Alternative to prophylactic antibiotics for the treatment of recurrent urinary tract infections in women: multicentre, open label, randomised, non-inferiority trialBMJ 2022; 376 doi: https://doi.org/10.1136/bmj-2021-0068229 (Published 09 March 2022) Cite this as: BMJ 2022;376:e068229
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Harding et al’s study on methenamine hippurate for recurrent urinary tract infections in women is a step forward in recognising that these infections are a major problem which is often overlooked or ignored . Frequent, distressing symptoms were reported by large numbers of women to a Woman’s Hour phone-in programme on the subject. (The condition is also known as the bladder pain syndrome and previously as the urethral syndrome.)
The action of methenamine hippurate depends on the production of formaldehyde . Information about its long-term safety is lacking . Manufacturers advise it is preferable to avoid it in pregnancy . For other women, a non-antibiotic treatment avoids the risk of increasing antibiotic resistance and the side effects of long-term prophylaxis with antibiotics such as trimethoprim, nitrofurantoin or cefalexin.
Methenamine hippurate brands usually contain an ingredient that helps to make the urine acidic [2, 4]. It is under acid conditions that formaldehyde is produced, so it may be useful to check the urine pH in patients who do not respond.
The underlying cause of this syndrome has been investigated by Dr Rosalind Maskell, who reported that the recurrent symptoms are due to antibiotics disturbing the protective commensal flora of the distal third of the urethra (the upper urethra is normally sterile) . She found that antibiotic courses allowed more resistant and fastidious bacteria from the commensal flora (often lactobacilli) to invade the sterile upper areas of the urethra. Progression of the condition sometimes resulted in interstitial cystitis with chronic inflammation of the bladder wall. Dr Maskell recommended avoiding antibiotics, apart from a 3 day course for a proven infection with a pathogen such as Escherichia coli. Then alkalinising the urine with citrate or bicarbonate preparations from a high street chemist may help with symptoms and prevent further invasion of the urinary tract, while the normal distribution and balance of the commensal flora is re-established. She commented that the earlier in the progression of the condition this is carried out, the greater the likelihood of success in gradually rendering the patient symptom-free.
D-mannose has been reported to help in this condition [6, 7]. It is thought to act by inhibiting bacterial adhesion to the urothelial cells [3, 4]. Use of non-steroid anti-inflammatory drugs, such as ibuprofen, may provide some help in addition to other therapies, by calming local nerve pathways. A consideration to keep in mind is that some vaginal preparations may occasionally irritate perineal areas. Cranberry juice is no longer thought to be useful and it may make symptoms worse. Like vitamin C, it acidifies the urine.
A short course of azithromycin may be useful in this condition, mainly for its anti-inflammatory effect and high tissue concentration (STDs having been ruled out). However, this needs further investigation.
1. Harding C, Mossop H, Homer T et al. Alternative to prophylactic antibiotics for the treatment of recurrent urinary tract infections in women BMJ 2022:376:e068229 doi: 10.1136/bmj-2021-0068229
2. Lo TS, Hammer KDP, Zegarra M, Cho WCS Methenamine: a forgotten drug for preventing recurrent urinary tract infection in a multidrug resistance era. Expert Review of Anti-infective Therapy 2014; 12 (5): 549-554 https://doi.org/10.1586/14787210.2014.904202
3. Hoffmann TC, Bakhit M, Del Mar C. Methenamine hippurate for recurrent urinary tract infections. Commentary. BMJ 2022; 376: o533 http://dx.doi.org/10.1136/bmj.o533
4. Methenamine hippurate / drug-BNF. https://bnf.nice.org.uk › drug › methenamine-hippurate
5. Maskell RM The natural history of urinary tract infection in women, Medical Hypothesis 2010;74:802-806 doi:10.1016/j.mehy.2009.12.011
6. Kranjčec B, Papeš D, Altarac S. D-mannose powder for prophylaxis of recurrent urinary tract infections in women: a randomized clinical trial. World J Urol. 2014 Feb;32(1):79-84. doi: 10.1007/s00345-013-1091-6. Epub 2013 Apr 30.
7. Domenici L; Monti M; Bracchi C; Giorgini M; Colagiovanni V; Muzii L; Benedetti Panici P. D-mannose: a promising support for acute urinary tract infections in women. A pilot study. European Review for Medical & Pharmacological Sciences. 2016; 20(13):2920-5. PMID: 27424995.
Competing interests: No competing interests
Re: ALTAR trial on alternatives to antibiotic prophylaxis: a step towards a more collective conversation
The publication of this trial data marks one of few major interventions in this topic area of urinary tract infection in the past fifty years, across both diagnostics and treatment. Quality evidence in this area is severely lacking and continued funding investment will greatly benefit both patient experience and antimicrobial stewardship, which are intimately related. This data can increase prescriber confidence to offer methenamine hippurate to patients experiencing hard-to-treat urinary tract infection.
Of note is the way patient and public involvement shaped the trial design. As of now, we have limited ways to formally account for the advantages of non-antibiotic treatments over antibiotic treatments in evidence review practices, including increased antimicrobial resistance in urinary isolates, altered microbiome and increased financial costs and burden of illness of multi-drug resistant infection. In this trial, this was captured by the PPI group defining the non-inferiority margin as one episode of urinary tract infection per person per year. Therefore, a major achievement of this trial is not only the production of quality evidence on a pharmaceutical intervention, but the way in which it accounts for the co-production of the societal and individual benefits of avoiding antibiotic treatment where possible. Too often, these benefits have been presented as societal in nature, opposed to individual patient wellbeing. Such ways of accounting for collective mobilisations between patients and healthcare practitioners on AMR and UTI can be seen as a model going forward.
Elsewhere, the benefits of non-antibiotic treatment have been harder to account for. In current NICE guidance on recurrent UTI [NG112], no recommendation is made on the use of methenamine given evidence that antibiotic prophylaxis with Nitrofurantoin was more effective. The generation of long term safety data on methenamine hippurate, as the authors of this trial paper note, is a priority, including in pregnancy. Methenamine can be a daunting option for patients, especially in pregnancy, as formaldehyde is a well-known carcinogen (1). In the absence of safety data, shared decision making between patients and clinicians will need to carefully balance this against the advantages of non-antibiotic therapy. Moreover, of particular relevance in pregnancy is the prior likelihood that a patient foregoing methenamine prophylaxis will experience an episode of UTI that will need to be treated with antibiotics, based on clinical history. Pregnancy was an exclusion criterion in this trial.
Further opportunities to utilise patient knowledge in decision making come from the experiences of patients already using methenamine as a grey-list drug, marked as ‘less suitable for prescribing’ in the formulary. These experiences suggests that some may find it hard to tolerate, with symptoms of burning. Patients already using this drug have developed practices, such as encapsulation, which will be useful in supporting patients to trial this option. This is one example of the significant expertise these patients have developed in the absence of effective antimicrobial treatment.
Current NICE guidance runs out of course in patients who continue to experience recurrence or relapse after trials of vaginal oestrogen and antibiotic prophylaxis, and SIGN guidance after antibiotic prophylaxis. The option of using methenamine hippurate is a very welcome addition to strategies for patients living with hard-to-treat UTI, who are often un-supported, living without any systematic approach from health care practitioners. It is hoped that access to methenamine hippurate can be improved, with MHRA's recent re-classification of the drug making it now unavailable over the counter, and some patients reporting reluctance to prescribe in general practice. Patients living with hard-to-treat UTI need recognition and effective treatment, and this is too often cast as demand for antibiotics. The ALTAR trial is a major intervention in moving towards a more collective conversation.
1) SCHER, scientific opinion on the risk assessment report on methenamine (CAS N° 100- 97-0), human health part, 23 April 2007
Competing interests: No competing interests