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A meta-analysis of randomized, controlled trials comparing short- and long-course antibiotic therapy for urinary tract infections in children |
Keren R, Chan E |
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Authors' objectives To determine whether long-course antibiotic therapy is more effective than short-course therapy for the treatment of urinary tract infections (UTIs) in children, and to explore potential sources of heterogeneity in the results of existing studies.
Searching MEDLINE was searched for all studies published in the English language that compared short- and long-course therapy for the treatment of acute UTI in children. The searches were indexed by the MeSH terms 'urinary tract infection' and 'antibiotics', and were limited to RCTs, children age 0 to 18 years, and humans. The references of all the retrieved articles, as well as a practice guideline on the management of UTIs in children, were scanned. In addition, the Cochrane Library website was searched for systematic reviews on the treatment of UTI. Experts in the field were also contacted for other published or unpublished trials.
Study selection Study designs of evaluations included in the reviewRandomised controlled trials (RCTs) were eligible for inclusion.
Specific interventions included in the reviewStudies comparing short- (3 days or less) and long- (7 to 14 days) course out-patient antibiotic therapy.
Participants included in the reviewChildren aged 0 to 18 years with UTIs. Studies that were restricted to children with recurrent UTI, or included children with asymptomatic bacteriuria, were excluded from the analysis.
Outcomes assessed in the reviewThe authors did not specify any inclusion criteria regarding the outcomes. Where possible, the outcomes from the primary studies were reclassified as 'treatment failure' or 'reinfection'.
How were decisions on the relevance of primary studies made?The authors do not state how the papers were selected for the review, or how many of the reviewers performed the selection.
Assessment of study quality The authors developed a 9-item scoring system to evaluate the quality of the RCTs included in the meta-analysis. This addressed the following methodologic issues: the exclusion of children with anatomic and/or functional urinary tract abnormalities; an attempt to distinguish lower from upper UTI by signs and symptoms (fever, vomiting, flank pain, and costo-vertebral angle tenderness) and/or laboratory tests (elevated white blood cell count, blood urea nitrogen, creatinine, erythrocyte sedimentation rate, and C-reactive protein); UTI defined by symptoms and bacteriologic findings; distinction made between persistent infection, relapse with the same organism and reinfection with a different organism; placebo-control for the short-course arm; blinding; the method of allocating the participants to the short- and long-course groups; intention to treat analysis; and equal surveillance and the duration of follow-up for treatment and control groups. The authors do not state how the papers were assessed for quality, or how many of the reviewers performed the quality assessment.
Data extraction Using a standardised data extraction form, the authors independently extracted the following information: year of publication; sample size; setting; mean participant age; definition of UTI; attempt to distinguish lower from upper UTI; exclusion criteria; method of allocation; definitions of short- and long-course, antibiotic(s) studied; follow-up period; treatment failure rate; and reinfection rate. Any disagreements were resolved by consensus after returning to the original publication.
Methods of synthesis How were the studies combined?Reanalysing the data with intention to treat whenever possible, the relative risk (RR) of treatment failure and reinfection was calculated, along with 95% confidence intervals (CIs), for each individual study comparing short and long-course therapy. To obtain the pooled RRs with 95% CIs for treatment failure and reinfection, the random-effects model of DerSimonian and Laird (see Other Publications of Related Interest no.1) was used.
The influence of publication bias was assessed using the tests of Begg and Mazumdar (see Other Publications of Related Interest no.2) and Egger et al. (see Other Publications of Related Interest no.3) and a funnel plot, which maps the log standard error against the log odds ratio of the individual studies.
How were differences between studies investigated?The Q test was used to test for the heterogeneity of the study results (see Other Publications of Related Interest no.4). To determine whether the anatomic level (upper versus lower) of UTI affects the relative efficacy of short- and long-course therapy, the pooled RRs were calculated for the subset of studies that attempted to restrict their participants to children with lower UTI. To determine whether there is a dose-response effect for the duration of short-course therapy, the pooled RRs were calculated for the subset of studies that compared single-dose or single-day therapy with long-course therapy, and the subset of studies that compared 3-day therapy with long-course therapy.
To explore other potential sources of heterogeneity in the results, such as study quality and the mean age of the sample, a random-effects regression model was developed that included these variables as covariates. In the meta-regression, the dependent variable was the odds ratio for the outcome of interest (treatment failure or reinfection), while the independent variables were study quality score and mean age of the sample.
Results of the review Seventeen RCTs (n=1,126) met the review's inclusion criteria.
None of the studies included in the meta-analysis satisfied all nine quality criteria. Only one study was placebo-controlled and double-blinded, and only three analysed their results on an intention to treat basis. However, in the meta-regression, neither study quality nor mean participant age was significantly associated with the odds ratio of treatment failure or reinfection.
The pooled estimate for the RR of treatment failure with short-course antibiotic therapy was 1.94 (95% CI: 1.19, 3.15) and for the RR of reinfection was 0.76 (95%: CI 0.39, 1.47). When 3 studies that did not attempt to restrict their participants to patients with lower UTI were excluded, the pooled RR was 1.74 (95% CI: 1.05, 2.88) for treatment failure and 0.69 (95% CI: 0.32, 1.52) for reinfection. The meta-analysis of the 11 studies comparing single-dose or 1-day therapy with long-course therapy, gave a pooled RR of 2.73 (95% CI: 1.38, 5.40) for treatment failure and 0.37 (95% CI: 0.12, 1.18) for reinfection. For the 5 studies comparing 3-day therapy with long-course therapy, the pooled RR was 1.36 (95% CI: 0.68, 2.72) for treatment failure and 0.99 (95% CI: 0.46, 2.13) for reinfection.
A funnel plot of all the included studies suggested that publication bias was not present, as did both the Begg's and Egger's test for publication bias (P=0.54 and P=0.22, respectively).
Authors' conclusions Long-course therapy was associated with fewer treatment failures without a concomitant increase in reinfections, even when studies including patients with evidence of pyelonephritis were excluded from the analysis. No additional comparative trials are warranted, and clinicians should continue to treat children with UTI for 7 to 14 days.
CRD commentary This meta-analysis had several limitations. Appropriate inclusion criteria relating to the interventions, study design and participants were used to select the studies for the review. Adequate details of the included trials were presented, and the quality of the individual RCTs was systematically addressed. However, as only English language studies were included and the database search for RCTs was limited to MEDLINE, relevant evidence may have been missed.
A quality assessment was carried out, but little data on the quality of the included studies were given in the report and it was not possible to determine which RCTs were of a higher methodological quality. Also, though the authors reported that a formal test of heterogeneity was carried out, no statistical data on heterogeneity were given in the results of the meta analysis. An examination of the 'reinfection' forest plot indicates that there is some heterogeneity between the six study results given for this outcome. While the quality score and mean age of the sample were not significantly associated with the outcome, the sources of heterogeneity may have included the type of antibiotic, the dose, and the duration of antibiotic treatment in the long- and short-course groups.
These limitations should be borne in mind when considering the appropriateness of the authors' conclusions.
Implications of the review for practice and research Practice: The authors state 'clinicians should continue to treat children with UTI for 7 to 14 days'.
Research: The authors state 'Until there are more accurate methods for distinguishing upper from lower UTI in children...no additional RCTs are needed at this time to address the question of whether short-course antibiotic therapy is sufficient for the treatment of UTI in children'. The authors go on to state: 'If and when more accurate tests are developed to distinguish upper from lower UTI, another RCT to evaluate the effectiveness of short course therapy for lower UTI may be warranted'. Several recommendations regarding the design of such an RCT are given.
Funding US Department of Health and Human Services, Health Resources and Services Administration, grant number T32 PE 10 018.
Bibliographic details Keren R, Chan E. A meta-analysis of randomized, controlled trials comparing short- and long-course antibiotic therapy for urinary tract infections in children. Pediatrics 2002; 109(5): E70 Other publications of related interest 1. DerSimonian R, Laird N. Meta-analysis in clinical trials. Control Clin Trials 1986;7:177-88. 2. Begg CB, Mazumdar M. Operating characteristics of a rank correlation test for publication bias. Biometrics 1994;50:1088-101. 3. Egger, M, Davey Smith G, Schneider M, Minder C. Bias in meta-analysis detected by a simple graphical test. BMJ 1997;315:629-34. 4. Petitti DB. Meta-analysis, decision analysis, and cost-effectiveness analysis: methods for quantitative synthesis in medicine. New York (NY): Oxford University Press; 1994.
This additional published commentary may also be of interest. Daniels J, DiCenso A. Review: antibiotic treatment for 7-14 days reduces treatment failure in children with urinary tract infection. Evid Based Nurs 2003;6:15.
Indexing Status Subject indexing assigned by NLM MeSH Adolescent; Adult; Ambulatory Care; Anti-Bacterial Agents /administration & Child; Child, Preschool; Dose-Response Relationship, Drug; Female; Humans; Infant; Male; Randomized Controlled Trials as Topic; Risk; Sex Factors; Treatment Failure; Treatment Outcome; Urinary Tract Infections /drug therapy; dosage /therapeutic use AccessionNumber 12002001117 Date bibliographic record published 28/02/2003 Date abstract record published 28/02/2003 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. |
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