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Database of Abstracts of Reviews of Effects (DARE): Quality-assessed Reviews [Internet]. York (UK): Centre for Reviews and Dissemination (UK); 1995-.

Database of Abstracts of Reviews of Effects (DARE): Quality-assessed Reviews [Internet].

Empirical antibiotics against Gram-positive infections for febrile neutropenia: systematic review and meta-analysis of randomized controlled trials

M Paul, S Borok, A Fraser, L Vidal, and L Leibovici.

Review published: 2005.

Link to full article: [Journal publisher]

CRD summary

This review assessed the effects of empirical anti-Gram-positive antibiotics for the treatment of febrile neutropenia. The authors concluded that it is safe to withhold empirical treatment with glycopeptides until a resistant Gram-positive infection is proven. This was generally a well-conducted review and the authors' conclusions appear robust.

Authors' objectives

To assess the effects of empirical anti-Gram-positive antibiotics for the treatment of febrile neutropenia.

Searching

The Cochrane CENTRAL Register, MEDLINE, EMBASE and LILACS were searched up to March 2004; the search terms were reported. The authors also searched three named sets of conference proceedings (from 1995 to 2003), ongoing clinical trials databases and all reference lists of included studies.

Study selection

Study designs of evaluations included in the review

Randomised controlled trials (RCTs) were eligible for inclusion. Studies reporting an efficacy analysis were excluded if the drop-out rate after randomisation was more than 30%.

Specific interventions included in the review

Studies that compared a standard antibiotic regimen alone versus the standard regimen plus an antibiotic active against Gram-positive organisms were eligible for inclusion. Studies of initial treatment and studies of treatment given at the time of reassessment for persistent fever were included. The review defined anti-Gram-positive antibiotics as glycopeptides, 1st generation cephalosporins, penicillinase- resistant penicillins, clindamycin, quinupristin/dalfopristin, and linezolid. The studies could use any standard antibiotic regimen provided the same regimen was used in both treatment arms. Most of the included studies used glycopeptides; other studies used cefalothin, flucloxacillin and trimethoprim/sulfamethoxazole. Details of standard regimens in the included studies were reported.

Participants included in the review

Studies of patients with febrile neutropenia were included.

Outcomes assessed in the review

The primary review outcome was all-cause mortality at the end of follow-up. The secondary review outcomes were: overall failure excluding treatment modifications; failure with modifications and the specific addition of amphotericin; duration of fever; treatment; hospitalisation; all adverse events and adverse events leading to the discontinuation of treatment or death. The review sought to assess the colonisation of resistant microorganisms but there were insufficient data for this.

How were decisions on the relevance of primary studies made?

Two reviewers independently selected studies.

Assessment of study quality

The studies were assessed for method of randomisation, allocation concealment, blinding, re-entries (where patients were entered more than once in the study), intention-to-treat data and the number of patients excluded from the efficacy analysis. Two reviewers independently assessed validity.

Data extraction

Two reviewers independently extracted the data. Attempts were made to obtain missing data from authors. Data were extracted on an intention-to-treat basis where possible; where this was not possible, data for available cases were extracted. Relative risks (RRs) and their associated 95% confidence intervals (CIs) were extracted.

Methods of synthesis

How were the studies combined?

Pooled RRs and 95% CIs were calculated using a fixed-effect meta-analysis. A funnel plot was used to assess publication bias.

How were differences between studies investigated?

Statistical heterogeneity was assessed using the chi-squared and the I-squared statistics.

Subgroup analyses were conducted for patients with documented Gram-positive infections and according to type of treatment (initial glycopeptides, other initial antibiotics and glycopeptides for persisting fever). A meta-regression was used to examine the association between rates of Gram-positive bacteraemia and treatment effects in individual studies. A sensitivity analysis was used to examine the influence of using intention-to-treat data and adequate allocation concealment.

Results of the review

Thirteen RCTs (n=2,392) were included.

Eleven RCTs described methods of randomisation while eight described adequate allocation concealment.

Mortality and treatment failure.

There was no significant difference between empirical anti- Gram-positive antibiotics and the control in all-cause mortality (RR 0.86, 95% CI: 0.58, 1.26; 7 RCTs with 852 patients) or overall treatment failure (RR 1.00, 95% CI: 0.79, 1.27; 6 RCTs with 943 patients). No statistically significant heterogeneity was found. The results were similar for data from studies with adequate allocation concealment and studies with intention-to-treat data. There were significantly more treatment failures associated with treatment modifications in the control arm than with empirical anti-Gram-positive antibiotic treatment (RR 0.70, 95% CI: 0.61, 0.80; 5 RCTs with 1,178 patients).

Superinfections.

Compared with the control, glycopeptides significantly reduced bacterial superinfections (RR 0.3, 95% CI: 0.24, 0.59; 8 RCTs with 1,628 patients) and Gram-positive superinfections (RR 0.21, 95% CI: 0.11, 0.37). There was no significant difference between treatments for fungal infections.

Adverse effects.

Adverse effects were significantly more common with empirical anti-Gram-positive antibiotic treatment than with the control (RR 1.79, 95% CI: 1.55, 2.08; 8 RCTs with 1,546 patients). The most common adverse effects were dermatological (RR 2.31, 95% CI: 1.47, 3.63; 7 RCTs with 1,526 patients). There was no significant difference in nephrotoxicity for all antibiotics compared with a control (RR 1.28, 95% CI: 0.96, 1.70), but nephrotoxicity was significantly more common with glycopeptides than with a control (RR 1.43, 95% CI: 1.06, 1.94).

The funnel plot showed no evidence of publication bias.

Other results were reported.

Authors' conclusions

It is safe to withhold empirical treatment with glycopeptides until a resistant Gram-positive infection is proven.

CRD commentary

The review question was clear in terms of the study design, intervention, participants and outcomes. Several relevant sources were searched and attempts were made to locate unpublished studies, thus limiting the possibility of publication bias. Appropriate methods were used to assess the presence of publication bias, but no evidence of it was found. It was unclear whether any language restrictions had been applied in the searches. Two reviewers independently selected studies, assessed validity and extracted the data, thus reducing the potential for reviewer bias and errors. Only RCTs with relatively low drop-out rates were included, and validity was assessed using established criteria and the results reported. Adequate details of each included study were given. The data were appropriately combined in a meta-analysis and statistical heterogeneity was assessed. Subgroup analyses were used to examine the influence on the results of various factors, including quality. This was generally a well-conducted review and the authors' conclusions appear robust.

Implications of the review for practice and research

Practice: The authors stated that cancer centres need to monitor pathogen prevalence to guide empirical treatment.

Research: The authors stated that further trials assessing empirical glycopeptides would be needed if infections in cancer patients progress towards Gram-positive infections. They stated that any such trials should follow recommendations (see Other Publications of Related Interest nos.1-2).

Bibliographic details

Paul M, Borok S, Fraser A, Vidal L, Leibovici L. Empirical antibiotics against Gram-positive infections for febrile neutropenia: systematic review and meta-analysis of randomized controlled trials. Journal of Antimicrobial Chemotherapy 2005; 55(4): 436-444. [PubMed: 15722392]

Other publications of related interest

1. Immunocompromised Host Society. The design, analysis, and reporting of clinical trials on the empirical antibiotic management of the neutropenic patient. Report of a consensus panel. J Infect Dis 1990;161:397-401. 2. Feld R, Paesmans M, Freifeld AG, Klastersky J, Pizzo PA, Rolston KV, et al. Methodology for clinical trials involving patients with cancer who have febrile neutropenia: updated guidelines of the Immunocompromised Host Society/Multinational Association for Supportive Care in Cancer, with emphasis on outpatient studies. Clin Infect Dis 2002;35:1463-8.

Indexing Status

Subject indexing assigned by NLM

MeSH

Anti-Bacterial Agents /therapeutic use; Fever; Glycopeptides /therapeutic use; Gram-Positive Bacterial Infections /drug therapy /etiology /mortality; Humans; Neutropenia /complications; Randomized Controlled Trials as Topic

AccessionNumber

12005009910

Database entry date

30/04/2006

Record Status

This is a critical abstract of a systematic review that meets the criteria for inclusion on DARE. Each critical abstract contains a brief summary of the review methods, results and conclusions followed by a detailed critical assessment on the reliability of the review and the conclusions drawn.

CRD has determined that this article meets the DARE scientific quality criteria for a systematic review.

Copyright © 2014 University of York.

PMID: 15722392

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