Description of the condition
Acute lower urinary tract infection (UTI), also known as cystitis, is a superficial bacterial infection of the bladder mucosa characterised by symptoms of burning on urination, urinary frequency including nocturia, and urgency. UTIs are considered uncomplicated if the patient is not pregnant or elderly, and if there are no known functional or anatomical abnormalities of the genitourinary tract (Hooton 1996).
UTIs are the most common bacterial infection presented by women in the primary care setting (Butler 2006; Foxman 2002; Little 2010). Around 40% to 50% of women experience one UTI episode during their lives (Kunin 1994). The impact of treating UTIs is substantial. UTIs were reported to account for between 1% and 3% of all consultations in general practice in the UK (Stapleton 1999), and nearly seven million office visits and one million emergency department visits, resulting in 100,000 hospitalisations in the US (Foxman 2002). The most common pathogens causing uncomplicated UTI are Escherichia coli (80% to 90%), Staphylococcus saprophyticus (5% to 10%), Proteus spp. and other gram-negative rods (Milo 2005).
Recurrent UTIs (RUTIs) are commonly defined in the literature as three UTI episodes in the last 12 months or two episodes in the last six months (Albert 2004). Between 20% and 30% of women who have had one UTI episode will have a recurrent UTI (Sanford 1975), and around 25% of these will develop subsequent recurrent episodes (Hooton 1996). RUTIs can have a significant negative effect on quality of life, and a high impact on healthcare costs as a result of outpatient visits, diagnostic tests and prescriptions. Precise estimates on the economic impact of UTIs are difficult to derive. In the US, approximately 15% of all community-prescribed antibiotics are dispensed for UTIs at an estimated annual cost of over USD 1 billion (Mazzulli 2002). The direct and indirect costs associated with community-acquired UTIs in the US are estimated at around USD 2 billion each year (Foxman 2002).
Antibiotics are currently the mainstay treatment for both acute and recurrent UTIs. Although antibiotics may be effective in reducing the duration of severe symptoms in acute episodes (Falagas 2008; Little 2010a), antibiotic resistance is currently estimated at 20% for trimethoprim and cephalosporins, and 50% for amoxicillin (Christiaens 2002). Antibiotic resistance and previous episodes of cystitis have been positively associated with an increased duration of severe symptoms of UTIs (Little 2010). It is predicted that antibiotic resistance will continue to increase (Kumarasamy 2010).
Antibiotic prophylaxis is used to prevent RUTIs. Treatment usually lasts for between six and 12 months but can be extended for up to five years (Franco 2005). A Cochrane systematic review of antibiotics used to prevent RUTIs in non-pregnant women found that antibiotics given continuously for six to 12 months were significantly more effective than placebo in preventing recurrent infection (RR 0.15, 95% CI 0.08 to 0.28; number needed to treat = 1.85, 95% CI 1.60 to 2.20) (Albert 2004). Severe side effects such as urticaria, nausea and vomiting, and less serious but unpleasant side effects including oral and vaginal candidiasis, and gastrointestinal disturbances may require treatment to be withdrawn. These side effects can cause considerable discomfort and may contribute to some women’s expressed preference to avoid using antibiotics (Leydon 2010).
Once prophylaxis is discontinued, even after extended periods of therapy, approximately 50% to 60% of women will become re-infected within three months (Car 2003; Harding 1982). Therefore, antibiotic prophylaxis does not exert a long-term effect on the baseline infection rate.
A number of complementary therapies are used to treat RUTIs. A recently revised Cochrane review of the use of cranberries for preventing UTIs (Jepson 2012) found that they had little effect in reducing the rate of recurrent infection. There is some preliminary evidence that Chinese herbal medicine (CHM) may be of use in the treatment of RUTI.
Description of the intervention
CHM is one part of a system of Traditional Chinese Medicine (TCM). CHM involves the use of complex herbal formulae usually comprising between 10 and 15 herbs that are delivered as decoctions, encapsulated herbal granules, or pills. CHM formulae may be standardised or individualised according to specific patient needs. Although biomedical diagnoses are commonly used in CHM practice to optimise treatment effectiveness, these may be differentiated into TCM syndromes according to analysis of presenting signs and symptoms.
CHM has a recorded history of use in treating the symptoms of UTIs for over 2000 years (Maciocia 1994). More recent clinical research in China suggests that CHM may alleviate UTI symptoms (Liu 1987; Xu 1989; Zhan 2007; Zhang 2005) and reduce one year post-treatment recurrence rates from 30% when antibiotics were used alone, to 4.4% when antibiotics and CHM were combined (Zhang 2005).
How the intervention might work
The herbal products used in CHM contain highly active compounds that have been extensively researched, and in some instances, developed as pharmaceutical drugs. Active compounds that have been refined to develop conventional medicines include ephedrine (Ma Huang, Radix Ephedra sinensis); artemisinin (Qing Hao, Herba Artemisiae annuae); and genistein (Glycine max).
The biological plausibility of CHM for RUTIs is supported by in vitro research suggesting that some CHM may have significant diuretic, antiblastic, immune enhancing, antipyretic, anti-inflammatory and pain relieving activities (Peng 2010; Zhu 1998). There is growing evidence that some herbal medicines can disable bacterial efflux pumps, which are an important mechanism underlying the development of bacterial resistance to antibiotic drugs (Stavri 2007) and may thereby serve as an important adjuvant treatment to conventional antibiotics.
Why it is important to do this review
There is a need to conduct a systematic review to evaluate the extent and quality of clinical evidence relating to CHM for RUTIs. If the benefits of these interventions, either as stand-alone or adjuvant treatment are confirmed by rigorous data, then CHM may make an important contribution to managing this common and problematic condition.
This review aims to look at the benefits and harms of CHM for the treatment of RUTIs in adult women, both as a stand-alone therapy and in conjunction with other pharmaceutical interventions.
Criteria for considering studies for this review
Types of studies
All randomised controlled trials (RCTs) comparing treatment using CHM with either an inactive placebo group or conventional biomedical treatment, will be reviewed. RCTs comparing different CHM strategies and treatments will also be considered. Quasi-randomised studies will be excluded from this review because they would introduce an unacceptable level of bias into the analysis.
Types of participants
We will include ambulatory, otherwise healthy women, aged 16 years or over, who have histories of three or more RUTIs in the preceding 12 months. At least one episode must have laboratory confirmation of bacterial infection (bacterial growth of at least 10² cfu/mL in urine (Franco 2005)) in association with symptoms and signs of UTI including dysuria, frequency, urgency including nocturia, pyuria and haematuria.
We will exclude women under the age of 16 years, pregnant women and older women (over the age of 65 years), those with complicated UTIs (such as pyelonephritis, diabetes, neurological conditions, urinary tract obstruction, or who are catheterised), or who do not have a laboratory confirmation of at least one UTI in the previous 12 months.
Types of interventions
- CHM versus placebo
- CHM versus biomedicine
- CHM + biomedicine versus biomedicine (with or without placebo)
- CHM versus CHM.
For our purposes, 'biomedicine' will refer to the practice of clinical medicine based on current biological understanding of pathophysiological processes. All forms of oral herbal interventions (pills, herbal granules, herbal decoctions) will be considered. Herbs administered as injection and CHM combined with acupuncture or another TCM therapy will be excluded.
Types of outcome measures
- Reduction in both symptomatic episodes, including urinary frequency, urgency, dysuria, haematuria; and bacteriologically-confirmed episodes of UTI during the study
- Rates of relapse within 12 months of completing the study.
- Reduction in severity (e.g. intensity of lower abdominal pain, urgency, frequency and burning) and duration of acute UTIs
- Reduction in the use of acute and prophylactic antibiotics
- Improvements in quality of life (as estimated by validated outcomes measures such as SF-36)
- Any recorded adverse events (including liver and renal toxicity)
- Health economic data relating to CHM treatment.
This review will not consider changes in surrogate biochemical markers reported in studies.
Search methods for identification of studies
We will search the Cochrane Renal Group's specialised register through contact with the Trials' Search Co-ordinator using search terms relevant to this review. The Cochrane Renal Group’s specialised register contains studies identified from:
- Quarterly searches of the Cochrane Central Register of Controlled Trials (CENTRAL)
- Weekly searches of MEDLINE OVID SP
- Handsearching of renal-related journals and the proceedings of major renal conferences
- Searching of the current year of EMBASE OVID SP
- Weekly current awareness alerts for selected renal journals
- Searches of the WHO International Clinical Trials Register Search Portal (ICTRP) and ClinicalTrials.gov.
Studies contained in the specialised register are identified through search strategies for CENTRAL, MEDLINE, and EMBASE based on the scope of the Cochrane Renal Group. Details of these strategies as well as a list of handsearched journals, conference proceedings and current awareness alerts are available in the specialised register section of information about the Cochrane Renal Group.
See Appendix 1 for search terms used in strategies for this review.
The following English language electronic databases will also be searched from their inception to the present:
- AMED (Allied and Complementary Medicine via OvidSP)
- CINAHL (Cumulative Index to Nursing and Allied Health via Ebsco)
The following Chinese language electronic databases will be searched from inception to the most recent date using the following terms: urinary tract infection, cystitis, recurrent urinary tract infection, Chinese medicine, herbal medicine, plant extract, complementary medicine.
- Chinese BioMedical Literature Database (CBM)
- CNKI (China Network on Knowledge Infrastructure)
- VIP database
- Wan Fang Database
Searching other resources
- Reference lists of nephrology textbooks, review articles and relevant studies.
- Handsearching of relevant journals and articles which may not be included in the electronic databases will also be undertaken.
Data collection and analysis
Selection of studies
The search strategy described will be used to obtain titles and abstracts of studies that may be relevant to the review. The titles and abstracts will be screened independently by two authors, who will discard studies that are not applicable, however studies and reviews that might include relevant data or information on trials will be retained initially. Two authors will independently assess retrieved abstracts and, if necessary the full text, of these studies to determine which studies satisfy the inclusion criteria.
Data extraction and management
Data extraction will be carried out independently by two authors using standard data extraction forms. Studies reported in non-English language journals will be translated before assessment. Where more than one publication of one study exists, these will be grouped together and the publication with the most complete data will be used in the analyses. Where relevant outcomes are only published in earlier versions these data will be used. Any discrepancy between published versions will be highlighted.
Assessment of risk of bias in included studies
- Was there adequate sequence generation (selection bias)?
- Was allocation adequately concealed (selection bias)?
- Was knowledge of the allocated interventions adequately prevented during the study (detection bias)?
- Participants and personnel
- Outcome assessors
- Were incomplete outcome data adequately addressed (attrition bias)?
- Are reports of the study free of suggestion of selective outcome reporting (reporting bias)?
- Was the study apparently free of other problems that could put it at a risk of bias?
Measures of treatment effect
For dichotomous outcomes (such as a reported UTI versus no reported UTI) results will be expressed as risk ratio (RR) with 95% confidence intervals (CI). Where continuous scales of measurement are used to assess the effects of treatment (for example, number of days reported with symptoms of a UTI), the mean difference (MD) will be used, or the standardised mean difference (SMD) if different scales have been used.
The decision to use either a fixed-effect or a random-effects model will be determined according to an assessment of study heterogeneity.
Because RUTIs are episodic and provide outcomes that are not stable and difficult to measure precisely, a meta-analysis of change scores, based on a comparison of changes from baseline, is both unlikely and not recommended. In the event that studies included in this review include both changes-from-baseline and final value scores, the method of analysis recommended in the Cochrane Handbook for Systematic Reviews of Interventions (section 18.104.22.168) will be adopted (Higgins 2011).
Unit of analysis issues
The unit of analysis will be the RCT considering individual patients. A single measurement for each outcome from each participant will be collected and analysed. If alternative designs such as cross-over studies, cluster RCTs or repeated measures on the same participants are used, then appropriate methods of statistical analysis will be employed under the advice of a statistician.
Dealing with missing data
Any further information required from the original author will be requested by written correspondence (by emailing and/or writing to corresponding author/s) and any relevant information obtained in this manner will be included in the review. Evaluation of important numerical data such as screened, randomised patients as well as intention-to-treat, as-treated and per-protocol population will be carefully performed. Attrition rates, such as drop-outs, losses to follow-up and withdrawals, will be investigated. Issues of missing data and imputation methods (for example, last-observation-carried-forward) will be critically appraised (Higgins 2011).
Assessment of heterogeneity
Heterogeneity will be analysed using a Chi² test on N-1 degrees of freedom, with an alpha of 0.05 used for statistical significance and with the I² test (Higgins 2011). I² values of 25%, 50% and 75% correspond to low, medium and high levels of heterogeneity.
Assessment of reporting biases
If possible, funnel plots will be used to assess for the potential existence of small study bias (Higgins 2011)
Data will be pooled using the random-effects model but the fixed-effect model will also be used to ensure robustness of the model chosen and susceptibility to outliers.
Subgroup analysis and investigation of heterogeneity
Subgroup analysis will be used to explore possible sources of heterogeneity (e.g. the effects of different formulations of CHM such as standardised formula versus tailored formula), the type of control group and the effects of treatment on diagnostic syndromes determined according to the theory of TCM.
Adverse effects will be tabulated and assessed with descriptive techniques because they are likely to be different for the various agents used. Where possible, the risk difference with 95% CI will be calculated for each adverse effect, either compared with no treatment or another agent.
We will perform sensitivity analyses in order to explore the influence of the following factors on effect size:
- repeating the analysis excluding unpublished studies
- repeating the analysis taking account of risk of bias
- repeating the analysis excluding any very long or large studies to establish how much they dominate the results
- repeating the analysis excluding studies using the following filters: diagnostic criteria, language of publication, source of funding (industry versus other), country.
We wish to thank the referees for their comments and feedback during the preparation of this protocol.
Appendix 1. Electronic search strategies
Appendix 2. Risk of bias assessment tool
Contributions of authors
- Draft the protocol: AF, JPL, GL, PL
- Study selection: QL, AF
- Extract data from studies: QL, AF
- Enter data into RevMan: QL, AF
- Carry out the analysis: AF, QL, JPL
- Interpret the analysis: AF, QL, JPL, GL, PL
- Draft the final review: AF
- Disagreement resolution: JPL, GL
- Update the review: AF
Declarations of interest
Andrew Flower is currently funded for a post doctoral Fellowship by the UK National Institute of Health Research to investigate the possible role of Chinese herbal medicine in the treatment of recurrent urinary tract infections .
Sources of support
- No sources of support supplied
- National Institute of Health Research, UK.