Confidential: For Review O
nly
Symptomatic therapy of uncomplicated lower urinary tract
infections in the ambulatory setting. A randomized, double blind Trial.
Journal: BMJ
Manuscript ID BMJ.2017.039317
Article Type: Research
BMJ Journal: BMJ
Date Submitted by the Author: 11-May-2017
Complete List of Authors: Kronenberg, Andreas; University of Bern, Institute for Infectious Diseases; University of Bern, Department of Infectious Diseases Bütikofer, Lukas; University of Bern, CTU Bern; Universitat Bern Institut fur Sozial- und Praventivmedizin Odutayo, Ayodele; University of Toronto, Faculty of Medicine; University of Oxford, Centre for Statistics in Medicine Mühlemann, Kathrin; University of Bern, Department of Infectious Diseases Da Costa, Bruno; Universität Bern, Berner Institut für Hausarztmedizin (BIHAM) Battaglia, Markus; Medix General Practice Netzwork Meli, Damian; Medix General Practice Network Frey, Peter; University of Bern, Institute of Primary Health Care (BIHAM)
Limacher, Andreas; University of Bern Reichenbach, Stephan; Universitat Bern Institut fur Sozial- und Praventivmedizin; University of Bern, Department of Rheumatology, Immunology and Allergology Juni, Peter; University of Toronto, St. Michael's Hospital, Applied Health Research Centre (AHRC)
Keywords: cystitis, urinary tract infection, antibiotic therapy, symptomatic, ambulatory, randomized, outpatient, anti-inflammatory drugs
https://mc.manuscriptcentral.com/bmj
BMJ
Confidential: For Review O
nly
page 1 / 26
Symptomatic therapy of uncomplicated lower urinary tract 1
infections in the ambulatory setting. A randomized, double blind 2
trial 3
Andreas Kronenberg,1,2,3 Lukas Bütikofer,4,5 Ayodele Odutayo,6 Kathrin 4
Mühlemann,1,2 � Bruno R. da Costa,7 Markus Battaglia,3 Damian N. Meli,3,7 Peter 5
Frey,7 Andreas Limacher, 4,5 Stephan Reichenbach,5,8 Peter Jüni 6,7 6
1 Institute for Infectious Diseases, University of Bern, Bern, Switzerland 7
2 Department of Infectious Diseases, Bern University Hospital, University of Bern, Bern, Switzerland 8
3 Medix General Practice Network, Bern, Switzerland 9
4 CTU Bern, University of Bern, Bern, Switzerland 10
5 Institute of Social and Preventive Medicine (ISPM), University of Bern, Bern, Switzerland 11
6Applied Health Research Centre (AHRC), Li Ka Shing Knowledge Institute of St. Michael’s Hospital, 12
and Department of Medicine, University of Toronto, Canada 13
7 Institute of Primary Health Care (BIHAM), University of Bern, Bern, Switzerland 14
8 Department of Rheumatology, Immunology and Allergology, Inselspital, Bern University Hospital, 15
University of Bern, Bern, Switzerland 16
17
Corresponding address: Andreas Kronenberg, MD 18
Institute for Infectious Diseases 19
University of Bern 20
Friedbühlstrasse 51 21
3010 Bern 22
Tel: +41 (0)31 632 32 65 / Fax: +41 (0)31 632 49 66 23
e-mail: [email protected] 24
25
26
Running title Symptomatic therapy of cystitis 27
Keywords cystitis, urinary tract infections, antibiotic therapy, anti-inflammatory drugs, 28
symptomatic, ambulatory, outpatient, randomized, double-blind 29
Word count abstract 378 30
Word count text 4278 31
Registration: www.clinicaltrials.gov (NCT01039545) 32
33
Page 1 of 85
https://mc.manuscriptcentral.com/bmj
BMJ
123456789101112131415161718192021222324252627282930313233343536373839404142434445464748495051525354555657585960
Confidential: For Review O
nly
page 2 / 26
ABSTRACT 1
Background: Antibiotic resistance is increasing globally and largely stems from increasing 2
antibiotic use. It has been suggested, that symptomatic therapy with non-steroidal anti-3
inflammatory drugs (NSAIDs) might be non-inferior to antibiotics in treatment of 4
uncomplicated lower urinary tract infection (UTI) in women, thus offering an opportunity to 5
reduce antibiotic use in ambulatory care. 6
Methods: In this randomized, double-blind, non-inferiority trial among 17 general practices in 7
Switzerland, women with uncomplicated lower UTI were randomly assigned 1:1 to 8
symptomatic therapy with diclofenac or antibiotic treatment with norfloxacin. The 9
randomization sequence was computer-generated, stratified by practice, blocked and 10
concealed using sealed, sequentially numbered drug containers. Primary and secondary 11
outcomes were symptom resolution up to day 3 and antibiotic use up to day 30, respectively. 12
Analysis was by intention-to-treat. We also performed a meta-analysis combining the results 13
of the current trial with previously published randomized controlled trials comparing NSAIDs 14
and antibiotic treatment in women with UTIs. 15
Findings: We randomly assigned 253 women to NSAIDs (133) and antibiotics (120). 16
Thereof 72 (54%) and 96 women (80%) experienced symptom resolution at day 3 in the 17
NSAID and antibiotic groups, respectively (risk difference 27%, 95%-CI 15% to 38%, p for 18
non-inferiority 0.98, p for superiority <0.0001). The median time until resolution of symptoms 19
was 4 days in the diclofenac group and 2 days in the norfloxacin group. A total of 82 (62%) 20
and 118 women (98%) used antibiotics up to day 30, respectively (risk difference 37%, 95%-21
CI 28 to 46%, p for superiority <0.0001). Six women in the NSAID group (5%) but none in the 22
antibiotic group received clinical diagnosis of a pyelonephritis (p=0.031). CRP levels > 10 23
mg/L at baseline were observed in 21 women in the NSAID group without pyelonephritis 24
(17%) and in 3 women with pyelonephritis (50%), which resulted in a positive likelihood ratio 25
of 3.02 (CI 1.07 to 5.98, p=0.037). Finally, our results were consistent with two previously 26
published clinical trials when combined in a meta-analysis. 27
Page 2 of 85
https://mc.manuscriptcentral.com/bmj
BMJ
123456789101112131415161718192021222324252627282930313233343536373839404142434445464748495051525354555657585960
Confidential: For Review O
nly
page 3 / 26
Interpretation: Diclofenac is inferior to norfloxacin in terms of symptom relief, but superior in 1
terms of reducing antibiotic use. Deferring antibiotic therapy in women without CRP elevation 2
and short symptom duration could be justifiable, but should be tested in a randomized trial. 3
Funding: Swiss National Foundation, Swiss Academy of Medical Sciences, SwissLife and 4
Else Kroener-Fresenius Foundation. 5
6
Page 3 of 85
https://mc.manuscriptcentral.com/bmj
BMJ
123456789101112131415161718192021222324252627282930313233343536373839404142434445464748495051525354555657585960
Confidential: For Review O
nly
page 4 / 26
INTRODUCTION 1
Antimicrobial stewardship aims at reducing antibiotic resistance by optimising or 2
decreasing antibiotic use,1 which includes the prevention of antibiotic treatment in cases of 3
viral infections, the tailored prescription of narrow-spectrum antibiotics, shortening the course 4
of therapy, and deferring therapy for low risk bacterial infections. Urinary tract infection (UTI) 5
is one of the most common bacterial infections in adults, affecting considerably more women 6
than men.2 Approximately half of women have at least one UTI in their lifetime, and 20% to 7
30% have two or more.3 Antibiotic prescriptions for UTI accounts for 10-20% of all antibiotic 8
prescriptions in ambulatory care and is second in number only to respiratory tract infections,4, 9
5. Reducing antibiotic prescriptions for UTI could potentially decrease the risk of antimicrobial 10
resistance. Therefore, the benefit of antibiotic treatment needs to be weigthed against the 11
potential for adverse effects, both at the level of the individual (adverse drug reactions) and 12
population (as a driver of antibiotic resistance). 13
Symptoms of UTI may arise from local increases in pro-inflammatory factors like 14
prostaglandins and non-steroidal anti-inflammatory drugs (NSAIDs) may be useful in 15
alleviating symptoms.6-8 A small randomized pilot trial, which compared the NSAID ibuprofen 16
with the antibiotic ciprofloxacin in 80 women with uncomplicated lower UTI, concluded that 17
symptomatic therapy with NSAIDs may be non-inferior to antibiotics, but suggested 18
confirmation in a larger trial.9 Two adequately powered randomized double-blind trials were 19
therefore initiated simultaneously in February 2012 in Germany and Switzerland. Results of 20
the German trial, which compared ibuprofen with fosfomycin in 494 women, were recently 21
published.10 Here, we report results of the Swiss trial, which compared diclofenac with 22
norfloxacin in 253 women with uncomplicated lower UTI. To put our results into context, we 23
also performed a meta-analysis of all available trials comparing NSAIDs with antibiotics in 24
women with lower UTI. 25
26
Page 4 of 85
https://mc.manuscriptcentral.com/bmj
BMJ
123456789101112131415161718192021222324252627282930313233343536373839404142434445464748495051525354555657585960
Confidential: For Review O
nly
page 5 / 26
METHODS 1
Study design 2
This randomized controlled patient and assessor blind trial was conducted in 17 general 3
practices in Switzerland. The funding bodies were not involved in the design or the conduct 4
of the trial, nor in the writing of the manuscript or the decision to submit the manuscript for 5
publication. The first and senior author wrote the manuscript, had final responsibility for the 6
decision to submit the manuscript for publication and vouch for the accuracy of the data and 7
analyses and for the fidelity of the trial to the protocol. The funding bodies only had access to 8
the data after finalization of the statistical analysis plan and completion of all analyses. The 9
study was conducted in accordance with the Declaration of Helsinki and was approved by 10
the local research ethics committee and the Swiss Agency for Therapeutic Products 11
Swissmedic. The trial was registered before start of patient recruitment at clinicaltrials.gov 12
(NCT01039545). All women provided written informed consent. 13
14 15
Patients, Randomization and Treatment 16
Women aged 18 to 70, who visited their general practitioners (GPs) because of one 17
or more symptoms or signs typical of acute lower UTI (dysuria, frequency, macrohaematuria, 18
cloudy or smelly urine) or self-diagnosed cystitis were eligible if their urine dipstick was 19
positive for nitrite and/or leucocytes. We excluded pregnant women and women with clinical 20
signs of upper UTI such as fever (axillary body temperature >38oC), costovertebral pain or 21
tenderness, rigors, nausea or vomiting. We also excluded women with known or suspected 22
anatomical or functional abnormality of the urinary tract and comorbidities such as diabetes 23
mellitus, active gastric or duodenal ulcer disease or gastrointestinal bleeding, inflammatory 24
bowel disease, severe liver dysfunction (liver cirrhosis and ascites), coagulopathy (including 25
therapy with coumarine derivates), renal insufficiency grade III or higher (calculated GFR <60 26
ml/min), known congestive heart failure (NYHA III or higher), psychiatric illness or dementia, 27
inability to to communicate in German or French language and any other serious comorbidity 28
Page 5 of 85
https://mc.manuscriptcentral.com/bmj
BMJ
123456789101112131415161718192021222324252627282930313233343536373839404142434445464748495051525354555657585960
Confidential: For Review O
nly
page 6 / 26
as judged by the treating physician. In addition we excluded women with documented 1
immunosuppression (e.g. prednisone equivalent >10mg per day for >14 days, chemotherapy, 2
radiotherapy, immunmodulators, HIV infection, neutropenia) or hypersensitivity to one of the 3
study medications or history of asthma, urticaria or hypersensitivity-like reactions after 4
consumption of salicylic acid or other non-steroidal anti-inflammatory drugs, as well as 5
women with vaginal symptoms (discharge, irritation), bladder catheter in situ or during the 6
past 30 days, recurrent urinary tract infection (more than 3 infections during the last 12 7
months), antibiotic treatment during the last 4 weeks or duration of UTI symptoms for more 8
than 7 days before physician’s visit. 9
Women were randomly allocated in a 1:1 ratio to NSAID or antibiotic therapy. The 10
randomization sequence was computer-generated, stratified by practice and blocked with 11
randomly varying block sizes of 4 and 6. Allocation was concealed with sealed, sequentially 12
numbered opaque drug containers of identical appearance that contained opaque hard 13
gelatine capsules of identical size and colour. Women allocated to NSAIDs received 14
capsules containing 75 mg diclofenac retard for three days (Olfen-75 duo release®, Mepha 15
Pharma, Basel, Switzerland) and women allocated to antibiotics received capsules 16
containing 400 mg norfloxacin for three days (Norfloxacin-Teva® 400mg, Teva Pharma, Tel 17
Aviv, Israel; Norflocin-Mepha® 400mg Lactab, Mepha Pharma, Basel, Switzerland from 18
October 2013 onwards due to delivery restrictions). We chose norfloxacin because of the 19
high susceptibility rates in Switzerland and diclofenac because of its identical frequency of 20
administration which facilitated patient blinding. Women started therapy immediately after 21
randomization on day 0 and were advised to take 2 capsules per day: one in the morning 22
and one in the evening. All women were given a single open-label package of fosfomycin 23
(Monuril® 3g, Zambon, Cadempino, Switzerland) to be taken as a rescue antibiotic after 24
completion of the study medication on day 3 at their discretion, if symptoms persisted. 25
26
Patient involvement 27
Page 6 of 85
https://mc.manuscriptcentral.com/bmj
BMJ
123456789101112131415161718192021222324252627282930313233343536373839404142434445464748495051525354555657585960
Confidential: For Review O
nly
page 7 / 26
No patients were involved in setting the research question or the outcome measures, nor 1
were they involved in developing plans for recruitment, design, or implementation of the 2
study. No patients were asked to advise on interpretation or writing up of results. We plan to 3
disseminate the results of the research to all the scientific community, including study 4
participants. 5
6
Procedures and outcomes 7
The pre-specified primary outcome was symptom resolution up to day 3 (12 hours 8
after intake of the last study medication). In the absence of antimicrobial resistance, the 9
mean duration of symptoms in women with uncomplicated UTIs treated with antibiotics is 3 10
days11. Women rated the severity of five UTI symptoms (dysuria; frequency; urgency; 11
abdominal pain when passing urine; pain or tenderness in the lower back or loin) daily from 12
days 0 (randomization) to 10 by self-report diary and on day 30 by telephone interview on a 13
Likert scale from 0 to 6, with their composite score ranging from 0 to 30; symptom resolution 14
was defined as ≤ 2 points ("slight problems”) on all 5 components.12-14 Complete absence of 15
symptoms was defined as 0 points on all components. The pre-specified principal secondary 16
outcome was the use of any antibiotic (including norfloxacin and fosfomycin as trial 17
medications) up to day 30. The remaining pre-specified outcomes are reported in the 18
Supplementary Appendix. Side effects, quality of life, working days lost and use of the rescue 19
antibiotic were assessed on day 3, general satisfaction on day 10. Serious adverse events, 20
adverse events ≥grade 3 severity, any additional unplanned medical visits, including 21
telephone contacts, and co-medications were assessed by telephone interviews of the 22
treating physician on day 10 and of an independent, blinded interviewer on day 30. The 23
clinical diagnosis of pyelonephritis required the occurrence of loin pain and fever, leading to 24
an unplanned ambulatory visit. Mid-stream urinary samples obtained on days 0 and 10 were 25
processed according to standard laboratory procedures, using a cut-off of ≥103 colony 26
forming units per ml for a urinary culture to be considered positive;15 mixed flora with no 27
predominant microorganism, Lactobacilli or Streptococcus viridans group were considered 28
Page 7 of 85
https://mc.manuscriptcentral.com/bmj
BMJ
123456789101112131415161718192021222324252627282930313233343536373839404142434445464748495051525354555657585960
Confidential: For Review O
nly
page 8 / 26
negative. Details of baseline assessments, diary and scores used are described in the 1
Supplemental Appendix. 2
3
Systematic Review 4
We conducted a systematic search of MEDLINE (inception to April 9th 2017) using a 5
combination MeSH and keyword searching for the following terms: “Anti-bacterial Agents”, 6
“Antibiotics”, “Non-Steroidal Anti-inflammatory Agents”, “Urinary Tract Infections”, and 7
“Cystitis”. We included randomized clinical trials which compared NSAIDs and antibiotics for 8
the treatment of UTIs. No language restrictions were applied. We extracted information on 9
event rates in the NSAID and antibiotic treatment groups for the following outcomes: 10
symptom resolution at day 3 or 4, symptom resolution at 7 days, recurrent UTI, 11
pyelonephritis and use of antibiotics. 12
13
14
Statistical methods 15
We originally planned to recruit 400 women, but recruitment was slow and financial 16
constraints led us to decide in June 2014 to stop patient recruitment by December 2014, 17
when an expected 260 women would be included. The decision was made without inspecting 18
the data and after repeating the power analysis based on a closed-form normal 19
approximation test of proportions, 16 which was less conservative than the simulation-based 20
approach originally used. With the original assumption of 70% of women reaching symptom 21
resolution up to day 3 in both groups and the original, pre-specified non-inferiority margin of 22
15% on a risk difference scale, the projected sample size of 260 women would yield a power 23
of 84% to detect non-inferiority at a one-sided type I error of 5%. 24
The primary outcome was evaluated using a risk difference with a corresponding two-sided 25
95% confidence interval, a one-sided normal approximation test for non-inferiority and a two-26
sided Chi-squared test for superiority. Secondary outcomes were compared using 27
Page 8 of 85
https://mc.manuscriptcentral.com/bmj
BMJ
123456789101112131415161718192021222324252627282930313233343536373839404142434445464748495051525354555657585960
Confidential: For Review O
nly
page 9 / 26
conventional two-sided p-values for superiority and corresponding two-sided 95% confidence 1
intervals. We used risk differences with Chi-squared tests for binary data, Poisson regression 2
with robust standard errors for counts, and linear regression with robust standard errors for 3
continuous data. Kaplan-Meier curves accompanied by hazard ratios from Cox models were 4
used to analyse time to symptom resolution and time to antibiotic use. All women were 5
included in the analysis in the groups they were originally allocated to (intention-to-treat 6
analysis), missing values were accounted for by multiple imputation (see Supplementary 7
Appendix and Supplementary Table 1). We performed pre-specified subgroup analyses of 8
the primary outcome accompanied by Mantel-Haenszel tests for interaction by age (< 45 vs ≥ 9
45 years), symptom severity at baseline (≤ 20 vs > 20), symptom duration (≤ 3 vs > 3 days), 10
and presence of a positive urinary culture at baseline; post-hoc subgroup analyses were 11
performed by urine leucocytes (≤ 2+ vs >2+) and the presence of norfloxacin-resistant 12
Enterbacteriaceae. In per-protocol analyses, we excluded women with protocol deviations 13
who were defined as women with no documented intake of at least one dose of study 14
medication, cross-overs, or women who used rescue antibiotics before day 3. All analyses 15
were pre-specified in a statistical analysis plan before recruitment end and inspection of the 16
data. In post-hoc analyses of women allocated to NSAIDs, we compared baseline 17
characteristics and outcomes between those who used antibiotics until day 30 and those 18
never on antibiotics, determined the time between symptom onset and diagnosis in those 19
clinically diagnosed with pyelonephritis, and explored whether blood or urine findings at 20
baseline were associated with pyelonephritis with clinically relevant positive or negative 21
likelihood ratios above 5 or below 0.2, respectively, which could be used to rule in or rule out 22
future clinical diagnosis of pyelonephritis. 23
In view of the expected low number of trials and the considerable difference in sample size 24
between the initially available pilot trial and subsequent trials, we refrained from performing 25
conventional frequentist random-effects meta-analysis because these methods may yield 26
either overly optimistic or overly conservative results.17-19 Therefore, trial specific risk 27
differences were combined with a Mantel-Haenszel fixed-effect model and a Bayesian 28
Page 9 of 85
https://mc.manuscriptcentral.com/bmj
BMJ
123456789101112131415161718192021222324252627282930313233343536373839404142434445464748495051525354555657585960
Confidential: For Review O
nly
page 10 / 26
random-effects model. We chose the risk difference as treatment effect estimate as odds-1
ratios were not directly interpretable because some control group event rates were above 2
20%, and risk ratios were heterogeneous because of the variation in control group event 3
rates between trials. The specifications of the Bayesian random-effects model are described 4
in the web-appendix. We conducted two analyses. The first combined all trials and the 5
second was restricted to large trials with more than 100 patients per group; trials which would 6
have more than 50% power to detect a 15% difference in the primary outcome of incomplete 7
or no symptom resolution at day 3 or 4. All analyses were done in 8
Stata Release 14 (StataCorp. 2014. Stata Statistical Software: Release 14. College Station, 9
TX: StataCorp LP), RStudio version 1.0.143 (RStudio: Integrated Development for R. 10
RStudio, Inc., Boston, MA URL http://www.rstudio.com/), and WinBUGS version 1.4.3. 11
12
13
Page 10 of 85
https://mc.manuscriptcentral.com/bmj
BMJ
123456789101112131415161718192021222324252627282930313233343536373839404142434445464748495051525354555657585960
Confidential: For Review O
nly
page 11 / 26
RESULTS 1
Between Feb 7, 2012 and Dec 3, 2014, 253 women were included in the trial. Thirty-2
six patients were recruited in seven single practices, 108 in nine group practices and 109 in 3
one big medical centre with 17 physicians in the centre of Bern, Switzerland. One-hundred 4
and thirty-three patients were randomly allocated to NSAIDs and 120 to antibiotics. A total of 5
125 women (94%) received treatment as allocated in the NSAID group, and 118 women 6
(98%) in the antibiotic group. 119 (89%) and 112 women (93%) had complete follow-up until 7
day 30 (Figure 1). Groups were similar (Table 1), with a mean age of 36.8 years (SD 14.1), a 8
mean duration of symptoms of 3.4 days (SD 2.6) and a mean composite symptom score of 9
13.7 points out of 30 (SD 3.8), and urgency, frequency and dysuria as the most prevalent 10
symptoms. Thirty-five urine samples were nitrite-positive (14%) and 191 had >2+ leucocytes 11
(75%). For 185 urine samples, we found positive urinary cultures (73%), which resulted in a 12
total of 193 isolates, of which 187 isolates (97%) had documented norfloxacin susceptibility. 13
173 isolates contained Enterobacteriaceae, 160 of which were tested for fosfomycin 14
susceptibility and 158 were found susceptible (99%). 15
Table 1. Baseline characteristics 16
NSAIDs (N=133) Antibiotics (N=120)
Age - yr 37.8 (14.2) 35.6 (14.0)
Age <45 yr 94 (71%) 89 (74%)
Symptom duration - days since UTI onset 3.6 (3.1) 3.2 (2.0)
Symptom duration ≤3 days 80 (60%) 83 (69%)
Number of UTIs in the last 12 months 0.6 (1.1) 0.6 (0.9)
Baseline UTI symptoms - score 0 to 6
Dysuria 3.3 (1.3) 3.3 (1.2)
Urgency 3.7 (1.0) 3.6 (0.9)
Night frequency 2.6 (1.5) 2.6 (1.4)
Day frequency 3.5 (0.9) 3.5 (0.9)
Lower abdominal pain while urinating 2.6 (1.5) 2.6 (1.6)
Back or loin pain 1.1 (1.4) 1.2 (1.5)
Total symptom score 13.7 (3.9) 13.8 (3.8)
Symptom score ≤20 127 (95%) 115 (96%)
Blood tests
CRP - mg/l 6.7 (10.5) 8.5 (13.7)
CRP >10 mg/ml 24 (18%) 29 (24%)
Leucocytes - 1000/µl 8.5 (2.4) 8.7 (2.2)
Page 11 of 85
https://mc.manuscriptcentral.com/bmj
BMJ
123456789101112131415161718192021222324252627282930313233343536373839404142434445464748495051525354555657585960
Confidential: For Review O
nly
page 12 / 26
Urinary dipstick
Nitrites - positive 17 (13%) 18 (15%)
Erythrocytes - 1 to 4+ (median, IQR) 3+ (2+ to 4+) 3+ (2+ to 4+)
Leucocytes - 1 to 4+ (median, IQR) 3+ (3+ to 4+) 3+ (3+ to 4+)
Leucocytes >2+ 101 (76%) 90 (75%)
Urinary culture†
Negative 36 (27%) 31 (26%)
Positive‡ 96 (72%) 89 (74%)
Escherichia coli 82 (62%) 75 (63%)
Other Enterobacteriaceae 10 (8%) 6 (5%)
Staphylococcus saprophyticus 4 (3%) 7 (6%)
Enterococcus faecalis* 1 (1%) 6 (5%)
Beta-hemolytic Streptococcus group B 1 (1%) 1 (1%)
Susceptibility to norfloxacin 92 (69%) 87 (73%)
Enterobacteriaceae 88 (66%) 79 (66%)
Susceptibility to fosfomycin§ 84 (63%) 71 (59%)
Continuous variables are presented as mean (sd), binary variables as no. of patients (%). 1 † Urinary culture missing in 1 patients in NSAID group. 2 ‡ Do not sum up because of 2 double mixed infections in the NSAID group and 4 double and 1 triple mixed infection in the 3
antibiotic group. 4 $ Enterobacteriaceae only. Two isolates from the NSAID group (1 Proteus mirabilis, 1 Enterobacter cloacae) were not 5
susceptible to fosfomycin 6 7
Clinical outcomes are presented in Table 2. The primary outcome, resolution of 8
symptoms at day 3, was observed in 72 (54%) and 96 (80%) women in the NSAID and 9
antibiotic groups, respectively (risk difference 27%, 95%-CI 15 to 38%, one-sided p for non-10
inferiority=0.98, two-sided p for superiority in favour of antibiotic group <0.0001). The 11
principal secondary outcome, use of any antibiotic up to day 30, was observed in 82 (62%) 12
and 118 (98%) women, respectively (risk difference -37%, 95%-CI -46 to -28%, p for 13
superiority in favour of NSAID group <0.0001). Among the 82 women in the NSAID group 14
who used antibiotics, 58 (71%) decided to take antibiotics during the first three days and 55 15
of the 58 (95%) took the rescue antibiotic fosfomycin. 16
17
Table 2. Primary and secondary outcomes. Positive differences indicate an advantage of 18 antibiotics, negative differences an advantage of NSAIDs throughout. 19
Outcome NSAIDs (N=133) Antibiotics (N=120) Risk or mean
difference (95% CI)
P value
no. of patients (%) or mean (sd)
Resolution of symptoms
Day 3 (primary outcome) 72 (54%) 96 (80%) 27% (15 to 38%) <0.0001
Day 7 111 (83%) 115 (96%) 12% (4 to 19%) 0.003
Day 10 126 (95%) 116 (97%) 2% (-3 to 7%) 0.45
Day 30 127 (95%) 111 (93%) -3% (-9 to 3%) 0.32
Page 12 of 85
https://mc.manuscriptcentral.com/bmj
BMJ
123456789101112131415161718192021222324252627282930313233343536373839404142434445464748495051525354555657585960
Confidential: For Review O
nly
page 13 / 26
Complete absence of symptoms
Day 3 10 (8%) 20 (17%) 9% (0 to 17%) 0.038
Day 7 44 (33%) 65 (54%) 21% (9 to 34%) 0.001
Day 10 70 (53%) 77 (64%) 12% (-1 to 24%) 0.07
Day 30 101 (76%) 99 (83%) 6% (-4 to 17%) 0.22
Change of symptom score
Day 3 -7.3 (4.7) -10.3 (4.1) 3.0 (1.9 to 4.1) <0.0001
Day 7 -11.0 (4.8) -12.6 (4.2) 1.6 (0.5 to 2.7) 0.005
Day 10 -12.2 (4.3) -12.9 (4.1) 0.7 (-0.4 to 1.7) 0.20
Day 30 -13.0 (4.4) -13.1 (4.3) 0.1 (-1.0 to 1.1) 0.88
Use of any antibiotic
Up to day 3 58 (44%) 116 (97%) -54% (-63 to -44%) <0.0001
Up to day 30 (principal secondary outcome) 82 (62%) 118 (98%) -37% (-46 to -28%) <0.0001
Use of rescue antibiotic
Up to day 3 55 (41%) 9 (8%) 34% (24 to 43%) <0.0001
Up to day 30 73 (55%) 18 (15%) 40% (29 to 51%) <0.0001
Negative urinary culture at day 10 96 (72%) 112 (93%) 21% (11 to 30%) <0.0001
Re-consultations because of UTI 27 (20%) 10 (8%) 12% (3 to 20%) 0.010
Quality of life - range 0 to 10
EuroQol health state 8.8 (2.2) 9.4 (1.5) 0.6 (0.2 to 1.0) 0.005
EuroQol visual analogue scale 7.4 (1.9) 8.3 (1.5) 1.0 (0.5 to 1.4) <0.0001
Patient satisfaction with UTI-management 5.7 (3.0) 8.2 (2.1) 2.5 (1.9 to 3.2) <0.0001
Number of working days lost due to UTI 0.6 (0.8) 0.5 (0.8) 0.2 (-0.1 to 0.5)* 0.18
* Relative rate increase calculated from Poisson regression 1 2
3
Figure 2 presents time to event curves for resolution of symptoms (Panel A) and use 4
of antibiotics (Panel B) until day 10 (Figure 2 and Supplementary Table 2). The course of 5
mean symptom scores is shown in Supplementary Figure 1. The median time until resolution 6
was 4 days in the NSAID versus 2 days in the antibiotic group (HR 1.64, CI 1.26-2.14, 7
p<0.0001,). The median times until antibiotic use were 5 and 0 days, respectively (HR 10.06, 8
CI 6.67 to 15.17, p<0.0001). Figure 3 shows subgroup analyses for the primary and the 9
principal secondary outcome. Results appeared consistent across all subgroups. Sensitivity 10
analyses revealed consistent results for the primary and main secondary outcome 11
(Supplementary Table 3). 12
Remaining pre-specified outcomes favoured antibiotic therapy except for change of 13
symptom score on day 30 (p=0.88) and working days lost (p=0.18, Table 2). Post-hoc 14
analyses of additional time-points revealed little evidence of a difference between groups for 15
Page 13 of 85
https://mc.manuscriptcentral.com/bmj
BMJ
123456789101112131415161718192021222324252627282930313233343536373839404142434445464748495051525354555657585960
Confidential: For Review O
nly
page 14 / 26
resolution or complete absence of symptoms on day 10 and 30 or change of symptom score 1
on day 10 (p≥0.07) and strong evidence for a difference in favour of the NSAID group for 2
antibiotic use up to day 3 (p<0.0001, Table 2). 3
Supplementary Table 4 shows a post-hoc comparison of baseline characteristics of 4
women who had never been on antibiotics (n=51) with women who had used any antibiotics 5
until day 30 (n=82) among those randomly allocated to NSAIDs. We found little evidence for 6
a difference between groups, except for one component of the symptom composite score. 7
Supplementary Table 5 presents a comparison of outcomes. Resolution and complete 8
absence of symptoms at day 3 were more frequent among women never on antibiotics 9
(p≤0.006), changes of symptom scores were more pronounced at day 3 (p=0.0001), 10
reconsultations were less frequent (p<0.0001), and scores on quality of life and satisfaction 11
with care were higher (p≤0.015). The median time until symptom resolution in women never 12
on antibiotics was 3 days and the median time in women who had used antibiotics was 5 13
days (HR 0.61, CI 0.42 to 0.88, p=0.003, Supplementary Figure 2 and Supplementary Table 14
6). Thirty-four urinary cultures had been positive at baseline among women never on 15
antibiotics, of these 16 had become spontaneously negative on day 10 (47%). 16
Table 3 presents adverse events that resulted in reconsultations: 43 events in 41 17
women in the NSAID group (31%), and 22 events 21 women in the antibiotic group (18%). 18
Adverse events related to UTI were more frequent in the NSAID-group (p=0.012), with 6 19
cases of clinically diagnosed pyelonephritis in the NSAID group (5%) and none in the 20
antibiotic group (p=0.031) and one woman with clinically diagnosed pyelonephritis in the 21
NSAID group classified to have experienced a serious adverse event since she was 22
hospitalized to receive intravenous antibiotic therapy. The median time from symptom onset 23
to clinical diagnosis of pyelonephritis was 5.5 days (range 5 to 8 days). CRP levels > 10 mg/L 24
at baseline were observed in 21 women in the NSAID group without pyelonephritis (17%) 25
and in 3 women with pyelonephritis (50%, Supplementary Table 7). This resulted in a 26
positive likelihood ratio of 3.02 (CI 1.07 to 5.98, p=0.037) for CRP levels > 10 mg/L. None of 27
the blood or urine findings at baseline were associated with clinically relevant positive or 28
Page 14 of 85
https://mc.manuscriptcentral.com/bmj
BMJ
123456789101112131415161718192021222324252627282930313233343536373839404142434445464748495051525354555657585960
Confidential: For Review O
nly
page 15 / 26
negative likelihood ratios suitable to rule in or out future diagnosis of a pyelonephritis. 1
Although the symptom score for women who developed pyelonephritis was higher at 2
baseline compared to women who did not develop pyelonephritis, there were no differences 3
in symptom score from day 3 to 30 (Supplementary Table 8). 4
Table 3: Adverse events resulting in reconsultations up to 30 days 5
Adverse event NSAIDs (N=133) Antibiotics (N=120) P value
no. of patients (%)
Related to UTI 26 (20%) 10 (8%) 0.012
Persistence of symptoms 16 (12%) 4 (3%) 0.011
Additional symptoms 6 (5%) 2 (2%) 0.29
Recurrent UTI* 5 (4%) 4 (3%) 1.00
Pyelonephritis† 6 (5%) 0 (0%) 0.031
Other adverse event 17 (13%) 12 (10%) 0.56
Exanthema 1 (1%) 2 (2%) 0.61
Vaginitis 3 (2%) 0 (0%) 0.25
Gastrointestinal complaints‡ 3 (2%) 3 (3%) 1.00
Low back pain§ 5 (4%) 2 (2%) 0.45
Viral infection 1 (1%) 3 (3%) 0.35
Trauma 3 (2%) 1 (1%) 0.62
Miscellaneous# 3 (2%) 1 (1%) 0.62
Reported are numbers of patients experiencing at least one adverse event for each category, therefore, numbers do not add up. 6 P values are from 2-sided Fisher’s exact test 7
* Recurrent UTI was defined as additional visits after day 14 because of recurrent UTI symptoms after symptoms had resolved 8 by day 10, and the physician decided to treat with antibiotics. 9
† One patient in NSAID group hospitalized on day 4 because of pyelonephritis. 10 ‡ Includes one case of diverticulitis in antibiotic group. 11 § Considered to be of musculoskeletal origin by treating physician. 12 # Includes one case of external otitis and two cases of tonsillitis in NSAID group and 1 case of hair loss in Antibiotic group. 13 14
15
16
Systematic Review and Meta-analysis 17
We reviewed 81 studies and excluded 78 in the abstract screen. Of the three articles 18
undergoing full-text review, one article was a published study protocol for an ongoing clinical 19
trial that may be indeed by eligible for inclusion upon completion. Therefore, three trials, 20
including our own, were included in the meta-analysis. Together, the studies included 806 21
women (410 randomized to NSAIDs and 382 randomized to antibiotics). Compared to the 22
antibiotics group, women randomized to NSAIDs had a higher incidence of incomplete or no 23
symptom resolution at 3 to 4 days (risk difference 18.0%, CI 11.3% to 24.7%; Number 24
Needed to Harm (NNH) 6, CI 4 to 9, Figure 4) and at 7 days (risk difference 9.6%, CI 4.1% to 25
Page 15 of 85
https://mc.manuscriptcentral.com/bmj
BMJ
123456789101112131415161718192021222324252627282930313233343536373839404142434445464748495051525354555657585960
Confidential: For Review O
nly
page 16 / 26
15.1%, NNH 10, CI 7 to 24). The incidence of pyelonephritis was also higher in women 1
randomized to NSAIDs compared to women randomized to antibiotics (risk difference 2.6%, 2
CI 0.8% to 4.5%, NNH 38, CI 22 to 126). However, antibiotic use was markedly lower in 3
women randomized to NSAIDs compared to women randomized to antibiotics (risk difference 4
-56.1 %, CI -60.8% to -51.4%, Number Needed to Treat 2, CI 2 to 2) and there was little 5
evidence of a difference in the frequency of recurrent UTIs between the groups (Figure 4). 6
Notably, point estimates for the fixed effect meta-analysis and the Bayesian random-effects 7
meta-analysis were similar, although confidence intervals were wider for the random effects 8
model (Figure 5). However, limiting our analysis to large trials increased the precision of the 9
effect estimate. There was little heterogeneity for all outcomes except for use of antibiotics, 10
for which the risk difference was lower in our study compared to the previous trials (Figure 5). 11
12
13
Page 16 of 85
https://mc.manuscriptcentral.com/bmj
BMJ
123456789101112131415161718192021222324252627282930313233343536373839404142434445464748495051525354555657585960
Confidential: For Review O
nly
page 17 / 26
DISCUSSION 1
In this randomized, double-blind trial in women with uncomplicated lower urinary tract 2
infection, symptomatic treatment with the NSAID diclofenac was inferior to antibiotic 3
treatment with norfloxacin in controlling symptoms. Those treated with diclofenac were 27% 4
less likely to have symptom resolution at day 3 and 12% less likely to have symptom 5
resolution at day 7 after randomization, with higher mean symptom scores, more frequent 6
reconsultations, a higher incidence of clinically diagnosed pyelonephritis and lower patient 7
satisfaction than those in the NSAID group. Conversely, women who received NSAIDs were 8
37% less likely to receive antibiotics until day 30 after randomization. 9
A meta-analysis of five trials concluded that antibiotics are clinically superior to 10
placebo in women with uncomplicated lower UTI.20 Our trial, in conjunction with the 11
accompanying meta-analysis, suggests that antibiotics are also clinically superior to 12
symptomatic treatment with NSAIDs. This contrasts with the conclusions of a small pilot trial 13
by Bleidorn et al,9 which found clinical outcomes of treatment with ibuprofen similar to those 14
of antibiotic therapy with ciprofloxacin. The pilot trial triggered both, our trial and the recently 15
published trial by Gágyor et al.10 Both of these trials were adequately powered, but failed to 16
detect non-inferiority of NSAIDs as compared with antibiotics in terms of symptom control. 17
Importantly, our trial and the accompanying meta-analysis suggest that symptomatic 18
treatment with NSAIDs is associated with an average 2.6% increase in the absolute risk of 19
clinically diagnosed pyelonephritis, which translates into a NNH of 38 as compared with 20
antibiotic treatment. The risk of pyelonephritis with NSAIDs is comparable to the risk of 0.4 to 21
2.6% observed with placebo in two earlier trials,21, 22 despite the previously described 22
antibacterial activity of diclofenac23 and ibuprofen.24 23
On the beneficial side, our meta-analysis suggests that antibiotic use can be halved 24
on average by initial symptomatic treatment with NSAIDs, with a corresponding number 25
needed to treat of 2 to prevent one instant of antibiotic use. Although there was moderate 26
heterogeneity for this outcome, it may relate to methodological differences in the conduct of 27
Page 17 of 85
https://mc.manuscriptcentral.com/bmj
BMJ
123456789101112131415161718192021222324252627282930313233343536373839404142434445464748495051525354555657585960
Confidential: For Review O
nly
page 18 / 26
our trial compared to prior trials. In particular, we provided women with a rescue antibiotic for 1
discretionary use after completion of study medication and reaching the primary endpoint. 2
This may have facilitated antibiotic use in the NSAID treatment arm of our trial. Nonetheless, 3
given the high global incidence of UTIs, the reduction in antibiotic use is highly relevant and 4
is likely to immediately decrease resistance rates for E. coli and even other microorganisms 5
in the affected population.25 6
Rising antibiotic resistance among uropathogens in general, and Escherichia coli (the 7
most common uropathogen), in particular, is a global concern. Many studies show a clear 8
correlation between antibiotic consumption and rising resistance rates. Accordingly, 9
antibiotics are often withheld in cases of self-limited, benign bacterial diseases as acute otitis 10
media, sinusitis and traveller’s diarrhoea at the cost of a prolongation of symptoms by 11
typically 1-3 days.26-33 Our results in women with uncomplicated lower UTI are well in line 12
with the prolongation of symptoms observed with symptomatic treatment of these conditions. 13
As many women in the NSAID group resorted to antibiotic therapy in our trial, a strategy of 14
selectively deferring rather than completely withholding antibiotic therapy may be preferable 15
for uncomplicated lower UTI.34 This can be achieved through a shared decision making 16
process, during which clinicians inquire about their patient’s ideas and expectations 17
regarding antibiotic treatment for uncomplicated UTI and also explore the option of delaying 18
antibiotic use as a treatment strategy. 19
Subgroup analyses did not provide evidence for any clinically relevant treatment by 20
subgroup interactions. In particular, in contrast to Gágyor et al.10, reduction in antibiotic 21
prescription was comparable in women with and without positive urinary cultures. Testing 22
initial urine samples for other biomarkers associated with UTI, like heparin-binding protein, 23
interleukin-6, acetic acid, trimethylamine, xanthine oxidase, myeloperoxidase, or others,35-37 24
might have resulted in promising treatment by subgroup interactions, but these tests are not 25
yet established in clinical practice, and we are unaware of any evidence to suggest that such 26
interactions would be likely. When comparing women who never had been on antibiotics with 27
women who had used antibiotics until day 30 among those allocated to NSAIDs in post-hoc 28
Page 18 of 85
https://mc.manuscriptcentral.com/bmj
BMJ
123456789101112131415161718192021222324252627282930313233343536373839404142434445464748495051525354555657585960
Confidential: For Review O
nly
page 19 / 26
analyses, we unsurprisingly found better clinical outcomes in those never on antibiotics, but 1
no relevant differences in baseline characteristics that would allow an early identification of 2
women likely to benefit from NSAIDs alone. However, in further post-hoc analyses, which are 3
purely hypothesis generating, we found that the clinical diagnosis of pyelonephritis was 4
established not earlier than 5 days after symptom onset, and that CRP values above 10 mg/L 5
were more frequent at baseline in women who subsequently were diagnosed with a 6
pyelonephritis. Taken together, these exploratory findings could support a tailored strategy of 7
immediate antibiotic use in women with CRP levels of >10 mg/L and early NSAID use in 8
remaining women for up to 3 to 4 days after symptom onset, followed by deferred, selective 9
antibiotic use in those women who did not show a clear improvement up by then. Naturally, 10
such a tailored strategy would need to be evaluated in an appropriately powered randomized 11
trial. 12
Our trial should be interpreted in view of its strengths and limitations. Strengths are its 13
randomized double blind design with appropriate concealment of allocation, blinding of 14
patients, therapists and outcome assessors, the low loss to follow-up, the robustness of 15
results in a series of sensitivity analyses and the multi-centric primary care setting. The 16
premature termination of patient recruitment before reaching the initially planned sample size 17
is an obvious limitation. However, the decision to stop recruitment was made without 18
inspecting the data and is therefore unlikely to have biased our findings.38 Despite the 19
smaller than originally planned sample size, our results are completely unequivocal. While 20
using slightly different symptom scores in different trials does affect the comparability 21
between trials, this will not affect the validity of our results. Nevertheless, we suggest that 22
future trials should consider to use the symptom score developed by Alidjanov et al.39 Finally, 23
our results are not generalizable to countries and clinical settings with lower rates of 24
susceptibility, which could decrease the effectiveness of antibiotics and render symptomatic 25
treatment with NSAIDs less inferior. 26
In conclusion, symptomatic therapy is inferior to antibiotic therapy for the treatment of 27
women with uncomplicated lower UTI in an ambulatory setting, as it increases median 28
Page 19 of 85
https://mc.manuscriptcentral.com/bmj
BMJ
123456789101112131415161718192021222324252627282930313233343536373839404142434445464748495051525354555657585960
Confidential: For Review O
nly
page 20 / 26
symptom duration by two days and is likely to be associated with an increased risk of 1
clinically diagnosed pyelonephritis. The observed impressive reduction in antibiotic use, 2
which would likely contribute directly to decreasing resistance rates in the affected population, 3
suggests that alternate approaches of combining symptomatic treatment with deferred, 4
selective antibiotic use should be developed and tested in future trials. 5
6
Page 20 of 85
https://mc.manuscriptcentral.com/bmj
BMJ
123456789101112131415161718192021222324252627282930313233343536373839404142434445464748495051525354555657585960
Confidential: For Review O
nly
page 21 / 26
Contributors 1
AK and KM were responsible for conception and design and obtained funding for 2
the study. AK, MB, DM, and PF were responsible for the acquisition of data. LB, BC, 3
AL, SR and PJ did the analysis and interpreted it in collaboration with all the 4
remaining authors. BC, AO and PJ performed the meta-analysis. AK and PJ had full 5
access to the final data, co-wrote the manuscript, had final responsibility for content, 6
and the decision to submit for publication. All authors critically revised the paper for 7
important intellectual content and approved the final version. 8
9
Transparency declarations 10
The authors affirm that the manuscript is an honest, accurate, and transparent 11
account of the study being reported; that no important aspects of the study have 12
been omitted; and that any discrepancies from the study as planned (and, if relevant, 13
registered) have been explained. 14
15
Competing interests: All authors declare: no support from any organisation for the 16
submitted work besides the acknowledged financial support. AK has received travel 17
grant and meeting expenses from Gilead, Viofor and the World Health Organisation 18
(WHO), is advisor of the Swiss Federal Office of Public Health concerning antibiotic 19
resistance epidemiology in Switzerland, and provides non-interpreted annual 20
resistance data to LEO pharmaceutic company and the Swiss government. PJ has 21
received research grants to the institution from Astra Zeneca, Biotronik, Biosensors 22
International, Eli Lilly and The Medicines Company for cardiovascular trials, and 23
serves as unpaid member of the steering group of cardiovascular trials funded by 24
Astra Zeneca, Biotronik, Biosensors, St. Jude Medical and The Medicines Company. 25
The remaining authors declare no financial relationships with any organisations that 26
might have an interest in the submitted work in the previous three years and no other 27
relationships or activities that could appear to have influenced the submitted work. 28
29
Page 21 of 85
https://mc.manuscriptcentral.com/bmj
BMJ
123456789101112131415161718192021222324252627282930313233343536373839404142434445464748495051525354555657585960
Confidential: For Review O
nly
page 22 / 26
Acknowledgments 1
We thank all patients participating in this study, all participating general physicians for 2
their meticulous data collection and the Clinical Trials Unit of the University of Bern 3
(CTU Bern) for the development of the database (Malcolm Sturdy), Monitoring (Lucia 4
Kacina) and telephone interview and data clearance (Madeleine Dähler). We thank 5
the Institute of General Practice BIHAM, for their organisational support and the 6
Hospital Pharmacy of the Inselspital for the production and blinding of the study 7
medications (Marco Eschenmoser). 8
9
Participating physicians. Peter Duner, Eggiwil; Christoph Fry, Belp; Ursula Grob, 10
Herzogenbuchsee; Felix Huber, Zürich; Beat Köstner-Mösching, Neuenegg; Andreas 11
Kronenberg, Bern; Corinna Kronenberg, Stettlen; Danielle Lemann, Langnau; 12
Damian Meli, Huttwil; Gabriele Reinheimer, Worb; Véronique Rigamonti Wermelinger, 13
Bern; Ralf Schäfer, Bern; Urs Schneeberger, Niederönz; Christian Studer, Luzern; 14
Fritz Weber, Buchs; Doris Zundel, Bätterkinden; Anne-Marie Zundel Funk, 15
Zollikofen. 16
17
Funding 18
This study was supported financially by the Swiss National Foundation (SNF project 19
32003B_130867), the Swiss Academy of Medical Sciences, the SwissLife foundation 20
and the Else Kroener-Fresenius foundation. 21
22
23
Figures and Supplements 24
See separate files 25
26
Page 22 of 85
https://mc.manuscriptcentral.com/bmj
BMJ
123456789101112131415161718192021222324252627282930313233343536373839404142434445464748495051525354555657585960
Confidential: For Review O
nly
page 23 / 26
References 1
1. Organization WH. Global Action Plan on Antimicrobial Resistance. WHO Library 2
Cataloguing-in-Publication Data; 2015. 3
2. Foxman B. Epidemiology of urinary tract infections: incidence, morbidity, and economic 4
costs. Am J Med. 2002; 113 Suppl 1A: 5S-13S. 5
3. Foxman B, Brown P. Epidemiology of urinary tract infections: transmission and risk 6
factors, incidence, and costs. Infect Dis Clin North Am. 2003; 17(2): 227-41. 7
4. Mühlemann K. Surveillance of antibiotic prescription in the outpatient setting using the 8
national Sentinel network (OP-159, http://www.smw.ch/docs/PdfContent/smw-12931.pdf). 9
WONCA World Organization of National Colleges, Academies and Academic 10
Associations of General Practitioners/Family Physicians; 2009; Basel. Switzerland; 2009. 11
5. Lundborg CS, Olsson E, Molstad S. Antibiotic prescribing in outpatients: a 1-week 12
diagnosis-prescribing study in 5 counties in Sweden. Scand J Infect Dis. 2002; 34(6): 13
442-8. 14
6. Farkas A, Alajem D, Dekel S, Binderman I. Urinary prostaglandin E2 in acute bacterial 15
cystitis. J Urol. 1980; 124(4): 455-7. 16
7. Schwarz NT, Jung SY, Kalff JC, Chancellor M, Bauer AJ. Bacterial toxin N-formyl-17
methionyl-leucyl-phenylalanine acutely contracts human and rabbit detrusor through the 18
release of eicosanoids. J Urol. 2002; 167(6): 2603-12. 19
8. Poljakovic M, Svensson ML, Svanborg C, Johansson K, Larsson B, Persson K. 20
Escherichia coli-induced inducible nitric oxide synthase and cyclooxygenase expression 21
in the mouse bladder and kidney. Kidney Int. 2001; 59(3): 893-904. 22
9. Bleidorn J, Gagyor I, Kochen MM, Wegscheider K, Hummers-Pradier E. Symptomatic 23
treatment (ibuprofen) or antibiotics (ciprofloxacin) for uncomplicated urinary tract 24
infection?--results of a randomized controlled pilot trial. BMC Med. 8: 30. 25
10. Gagyor I, Bleidorn J, Kochen MM, Schmiemann G, Wegscheider K, Hummers-Pradier E. 26
Ibuprofen versus fosfomycin for uncomplicated urinary tract infection in women: 27
randomised controlled trial. BMJ. 2015; 351: h6544. 28
11. Little P, Merriman R, Turner S, Rumsby K, Warner G, Lowes JA, et al. Presentation, 29
pattern, and natural course of severe symptoms, and role of antibiotics and antibiotic 30
resistance among patients presenting with suspected uncomplicated urinary tract 31
infection in primary care: observational study. BMJ. 2010; 340: b5633. 32
12. Gupta K, Hooton TM, Roberts PL, Stamm WE. Short-course nitrofurantoin for the 33
treatment of acute uncomplicated cystitis in women. Arch Intern Med. 2007; 167(20): 34
2207-12. 35
Page 23 of 85
https://mc.manuscriptcentral.com/bmj
BMJ
123456789101112131415161718192021222324252627282930313233343536373839404142434445464748495051525354555657585960
Confidential: For Review O
nly
page 24 / 26
13. McNulty CA, Richards J, Livermore DM, Little P, Charlett A, Freeman E, et al. Clinical 1
relevance of laboratory-reported antibiotic resistance in acute uncomplicated urinary 2
tract infection in primary care. J Antimicrob Chemother. 2006; 58(5): 1000-8. 3
14. Clayson D, Wild D, Doll H, Keating K, Gondek K. Validation of a patient-administered 4
questionnaire to measure the severity and bothersomeness of lower urinary tract 5
symptoms in uncomplicated urinary tract infection (UTI): the UTI Symptom Assessment 6
questionnaire. BJU Int. 2005; 96(3): 350-9. 7
15. Grabe M (chairman) B-JT, Botto H, Çek M, Naber KG, Pickard RS, Tenke P, 8
Wagenlehner F, Wullt B. Guidelines on Urological Infections. 2013 [cited 2015 9
9.7.2015]; Available from: http://uroweb.org/wp-content/uploads/18_Urological-10
infections_LR.pdf 11
16. Chow SC SJ, Wang H Sample Size Calculations in Clinical Research. Second Edition 12
ed: Chapman & Hall/CRC; 2008. 13
17. Chung Y, Rabe-Hesketh S, Choi IH. Avoiding zero between-study variance estimates in 14
random-effects meta-analysis. Stat Med. 2013; 32(23): 4071-89. 15
18. Friede T, Rover C, Wandel S, Neuenschwander B. Meta-analysis of few small studies in 16
orphan diseases. Res Synth Methods. 2017; 8(1): 79-91. 17
19. Higgins JP, Thompson SG, Spiegelhalter DJ. A re-evaluation of random-effects meta-18
analysis. J R Stat Soc Ser A Stat Soc. 2009; 172(1): 137-59. 19
20. Falagas ME, Kotsantis IK, Vouloumanou EK, Rafailidis PI. Antibiotics versus placebo in 20
the treatment of women with uncomplicated cystitis: a meta-analysis of randomized 21
controlled trials. J Infect. 2009; 58(2): 91-102. 22
21. Ferry SA, Holm SE, Stenlund H, Lundholm R, Monsen TJ. Clinical and bacteriological 23
outcome of different doses and duration of pivmecillinam compared with placebo therapy 24
of uncomplicated lower urinary tract infection in women: the LUTIW project. Scand J 25
Prim Health Care. 2007; 25(1): 49-57. 26
22. Christiaens TC, De Meyere M, Verschraegen G, Peersman W, Heytens S, De 27
Maeseneer JM. Randomised controlled trial of nitrofurantoin versus placebo in the 28
treatment of uncomplicated urinary tract infection in adult women. The British journal of 29
general practice : the journal of the Royal College of General Practitioners. 2002; 30
52(482): 729-34. 31
23. Mazumdar K, Dutta NK, Dastidar SG, Motohashi N, Shirataki Y. Diclofenac in the 32
management of E. coli urinary tract infections. In Vivo. 2006; 20(5): 613-9. 33
24. Obad J, Suskovic J, Kos B. Antimicrobial activity of ibuprofen: new perspectives on an 34
"Old" non-antibiotic drug. Eur J Pharm Sci. 2015; 71: 93-8. 35
25. Gottesman BS, Carmeli Y, Shitrit P, Chowers M. Impact of quinolone restriction on 36
resistance patterns of Escherichia coli isolated from urine by culture in a community 37
Page 24 of 85
https://mc.manuscriptcentral.com/bmj
BMJ
123456789101112131415161718192021222324252627282930313233343536373839404142434445464748495051525354555657585960
Confidential: For Review O
nly
page 25 / 26
setting. Clinical infectious diseases : an official publication of the Infectious Diseases 1
Society of America. 2009; 49(6): 869-75. 2
26. Glasziou PP, Del Mar CB, Sanders SL, Hayem M. Antibiotics for acute otitis media in 3
children. Cochrane Database Syst Rev. 2004; (1): CD000219. 4
27. Falagas ME, Giannopoulou KP, Vardakas KZ, Dimopoulos G, Karageorgopoulos DE. 5
Comparison of antibiotics with placebo for treatment of acute sinusitis: a meta-analysis 6
of randomised controlled trials. Lancet Infect Dis. 2008; 8(9): 543-52. 7
28. Ahovuo-Saloranta A, Borisenko OV, Kovanen N, Varonen H, Rautakorpi UM, Williams 8
JW, Jr., et al. Antibiotics for acute maxillary sinusitis. Cochrane Database Syst Rev. 9
2008; (2): CD000243. 10
29. Del Mar CB, Glasziou PP, Spinks AB. Antibiotics for sore throat. Cochrane Database 11
Syst Rev. 2006; (4): CD000023. 12
30. de Bruyn GH, S. Borwick, A. Antibiotic treatment for travellers' diarrhoea. Cochrane 13
Database of Systematic Reviews, Issue 3, 2009. 2009. 14
31. Genton B, D'Acremont V. Evidence of efficacy is not enough to develop 15
recommendations: antibiotics for treatment of traveler's diarrhea. Clin Infect Dis. 2007; 16
44(11): 1520; author reply 1-2. 17
32. Tan T, Little P, Stokes T. Antibiotic prescribing for self limiting respiratory tract infections 18
in primary care: summary of NICE guidance. Bmj. 2008; 337: a437. 19
33. Rovers MM, Glasziou P, Appelman CL, Burke P, McCormick DP, Damoiseaux RA, et al. 20
Antibiotics for acute otitis media: a meta-analysis with individual patient data. Lancet. 21
2006; 368(9545): 1429-35. 22
34. Little P, Moore MV, Turner S, Rumsby K, Warner G, Lowes JA, et al. Effectiveness of 23
five different approaches in management of urinary tract infection: randomised controlled 24
trial. BMJ. 2010; 340: c199. 25
35. Kjolvmark C, Pahlman LI, Akesson P, Linder A. Heparin-binding protein: a diagnostic 26
biomarker of urinary tract infection in adults. Open Forum Infect Dis. 2014; 1(1): ofu004. 27
36. Lam CW, Law CY, To KK, Cheung SK, Lee KC, Sze KH, et al. NMR-based metabolomic 28
urinalysis: a rapid screening test for urinary tract infection. Clin Chim Acta. 2014; 436: 29
217-23. 30
37. Ciragil P, Kurutas EB, Miraloglu M. New markers: urine xanthine oxidase and 31
myeloperoxidase in the early detection of urinary tract infection. Dis Markers. 2014; 32
2014: 269362. 33
38. Bassler D, Briel M, Montori VM, Lane M, Glasziou P, Zhou Q, et al. Stopping randomized 34
trials early for benefit and estimation of treatment effects: systematic review and meta-35
regression analysis. Jama. 2010; 303(12): 1180-7. 36
Page 25 of 85
https://mc.manuscriptcentral.com/bmj
BMJ
123456789101112131415161718192021222324252627282930313233343536373839404142434445464748495051525354555657585960
Confidential: For Review O
nly
page 26 / 26
39. Alidjanov JF, Abdufattaev UA, Makhsudov SA, Pilatz A, Akilov FA, Naber KG, et al. New 1
self-reporting questionnaire to assess urinary tract infections and differential diagnosis: 2
acute cystitis symptom score. Urol Int. 2014; 92(2): 230-6. 3
4 5
Page 26 of 85
https://mc.manuscriptcentral.com/bmj
BMJ
123456789101112131415161718192021222324252627282930313233343536373839404142434445464748495051525354555657585960
Confidential: For Review O
nly
Kronenberg A. et al. Symptomatic therapy of uncomplicated lower urinary tract infections (UTI)
in the ambulatory setting. A randomized, double blind trial.
1
Figures for publication
Figure 1: Patient flow
Page 27 of 85
https://mc.manuscriptcentral.com/bmj
BMJ
123456789101112131415161718192021222324252627282930313233343536373839404142434445464748495051525354555657585960
Confidential: For Review O
nly
Kronenberg A. et al. Symptomatic therapy of uncomplicated lower urinary tract infections (UTI)
in the ambulatory setting. A randomized, double blind trial.
2
Figure 2: KM plot for (A) time until definite resolution of symptoms and (B) time until antibiotic up to day 10.
Page 28 of 85
https://mc.manuscriptcentral.com/bmj
BMJ
123456789101112131415161718192021222324252627282930313233343536373839404142434445464748495051525354555657585960
Confidential: For Review O
nly
Kronenberg A. et al. Symptomatic therapy of uncomplicated lower urinary tract infections (UTI)
in the ambulatory setting. A randomized, double blind trial.
3
Figure 3: Stratified analyses of (A) primary outcome and (B) principal secondary outcome. Positive differences indicate an advantage of antibiotics, negative differences an advantage of NSAIDs throughout.
NSAIDs Antibiotics
Risk difference (95% CI) P value for interaction
no. of patients/total no. (%)
A. Resolution of symptoms at day 3
Overall 72/133 (54%) 96/120 (80%)
27% (15 to 38%)
Age (y) 0.39
<45 yr 52/94 (55%) 69/89 (78%) 23% (9 to 37%)
≥45 yr 20/39 (51%) 27/31 (87%) 36% (16 to 55%)
Symptom score 0.36
≤20 71/127 (56%) 93/115 (81%) 26% (14 to 37%)
>20 1/6 (17%) 3/5 (60%) 43% (-9 to 96%)
Symptom duration 0.86
≤3 days 43/80 (54%) 66/83 (80%) 27% (12 to 41%)
>3 days 29/53 (55%) 30/37 (81%) 27% (8 to 45%)
Urine culture 0.84
Negative 21/36 (58%) 28/31 (90%) 30% (9 to 50%)
Positive 50/97 (52%) 69/89 (78%) 26% (12 to 39%)
Urine leucocytes* 0.37
≤2+ 18/32 (56%) 22/30 (73%) 16% (-8 to 40%)
>2+ 54/101 (53%) 75/90 (83%) 30% (17 to 43%)
Documented norfloxacin-susceptible Enterobacteriaceae 0.84
No 25/45 (56%) 34/41 (83%) 27% (7 to 47%)
Yes 47/88 (53%) 63/79 (80%) 26% (12 to 40%)
B. Use of any antibiotic up to day 30
Overall 82/133 (62%) 118/120 (98%) -37% (-46 to -28%)
Age (y) 0.38
<45 yr 60/94 (64%) 87/89 (98%) -34% (-45 to -24%)
≥45 yr 22/39 (56%) 31/31 (100%) -44% (-59 to -28%)
Symptom score 0.82
≤20 78/127 (61%) 113/115 (98%) -37% (-46 to -28%)
>20 4/6 (67%) 5/5 (100%) -33% (-71 to 4%)
Symptom duration 0.89
≤3 days 49/80 (61%) 81/83 (98%) -36% (-48 to -25%)
>3 days 33/53 (62%) 37/37 (100%) -38% (-51 to -25%)
Urine culture 0.25
Negative 19/36 (53%) 31/31 (100%) -46% (-63 to -29%)
Positive 63/97 (65%) 87/89 (98%) -33% (-44 to -23%)
Urine leucocytes* 0.38
≤2+ 17/32 (53%) 30/30 (100%) -44% (-62 to -26%)
>2+ 64/101 (63%) 89/90 (99%) -35% (-44 to -25%)
Documented norfloxacin-susceptible Enterobacteriaceae 0.45
No 26/45 (58%) 41/41 (100%) -42% (-57 to -27%)
Yes 56/88 (64%) 77/79 (97%) -34% (-45 to -23%)
*Post-hoc analysis
Page 29 of 85
https://mc.manuscriptcentral.com/bmj
BMJ
123456789101112131415161718192021222324252627282930313233343536373839404142434445464748495051525354555657585960
Confidential: For Review O
nly
Kronenberg A. et al. Symptomatic therapy of uncomplicated lower urinary tract infections (UTI)
in the ambulatory setting. A randomized, double blind trial.
4
Figure 4: Mantel-Haenszel fixed-effect meta-analysis of randomized double-blind trials comparing non-steroidal anti-inflammatory drugs with antibiotics in women with uncomplicated lower UTI.
Page 30 of 85
https://mc.manuscriptcentral.com/bmj
BMJ
123456789101112131415161718192021222324252627282930313233343536373839404142434445464748495051525354555657585960
Confidential: For Review O
nly
Kronenberg A. et al. Symptomatic therapy of uncomplicated lower urinary tract infections (UTI)
in the ambulatory setting. A randomized, double blind trial.
5
Figure 5: Mantel-Haenszel fixed-effect meta-analysis and Bayesian random effects meta-analysis of all
randomized double-blind trials and large randomized double-blind trials comparing non-steroidal anti-inflammatory
drugs with antibiotics in women with uncomplicated lower UTI
Page 31 of 85
https://mc.manuscriptcentral.com/bmj
BMJ
123456789101112131415161718192021222324252627282930313233343536373839404142434445464748495051525354555657585960
Confidential: For Review O
nly
page 1 / 19
Supplementary Appendix
This appendix has been provided by the authors to give readers additional information about
their work.
Supplement to: Kronenberg A. et al. Symptomatic therapy of uncomplicated lower urinary
tract infections in the ambulatory setting. A randomized, double blind trial.
Page 32 of 85
https://mc.manuscriptcentral.com/bmj
BMJ
123456789101112131415161718192021222324252627282930313233343536373839404142434445464748495051525354555657585960
Confidential: For Review O
nly
page 2 / 19
Supplementary Appendix
Table of contents
1. Investigator and committee members ................................................................. 3
2. Collaborators ......................................................................................................... 4
3. Supplementary methods ...................................................................................... 5
4. Supplementary tables and figures ..................................................................... 10
Page 33 of 85
https://mc.manuscriptcentral.com/bmj
BMJ
123456789101112131415161718192021222324252627282930313233343536373839404142434445464748495051525354555657585960
Confidential: For Review O
nly
page 3 / 19
1. Investigator and committee members
The members of the HWI trial study group are as follows
Steering committee:
K. Mühlemann, A. Kronenberg, P. Jüni
Clinical events committee
K. Mühlemann, A. Kronenberg
Data safety monitoring board
K. Mühlemann, A. Kronenberg, P. Jüni
Study investigators, recruiting patients: (in alphabetical order)
Investigator Study center (practice)
Duner Peter Eggiwil Fry Christoph Belp Grob Ursula Herzogenbuchsee Huber Felix Zürich Köstner-Mösching Beat Neuenegg Kronenberg Andreas Bern Kronenberg Corinna Stettlen Lemann Danielle Langnau Meli Damian Huttwil Reinheimer Gabriele Worb Rigamonti Wermelinger Véronique Bern Schäfer Ralf Bern Schneeberger Urs Niederönz Studer Christian Luzern Weber Fritz Buchs Zundel Doris Bätterkinden Zundel Funk Anne-Marie Zollikofen
Page 34 of 85
https://mc.manuscriptcentral.com/bmj
BMJ
123456789101112131415161718192021222324252627282930313233343536373839404142434445464748495051525354555657585960
Confidential: For Review O
nly
page 4 / 19
2. Collaborators
Collaborators Function
Nartey Linda Study coordination Heuer Sarah Study coordination Gnahoré Thierry Study coordination Dähler Madeleine Study coordination, telephone interview day 30 Sager Ursina Study coordination, telephone interview day 30 Jäggi Regula Study coordination, telephone interview day 30 Kacina Lucia Monitoring Sturdy Malcolm Development of database Trelle Sven Randomisation Eschenmoser Marco Production of study drugs Droz Sara Microbiological analysis
Page 35 of 85
https://mc.manuscriptcentral.com/bmj
BMJ
123456789101112131415161718192021222324252627282930313233343536373839404142434445464748495051525354555657585960
Confidential: For Review O
nly
page 5 / 19
3. Supplementary methods
Outcome definitions
Primary outcome
- proportion of patients whose symptoms resolved 3 days after they began treatment.
Main secondary outcome
- proportion of patients who took any antibiotics between the time they were
randomized and day 30 of follow-up
Additional secondary outcomes
- proportion of patients whose symptoms resolved 7 days after treatment began
- proportion of patients who had no symptoms at all on day 3 and on day 7 after
treatment began
- proportion of patients who took single dose fosfomycin as rescue therapy
- proportion of patients whose urinary culture was negative 10 days after treatment
began
- proportion of patients who came back to consult about UTI within 30 days after
treatment began
- mean composite symptom scores 3, 7 and 30 days after treatment began
- time to resolution of symptoms
- proportion of patients who had adverse events
- proportion of patients how had serious adverse events (based on ICH GCP 24)
- quality of life and working days lost on day 3
- overall satisfaction with the way their UTI was managed on day 10
Baseline assessment
At baseline, we determined how long patients had had symptoms before going to the doctor,
and took a capillary blood sample and a mid-stream urinary sample from each participant.
The blood was locally analyzed for C-reactive protein and leukocyte count. The urine was
used for pregnancy testing and dipstick analysis, also locally. The results of the dipstick tests
were semiquantitative categories from 0 to 4+ for erythrocytes and leucocytes, and
dichotome results for nitrites (yes-no). A urine sample (4ml volume) was sent in containers
pre-filled with boric acid preservative (Becton Dickinson, Franklin Lakes, NJ) to the Institute
Page 36 of 85
https://mc.manuscriptcentral.com/bmj
BMJ
123456789101112131415161718192021222324252627282930313233343536373839404142434445464748495051525354555657585960
Confidential: For Review O
nly
page 6 / 19
for Infectious Diseases, University of Bern, to be cultured. Standard laboratory procedures
were used to analyze and identify all microbiological samples. We used a cut-off of >103
cfu/ml to define a urinary culture as positive, according to European guidelines. Mixed flora
with no predominant microorganism, Lactobacilli and Streptococcus viridans group were
judged negative.
Diary
Patients received a printed paper booklet at the initiation visit. They were told to fill it out
every day at the same time, for 10 days, starting 24 hours after they began therapy. Every
day started on a new page, on which was printed the number of days since they began
therapy, and the calendar date. All pages began with a cross table where participants
rated symptom severity in following six dimensions; dysuria, daytime frequency, night time
frequency, urgency, abdominal pain when passing urine, pain or tenderness in the lower
back or loin. During the initiation visit (day 0) physicians filled out the cross-table with
patients to assess symptom severity before therapy and show patients how to fill out the form.
Day 0 included a question about duration of symptoms and number of UTI during the last 12
months. Pages for day 1 to 3 had blanks where participants fed out the date and time they
took their study medications. Day 3 included a total of four pages; the additional pages
assessed quality of life, recorded their decision to take or not take fosfomycin, and gave
patients the opportunity to note lost working days and side effects. We asked for following
specific side effects: nausea-vomiting, headache, vertigo, tiredness, skin eruptions, difficulty
breathing (e.g. asthma), gastric pain/retrosternal burning, abdominal discomfort/cramps,
diarrhea, or constipation. Three lines were left blank to give patients the opportunity to add
and rate additional side effects. Patients rated severity of each side effect on a Likert scale
from 0 (“no side effects”) to 6 (“worst possible side effects”). At the end of each page there
was a section for free text. Instructions were printed on the last pages. These told patients
that they should now mail the diary, including all unused medications, all empty medication
packages, and a new urine sample to the Institute for Infectious Diseases, University of Bern.
Follow-up
Following UTI symptoms were assessed: dysuria; daytime frequency; night time
frequency; urgency; abdominal pain when passing urine; and, pain or tenderness in the lower
back or loin. The severity of each symptom was recorded on a Likert scale (0 to 6; 0
indicated “normal”, 1 “very little” problems, 2 “slight” problems, 3 “moderately bad”, 4 “bad”, 5
“very bad”, and 6 “as bad as it could be”). We used the mean of daytime and nighttime for
frequency. Quality of Life was assessed using the five dimensions and the visual analogue
Page 37 of 85
https://mc.manuscriptcentral.com/bmj
BMJ
123456789101112131415161718192021222324252627282930313233343536373839404142434445464748495051525354555657585960
Confidential: For Review O
nly
page 7 / 19
scale (VAS) from the European Quality of Life questionnaire (EQ-5D) 28. General satisfaction
on day 10 was assessed using a numeric scale that ranged from 1 (“not satisfied at all, would
never do this again”) to 10 (“very satisfied”).
Side effects were systematically assessed in the diary on day 3 with a Likert scale
scored from 0 (“no side effects”) to 6 (“worst possible side effects”). We asked them if they
had the following specific side effects: nausea-vomiting, headache, vertigo, tiredness, skin
eruptions, difficulty breathing (e.g. asthma), gastric pain/retrosternal burning, abdominal
discomfort/cramps, diarrhea, or constipation. Three lines were left blank to give patients the
opportunity to add and rate additional side effects. All participating physicians were required
to immediately and systematically report serious adverse events (SAE) and adverse events >
grade 3, according to GCP guidelines.
Additional visits were grouped by the primary investigator, based on the diary and, if
necessary, original documents. Recurrent UTI was defined as additional visits after day 14
because of recurrent UTI symptoms after symptoms had resolved by day 10 (missing data in
2/9), and the physician decided to treat with antibiotics. To assess compliance we used
entries in the diary. If we did not receive information about patient adherence, or if patients
did not document the intake of at least one tablet of study medication, they were excluded
from the per-protocol analysis.
Data management
Baseline urinary samples and baseline local laboratory results on paper forms, second
urinary sample, diaries and unused study medications, were all sent to the Institute for
Infectious Diseases, University of Bern, Switzerland. Urinary samples were analysed locally;
all other material was forwarded to an academic clinical trials unit (CTU Bern, University of
Bern, Switzerland) where data managers fed the data into a central database. The
CTU continuously assessed data quality and completeness, completed missing data as far
as possible, and conducted telephone interviews on day 30. An independent study monitor
from the CTU verified the complete source data for the first two patients enrolled at each
study site, and for 10% of a random sample per study site thereafter. The independent
monitor checked informed consent forms, eligibility, serious adverse events and the primary
endpoint for all included patient.
Statistical analysis
Symptom scores at day 3 were imputed together with baseline symptom scores, based on
patient age, treatment group, baseline laboratory measurements (blood CRP and leucocytes,
urine leucocytes, erythrocytes and nitrite), presence of a positive urinary culture (at baseline
and day 10), duration of UTI symptoms before study start, recurrence of UTI in the last 12
Page 38 of 85
https://mc.manuscriptcentral.com/bmj
BMJ
123456789101112131415161718192021222324252627282930313233343536373839404142434445464748495051525354555657585960
Confidential: For Review O
nly
page 8 / 19
months, number of working days lost due to UTI. All other outcomes were imputed
separately, based on symptom scores at baseline and day 3 and the same covariates.
Predictive mean matching was used to impute continuous outcomes, binary outcomes were
imputed by using logistic regression. In total, we generated 20 imputed data sets and used
Rubin’s rules to analyzed them, as described above (Rubin DB. Multiple Imputation for
Nonresponse in Surveys. New York: J Wiley & Sons. 1987).
Bayesian Random Effects Meta-analysis
We used a Bayesian approach developed for random effects meta-analysis on the risk
difference scale [Warn et al.]. The model adequately restricts the risk difference (RD) and its
95% credibility interval (95% CrI) within the plausible values of -1 and 1 and accounts for
situations with sparse event data, including zero cells in one or both treatment groups.
Monte-Carlo Markov Chain simulation methods were used to obtain posterior distributions of
the RDs of outcomes of interest and . Pooled RDs were estimated from the median of the
respective posterior distributions. A RD below zero indicates a benefit of NSAIDs as
compared with antibiotics. 95% CrI were obtained from the 2.5th and the 97.5th percentile of
the posterior distribution, which can be interpreted similarly to a conventional 95%
confidence interval if priors are minimally informative. Between-trial heterogeneity was
considered low if the median of the posterior distribution of was around 0.001, which
corresponds to a 95% reference range of RDs from -0.062 to 0.062 if RDs are normally
distributed around 0. Heterogeneity was considered moderate if the median of the posterior
distribution of was around 0.005, which corresponds to a 95% reference range of RDs
from -0.139 to 0.139. Heterogeneity was considered high if the median of the posterior
distribution of was around 0.010, which corresponds to a 95% reference range of RDs
from -0.196 to 0.196 [see Spiegelhalter et al, pages 168 ff for an explanation of the concept].
The prior chosen for treatment effects on an RD scale followed a normal distribution with
mean 0 and standard deviation of 0.53 for all outcomes except pyelonephritis, which resulted
in a 95% reference range from -0.98 to 0.98. The prior for the baseline risk in the control
group followed a beta distribution with shape parameters (1,1) for all outcomes, except
pyelonephritis and antibiotic use, corresponding to a uniform distribution from 0 to 1 and a
95% reference range from 0.02 to 0.98. The prior for followed a beta distribution with shape
parameters (1,9) for all outcomes except pyelonephritis, which resulted in a mode of 0 and
an upper limit of the one-sided 95% reference range of 0.336.
The risk of pyelonephritis is less than 0.026 in women with lower uncomplicated urinary tract
infection,[Falagas et al] therefore RDs more extreme than +/- 0.05 were considered clinically
Page 39 of 85
https://mc.manuscriptcentral.com/bmj
BMJ
123456789101112131415161718192021222324252627282930313233343536373839404142434445464748495051525354555657585960
Confidential: For Review O
nly
page 9 / 19
implausible, and the corresponding maximally possible would be around 0.03,
corresponding to a of 0.0009. Priors used for pyelonephritis were therefore following a
normal distribution with mean 0 and standard deviation of 0.051 for the treatment effect,
which resulted in a 95% reference range from -0.1 to 0.1, and a beta distribution with shape
parameters (1,40) for and for the baseline risk in the control group, which resulted in a
mode of 0 and an upper limit of the one-sided 95% reference range of 0.072. The probability
to receive antibiotics in control groups that were actually allocated to antibiotics was likely to
be above 0.85 in western settings. We therefore chose a beta distribution with shape
parameters (9,1) for the baseline risk of antibiotic use in the control group, which resulted in
a mode of 1 and a lower limit of the one-sided 95% reference range of 0.72. Models were ran
with 2 chains. Results were obtained after a burn-in of 30000 iterations, retaining every 2nd
out of 50000 iterations. Model convergence was assessed visually using trace plots and
Gelman-Rubin plots. All Bayesian analyses were conducted in R and WinBUGS.
References
Warn DE, Thompson SG, Spiegelhalter DJ. Bayesian random effects meta-analysis of trials
with binary outcomes: methods for the absolute risk difference and relative risk scales. Stat
Med. 2002 Jun 15;21(11):1601-23.
Spiegelhalter D, Abrams K, Myles J. Bayesian approaches to clinical trials and health care
evaluation. Chichester: John Wiley & Sons, 2004.
Falagas ME, Kotsantis IK, Vouloumanou EK, Rafailidis PI. Antibiotics versus placebo in the
treatment of women with uncomplicated cystitis: a meta-analysis of randomized controlled
trials. J. Infect. 2009;58(2):91–102.
Page 40 of 85
https://mc.manuscriptcentral.com/bmj
BMJ
123456789101112131415161718192021222324252627282930313233343536373839404142434445464748495051525354555657585960
Confidential: For Review O
nly
page 10 / 19
4. Supplementary tables and figures
Supplementary Table 1: Missing data for primary and secondary outcomes
Total (N=253) NSAIDs (N=133) Antibiotics (N=120)
no. and precentage of missing observations
Resolution of symptoms
Day 3 (primary outcome) 22 (9%) 14 (11%) 8 (7%)
Day 7 19 (8%) 11 (8%) 8 (7%)
Day 10 21 (8%) 10 (8%) 11 (9%)
Day 30 0 (0%) 0 (0%) 0 (0%)
Complete absence of symptoms
Day 3 22 (9%) 14 (11%) 8 (7%)
Day 7 19 (8%) 11 (8%) 8 (7%)
Day 10 21 (8%) 10 (8%) 11 (9%)
Day 30 9 (4%) 5 (4%) 4 (3%)
Change of symptom score
Day 3 27 (11%) 15 (11%) 12 (10%)
Day 7 24 (9%) 12 (9%) 12 (10%)
Day 10 26 (10%) 11 (8%) 15 (13%)
Day 30 24 (9%) 11 (8%) 13 (11%)
Use of any antibiotic
Up to day 3 9 (4%) 4 (3%) 5 (4%)
Up to day 30 (principal secondary outcome) 9 (4%) 4 (3%) 5 (4%)
Use of rescue antibiotic
Up to day 3 12 (5%) 5 (4%) 7 (6%)
Up to day 30 15 (6%) 6 (5%) 9 (8%)
Negative urinary culture at day10 24 (9%) 12 (9%) 12 (10%)
Re-consultations because of UTI 9 (4%) 4 (3%) 5 (4%)
Quality of life (scaled to 0-10)
EuroQol health state 17 (7%) 9 (7%) 8 (7%)
EuroQol visual analogue scale 15 (6%) 8 (6%) 7 (6%)
Patient satisfaction with UTI-management 8 (3%) 5 (4%) 3 (3%)
Number of working days lost due to UTI 19 (8%) 10 (8%) 9 (8%)
Page 41 of 85
https://mc.manuscriptcentral.com/bmj
BMJ
123456789101112131415161718192021222324252627282930313233343536373839404142434445464748495051525354555657585960
Confidential: For Review O
nly
page 11 / 19
Supplementary Table 2: Number of participants censored until day 10 for time to event curves for resolution of symptoms and use of antibiotics (Corresponding to Figure 2)
Days since
randomisation
No. of patients
censored
A. Definite resolution NSAIDs 0 9
NSAIDs 10 7
Antibiotics 0 7
Antibiotics 4 1
Antibiotics 10 4
B: Antibiotic use NSAIDs 0 4
NSAIDs 10 54
Antibiotics 0 3
Antibiotics 10 2
Page 42 of 85
https://mc.manuscriptcentral.com/bmj
BMJ
123456789101112131415161718192021222324252627282930313233343536373839404142434445464748495051525354555657585960
Confidential: For Review O
nly
page 12 / 19
Supplementary Table 3: Sensitivity analyses for (A) primary outcome and (B) principal secondary outcome
Analysis Set NSAIDs Antibiotics Risk difference (95%
CI)
P value†
no. of patients/total no. (%)
A. Resolution of symptoms at day 3
Intention-to-treat analysis* 72/133 (54%) 96/120 (80%) 27% (15 to 38%) <0.0001
Complete case analysis 64/119 (54%) 90/112 (80%) 27% (15 to 38%) <0.0001
Per protocol analysis, multiple imputation 68/122 (55%) 91/111 (82%) 26% (15 to 38%) <0.0001
Per protocol analysis, complete case 64/114 (56%) 88/108 (81%) 25% (14 to 37%) <0.0001
Patients with CRP <30 at baseline 68/125 (54%) 91/113 (81%) 27% (15 to 39%) <0.0001
B. Use of any antibiotic up to day 30
Intention-to-treat analysis* 82/133 (62%) 118/120 (98%) -37% (-46 to -28%) <0.0001
Complete case analysis 79/129 (61%) 115/115 (100%) -39% (-47 to -30%) <0.0001
Per protocol analysis, multiple imputation 72/122 (59%) 111/111 (100%) -41% (-50 to -32%) <0.0001
Per protocol analysis, complete case 71/121 (59%) 111/111 (100%) -41% (-50 to -33%) <0.0001
Patients with CRP <30 at baseline 78/125 (62%) 111/113 (98%) -36% (-45 to -27%) <0.0001
* Primary analysis, 14 and 8 patients in NSAID and antibiotic group with multiple imputation for resolution of symptoms, 4 and 5
in NSAID and antibiotic group with multiple imputation for use of any antibiotic.
† P value for superiority, p value for non-inferiority = 0.977 for resolution of symptoms (primary analysis).
Page 43 of 85
https://mc.manuscriptcentral.com/bmj
BMJ
123456789101112131415161718192021222324252627282930313233343536373839404142434445464748495051525354555657585960
Confidential: For Review O
nly
page 13 / 19
Supplementary Table 4. Baseline characteristics for patients in NSAID group based on antibiotic use.
Never on
antibiotics (N=51)
Use of antibiotics
(N=82) P value
Age - yr 38.4 (14.6) 37.5 (14.1) 0.75
Age <45 yr 34 (67%) 60 (73%) 0.44
Symptom duration - days since UTI onset 3.7 (4.2) 3.5 (2.1) 0.56
Symptom duration ≤3 days 31 (61%) 49 (60%) 1.00
Number of UTIs in the last 12 months 0.5 (0.8) 0.7 (1.3) 0.58
Baseline UTI symptoms - score 0 to 6
Dysuria 3.0 (1.4) 3.4 (1.2) 0.07
Urgency 3.6 (1.0) 3.8 (1.1) 0.14
Night frequency 2.5 (1.6) 2.6 (1.4) 0.73
Day frequency 3.3 (0.9) 3.6 (1.0) 0.012
Lower abdominal pain while urinating 2.7 (1.5) 2.6 (1.6) 0.74
Back or loin pain 1.3 (1.4) 1.0 (1.4) 0.25
Total symptom score 13.4 (3.6) 13.9 (4.1) 0.53
Symptom score ≤20 49 (96%) 78 (95%) 1.00
Blood tests
CRP - mg/l 7.1 (13.0) 6.4 (8.6) 0.37
CRP >10 mg/ml 7 (14%) 17 (21%) 0.36
Leucocytes - 1000/µl 8.2 (2.3) 8.7 (2.5) 0.43
Urinary dipstick
Nitrites - positive 7 (14%) 10 (12%) 0.80
Erythrocytes - 1 to 4+ (median, IQR) 3+ (1+ to 4+) 4+ (2+ to 4+) 0.07
Leucocytes - 1 to 4+ (median, IQR) 3+ (2+ to 4+) 4+ (3+ to 4+) 0.12
Leucocytes >2+ 37 (73%) 64 (78%) 0.53
Urinary culture* 0.23
Negative 17 (33%) 19 (23%)
Positive 34 (67%) 62 (76%)
Escherichia coli 30 (59%) 52 (63%) 0.71
Other Enterobacteriaceae 3 (6%) 6 (7%) 1.00
Staphylococcus saprophyticus 0 (0%) 3 (4%) 0.29
Enterococcus faecalis 0 (0%) 1 (1%) 1.00
Beta-hemolytic Streptococcus group B 1 (2%) 0 (0%) 0.38
Susceptibility to norfloxacin 32 (63%) 60 (73%) 0.25
Enterobacteriaceae 32 (63%) 56 (68%) 0.57
Susceptibility to fosfomycin† 29 (57%) 55 (67%) 0.27
Continuous variables are presented as mean (sd), binary variables as no. of patients (%).
* Urinary culture missing in 1 patients in “Use of antibiotics” group.
† Enterobacteriaceae only
Page 44 of 85
https://mc.manuscriptcentral.com/bmj
BMJ
123456789101112131415161718192021222324252627282930313233343536373839404142434445464748495051525354555657585960
Confidential: For Review O
nly
page 14 / 19
Supplementary Table 5. Post-hoc analysis in NSAID group. Positive differences indicate an advantage of “Use of antibiotics”, negative differences an advantage of “Never on antibiotics” throughout.
Outcome
Never on antibiotics
(N=51)
Use of antibiotics
(N=82)
Risk or mean
difference (95% CI)
P value
no. of patients (%) or mean (sd)
Resolution of symptoms
Day 3 40 (78%) 32 (39%) -39% (-55 to -24%) <0.0001
Day 7 45 (88%) 66 (80%) -7% (-20 to 5%) 0.28
Day 10 48 (94%) 78 (95%) 1% (-7 to 9%) 0.83
Day 30 48 (94%) 79 (96%) 2% (-6 to 10%) 0.61
Complete absence of symptoms
Day 3 8 (16%) 2 (2%) -13% (-24 to -2%) 0.006
Day 7 24 (47%) 21 (26%) -21% (-37 to -4%) 0.017
Day 10 30 (59%) 41 (50%) -8% (-26 to 9%) 0.36
Day 30 37 (73%) 64 (78%) 6% (-9 to 21%) 0.44
Change of symptom score
Day 3 -9.2 (4.3) -6.1 (4.5) -3.1 (-4.7 to -1.6) 0.0001
Day 7 -11.3 (4.6) -10.8 (4.9) -0.4 (-2.1 to 1.2) 0.62
Day 10 -12.2 (4.4) -12.2 (4.3) 0.0 (-1.5 to 1.6) 0.98
Day 30 -12.5 (4.4) -13.3 (4.3) 0.8 (-0.7 to 2.3) 0.30
Negative urinary culture at day 10 33 (65%) 63 (77%) 13% (-4 to 29%) 0.12
Re-consultations because of UTI 1 (2%) 26 (32%) -30% (-41 to -19%) <0.0001
Quality of life (scaled to 0-10)
EuroQol health state 9.3 (1.4) 8.5 (2.4) -0.8 (-1.4 to -0.2) 0.011
EuroQol visual analogue scale 7.8 (1.6) 7.0 (2.1) -0.8 (-1.4 to -0.2) 0.015
Patient satisfaction with UTI-management 7.4 (2.3) 4.7 (3.0) -2.7 (-3.6 to -1.8) <0.0001
Number of working days lost due to UTI 0.6 (0.7) 0.7 (0.5) -0.1 (-0.3 to 0.3)* 0.54
* Relative rate reduction calculated from Poisson regression.
Page 45 of 85
https://mc.manuscriptcentral.com/bmj
BMJ
123456789101112131415161718192021222324252627282930313233343536373839404142434445464748495051525354555657585960
Confidential: For Review O
nly
page 15 / 19
Supplementary Table 6: Number of participants censored until day 10 for time to event curves for definite resolution of symptoms in the NSAID group (Corresponding to Supplementary Figure 2)
Days since
randomisation
No. of patients
censored
Definite resolution Never on antibiotics 0 1
Never on antibiotics 10 3
Use of antibiotics 0 8
Use of antibiotics 10 4
Page 46 of 85
https://mc.manuscriptcentral.com/bmj
BMJ
123456789101112131415161718192021222324252627282930313233343536373839404142434445464748495051525354555657585960
Confidential: For Review O
nly
page 16 / 19
Supplementary table 7: Baseline characteristics for patients in the NSAID group with and without pyelonephritis
Pyelonephritis
(N=6)
No pyelonephritis
(N=127) P value
Age - yr 34.2 (17.4) 38.0 (14.1) 0.37
Age <45 yr 5 (83%) 89 (70%) 0.67
Symptom duration - days since UTI onset 2.8 (1.7) 3.6 (3.1) 0.51
Symptom duration ≤3 days 5 (83%) 75 (59%) 0.40
Number of UTIs in the last 12 months 0.2 (0.4) 0.6 (1.1) 0.29
Baseline UTI symptoms - score 0 to 6
Dysuria 4.2 (0.8) 3.2 (1.3) 0.05
Urgency 4.2 (1.0) 3.7 (1.0) 0.31
Night frequency 3.0 (0.6) 2.6 (1.5) 0.49
Day frequency 4.0 (0.6) 3.5 (0.9) 0.13
Lower abdominal pain while urinating 3.7 (1.2) 2.6 (1.5) 0.10
Back or loin pain 1.7 (2.0) 1.1 (1.3) 0.37
Total symptom score 17.1 (4.0) 13.5 (3.8) 0.041
Symptom score ≤20 5 (83%) 122 (96%) 0.25
Blood tests
CRP - mg/l 14.2 (13.5) 6.3 (10.2) 0.05
CRP >10 mg/ml 3 (50%) 21 (17%) 0.07
Leucocytes - 1000/µl 9.8 (2.2) 8.4 (2.4) 0.13
Urinary dipstick
Nitrites - positive 1 (17%) 16 (13%) 0.57
Erythrocytes - 1 to 4+ (median, IQR) 4+ (3+ to 4+) 3+ (2+ to 4+) 0.30
Leucocytes - 1 to 4+ (median, IQR) 4+ (3+ to 4+) 3+ (2+ to 4+) 0.18
Leucocytes >2+ 6 (100%) 95 (75%) 0.33
Urinary culture* 0.19
Negative 0 (0%) 36 (28%)
Positive 6 (100%) 90 (71%)
Escherichia coli 5 (83%) 77 (61%) 0.41
Other Enterobacteriaceae 1 (17%) 8 (6%) 0.35
Staphylococcus saprophyticus 0 (0%) 3 (2%) 1.00
Enterococcus faecalis 0 (0%) 1 (1%) 1.00
Beta-hemolytic Streptococcus group B 0 (0%) 1 (1%) 1.00
Susceptibility to norfloxacin 6 (100%) 86 (68%) 0.18
Enterobacteriaceae 6 (100%) 82 (65%) 0.10
Susceptibility to fosfomycin† 6 (100%) 78 (61%) 0.08
Continuous variables are presented as mean (sd), binary variables as no. of patients (%).
P values from Wilcoxon rank sum tests for continuous and Fisher’s exact tests for binary variables.
* Urinary culture missing in 1 patients in “No pyelonephritis” group.
† Enterobacteriaceae only
Page 47 of 85
https://mc.manuscriptcentral.com/bmj
BMJ
123456789101112131415161718192021222324252627282930313233343536373839404142434445464748495051525354555657585960
Confidential: For Review O
nly
page 17 / 19
Supplementary Table 8: Symptom score for patients with and without pyelonephritis in the NSAID group.
Pyelonephritis
(N = 6)
No pyelonephritis
(N = 127) P value
mean (sd)
Symptom score at baseline 17.1 (4.0) 13.5 (3.8) 0.041
Symptom score at day 3 9.0 (3.9) 6.2 (4.6) 0.09
Symptom score at day 7 3.4 (3.2) 2.6 (3.2) 0.42
Symptom score at day 10 1.2 (2.0) 1.4 (2.4) 0.67
Symptom score at day 30 0.6 (1.4) 0.6 (1.7) 0.79
P values from Wilcoxon rank sum tests
Page 48 of 85
https://mc.manuscriptcentral.com/bmj
BMJ
123456789101112131415161718192021222324252627282930313233343536373839404142434445464748495051525354555657585960
Confidential: For Review O
nly
page 18 / 19
Supplementary Figure 1. Boxplot showing development of symptom score up to day 10 after randomisation in the NSAID and antibiotic group. (Boxes show median and 25 / 75 quartiles, whiskers +/- 1.5 * upper/lower IQR, values outside the whisker-range are depicted as points).
Page 49 of 85
https://mc.manuscriptcentral.com/bmj
BMJ
123456789101112131415161718192021222324252627282930313233343536373839404142434445464748495051525354555657585960
Confidential: For Review O
nly
page 19 / 19
Supplementary Figure 2. KM plot for time until definite resolution of symptoms in the NSAID group. Observation time was set to 1h for patients with resolution at baseline. Patients with missing observation times are censored after 1h. Only definite resolution is considered an event.
Page 50 of 85
https://mc.manuscriptcentral.com/bmj
BMJ
123456789101112131415161718192021222324252627282930313233343536373839404142434445464748495051525354555657585960
Confidential: For Review O
nly
page 1 / 23
Symptomatic therapy of uncomplicated lower urinary tract 1
infections in the ambulatory setting. A randomized, double blind 2
trial 3
Andreas Kronenberg,1,2,3 Lukas Bütikofer,4,5 Ayodele Odutayo,6 Kathrin 4
Mühlemann,1,2 � Bruno R. da Costa,7 Markus Battaglia,3 Damian N. Meli,3,7 Peter 5
Frey,7 Andreas Limacher, 4,5 Stephan Reichenbach,5,8 Peter Jüni 6,7 6
1 Institute for Infectious Diseases, University of Bern, Bern, Switzerland 7
2 Department of Infectious Diseases, Bern University Hospital, University of Bern, Bern, Switzerland 8
3 Medix General Practice Network, Bern, Switzerland 9
4 CTU Bern, University of Bern, Bern, Switzerland 10
5 Institute of Social and Preventive Medicine (ISPM), University of Bern, Bern, Switzerland 11
6Applied Health Research Centre (AHRC), Li Ka Shing Knowledge Institute of St. Michael’s Hospital, 12
and Department of Medicine, University of Toronto, Canada 13
7 Institute of Primary Health Care (BIHAM), University of Bern, Bern, Switzerland 14
8 Department of Rheumatology, Immunology and Allergology, Inselspital, Bern University Hospital, 15
University of Bern, Bern, Switzerland 16
17
Corresponding address: Andreas Kronenberg, MD 18
Institute for Infectious Diseases 19
University of Bern 20
Friedbühlstrasse 51 21
3010 Bern 22
Tel: +41 (0)31 632 32 65 / Fax: +41 (0)31 632 49 66 23
e-mail: [email protected] 24
25
26
Running title Symptomatic therapy of cystitis 27
Keywords cystitis, urinary tract infections, antibiotic therapy, anti-inflammatory drugs, 28
symptomatic, ambulatory, outpatient, randomized, double-blind 29
Word count abstract 286378 30
Word count text 31894278 31
Registration: www.clinicaltrials.gov (NCT01039545) 32
33
Page 51 of 85
https://mc.manuscriptcentral.com/bmj
BMJ
123456789101112131415161718192021222324252627282930313233343536373839404142434445464748495051525354555657585960
Confidential: For Review O
nly
page 2 / 23
ABSTRACT 1
Background: Antibiotic resistance is increasing globally and largely stems from increasing 2
antibiotic use. It has been suggested, that symptomatic therapy with non-steroidal anti-3
inflammatory drugs (NSAIDs) might be non-inferior to antibiotics in treatment of 4
uncomplicated lower urinary tract infection (UTI) in women, thus offering an opportunity to 5
reduce antibiotic use in ambulatory care. 6
Methods: In this randomized, double-blind, non-inferiority trial among 17 general practices in 7
Switzerland, women with uncomplicated lower UTI were randomly assigned 1:1 to 8
symptomatic therapy with diclofenac or antibiotic treatment with norfloxacin. The 9
randomization sequence was computer-generated, stratified by practice, blocked and 10
concealed using sealed, sequentially numbered drug containers. Primary and secondary 11
outcomes were symptom resolution up to day 3 and antibiotic use up to day 30, respectively. 12
Analysis was by intention-to-treat. We also performed a meta-analysis combining the results 13
of the current trial with previously published randomized controlled trials comparing NSAIDs 14
and antibiotic treatment in women with UTIs. 15
Findings: We randomly assigned 253 women to NSAIDs (133) and antibiotics (120). 16
Thereof 72 (54%) and 96 women (80%) experienced symptom resolution at day 3 in the 17
NSAID and antibiotic groups, respectively (risk difference 27%, 95%-CI 15% to 38%, p for 18
non-inferiority 0.98, p for superiority <0.0001). The median time until resolution of symptoms 19
was 4 days in the diclofenac group and 2 days in the norfloxacin group. A total of 82 (62%) 20
and 118 women (98%) used antibiotics up to day 30, respectively (risk difference 37%, 95%-21
CI 28 to 46%, p for superiority <0.0001). Six women in the NSAID group (5%) but none in the 22
antibiotic group received clinical diagnosis of a pyelonephritis (p=0.031). CRP levels > 10 23
mg/L at baseline were observed in 21 women in the NSAID group without pyelonephritis 24
(17%) and in 3 women with pyelonephritis (50%), which resulted in a positive likelihood ratio 25
of 3.02 (CI 1.07 to 5.98, p=0.037). Finally, our results were consistent with two previously 26
published clinical trials when combined in a meta-analysis. 27
Page 52 of 85
https://mc.manuscriptcentral.com/bmj
BMJ
123456789101112131415161718192021222324252627282930313233343536373839404142434445464748495051525354555657585960
Confidential: For Review O
nly
page 3 / 23
Interpretation: Diclofenac is inferior to norfloxacin in terms of symptom relief, but superior in 1
terms of reducing antibiotic use. Deferring antibiotic therapy in women without CRP elevation 2
and short symptom duration could be justifiable, but should be tested in a randomized trial. 3
Funding: Swiss National Foundation, Swiss Academy of Medical Sciences, SwissLife and 4
Else Kroener-Fresenius Foundation. 5
6
Page 53 of 85
https://mc.manuscriptcentral.com/bmj
BMJ
123456789101112131415161718192021222324252627282930313233343536373839404142434445464748495051525354555657585960
Confidential: For Review O
nly
page 4 / 23
INTRODUCTION 1
Antimicrobial stewardship aims at reducing antibiotic resistance by optimising or 2
decreasing antibiotic use,1 which includes the prevention of antibiotic treatment in cases of 3
viral infections, the tailored prescription of narrow-spectrum antibiotics, shortening the course 4
of therapy, and deferring therapy for low risk bacterial infections. Urinary tract infection (UTI) 5
is one of the most common bacterial infections in adults, affecting considerably more women 6
than men.2 Approximately half of women have at least one UTI in their lifetime, and 20% to 7
30% have two or more.3 Antibiotic prescriptions for UTI accounts for 10-20% of all antibiotic 8
prescriptions in ambulatory care and is second in number only to respiratory tract infections,4, 9
5. Reducing antibiotic prescriptions for UTI could potentially decrease the risk of antimicrobial 10
resistance. Therefore, the benefit of antibiotic treatment needs to be weigthed against the 11
potential for adverse effects, both at the level of the individual (adverse drug reactions) and 12
population (as a driver of antibiotic resistance). 13
Symptoms of UTI may arise from local increases in pro-inflammatory factors like 14
prostaglandins and non-steroidal anti-inflammatory drugs (NSAIDs) may be useful in 15
alleviating symptoms.6-8 A small randomized pilot trial, which compared the NSAID ibuprofen 16
with the antibiotic ciprofloxacin in 80 women with uncomplicated lower UTI, concluded that 17
symptomatic therapy with NSAIDs may be non-inferior to antibiotics, but suggested 18
confirmation in a larger trial.9 Two adequately powered randomized double-blind trials were 19
therefore initiated simultaneously in February 2012 in Germany and Switzerland. Results of 20
the German trial, which compared ibuprofen with fosfomycin in 494 women, were recently 21
published.10 Here, we report results of the Swiss trial, which compared diclofenac with 22
norfloxacin in 253 women with uncomplicated lower UTI. To put our results into context, we 23
also performed a meta-analysis of all available trials comparing NSAIDs with antibiotics in 24
women with lower UTI. 25
26
Page 54 of 85
https://mc.manuscriptcentral.com/bmj
BMJ
123456789101112131415161718192021222324252627282930313233343536373839404142434445464748495051525354555657585960
Confidential: For Review O
nly
page 5 / 23
METHODS 1
Study design 2
This randomized controlled patient and assessor blind trial was conducted in 17 general 3
practices in Switzerland. The funding bodies were not involved in the design or the conduct 4
of the trial, nor in the writing of the manuscript or the decision to submit the manuscript for 5
publication. The first and senior author wrote the manuscript, had final responsibility for the 6
decision to submit the manuscript for publication and vouch for the accuracy of the data and 7
analyses and for the fidelity of the trial to the protocol. The funding bodies only had access to 8
the data after finalization of the statistical analysis plan and completion of all analyses. The 9
study was conducted in accordance with the Declaration of Helsinki and was approved by 10
the local research ethics committee and the Swiss Agency for Therapeutic Products 11
Swissmedic. The trial was registered before start of patient recruitment at clinicaltrials.gov 12
(NCT01039545). All women provided written informed consent. 13
14
15
Patients, Randomization and Treatment 16
Women aged 18 to 70, who visited their general practitioners (GPs) because of one 17
or more symptoms or signs typical of acute lower UTI (dysuria, frequency, macrohaematuria, 18
cloudy or smelly urine) or self-diagnosed cystitis were eligible if their urine dipstick was 19
positive for nitrite and/or leucocytes. Women with relevant comorbidities or pregnancy, signs 20
of invasiveness, recurrent UTI, recent antibiotic therapy within the previous 4 weeks or 21
prolonged duration of symptoms (>7 days) were ineligible (for details see Supplementary 22
Appendix).We excluded pregnant women and women with clinical signs of upper UTI such 23
as fever (axillary body temperature >38oC), costovertebral pain or tenderness, rigors, nausea 24
or vomiting. We also excluded women with known or suspected anatomical or functional 25
abnormality of the urinary tract and comorbidities such as diabetes mellitus, active gastric or 26
duodenal ulcer disease or gastrointestinal bleeding, inflammatory bowel disease, severe liver 27
dysfunction (liver cirrhosis and ascites), coagulopathy (including therapy with coumarine 28
Formatted: Normal, Indent: First line: 0",Line spacing: single
Page 55 of 85
https://mc.manuscriptcentral.com/bmj
BMJ
123456789101112131415161718192021222324252627282930313233343536373839404142434445464748495051525354555657585960
Confidential: For Review O
nly
page 6 / 23
derivates), renal insufficiency grade III or higher (calculated GFR <60 ml/min), known 1
congestive heart failure (NYHA III or higher), psychiatric illness or dementia, inability to to 2
communicate in German or French language and any other serious comorbidity as judged by 3
the treating physician. In addition we excluded women with documented immunosuppression 4
(e.g. prednisone equivalent >10mg per day for >14 days, chemotherapy, radiotherapy, 5
immunmodulators, HIV infection, neutropenia) or hypersensitivity to one of the study 6
medications or history of asthma, urticaria or hypersensitivity-like reactions after consumption 7
of salicylic acid or other non-steroidal anti-inflammatory drugs, as well as women with vaginal 8
symptoms (discharge, irritation), bladder catheter in situ or during the past 30 days, recurrent 9
urinary tract infection (more than 3 infections during the last 12 months), antibiotic treatment 10
during the last 4 weeks or duration of UTI symptoms for more than 7 days before physician’s 11
visit. 12
Women were randomly allocated in a 1:1 ratio to NSAID or antibiotic therapy. The 13
randomization sequence was computer-generated, stratified by practice and blocked with 14
randomly varying block sizes of 4 and 6. Allocation was concealed with sealed, sequentially 15
numbered opaque drug containers of identical appearance that contained opaque hard 16
gelatine capsules of identical size and colour. Women allocated to NSAIDs received 17
capsules containing 75 mg diclofenac retard for three days (Olfen-75 duo release®, Mepha 18
Pharma, Basel, Switzerland),) and women allocated to antibiotics received capsules 19
containing 400 mg norfloxacin for three days (Norfloxacin-Teva® 400mg, Teva Pharma, Tel 20
Aviv, Israel; Norflocin-Mepha® 400mg Lactab, Mepha Pharma, Basel, Switzerland from 21
October 2013 onwards due to delivery restrictions). WomenWe chose norfloxacin because of 22
the high susceptibility rates in Switzerland and diclofenac because of its identical frequency 23
of administration which facilitated patient blinding. Women started therapy immediately after 24
randomization on day 0 and were advised to take 2 capsules per day: one in the morning 25
and one in the evening. All women were given a single open-label package of fosfomycin 26
(Monuril® 3g, Zambon, Cadempino, Switzerland) to be taken as a rescue antibiotic after 27
completion of the study medication on day 3 at their discretion, if symptoms persisted. 28
Page 56 of 85
https://mc.manuscriptcentral.com/bmj
BMJ
123456789101112131415161718192021222324252627282930313233343536373839404142434445464748495051525354555657585960
Confidential: For Review O
nly
page 7 / 23
Patient involvement 1
No patients were involved in setting the research question or the outcome measures, nor 2
were they involved in developing plans for recruitment, design, or implementation of the 3
study. No patients were asked to advise on interpretation or writing up of results. We plan to 4
disseminate the results of the research to all the scientific community, including study 5
participants. 6
7
Procedures and outcomes 8
The pre-specified primary outcome was symptom resolution up to day 3. (12 hours 9
after intake of the last study medication). In the absence of antimicrobial resistance, the 10
mean duration of symptoms in women with uncomplicated UTIs treated with antibiotics is 3 11
days11. Women rated the severity of five UTI symptoms (dysuria; frequency; urgency; 12
abdominal pain when passing urine; pain or tenderness in the lower back or loin) daily from 13
days 0 (randomization) to 10 by self-report diary and on day 30 by telephone interview on a 14
Likert scale from 0 to 6, with their composite score ranging from 0 to 30; symptom resolution 15
was defined as ≤ 2 points ("slight problems”) on all 5 components.12-14 Complete absence of 16
symptoms was defined as 0 points on all components. The pre-specified principal secondary 17
outcome was the use of any antibiotic (including norfloxacin and fosfomycin as trial 18
medications) up to day 30. The remaining pre-specified outcomes are reported in the 19
Supplementary Appendix. Side effects, quality of life, working days lost and use of the rescue 20
antibiotic were assessed on day 3, general satisfaction on day 10. Serious adverse events, 21
adverse events ≥grade 3 severity, any additional unplanned medical visits, including 22
telephone contacts, and co-medications were assessed by telephone interviews of the 23
treating physician on day 10 and of an independent, blinded interviewer on day 30. The 24
clinical diagnosis of pyelonephritis required the occurrence of loin pain and fever., leading to 25
an unplanned ambulatory visit. Mid-stream urinary samples obtained on days 0 and 10 were 26
processed according to standard laboratory procedures, using a cut-off of >≥103 colony 27
forming units per ml for a urinary culture to be considered positive;1415 mixed flora with no 28
Formatted: English (U.S.)
Page 57 of 85
https://mc.manuscriptcentral.com/bmj
BMJ
123456789101112131415161718192021222324252627282930313233343536373839404142434445464748495051525354555657585960
Confidential: For Review O
nly
page 8 / 23
predominant microorganism, Lactobacilli or Streptococcus viridans group were considered 1
negative. Details of baseline assessments, diary and scores used are described in the 2
Supplemental Appendix. 3
4
Systematic Review 5
We conducted a systematic search of MEDLINE (inception to April 9th 2017) using a 6
combination MeSH and keyword searching for the following terms: “Anti-bacterial Agents”, 7
“Antibiotics”, “Non-Steroidal Anti-inflammatory Agents”, “Urinary Tract Infections”, and 8
“Cystitis”. We included randomized clinical trials which compared NSAIDs and antibiotics for 9
the treatment of UTIs. No language restrictions were applied. We extracted information on 10
event rates in the NSAID and antibiotic treatment groups for the following outcomes: 11
symptom resolution at day 3 or 4, symptom resolution at 7 days, recurrent UTI, 12
pyelonephritis and use of antibiotics. 13
14
15
Statistical methods 16
We originally planned to recruit 400 women, but recruitment was slow and financial 17
constraints led us to decide in June 2014 to stop patient recruitment by December 2014, 18
when an expected 260 women would be included. The decision was made without inspecting 19
the data and after repeating the power analysis based on a closed-form normal 20
approximation test of proportions, 16 which was less conservative than the simulation-based 21
approach originally used. With the original assumption of 70% of women reaching symptom 22
resolution up to day 3 in both groups and the original, pre-specified non-inferiority margin of 23
15% on a risk difference scale, the projected sample size of 260 women would yield a power 24
of 84% to detect non-inferiority at a one-sided type I error of 5%. 25
The primary outcome was evaluated using a risk difference with a corresponding two-sided 26
95% confidence interval, a one-sided normal approximation test for non-inferiority and a two-27
Formatted: English (U.S.)
Formatted: Indent: First line: 0", Linespacing: Double
Page 58 of 85
https://mc.manuscriptcentral.com/bmj
BMJ
123456789101112131415161718192021222324252627282930313233343536373839404142434445464748495051525354555657585960
Confidential: For Review O
nly
page 9 / 23
sided Chi-squared test for superiority. Secondary outcomes were compared using 1
conventional two-sided p-values for superiority and corresponding two-sided 95% confidence 2
intervals. We used risk differences with Chi-squared tests for binary data, Poisson regression 3
with robust standard errors for counts, and linear regression with robust standard errors for 4
continuous data. Kaplan-Meier curves accompanied by hazard ratios from Cox models were 5
used to analyse time to symptom resolution and time to antibiotic use. All women were 6
included in the analysis in the groups they were originally allocated to (intention-to-treat 7
analysis), missing values were accounted for by multiple imputation (see Supplementary 8
Appendix). and Supplementary Table 1). We performed pre-specified subgroup analyses of 9
the primary outcome accompanied by Mantel-Haenszel tests for interaction by age (< 45 vs ≥ 10
45 years), symptom severity at baseline (≤ 20 vs > 20), symptom duration (≤ 3 vs > 3 days), 11
and presence of a positive urinary culture at baseline; post-hoc subgroup analyses were 12
performed by urine leucocytes (≤ 2+ vs >2+) and the presence of norfloxacin-resistant 13
Enterbacteriaceae. In per-protocol analyses, we excluded women with protocol deviations 14
who were defined as women with no documented intake of at least one dose of study 15
medication, cross-overs, or women who used rescue antibiotics before day 3. All analyses 16
were pre-specified in a statistical analysis plan before recruitment end and inspection of the 17
data. In post-hoc analyses of women allocated to NSAIDs, we compared baseline 18
characteristics and outcomes between those who used antibiotics until day 30 and those 19
never on antibiotics, determined the time between symptom onset and diagnosis in those 20
clinically diagnosed with pyelonephritis, and explored whether blood or urine findings at 21
baseline were associated with pyelonephritis with clinically relevant positive or negative 22
likelihood ratios above 5 or below 0.2, respectively, which could be used to rule in or rule out 23
future clinical diagnosis of pyelonephritis. 24
In view of the expected low number of trials and the considerable difference in sample size 25
between the initially available pilot trial and subsequent trials, we refrained from performing 26
conventional frequentist random-effects meta-analysis because these methods may yield 27
either overly optimistic or overly conservative results.17-19 Therefore, trial specific risk 28
Page 59 of 85
https://mc.manuscriptcentral.com/bmj
BMJ
123456789101112131415161718192021222324252627282930313233343536373839404142434445464748495051525354555657585960
Confidential: For Review O
nly
page 10 / 23
differences were combined with a Mantel-Haenszel fixed-effect model and a Bayesian 1
random-effects model. We chose the risk difference as treatment effect estimate as odds-2
ratios were not directly interpretable because some control group event rates were above 3
20%, and risk ratios were heterogeneous because of the variation in control group event 4
rates between trials. The specifications of the Bayesian random-effects model are described 5
in the web-appendix. We conducted two analyses. The first combined all trials and the 6
second was restricted to large trials with more than 100 patients per group; trials which would 7
have more than 50% power to detect a 15% difference in the primary outcome of incomplete 8
or no symptom resolution at day 3 or 4. All analyses were done in 9
Stata Release 14 (StataCorp. 2014. Stata Statistical Software: Release 14. College Station, 10
TX: StataCorp LP), RStudio version 1.0.143 (RStudio: Integrated Development for R. 11
RStudio, Inc., Boston, MA URL http://www.rstudio.com/), and WinBUGS version 1.4.3. 12
13
14
15
16
Formatted: Indent: First line: 0.49"
Page 60 of 85
https://mc.manuscriptcentral.com/bmj
BMJ
123456789101112131415161718192021222324252627282930313233343536373839404142434445464748495051525354555657585960
Confidential: For Review O
nly
page 11 / 23
RESULTS 1
Between Feb 7, 2012 and Dec 3, 2014, 253 women were included in the trial, 133. 2
Thirty-six patients were recruited in seven single practices, 108 in nine group practices and 3
109 in one big medical centre with 17 physicians in the centre of Bern, Switzerland. One-4
hundred and thirty-three patients were randomly allocated to NSAIDs and 120 to antibiotics. 5
A total of 125 women (94%) received treatment as allocated in the NSAID group, and 118 6
women (98%) in the antibiotic group. 119 (89%) and 112 women (93%) had complete follow-7
up until day 30 (Figure 1). Groups were similar (Table 1), with a mean age of 36.8 years (SD 8
14.1), a mean duration of symptoms of 3.4 days (SD 2.6) and a mean composite symptom 9
score of 13.7 points out of 30 (SD 3.8), and urgency, frequency and dysuria as the most 10
prevalent symptoms. Thirty-five urine samples were nitrite-positive (14%) and 191 had >2+ 11
leucocytes (75%). For 185 urine samples, we found positive urinary cultures (73%), which 12
resulted in a total of 193 isolates, of which 187 isolates (97%) had documented norfloxacin 13
susceptibility. 173 isolates contained Enterobacteriaceae, 160 of which were tested for 14
fosfomycin susceptibility and 158 were found susceptible (99%). 15
Clinical outcomes are presented in Table 2. The primary outcome, resolution of 16
symptoms at day 3, was observed in 72 (54%) and 96 (80%) women in the NSAID and 17
antibiotic groups, respectively (risk difference 27%, 95%-CI 15 to 38%, one-sided p for non-18
inferiority=0.98, two-sided p for superiority in favour of antibiotic group <0.0001). The 19
principal secondary outcome, use of any antibiotic up to day 30, was observed in 82 (62%) 20
and 118 (98%) women, respectively (risk difference -37%, 95%-CI -46 to -28%, p for 21
superiority in favour of NSAID group <0.0001). Among the 82 women in the NSAID group 22
who used antibiotics, 58 (71%) decided to take antibiotics during the first three days and 55 23
of the 58 (95%) took the rescue antibiotic fosfomycin. 24
Figure 2 presents time to event curves for resolution of symptoms (Panel A) and use 25
of antibiotics (Panel B) until day 10. (Figure 2 and Supplementary Table 2). The course of 26
mean symptom scores is shown in Supplementary Figure 1. The median time until resolution 27
Page 61 of 85
https://mc.manuscriptcentral.com/bmj
BMJ
123456789101112131415161718192021222324252627282930313233343536373839404142434445464748495051525354555657585960
Confidential: For Review O
nly
page 12 / 23
was 4 days in the NSAID vs.versus 2 days in the antibiotic group (HR 1.64, CI 1.26-2.14, 1
p<0.0010001,). The median times until antibiotic use were 05 and 50 days, respectively (HR 2
10.06, CI 6.67 to 15.17, p<0.0010001). Figure 3 shows subgroup analyses for the primary 3
and the principal secondary outcome. Results appeared consistent across all subgroups. 4
Sensitivity analyses revealed consistent results for the primary and main secondary outcome 5
(Supplementary Table 13). 6
Remaining pre-specified outcomes favoured antibiotic therapy except for change of 7
symptom score on day 30 (p=0.88) and working days lost (p=0.18, Table 2). Post-hoc 8
analyses of additional time-points revealed little evidence of a difference between groups for 9
resolution or complete absence of symptoms on day 10 and 30 or change of symptom score 10
on day 10 (p≥0.07) and strong evidence for a difference in favour of the NSAID group for 11
antibiotic use up to day 3 (p<0.0001, Table 2). 12
Supplementary Table 24 shows a post-hoc comparison of baseline characteristics of 13
women who had never been on antibiotics (n=51) with women who had used any antibiotics 14
until day 30 (n=82) among those randomly allocated to NSAIDs. We found little evidence for 15
a difference between groups, except for one component of the symptom composite score. 16
Supplementary Table 35 presents a comparison of outcomes. Resolution and complete 17
absence of symptoms at day 3 were more frequent among women never on antibiotics 18
(p≤0.006), changes of symptom scores were more pronounced at day 3 (p=0.0001), 19
reconsultations were less frequent (p<0.0001), and scores on quality of life and satisfaction 20
with care were higher (p≤0.015). The median time until symptom resolution in women never 21
on antibiotics was 3 days and the median time in women who had used antibiotics was 5 22
days (HR 0.61, CI 0.42 to 0.88, p=0.003, Supplementary Figure 2 and Supplementary Table 23
6). Thirty-four urinary cultures had been positive at baseline among women never on 24
antibiotics, of these 16 had become spontaneously negative on day 10 (47%). 25
Table 3 presents adverse events that resulted in reconsultations: 43 events in 41 26
women in the NSAID group (31%), and 22 events 21 women in the antibiotic group (18%). 27
Adverse events related to UTI were more frequent in the NSAID-group (p=0.012), with 6 28
Page 62 of 85
https://mc.manuscriptcentral.com/bmj
BMJ
123456789101112131415161718192021222324252627282930313233343536373839404142434445464748495051525354555657585960
Confidential: For Review O
nly
page 13 / 23
cases of clinically diagnosed pyelonephritis in the NSAID group (5%) and none in the 1
antibiotic group (p=0.031) and one woman with clinically diagnosed pyelonephritis in the 2
NSAID group classified to have experienced a serious adverse event since she was 3
hospitalized to receive intravenous antibiotic therapy. The median time from symptom onset 4
to clinical diagnosis of pyelonephritis was 5.5 days (range 5 to 8 days). CRP levels > 10 mg/L 5
at baseline were observed in 21 women in the NSAID group without pyelonephritis (17%) 6
and in 3 women with pyelonephritis (50%), which%, Supplementary Table 7). This resulted in 7
a positive likelihood ratio of 3.02 (CI 1.07 to 5.98, p=0.037) for CRP levels > 10 mg/L. None 8
of the blood or urine findings at baseline were associated with clinically relevant positive or 9
negative likelihood ratios suitable to rule in or out future diagnosis of a pyelonephritis. 10
Although the symptom score for women who developed pyelonephritis was higher at 11
baseline compared to women who did not develop pyelonephritis, there were no differences 12
in symptom score from day 3 to 30 (Supplementary Table 8). 13
14
Systematic Review and Meta-analysis 15
We reviewed 81 studies and excluded 78 in the abstract screen. Of the three articles 16
undergoing full-text review, one article was a published study protocol for an ongoing clinical 17
trial that may be indeed by eligible for inclusion upon completion. Therefore, three trials, 18
including our own, were included in the meta-analysis. Together, the studies included 806 19
women (410 randomized to NSAIDs and 382 randomized to antibiotics). Compared to the 20
antibiotics group, women randomized to NSAIDs had a higher incidence of incomplete or no 21
symptom resolution at 3 to 4 days (risk difference 18.0%, CI 11.3% to 24.7%; Number 22
Needed to Harm (NNH) 6, CI 4 to 9, Figure 4) and at 7 days (risk difference 9.6%, CI 4.1% to 23
15.1%, NNH 10, CI 7 to 24). The incidence of pyelonephritis was also higher in women 24
randomized to NSAIDs compared to women randomized to antibiotics (risk difference 2.6%, 25
CI 0.8% to 4.5%, NNH 38, CI 22 to 126). However, antibiotic use was markedly lower in 26
women randomized to NSAIDs compared to women randomized to antibiotics (risk difference 27
-56.1 %, CI -60.8% to -51.4%, Number Needed to Treat 2, CI 2 to 2) and there was little 28
Page 63 of 85
https://mc.manuscriptcentral.com/bmj
BMJ
123456789101112131415161718192021222324252627282930313233343536373839404142434445464748495051525354555657585960
Confidential: For Review O
nly
page 14 / 23
evidence of a difference in the frequency of recurrent UTIs between the groups (Figure 4). 1
Notably, point estimates for the fixed effect meta-analysis and the Bayesian random-effects 2
meta-analysis were similar, although confidence intervals were wider for the random effects 3
model (Figure 5). However, limiting our analysis to large trials increased the precision of the 4
effect estimate. There was little heterogeneity for all outcomes except for use of antibiotics, 5
for which the risk difference was lower in our study compared to the previous trials (Figure 5). 6
7
8
Page 64 of 85
https://mc.manuscriptcentral.com/bmj
BMJ
123456789101112131415161718192021222324252627282930313233343536373839404142434445464748495051525354555657585960
Confidential: For Review O
nly
page 15 / 23
DISCUSSION 1
In this randomized, double-blind trial in women with uncomplicated lower urinary tract 2
infection, symptomatic treatment with the NSAID diclofenac was inferior to antibiotic 3
treatment with norfloxacin in controlling symptoms. Those treated with diclofenac were 27% 4
less likely to have symptom resolution at day 3 and 12% less likely to have symptom 5
resolution at day 7 after randomization, with higher mean symptom scores, more frequent 6
reconsultations, a higher incidence of clinically diagnosed pyelonephritis and lower patient 7
satisfaction than those in the NSAID group. Conversely, women who received NSAIDs were 8
37% less likely to receive antibiotics until day 30 after randomization. 9
A meta-analysis of five trials concluded that antibiotics are clinically superior to 10
placebo in women with uncomplicated lower UTI.20 Our trial, in conjunction with the 11
accompanying meta-analysis, suggests that antibiotics are also clinically superior to 12
symptomatic treatment with NSAIDs. This contrasts with the conclusions of a small pilot trial 13
by Bleidorn et al,9 which found clinical outcomes of treatment with ibuprofen similar to those 14
of antibiotic therapy with ciprofloxacin. The pilot trial triggered both, our trial and the recently 15
published trial by Gágyor et al.10 Both of these trials were adequately powered, but failed to 16
detect non-inferiority of NSAIDs as compared with antibiotics in terms of symptom control. 17
Importantly, our trial and the accompanying meta-analysis suggest that symptomatic 18
treatment with NSAIDs is associated with an average 2.6% increase in the absolute risk of 19
clinically diagnosed pyelonephritis, which translates into a NNH of 38 as compared with 20
antibiotic treatment. The risk of pyelonephritis with NSAIDs is comparable to the risk of 0.4 to 21
2.6% observed with placebo in two earlier trials,21, 22 despite the previously described 22
antibacterial activity of diclofenac23 and ibuprofen.24 23
On the beneficial side, our meta-analysis suggests that antibiotic use can be halved 24
on average by initial symptomatic treatment with NSAIDs, with a corresponding number 25
needed to treat of 2 to prevent one instant of antibiotic use. GivenAlthough there was 26
moderate heterogeneity for this outcome, it may relate to methodological differences in the 27
Page 65 of 85
https://mc.manuscriptcentral.com/bmj
BMJ
123456789101112131415161718192021222324252627282930313233343536373839404142434445464748495051525354555657585960
Confidential: For Review O
nly
page 16 / 23
conduct of our trial compared to prior trials. In particular, we provided women with a rescue 1
antibiotic for discretionary use after completion of study medication and reaching the primary 2
endpoint. This may have facilitated antibiotic use in the NSAID treatment arm of our trial. 3
Nonetheless, given the high global incidence of UTIs, the reduction in antibiotic use is highly 4
relevant and is likely to immediately decrease resistance rates for E. colicoli and even other 5
microorganisms in the affected population.25 6
Rising antibiotic resistance among uropathogens in general, and Escherichia coli (the 7
most common uropathogen), in particular, is a global concern. Many studies show a clear 8
correlation between antibiotic consumption and rising resistance rates. Accordingly, 9
antibiotics are often withheld in cases of self-limited, benign bacterial diseases as acute otitis 10
media, sinusitis and traveller’s diarrhoea at the cost of a prolongation of symptoms by 11
typically 1-3 days.26-33 Our results in women with uncomplicated lower UTI are well in line 12
with the prolongation of symptoms observed with symptomatic treatment of these conditions. 13
As many women in the NSAID group resorted to antibiotic therapy in our trial, a strategy of 14
selectively deferring rather than completely withholding antibiotic therapy may be preferable 15
for uncomplicated lower UTI.34 This can be achieved through a shared decision making 16
process, during which clinicians inquire about their patient’s ideas and expectations 17
regarding antibiotic treatment for uncomplicated UTI and also explore the option of delaying 18
antibiotic use as a treatment strategy. 19
Subgroup analyses did not provide evidence for any clinically relevant treatment by 20
subgroup interactions. In particular, we were unablein contrast to find the interaction with 21
urine culture suggested by GagyorGágyor et al.10 , reduction in antibiotic prescription was 22
comparable in women with and without positive urinary cultures. Testing initial urine samples 23
for other biomarkers associated with UTI, like heparin-binding protein, interleukin-6, acetic 24
acid, trimethylamine, xanthine oxidase, myeloperoxidase, or others,35-37 might have resulted 25
in promising treatment by subgroup interactions, but these tests are not yet established in 26
clinical practice, and we are unaware of any evidence to suggest that such interactions would 27
be likely. When comparing women who never had been on antibiotics with women who had 28
Page 66 of 85
https://mc.manuscriptcentral.com/bmj
BMJ
123456789101112131415161718192021222324252627282930313233343536373839404142434445464748495051525354555657585960
Confidential: For Review O
nly
page 17 / 23
used antibiotics until day 30 among those allocated to NSAIDs in post-hoc analyses, we 1
unsurprisingly found better clinical outcomes in those never on antibiotics, but no relevant 2
differences in baseline characteristics that would allow an early identification of women likely 3
to benefit from NSAIDs alone. However, in further post-hoc analyses, which are purely 4
hypothesis generating, we found that the clinical diagnosis of pyelonephritis was established 5
not earlier than 5 days after symptom onset, and that CRP values above 10 mg/L were more 6
frequent at baseline in women who subsequently were diagnosed with a pyelonephritis. 7
Taken together, these exploratory findings could support a tailored strategy of immediate 8
antibiotic use in women with CRP levels of >10 mg/L and early NSAID use in remaining 9
women for up to 3 to 4 days after symptom onset, followed by deferred, selective antibiotic 10
use in those women who did not show a clear improvement up by then. Naturally, such a 11
tailored strategy would need to be evaluated in an appropriately powered randomized trial. 12
Our trial should be interpreted in view of its strengths and limitations. Strengths are its 13
randomized double blind design with appropriate concealment of allocation, blinding of 14
patients, therapists and outcome assessors, the low loss to follow-up, the robustness of 15
results in a series of sensitivity analyses and the multi-centric primary care setting. The 16
premature termination of patient recruitment before reaching the initially planned sample size 17
is an obvious limitation. However, the decision to stop recruitment was made without 18
inspecting the data and is therefore unlikely to have biased our findings.38 Despite the 19
smaller than originally planned sample size, our results are completely unequivocal. While 20
using slightly different symptom scores in different trials does affect the comparability 21
between trials, this will not affect the validity of our results. Nevertheless, we suggest that 22
future trials should consider to use the symptom score developed by Alidjanov et al.39 Finally, 23
our results are not generalizable to countries and clinical settings with lower rates of 24
susceptibility, which could decrease the effectiveness of antibiotics and render symptomatic 25
treatment with NSAIDs less inferior. 26
In conclusion, symptomatic therapy is inferior to antibiotic therapy for the treatment of 27
women with uncomplicated lower UTI in an ambulatory setting, as it increases median 28
Page 67 of 85
https://mc.manuscriptcentral.com/bmj
BMJ
123456789101112131415161718192021222324252627282930313233343536373839404142434445464748495051525354555657585960
Confidential: For Review O
nly
page 18 / 23
symptom duration by two days and is likely to be associated with an increased risk of 1
clinically diagnosed pyelonephritis. The observed impressive reduction in antibiotic use, 2
which would likely contribute directly to decreasing resistance rates for E. coli in the affected 3
population, suggests that alternate approaches of combining symptomatic treatment with 4
deferred, selective antibiotic use should be developed and tested in future trials. 5
6
Page 68 of 85
https://mc.manuscriptcentral.com/bmj
BMJ
123456789101112131415161718192021222324252627282930313233343536373839404142434445464748495051525354555657585960
Confidential: For Review O
nly
page 19 / 23
Contributors 1
AK and KM were responsible for conception and design and obtained funding for 2
the study. AK, MB, DM, and PF were responsible for the acquisition of data. BC, AO 3
and PJ performed the meta-analysis. LB, BC, AL, SR and PJ did the analysis and 4
interpreted it in collaboration with all the remaining authors. AK and PJ had full 5
access to the final data, co-wrote the manuscript, had final responsibility for content, 6
and the decision to submit for publication. All authors critically revised the paper for 7
important intellectual content and approved the final version. 8
9
Transparency declarations 10
The authors affirm that the manuscript is an honest, accurate, and transparent 11
account of the study being reported; that no important aspects of the study have 12
been omitted; and that any discrepancies from the study as planned (and, if relevant, 13
registered) have been explained. 14
15
Competing interests: All authors declare: no support from any organisation for the 16
submitted work besides the acknowledged financial support. AK has received travel 17
grant and meeting expenses from Gilead, Viofor and the World Health Organisation 18
(WHO), is advisor of the Swiss Federal Office of Public Health concerning antibiotic 19
resistance epidemiology in Switzerland, and provides non-interpreted annual 20
resistance data to LEO pharmaceutic company and the Swiss government. PJ has 21
received research grants to the institution from Astra Zeneca, Biotronik, Biosensors 22
International, Eli Lilly and The Medicines Company for cardiovascular trials, and 23
serves as unpaid member of the steering group of cardiovascular trials funded by 24
Astra Zeneca, Biotronik, Biosensors, St. Jude Medical and The Medicines Company. 25
The remaining authors declare no financial relationships with any organisations that 26
might have an interest in the submitted work in the previous three years and no other 27
relationships or activities that could appear to have influenced the submitted work. 28
29
Page 69 of 85
https://mc.manuscriptcentral.com/bmj
BMJ
123456789101112131415161718192021222324252627282930313233343536373839404142434445464748495051525354555657585960
Confidential: For Review O
nly
page 20 / 23
Acknowledgments 1
We thank all patients participating in this study, all participating general physicians for 2
their meticulous data collection and the Clinical Trials Unit of the University of Bern 3
(CTU Bern) for the development of the database (Malcolm Sturdy), Monitoring (Lucia 4
Kacina) and telephone interview and data clearance (Madeleine Dähler). We thank 5
the Institute of General Practice BIHAM, for their organisational support and the 6
Hospital Pharmacy of the Inselspital for the production and blinding of the study 7
medications (Marco Eschenmoser). 8
9
Participating physicians. Peter Duner, Eggiwil; Christoph Fry, Belp; Ursula Grob, 10
Herzogenbuchsee; Felix Huber, Zürich; Beat Köstner-Mösching, Neuenegg; Andreas 11
Kronenberg, Bern; Corinna Kronenberg, Stettlen; Danielle Lemann, Langnau; 12
Damian Meli, Huttwil; Gabriele Reinheimer, Worb; Véronique Rigamonti Wermelinger, 13
Bern; Ralf Schäfer, Bern; Urs Schneeberger, Niederönz; Christian Studer, Luzern; 14
Fritz Weber, Buchs; Doris Zundel, Bätterkinden; Anne-Marie Zundel Funk, 15
Zollikofen. 16
17
Funding 18
This study was supported financially by the Swiss National Foundation (SNF project 19
32003B_130867), the Swiss Academy of Medical Sciences, the SwissLife foundation 20
and the Else Kroener-Fresenius foundation. 21
22
23
Figures and Tables 24
See separate file 25
26 Formatted: Heading 2, Space Before: 22 pt,Line spacing: Multiple 1.15 li
Page 70 of 85
https://mc.manuscriptcentral.com/bmj
BMJ
123456789101112131415161718192021222324252627282930313233343536373839404142434445464748495051525354555657585960
Confidential: For Review O
nly
page 21 / 23
1. References 1
1. Organization WH. Global Action Plan on Antimicrobial Resistance. WHO Library 2
Cataloguing-in-Publication Data; 2015. 3
2. Foxman B. Epidemiology of urinary tract infections: incidence, morbidity, and 4
economic costs. Am J Med. 2002; 113 Suppl 1A: 5S-13S. 5
3. Foxman B, Brown P. Epidemiology of urinary tract infections: transmission and risk 6
factors, incidence, and costs. Infect Dis Clin North Am. 2003; 17(2): 227-41. 7
4. Mühlemann K. Surveillance of antibiotic prescription in the outpatient setting using the 8
national Sentinel network (OP-159, http://www.smw.ch/docs/PdfContent/smw-12931.pdf). 9
WONCA World Organization of National Colleges, Academies and Academic Associations of 10
General Practitioners/Family Physicians; 2009; Basel. Switzerland; 2009. 11
5. Lundborg CS, Olsson E, Molstad S. Antibiotic prescribing in outpatients: a 1-week 12
diagnosis-prescribing study in 5 counties in Sweden. Scand J Infect Dis. 2002; 34(6): 442-8. 13
6. Farkas A, Alajem D, Dekel S, Binderman I. Urinary prostaglandin E2 in acute 14
bacterial cystitis. J Urol. 1980; 124(4): 455-7. 15
7. Schwarz NT, Jung SY, Kalff JC, Chancellor M, Bauer AJ. Bacterial toxin N-formyl-16
methionyl-leucyl-phenylalanine acutely contracts human and rabbit detrusor through the 17
release of eicosanoids. J Urol. 2002; 167(6): 2603-12. 18
8. Poljakovic M, Svensson ML, Svanborg C, Johansson K, Larsson B, Persson K. 19
Escherichia coli-induced inducible nitric oxide synthase and cyclooxygenase expression in 20
the mouse bladder and kidney. Kidney Int. 2001; 59(3): 893-904. 21
9. Bleidorn J, Gagyor I, Kochen MM, Wegscheider K, Hummers-Pradier E. Symptomatic 22
treatment (ibuprofen) or antibiotics (ciprofloxacin) for uncomplicated urinary tract infection?--23
results of a randomized controlled pilot trial. BMC Med. 8: 30. 24
10. Gagyor I, Bleidorn J, Kochen MM, Schmiemann G, Wegscheider K, Hummers-Pradier 25
E. Ibuprofen versus fosfomycin for uncomplicated urinary tract infection in women: 26
randomised controlled trial. BMJ. 2015; 351: h6544. 27
11. Little P, Merriman R, Turner S, Rumsby K, Warner G, Lowes JA, et al. Presentation, 28
pattern, and natural course of severe symptoms, and role of antibiotics and antibiotic 29
resistance among patients presenting with suspected uncomplicated urinary tract infection in 30
primary care: observational study. BMJ. 2010; 340: b5633. 31
12. Gupta K, Hooton TM, Roberts PL, Stamm WE. Short-course nitrofurantoin for the 32
treatment of acute uncomplicated cystitis in women. Arch Intern Med. 2007; 167(20): 2207-33
12. 34
13. McNulty CA, Richards J, Livermore DM, Little P, Charlett A, Freeman E, et al. Clinical 35
relevance of laboratory-reported antibiotic resistance in acute uncomplicated urinary tract 36
infection in primary care. J Antimicrob Chemother. 2006; 58(5): 1000-8. 37
14. Clayson D, Wild D, Doll H, Keating K, Gondek K. Validation of a patient-administered 38
questionnaire to measure the severity and bothersomeness of lower urinary tract symptoms 39
in uncomplicated urinary tract infection (UTI): the UTI Symptom Assessment questionnaire. 40
BJU Int. 2005; 96(3): 350-9. 41
15. Grabe M (chairman) B-JT, Botto H, Çek M, Naber KG, Pickard RS, Tenke P, 42
Wagenlehner F, Wullt B. Guidelines on Urological Infections. 2013 [cited 2015 9.7.2015]; 43
Available from: http://uroweb.org/wp-content/uploads/18_Urological-infections_LR.pdf 44
16. Chow SC SJ, Wang H Sample Size Calculations in Clinical Research. Second Edition 45
ed: Chapman & Hall/CRC; 2008. 46
17. Chung Y, Rabe-Hesketh S, Choi IH. Avoiding zero between-study variance estimates 47
in random-effects meta-analysis. Stat Med. 2013; 32(23): 4071-89. 48
18. Friede T, Rover C, Wandel S, Neuenschwander B. Meta-analysis of few small studies 49
in orphan diseases. Res Synth Methods. 2017; 8(1): 79-91. 50
19. Higgins JP, Thompson SG, Spiegelhalter DJ. A re-evaluation of random-effects meta-51
analysis. J R Stat Soc Ser A Stat Soc. 2009; 172(1): 137-59. 52
Formatted: Font: 16 pt, Font color: Auto
Page 71 of 85
https://mc.manuscriptcentral.com/bmj
BMJ
123456789101112131415161718192021222324252627282930313233343536373839404142434445464748495051525354555657585960
Confidential: For Review O
nly
page 22 / 23
20. Falagas ME, Kotsantis IK, Vouloumanou EK, Rafailidis PI. Antibiotics versus placebo 1
in the treatment of women with uncomplicated cystitis: a meta-analysis of randomized 2
controlled trials. J Infect. 2009; 58(2): 91-102. 3
21. Ferry SA, Holm SE, Stenlund H, Lundholm R, Monsen TJ. Clinical and bacteriological 4
outcome of different doses and duration of pivmecillinam compared with placebo therapy of 5
uncomplicated lower urinary tract infection in women: the LUTIW project. Scand J Prim 6
Health Care. 2007; 25(1): 49-57. 7
22. Christiaens TC, De Meyere M, Verschraegen G, Peersman W, Heytens S, De 8
Maeseneer JM. Randomised controlled trial of nitrofurantoin versus placebo in the treatment 9
of uncomplicated urinary tract infection in adult women. The British journal of general 10
practice : the journal of the Royal College of General Practitioners. 2002; 52(482): 729-34. 11
23. Mazumdar K, Dutta NK, Dastidar SG, Motohashi N, Shirataki Y. Diclofenac in the 12
management of E. coli urinary tract infections. In Vivo. 2006; 20(5): 613-9. 13
24. Obad J, Suskovic J, Kos B. Antimicrobial activity of ibuprofen: new perspectives on 14
an "Old" non-antibiotic drug. Eur J Pharm Sci. 2015; 71: 93-8. 15
25. Gottesman BS, Carmeli Y, Shitrit P, Chowers M. Impact of quinolone restriction on 16
resistance patterns of Escherichia coli isolated from urine by culture in a community setting. 17
Clinical infectious diseases : an official publication of the Infectious Diseases Society of 18
America. 2009; 49(6): 869-75. 19
26. Glasziou PP, Del Mar CB, Sanders SL, Hayem M. Antibiotics for acute otitis media in 20
children. Cochrane Database Syst Rev. 2004; (1): CD000219. 21
27. Falagas ME, Giannopoulou KP, Vardakas KZ, Dimopoulos G, Karageorgopoulos DE. 22
Comparison of antibiotics with placebo for treatment of acute sinusitis: a meta-analysis of 23
randomised controlled trials. Lancet Infect Dis. 2008; 8(9): 543-52. 24
28. Ahovuo-Saloranta A, Borisenko OV, Kovanen N, Varonen H, Rautakorpi UM, 25
Williams JW, Jr., et al. Antibiotics for acute maxillary sinusitis. Cochrane Database Syst Rev. 26
2008; (2): CD000243. 27
29. Del Mar CB, Glasziou PP, Spinks AB. Antibiotics for sore throat. Cochrane Database 28
Syst Rev. 2006; (4): CD000023. 29
30. de Bruyn GH, S. Borwick, A. Antibiotic treatment for travellers' diarrhoea. Cochrane 30
Database of Systematic Reviews, Issue 3, 2009. 2009. 31
31. Genton B, D'Acremont V. Evidence of efficacy is not enough to develop 32
recommendations: antibiotics for treatment of traveler's diarrhea. Clin Infect Dis. 2007; 33
44(11): 1520; author reply 1-2. 34
32. Tan T, Little P, Stokes T. Antibiotic prescribing for self limiting respiratory tract 35
infections in primary care: summary of NICE guidance. Bmj. 2008; 337: a437. 36
33. Rovers MM, Glasziou P, Appelman CL, Burke P, McCormick DP, Damoiseaux RA, et 37
al. Antibiotics for acute otitis media: a meta-analysis with individual patient data. Lancet. 38
2006; 368(9545): 1429-35. 39
34. Little P, Moore MV, Turner S, Rumsby K, Warner G, Lowes JA, et al. Effectiveness of 40
five different approaches in management of urinary tract infection: randomised controlled trial. 41
BMJ. 2010; 340: c199. 42
35. Kjolvmark C, Pahlman LI, Akesson P, Linder A. Heparin-binding protein: a diagnostic 43
biomarker of urinary tract infection in adults. Open Forum Infect Dis. 2014; 1(1): ofu004. 44
36. Lam CW, Law CY, To KK, Cheung SK, Lee KC, Sze KH, et al. NMR-based 45
metabolomic urinalysis: a rapid screening test for urinary tract infection. Clin Chim Acta. 46
2014; 436: 217-23. 47
37. Ciragil P, Kurutas EB, Miraloglu M. New markers: urine xanthine oxidase and 48
myeloperoxidase in the early detection of urinary tract infection. Dis Markers. 2014; 2014: 49
269362. 50
38. Bassler D, Briel M, Montori VM, Lane M, Glasziou P, Zhou Q, et al. Stopping 51
randomized trials early for benefit and estimation of treatment effects: systematic review and 52
meta-regression analysis. Jama. 2010; 303(12): 1180-7. 53
39. Alidjanov JF, Abdufattaev UA, Makhsudov SA, Pilatz A, Akilov FA, Naber KG, et al. 54
New self-reporting questionnaire to assess urinary tract infections and differential diagnosis: 55
acute cystitis symptom score. Urol Int. 2014; 92(2): 230-6. 56
Page 72 of 85
https://mc.manuscriptcentral.com/bmj
BMJ
123456789101112131415161718192021222324252627282930313233343536373839404142434445464748495051525354555657585960
Confidential: For Review O
nly
page 23 / 23
1
2
3 Formatted: Indent: Left: 0", First line: 0"
Page 73 of 85
https://mc.manuscriptcentral.com/bmj
BMJ
123456789101112131415161718192021222324252627282930313233343536373839404142434445464748495051525354555657585960
Confidential: For Review O
nlyManuscript Title: Symptomatic therapy of uncomplicated lower urinary tract infections in
the ambulatory setting. A randomized, double blind trial
Dear Editor,
Thank you for considering our manuscript for potential publication in the BMJ. The manuscript was
first submitted to the Lancet Infectious Disease and was rejected after review.
To facilitate with the assessment of our manuscript by the BMJ, we enclose the reviewer comments
received from the Lancet Infectious Disease below. We have also provided a point-by-point response
to each of the reviewer comments (lines and pages refer to the TRACK-CHANGE version).
Thank you for your kind consideration.
Prof. Peter Juni
Reviewer Comments Received from Lancet Infectious Disease
Reviewer #1: This paper describes a randomised double-blind trial comparing the effect of a NSAID versus
norfloxacin, with optional rescue antibiotic treatment, on symptomatic resolution in women with
lower UTI.
The majority of the manuscript is written clearly, and the statistical components appear to be
conducted well. However, I have some concerns about some aspects of the study that potentially
accumulate to major revisions. I outline these below:
1. The primary outcome on clinicaltrials.gov is at day 4. In paper (and elsewhere) it is at day 3.
Could the authors clarify this apparent discrepancy between sources?
We agree that this may be a point of confusion for readers. We initially referred to the day of
inclusion and randomization as day one (see secondary outcome on clinicaltrial.gov: “The proportion
of patients ever on antibiotics between randomization at day 1 and follow-up at day 30”). For the
purpose of this report, we refer to the day of randomization as day 0. According to this definition, the
primary outcome was ascertained at day 3, i.e. 72 hours after randomization and start of therapy.
We clarified this (page 7, line 9-12)
2. Can the authors justify why norfloxacin was chosen as the antibiotic of interest? This seems
relevant, given the international readership of the journal. In most places in the manuscript, the
findings were interpreted as "antibiotic therapy" as an umbrella term. I wonder if the choice of
antibiotic may have influenced the outcome, and whether the interpretation should be made more
specific to norfloxacin?
We agree that especially in view of the increasing resistance rates, quinolones are not considered as
first line therapy for uncomplicated lower urinary tract infections and should be used for more
invasive infections such as pyelonephritis. As nitrofurantoin and fosfomycin were not widely used in
Switzerland when our study started, we initially considered trimethoprim-sulfamethoxazole as a
comparator (see history on clinicaltrial.gov). Because of rather high resistance levels (26% in
Switzerland in 2015, www.anresis.ch), we decided to use an antibiotic with lower resistance levels to
ensure our antibiotic therapy was effective and to preserve the validity of our results. Indeed 97% of
all microorganisms detected proved to be susceptible to norfloxacin (page 11, line 13). As shown in
the meta-analysis our results are comparable to other similar studies using different antibiotic
regimens and there is no indication that the choice of antibiotic regimen would influence the results
Page 74 of 85
https://mc.manuscriptcentral.com/bmj
BMJ
123456789101112131415161718192021222324252627282930313233343536373839404142434445464748495051525354555657585960
Confidential: For Review O
nly(as long as resistance rates are low). In view of the concomitant meta-analysis we retained the
wording as “antibiotic group”.
3. Similarly, can the authors justify the choice of NSAID, and consider the points I raise previously?
We are not aware of any body of literature to argue for or against a specific NSAID for the treatment
of UTI. The decision to select diclofenac was a practical one, because it is given twice daily as the
comparator norfloxacin and could be easily capsuled without any bulging.
We added the following sentence: “We chose norfloxacin because of the high susceptibility rates in
Switzerland and diclofenac because of its identical frequency of administration which facilitated
patient blinding (page 6, line 22-24).
4. For the analysis of urine samples, can the authors clarify how "predominant" was defined?
Predominance was judged by the microbiologist according to the distribution of the different
colonies on the agar plate. There is no clear cut in this definition, but is done in routine in daily
practice. As there is no clear cut definition we did not adapt the text.
5. Can the authors justify their choice of non-inferiority margin and choice of primary time point
(whether it is day 3 or 4)? Given the increasing concerns around the consequences of antibiotic
resistance, these two components of the trial are critical.
The latest meta-analysis available at the time of planning the trial (Falagas et al, J Infect 2009)
indicated that the largest trial comparing antibiotics with placebo (Ferry et al, Scand J Prim Health
Care 2007) found a risk difference of 35% for clinical cure at the end of treatment (25% with placebo
and 60% with antibiotics). The pre-specified non-inferiority margin is below half of this gain over
placebo. In view of a head-to-head trial of two antibiotics by Gupta K et al (Arch Intern Med
2007;167(20):2207-12), which found higher clinical cure rates than Ferry et al (79 and 84%), we
conservatively assumed rates of the primary outcome of symptom resolution to be at 70%. The time-
point was selected to target the end of protocol mandated treatments, before differences would get
diluted by the potential use of rescue antibiotics or other interventions in a large proportion of
patients after completion of study treatments in this non-inferiority trial.
6. In terms of sampling, and the risk of selection bias, can the authors describe how practices were
selected? Along the same lines, there is no description of how many eligible patients presented to
general practice (for example, using screening logs). Could the authors confirm what proportion of
eligible / potentially eligible patients presented, how many of those were approached, and (if
available) whether there were any distinguishing characteristics when comparing those who did
and did not participate in the trial?
There is no established network of primary care physicians interested in scientific collaboration in
Bern. In a first step, we therefore contacted all primary care physicians teaching students in their
practice. All interested physicians were invited to an information session on this study. Physicians
willing to participate had to pass a clinical investigator training (which was the main barrier for most
physicians), which was combined with a training on specific issues of this trial.
In order to minimize the administrative burden, we did not use screening logs. Therefore we are
unable to give you any information on how many patients declined participation in this study. During
the planning of this study, one practice asked about 20 patients, whether they would be willing to
participate (on a theoretical basis). About 60% of these patients declared their hypothetical
willingness. As the trial involved randomization to treatment arms, we do not think, that selection of
patients might have influenced the results.
Reviewer #2:
Page 75 of 85
https://mc.manuscriptcentral.com/bmj
BMJ
123456789101112131415161718192021222324252627282930313233343536373839404142434445464748495051525354555657585960
Confidential: For Review O
nlyReview: This is an interesting RCT on non-antimicrobial vs antimicrobial therapy of acute
uncomplicated lower UTI in women. Because antibiotic resistance is increasing, any possibility to
reduce antibiotic consumption is highly appreciated. Women with acute symptoms of uUTI were
randomly assigned to a 3-day therapy either with diclofenac or with norfloxacin. The overall results
show that diclofenac is inferior to norfloxacin in terms of symptom relief, but superior in terms of
reducing antibiotic use.
The study is well designed, performed and presented. The study was closed earlier because of slow
recruitment. There is, however, no hint that the main results would have been altered if more
patients would have been included into the study.
One concern of the non-antimicrobial therapy was the significantly higher number of
pyelonephritis (6 vs 0), which all occurred after day 3, which means which developed as ascending
infection from lower to upper UTI. A similar tendency was seen in an earlier study comparing
ibuprofen with fosfomycin, which is also discussed in the present manuscript. The authors could
found, that CRP as biomarker could be helpful to identify these patients early enough and start
antibiotic therapy delayed but probably early enough to prevent upper UTI (pyelonephritis). This of
course is an interesting aspect, but probably not practical, because acute cystitis in women is
usually treated empirically by oral drugs and monitoring CRP would need an additional blood
sample and additional cost. In general practice short term follow ups are also not performed
regularly. Nevertheless this is an very interesting aspect and opens the question whether other
biomarkers, e.g. obtained from urine, or better analysis of clinical symptoms by validated
questionairs, could be used to detect patients at risk to develop an upper UTI. In this case non-
antimicrobial therapy with the option of delayed antibiotic therapy in patients at risk could be the
best alternative to treat women with acute uUTI safely and reduce antibiotic consumption
significantly.
Thanks for this comment. We agree that uncomplicated lower UTI are usually treated without
additional analyses. Nevertheless, if a marker could have been identified, which would allow sparing
antibiotic therapy, this could even be cost-effective. This is speculative and our trial does not support
such strategies. However, we hope our work will trigger additional interventional studies on this
subject.
Reviewer #3: The authors present the results of an RCT comparing norflaxacin versus diclofenac in
uncomplicated urinary tract infections in women.
Women with typical complaints and a positive dipstick were included.
Overall the article is well written, the hypothesis clearly stated and the results and discussion easy
to read and including the relevant research on the topic. Despite not reaching the originally
intended sample size the article is well conducted and an important piece of work regarding the
discussion about antibiotic therapy in uncomplicated bacterial infections.
Major comments:
1. The effectiveness of both strategies in reducing the symptom burden was measured as the
percentage of patients reaching symptom resolution. This was defined as a symptom score of ≤ 10
points . Patients included had an average symptom score of 13.7 (SD 3.8) on a scale from 0-30.
Therefore the symptom score at the start was already very close to the primary outcome and the
difference between both groups might by very small. Therefore I am missing the discussion of a
minimally clinical important difference (and the necessary data to judge this).
I would ask the authors to present the data on symptom scores in both groups and the
development of the symptom score over the course of time in both groups.
My personal point of view would be that a difference of less than 2 points on a 0-30 scale has no
clinical relevance.
Page 76 of 85
https://mc.manuscriptcentral.com/bmj
BMJ
123456789101112131415161718192021222324252627282930313233343536373839404142434445464748495051525354555657585960
Confidential: For Review O
nlyWith respect to the minimally clinically important difference, the latest meta-analysis available at the
time of planning the trial (Falagas et al, J Infect 2009) indicated that the largest trial comparing
antibiotics with placebo (Ferry et al, Scand J Prim Health Care 2007) found a risk difference of 35% for
clinical cure at the end of treatment (25% with placebo and 60% with antibiotics). Consistent with
guidelines for the specification of non-inferiority margins, the pre-specified non-inferiority margin in
our trial is below half of this gain over placebo (U.S. Department of Health and Human Services. Non-
Inferiority Clinical Trials to Establish Effectiveness, Guidance for Industry, Nov 2016)
We thank the reviewer for their comment with respect to the difference in symptom scores but we
respectfully disagree. Symptom resolution was not defined as a total symptom score below 10, but
as “a slight problem”, defined as no more than 2 out of a maximum of 6 points on a Likert scale in
each single symptom dimension (dysuria, urgency, night frequency, frequency, lower abdominal pain
while urinating and back or loin pain). Symptom scores for the different complaint dimensions
differed at baseline, with “frequency” being the most and “back or loin pain” the least prevalent
symptom (table 1). In analogy to the study published by Little et al (BMJ 2010;340:c199,
doi:10.1136/bmj.c199), we selected “slight problems” as primary end point, because it is well known,
that slight problems may persist after clearing of the infection, but usually do not hamper daily
activity. Analyzing complete absence of symptoms (symptom score = 0) did not reveal any different
results (table 2).
As suggested by the reviewer we added an analysis on the development of the symptom score over
the course of time in both groups (Supplementary Figure 1). Because development of symptom
score was not a predefined outcome and results do not alter the messages of this study, we did not
discuss them in detail in the text.
2. In addition to the planned intervention all women were equipped with an antibiotic rescue
medication (fosfomycin) to be taken at the patients discretion (if symptoms persisted). Was there
any further instruction for the patients?
No, there were no additional instructions. We intended to have a low barrier for patients to gain
access to an (additional) antibiotic therapy. On one hand, this explains the higher use of antibiotics in
the control group observed in our study (see meta-analysis. On the other hand, this strengthens our
hypothesis, that antibiotic consumption may be reduced even in settings, where antibiotic therapy is
easily accessible.
3. I do not understand the rationale behind this intervention as from previous observational
studies (Little 2010 BMJ 2010;340:b5633) the mean symptom duration in UTI is slightly longer than
3 days, thus a second antibiotic at day three is likely to bias the results in favour of primary
antibiotic use.
The implications of this early rescue intervention should be discussed.
Thank you for this comment. In the observational study referred to by the reviewer, the overall mean
symptom duration of uncomplicated UTI in the study includes situations where the infectious
organism was resistant to the antibiotic prescribed. Indeed, when there was no antimicrobial
resistance, the duration of symptoms of dysuria, urgency, frequency, and abdominal pain is ≤3 days.
We chose norfloxacin as the primary antibiotic in our trial given the low resistance rates in
Switzerland to this antibiotic and the duration of 3 days is the established treatment regimen for
norfloxacin in uncomplicated UTI.
A potential use of the rescue antibiotic was mainly anticipated after completion of the regular,
protocol mandated regimen, i.e. once the first 3 days of treatment were over. A delay until the
rescue antibiotic was used would not have corresponded to clinical routine and would have been
difficult to defend with IRBs.
Page 77 of 85
https://mc.manuscriptcentral.com/bmj
BMJ
123456789101112131415161718192021222324252627282930313233343536373839404142434445464748495051525354555657585960
Confidential: For Review O
nly
Please note that 9 patients (8%) in the antibiotic group used the rescue antibiotic before day 3, at
their own discretion, and another 9 patients (8%) between days 4 and 30; corresponding numbers in
the NSAID group were 55 (41%) up to day 3, and 18 patients (14%). The trial protocol is therefore
unlikely to have biased results in favor of antibiotics.
4. Patients included only had light to moderate symptom scores (average 13 out of 30). This
suggests a selection bias as already described in the ICUTI study- could you comment on this. Did
you assess non-responders? If so, please give some information on symptom severity or other data
assessed.
We agree, that our study design might have selected for women with less severe symptoms, and as
we did not use screening logs (see last question of reviewer 1), we are not able to quantify this
effect. Although only few women had symptom scores above 20, we were not able to detect any
difference in this sub-group (fig. 1). We agree that our results cannot be extrapolated to women
suffering from very severe symptoms, nevertheless the impact on overall antibiotic prescription,
would be relevant, even if women with very severe symptoms would be treated with antibiotics
primarily.
Non-responders correspond to patients in the NSAID group, switching to antibiotic therapy. This
group was compared to patients in the NSAID group, never treated with antibiotics in a post-hoc
analysis. Results are summarized in the supplementary table 4. We did not find any relevant
differences between these two groups.
5. Patients were included by 17 GP could you give some information about the recruited patients
per practice
Following practice types participated in our study:
- 7 practices with only one physician recruited 1-10 patients each, total 36 patients
- 9 group practices recruiting 3 to 26 patients each, total 108 patients
- One big group practice, with 2 locations in Bern, where 17 practitioners included a total of
109 patients. Patient inclusion in this practice was very high, because the size of the practice,
the location in the center of town (which is very popular for young, otherwise healthy
patients going to work) and the fact, that the first author is working in this practice, working
constantly on motivation of the colleagues. In addition this was the first practice starting with
inclusion of patients.
We added the following sentence in the first paragraph of the results: “Thirty-six patients were
recruited in seven single practices, 108 in 9 group practices and 109 in one big medical centre with 17
physicians in the centre of Bern.” (page 11, line 3-5)
6. The number of women developing pyelonephritis was quite high. Of special interest would be
the symptom score in women developing a pyelonephritis- could you present this data
additionally. Were there any hints on this serious adverse event? Might pain medication lead to
non detection of PN?
How did the symptom score change during the study.
Indeed, it would be desirable if any hints towards a serious adverse event could have been detected,
but unfortunately this was not the case. As stated in the last paragraph of the result section, CRP
level at baseline was the only parameter with a positive likelihood to develop a pyelonephritis. We
looked in detail at the symptom scores, but were not able to detect any additional risk factors. We
added details in Supplementary table 7, a comprehensive summary of these additional analysis in the
result section (page 13, line 11-13) and give data on symptom scores of patients developing
pyelonephritis in the supplementary table 8.
Development of symptom score during the study in depicted in supplementary figure 1 (see answer
1, reviewer 3).
Page 78 of 85
https://mc.manuscriptcentral.com/bmj
BMJ
123456789101112131415161718192021222324252627282930313233343536373839404142434445464748495051525354555657585960
Confidential: For Review O
nly7. In the discussion I am missing the patient perspective. The results of this and the comparable
trials cited are a valuable basis for shared decision making as, at least from qualitative data
patients are willing to delay or to avoid antibiotic use due to the side effects
We agree with the reviewer that shared decision making probably is appropriate in handling
uncomplicated UTI. Our data help to inform the patient on a scientific basis. Of course in our study,
all participating patients were willing to (possibly) delay or avoid antibiotic therapy, otherwise there
would not have participated. We have added a sentence to our discussion in this regard (page 16,
line 16-19).
All further comments are on minor points only.
8. P 6 Patients
Exclusion criteria were stated, I would suggest to mention fever explicitly here (not only in the
supplement)
As suggested by others we included the complete set of inclusion and exclusion criteria in the main
text (and not in the supplement only, page 5-6)
9. P 7
"general satisfaction on day 10"
Again some information on the method (for example 10 point likert scale) would be helpful,
otherwise the reader would have to look up the supplement
For the symptom score we used a 6 point-likert scale, which is briefly described in procedures and
outcomes (page 7, line 15), Quality of Life was rated from 0-10, which is mentioned directly in table
2.
10. P 7 Cut off >103 cfu is not supported by the citation (EAU guideline) and is different from the
study protocol ( Instead ≥ 103 cfu is mentioned in this guideline and commonly used in practice).
We have adapted this typographical error accordingly (page 7, line 27)
11. P14 "unable to find the interaction with urine culture" to what kind of interaction is this
comment referring to?
As shown in figure 1B we were not able to see any risk difference in antibiotic prescription between
women with and without positive urinary cultures, while Gagyor et al. found a significantly higher
reduction of antibiotic treatment courses in the ibuprofen vs. the fosfomycin group in women with
negative urinary cultures (90.7%, CI 74.3% to 99.9%) than in women with positive urinary cultures
(58.5%, CI 49.8% to 67.0%).
We clarified this sentence: “In particular, in contrast to Gagyor et al. , reduction in antibiotic
prescription was comparable in women with and without positive urinary cultures” (page 16, line 21-
23).
Reviewer #4: The authors present a randomized trial comparing ibuprofen versus norfloxacin in patients with
uncomplicated cystitis.
The topic of the study is timely.
There was some recalcuation of recruitment power due to slow recruitment, however the final
results revealed significant findings.
1. Comments:
Page 79 of 85
https://mc.manuscriptcentral.com/bmj
BMJ
123456789101112131415161718192021222324252627282930313233343536373839404142434445464748495051525354555657585960
Confidential: For Review O
nlyThe comparator of this study was norfloxacin, which is in most guidelines not a first choice
antibiotic. There should be some explanations why the authors have choosen norfloxacin in this
study.
Please see answer 2 reviewer 1
2. The primary outcome was symptom resolution at day 3. There should be some note how this
date was selected, why not 7 days or 5 days. Is there any data showing a preference for 3 days?
The measurement of symptoms was performed by a self-reported diary. Is this questionaire a
validated questionaire, which is measuring what it is intended to measure?
In the absence of antimicrobial resistance, the mean duration of symptoms in women with
uncomplicated UTIs treated with antibiotics is 3 days (Little P et al. : BMJ 2010;340:b5633
doi:10.1136/bmj.b5633).
As discussed by Alidjanov et al (Urol Int 2014;92:230-36), there was no single accepted symptom
score measurement for lower UTI. In this review – which was published after the development of our
trial - Adlidjanov et al proposes (and assesses) an 18-item questionnaire including 6 typical symptoms
(“frequency”, “urgency”, “painful urination”, “incomplete emptying”, “suprapubic pain” and
“haematuria”), 4 items concerning potential differential diagnosis as STD or pyelonephritis, 3 items
on Quality of Life and 5 additional questions, which may affect therapy (as pregnancy, diabetes …).
Other studies focused on slightly different typical symptoms as “frequency”, “urgency”, “pain or
burning when passing urine”, “pain or uncomfortable pressure in the lower abdomen/pelvic area”,
“low back pain”, “not being able to empty the bladder completely/passing only small amounts of
urine” and “blood in urine” (Clayson D, et al. BJU Int. 2005 Aug;96(3):350-9); “dysuria”,
“haematuria”, “frequency during day and night”, “smelly urine,” “tummy pain”, “generally feeling
unwell”, and “restriction of daily activities” (Little et al. BMJ 2010;340:c199); “dysuria”, “frequency”
and “low abdominal pain” (Bleidorn et al. BMC Medicine 2010, 8:30); or “dysuria”,
“frequency/urgency of micturition” and “low abdominal pain” (Gagyor et al. BMJ 2015;351:h6544). In
addition Little et al. showed that nocturia and dysuria were the most sensitive symptoms to diagnose
lower UTI, but negative predictive value still was poor (Little et al. Health Technology Assessment
2009; Vol. 13: No. 19).
The selection of our symptom score (“dysuria”, “frequency”, “urgency”, “abdominal pain when
passing urine”, “pain or tenderness in the lower back or loin”) was based on the available literature
at that time and is close to the questionnaire suggested by Alidjanov in 2014. We did not include
“incomplete emptying” and “haematuria”, although the latter was included in the inclusion criteria.
Items concerning differential diagnoses were included in the exclusion criteria and quality of life was
assessed on day 3 only. In addition Alidjanov et al use a 4 point-Likert scale (0-3), while we used a 7
point Likert-scale (0-6). Taking into account the available literature, we still are convinced that our
symptom score addresses the most important symptoms and is valuable in comparing the two
treatment groups. We agree, that using a standardized questionnaire as suggested by Adlidjanov et
al. would ease the comparability between different trials, and should therefore be promoted.
We briefly discuss these considerations in the paragraph on strengths and limitations (page 17, line
20-23).
3. It would be interesting to see a subcohort analysis, which patients would have had a benefit
from ibuprofen and which not. Is this feasable from the data, perhaps from those with lower
symptoms?
This indeed is an interesting point and that is what we intended to do in the post-hoc analysis. The
patients in the NSAIDs group that never used antibiotics can be seen as those that benefitted from
the NSAIDs (in comparison to those that used antibiotics). However, as discussed in the text, we
Page 80 of 85
https://mc.manuscriptcentral.com/bmj
BMJ
123456789101112131415161718192021222324252627282930313233343536373839404142434445464748495051525354555657585960
Confidential: For Review O
nlycould not identify baseline characteristics that are clearly different between the two groups
(Supplemental table 4).
4. It seems that the patients were not seen by a physician at follow up visits. This needs to be
clarified. Also if the diagnosis pyelonephritis was only done per telefone interview or if patients
reported to the study centers.
The reviewer is right, a scheduled follow up visit was not pre-planned, in order to keep the procedure
as simple and easy as possible. The follow-up is described in detail in “procedures and outcomes”.
As study physicians were the family physicians, follow-up was very close in case of any problems.
Indeed pyelonephritis was never diagnosed per telephone, all patients diagnosed with pyelonephritis
at least had one unplanned ambulatory visit. In the section “procedures and outcomes” we specified
that “The clinical diagnosis of pyelonephritis required the occurrence of loin pain and fever, leading
to an unplanned ambulatory visit.” (page 7,line 25)
5. It is also debatable, if the rescue antibiotic fosfomycin trometamol that was handed at study
inclusion would have facilitated antibiotic treatment.
We agree that providing the rescue antibiotic has probably facilitated the antibiotic treatment and
this is the most probable explanation for the higher antibiotic prescription in the NSAID group
compared the other studies as depicted in the Meta-analysis.
We have amended the discussion section of our meta-analysis as follows:
“On the beneficial side, our meta-analysis suggests that antibiotic use can be halved on average by
initial symptomatic treatment with NSAIDs, with a corresponding number needed to treat of 2 to
prevent one instant of antibiotic use. Although there was moderate heterogeneity for this outcome,
it may relate to methodological differences in the conduct of our trial compared to prior trials. In
particular, we provided women with a rescue antibiotic for discretionary use after completion of
study medication and reaching the primary endpoint. This may have facilitated antibiotic use in the
NSAID treatment arm of our trial. Nonetheless, given the high global incidence of UTIs, the reduction
in antibiotic use is highly relevant and is likely to immediately decrease resistance rates for E. coli and
even other microorganisms in the affected population.21
”
Reviewer #5:
GENERAL COMMENTS
The study conducted poses a relevant question with appropriate methods to answer. In an era of
increase in antimicrobial resistance primarily driven by increased environmental antibiotic
pressure every effort to improve is most important. Unfortunately, the authors identified an
inferiority of the non-antimicrobial approach compared to antimicrobial approaches. The main
conclusion driving outcome has been 3 day symptom recovery. Another important issue is the risk
of developing more serious UTIs (pyelonephritis) in patients treated for symptoms. As authors,
have highlighted further studies to detect the patients under the risk of transitioning to more
severe infections can now be better justified. This would be useful for individualized treatment
strategies in women with cystitis and ensure a lower antimicrobial pressure.
METHODS:
1. The study has been terminated earlier due to recruitment difficulties. Although, this is a
limitation I agree with the methods of handling the issue. Nevertheless, my interest is related to
with the reasons of low recruitment. Could you please elaborate on the reasons of why the
recruitment targets were not satisfied?
Page 81 of 85
https://mc.manuscriptcentral.com/bmj
BMJ
123456789101112131415161718192021222324252627282930313233343536373839404142434445464748495051525354555657585960
Confidential: For Review O
nlyThere are several reasons for the low recruiting. Because we did not analyze this reasons
scientifically, we do not detail them in the revision, nevertheless I give some reasons below:
• So far there was no network of general physicians, interested in scientific collaborations. A
side effect of this study, was to establish this network. However we invested a lot of time in
recruiting physicians, who finally did not include patients or only 1-2. We added some details
about the recruiting physician in the first paragraph or the results.
• The obligations from the Swiss authorities were higher than expected. Every physician had to
perform a clinical investigator training, which withheld some colleagues from participating in
this study.
• Some delay, was due to the long illness and death of Kathrin Mühlemann, the initial primary
investigator.
• In a qualitative survey among clinical investigators during the recruitment phase revealed
two main reasons, for not including more patients: First missing time during daily business to
inform patients properly about this trial and second more patients than expected (see also
reviewer 1, answer 6), denied to participate. Because we did not have screening logs we are
not able to quantify the magnitude of this effect.
2. Similar previous studies cited in the paper have recruited the similar numbers as the established
target in the current study. At this point the results of the trial log-book would be relevant. What is
the rate of willingness to participate in the study from patients approached for the study? If
available please provide in supplement. Did you identify a lack of equipoise in either patients or
clinicians? For those patients who did not participate in the study do you know their treatment
preferences (i.e NSAID vs antibiotics)?
To make recruitment as easy as possible, we did not use screening logs (see answer 1 and answer 6
of reviewer 1) and therefore are not able to give more details on this issue. Because the study was
randomized, these issues should not affect the results of this study.
3. Could you please further elaborate and report the pattern of missing data of questionnaires
(missing completely at random, missing at random and missing not at random).
The proportion of missing data was too low to be able to meaningfully determine whether there are
associations of patient characteristics with data missingness. Therefore, we are unable to come to
any conclusions as to the type of missing data. Since the proportion of missing data was small and
the distribution similar between groups, our estimates are unlikely to be biased even if data had
bveen missing not at random.
To address this reviewer’s comment, we report the numbers of patients with missing data per
outcome in the web-appendix (Supplemental Table 1).
4. Recovery has been described by a symptom score of 2 or less at follow-up. Papers cited for this
purpose are: Gupta et al. 2007, McNulty et al 2006 and Clayson D et al 2005. Nevertheless, I did not
come across with this definition in these papers. For instance, McNulty et al used complete
resolution in follow-up symptom scores as the primary outcome. Could you please further
elaborate on why and how the cut-off value of 2 or less symptom score was selected.
We agree with the reviewer, that different definitions of symptom resolution are used in previous
studies and discuss this issue in answer 1 of reviewer 3. Because different end-points have been
used, we operationalized the outcome of symptom resolution three ways: symptom resolution on
day 3 and 7, complete absence of symptoms at day 3 and 7 and change of symptom score. In
addition we added an analysis of development of symptom score as suggested by two reviewers
(Supplementary Figure 1). All analyses revealed comparable results, reinforcing our results.
5. The primary outcome of the study is 3 day symptom recovery. Why did you prefer to limit this
with 3 days? By selecting this point in time only to compare these management options there is a
preference introduced. The overall effect on symptoms of these treatments (0 to 30 days) with
Page 82 of 85
https://mc.manuscriptcentral.com/bmj
BMJ
123456789101112131415161718192021222324252627282930313233343536373839404142434445464748495051525354555657585960
Confidential: For Review O
nlyappropriate methods might summarize the overall situation better for future patients to make
choices.
See also reviewer 1, answer 5. Because we expected, that many patients would use “rescue
antibiotics” on day 3, we chose the primary end point at day 3, directly before the eventual intake of
the rescue antibiotic, which would influence the outcome. The predefined secondary outcome
symptom score on day 7 as well as change of symptom scores at day 3 and 7 did not reveal any
different results. In the supplemental figure 1 we added a boxplot analysis of symptom scores day 0 –
10 (see also reviewer 3, answer 1).
6. Measurement of symptoms was conducted by rating the severity of five UTI symptoms ((i)
dysuria; (ii) frequency, (iii) urgency, (iv) abdominal pain when passing urine, (v) pain or tenderness
in the lower back or loin). The originally developed questionnaire by Clyson D et al. BJUi 2005
determined that there are seven signs and symptoms with three domains. Please justify the
reasons you used a shorter version.
See reviewer 4, answer 2
7. Has the questionnaires used been translated into French and German and if so please cite the
validation study also. This process has been done for EuroQol and necessary citations would be
useful.
We eventually did not include French speaking patients and did not translate the diary or the
informed consent into French.
8. In 2014 a more comprehensive and specific questionnaire was developed for measuring patient
reported outcomes in patients with acute cystitis. This of course was after the study started but I
think it may be relevant for the authors to briefly mention in discussion that future studies could
consider this also. (New Self-Reporting Questionnaire to Assess Urinary Tract Infections and
Differential Diagnosis: Acute Cystitis Symptom Score. Alidjanov J.F.a · Abdufattaev
U.A.a · Makhsudov S.A.a · Pilatz A.c · Akilov F.A.a ·Naber K.G.b · Wagenlehner F.M.c )
We thank the reviewer for this valuable comment. We discuss this issue in detail in answer 2 of
reviewer 4 and briefly in the section on strengths and limitations in the manuscript.
9. Secondary outcome has been specified as use of antibiotics up to 30 days. It is not clear if this
includes the treatment given to the antibiotic group or is it only additional treatments given.
Intuitively it seems like it includes antibiotics given for randomized patients (Norfloxacin).
However, in figure 2b Norfloxacin arm day 1 antibiotic probability is less than 100%. Could you
please explain and make clearer in the manuscript.
In the section procedures and outcomes we describe the secondary outcome as “use of any
antibiotic up to day 30”. We specified now to “use of any antibiotic (including norfloxacin and
fosfomycin as trial medications) up to day 30” (page 7, line 18). As depicted in figure 1, 2/120
patients in the antibiotic treatment arm did not take antibiotics, which translates in probability to
take antibiotics below 100% even in the antibiotic treatment arm in figure 2b.
10. Rescue treatment:
The susceptibility profile of cases with positive urine culture is known at baseline (probably latest
2 days). In cases from the NASID group where fosfomycin resistance was measured were patients
informed? Please give reason if no and if yes the implications (for instance has the rescue
treatment option been changed in these patients?).
Could you explain why was fosfomycin selected as the rescue treatment option?
Patients were not informed on susceptibility results and rescue therapy was not changed for several
reasons: 1) susceptibility to fosfomycin was known to be very high in Switzerland (99% in our trial), 2)
the treating physician was not aware of the treatment group and 3) scheduled follow-up or any
active interaction was not planned during the first 10 days, to make the study as easy as possible.
Page 83 of 85
https://mc.manuscriptcentral.com/bmj
BMJ
123456789101112131415161718192021222324252627282930313233343536373839404142434445464748495051525354555657585960
Confidential: For Review O
nlyNevertheless susceptibility results were provided to the treating physician in case of any
complication.
Fosfomycin was selected because of the very high susceptibility rate in Switzerland and the easy
administration.
We did not elaborate on these issues further in the manuscript.
RESULTS
11. table 1 please provide the p values to prove that at baseline groups were similar.
In accordance with the CONSORT guidelines of reporting of randomized trials, we refrained from
performing significance tests of baseline differences between groups. As our study was a randomized
trial, any differences would have occurred by chance and therefore statistically significant p-values
would be unnecessary and potentially misleading to readers.
12. Figure 2A: please also show censored cases on the plot.
In our experience, a clinical readership has difficulty in understanding the ticks indicating censored
cases on time-to-event curves. We therefore indicated the numbers of censored cases in
Supplementary Table 2 and 6.
13. Typo in page 11paragraph 2 last sentence (rescue).
Done
14. Paragraph 3: “Median time until antibiotics use were 0 and 5 days respectively.”. This means
that it was 0 for the NSAID group, in relation to the previous sentence.
Thank you for this comment. You are completely right, we have changed this sentence accordingly.
15. Have you repeated the sensitivity outcomes for other outcomes such as complete resolution
rates, time to complete resolution etc?
No we did not do so. Our sensitivity analysis was done as pre-specified and we did not elaborate
further because there was no hint for any inconsistency.
16. It might be useful to have a more detailed table or plot for susceptibility profiles of pathogens
in each group in the supplement. As it stands it is difficult for a reader interested in details to
follow.
For instance, Enterobacteriaceae was detected in 173 cases. Fosfomycin susceptibility tested for
160 and 158 were sensitive. From supplement table 2 it is understood that urine culture was
negative in 46 (34%) of NSAID group and Enterobacteriaceae was detected in 88 cases (66%).
Susceptibility was only tested for Enterobacteriaceae and 84 were sensitive. This means either 4
cases in NSAID were resistant or not measured for susceptibility.
With respect to my previous question I think this information becomes relevant for rescue
treatment method question above.
The table below lists the detailed information for the 160 isolates tested against fosfomycin. We
believe that an additional table in the supplement to show this data is not needed. We propose to
add an additional comment in the notes of table 1 (“Two isolates from the NSAID group (1 Proteus
mirabilis, 1 Enterobacter cloacae) were not susceptible to fosfomycin”) instead. However, we could
add the table in the supplement, if deemed necessary by the editor.
Page 84 of 85
https://mc.manuscriptcentral.com/bmj
BMJ
123456789101112131415161718192021222324252627282930313233343536373839404142434445464748495051525354555657585960
Confidential: For Review O
nlyFosfomycin-susceptibility NSAIDs Antibiotics
E. coli 78/78 68/68
K. pneumoniae 1/1* 1/1
Citrobacter spp. 4/4 1/1
Proteus mirabilis 2/3 1/1*
Pantoea agglomerans 1/1*
Enterobacter cloacae 0/1 1/1
total 85/87 73/73
* in double mixed infection with fosfomycin-susceptible E. coli
17. Although the sample size of patients developing pyelonephritis is low it is very important.
Therefore, it is appreciable that the authors have tried to detect any baseline variables that might
be useful. Was there any other analysis done to determine if post treatment variables such as
response in symptoms, use of rescue treatment etc that could be useful. I appreciate the limited
number of events and difficulty to propose any inferences but it would be a useful hypothesis
generating exercise and help future research.
We have added some additional information in the text and in the supplementary table 7 and 8 (see
answer 6 of reviewer 3)
Discussion is very well written. I only have a few minor comments.
Please try to avoid abbreviations of terms not used before in the text to allow the general to follow
easier.
We replaced “NNT” by “number needed to treat”
In the final conclusion, one potential implication of reduced antibiotic usage is described as future
reduction in E.coli resistance. I would propose a more wider perspective where we shift to a lower
antibiotic pressure environment and ultimately avoid emergence of resistance (not only for E.coli).
A similar argument is made in the discussion section. One of the recent reviews paper to support
this argument is published by Alison Holmes et al: Understanding the mechanisms and drivers of
antimicrobial resistance Lancet 2016; 387
We agree with the reviewer, that reduction in quinolone has to potential to reduce quinolone
resistance not only in E. coli but also in other microorganisms and adapted the corresponding
sentences in the discussion (“…and is likely to immediately decrease resistance rates for E. coli and
even other microorganisms in the affected population” (page 16, line 5)) and the conclusion
(“…decreasing resistance rates for E. coli in the affected population” (page 18, line 3).
Page 85 of 85
https://mc.manuscriptcentral.com/bmj
BMJ
123456789101112131415161718192021222324252627282930313233343536373839404142434445464748495051525354555657585960