|Antibiotic prophylaxis of bacterial infections in cirrhotic inpatients: a meta-analysis of randomized controlled trials
|Soares-Weiser K, Brezis M, Tur-Kaspa R, Paul M, Yahav J, Leibovici L
This review assessed antibiotic prophylaxis among in-patients with cirrhosis. The authors concluded that antibiotic prophylaxis reduced deaths and bacterial infections, regardless of the underlying risk factors. This was a well-conducted and clearly presented review, and the authors' conclusions are likely to be reliable.
To assess the efficacy of antibiotic prophylaxis for bacterial infections among in-patients with cirrhosis, regardless of the underlying risk factors leading to hospitalisation. This review was partially based on a Cochrane review (see Other Publications of Related Interest).
The Cochrane Library (Issue 2, 2001), the Cochrane Hepato-Biliary Group's Controlled Trials Register (May 2001), EMBASE (from 1980 to May 2001) and MEDLINE (from 1966 to May 2001) were searched; the key terms were stated. References from identified studies and two previous reviews were also checked. The corresponding authors of identified studies were contracted for details of unpublished studies and additional information. Studies published in any language were eligible.
Study designs of evaluations included in the review
Randomised controlled trials (RCTs) were eligible for inclusion.
Specific interventions included in the review
Studies that compared different types of antibiotic prophylaxis with placebo or no treatment were eligible for inclusion. The included studies used cefotaxime, ciprofloxacin with and without amoxicillin-clavulanic acid, norfluoxacin, ofloxacin plus amoxicillin-clavulanic acid, imipenem and non-absorbable antibiotics (gentamicin, vancomycin, nystatin or neomycin, colistin and nystatin). The duration of treatment ranged from up to 7 days to 12 months.
Participants included in the review
Studies of hospitalised patients with cirrhosis were eligible for inclusion. The participants in the included studies presented with gastrointestinal bleeding, low-protein ascitic fluid, or had suffered a previous episode of spontaneous peritonitis. The participants had varying severity of cirrhosis, ranging from mild to moderate to severe (classified as Child-Pugh C).
Outcomes assessed in the review
The primary outcomes in the review were the fatality rate and bacterial infections. The secondary outcomes were Gram-negative bacterial infections, the development of resistance to the given antibiotic in at least one follow-up culture, any fatal or life-threatening adverse event, and any adverse event requiring hospitalisation or withdrawal of the drug. The review also assessed the fatality rate for bacterial infections. The duration of follow-up ranged from up to 30 days to 12 months.
How were decisions on the relevance of primary studies made?
Two reviewers independently selected the studies. Any disagreements were resolved by discussion, with the aid of a third reviewer in cases where disagreements persisted.
Assessment of study quality
Studies were assessed on the basis of the adequacy of allocation concealment (adequate or unclear), exclusions after randomisation (reported or not), sample size (fewer than 100 or more than 100 patients) and length of follow-up (up to 3 months, or 6 to 12 months). Two reviewers independently assessed validity. Any disagreements were resolved by discussion, with the aid of a third reviewer in cases where disagreements persisted.
Two reviewers independently extracted the data. Any disagreements were resolved by discussion, with the aid of a third reviewer in cases where disagreements persisted. Data were extracted on the participants and antibiotic treatment regimens, the number of patients in each treatment group, the length of treatment and follow-up, exclusions, and severity of cirrhosis (measured using Child Pugh score). The relative risk (RR) and 95% confidence interval (CI) were calculated for each study.
Methods of synthesis
How were the studies combined?
The studies were combined using a meta-analysis. Pooled RRs and 95% CIs were calculated using a fixed-effect model. A funnel plot was generated to investigate publication bias.
How were differences between studies investigated?
Statistical heterogeneity was assessed by inspecting forest plots and using the chi-squared statistic. Subgroup analyses were conducted to explore the effect on fatality and bacterial infections of allocation concealment, exclusions, sample size, length of follow-up, severity of cirrhosis (more than 30% of patients with severe cirrhosis versus less than 30%), the use of quinolone antibiotics and patient characteristics (defined according to presenting signs). Pooled RRs and 95% CIs were also calculated according to the type of bacterial infection (bacteraemia, pneumonia, spontaneous bacterial peritonitis and urinary tract infection).
Results of the review
Thirteen RCTs (1,234 patients) were included.
Five RCTs reported adequate allocation concealment. Nine RCTs reported exclusions, with rates ranging from 3 to 22% of the patients.
The meta-analysis showed that antibiotic prophylaxis significantly reduced the overall fatality rate and the fatality rate for bacterial infections compared with placebo or no antibiotic treatment. The RR for fatality was 0.70 (95% CI: 0.56, 0.89). No significant statistical heterogeneity was detected (P=1). The RR for fatality from bacterial infection (5 RCTs, 594 patients) was 0.22 (95% CI: 0.08, 0.61).
The meta-analysis showed that antibiotic prophylaxis significantly reduced bacterial infections and Gram-negative bacterial infections compared with placebo or no antibiotic treatment. The RR for bacterial infections was 0.39 (95% CI: 0.32, 0.48). No significant statistical heterogeneity was detected (P=0.19). The RR for Gram-negative bacterial infections (10 RCTs, 922 patients) was 0.15 (95% CI: 0.09, 0.24). Significant reductions were also found for other types of specific infections (the results were reported). A subgroup analysis of 9 trials of quinolone antibiotics found a marginally significant benefit on fatalities and a highly significant effect on bacterial infection (the results were reported).
Adverse effects were reported for quinolones (nausea, diarrhoea, headache, fever, hypersomnia, skin rash and candidiasis) and for trimethoprim-sulfamethoxazole (diarrhoea). Such adverse effects were not life threatening and required the withdrawal of only one patient.
Two studies reported superinfection and isolation of resistant stains, but no further analysis was conducted.
The funnel plot showed asymmetry suggesting the possibility of publication bias.
Sensitivity analyses found that studies with a sample size of fewer than 100 patients and no report of exclusions showed greater benefit for antibiotics than larger RCTs. None of the other quality criteria influenced the fatality rates. The results were reported.
Antibiotic prophylaxis reduced deaths and bacterial infections among in-patients with cirrhosis, regardless of the underlying risk factors.
The review question was clear in terms of the study design, intervention, participants and outcomes. Several relevant sources were searched and the search terms were stated. Attempts were made to minimise language and publication bias. Two reviewers independently selected the studies, assessed validity and extracted the data, which reduces the potential for bias and errors. Validity was assessed using specified established criteria. The data were combined in a meta- analysis and statistical heterogeneity was assessed. Subgroup analyses were conducted to explore the influence of various factors, including quality criteria, on the results. This was a well-conducted and clearly presented review, and the authors' conclusions are likely to be reliable.
Implications of the review for practice and research
Practice: The authors stated that the results of the review indicate that antibiotic prophylaxis should be considered for every in-patient with cirrhosis.
Research: The authors stated that a large RCT is required to assess antibiotic prophylaxis in every patient with cirrhosis, regardless of any additional risk factor.
EU 5th Framework, grant number TREAT, IST 1999-11459; Cochrane Hepato-Biliary Group; Danish Medical Research Council.
Soares-Weiser K, Brezis M, Tur-Kaspa R, Paul M, Yahav J, Leibovici L. Antibiotic prophylaxis of bacterial infections in cirrhotic inpatients: a meta-analysis of randomized controlled trials. Scandinavian Journal of Gastroenterology 2003; 38(2): 193-200
Other publications of related interest
Soares-Weiser K, Brezis M, Tur-Kaspa R, Leibovici L. Antibiotics prophylaxis for bacterial infections in cirrhotic patients with gastrointestinal bleeding (Cochrane Review). In: The Cochrane Library, Issue 2, 2002. Oxford: Update Software.
Subject indexing assigned by NLM
Antibiotic Prophylaxis; Bacterial Infections /prevention & control; Cross Infection /prevention & control; Humans; Liver Cirrhosis /microbiology; Randomized Controlled Trials as Topic; Risk Factors
Database entry date
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.