Elsevier

The Lancet Infectious Diseases

Volume 20, Issue 9, September 2020, Pages 1080-1088
The Lancet Infectious Diseases

Articles
Reappraisal of the treatment duration of antibiotic regimens for acute uncomplicated cystitis in adult women: a systematic review and network meta-analysis of 61 randomised clinical trials

https://doi.org/10.1016/S1473-3099(20)30121-3Get rights and content

Summary

Background

Evidence from numerous randomised clinical trials suggest that shorter-term antimicrobial therapy is as effective as—and has other advantages over—longer-term antimicrobial regimens at achieving symptomatic cure for acute uncomplicated cystitis. Nevertheless, not all shorter regimens are adopted in clinical guidelines. This study was done to reappraise the treatment duration of each antibiotic in current guidelines for acute uncomplicated cystitis to investigate whether the regimen lengths of guideline approved antibiotics could be reduced.

Methods

We systematically searched the PubMed, Embase, and Cochrane Library databases for relevant publications from inception of the databases until Dec 31, 2019. Only randomised clinical trials of women with acute uncomplicated cystitis that assessed antibiotic therapy and reported clinical or microbial response outcome values were included. A network meta-analysis was done and the quality of evidence of all of the included studies was rated. Clinical response was the primary outcome, defined as the complete disappearance of all baseline symptoms at the test-of-cure visit. Bayesian hierarchical random-effects model for dichotomous outcomes was used to compare the efficacy of each antibiotic treatment regimen directly and indirectly. This systematic review is registered in PROSPERO, CRD42018093529.

Findings

Overall, 61 randomised clinical trials—which included 20 780 patients—were assessed in our systematic review. For the third-generation and fourth-generation fluoroquinolones, a 3-day regimen had similar effect to a single-dose regimen for clinical response (risk ratio [RR] 0·994 [95% credible interval 0·939–1·052] vs 1·024 [0·974–1·083]), with moderate quality of evidence. For pivmecillinam, 5-day and 7-day regimens were similar to a 3-day regimen for clinical response, with moderate quality of evidence (RR 1·041 [0·910–1·193] for the 5-day regimen and 1·095 [0·999–1·203] for the 7-day regimen). Meanwhile, for third-generation cephalosporins and amoxicillin and clavulanate, there was no difference between single-dose and 3-day regimens, but quality of evidence supporting this conclusion was low. For second-generation quinolones and co-trimoxazole, single-dose regimen was less effective than 3-day regimen in clinical response, with moderate quality of evidence.

Interpretation

Treatment duration of the third-generation and fourth-generation quinolones and pivmecillinam could be shorter than the currently recommended regimens for acute uncomplicated cystitis. For other antibiotics, shorter duration of regimens could be considered, but further research is needed because of the low quality of supporting evidence.

Funding

None.

Introduction

Uncomplicated urinary tract infection is defined as an infection that occurs in a healthy person, who is not pregnant or has not recently been instrumented, without anatomical or functional urinary tract abnormalities.1 Women are more likely to experience uncomplicated urinary tract infection than are men, with 40–50% of women having at least one infection in their lifetime.2 Most infections in women are acute uncomplicated cystitis,3 and its most common symptoms are frequency, urgency, and dysuria, which can significantly affect the patient's quality of life.4 80% of cases of uncomplicated urinary tract infection are caused by Escherichia coli, 5–15% of cases are attributable to Staphylococcus saprophyticus, and the remainder are caused by the Proteus species and other Gram-negative rod bacteria.5, 6 Urine cultures are used for diagnosing uncomplicated urinary tract infection before patient recruitment into most clinical trials of antibiotic treatments.7 However, urine culture is not mandatory in real-world practice; instead history, physical examination, and urinalysis are important tools for diagnosis. Therefore, clinical guidelines for uncomplicated cystitis recommend empirical antibiotic treatment.

According to the guidelines for uncomplicated urinary tract infection, nitrofurantoin, fosfomycin trometamol, trimethoprim and sulfamethoxazole (co-trimoxazole), trimethoprim, and pivmecillinam are recommended as the first-choice antibiotics, with fluoroquinolones and other β-lactams listed as potential alternatives.8, 9, 10 Prescriptions of these antibiotics range from 3-day to 7-day courses, except for fosfomycin trometamol, which is a single-dose therapy. Shorter-term antimicrobial therapies are also advantageous because they have fewer adverse effects, are more cost effective, and are associated with a reduced potential of emergence of antibiotic-resistant organisms.11 A meta-analysis showed that 3-day regimens have a similar ability to achieve symptomatic cure for cystitis as prolonged therapies of 5 days or more.7 Several studies reported that single-dose therapies have similar efficacy to longer-term therapies of 3 days or more.12, 13, 14, 15 Nevertheless, fosfomycin trometamol is the only available single-dose regimen for uncomplicated cystitis, and not all shorter regimens (eg, a 3-day β-lactam regimen) have been incorporated into clinical guidelines despite evidence from randomised clinical trials.8, 9, 10 For these reasons, we undertook a systematic review and network meta-analysis of randomised controlled trial data to investigate whether the treatment duration of each antibiotic could be shorter than the currently recommended duration—for example, reducing the regimen length from 5 days to 3 days, or from 3 days to a single-dose.

Research in context

Evidence before this study

The Infectious Diseases Society of America and European Society for Clinical Microbiology and Infectious Diseases collaboratively updated the International Clinical Practice guidelines for the treatment of acute uncomplicated cystitis in women in 2010. They recommended nitrofurantoin 5-day, co-trimoxazole 3-day, fosfomycin trometamol single-dose, and pivmecillinam 3–7-day regimens as appropriate choices, and other antimicrobial regimens as alternatives. Evidence from various randomised clinical trials and previous meta-analyses suggest that shorter-term antimicrobial therapy are as effective as prolonged therapy, but not all shorter regimens were adopted into clinical guidelines. This study was done to reappraise the treatment duration of each of the antibiotics in current guidelines.

We searched PubMed, Embase, and Cochrane Library databases for randomised controlled trials published from the inception of each database until Dec 31, 2019. The following search terms were used: “uncomplicated”, “cystitis”, “urinary infection”, “antibiotic treatment”, and relevant variants (appendix p 1). Only randomised controlled trials that compared the clinical and microbial effectiveness of antibiotics in female patients with acute uncomplicated cystitis were included. A network meta-analysis was done to compare the efficacy of each antibiotic treatment regimen directly and indirectly.

Added value of this study

We reassessed the evidence supporting the current international guidelines with a network meta-analysis and rating the quality of evidence. Single-dose third-generation and fourth-generation fluoroquinolones had a similar effect on clinical and microbial responses as 3-day regimens, supported by a moderate quality of evidence. 3-day pivmecillinam had similar clinical and microbial responses to that of 5-day and 7-day regimens, supported by a moderate quality of evidence. Moderate quality of evidence suggests that the true effect is likely to be close to the estimate of the effect. However, there was no difference in both clinical and microbial responses between single-dose and 3-day regimens of third-generation cephalosporin, but the quality of evidence supporting this was either low or very low. This finding suggested a poor confidence in the effect estimate; therefore, there is insufficient power to affect the current clinical practices and guidelines. A 3-day regimen of nitrofurantoin appears to have a similar effect on clinical and microbial responses as the 5-day regimen, but the quality of evidence supporting this was very low. For co-trimoxazole and second-generation quinolones, single-dose therapy was less effective than the 3-day regimen, with moderate quality of evidence supporting this conclusion.

Implications of all the available evidence

In acute uncomplicated cystitis, treatment duration of pivmecillinam, third-generation and fourth-generation fluoroquinolones could be shorter than the recommended durations. The effect of shorter course regimens of nitrofurantoin (3-day), trimethoprim (3-day), and first-generation and third-generation cephalosporins (single-dose) might be similar to the conventional durations of each antibiotic; however, further research is needed because of the low quality of evidence associated with these conclusions. The currently recommended 3-day regimens of co-trimoxazole and second-generation quinolone appear to be appropriate. Given the significant rise in antibiotic resistance worldwide, our findings might add value to the literature because if regimens can be reduced in length, the adverse event and risk of resistance can be reduced.

Section snippets

Search strategy and selection criteria

In this systematic review and network meta-analysis we systematically searched the PubMed, Embase, and Cochrane Library databases for English language randomised controlled trials published from the inception of each database until Dec 31, 2019. The search terms included “uncomplicated”, “cystitis”, “urinary infection”, and “antibiotic treatment”; a full list of search terms are included in the appendix (p 1). All conference and meeting abstracts, and non-English language articles were

Results

The systematic database search identified 3327 articles, of which 2599 remained after removing duplicates (figure 1). After reviewing the titles and abstracts of all available literature and excluding animal studies, non-English articles, editorials, letters, reviews, case reports, guidelines, and articles not related to this study, the full texts of 213 articles were reviewed to evaluate compliance with the inclusion criteria. Finally, the present study included 61 randomised clinical trials,

Discussion

Our network meta-analysis showed that single-dose third-generation and fourth-generation fluoroquinolone induced similar clinical and microbial responses to 3-day regimens, and the effect of 3-day pivmecillinam was also similar to that of 5-day and 7-day regimens. Quality of evidence for these comparisons was graded as moderate, which suggests that the true effect is likely to be close to the estimated effect.19 On the basis of this evidence, single-dose regimens of third-generation (eg,

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