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%. 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. 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. ClinicalTrials.gov NCT01849926 EU Clinical Trials Register (EU-CTR), EudraCT Number 2012-002776-14

Background: The risk of pyelonephritis following uncomplicated lower urinary tract infection (cystitis) in women has not been studied in well-powered samples. This is likely due to the previous lack of nationwide primary healthcare data. We aimed to examine the risks of pyelonephritis following cystitis in women and explore if antibiotic treatment, cervical cancer, parity, and sociodemographic factors are related to these risks. Methods: This was a nationwide cohort study (2006–2018) of 752,289 women diagnosed with uncomplicated cystitis in primary healthcare settings. Of these, 404 696 did not redeem an antibiotic prescription within five days from cystitis. Logistic regression models were used to calculate odds ratios for pyelonephritis within 30 days and 90 days following the cystitis event. Results: Around one percent (7454) of all women with cystitis were diagnosed with pyelonephritis within 30 days, of which 78.2% had not redeemed an antibiotic for their cystitis. Antibiotic treatment was inversely associated with both outpatient registration and hospitalization due to pyelonephritis, with odds ratios of 0.85 (95% CI 0.80 to 0.91) and 0.65 (95% CI 0.55 to 0.77), respectively. Sociodemographic factors, parity, and cervical cancer were, with few exceptions (e.g., age and region of residency), not associated with pyelonephritis. Conclusions: Antibiotic treatment was inversely associated with pyelonephritis, but the absolute risk reduction was low. Non-antibiotic treatment for cystitis might be a safe option for most women. Future studies identifying the women at the highest risks will help clinicians in their decision making when treating cystitis, while keeping the ecological costs of antibiotics in mind.

Although uncomplicated cystitis is often self-limiting, most such patients will be prescribed antibiotic treatment. We are investigating whether treatment of cystitis with an NSAID is as effective as an antibiotic in achieving symptomatic resolution. This is a randomized, controlled, double blind trial following the principles of Good Clinical Practice. Women between the ages of 18 to 60 presenting with symptoms of uncomplicated cystitis are screened for eligibility. 500 women from four sites in Norway, Sweden and Denmark are allocated to treatment with 600 mg ibuprofen three times a day or 200 mg mecillinam three times a day for three days. Allocation is conducted using block randomization. The primary outcome is the number of patients who feel cured by day four as recorded in a diary. Adverse events will be handled and reported in accordance with Good Clinical Practice. If treatment of uncomplicated cystitis with ibuprofen is as effective as mecillinam for symptom relief, we can potentially reduce the use of antibiotics on a global scale. EudraCTnr: 2012-002776-14. ClinicalTrials.gov: NCT01849926 .

Background: Uncomplicated urinary tract infections in women are common, and urine samples from these patients are not routinely cultured. Empirical treatment is based on knowledge of resistance patterns for common uropathogens.Aim: To evaluate the bacteriological findings and resistance patterns in urine samples from women with uncomplicated urinary tract infections, and to assess the relationship between antimicrobial use and resistance patterns from 2000–2015 in Norway.Method: Bacteriology and resistance patterns were compared in 184 urine cultures from 2001, 406 urine cultures from 2010–2011 and 259 urine cultures from 2013–2015. Antibiotic use data from 2000–2015 were obtained from national databases.Results: Escherichia coli (E. coli) was the main bacterial agent in 80% of the cultures. Staphylococcus saprophyticus (Staph. saprophyticus) represented 6–17%. For E. coli, resistance to mecillinam showed some variation but remained below 9%. There was negligible resistance to nitrofurantoin. Resistance to trimethoprim seemed to stabilise over the last 5 years at around 20%. Amoxicillin resistance had some variations, but remained stable around 30%. There was a steady rise in total consumption of selected antibiotics commonly used to treat urinary tract infections for the period 2000–2015.Conclusion: Mecillinam and nitrofurantoin are both excellent first choices for empirical treatment of uncomplicated urinary tract infections. This study suggests that increasing resistance to trimethoprim challenges the rationale for its use as a first-line agent.

Objective: To identify baseline predictors of symptom duration after empirical treatment for uncomplicated urinary tract infection (UTI) and significant bacteriuria in a cohort of women treated for UTI. Design: Prospective single-centre cohort study. Setting: Outpatient clinic in Norway. Patients: From September 2010 to November 2011, 441 women aged 16–55 years with symptoms of uncomplicated UTI were included. Results: Dipstick findings of leukocyte esterase 1 + (incidence rate ratio (IRR) 1.93, 95% confidence interval (CI) 1.23–3.01, p < 0.01) and microbe resistant to mecillinam treatment (IRR 1.41, 95% CI 1.07–1.89, p = 0.02) predicted longer symptom duration. More pronounced symptoms did not predict longer symptom duration (IRR 1.18, 95% CI 0.94–1.46, p = 0.15) or significant bacteriuria (odds ratio [OR] 1.16, 95% CI 0.72–1.88, p = 0.54). Leukocyte esterase 2 + (OR 2.51, 95% CI 0.92–6.83, p = 0.07) or 3 + (OR 2.40, 95% CI 0.88–6.05, p = 0.09) and nitrite positive urine dipstick test (OR 3.22, 95% CI 1.58–7.01, p = <0.01) were associated with bacteriuria. Conclusion: More pronounced symptoms did not correlate with significant bacteriuria or symptom duration after empirical treatment for acute cystitis. One might reconsider the current practice of treating uncomplicated UTI based on symptoms alone.

Objectives: To investigate pivmecillinam´s efficacy in uncomplicated lower urinary tract infection (UTI) caused by Staphylococcus saprophyticus—considered non-susceptible to mecillinam. Methods: Participants with confirmed UTIs caused by S. saprophyticus from four randomized controlled trials, where pivmecillinam was empirically given to females with symptoms of UTIs. The primary outcome was defined as a cumulative clinical effect—symptom resolution during the first eight days of therapy, without a recurrence of UTI symptoms in the long-term follow-up (approximately four weeks). Secondary outcomes included the bacteriological effect—elimination of the causative agent, with or without new uropathogenic bacteria present in the first control urine sample. Significant bacteriuria was defined as ≥10³ bacteria/mL. The antibiotic susceptibility testing was done by disc diffusion methodology, according to the European Committee on Antimicrobial Susceptibility Testing (EUCAST). Results: Seventy-four females (18–55 years) were empirically treated with pivmecillinam for UTIs caused by S. saphrophyticus (mean age 25 years; standard deviation (SD) 5.8). The cumulative clinical effect was 53/74 (72%), and the bacteriological effect was 51/59 (86%). Conclusion: Pivmecillinam showed a high clinical and bacteriological effect in UTIs caused by S. saprophyticus in these four clinical trials. The characterization of non-susceptibility for mecillinam regarding the treatment of UTIs caused by this common pathogen may need to be revised.