Vitamin C and Hiprex: Does Vitamin C improve the efficacy of Methenamine Hippurate (Hiprex®) in the Prophylaxis of recurrent Urinary Tract Infections? A proof of concept study

Dec 1, 2024

6 min read

Tina Mistry Pain1, Mark Kitchen1

Consultant Urologists, University Hospitals North Midlands, Newcastle Road, Stoke-on-Trent, ST4 6QG

Background: Vitamin C and Hiprex

UTIs are extremely common and especially prevalent in women, with 50% of women experiencing at least one UTI in their lifetime [1]. 10% of women will have at least one UTI per year, with 2.4% of all women going on to experience very frequent UTIs [2]. Recurrent UTIs (rUTIs) are commonly defined as the occurrence of more than two proven infections in six months or three or more infections in one year [3]. They are responsible for a significant proportion of primary and secondary care consultations, and hence constitute a significant economic burden to healthcare systems. Some patients may also develop severe infections requiring hospital admission, with a small proportion progressing to life-threatening sepsis. Furthermore, rUTIs often have substantial effects on patients’ quality of life, personal relationships and ability to work.

The potential role of Vitamin C and Hiprex in preventing recurrent UTIs is therefore an important area for further research.

Short courses of antibiotics are normally used to treat symptomatic UTIs, and patients with rUTIs will often receive treatment with multiple courses of antibiotics in a year. Around 4 million antibiotic prescriptions for UTI were issued in 2020-21, at a cost of approximately £37 million [4]. Additionally, longer courses of low-dose antibiotics, are often utilised for the prevention of rUTIs with some patients remaining on them for six months or more or even indefinitely.

Like any medication, antibiotics can cause side effects such as gastrointestinal symptoms such as nausea, vomiting and diarrhoea due to the disruption of normal healthy gut flora, as well as having the risk of serious allergic reactions. A wider risk of antibiotic use is that of antimicrobial resistance (AMR) which is a serious worldwide problem, accounting for approximately 1.27 million deaths globally in 2019; AMR has been designated one of the top ten major public health threats by the World Health Organisation. AMR results from widespread overuse and misuse of antibiotics, resulting in infections that are harder to treat with conventional antibiotics, thus increasing the risk of severe illness and death. The U.K. government has developed a new AMR 5-year national action plan (2024 – 2029), which has “reducing the need for, and unintentional exposure to, antibiotics” as one of its overall aims. One facet of this plan is to prevent infections, and hence the need to develop and enhance UTI prevention strategies is imperative.

Methenamine Hippurate (Hiprex®) has gained popularity as a UTI preventative agent following a Cochrane review in 2012 which concluded that it may be effective in reducing UTIs. The recently published ALTAR study supports the use of methenamine hippurate as a non-inferior alternative to low-dose antibiotics in the prevention of rUTIs in women. As such, rUTI prophylaxis with methenamine hippurate is recommended in guidelines published by both NICE and the European Association of Urology [3, 5]. It has been well documented in laboratory studies that methenamine hippurate requires the presence of acidic urine for its antimicrobial activity. Based on this, many clinicians will often advise patients to take vitamin C in addition to methenamine hippurate to enhance its efficacy. There is no clear evidence to support the use of vitamin C in urinary acidification in vivo, and furthermore, there is a paucity of evidence to demonstrate that concurrent vitamin C use enhances the efficacy or methenamine hippurate in the reduction of rUTIs. There is also widespread disparity amongst clinicians between the dosing regimens of vitamin C that patients are advised to take.

The evidence to support the use of Vitamin C as a urinary acidification agent is conflicting [6], and evidence to support its ability to enhance the efficacy of methenamine hippurate is also lacking. Furthermore, while Vitamin C itself has been shown to have bactericidal effects in vitro, its ability to do so reliably in clinical practice has not been proven [7].

Vitamin C is cheap and readily available in a variety of preparations and doses and is widely used by many people for a variety of health benefits. Whilst being often recommended by clinicians as an adjunct to methenamine hippurate treatment, it is needs to be purchased independently by patients. Hence there is an associated financial and poly-pharmaceutical burden to patients, with little data to justify its use.

Aims and Objectives

We aim to undertake a proof-of-concept study to assess whether high dose vitamin C enhances the ability of methenamine hippurate to reduce symptomatic rUTIs in adult women, to justify the promotion of concomitant high dose vitamin C use in this group of patients.

The primary objective is to assess whether the addition of vitamin C to methenamine hippurate enhances its ability to reduce symptomatic rUTIs in women over six months.

Secondary objectives of the study include:

to determine the number of microbiologically proven UTIs during each six-month treatment phase of methenamine hippurate alone or methenamine hippurate plus vitamin C.
to determine whether high dose vitamin C has any effect on urinary pH over six months.
To assess patient satisfaction of treatment with either methenamine hippurate alone or methenamine hippurate with vitamin C using a validated questionnaire
To determine if high dose vitamin C administration affects urinary uric acid and oxalate levels which could result in urinary tract stone formation
to determine if treatment with either methenamine hippurate alone or methenamine hippurate with vitamin C effects symptoms and quality life, using validated questionnaires.
To obtain qualitative data on symptoms, side effects, tolerability and antibiotic usage via patient diaries.
To deliver a patient focus group to ascertain participants views on the feasibility, acceptability, and tolerability of combination treatment with methenamine hippurate and Vitamin C.

Methods

This will be a prospective, “A-B-A” study design, to determine whether there is an indication of an effect, rather than to undertake formal hypothesis testing. Patients’ acceptability and tolerability of treatment will also be assessed using validated questionnaires as well as bladder diaries, with the view to assess the feasibility of undertaking a larger study.

Adult female patients (n = 10-20) will be recruited from urology secondary care services (out-patient clinics, urology admissions). Eligible patients will undergo sequential treatment with Hiprex alone, Hiprex + Vitamin C, Hiprex alone (six months each). Participants will be given equipment to test their urine pH every month, and undergo urinalysis, blood tests and complete validated questionnaires at 0, 6, 12 and 18 months (standard care), as well as symptom diaries to complete whenever indicated throughout the duration of the study.

All patients will be provided with written information and informed consent will be obtained. Patients will be asked if they would be willing to participate in a patient focus group with the view to designing a larger study.

Conclusion

This study has the potential to impact patient care by providing evidence to indicate whether Vitamin C has an effect on enhancing the ability of methenamine hippurate to reduced symptomatic rUTIs in adult women, thereby lending weight to support the financial expense to patients of purchasing vitamin C tablets. If no effect is detected then this study could also potentially reduce unnecessary polypharmacy in these patients. This study would also supporting national and international efforts to reduce AMR by enhancing the efficacy of non-antimicrobial prophylactic agents and thus reducing antibiotic use.

References

[1] Foxman B, Barlow R, D'Arcy H, et al. Urinary tract infection: self-reported incidence and associated costs. Ann Epidemiol 2000;10(8):509-15.

[2] Brumbaugh AR, Mobley HL. Preventing urinary tract infection: progress toward an effective Escherichia coli vaccine. Expert Rev Vaccines 2012;11(6):663-76.

[3] G. Bonkat et al. European Association of Urology Guidelines on Urological Infections. In: EAU Guidelines Edn. presented at the EAU Annual Congress Paris 2024. ISBN 978-94-92671-23-3.

[4] The Cost of Poor Bladder Care Report, 2021. https://bladderinterestgroup.co.uk/wp-content/uploads/2021/12/Cost-of-Poor-Bladder-Management-Report-2021.pdf

[5] Harding C., Mossop H., Homer T., et al. Alternative to prophylactic antibiotics for the treatment of recurrent urinary tract infections in women: multicentre, open label, randomised, non-inferiority trial. British Medical Journal 2022;376:e068229

[6] Keogh K., Collin H., Dowling C., Roberts M. Vitamin C as an adjunct to methenamine hippurate use after ALTAR: ego or evidence-based? BJU Int 2024; 133: Supplement 3: 6–7 doi:10.1111/bju.16096

[7] Carlsson S, Govoni M, Wiklund NP, Weitzberg E, Lundberg JO. In vitro evaluation of a new treatment for urinary tract infections caused by nitrate-reducing bacteria. Antimicrob Agents Chemother 2003; 47: 3717–8