Quinolones for uncomplicated acute cystitis
Rafalsky V, Andreeva I, Rjabkova E
This protocol should be cited as:
Rafalsky V, Andreeva I, Rjabkova E
Quinolones for uncomplicated acute cystitis (Protocol for a Cochrane Review).
In: The Cochrane Library, Issue 1, 2002. Oxford: Update Software.
Urinary tract infections (UTIs) are common with an estimated annual global incidence of at least 250 million cases, and are costly to both patients and health care funding systems (Ronald 2001). Uncomplicated infections account for the greatest number of UTIs. The distinction between uncomplicated and complicated UTIs is important because of implications regarding pre- and post-treatment evaluation, type and duration of antimicrobial regimens and extent of evaluation of the urinary tract (Bacheller 1997). Acute cystitis is the most prevalent form of uncomplicated UTI. In the USA over seven million cases of acute cystitis are registered each year, equating to approximately one billion US dollars (1994 Schappert). The percentage of women who have at least one episode of acute cystitis is estimated to be 40-50% (Kunin 1994).
The organisms most often responsible for UTIs are the enteric gram-negative bacteria of the group Enterobacteriaceae. Escherichia coli (E.coli) cause approximately 80% of UTIs and Staphylococcus saprophyticus is the second most common pathogen, particularly in young women (Johnson 1989).
Factors that should be considered in selecting drugs for the treatment of uncomplicated acute cystitis include the spectrum (broad or narrow) of the agent, pharmacokinetics favouring wider dosing intervals, the prevalence of resistance in local urinary pathogens, the duration of adequate urinary antimicrobial levels, the effect on the faecal and vaginal flora, the potential for undesirable side effects and the cost of the treatment regimen (Hooton 1991; Hooton 1997; Neu 1992).
Antimicrobials with proven efficacy in acute cystitis are co-trimoxazole, nitrofurantoin, quinolones, fluoroquinolones and phosphomycine trometamole (Warren 1999; Naber 1999; Naber 2000). Increased resistance to co-trimoxazole however, may reduce its effectiveness in the treatment of uncomplicated acute cystitis as there has been shown to be a correlation between resistance and eradication of E.coli. (Minassian 1998).
Quinolones have good activity against E.coli, achieve high urinary concentrations and have minimal effect on the natural vaginal protective flora (lactobacilli and anaerobes) (Anderson 1999). Once or twice-daily dose regimens may be used for administering these antimicrobials, providing the possibility of enhanced compliance. In addition, urinary pathogen resistance is rarer for quinolones when compared with co-trimoxazole. Treatment regimens for quinolones include single dose, three- or seven-day schedules, however the single dose regimen is not considered suitable because of fewer cures and increased recurrence rates (Norrby 1990). The seven-day course has greater potential for side effects, is more expensive and has not been shown to have an improved the therapeutic effect. The short (three-day) course appears to offer the best combination of efficacy and decreased risk of side effects and toxicity (Warren 1999).
People diagnosed with acute cystitis are usually treated as out-patients and therefore tolerance and antimicrobial safety needs to be carefully considered. Adverse reactions may result in non-compliance, administration of another drug and, in some cases, hospitalisation. These factors lead to an increase in cost and reduction in quality of life.
Recent reviews by Warren 1999 and Echols 1999 have focused on the microbiological efficacy and factors influencing therapy outcomes of several different antimicrobials. However neither looked at the adverse reactions of quinolones. Hooton 1997 has suggested that clinically significant differences in safety and tolerance may exist between different quinolones.
The aim of this systematic review is to evaluate the efficacy, safety and tolerance of different quinolones for the treatment of acute, uncomplicated cystitis.
- To compare the efficacy, safety and tolerance of different quinolones in patients with acute, uncomplicated cystitis.
- To compare different quinolones given as either a single dose, short course (three to seven days) or as a long course (seven to 14 days).
Criteria for considering studies for this review
Types of studies
We will select all randomised and quasi-randomised controlled trials comparing two or more quinolones in patients with acute uncomplicated cystitis. We will select trials that included only women, and trials in which data are available separately for women. We will contact the authors of the trials in which both men and women are included but for which no details of the results for women are given, to ask for the separate data about women patients.
Types of participants
Non-pregnant and non-lactating women, 16-60 years old, with acute uncomplicated cystitis with the following:
- symptoms of acute cystitis (dysuria, urgency, frequency or suprapubic pain);
- significant positive urine culture: ≥1000 colony forming units/ml + pyuria ≥10 leukocytes/mm3 or positive urine culture ≥10000 colony forming units/ml alone (ECLM - European Urinalysis Group, 2000).
Patients with symptoms of pyelonephritis (fever or flank pain) and with complicating factors such as indwelling or intermittent urinary catheters, obstructive uropathy, vesicoureteric reflux and other urological abnormalities, azotemia due to intrinsic renal disease or renal transplantation will be excluded. Patients with asymptomatic bacteriuria and urinary tract infections in men will also be excluded.
Types of intervention
All studies comparing effectiveness and/or safety and/or tolerability of two or more oral quinolones (norfloxacin, ciprofloxacin, ofloxacin, pefloxacin, levofloxacin and others) in patients with acute uncomplicated cystitis will be included. Data will be analysed in accordance with the duration of treatment. We have defined the following scale of the treatment durations:
- Single dose.
- Short course (three to six days).
- Long course (seven to 14 days).
Longer as well as prophylactic treatments will be excluded.
Types of outcome measures
We are anticipating that trials will report the outcomes at different time points. If possible the outcomes will be recalculated for common time points from the raw data. If this is not possible, the outcomes will be pooled for short-term effects (i.e. during, immediately after or up to two weeks post-treatment) and long-term effects (> two weeks post-treatment).
- Bacteriological response - elimination of bacteriuria.
- Clinical response - elimination of dysuria, urgency, frequency or suprapubic pain.
- Recurrence rate three months after treatment.
- Frequency of recurrence three months after treatment.
- Development of pyelonephritis or urosepsis.
- Long-term mortality (all cause and related to UTI).
- Average difference in the quality of life score (measured by any scale) between groups.
- Number of people dropped out from the study after randomisation.
- Frequency of quinolones withdrawal due to: clinical failure, adverse event, patient decision.
- Adverse events:
- Any serious adverse events that are fatal, life-threatening, or requiring inpatient hospitalisation or prolongation of existing hospitalisation;
- Any adverse events that result in significant disability or incapacity;
- Any important medical events that may not be immediately life-threatening or result in death or hospitalisation, but may jeopardise the patient or may require intervention to prevent one of the above outcomes;
- Any adverse events that require discontinuation of medication.
Search strategy for identification of studies
The literature search by electronic database MEDLINE PubMed version (1966 to most recent), EMBASE CD Silverplatter version (January 1980 to most recent), the Cochrane Library (most recent issue), the trials register of the Cochrane Renal Group (most recent), and other available databases will be performed independently by two reviewers.
Search strategy (MEDLINE):
- randomized controlled trial.pt.
- randomized controlled trials/
- controlled clinical trial.pt.
- random allocation/
- double blind method/
- single-blind method/
- clinical trial.pt.
- exp clinical trials/
- (clin$ adj25 trial$).tw.
- ((singl$ or doubl$ or trebl$ or tripl$) adj25 (blind$ or mask$)).tw.
- research design/
- comparative study/
- exp evaluation studies/
- follow up studies/
- prospective studies/
- (control$ or prospectiv$ or volunteer$).tw.
- animal/ not (human/ and animal/)
- 7 or 16 or 22
- 24 not 23
- urinary tract infections.me
- acute cystitis.tw
- Escherichia coli Infections.me
- 26 OR 27 OR 28 OR 29 OR 30
- 34 AND 31 AND 25
For other databases (e.g. EMBASE) a similar search strategy will be used and help will be obtained from those experienced in searching these databases. In addition, the reference lists of identified articles, reviews, books and book chapters on the treatment of uncomplicated acute cystitis will be searched. Available abstracts of conferences in the fields of infectious diseases, urology and pharmacology will also be screened. Unpublished studies and data which are not included in bibliographical retrieval system will be sought from identified authors as well as from pharmaceutical companies marketing antibiotics that are used for urinary tract infections. No language restriction will be applied.
Extraction of data
Two reviewers independently using a data extraction form will extract data of patients, methods, interventions, outcomes and results. Missing data will be obtained from the authors whenever possible. The two reviewers will review each study independently. In case of duplicate publications, data will be extracted from the most recent and/or the most complete report.
Methods of the review
Two reviewers (VR and IA) will independently select the trials to be included in the review. A third reviewer (ER) will settle disagreements. Independently, two reviewers will apply the inclusion criteria to all potential studies. The reviewers will not be masked to the report authors, journals, date of publication, sources of financial support or results. Initially, the reviewers will ascertain that the study is a randomised clinical trial and they will analyse the allocation concealment as is described below.
Critical appraisal of studies
The quality items to be assessed are allocation concealment, intention-to-treat analysis, completeness of follow-up and blinding of outcome assessment.
1. Allocation concealment
2. Intention-to-treat analysis
Blinding of investigator
Blinding of participant
Blinding of outcome assessor
4. Completeness of follow-up
All data will be analysed together, and then a sensitivity analysis will be performed to determine if the inclusion of lower quality trials affects the overall result.
The following data will be extracted systematically for each study:
- trial design
- method of randomisation
- blinding (of participants, investigators and outcome assessor/s)
- Intention to treat analysis
- allocation concealment
- number of participants
- exclusions after randomisation
- duration of follow-up
- completeness of follow-up
- setting (community, long-stay institution, hospital)
- description of the trial population
- detailed description of the treatment used (substance, galenic form, dosage, duration of treatment)
- description and results of all measured outcomes
Where appropriate, the studies will be sub-grouped for meta-analysis according to the assessment of the above mentioned items and also for clinical heterogeneity.
Extraction of data
Two reviewers, independently using a data extraction form, will extract data of patients, methods, interventions, outcomes and results. The reviewers will crosscheck the recorded data. Missing data will be obtained from the authors whenever possible. The two reviewers will review each study independently. In case of duplicate publications, data will be extracted from the most recent and/or the most complete report.
For dichotomous outcomes (e.g. recurrence versus no recurrence) results will be expressed as relative risk (RR) with 95% confidence intervals (95% CI). Data will be pooled using the random effects model. Where continuous scales of measurement are used to assess the effects of treatment (e.g. quality of life), the weighted mean difference (WMD) will be used, or the standardised mean difference (SMD) if different scales have been used. We will analyse all the primary and secondary outcomes under consideration. The results will also be expressed as relative risk reduction (RRR), number needed to treat (NNT) and number needed to harm (NNH).
Statistical heterogeneity in trial results will be assessed both by the inspection of graphical presentations («funnel plot»: plotting the study weight or sample size [on the Y axis] against the RR [on the X axis]) and by using the Cochran Q test of N-1 degrees of freedom, with a probability of 0.05 used for statistical significance. Three possible reasons for heterogeneity will be pre-specified:
(i) that response differs according to the difference in the quality of the trial;
(ii) that response differs according to sample size;
(iii) that response differs according to clinical heterogeneity.
In case significant heterogeneity is found, its potential causes will be explored by the performance of subgroup analyses. We will also use the funnel plot approach to assess the likelihood of publication bias.
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Quinolones for uncomplicated acute cystitis [protocol]
Vladimir Rafalsky, Irina Andreeva, Elena Rjabkova
Dr Vladimir Rafalsky
Institute of Antimicrobial Chemotherapy Smolensk State Medical Academy
28 Krupskaya, P.O.Box 5
214019, Smolensk, Russia
Extramural sources of support to the review
No sources of support supplied
Intramural sources of support to the review
No sources of support supplied