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What is the effect of 5-day nitrofurantoin, compared with single-dose fosfomycin, on clinical resolution of uncomplicated lower urinary tract infection (UTI) in women?
In this randomized clinical trial that included 513 women with uncomplicated UTI, clinical resolution at 28 days occurred in 70% of patients in the nitrofurantoin group vs 58% of patients in the fosfomycin group, a statistically significant difference.
Five-day nitrofurantoin may be a better alternative to single-dose fosfomycin for treating uncomplicated UTI in women.
The use of nitrofurantoin and fosfomycin has increased since guidelines began recommending them as first-line therapy for lower urinary tract infection (UTI).
To compare the clinical and microbiologic efficacy of nitrofurantoin and fosfomycin in women with uncomplicated cystitis.
Design, Setting, and Participants
Multinational, open-label, analyst-blinded, randomized clinical trial including 513 nonpregnant women aged 18 years and older with symptoms of lower UTI (dysuria, urgency, frequency, or suprapubic tenderness), a positive urine dipstick result (with detection of nitrites or leukocyte esterase), and no known colonization or previous infection with uropathogens resistant to the study antibiotics. Recruitment took place from October 2013 through April 2017 at hospital units and outpatient clinics in Geneva, Switzerland; Lodz, Poland; and Petah-Tiqva, Israel.
Participants were randomized in a 1:1 ratio to oral nitrofurantoin, 100 mg 3 times a day for 5 days (n = 255), or a single 3-g dose of oral fosfomycin (n = 258). They returned 14 and 28 days after therapy completion for clinical evaluation and urine culture collection.
Main Outcomes and Measures
The primary outcome was clinical response in the 28 days following therapy completion, defined as clinical resolution (complete resolution of symptoms and signs of UTI without prior failure), failure (need for additional or change in antibiotic treatment due to UTI or discontinuation due to lack of efficacy), or indeterminate (persistence of symptoms without objective evidence of infection). Secondary outcomes included bacteriologic response and incidence of adverse events.
Among 513 patients who were randomized (median age, 44 years [interquartile range, 31-64]), 475 (93%) completed the trial and 377 (73%) had a confirmed positive baseline culture. Clinical resolution through day 28 was achieved in 171 of 244 patients (70%) receiving nitrofurantoin vs 139 of 241 patients (58%) receiving fosfomycin (difference, 12% [95% CI, 4%-21%]; P = .004). Microbiologic resolution occurred in 129 of 175 (74%) vs 103 of 163 (63%), respectively (difference, 11% [95% CI, 1%-20%]; P = .04). Adverse events were few and primarily gastrointestinal; the most common were nausea and diarrhea (7/248 [3%] and 3/248 [1%] in the nitrofurantoin group vs 5/247 [2%] and 5/247 [1%] in the fosfomycin group, respectively).
Conclusions and Relevance
Among women with uncomplicated UTI, 5-day nitrofurantoin, compared with single-dose fosfomycin, resulted in a significantly greater likelihood of clinical and microbiologic resolution at 28 days after therapy completion.
ClinicalTrials.gov Identifier: NCT01966653
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Corresponding Author: Stephan Harbarth, MD, Infection Control Program, Division of Infectious Diseases, Geneva University Hospitals and Faculty of Medicine, Rue Gabrielle-Perret-Gentil 4, 1205 Geneva, Switzerland (email@example.com).
Accepted for Publication: March 9, 2018.
Published Online: April 22, 2018. doi:10.1001/jama.2018.3627
Author Contributions: Dr Harbarth had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.
Concept and design: Huttner, Theuretzbacher, Leibovici, Godycki-Ćwirko, Mouton, Harbarth.
Acquisition, analysis, or interpretation of data: Huttner, Kowalczyk, Turjeman, Babich, Brossier, Eliakim-Raz, Kosiek, Martinez de Tejada, Roux, Schiber, von Dach, Yahav, Leibovici, Godycki-Ćwirko, Mouton, Harbarth.
Drafting of the manuscript: Huttner, Eliakim-Raz, Leibovici, Mouton, Harbarth.
Critical revision of the manuscript for important intellectual content: Huttner, Kowalczyk, Turjeman, Babich, Brossier, Kosiek, Martinez de Tejada, Roux, Schiber, Theuretzbacher, von Dach, Yahav, Leibovici, Godycki-Ćwirko, Mouton, Harbarth.
Statistical analysis: Huttner, Leibovici, Mouton.
Obtained funding: Kowalczyk, Leibovici, Godycki-Ćwirko, Mouton, Harbarth.
Administrative, technical, or material support: Huttner, Kowalczyk, Turjeman, Brossier, Eliakim-Raz, Kosiek, Martinez de Tejada, Roux, Schiber, von Dach, Yahav, Mouton, Harbarth.
Supervision: Huttner, Martinez de Tejada, Theuretzbacher, Leibovici, Godycki-Ćwirko, Harbarth.
Conflict of Interest Disclosures: All authors have completed and submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Ms Kowalczyk reported receiving grants from the European Commission and the Ministry of Science and Higher Education of Poland. Ms Turjeman and Ms Babich reported receiving grants from the European Union’s FP7 Framework. Dr Eliakim-Raz reported receiving grants from the European Commission under the Life Science Health Priority of the 7th Framework Program. Dr Kosiek reported receiving grants from the European Commission and the Ministry of Science and Higher Education. Dr Godycki-Ćwirko reported receiving grants from the European Commission and the Ministry of Science and Higher Education of Poland. Dr Mouton reported receiving grants from Adenium, AstraZeneca, Basilea, Cubist, Polyphor, Roche, Eumedica, Venatorx, Aicuris, and Wockhardt. Dr Harbarth reported receiving grants from the European Commission and personal fees from DNA Electronics, Bayer, GlaxoSmithKline, and Takeda. No other disclosures were reported.
Funding/Support: The study was funded by the European Commission under the Life Science Health Priority of the 7th Framework Program (Assessment of Clinical Efficacy by a Pharmacokinetic/Pharmacodynamic Approach to Optimize Effectiveness and Reduce Resistance for Off-Patent Antibiotics project, grant agreement 278348). The Lodz site received additional funding from the Polish Ministry of Science and Higher Education (2014-2017, contract 2979/7.PR/2014/2).
Role of the Funder/Sponsor: The funders had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication.
Additional Contributions: We thank all trial participants for their efforts and Ilker Uçkay, MD, and Virginie Prendki, MD, for their help in recruitment and Angèle Gayet-Ageron, MD, PhD, for statistical support including mixed effects modeling and multiple imputation; all are with Geneva University Hospitals and none received compensation. We also thank Jocelyne Chabert, PhD, as well as Serenella Ferro-Rojas, PhD, and Khaled Mostaguir, PhD, of the Clinical Research Center of Geneva University Hospitals and Faculty of Medicine for external monitoring and data management, respectively; they received no compensation.
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