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Journal of Antimicrobial Chemotherapy (2009) 63, 389 – 395doi:10.1093/jac/dkn489Advance Access publication 28 November 2008 Cranberry or trimethoprim for the prevention of recurrent urinary tract infections? A randomized controlled trial in older women Marion E. T. McMurdo1*, Ishbel Argo1, Gabby Phillips2, Fergus Daly3 and Peter Davey3 1Ageing and Health, Division of Medicine and Therapeutics, Ninewells Hospital and Medical School, University of Dundee, Dundee DD1 9SY, Scotland, UK; 2Department of Medical Microbiology NHS Tayside, Ninewells Hospital and Medical School, University of Dundee, Dundee DD1 9SY, Scotland, UK; 3Mackenzie Building, Division of Community Health Sciences, Ninewells Hospital and Medical School, University of Dundee, Received 22 July 2008; returned 30 October 2008; revised 5 November 2008; accepted 5 November 2008 Objectives: To compare the effectiveness of cranberry extract with low-dose trimethoprim in theprevention of recurrent urinary tract infections (UTIs) in older women.
Patients and methods: One hundred and thirty-seven women with two or more antibiotic-treated UTIs in the previous 12 months were randomized to receive either 500 mg of cranberry extract or 100 mg oftrimethoprim for 6 months. Trial registration: ISRCTN80031108.
Results: Thirty-nine of 137 participants (28%) had an antibiotic-treated UTI (25 in the cranberry groupand 14 in the trimethoprim group); difference in proportions relative risk 1.616 (95% CI: 0.93, 2.79) P 50.084. The time to first recurrence of UTI was not significantly different between the groups (P 5 0.100).
The median time to recurrence of UTI was 84.5 days for the cranberry group and 91 days for the tri-methoprim group (U 5 166, P 5 0.479). There were 17/137 (12%) withdrawals from the study, 6/69 (9%) from the cranberry group and 11/68 (16%) from the trimethoprim group (P 5 0.205), with a relative riskof withdrawal from the cranberry group of 0.54 (95% CI: 0.19, 1.37).
Conclusions: Trimethoprim had a very limited advantage over cranberry extract in the prevention ofrecurrent UTIs in older women and had more adverse effects. Our findings will allow older women withrecurrent UTIs to weigh up with their clinicians the inherent attractions of a cheap, natural product likecranberry extract whose use does not carry the risk of antimicrobial resistance or super-infection withClostridium difficile or fungi.
Keywords: urinary infections, UTIs, antibiotics 1.85, but side effects severe enough to stop treatment wereequally common (NNT for severe side effects was 1.58).
Urinary infection is the most common bacterial infection in The main side effects measured in the trial were fungal super-in- older people and recurrent urinary tract infection (UTI) is par- fection (oral or vaginal thrush) and gastrointestinal infections.
ticularly common in older women. The current management of However, a growing reluctance to prescribe antibiotics is emer- recurrent UTI involves either repeated courses of antibiotics or ging because of concerns about antimicrobial resistance and low-dose long-term antibiotic prophylaxis.1 The evidence in other adverse effects on the normal bacterial flora, such as support of antibiotic prophylaxis is strong, with 11 placebo con- super-infection with Clostridium difficile. At the same time, trolled trials of which 10 show a significant treatment benefit.1 there has been a resurgence of interest in the role of cranberry In these trials, antibiotic prophylaxis was highly effective: products, stimulated by the conclusion of a Cochrane review that number needed to treat (NNT) to prevent one recurrence was ‘there is some evidence from two good quality RCTs that . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
*Corresponding author. E-mail: [email protected] . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
# The Author 2008. Published by Oxford University Press on behalf of the British Society for Antimicrobial Chemotherapy. All rights reserved. For Permissions,please e-mail: [email protected] online version of this article has been published under an open access model. Users are entitled to use, reproduce, disseminate, or display the open accessversion of this article for non-commercial purposes provided that: the original authorship is properly and fully attributed; the Journal and Oxford UniversityPress are attributed as the original place of publication with the correct citation details given; if an article is subsequently reproduced or disseminated not in itsentirety but only in part or as a derivative work this must be clearly indicated. For commercial re-use, please contact [email protected] cranberry juice may decrease the number of symptomatic UTIs Cranberry product and trimethoprim preparation over a 12 month period in younger women’ (mean ages 32 and DHP pharma over-encapsulated 100 mg trimethoprim tablets into red size 00 capsules, and filled red size 00 capsules with 500 mg of The Cochrane review of antibiotic prophylaxis and SIGN cranberry extract (Cran-MaxTM). Both sets of capsules were guideline 88 stated that a head-to-head trial of cranberry versus low-dose antibiotic in the prevention of recurrent UTI wasrequired because previous placebo controlled trials had demon-strated effectiveness for both, with the effectiveness of antibiotic therapy being considerably superior.2,3 While cranberry juice has A urine specimen was obtained at baseline from all participants and been studied in an underpowered trial of UTI prevention in 376 cultured in the Medical Microbiology Laboratory using standard hospitalized older people,4 there is a dearth of evidence concern- protocols. Identification and susceptibility testing on positive cul- ing its effectiveness in recurrent urinary infections in old age.
tures were performed by Vitek I (bioMe´rieux) or Stokes’ suscepti- This is a surprising gap in the literature, given that UTI occurs bility testing and chromogenic agar for speciation of Escherichia more frequently in old age than at any other time of life. In con- coli. Baseline results were not reported to clinical or research staff.
trast, the literature on antibiotic prophylaxis does suggest that Specimens from participants who developed symptoms of UTI this is likely to be effective in older women. Of the 11 trials during the trial were processed in the same way.
identified in the Cochrane review of antibiotic prophylaxis forrecurrent UTI, eight included post-menopausal women.1 Wetherefore designed a trial to compare the effectiveness and acceptability of low-dose trimethoprim with cranberry productsin the prevention of recurrent UTI in older women. Trialregistration: ISRCTN80031108.
This was the proportion of participants in each group experiencing arecurrence of an antibiotic-treated UTI and the time to first recurrence.
Participants were censored (i.e. withdrawn from study partici- pation) after their first UTI. UTI was defined as clinical symptoms of dysuria and frequency in the absence of vaginal discharge withor without microbiological confirmation.
Inclusions: community dwelling women aged 45 years with atleast two antibiotic-treated UTIs or episodes of cystitis in the pre-vious 12 months confirmed by their general practitioner (GP) but not necessarily confirmed by microbiological culture. Participants were recruited predominantly through the eastern node of the Adherence. The participants were provided with two sealed tubs at Scottish Primary Care Research Network and also from responses to baseline each with 200 capsules containing either 100 mg of tri- an article in a local newspaper featuring the study.
methoprim or 500 mg of cranberry extract. Adherence was assessed Exclusions: previous urological surgery, stones or anatomical by capsule counting at 3 and 6 months and expressed as the number abnormalities of the urinary tract; urinary catheter; diabetes melli- of capsules consumed divided by the number of capsules that tus; immunocompromised; pyelonephritis; severe renal impairment; should have been consumed during the duration of each individual’s blood dyscrasias; symptomatic UTI at baseline; cognitive impair- ment precluding informed consent; resident in institutional care; on Adverse events and follow-up. After the baseline visit, further home long-term antibiotic therapy; on warfarin therapy; regular cranberry visits occurred at 3 and 6 months to re-check study eligibility, consumers; child bearing potential; unwilling to participate.
record adverse events, check adherence and to note the courses of As a number of potential participants were occasional cranberry antibiotics that had been prescribed for any indications. Participants consumers, it was decided that such individuals could participate were telephoned at 1, 2, 4 and 5 months to encourage participation provided that there was a 2 week washout period prior to commen- and adherence, and to record any adverse events.
Written informed consent was obtained from participants and the study was approved by the Tayside Committee on Medical Research Ethics (06/S1402/23) and the MHRA (Eudract no: 2006-001313-15).
Sample size. Based on the available literature, it was predicted that afinal sample of 102 participants would be required to have 80% power at P ¼ 0.05 of detecting a reduction in occurrences of urinaryinfection from 16% in the cranberry group to 1% in the trimetho- Participants were randomized to receive either one capsule of prim group.5,6 In anticipation of a dropout rate of 15%, we intended 500 mg of cranberry extract (Cran-MaxTM; Buckton Scott Health to recruit at least 120 participants.
Products Ltd, UK) taken at bedtime for 6 months or one capsule of100 mg of trimethoprim. Randomization was performed off-site by Statistical analysis. Data were entered onto an Excel database and DHP pharma in Powys, UK, which is an MHRA-approved manufac- then analysed using a Statistical Calculator v.2.06 (Mole Software, turing site. Randomization was performed in blocks of four using Alpes de Haute-Provence 04230, France). Full statistical analysis Prisym PFW clin software to generate random numbers. Participants was completed prior to breaking the treatment code. Analysis was were given a study number sequentially by the research nurses.
by intention to treat. Time to first recurrence of infection is pre- A copy of the treatment code was held by the Clinical Trials sented as a Kaplan – Meier curve and differences between the groups Pharmacist in Ninewells Hospital, Dundee.
were assessed using the log-rank test.
A total of 137 women were randomized, 69 to cranberry and 68 Withdrawals. There were 17/137 (12%) withdrawals from the study, 6/69 (9%) from the cranberry group and 11/68 (16%) from There were no significant differences between the groups at the trimethoprim group (P ¼ 0.205), with a relative risk of with- drawal from the cranberry group of 0.54 (95% CI: 0.19, 1.37).
The reasons were as follows: for the cranberry group, gastro- intestinal upset n ¼ 4; increased nocturia n ¼ 1; sensitiveswollen nipples n ¼ 1 and the trimethoprim group, gastrointesti- nal upset n ¼ 4; itch/rash n ¼ 3; lost to follow-up n ¼ 2; restless A total of 39/137 (28%) of participants had a symptomatic legs n ¼ 1; increased lethargy n ¼ 1. While gastrointestinal antibiotic-treated UTI (25 in the cranberry group and 14 in the upsets were equally common in both groups, itch/rash and loss to trimethoprim group); the difference in proportions was relative follow-up occurred more commonly in the trimethoprim group.
risk 1.616 (95% CI: 0.93, 2.79) P ¼ 0.084.
The time to first recurrence of UTI was not significantly Other adverse events. Other adverse events were similar different between the groups [log-rank test: D ¼ 2.7, x2 (2.7, 1) The median time to recurrence of UTI was 84.5 days for the Adherence. Adherence was good in both groups. Median (range) cranberry group and 91 days for the trimethoprim group adherence was 99 (25 – 149)% and 100 (66 – 112)% in the cranberry and trimethoprim groups, respectively.
Number of self-reported UTIs in past 12 months Number of antibiotic-treated UTIs in past 12 monthsa Table 2. Adverse events other than those resulting in withdrawal Difficulty swallowing capsules/aftertaste/dry mouth Antibiotic use. A total of 15/69 (22%) participants in the Causative organisms. For the 39 women who developed a cranberry group and 17/68 (25%) in the trimethoprim group symptomatic UTI during the trial, the urine culture results were prescribed antibiotics for indications other than UTI during were as follows: E. coli, 16 (9 in the cranberry group and 7 in the trimethoprim group); Klebsiella pneumoniae, 3 (2 in the cranberry group and 1 in the trimethoprim group); no conferred fewer than 7 additional UTI-free days. Our primary end- growth, 4 (2 in each group); mixed growth, 1 (in the cranberry point was symptomatic UTI treated by the GP. However, recur- group); no significant bacteriuria, 6 (4 in the cranberry group rence rates for microbiologically confirmed symptomatic UTI were and 2 in the trimethoprim group). No urine specimen was also similar (16% for cranberry versus 12% for trimethoprim).
obtained in 9 (7 in the cranberry group and 2 in the trimetho-prim group).
Antibiotic resistance patterns. At baseline testing, 12 women Our target of 120 participants for the trial was set to have 80% had positive urine cultures with 104 cfu/mL. Of these, 8 were power to detect a difference in effectiveness of 15% in risk of E. coli (6 susceptible to trimethoprim), 2 group B Streptococcus recurrence between trimethoprim and cranberry, and assumed a (not tested against trimethoprim) and one each of K. pneumoniae 15% dropout rate. In fact we recruited 137 participants, of whom 17 (12%) withdrew but only two (1.5%) were lost to follow-up.
(trimethoprim-resistant). Overall, therefore, 7/9 (78%) subjects The remaining withdrawals were because of side effects, which was one of the secondary outcomes for the trial. The participants represented 29% of the 470 people who were screened and met Nineteen out of 39 (49%) women had symptomatic recur- the inclusion criteria. Most participants were recruited by screen- rences with positive urine cultures of 104 cfu/mL. All were ing patient records from 16 GP practices, which is 20% of all the Gram-negative isolates. Of those with E. coli cultures, 11/16 were practices in Tayside. The primary outcome was objective (first trimethoprim-susceptible, and of those with K. pneumoniae, 2/3 recurrence of clinical UTI treated by the GP) and could not be were trimethoprim-susceptible isolates. Thus, 13/19 of this sub- influenced by the investigators. Moreover, participants and inves- group of participants had trimethoprim-susceptible isolates.
tigators were unaware of the participants’ treatment group untilthe statistical analysis had been completed. Adherence to treat-ment in our study was very good in both groups, which together with the modest withdrawal rate lends further support to theacceptability of encapsulated cranberry extracts.2 Our head-to-head trial has shown that for older women with recur- The internal validity of the trial therefore seems good and we rent urinary infections, the 6 month risk of developing a UTI on also believe that the results should be applicable to other cranberry products is only 60% greater than that on low-dose tri- primary care populations. Nonetheless, the trial result was not methoprim; this difference was not statistically significant.
what we expected. The literature had led us to predict that tri- Compared with cranberry extract, treatment with trimethoprim methoprim would prove considerably more effective, but only at Cranberry
Trimethoprim
Log-rank test: Δ = 2.7, χ2 (2.7, 1) P = 0.100 Figure 2. Time to first recurrence of UTI.
the expense of more adverse events. Withdrawals were indeed Our power calculation estimated the difference in effect size higher in the trimethoprim group, but other adverse event rates to be 15%. In our trial, the difference in effect size was 15% turned out to be low and remarkably similar between the groups.
(40% for cranberry versus 25% for trimethoprim), which wasnot statistically significant because the efficacy of both treat-ments was lower than we had predicted. We estimated that recurrence with cranberry would be 16% to 20% and 1% to 5% We have considered the possibility that neither treatment was with antibiotics.1,5,11 Our data regarding time to first recurrence effective. At the design stage, we considered the inclusion of a suggest that the added benefit to patients from antibiotics is placebo group but rejected this option because Cochrane sys- likely to be modest (Figure 2) and therefore that the value of tematic reviews have concluded that both antibiotics and cran- information from a larger trial in older women is unlikely to berry products are effective in preventing UTIs.1,2 There is uncertainty about how effective both treatments are in olderwomen, especially for cranberry but we did not consider thatthis was sufficient justification for inclusion of a placebo group. Moreover our eligibility criteria required two or more Our trial is the first to evaluate cranberry in the prevention of antibiotic-treated UTIs in the previous 12 months so it was recurrent UTIs specifically in older women, and the first reasonable to expect that without prophylaxis most women head-to-head double-blind comparison of cranberry versus anti- would experience a recurrence within 6 months. It is therefore Trimethoprim had a very limited advantage over cranberry allowed 81 (59%) of the 137 participants to have completed 6 extract in the prevention of recurrent UTIs in older women and months of treatment free of UTI recurrence.
had more adverse effects. Our findings will allow older women We selected trimethoprim for antibiotic prophylaxis because with recurrent UTIs to weigh up with their clinicians the it is as effective as co-trimoxazole for treatment of UTI but has inherent attractions of a cheap, natural product like cranberry fewer side effects.7 Trimethoprim was included in one of the extract whose use does not carry the risk of antimicrobial resist- placebo controlled clinical trials of antibiotic prophylaxis for ance or super-infection with C. difficile or fungi.
UTI and proved as effective as co-trimoxazole and nitrofuran- Further research is now required to discover if our findings toin.6 Resistance to trimethoprim in bacteria causing UTIs has might apply to younger individuals with recurrent urinary increased in Northern European and American countries from 10% to 15% in the 1970s to 15% to 20% in the 1980s.8 Theprevalence of trimethoprim resistance in the E. coli isolatesfrom our patients was 29%, which is only slightly higher than the average resistance for all primary care isolates from mid- stream urines in our laboratory (excluding catheter urine Moulton Charitable Foundation. Buckton Scott Health Products samples) of 24% in 2004. Resistance has yet to reach a level Ltd, UK supplied the Cran-MaxTM free of charge. Neither the that should markedly reduce the effectiveness of trimethoprim in funder nor the supplier had any role in the concept, design, lower UTI. The recurrence rate after treatment of symptomatic running, analysis, interpretation or reporting of the study.
lower UTI has been estimated for different levels of resistanceto co-trimoxazole.9 At a resistance rate of zero, the recurrencerate was estimated to be 5%, rising to 12% at 20% resistance and 15% at 30% resistance.9 These calculations assumed that60% of women would respond to co-trimoxazole if their infec- No conflicts of interest to declare.
tion was caused by a resistant organism. In a recent UK study, Contributions: M. E. T. M., P. D. and G. P. participated in 61% of women with lower UTI caused by trimethoprim-resistant study design, I. A. participated in recruitment and data collec- bacteria were symptom-free 1 week after trimethoprim treatment tion, F. D. participated in the analysis, and all participated in and 58% were free of bacteriuria 1 month after treatment.10 We the interpretation of the data, drafting and revising the paper believe that trimethoprim prophylaxis should be effective at the and approving the final version. M. E. T. M. is the guarantor for levels of resistance observed in our study and in the Tayside population. It is possible that nitrofurantoin might have provedmore effective as resistance is less common; however, the evi-dence suggests that it has more side effects.1 We selected cranberry extract in preference to juice for our study because previous work has shown equivalent efficacy 1. Albert X, Huertas I, Pereiro II et al. Antibiotics for preventing between cranberry capsules (containing at least 1:30 parts con- recurrent urinary tract infection in non-pregnant women. Cochrane centrated juice) and cranberry juice.11 Furthermore, cranberry capsules have potential advantages over juice; capsules are more 2. Jepson RG, Craig JC. Cranberries for preventing urinary tract convenient, cheaper (costs for 1 year of treatment are from £42 infections. Cochrane Database Syst Rev 2008; CD001321.
to £125 for cranberry tablets or capsules versus £175 to £257 for 3. Scottish Intercollegiate Guidelines Network. Management of cranberry juice) and may overcome compliance issues for some Suspected Bacterial Urinary Tract Infection in Adults. SIGN 88.
individuals.12 The high rates of withdrawal from some previous studies suggest that cranberry juice may not be an acceptable 4. McMurdo ME, Bissett LY, Price RJ et al. Does ingestion of cranberry juice reduce symptomatic urinary tract infections in older people in hospital? A double-blind, placebo-controlled trial. Age Ageing 9. Gupta K, Hooton TM, Stamm WE. Increasing antimicrobial resistance and the management of uncomplicated community-acquired 5. Kontiokari T, Sundqvist K, Nuutinen M et al. Randomised urinary tract infections. Ann Intern Med 2001; 135: 41– 50.
trial of cranberry-lingonberry juice and Lactobacillus GG drink for 10. McNulty CA, Richards J, Livermore DM et al. Clinical relevance of the prevention of urinary tract infections in women. BMJ 2001; 322: laboratory-reported antibiotic resistance in acute uncomplicated urinary tract infection in primary care. J Antimicrob Chemother 2006; 58: 6. Stamm WE, Counts GW, Wagner KF et al. Antimicrobial prophy- laxis of recurrent urinary tract infections: a double-blind, placebo- 11. Stothers L. A randomized trial to evaluate effectiveness controlled trial. Ann Intern Med 1980; 92: 770 – 5.
and cost effectiveness of naturopathic cranberry products as pro- 7. Warren JW, Abrutyn E, Hebel JR et al. Guidelines for antimicro- phylaxis against urinary tract infection in women. Can J Urol 2002; 9: bial treatment of uncomplicated acute bacterial cystitis and acute pyelo- nephritis in women. Infectious Diseases Society of America (IDSA).
12. Foda MM, Middlebrook PF, Gatfield CT et al. Efficacy of Clin Infect Dis 1999; 29: 745 – 58.
cranberry in prevention of urinary tract infection in a susceptible pedi- 8. Huovinen P, Sundstrom L, Swedberg G et al. Trimethoprim and atric population. Can J Urol 1995; 2: 98– 102.
sulfonamide resistance. Antimicrob Agents Chemother 1995; 39: 13. Claxton K, Posnett J. An economic approach to clinical trial design and research priority-setting. Health Econ 1996; 5: 513 –24.

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