Department of Urology, Freeman Hospital, Newcastle upon Tyne, UK.
Translational and Clinical Research Institute, Newcastle University, Newcastle upon Tyne, UK.
Health Technol Assess. 2022 May;26(23):1-172. doi: 10.3310/QOIZ6538.
Daily, low-dose antibiotic prophylaxis is the current standard care for women with recurrent urinary tract infection. Emerging antimicrobial resistance is a global health concern, prompting research interest in non-antibiotic agents such as methenamine hippurate, but comparative data on their efficacy and safety are lacking.
To assess the clinical effectiveness and cost-effectiveness of methenamine hippurate (Hiprex; Mylan NV, Canonsburg, PA, USA) compared with current standard care (antibiotic prophylaxis) for recurrent urinary tract infection prevention in adult women.
Multicentre, pragmatic, open-label, randomised, non-inferiority trial of 12 months' treatment with the allocated intervention, including an early, embedded qualitative study and a 6-month post-treatment observation phase. The predefined non-inferiority margin was one urinary tract infection per person-year.
Eight UK NHS secondary care sites.
A total of 240 adult women with recurrent urinary tract infection requiring preventative treatment participated in the trial.
A central randomisation system allocated participants 1 : 1 to the experimental (methenamine hippurate: 1 g twice daily) or control (once-daily low-dose antibiotics: 50/100 mg of nitrofurantoin, 100 mg of trimethoprim or 250 mg of cefalexin) arm. Crossover between treatment arms was permitted.
The primary clinical outcome was incidence of symptomatic antibiotic-treated urinary tract infection during the 12-month treatment period. Cost-effectiveness was assessed by incremental cost per quality-adjusted life-year gained, extrapolated over the patient's expected lifetime using a Markov cohort model. Secondary outcomes included post-treatment urinary tract infections, total antibiotic use, microbiologically proven urinary tract infections, antimicrobial resistance, bacteriuria, hospitalisations and treatment satisfaction.
Primary modified intention-to-treat analysis comprised 205 (85%) randomised participants [102/120 (85%) participants in the antibiotics arm and 103/120 (86%) participants in the methenamine hippurate arm] with at least 6 months' data available. During treatment, the incidence rate of symptomatic, antibiotic-treated urinary tract infections decreased substantially in both arms to 1.38 episodes per person-year (95% confidence interval 1.05 to 1.72 episodes per person-year) for methenamine hippurate and 0.89 episodes per person year (95% confidence interval 0.65 to 1.12 episodes per person-year) for antibiotics (absolute difference 0.49; 90% confidence interval 0.15 to 0.84). This absolute difference did not exceed the predefined, strict, non-inferiority limit of one urinary tract infection per person-year. On average, methenamine hippurate was less costly and more effective than antibiotics in terms of quality-adjusted life-years gained; however, this finding was not consistent over the longer term. The urinary tract infection incidence rate 6 months after treatment completion was 1.72 episodes per year in the methenamine hippurate arm and 1.19 in the antibiotics arm. During treatment, 52% of urine samples taken during symptomatic urinary tract infections were microbiologically confirmed and higher proportions of participants taking daily antibiotics (46/64; 72%) demonstrated antibiotic resistance in cultured from perineal swabs than participants in the methenamine hippurate arm (39/70; 56%) (-value = 0.05). Urine cultures revealed that during treatment higher proportions of participants and samples from the antibiotic arm grew resistant to trimethoprim/co-trimoxazole and cephalosporins, respectively. Conversely, post treatment, higher proportions of participants in the methenamine hippurate arm (9/45; 20%) demonstrated multidrug resistance in isolated from perineal swabs than participants in the antibiotic arm (2/39; 5%) ( = 0.06). All other secondary outcomes and adverse events were similar in both arms.
This trial could not define whether or not one particular antibiotic was more beneficial, and progressive data loss hampered economic evaluation.
This large, randomised, pragmatic trial in a routine NHS setting has clearly shown that methenamine hippurate is not inferior to current standard care (daily low-dose antibiotics) in preventing recurrent urinary tract infections in women. The results suggest that antimicrobial resistance is proportionally higher in women taking prophylactic antibiotics.
Future research should include evaluation of other non-antibiotic preventative treatments in well-defined homogeneous patient groups, preferably with the comparator of daily antibiotics.
This trial is registered as ISRCTN70219762 and EudraCT 2015-003487-36.
This project was funded by the National Institute for Health and Care Research (NIHR) Health Technology Assessment programme and will be published in full in ; Vol. 26, No. 23. See the NIHR Journals Library website for further project information.
每日低剂量抗生素预防是复发性尿路感染女性的当前标准护理。新兴的抗生素耐药性是一个全球健康问题，促使人们对非抗生素药物（如乌洛托品）产生研究兴趣，但关于其疗效和安全性的比较数据仍然缺乏。
评估乌洛托品（Hiprex；Mylan NV，宾夕法尼亚州坎农斯堡）与当前的标准护理（抗生素预防）相比，在预防成年女性复发性尿路感染方面的临床效果和成本效益。
一项为期 12 个月的治疗的多中心、实用、开放性、随机、非劣效性试验，包括早期、嵌入式定性研究和 6 个月的治疗后观察期。预设的非劣效性边界为每人每年尿路感染 1 次。
英国 8 个 NHS 二级保健站点。
共有 240 名需要预防性治疗的复发性尿路感染成年女性参加了试验。
中央随机化系统将参与者以 1:1 的比例随机分配到实验组（乌洛托品：1g，每日两次）或对照组（每日低剂量抗生素：50/100mg 呋喃妥因、100mg 甲氧苄啶或 250mg 头孢氨苄）。允许治疗组之间交叉。
主要临床结局是在 12 个月治疗期间发生有症状的抗生素治疗的尿路感染的发生率。成本效益通过增量成本每获得的质量调整生命年进行评估，使用马尔可夫队列模型推断患者预期寿命的成本效益。次要结局包括治疗后尿路感染、总抗生素使用、微生物学证实的尿路感染、抗菌药物耐药性、菌尿症、住院和治疗满意度。
主要的改良意向治疗分析包括 205 名（85%）随机参与者[抗生素组 102/120（85%）名参与者和乌洛托品组 103/120（86%）名参与者]至少有 6 个月的数据可用。在治疗期间，两组的有症状、抗生素治疗的尿路感染发生率均显著下降，乌洛托品组为 1.38 例/人年（95%置信区间 1.05 至 1.72 例/人年），抗生素组为 0.89 例/人年（95%置信区间 0.65 至 1.12 例/人年）（绝对差异 0.49；90%置信区间 0.15 至 0.84）。这一绝对差异没有超过预先设定的严格非劣效性界限，即每人每年尿路感染 1 次。平均而言，乌洛托品在获得质量调整生命年方面比抗生素更便宜且更有效；然而，这种发现并不能长期持续。治疗完成后 6 个月的尿路感染发生率为乌洛托品组 1.72 例/年，抗生素组为 1.19 例/年。在治疗期间，有症状尿路感染期间采集的 52%尿液样本经微生物学证实，服用每日抗生素的参与者（46/64；72%）在会阴部拭子中培养出的抗生素耐药性比例高于乌洛托品组（39/70；56%）（-值=0.05）。尿液培养显示，在治疗期间，抗生素组中更多的参与者和样本对甲氧苄啶/复方磺胺甲噁唑和头孢菌素的耐药性分别增加。相反，治疗后，乌洛托品组中更多的参与者（9/45；20%）在会阴部拭子中培养出的耐药性比抗生素组（2/39；5%）更高（=0.06）。两组的所有其他次要结局和不良事件均相似。
本试验无法确定是否一种特定的抗生素更有益，并且数据逐渐丢失妨碍了经济评估。
本研究在常规 NHS 环境中进行的这项大型、随机、实用试验清楚地表明，乌洛托品在预防女性复发性尿路感染方面并不逊于当前的标准护理（每日低剂量抗生素）。结果表明，服用预防性抗生素的女性的抗菌药物耐药性比例较高。
未来的研究应包括评估其他非抗生素预防治疗方法在明确的同质患者群体中的效果，最好将每日抗生素作为对照。
本研究由英国国家卫生与保健优化研究所（NIHR）卫生技术评估计划资助，并将在 ; Vol. 26, No. 23 中全文发表。有关该项目的更多信息，请访问 NIHR 期刊库网站。
