[Skip to Content]
Access to paid content on this site is currently suspended due to excessive activity being detected from your IP address 35.172.233.215. Please contact the publisher to request reinstatement.
[Skip to Content Landing]

Effect of 5-Day Nitrofurantoin vs Single-Dose Fosfomycin on Clinical Resolution of Uncomplicated Lower Urinary Tract Infection in WomenA Randomized Clinical Trial

Educational Objective
To compare the clinical and microbiologic efficacy of nitrofurantoin vs fosfomycin for the treatment of uncomplicated lower urinary tract infection (UTI) in women.
1 Credit CME
Key Points

Question  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?

Findings  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.

Meaning  Five-day nitrofurantoin may be a better alternative to single-dose fosfomycin for treating uncomplicated UTI in women.

Abstract

Importance  The use of nitrofurantoin and fosfomycin has increased since guidelines began recommending them as first-line therapy for lower urinary tract infection (UTI).

Objective  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.

Interventions  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.

Results  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.

Trial Registration  ClinicalTrials.gov Identifier: NCT01966653

Sign in to take quiz and track your certificates

Buy This Activity

JN Learning™ is the home for CME and MOC from the JAMA Network. Search by specialty or US state and earn AMA PRA Category 1 CME Credit™ from articles, audio, Clinical Challenges and more. Learn more about CME/MOC

Article Information

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 (stephan.harbarth@hcuge.ch).

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.

References
1.
Gupta  K, Hooton  TM, Naber  KG,  et al; Infectious Diseases Society of America; European Society for Microbiology and Infectious Diseases.  International clinical practice guidelines for the treatment of acute uncomplicated cystitis and pyelonephritis in women: a 2010 update by the Infectious Diseases Society of America and the European Society for Microbiology and Infectious Diseases.  Clin Infect Dis. 2011;52(5):e103-e120.PubMedGoogle ScholarCrossref
2.
European Centre for Disease Prevention and Control. Trend of antimicrobial consumption by country. https://ecdc.europa.eu/en/antimicrobial-consumption/database/trend-country. Accessed February 25, 2018.
3.
Huttner  A, Verhaegh  EM, Harbarth  S, Muller  AE, Theuretzbacher  U, Mouton  JW.  Nitrofurantoin revisited: a systematic review and meta-analysis of controlled trials.  J Antimicrob Chemother. 2015;70(9):2456-2464.PubMedGoogle ScholarCrossref
4.
Zalmanovici Trestioreanu  A, Green  H, Paul  M, Yaphe  J, Leibovici  L.  Antimicrobial agents for treating uncomplicated urinary tract infection in women.  Cochrane Database Syst Rev. 2010;(10):CD007182.PubMedGoogle Scholar
5.
 Fosfomycin for urinary tract infections.  Med Lett Drugs Ther. 1997;39(1005):66-68.PubMedGoogle Scholar
6.
Kahan  FM, Kahan  JS, Cassidy  PJ, Kropp  H.  The mechanism of action of fosfomycin (phosphonomycin).  Ann N Y Acad Sci. 1974;235(0):364-386.PubMedGoogle ScholarCrossref
7.
Maraki  S, Samonis  G, Rafailidis  PI, Vouloumanou  EK, Mavromanolakis  E, Falagas  ME.  Susceptibility of urinary tract bacteria to fosfomycin.  Antimicrob Agents Chemother. 2009;53(10):4508-4510.PubMedGoogle ScholarCrossref
8.
Oteo  J, Bautista  V, Lara  N,  et al; Spanish ESBL-EARS-Net Study Group.  Parallel increase in community use of fosfomycin and resistance to fosfomycin in extended-spectrum beta-lactamase (ESBL)-producing Escherichia coli.  J Antimicrob Chemother. 2010;65(11):2459-2463.PubMedGoogle ScholarCrossref
9.
Michalopoulos  AS, Livaditis  IG, Gougoutas  V.  The revival of fosfomycin.  Int J Infect Dis. 2011;15(11):e732-e739.PubMedGoogle ScholarCrossref
10.
Mazzei  T, Cassetta  MI, Fallani  S, Arrigucci  S, Novelli  A.  Pharmacokinetic and pharmacodynamic aspects of antimicrobial agents for the treatment of uncomplicated urinary tract infections.  Int J Antimicrob Agents. 2006;28(suppl 1):S35-S41.PubMedGoogle ScholarCrossref
11.
Wijma  RA, Koch  BCP, van Gelder  T, Mouton  JW.  High interindividual variability in urinary fosfomycin concentrations in healthy female volunteers  [published online September 1, 2017].  Clin Microbiol Infect. doi:10.1016/j.cmi.2017.08.023PubMedGoogle Scholar
12.
Stein  GE.  Comparison of single-dose fosfomycin and a 7-day course of nitrofurantoin in female patients with uncomplicated urinary tract infection.  Clin Ther. 1999;21(11):1864-1872.PubMedGoogle ScholarCrossref
13.
Van Pienbroek  E, Hermans  J, Kaptein  AA, Mulder  JD.  Fosfomycin trometamol in a single dose versus seven days nitrofurantoin in the treatment of acute uncomplicated urinary tract infections in women.  Pharm World Sci. 1993;15(6):257-262.PubMedGoogle ScholarCrossref
14.
Nicolle  LE.  Uncomplicated urinary tract infection in adults including uncomplicated pyelonephritis.  Urol Clin North Am. 2008;35(1):1-12, v. v.PubMedGoogle ScholarCrossref
15.
Borsa  F, Leroy  A, Fillastre  JP, Godin  M, Moulin  B.  Comparative pharmacokinetics of tromethamine fosfomycin and calcium fosfomycin in young and elderly adults.  Antimicrob Agents Chemother. 1988;32(6):938-941.PubMedGoogle ScholarCrossref
16.
Horan  TC, Andrus  M, Dudeck  MA.  CDC/NHSN surveillance definition of health care-associated infection and criteria for specific types of infections in the acute care setting.  Am J Infect Control. 2008;36(5):309-332.PubMedGoogle ScholarCrossref
17.
Garcia  LS, Isenberg  HD.  Clinical Microbiology Procedures Handbook. 3rd ed. Washington, DC: ASM Press; 2010.Crossref
18.
CLSI.  M100-S25 Performance Standards for Antimicrobial Susceptibility Testing: Twenty-Fifth Informational Supplement. Wayne, PA: Clinical and Laboratory Standards Institute; 2015.
19.
European Committee on Antimicrobial Susceptibility Testing. http://www.eucast.org/. Accessed November 28, 2017.
20.
Gupta  K, Hooton  TM, Stamm  WE.  Isolation of fluoroquinolone-resistant rectal Escherichia coli after treatment of acute uncomplicated cystitis.  J Antimicrob Chemother. 2005;56(1):243-246.PubMedGoogle ScholarCrossref
21.
Ernst  EJ, Ernst  ME, Hoehns  JD, Bergus  GR.  Women’s quality of life is decreased by acute cystitis and antibiotic adverse effects associated with treatment.  Health Qual Life Outcomes. 2005;3:45.PubMedGoogle ScholarCrossref
22.
Infectious Diseases Society of America.  White paper: recommendations on the conduct of superiority and organism-specific clinical trials of antibacterial agents for the treatment of infections caused by drug-resistant bacterial pathogens.  Clin Infect Dis. 2012;55(8):1031-1046.PubMedGoogle ScholarCrossref
23.
White  IR, Royston  P, Wood  AM.  Multiple imputation using chained equations: issues and guidance for practice.  Stat Med. 2011;30(4):377-399.PubMedGoogle ScholarCrossref
24.
Huttner  A, Brossier  C, von Dach  E,  et al. Increasing nitrofurantoin resistance in Escherichia coli urinary isolates in a country with over-the-counter antibiotic sales. Presented at: 27th European Congress on Clinical Microbiology and Infection; April 22, 2017; Vienna, Austria.
25.
Giesen  LG, Cousins  G, Dimitrov  BD, van de Laar  FA, Fahey  T.  Predicting acute uncomplicated urinary tract infection in women: a systematic review of the diagnostic accuracy of symptoms and signs.  BMC Fam Pract. 2010;11:78.PubMedGoogle ScholarCrossref
26.
Abbott  IJ, Meletiadis  J, Belghanch  I,  et al.  Fosfomycin efficacy and emergence of resistance among Enterobacteriaceae in an in vitro dynamic bladder infection model  [published online December 14, 2017].  J Antimicrob Chemother. doi:10.1093/jac/dkx441PubMedGoogle Scholar
27.
Neuner  EA, Sekeres  J, Hall  GS, van Duin  D.  Experience with fosfomycin for treatment of urinary tract infections due to multidrug-resistant organisms.  Antimicrob Agents Chemother. 2012;56(11):5744-5748.PubMedGoogle ScholarCrossref
28.
Iravani  A, Klimberg  I, Briefer  C, Munera  C, Kowalsky  SF, Echols  RM.  A trial comparing low-dose, short-course ciprofloxacin and standard 7 day therapy with co-trimoxazole or nitrofurantoin in the treatment of uncomplicated urinary tract infection.  J Antimicrob Chemother. 1999;43(suppl A):67-75.PubMedGoogle ScholarCrossref
29.
Mezzatesta  ML, La Rosa  G, Maugeri  G,  et al.  In vitro activity of fosfomycin trometamol and other oral antibiotics against multidrug-resistant uropathogens.  Int J Antimicrob Agents. 2017;49(6):763-766.PubMedGoogle ScholarCrossref
30.
Spencer  RC, Moseley  DJ, Greensmith  MJ.  Nitrofurantoin modified release versus trimethoprim or co-trimoxazole in the treatment of uncomplicated urinary tract infection in general practice.  J Antimicrob Chemother. 1994;33(suppl A):121-129.PubMedGoogle ScholarCrossref
31.
Slekovec  C, Leroy  J, Huttner  A,  et al.  When the precautionary principle disrupts 3 years of antibiotic stewardship: nitrofurantoin in the treatment of urinary tract infections.  J Antimicrob Chemother. 2014;69(1):282-284.PubMedGoogle ScholarCrossref
32.
Stewardson  AJ, Vervoort  J, Adriaenssens  N,  et al; SATURN WP1 Study Group; SATURN WP3 Study Group.  Effect of outpatient antibiotics for urinary tract infections on antimicrobial resistance among commensal Enterobacteriaceae: a multinational prospective cohort study.  Clin Microbiol Infect. 2018;S1198-743X(18)30031-4.PubMedGoogle Scholar
33.
Muller  AE, Verhaegh  EM, Harbarth  S, Mouton  JW, Huttner  A.  Nitrofurantoin’s efficacy and safety as prophylaxis for urinary tract infections: a systematic review of the literature and meta-analysis of controlled trials.  Clin Microbiol Infect. 2017;23(6):355-362.PubMedGoogle ScholarCrossref
If you are not a JN Learning subscriber, you can either:
Subscribe to JN Learning for one year
Buy this activity
jn-learning_Modal_LoginSubscribe_Purchase
Close
If you are not a JN Learning subscriber, you can either:
Subscribe to JN Learning for one year
Buy this activity
jn-learning_Modal_LoginSubscribe_Purchase
Close
With a personal account, you can:
  • Access free activities and track your credits
  • Personalize content alerts
  • Customize your interests
  • Fully personalize your learning experience
Education Center Collection Sign In Modal Right
Close

Name Your Search

Save Search
Close
With a personal account, you can:
  • Track your credits
  • Personalize content alerts
  • Customize your interests
  • Fully personalize your learning experience
jn-learning_Modal_SaveSearch_NoAccess_Purchase
Close

Lookup An Activity

or

Close

My Saved Searches

You currently have no searches saved.

Close
With a personal account, you can:
  • Access free activities and track your credits
  • Personalize content alerts
  • Customize your interests
  • Fully personalize your learning experience
Education Center Collection Sign In Modal Right
Close