Symptomatic treatment of uncomplicated lower urinary tract infections in the ambulatory setting: randomised, double blind trialBMJ 2017; 359 doi: https://doi.org/10.1136/bmj.j4784 (Published 08 November 2017) Cite this as: BMJ 2017;359:j4784
- Andreas Kronenberg, senior lecturer1 2 3,
- Lukas Bütikofer, senior statistician4 5,
- Ayodele Odutayo, postdoctoral fellow6,
- Kathrin Mühlemann, professor1 2,
- Bruno R da Costa, assistant professor and associate director6 7,
- Markus Battaglia, primary care physician3,
- Damian N Meli, primary care physician3 7,
- Peter Frey, consultant7,
- Andreas Limacher, consultant4 5,
- Stephan Reichenbach, associate professor and attending physician5 8,
- Peter Jüni, professor and director6 7
- 1Institute for Infectious Diseases, University of Bern, Bern, Switzerland
- 2Department of Infectious Diseases, Bern University Hospital, University of Bern, Bern, Switzerland
- 3Medix General Practice Network, Bern, Switzerland
- 4CTU Bern, University of Bern, Bern, Switzerland
- 5Institute of Social and Preventive Medicine, University of Bern, Bern, Switzerland
- 6Applied Health Research Centre, Li Ka Shing Knowledge Institute of St Michael’s Hospital, Department of Medicine and Institute of Health Policy, Management and Evaluation, University of Toronto, Canada
- 7Institute of Primary Health Care, University of Bern, Bern, Switzerland
- 8Department of Rheumatology, Immunology and Allergology, Inselspital, Bern University Hospital, University of Bern, Bern, Switzerland
- Correspondence to: A Kronenberg
- Accepted 9 October 2017
Objective To investigate whether symptomatic treatment with non-steroidal anti-inflammatory drugs (NSAIDs) is non-inferior to antibiotics in the treatment of uncomplicated lower urinary tract infection (UTI) in women, thus offering an opportunity to reduce antibiotic use in ambulatory care.
Design Randomised, double blind, non-inferiority trial.
Setting 17 general practices in Switzerland.
Participants 253 women with uncomplicated lower UTI were randomly assigned 1:1 to symptomatic treatment with the NSAID diclofenac (n=133) or antibiotic treatment with norfloxacin (n=120). The randomisation sequence was computer generated, stratified by practice, blocked, and concealed using sealed, sequentially numbered drug containers.
Main outcome measures The primary outcome was resolution of symptoms at day 3 (72 hours after randomisation and 12 hours after intake of the last study drug). The prespecified principal secondary outcome was the use of any antibiotic (including norfloxacin and fosfomycin as trial drugs) up to day 30. Analysis was by intention to treat.
Results 72/133 (54%) women assigned to diclofenac and 96/120 (80%) assigned to norfloxacin experienced symptom resolution at day 3 (risk difference 27%, 95% confidence interval 15% to 38%, P=0.98 for non-inferiority, P<0.001 for superiority). The median time until resolution of symptoms was four days in the diclofenac group and two days in the norfloxacin group. A total of 82 (62%) women in the diclofenac group and 118 (98%) in the norfloxacin group used antibiotics up to day 30 (risk difference 37%, 28% to 46%, P<0.001 for superiority). Six women in the diclofenac group (5%) but none in the norfloxacin group received a clinical diagnosis of pyelonephritis (P=0.03).
Conclusion Diclofenac is inferior to norfloxacin for symptom relief of UTI and is likely to be associated with an increased risk of pyelonephritis, even though it reduces antibiotic use in women with uncomplicated lower UTI.
Trial registration ClinicalTrials.gov NCT01039545.
We thank the patient participants; the doctor participants for their meticulous data collection; CTU Bern, the clinical trials unit of the University of Bern for the development of the database (Malcolm Sturdy), monitoring (Lucia Kacina), and telephone interview and data clearance (Madeleine Dähler); the Institute of Primary Health Care BIHAM (Berner Institut für Hausarztmedizin), for its organisational support; and the hospital pharmacy of Inselspital for the production and blinding of the study drugs (Marco Eschenmoser).
Participating doctors: Peter Duner, Eggiwil; Christoph Fry, Belp; Ursula Grob, Herzogenbuchsee; Felix Huber, Zürich; Beat Köstner-Mösching, Neuenegg; Andreas Kronenberg, Bern; Corinna Kronenberg, Stettlen; Danielle Lemann, Langnau; Damian Meli, Huttwil; Gabriele Reinheimer, Worb; Véronique Rigamonti Wermelinger, Bern; Ralf Schäfer, Bern; Urs Schneeberger, Niederönz; Christian Studer, Luzern; Fritz Weber, Buchs; Doris Zundel, Bätterkinden; and Anne-Marie Zundel Funk, Zollikofen.
Contributors: AK, KM, and PJ conceived and designed the study and obtained funding. AK, MB, DM, and PF acquired the data. LB, BRdC, AL, SR, and PJ did the analysis and interpreted it in collaboration with the remaining authors. AK and PJ are the guarantors of the study results, had full access to the final data, cowrote the manuscript, and had final responsibility for content and the decision to submit for publication. All authors critically revised the paper for important intellectual content and approved the final version.
Funding: This study was supported by the Swiss National Foundation (project 32003B_130867), Swiss Academy of Medical Sciences, SwissLife foundation, and Else Kroener-Fresenius foundation. PJ is a tier 1 Canada research chair in clinical epidemiology of chronic diseases. This research was completed, in part, with funding from the Canada research chairs programme. The funding bodies were not involved in the design or the conduct of the trial, nor in the writing of the manuscript or the decision to submit the manuscript for publication. The funding bodies only had access to the data after finalisation of the statistical analysis plan and completion of all analyses.
Competing interests: All authors have completed the ICMJE uniform disclosure form at www.icmje.org/coi_disclosure.pdf and declare: no support from any organisation for the submitted work besides the acknowledged financial support. AK has received travel grant and meeting expenses from Gilead, Viofor, and the World Health Organization, is advisor of the Swiss Federal Office of Public Health concerning antibiotic resistance epidemiology in Switzerland, and provides non-interpreted annual resistance data to LEO Pharma and the Swiss government. PJ has received research grants to the institution from Astra Zeneca, Biotronik, Biosensors International, Eli Lilly, and The Medicines Company for cardiovascular trials, and serves as unpaid member of the steering group of cardiovascular trials funded by Astra Zeneca, Biotronik, Biosensors, St Jude Medical, and The Medicines Company. The remaining authors declare no financial relationships with any organisations that might have an interest in the submitted work in the previous three years and no other relationships or activities that could appear to have influenced the submitted work.
Ethical approval: This study was conducted in accordance with the Declaration of Helsinki and was approved by the local research ethics committee and the Swiss Agency for Therapeutic Products, swissmedic.
Data sharing: The statistical analysis plan and the final version of the study protocol are available from the corresponding author. Anonymised patient level data will be made available from the corresponding author at the Institute for Infectious Diseases, University Bern on reasonable request. Consent was not obtained for data sharing but the presented data are anonymised and risk of identification is low. No additional data are available.
Transparency: The lead authors (AK and PJ) affirm that the manuscript is an honest, accurate, and transparent account of the study being reported; that no important aspects of the study have been omitted; and that any discrepancies from the study as planned (and, if relevant, registered) have been explained.
This is an Open Access article distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/.