NIHR Signal Nitrofurantoin is as effective as other long-term antibiotics for preventing recurrent urinary tract infections

Published on 19 December 2016

The antibiotic nitrofurantoin works as well as other long-term antibiotics for preventing recurrent urinary tract infections in women. However gastrointestinal side effects were more common in people on nitrofurantoin. The potential for inducing less antibiotic resistance compared to trimethoprim is a potential advantage of nitrofurantoin but this wasn’t a specified outcome for this review.

This review of 12 trials, with 1,063 women, compared nitrofurantoin with other antibiotics such as trimethoprim, or oestrogen cream. It was hoped that this older antibiotic could be a first-line strategy when long-term use is indicated for people with recurrent urinary tract infections.

Trimethoprim is likely to remain the drug of choice, reserving nitrofurantoin for cases where it is ineffective or not tolerated.

Some caution should be used in the interpretation of the results as only one of the trials was done in the past ten years, so new data in this area would be useful.

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Why was this study needed?

Urinary tract infections are common and mainly affect women. Around half the women in the UK are likely to have at least one in their life. Of these, 25% experience recurrent infections, defined as at least two infections in six months or three in one year.

Previous evidence has found that giving prophylactic antibiotics is more likely to prevent a urinary tract infection than placebo. However antibiotic resistance is a growing problem worldwide and is thought to be one cause of recurrent infections.

Fewer urinary tract infections become resistant to nitrofurantoin, so it could be a better choice of antibiotic when it comes to preventing further antibiotic resistance.

This review aimed to shed some light on the evidence available around the different treatment options and the relative benefits and harms of their use for recurrent urinary tract infections.

What did this study do?

This systematic review included 12 randomised controlled trials involving 1,063 people. Studies included non-pregnant adult women being treated as an outpatient to prevent recurrent urinary tract infections. Trial size ranged from 30 to 222 women.

The trials compared nitrofurantoin prophylaxis with other commonly used antibiotics and treatments. Doses varied between the studies and people were treated for a minimum of six months. The authors pooled the results in standard meta-analysis.

The authors also analysed the number of adverse events occurring during treatment.

Four of the studies took place in the UK, so are likely to be relevant. Outcome assessors were often aware of the treatments but, on its own, this bias is unlikely to have led to the ‘no difference’ conclusion.

What did it find?

  • The analysis of 12 trials found no difference in successful cure of urinary tract infections in adult women with recurrent urinary tract infections between nitrofurantoin and any of the other treatments when results were combined (relative risk ratio [RR], 1.06, 95% confidence interval [CI] 0.90 to 1.26). The alternative antibiotics were norfloxacin, trimethoprim, sulfamethoxazole/trimethoprim, methamine hippurate (not currently used in the UK) and cefaclor, and the hormonal treatment estriol, an oestrogen vaginal cream.
  • There was no significant difference between treatments when trials were grouped according to the comparison treatment, for example when the three studies that compared nitrofurantoin with trimethoprim were analysed.
  • There was an increased risk of having an adverse event, mainly involving gastrointestinal symptoms, when being treated with nitrofurantoin compared to other treatment (relative RR 1.83, 95% CI 1.18 to 2.84; 10 trials, 948 women).
  • There were not enough participants to accurately assess the likelihood of more severe side effects and insufficient data to report differences between relapse versus reinfection in the comparison groups.

What does current guidance say on this issue?

A 2015 NICE Clinical Knowledge Summary of current evidence and practical guidance, recommends that women who experience unacceptable discomfort or disruption from recurrent urinary tract infections be given antibiotics to try to prevent them. NICE advises that while there is currently no evidence to recommend one particular antibiotic over another, trimethoprim and nitrofurantoin are preferred antibiotics.

NICE recommends that when deciding whether or not to prescribe an antimicrobial drug, clinicians should take into account the risk of antimicrobial resistance for individual patients and the population as a whole.

What are the implications?

The review findings support current guidelines that nitrofurantoin can be used to treat recurrent urinary tract infections in adults but it is not necessarily preferable to other options. Clinicians may consider prescribing it to reduce the effects on antimicrobial resistance, but patients should understand the increased probability of more gastrointestinal side effects.

Knowledge about antibiotic resistance continues to evolve, so up to date studies are needed to identify the antibiotics least prone to resistance and yet still beneficial to patients.

Furthermore, research into non-antibiotic treatment of recurrent urinary tract infections would provide an alternative that could reduce widespread antibiotic resistance.

Citation and Funding

Price J, Guran L, Gregory W, et al. Nitrofurantoin versus other prophylactic agents in reducing recurrent urinary tract infections in adult women: a systematic review and meta-analysis. Am J Obstet Gynecol. 2016;215(5):548-60.

No funding information was provided for this study.

Bibliography

Albert X, Huertas I, Pereiro II, et al. Antibiotics for preventing recurrent urinary tract infection in non-pregnant women. Cochrane Database Syst Rev. 2004 (3):CD001209.

Flower A, Wang L, Lewith G, et al. Chinese herbal medicine for treating recurrent urinary tract infections in women. Cochrane Database Syst Rev. 2015;(6):CD010446.

NICE. Antimicrobial stewardship: systems and processes for effective antimicrobial medicine use. NG15. London: National Institute for Health and Care Excellence; 2015.

NICE Clinical Knowledge Summaries. Urinary tract infection (lower) women. London: National Institute for Health and Care Excellence; 2015.

Patient. Recurrent cystitis in women. Leeds: EMIS Group; 2015.

The Urology Foundation. Bladder-related statistics. London: The Urology Foundation; undated.

Why was this study needed?

Urinary tract infections are common and mainly affect women. Around half the women in the UK are likely to have at least one in their life. Of these, 25% experience recurrent infections, defined as at least two infections in six months or three in one year.

Previous evidence has found that giving prophylactic antibiotics is more likely to prevent a urinary tract infection than placebo. However antibiotic resistance is a growing problem worldwide and is thought to be one cause of recurrent infections.

Fewer urinary tract infections become resistant to nitrofurantoin, so it could be a better choice of antibiotic when it comes to preventing further antibiotic resistance.

This review aimed to shed some light on the evidence available around the different treatment options and the relative benefits and harms of their use for recurrent urinary tract infections.

What did this study do?

This systematic review included 12 randomised controlled trials involving 1,063 people. Studies included non-pregnant adult women being treated as an outpatient to prevent recurrent urinary tract infections. Trial size ranged from 30 to 222 women.

The trials compared nitrofurantoin prophylaxis with other commonly used antibiotics and treatments. Doses varied between the studies and people were treated for a minimum of six months. The authors pooled the results in standard meta-analysis.

The authors also analysed the number of adverse events occurring during treatment.

Four of the studies took place in the UK, so are likely to be relevant. Outcome assessors were often aware of the treatments but, on its own, this bias is unlikely to have led to the ‘no difference’ conclusion.

What did it find?

  • The analysis of 12 trials found no difference in successful cure of urinary tract infections in adult women with recurrent urinary tract infections between nitrofurantoin and any of the other treatments when results were combined (relative risk ratio [RR], 1.06, 95% confidence interval [CI] 0.90 to 1.26). The alternative antibiotics were norfloxacin, trimethoprim, sulfamethoxazole/trimethoprim, methamine hippurate (not currently used in the UK) and cefaclor, and the hormonal treatment estriol, an oestrogen vaginal cream.
  • There was no significant difference between treatments when trials were grouped according to the comparison treatment, for example when the three studies that compared nitrofurantoin with trimethoprim were analysed.
  • There was an increased risk of having an adverse event, mainly involving gastrointestinal symptoms, when being treated with nitrofurantoin compared to other treatment (relative RR 1.83, 95% CI 1.18 to 2.84; 10 trials, 948 women).
  • There were not enough participants to accurately assess the likelihood of more severe side effects and insufficient data to report differences between relapse versus reinfection in the comparison groups.

What does current guidance say on this issue?

A 2015 NICE Clinical Knowledge Summary of current evidence and practical guidance, recommends that women who experience unacceptable discomfort or disruption from recurrent urinary tract infections be given antibiotics to try to prevent them. NICE advises that while there is currently no evidence to recommend one particular antibiotic over another, trimethoprim and nitrofurantoin are preferred antibiotics.

NICE recommends that when deciding whether or not to prescribe an antimicrobial drug, clinicians should take into account the risk of antimicrobial resistance for individual patients and the population as a whole.

What are the implications?

The review findings support current guidelines that nitrofurantoin can be used to treat recurrent urinary tract infections in adults but it is not necessarily preferable to other options. Clinicians may consider prescribing it to reduce the effects on antimicrobial resistance, but patients should understand the increased probability of more gastrointestinal side effects.

Knowledge about antibiotic resistance continues to evolve, so up to date studies are needed to identify the antibiotics least prone to resistance and yet still beneficial to patients.

Furthermore, research into non-antibiotic treatment of recurrent urinary tract infections would provide an alternative that could reduce widespread antibiotic resistance.

Citation and Funding

Price J, Guran L, Gregory W, et al. Nitrofurantoin versus other prophylactic agents in reducing recurrent urinary tract infections in adult women: a systematic review and meta-analysis. Am J Obstet Gynecol. 2016;215(5):548-60.

No funding information was provided for this study.

Bibliography

Albert X, Huertas I, Pereiro II, et al. Antibiotics for preventing recurrent urinary tract infection in non-pregnant women. Cochrane Database Syst Rev. 2004 (3):CD001209.

Flower A, Wang L, Lewith G, et al. Chinese herbal medicine for treating recurrent urinary tract infections in women. Cochrane Database Syst Rev. 2015;(6):CD010446.

NICE. Antimicrobial stewardship: systems and processes for effective antimicrobial medicine use. NG15. London: National Institute for Health and Care Excellence; 2015.

NICE Clinical Knowledge Summaries. Urinary tract infection (lower) women. London: National Institute for Health and Care Excellence; 2015.

Patient. Recurrent cystitis in women. Leeds: EMIS Group; 2015.

The Urology Foundation. Bladder-related statistics. London: The Urology Foundation; undated.

Nitrofurantoin versus other prophylactic agents in reducing recurrent urinary tract infections in adult women. A Systematic Review and Meta-analysis

Published on 28 July 2016

Price, J. R.,Guran, L. A.,Gregory, W. T.,McDonagh, M. S.

Am J Obstet Gynecol , 2016

OBJECTIVE: The objective of this review was to provide current pooled estimates of randomized controlled trials (RCTs) comparing the effects of nitrofurantoin versus all other treatments including other antibiotics in reducing recurrent urinary tract infections in adult, non-pregnant women and assess relative adverse side effects. DATA SOURCES: MEDLINE January 1, 1946 to January 31, 2015; Cochrane Central Register of Controlled Trials (CENTRAL), tCochrane Database of Systematic Reviews, ClinicalTrials.gov, and Web sites of the National Institute for Clinical Excellence, and the National Guideline Clearinghouse from 2000 to 2015. STUDY ELIGIBILITY CRITERIA: This systematic review aims to provide guidance on gaps in evidence to guide future research. A description of the inclusion criteria is available online. (www.crd.york.ac.uk/PROSPERO; Record number 23966) STUDY APPRAISAL AND SYNTHESIS METHODS: Quality of included studies was assessed using the Drug Effectiveness Review Project (DERP) tool. Studies were synthesized by pooling data on similar outcomes across studies with similar design, methodology, and patient populations. RESULTS: Twelve RCTs involving 1063 patients were included. One study that had a serious flaw was rated poor in quality, one study rated good, and the remainder fair. No significant differences in prophylactic antibiotic treatment with nitrofurantoin and norfloxacin, trimethoprim, sulfamethoxazole/trimethoprim, methenamine hippurate, estriol, or cefaclor were found in clinical (9 RCTs, 673 patients, RR = 1.06, 95% CI = 0.89 - 1.27, I2 65%) or microbiological cure in adult non-pregnant women with recurrent UTIs (12 RCTs, 1063 patients, RR = 1.06, 95% CI = 0.90 to 1.26, I2 76% ). Duration of prophylaxis also did not significantly impact outcomes. There was a statistically significant difference in overall adverse effects with nitrofurantoin resulting in greater risk than other prophylactic treatments (10 RCTS, 948 patients, RR = 2.17, 95% CI = 1.34 to 3.50; I2 61%) with a significant difference for withdrawals (12 RCTs, 1063 patients, RR = 2.14, 95% CI = 1.28 to 3.56, I2 8%). Overall, the majority of nitrofurantoin adverse effects were gastrointestinal. CONCLUSIONS: Nitrofurantoin had similar efficacy, but greater risk of adverse events than other prophylactic treatments. Balancing the risks of adverse events, particularly gastrointestinal symptoms, should be considered if selecting nitrofurantoin.

Nitrofurantoin is a commonly used antibiotic that is well known and widely used. It has low resistance rates. Nitrofurantoin acts specifically in the urinary tract and it doesn’t cause changes in flora elsewhere in the body.

Expert commentary

Urinary tract infections are painful. They cause flu-like symptoms even in women with uncomplicated infections. Without external signs, their effects are under-estimated. Although inexpensive to treat, recurrent urinary tract infections create significant personal and healthcare costs, affecting up to 50% of women.

Continuous antibiotics for 6-12 months reduce urinary tract infections, but only during treatment. Nitrofurantoin resistance develops uncommonly. A previous review suggested greater effectiveness than trimethoprim but at the expense of increased side-effects. This review shows mere equal efficacy with trimethoprim and other treatments, whilst confirming a greater risk of side-effects, predominantly gastro-intestinal. Nitrofurantoin, therefore, remains a useful but second-line antibiotic.

Dr James Larcombe, GP, NHS Durham Dales, Easington and Sedgefield CCG