Duration of antibacterial treatment for uncomplicated urinary tract infection in women
Abstract
This is a protocol for a Cochrane Review (Intervention). The objectives are as follows:
The objective of this review is to assess the evidence, as found in randomized controlled trials (RCTs) or quasi‐RCTs, for the relative effectiveness of different regimens of antibacterial treatments in acute, uncomplicated lower UTI in otherwise healthy 16‐65 years old females.
Specific objectives are:
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To assess the evidence for the relative effectiveness as assessed in RCT's comparing three day versus multi‐day therapy on:
‐ Relief of symptoms within two weeks after start of treatment.
‐ Resolution of bacteriuria within two weeks after start of treatment (bacteriological cure).
‐ Recurrence of symptoms or bacteriuria between cure and up‐to eight weeks after start of treatment.
‐ To assess the frequency of adverse events in the different regimens
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To assess the evidence for the relative effectiveness of the different antibacterial drugs used in the RCTs.
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To assess the evidence for development of resistance for different durations of treatment with different drugs. (comparing resistance of grown bacteria before and after therapy)
Background
Uncomplicated urinary tract infection (UTI) is a common disease, occurring frequently in young sexually active women. In one cohort study the incidence of the disease was estimated to be 0.5‐0.7/person year(Hooton 1996). All over the world the most common pathogens in uncomplicated UTI are similar: 80‐90% Escherichia coli, 5‐10% Staphylococcus saprophyticus, the remaining infections being caused by Proteus spp., and other Gram negative rods. Most are bacteria from the gut that colonize the perineum and then ascend through the urethra to infect the bladder mucosa. The infection causes specific symptoms, mainly the triad of dysuria (painful micturition), urgency (the urgent need to void) and frequency (very frequent urination). In randomized clinical trials the diagnosis is based on positive urine cultures in symptomatic subjects. In the past, the threshold for diagnosis of UTI was >105 colony forming units (cfu) per ml of voided midstream urine (MSU) (Stamm 1982). However already two decades ago studies have shown that in young symptomatic women with leucocyturia even 100 cfu/L voided MSU can establish the diagnosis (Stamm 1980; Stamm 1982; Kunin 1993).
A large range of antimicrobials with different rates of cure and side‐effects, are used in the treatment of UTI. It is thought that a short course therapy consisting of a three day antibacterial regimen is sufficient for uncomplicated UTI, as it is probably as effective as seven to ten days therapy, and may be associated with less side effects and lower costs (Hooton 1997). Single dose therapy has been advocated for years but recent reviews have raised doubts on its use because of a higher frequency of bacteriological recurrence (Norrby 1990; Leibovici 1991). On the other hand, single‐dose treatment probably achieve symptomatic relief more rapidly than seven days treatment (Arav‐Boger 1994)
In most clinical trials assessing effectiveness of therapy, cure is defined as bacteriological cure, rather than symptomatic relief. Uncomplicated UTI is not considered a serious disease. It is not completely known whether untreated UTI can progress to pyelonephritis, and how often. Progression to pyelonephritis probably occurs at a very low rate; while asymptomatic bacteriuria in young, healthy and non‐pregnant women is not associated with renal damage (Stamm 1991).
A previous systematic review by our group (Leibovici 1991) raised the following questions:
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What is the relative effectiveness of three days treatment compared with multi‐day treatment?
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Is any difference modified by the antibiotic used (old vs. new) or CFU/ml count?
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Do persistent positive cultures lead to persistent symptoms?
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What is the relative effectiveness of single dose and three days treatment, compared with seven days treatment, when the outcome of interest is symptomatic cure rather than bacteriological one?
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Does the duration of treatment influence the development of resistant strains during treatment?
Objectives
The objective of this review is to assess the evidence, as found in randomized controlled trials (RCTs) or quasi‐RCTs, for the relative effectiveness of different regimens of antibacterial treatments in acute, uncomplicated lower UTI in otherwise healthy 16‐65 years old females.
Specific objectives are:
-
To assess the evidence for the relative effectiveness as assessed in RCT's comparing three day versus multi‐day therapy on:
‐ Relief of symptoms within two weeks after start of treatment.
‐ Resolution of bacteriuria within two weeks after start of treatment (bacteriological cure).
‐ Recurrence of symptoms or bacteriuria between cure and up‐to eight weeks after start of treatment.
‐ To assess the frequency of adverse events in the different regimens
-
To assess the evidence for the relative effectiveness of the different antibacterial drugs used in the RCTs.
-
To assess the evidence for development of resistance for different durations of treatment with different drugs. (comparing resistance of grown bacteria before and after therapy)
Methods
Criteria for considering studies for this review
Types of studies
All RCTs and quasi‐RCTs comparing the relative effectiveness of three day versus five days or longer oral antibacterial therapy for UTI in women.
Types of participants
We will include studies on ambulatory, otherwise healthy women, aged 16‐65 years, with uncomplicated UTI defined by the presence of urinary complaints and a positive urine culture of more than 100 cfu/ml of voided MSU or obtained via urinary catheter.
Uncomplicated UTI is defined as the absence of all the following:
‐ Costovertebral pain or tenderness,
‐ Fever (more than 37.8°C),
‐ Positive blood cultures.
In addition, trials of the following groups of people will be excluded from the review:
‐ Multiple vomiting
‐ Sepsis
‐ Children up to the age of 16 years
‐ Hospital acquired infection
‐ Pregnancy
‐ Indwelling urinary catheter
‐ Recent urinary tract instrumentation
‐ Known pathological, functional or anatomic abnormality of the urinary tract
‐ Diabetes mellitus
‐ Immunocompromized patients
Types of interventions
Three days oral antibacterial treatment versus antibacterial treatment for greater than or equal to five days.
Types of outcome measures
1. Symptomatic relief
2. Symptomatic recurrences‐ defined as recurrence of urinary symptoms two to eight weeks after start of treatment.
3. Bacteriological cure defined as a negative urine culture at the last follow‐up within two weeks after start of treatment (or persistent positive urine culture at the end of therapy will be considered bacteriological failure)
4. Bacteriologic recurrences‐ defined as a positive urine culture between cure and up‐to 8 weeks after start of treatment.
5. Side‐effects:
‐ Any serious adverse events that are fatal, life‐threatening, or requiring hospitalization;
‐ 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 hospitalization, but may jeopardize the patient or may require intervention to prevent one of the above outcomes;
‐ Any adverse events that require discontinuation of medication
6. The percentage of pathogens resistant to the study drug two to eight weeks after start of treatment, compared with before treatment.
Search methods for identification of studies
1. Cochrane Central Register of Controlled Trials (CENTRAL ‐ The Cochrane Library, Most recent issue)
2. The Cochrane Renal Group's specialized register of randomized controlled trials
3. EMBASE (1980 to most recent),
4. MEDLINE (1966 ‐ to most recent) will be searched with the phrase:
[(urinary near infection*) or cystitis or UTI] and [(single near dos*) or (3 near day*) or (three near day*)]
5. Reference searching and personal contact
6. The references of all identified studies will be inspected for more studies. Additionally, the first or corresponding author of each included study will be contacted for complementary information on their own trial as needed.
We will include all languages. The terms used will not attempt to filter out articles that are not RCT's, and by leaving single dose in the search strategy we will find articles that include single and three day doses versus multi‐day.
Data collection and analysis
Two reviewers will independently assess each reference identified by the search and apply the inclusion criteria. For possible relevant articles, or in cases of disagreement between the two reviewers, the full article will be obtained and inspected independently by the two reviewers. Where resolving disagreement by discussion are not possible, the article will be added to those 'awaiting assessment' and the authors of the study will be contacted for clarification. In an event of no reply from the authors within three months, a third reviewer will check the article to solve the disagreements.
QUALITY ASSESSMENT
Trials fulfilling the review inclusion criteria will be assessed for methodological quality by two reviewers. This will be done using the criteria described in the Cochrane Handbook (Clarke 1999), based on the evidence of a strong association between poor allocation concealment and overestimation of effect (Schulz 1995) and defined as below:
A. Low risk of bias (adequate allocation concealment)
B. Moderate risk of bias (some doubt about the allocation concealment)
C. High risk of bias (inadequate allocation concealment)
For the purpose of the analyses in this review, trials will be included if they meet the criteria A or B in the Handbook (Kunz 1998; Clarke 1999).
DATA COLLECTION
Two reviewers independently will extract the data of included trials. In case of any disagreement between the two reviewers, a third reviewer will extract the data. The data extraction will be discussed, decisions will be documented and, where necessary, the authors of the studies will be contacted for clarification and for missing information. Justification for excluding studies from the review will also documented.
Trials will be identified by the name of the first author and year in which the trial was first published and ordered chronologically. The following data will be extracted, checked and recorded:
Characteristics of trials
‐ Date, location, period of data collection, year of publication;
‐ Publication status;
‐ Case definitions (symptomatic, bacteriologic, both)
‐ bacteriologic definition (105 or 102 cfu/ml)
‐ Sponsor of trial (commercial, academic, pharmaceutical, or unknown)
‐ Blinding
‐ Allocation concealment ( yes, no and method)
‐ Definitions of cure (symptomatic, bacteriologic or both)
Characteristics of participants
‐ Number of participants in each group;
‐ Age (as described in the article: mean, median or range);
Characteristics of interventions
‐ Type, dose and duration of antibacterial therapy;
Characteristics of outcome measures
‐ Number of days to symptomatic relief;
‐ Number of patients with bacteriological cure (as defined above) in each group;
‐ Number of patients with symptomatic recurrence (as defined above) in each group, divided into local and systemic recurrences.
‐ Number of patients with bacteriologic recurrence (as defined above) in each group;
‐ Number of patients with adverse reactions, per type and total.
‐ Number of patients with resistant microorganisms, as defined above.
‐ Lost to follow‐up (dropouts) before end of study.
DATA SYNTHESIS
Dichotomous data will be analyzed by calculating the relative risk (RR) for each trial with the uncertainty in each result being expressed using 95% confidence interval (CI). Whenever comparisons made between the mean duration of symptoms in the two groups will be normally distributed, these continuous data will be analyzed by using the mean and standard deviation of each trial and calculating the effect size (standard mean difference ‐ SMD) and the 95% CI.
Heterogeneity and publication bias
Heterogeneity in the results of the trials will initially be assessed by inspection of graphical
presentations and by calculating a test of heterogeneity (Cochran Q statistic). We anticipate between‐trial variation in estimation of morbidity for those patients who were treated with different antibiotics. Subgroup analyses will be performed in order to assess the impact of this possible source of heterogeneity in the main results.
A funnel plot estimating the precision of trials (plots of RR for efficacy against the sample size) will be examined in order to estimate potential asymmetry. In addition, a fixed effect model will be used throughout the review, except in the event of significant heterogeneity between the trials (P< 0.10), when the random effect model will be chosen.
