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

Abstract

BackgroundAlthough 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 findingsThis 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.ConclusionsIbuprofen 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 registrationClinicalTrials.gov NCT01849926EU Clinical Trials Register (EU-CTR), EudraCT Number 2012-002776-14

UTI − quo vadis? New alternatives to treat uncomplicated urinary tract infections

“…In the four larger studies [4,14,16,17] in the nonantibiotic treatment arm 5-7 cases per study experienced pyelonephritis as comparted to 0-1 case treated with antibiotics.…”

“…Wagenlehner presented four comparative studies showing that initial treatment with a non-steroidal antiinflammatory drug (NSAID) can reduce the use of antibiotics in women with uncomplicated UTI (Table 1) [14][15][16][17]. Disregarding the pilot trial with small sample size comparing ibuprofen 400 mg TID for 3 days with ciprofloxacin 250 mg BID for 3 days [15], in the three larger studies ibuprofen 400 mg or 600 mg TID for 3 days compared with fosfomycin trometamol (3 g fosfomycin) single dose or with pivmecillinam 200 mg TID for 3 days, respectively, the NSAID showed inferior results to the results obtained with the antibiotics [14,16]. The same was true comparing diclofenac 75 mg BID with norfloxacin 400 mg BID for 3 days [17].…”

Is Non-Steroidal Anti-Inflammatory Therapy Non-Inferior to Antibiotic Therapy in Uncomplicated Urinary Tract Infections: a Systematic Review

“…Four studies 22,23,28,29 included adult women over the age of 18 while one study 30 included women over the age of 15. Upper age limits ranged from 50 to 70 years, with one study 22 having no upper age limit ( Table 1).…”

“…One study 28 included individuals with self-diagnosed symptomatic cystitis if they had urine dipstick results positive for nitrites, leukocyte esterase, or both. Four studies 22,23,28,29 excluded patients with upper UTI signs (i.e., fever and back pain), pregnancy, diabetes, prior urological interventions, immunosuppressive states, urinary catheterization, recent UTI, current antibiotic or NSAID use, or contraindications to study drugs. Four studies 22,23,28,29 included baseline urine culture results at the time of inclusion, though culture results were not used as eligibility criteria ( Table 1).…”

“…One study 30 used potassium citrate in addition to NSAID therapy in the treatment arm. The NSAID was ibuprofen in three trials, 22,23,29 flurbiprofen in one trial, 30 and diclofenac in one trial. 28 Antibiotic therapy also varied across studies with two studies 22,30 using ciprofloxacin, one study 23 using fosfomycin-trometamol, one study 28 using norfloxacin, and one study 29 using pivmecillinam.…”