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Having recently published a meta-analysis on the same clinical question,1 it was with great interest that we read Michael et al’s systematic review of short versus standard duration antibiotics for urinary tract infections (UTIs) in children.2 Given the publication (in close succession) of two meta-analyses on the same question with (on the surface) strikingly different results, we thought a comment was in order.
First, we applaud the authors on their methodologically sound review. The literature search was explicitly described and exhaustive. In fact, the authors identified a few studies that we had missed.3–6 The study outcomes for meta-analysis (frequency of positive urine cultures at 0–7 days after treatment and at 10 days to 15 months after treatment, and development of resistant organisms and recurrent UTI) were relevant and clearly defined.
The authors provided appropriate and important meta-analysis measures including summary relative risks (RRs) and a quasi-NNT calculation with varying risk of treatment failure in the standard treatment group and confidence intervals corresponding to “best” and “worst” case scenarios.
For their primary outcome, frequency of positive urine cultures 0–7 days after treatment, the authors found no significant difference between short (2–4 days) and standard (7–14 days) treatment (RR 1.06; 95% CI 0.64 to 1.76). This is in contrast to our finding of a 94 % increased pooled risk of treatment failure with short course treatment (≤3 days) compared to standard treatment (7–14 days) (RR 1.94, 95% CI 1.19 to 3.15; NNT=13, 95% CI 100 to 7). Why the discrepancy? We postulate a few possible explanations and conclude that the two meta-analyses, on closer inspection, actually have very similar results.
Our omission of certain studies identified by Michael and colleagues may have biased our results. However, of the three studies3–5 that we missed and that they included in their analysis of treatment failure at 0–7 days after completion of treatment, two favoured standard duration treatment, which would have supported our pooled RR result. Another possible explanation for the divergent results was the use of different definitions of treatment failure. For our definition of treatment failure we pooled persistent infection (failure to eradicate the organism within 1 to 2 days of initiation of treatment) and relapse (recurrence of symptoms and reinfection within 2 weeks of cessation of treatment after initial bacteriologic cure), whereas Michael et al used frequency of positive cultures 0–7 days after cessation of treatment as their primary outcome measure of treatment failure. If reinfections later than 7 days after cessation of treatment occurred more often in recipients of short course treatment, then Michael et al ’s definition of treatment failure could have failed to capture the therapeutic advantage of standard duration treatment.
However, the most likely explanation for the divergent results was the different ways in which the study question was framed and the resulting differences in studies included in the meta-analyses. We compared ≤3 days of treatment to 7–14 days of treatment, whereas Michael et al compared 2–4 days of treatment to 7–14 days of treatment and excluded 11 studies comparing single-dose or single-day treatment to standard duration treatment.7–17
The reasons for this exclusion are unclear, although we presume that they felt single-dose or single-day treatment was not a fair comparison with 7–14 day treatment. However, a number of randomised controlled trials (RCTs) made this comparison, suggesting that clinicians are, in fact, interested in the potential efficacy (and significantly increased ease and savings) of single-dose or single-day treatment. Inclusion of these studies in our analysis strongly influenced the pooled risk of treatment failure with short-course treatment. When we excluded these studies in a sub-group analysis of 3-day versus long course (7–14 day) treatment, the risk of treatment failure fell to 1.36 (95% CI 0.68 to 2.72) (NNT=50; 95% CI 33 - 13).
Thus, our meta-analysis demonstrates clearly that single dose or single day antibiotic treatment is not as effective as long-course treatment for UTIs in children. The two meta-analyses together suggest that:
“longer” short-course therapies may be as effective as 7–14 days of antibiotics and
there is probably a duration of treatment threshold for “short-course” antibiotic treatment, above which longer duration of treatment confers no therapeutic advantage.
Michael and colleagues suggest that as little as 2 days of treatment may be sufficient. However, only one of the trials in their meta-analysis studied 2-day treatment4 and that one favoured long-course treatment with a RR of UTI 0–7 days after completing short course treatment of 2.17 (95% CI 0.48 to 9.76). The duration of treatment threshold may be 3 days, but the point estimate of relative risk of treatment failure with 3 day treatment in our meta-analysis suggests otherwise. If the duration of short-course treatment for which there is no difference in efficacy compared with standard treatment is actually greater than 3 days, then the added convenience and cost-savings of “short-course” treatment become marginal. In the absence of appropriately powered RCTs (or meta-analyses) examining outcomes (treatment failure, reinfection, emergence of resistant organisms and cost) with “longer” short course treatment regimens (3, 4, and 5 days), we think that clinicians should continue to treat UTIs in children with at least 7 days of antibiotics.
In response to Keren and Chan’s thoughtful letter regarding our recent systematic review,1 we need to emphasise that the study question we addressed was different from that addressed by Keren and Chan in their own systematic review2 of randomised controlled trials comparing short with standard duration treatment in the treatment of children with urinary tract infection (UTI). The aim of our study was to determine the relative efficacies of short (2–4 days) and standard duration (7–14 days) treatment with the hypothesis that short duration may be as effective as standard duration treatment and provide potential advantages such as improved compliance. Therefore, we did not include trials in which single dose treatment was compared with standard duration treatment. In addition we chose to limit the review to trials in which the same antibiotic was used to treat each group, to avoid confounding.
The response to single dose treatment appears different from short course, suggesting that it is inappropriate to pool studies comparing single dose and standard treatment with those comparing short course and standard treatment. Three systematic reviews1–3 have now demonstrated that there is no significant difference in the number of children with persistent bacteriuria after short duration or standard duration treatment (see table 1). In contrast, Keren and Chan2 found that significantly more children had persistent bacteriuria following single dose compared with standard duration treatment (7 data sets: RR 2.73, 95% CI 1.38 to 5.40). Similarly, Tran et al3 in their meta-analysis of 22 studies comparing both single dose and short duration treatment with standard duration treatment found the latter to be more effective (risk difference 6.38; 95% CI 1.88 to 10.89).
Because there is no significant difference between short duration and standard duration treatment in the number of children with persistent UTI after treatment, it is not possible to calculate a number needed to treat to prevent one episode of persistent bacteriuria.
From our systematic review, we are not able to determine whether there is an “optimum duration of treatment threshold” as postulated by Keren and Chan.2 Only one study4 included in the meta-analysis, examining the effects of short duration and standard duration treatment in clearing bacteriuria, compared 2 days of treatment with 10 days’ treatment. In their letter above, Keren and Chan argue that this study favours standard duration treatment. However, there was no significant difference between treatments in the number of children with persistent bacteriuria at the end of treatment (RR 2.17; 95% CI 0.48 to 9.76) although the wide confidence intervals do not exclude the possibility that short duration treatment could be more or less effective than standard duration treatment.
No significant differences in the number of children with persistent UTI after treatment between short duration and standard duration antibiotic treatment have been found in three systematic reviews of randomised controlled trials despite different study inclusion criteria and definitions of persistent infection. As addressed in our review, the wide confidence intervals around the summary estimates indicate residual imprecision in the results. However, this statistical imprecision is of doubtful significance for most children, who are at a low risk (1–3%) of persistent UTI at the end of treatment following their first lower tract UTI.5,6 Therefore, we do not support Keren and Chan’s conclusion that clinicians should continue to treat lower tract UTI with standard duration treatment. Instead, we believe that short duration treatment may be used to treat children with lower tract UTI.