analogs & derivatives / Q000627:therapeutic use; D010878:Piperacillin / Q000627:therapeutic use; D000077725:Piperacillin, Tazobactam Drug Combination; D011552:Pseudomonas Infections / Q000188:drug therapy*; D011550:Pseudomonas aeruginosa; D016032:Randomized Controlled Trials as Topic; D013845:Thienamycins / Q000627:therapeutic use; D047090:beta-Lactams / Q000627:therapeutic use*
D000900:Anti-Bacterial Agents; D002511:Cephalosporins; D013845:Thienamycins; D047090:beta-Lactams; D000077725:Piperacillin, Tazobactam Drug Combination; D015378:Imipenem; D000077723:Cefepime; D010397:Penicillanic Acid; D002442:Ceftazidime; D000077731:Meropenem; D010878:Piperacillin