Abstract
Introduction
Cystitis is a bacterial infection of the lower urinary tract which causes pain when passing urine, and causes urgency, haematuria, and suprapubic pain not associated with passing urine. Recurrent cystitis is usually defined as three episodes of urinary tract infection in the previous 12 months, or two episodes in the previous 6 months.
Methods and outcomes
We conducted a systematic review and aimed to answer the following clinical question: Which interventions prevent further recurrence of cystitis in women experiencing at least two infections per year? We searched: Medline, Embase, The Cochrane Library, and other important databases up to April 2007 (BMJ Clinical Evidence reviews are updated periodically, please check our website for the most up-to-date version of this review). We included harms alerts from relevant organisations such as the US Food and Drug Administration (FDA) and the UK Medicines and Healthcare products Regulatory Agency (MHRA).
Results
We found 14 systematic reviews, RCTs, or observational studies that met our inclusion criteria. We performed a GRADE evaluation of the quality of evidence for interventions.
Conclusions
In this systematic review we present information relating to the effectiveness and safety of the following interventions: continuous antibiotic prophylaxis (trimethoprim, co-trimoxazole, nitrofurantoin, cefaclor, or a quinolone or cephalexin); continuous prophylaxis with methenamine hippurate; cranberry juice and cranberry products; oestrogen (topical) in postmenopausal women; passing urine after intercourse; postcoital antibiotic prophylaxis; single-dose self-administered antibiotic.
Key Points
Cystitis is a bacterial infection of the lower urinary tract which causes pain when passing urine, and causes frequency, urgency, haematuria, and suprapubic pain not associated with passing urine.
Recurrent cystitis is usually defined as three episodes of UTI in the previous 12 months, or two episodes in the previous 6 months.
It is common in young, healthy women, with one study finding 27% of women developing a second infection within 6 months of the first, and 2.7% having a second recurrence during this period.
Continuous antibiotic prophylaxis lasting 6–12 months reduces the rate of recurrence, although there is no consensus about when to start the treatment, or about how long it should last.
Trimethoprim, trimethoprim–sulfamethoxazole (co-trimoxazole), nitrofurantoin, cefaclor, or quinolones all seem equally effective at reducing recurrence rates.
Postcoital antibiotics (taken within 2 hours of intercourse) reduce the rate of clinical recurrence of cystitis as effectively as continuous treatment.
We don't know whether single-dose self-administered trimethoprim–sulfamethoxazole or continuous prophylaxis with methenamine hippurate are effective in preventing recurrence of cystitis, as the studies were too small to show any clinically relevant differences.
Cranberry products (either juice or capsules) seem to significantly reduce the recurrence of symptomatic cystitis.
There is no clear evidence about the amount and concentration of cranberry juice that needs to be consumed, or about the length of time needed for the treatment to be most effective.
There is no evidence examining whether passing urine after intercourse is effective at preventing UTI.
We found insufficient evidence on the effects of topical oestrogen in postmenopausal women in the prophylaxis of recurrent cystitis.
About this condition
Definition
In most cases, cystitis is a bacterial infection of the lower urinary tract which causes pain when passing urine, and causes frequency, urgency, haematuria, and suprapubic pain not associated with passing urine. White blood cells and bacteria are almost always present in the urine. A recurrent UTI is a symptomatic UTI that follows clinical resolution of an earlier infection generally, but not necessarily, after treatment. Recurrent cystitis is usually defined in the literature as three episodes of UTI in the previous 12 months or two episodes in the previous 6 months. Recurrent UTIs cause serious discomfort to women, and have a high impact on ambulatory healthcare costs, through outpatient visits, diagnostic tests, and prescriptions.
Incidence/ Prevalence
Recurrent cystitis is common among young, healthy women, even though they generally have anatomically and physiologically normal urinary tracts. One study found that nearly half of the women whose uncomplicated UTIs resolved spontaneously developed a recurrent UTI within a year. In a study of college women with their first UTI, 27% experienced at least one culture-confirmed recurrence within 6 months of the initial infection, and 2.7% had a second recurrence during this period. In a Finnish study of women aged 17–82 years who had Escherichia Coli cystitis, 44% had a recurrence within 1 year (53% in women older than 55 years, 36% in younger women). No large population-based studies have been done to determine proportionately how many women with UTI develop a pattern of high-frequency recurrence. Occasionally, recurrences are due to a persistent focus of infection, but the vast majority is thought to represent reinfection. A recurrence is defined clinically as a relapse if it is caused by the same species as caused the original UTI, and if it occurs within 2 weeks after treatment. It is considered reinfection if it occurs more than 2 weeks after treatment of the original infection. Most women are able to diagnose their own episodes of recurrent cystitis from symptoms (positive predictive value in one RCT 92%).
Aetiology/ Risk factors
Cystitis is caused by uropathogenic bacteria in the faecal flora, that colonise the vaginal and periurethral openings and ascend the urethra into the bladder. Sexual intercourse, diaphragm–spermicide use, and a history of recurrent UTI have been shown to be strong and independent risk factors for cystitis. Use of spermicide-coated condoms may also increase the risk of UTI. Antimicrobial use has been shown to adversely affect the vaginal flora in animals and humans, and recent use of antibiotics is strongly associated with risk of cystitis. However, risk factors specific to women with recurrent cystitis have received little study. In a large, case controlled study of women with and without a history of recurrent UTI, comprising 229 cases and 253 controls, the strongest risk factor for recurrence in a multivariate analysis was the frequency of sexual intercourse. Other risk factors included spermicide use in the past year, new sex partner during the past year, having a first UTI at or before 15 years of age, and having a mother with history of UTI. Urine-voiding disorders, such as those associated with prolapse, multiple sclerosis, bladder cancer, or bladder stones, are also associated with increased risk. An association has been found with pre- and postcoital voiding, frequency of urination, delayed voiding habits, douching, and BMI. A possible association between smoking (which is strongly associated with bladder cancer) and recurrent cystitis has not been assessed. These behavioural patterns have never been evaluated in prospective, randomised trials. Data suggest that pelvic anatomical differences may have a role in predisposing some young women to recurrent UTI, especially those without other risk factors. In postmenopausal women, reduced oestrogen levels seem to contribute to recurrent cystitis in healthy women. The vagina, bladder, and urethra respond to oestrogen, and when the hormonal level in the body is reduced, the tissues of these organs become thinner, weaker, and dry. The changes in the tissues of the bladder and urethra, and the associated loss of protection against infection-causing germs, may increase the risk of UTI in postmenopausal women. Cystitis is also more common during pregnancy because of changes in the urinary tract. As the uterus grows, its increased weight can block the drainage of urine from the bladder, causing an infection. Women are at increased risk for recurrent cystitis from weeks 6–24 of pregnancy.
Prognosis
We found little evidence on the long-term effects of untreated cystitis. One study found that progression to pyelonephritis was infrequent, and that most cases of cystitis regressed spontaneously, although symptoms sometimes persisted for several months. However, bacteriuria in pregnant women carries a much greater risk of progressing to pyelonephritis than in non-pregnant women (28% v 1%), and is associated with serious risks.
Aims of intervention
To prevent recurrent cystitis in women with three episodes of UTI in the past 12 months or two episodes in the past 6 months, with minimal adverse effects of treatment. A recurrence is defined clinically as a relapse if it is caused by the same species which caused the original UTI, and if it occurs within 2 weeks after treatment. It is considered reinfection if it occurs more than 2 weeks after treatment of the original infection. We aim to consider both.
Outcomes
Rates of recurrent infection, based on symptoms and urine culture, quality of life, adverse effects of treatment.
Methods
BMJ Clinical Evidence search and appraisal April 2007. The following databases were used to identify studies for this systematic review: Medline 1966 to April 2007, Embase 1980 to April 2007, and The Cochrane Library (all databases) 2007, Issue 1. Additional searches used these websites: NHS Centre for Reviews and Dissemination (CRD) — for all databases, Turning Research into Practice (TRIP) and NICE. Abstracts of the studies retrieved from the initial search were assessed by an information specialist. Selected studies were then sent to the author for additional assessment, using pre-determined criteria to identify relevant studies. Study design criteria for evaluation in this review were: published systematic reviews and RCTs in any language, at least single blinded, and containing at least 20 individuals of whom more than 80% were followed up. There was no minimum length of follow-up required to include studies. We excluded all studies described as “open”, “open label”, or not blinded unless blinding was impossible. The author also did his own supplementary internet search on the terms "recurrent cystitis" and "meta-analysis" in the Google search engine. In addition, we use a regular surveillance protocol to capture harms alerts from organisations such as the FDA and the UK Medicines and Healthcare products Regulatory Agency (MHRA), which are added to the reviews as required. We reviewed all systematic reviews and RCTs comparing different forms of prophylaxis, or comparing prophylaxis versus placebo in non-pregnant women with a history of recurrent cystitis. We excluded studies in populations consisting mainly of men or pregnant women. We have performed a GRADE evaluation of the quality of evidence for interventions included in this review (see table ).
Table 1.
GRADE evaluation of interventions for recurrent cystitis in non-pregnant women
| Important outcomes | Infection recurrence rates, quality of life, adverse effects | ||||||||
| Number of studies (participants) | Outcome | Comparison | Type of evidence | Quality | Consistency | Directness | Effect size | GRADE | Comment |
| Which interventions prevent further recurrence of cystitis in women experiencing at least two infections per year? | |||||||||
| 17 (629) | Recurrence of infections | Continuous antibiotic prophylaxis v placebo | 4 | 0 | –1 | –1 | 0 | Low | Consistency point deducted for conflicting results. Directness point deducted for uncertainty about whether previous recurrences of cystitis affect antibiotic effectiveness |
| 6 (458) | Recurrence of infections | Continuous antibiotic prophylaxis v each other | 4 | –2 | –1 | 0 | 0 | Very low | Quality points deducted for weak methods and incomplete reporting of results. Consistency point deducted for heterogeneity between RCTs |
| 2 (154) | Recurrence of infections | Continuous antibiotic prophylaxis v continuous methenamine hippurate | 4 | –1 | –1 | –1 | 0 | Very low | Quality point deducted for sparse data. Consistency point deducted for conflicting results. Directness point deducted for uncertainty about whether previous recurrences of cystitis affect antibiotic effectiveness |
| 1 (27) | Recurrence of infections | Postcoital antibiotic prophylaxis v placebo/no treatment | 4 | –1 | 0 | –1 | 0 | Low | Quality point deducted for sparse data. Directness point deducted for narrowness of population |
| 1 (135) | Recurrence of infections | Postcoital antibiotic prophylaxis v continuous antibiotic treatment | 4 | –2 | 0 | 0 | 0 | Low | Quality points deducted for sparse data and incomplete reporting of results |
| 1 (38) | Recurrence of infections | Single-dose v continuous trimethoprim–sulfamethoxazole | 4 | –3 | 0 | 0 | 0 | Very low | Quality points deducted for sparse data, incomplete reporting of results, no intention-to-treat analysis and, poor follow-up |
| 2 (241) | Recurrence of infections | Cranberry juice and cranberry products v placebo | 4 | 0 | 0 | –2 | 0 | Low | Directness points deducted for different doses used and uncertainty about effective doses and length of treatment |
| 3 (372) | Recurrence of infections | Prophylaxis with methenamine hippurate v placebo | 4 | –2 | 0 | –1 | 0 | Very low | Quality points deducted for methodological weaknesses and incomplete reporting of results. Directness point deducted for inclusion of women with chronic pylonephritis |
| 3 (189) | Recurrence of infections | Topical (intravaginal) oestrogen v placebo/no treatment | 4 | –3 | 0 | –2 | 0 | Very low | Quality points deducted for sparse data and for methodological weaknesses in one RCT (open study with control group not receiving treatment). Directness points deducted for different regimens, duration of treatment, and uncertainty about disease severity |
| 2 (215) | Recurrence of infections | Topical (intravaginal) oestrogen v antibiotics | 4 | 0 | –1 | –2 | 0 | Very low | Consistency point deducted for conflicting results. Directness points deducted for differences in doses, regimens, and duration of treatment, and for uncertainty about disease severity |
Type of evidence: 4 = RCT; 2 = Observational Consistency: similarity of results across studies Directness: generalisability of population or outcomes Effect size: based on relative risk or odds ratio
Glossary
- Low-quality evidence
Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate.
- Very low-quality evidence
Any estimate of effect is very uncertain.
Pyelonephritis (acute) in non-pregnant women
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