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Ibuprofen versus pivmecillinam for uncomplicated urinary tract infection in women-A double-blind, randomized non-inferiority trial.

ABSTRACT: BACKGROUND:Although uncomplicated urinary tract infections (UTIs) are often self-limiting, most patients will be prescribed antibiotic treatment. We assessed whether treatment with ibuprofen was non-inferior to pivmecillinam in achieving symptomatic resolution by day 4, with a non-inferiority margin of 10%. METHODS AND FINDINGS:This was a randomized, controlled, double-blind non-inferiority trial. We recruited patients from 16 sites in a general practice setting in Norway, Sweden, and Denmark. Non-pregnant women aged 18-60 years presenting with symptoms of uncomplicated UTI were screened for eligibility from 11 April 2013 to 22 April 2016. Patients with informed consent were randomized (1:1 ratio) to treatment with either 600 mg ibuprofen or 200 mg pivmecillinam 3 times a day for 3 days. The patient, treating physician, and study personnel were blinded to treatment allocation. The primary outcome was the proportion of patients who felt cured by day 4, as assessed from a patient diary. Secondary outcomes included the proportion of patients in need of secondary treatment with antibiotics and cases of pyelonephritis. A total of 383 women were randomly assigned to treatment with either ibuprofen (n = 194, 181 analyzed) or pivmecillinam (n = 189, 178 analyzed). By day 4, 38.7% of the patients in the ibuprofen group felt cured versus 73.6% in the pivmecillinam group. The adjusted risk difference with 90% confidence interval was 35% (27% to 43%) in favor of pivmecillinam, which crossed the prespecified non-inferiority margin. Secondary endpoints were generally in favor of pivmecillinam. After 4 weeks' follow-up, 53% of patients in the ibuprofen group recovered without antibiotic treatment. Seven cases of pyelonephritis occurred, all in the ibuprofen group, giving a number needed to harm of 26 (95% CI 13 to 103). Five of these patients were hospitalized and classified as having serious adverse events; 2 recovered as outpatients. A limitation of the study was the extensive list of exclusion criteria, eliminating almost half of the patients screened. We did not register symptoms in the screening process; hence, we do not know the symptom burden for those who declined to participate. This might make our results less generalizable. CONCLUSIONS:Ibuprofen was inferior to pivmecillinam for treating uncomplicated UTIs. More than half of the women in the ibuprofen group recovered without antibiotics. However, pyelonephritis occurred in 7 out of 181 women using ibuprofen. Until we can identify those women who will develop complications, we cannot recommend ibuprofen alone as initial treatment to women with uncomplicated UTIs. TRIAL REGISTRATION:ClinicalTrials.gov NCT01849926 EU Clinical Trials Register (EU-CTR), EudraCT Number 2012-002776-14.

SUBMITTER: Vik I

PROVIDER: S-EPMC5953442 | biostudies-literature | 2018 May

REPOSITORIES: biostudies-literature

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Ibuprofen versus pivmecillinam for uncomplicated urinary tract infection in women-A double-blind, randomized non-inferiority trial.

Vik Ingvild I Bollestad Marianne M Grude Nils N Bærheim Anders A Damsgaard Eivind E Neumark Thomas T Bjerrum Lars L Cordoba Gloria G Olsen Inge Christoffer IC Lindbæk Morten M

PLoS medicine 20180515 5

<h4>Background</h4>Although uncomplicated urinary tract infections (UTIs) are often self-limiting, most patients will be prescribed antibiotic treatment. We assessed whether treatment with ibuprofen was non-inferior to pivmecillinam in achieving symptomatic resolution by day 4, with a non-inferiority margin of 10%.<h4>Methods and findings</h4>This was a randomized, controlled, double-blind non-inferiority trial. We recruited patients from 16 sites in a general practice setting in Norway, Sweden, ...[more]

PMID: 29763434

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Project description:Background:To investigate if a 5-day course pivmecillinam (amdinocillin pivoxil) 400?mg three times daily is superior to a 3-day course in women with uncomplicated urinary tract infection (UTI). Methods:A randomised, double-blind, placebo-controlled trial conducted at nine primary care centres in Denmark. 368 women (18-70?years) with symptoms compatible with UTI were randomised to blinded therapy of 5 days [5d] or 3 days followed by 2 days of placebo [3d] from May 2015 to November 2017. Clinical data were assessed using a validated questionnaire at inclusion (day-0), daily the following 7 days and once again within the 2nd to 6th week after intervention. Bacteriological data were collected prior to intervention and twice between day 7 and 42. Main clinical endpoints were days to symptom resolution within 7?days after inclusion and proportions with clinical success at the end of intervention. Main bacteriological endpoint was proportion of participants with significant reduction of bacteriuria (? 102 CFU/mL) in 1st control urine sample. ClinicalTrialsRegister.eu: 2014-001321-32. Findings:180 (5d) and 188 (3d) participants were included in the study (mean age: 35.4 [5d] and 34.9 [3d]). Of these, 125 (70% [5d]) and 122 (66% [3d]) had a positive baseline urine culture. Forty-four participants were lost to follow-up, leaving 161 [5d] and 163 [3d] participants for analysis, respectively. Mean time to symptom resolution was 2.91 (SD 1.46; [5d]) days and 2.94 (SD 1.42; [3d]) days (P?=?.894). Clinical success at the end of treatment occurred for 117 of 153 (76%) receiving the 5d-course and for 115 of 157 (73%) receiving the 3d course (difference 3.2% [95% CI -7.1% - 13.5%]; P?=?.601). Bacteriological success was seen in 92 of 104 (88%) participants given the 5d course and in 86 of 99 (87%) given the 3d course (difference 1.6% [95% CI -8.4%-11.6%]; P?=?.895). Interpretations:A 5-day course of pivmecillinam was not superior to a 3-day course in clinical or bacteriological outcomes for UTI. Primary funding source:The Danish Regions [no. 14/217].

Project description:Study questionCan treatment of the symptoms of uncomplicated urinary tract infection (UTI) with ibuprofen reduce the rate of antibiotic prescriptions without a significant increase in symptoms, recurrences, or complications?MethodsWomen aged 18-65 with typical symptoms of UTI and without risk factors or complications were recruited in 42 German general practices and randomly assigned to treatment with a single dose of fosfomycin 3 g (n=246; 243 analysed) or ibuprofen 3 × 400 mg (n=248; 241 analysed) for three days (and the respective placebo dummies in both groups). In both groups additional antibiotic treatment was subsequently prescribed as necessary for persistent, worsening, or recurrent symptoms. The primary endpoints were the number of all courses of antibiotic treatment on days 0-28 (for UTI or other conditions) and burden of symptoms on days 0-7. The symptom score included dysuria, frequency/urgency, and low abdominal pain.Study answer and limitationsThe 248 women in the ibuprofen group received significantly fewer course of antibiotics, had a significantly higher total burden of symptoms, and more had pyelonephritis. Four serious adverse events occurred that lead to hospital referrals; one of these was potentially related to the trial drug. Results have to be interpreted carefully as they might apply to women with mild to moderate symptoms rather than to all those with an uncomplicated UTI.What this paper addsTwo thirds of women with uncomplicated UTI treated symptomatically with ibuprofen recovered without any antibiotics. Initial symptomatic treatment is a possible approach to be discussed with women willing to avoid immediate antibiotics and to accept a somewhat higher burden of symptoms.Funding, competing interests, data sharingGerman Federal Ministry of Education and Research (BMBF) No 01KG1105. Patient level data are available from the corresponding author. Patient consent was not obtained but the data are anonymised and risk of identification is low.Trial registration No ClinicalTrialGov Identifier NCT01488955.

Project description:BACKGROUND:Febrile Urinary Tract Infection (FUTI) is frequently treated initially with intravenous antibiotics, followed by oral antibiotics guided by clinical response and bacterial susceptibility patterns. Due to increasing infection rates with multiresistant Enterobacteriaceae, antibiotic options for stepdown treatment decline and patients more frequently require continued intravenous antibiotic treatment for FUTI. Fosfomycin is an antibiotic with high bactericidal activity against Escherichia coli and current resistance rates are low in most countries. Oral Fosfomycin-Trometamol 3000?mg (FT) reaches appropriate antibiotic concentrations in urine and blood and is considered safe. As such, it is a potential alternative for stepdown treatment. METHODS:The FORECAST study (Fosfomycin Randomized controlled trial for E.coli urinary tract infections as Alternative Stepdown Treatment) is a randomized, double-blind, double-dummy, non-inferiority trial in which 240 patients will be randomly allocated to a stepdown treatment with FT or ciprofloxacin (standard of care) for FUTI, caused by Escherichia coli with in vitro susceptibility to both antibiotics. The study population consists of consenting female patients (?18?years) with community acquired E. coli FUTI. After intravenous antibiotic treatment during at least 48 (but less than 120) hours, and if eligibility criteria for iv-oral switch are met, patients receive either FT (3?g every 24?h) or ciprofloxacin (500?mg every 12?h) for a total antibiotic duration of 10?days. The primary endpoint is clinical cure (resolution of symptoms) 6-10?days post-treatment. Secondary endpoints are microbiological cure 6-10?days post-treatment, clinical cure, mortality, ICU admittance, relapse, reinfection, readmission, additional antibiotic use for UTI, early study discontinuation, adverse events, days of hospitalization and days of absenteeism within 30-35?days post-treatment. The sample size is based on achieving non-inferiority on the primary endpoint, applying a non-inferiority margin of 10%, a two-sided p-value of <?0.05 and a power of 80%. DISCUSSION:The study aims to demonstrate non-inferiority of oral fosfomycin, compared to oral ciprofloxacin, in the stepdown treatment of E. coli FUTI. TRIAL REGISTRATION:Registered at the Nederlands trial register (Dutch trial register) on 4-10-2017. TRIAL REGISTRATION NUMBER:NTR6449 . Secondary ID (national authority): NL60186.041.17.

Project description:BackgroundIn adults with febrile urinary tract infection (fUTI), data on optimal treatment duration in patients other than non-pregnant women without comorbidities are lacking.MethodsA randomized placebo-controlled, double-blind, non-inferiority trial among 35 primary care centers and 7 emergency departments of regional hospitals in the Netherlands. Women and men aged ≥ 18 years with a diagnosis of fUTI were randomly assigned to receive antibiotic treatment for 7 or 14 days (the second week being ciprofloxacin 500 mg or placebo orally twice daily). Patients indicated to receive antimicrobial treatment for at least 14 days were excluded from randomization. The primary endpoint was the clinical cure rate through the 10- to 18-day post-treatment visit with preset subgroup analysis including sex. Secondary endpoints were bacteriologic cure rate at 10-18 days post-treatment and clinical cure at 70-84 days post-treatment.ResultsOf 357 patients included, 200 were eligible for randomization; 97 patients were randomly assigned to 7 days and 103 patients to 14 days of treatment. Overall, short-term clinical cure occurred in 85 (90%) patients treated for 7 days and in 94 (95%) of those treated for 14 days (difference -4.5%; 90% CI, -10.7 to 1.7; P non-inferiority = 0.072, non-inferiority not confirmed). In women, clinical cure was 94% and 93% in those treated for 7 and 14 days, respectively (difference 0.9; 90% CI, -6.9 to 8.7, P non-inferiority = 0.011, non-inferiority confirmed) and, in men, this was 86% versus 98% (difference -11.2; 90% CI -20.6 to -1.8, P superiority = 0.025, inferiority confirmed). The bacteriologic cure rate was 93% versus 97% (difference -4.3%; 90% CI, -9.7 to 1.2, P non-inferiority = 0.041) and the long-term clinical cure rate was 92% versus 91% (difference 1.6%; 90% CI, -5.3 to 8.4; P non-inferiority = 0.005) for 7 days versus 14 days of treatment, respectively. In the subgroups of men and women, long-term clinical cure rates met the criteria for non-inferiority, indicating there was no difference in the need for antibiotic retreatment for UTI during 70-84 days follow-up post-treatment.ConclusionsWomen with fUTI can be treated successfully with antibiotics for 7 days. In men, 7 days of antibiotic treatment for fUTI is inferior to 14 days during short-term follow-up but it is non-inferior when looking at longer follow-up.Trial registrationThe study was registered at ClinicalTrials.gov [ NCT00809913 ; December 16, 2008] and trialregister.nl [ NTR1583 ; December 19, 2008].

Project description:Objective To investigate whether symptomatic treatment with non-steroidal anti-inflammatory drugs (NSAIDs) is non-inferior to antibiotics in the treatment of uncomplicated lower urinary tract infection (UTI) in women, thus offering an opportunity to reduce antibiotic use in ambulatory care.Design Randomised, double blind, non-inferiority trial.Setting 17 general practices in Switzerland.Participants 253 women with uncomplicated lower UTI were randomly assigned 1:1 to symptomatic treatment with the NSAID diclofenac (n=133) or antibiotic treatment with norfloxacin (n=120). The randomisation sequence was computer generated, stratified by practice, blocked, and concealed using sealed, sequentially numbered drug containers.Main outcome measures The primary outcome was resolution of symptoms at day 3 (72 hours after randomisation and 12 hours after intake of the last study drug). The prespecified principal secondary outcome was the use of any antibiotic (including norfloxacin and fosfomycin as trial drugs) up to day 30. Analysis was by intention to treat.Results 72/133 (54%) women assigned to diclofenac and 96/120 (80%) assigned to norfloxacin experienced symptom resolution at day 3 (risk difference 27%, 95% confidence interval 15% to 38%, P=0.98 for non-inferiority, P<0.001 for superiority). The median time until resolution of symptoms was four days in the diclofenac group and two days in the norfloxacin group. A total of 82 (62%) women in the diclofenac group and 118 (98%) in the norfloxacin group used antibiotics up to day 30 (risk difference 37%, 28% to 46%, P<0.001 for superiority). Six women in the diclofenac group (5%) but none in the norfloxacin group received a clinical diagnosis of pyelonephritis (P=0.03).Conclusion Diclofenac is inferior to norfloxacin for symptom relief of UTI and is likely to be associated with an increased risk of pyelonephritis, even though it reduces antibiotic use in women with uncomplicated lower UTI.Trial registration ClinicalTrials.gov NCT01039545.

Dataset Information

Ibuprofen versus pivmecillinam for uncomplicated urinary tract infection in women-A double-blind, randomized non-inferiority trial.

Publications

Ibuprofen versus pivmecillinam for uncomplicated urinary tract infection in women-A double-blind, randomized non-inferiority trial.

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