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

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.

Clinical and bacteriological efficacy of pivmecillinam treatment for uncomplicated urinary tract infections caused by ESBL-producing Escherichia coli: a prospective, multicentre, observational cohort study.

Objectives: To compare the clinical and bacteriological outcomes of pivmecillinam treatment for community-acquired urinary tract infections (UTIs) caused by ESBL-producing Escherichia coli versus non-ESBL-producing E. coli in an outpatient setting. Methods: A prospective, multicentre, observational cohort study of women aged ≥16 years, with pivmecillinam-treated community-acquired UTIs caused by E. coli with or without ESBL production, recruited from primary care, was conducted in the period from April 2013 to August 2016. Eighty-eight women (mean age 49.4 years) with community-acquired UTIs caused by ESBL-producing E. coli were compared with a control group of 74 women (mean age 50.1 years). Trial registration: Regional Committees for Medical and Health Research Ethics (REC) in Norway, ID 2011/2214, and ClinicalTrials.gov, ID NCT01531023. Results: The median time until symptom resolution after treatment initiation was 5 days for the ESBL cases and 3 days for the non-ESBL controls (P < 0.01). The proportion of women warranting a second antibiotic prescription in the follow-up period was higher for the ESBL cases [30/88 (34.1%) versus 10/72 (13.9%), P < 0.01]. Persistent bacteriuria was non-significantly more common among ESBL cases than in the control group [15/81 (18.5%) versus 6/67 (9.0%), P = 0.10]. A pivmecillinam dosage of 200 mg given three times daily for ≤5 days was associated with treatment failure (OR 4.77, 95% CI 1.40-19.44, P = 0.03) for the ESBL E. coli group. For the subgroup treated with 400 mg of pivmecillinam given three times daily there was no significantly increased OR for treatment failure between ESBL cases and the control group irrespective of treatment duration. Conclusions: Pivmecillinam given at 400 mg three times daily gave comparable clinical and bacteriological cure rates in women with community-acquired E. coli UTIs irrespective of ESBL production.

Predictors of Symptom Duration and Bacteriuria in Uncomplicated Urinary Tract Infection.

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. Key Points Treatment strategies for milder infectious diseases must consider ways of reducing antibiotic consumption to decelerate the increase in antibiotic resistance. Our findings suggest that more emphasis should be put on urine dipstick results and bacteriological findings in the clinical setting. One might reconsider the current practice of treating uncomplicated UTIs based on symptoms alone.

A randomized controlled trial of a diagnostic algorithm for symptoms of uncomplicated cystitis at an out-of-hours service.

OBJECTIVE: To compare the clinical outcome of patients presenting with symptoms of uncomplicated cystitis who were seen by a doctor, with patients who were given treatment following a diagnostic algorithm. DESIGN: Randomized controlled trial. SETTING: Out-of-hours service, Oslo, Norway. INTERVENTION: Women with typical symptoms of uncomplicated cystitis were included in the trial in the time period September 2010-November 2011. They were randomized into two groups. One group received standard treatment according to the diagnostic algorithm, the other group received treatment after a regular consultation by a doctor. SUBJECTS: Women (n = 441) aged 16-55 years. Mean age in both groups 27 years. MAIN OUTCOME MEASURES: Number of days until symptomatic resolution. RESULTS: No significant differences were found between the groups in the basic patient demographics, severity of symptoms, or percentage of urine samples with single culture growth. A median of three days until symptomatic resolution was found in both groups. By day four 79% in the algorithm group and 72% in the regular consultation group were free of symptoms (p = 0.09). The number of patients who contacted a doctor again in the follow-up period and received alternative antibiotic treatment was insignificantly higher (p = 0.08) after regular consultation than after treatment according to the diagnostic algorithm. There were no cases of severe pyelonephritis or hospital admissions during the follow-up period. CONCLUSION: Using a diagnostic algorithm is a safe and efficient method for treating women with symptoms of uncomplicated cystitis at an out-of-hours service. This simplification of treatment strategy can lead to a more rational use of consultation time and a stricter adherence to National Antibiotic Guidelines for a common disorder.

Ibuprofen versus mecillinam for uncomplicated cystitis--a randomized controlled trial study protocol.

BACKGROUND: 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. METHODS/DESIGN: 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. DISCUSSION: 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. TRIAL REGISTRATION: EudraCTnr: 2012-002776-14. ClinicalTrials.gov: NCT01849926.

Predicting the use of antibiotics after initial symptomatic treatment of an uncomplicated urinary tract infection: analyses performed after a randomised controlled trial.

OBJECTIVE: To predict antibiotic use after initial treatment with ibuprofen using data from a randomised controlled trial comparing ibuprofen to pivmecillinam in the treatment of women with symptoms of an uncomplicated urinary tract infection (UTI). SETTING: 16 sites in a primary care setting in Norway, Sweden and Denmark. PARTICIPANTS: Data from 181 non-pregnant women aged 18-60 presenting with symptoms of uncomplicated UTI, initially treated with ibuprofen. METHODS: Using the least absolute shrinkage and selection operator logistic regression model, we conducted analyses to see if baseline information could help us predict which women could be treated with ibuprofen without risking treatment failure and which women should be recommended antibiotics. RESULTS: Of the 143 women included in the final analysis, 77 (53.8%) recovered without antibiotics and 66 (46.2 %) were subsequently prescribed antibiotics. In the unadjusted binary logistic regression, the number of days with symptoms before inclusion (<3 days) and feeling moderately unwell or worse (≥4 on a scale of 0-6) were significant predictors for subsequent antibiotic use. In the adjusted model, no predictors were significantly associated with subsequent antibiotic use. The area under the curve of the final model was 0.66 (95% CI: 0.57 to 0.74). CONCLUSION: We did not find any baseline information that significantly predicted the use of antibiotic treatment. Identifying women who need antibiotic treatment to manage their uncomplicated UTI is still challenging. Larger data sets are needed to develop models that are more accurate. TRIAL REGISTRATION NUMBER: ClinicalTrials.gov (NCT01849926).

Microbial risk factors for treatment failure of pivmecillinam in community-acquired urinary tract infections caused by ESBL-producing Escherichia coli.

The aim of this study was to identify microbial risk factors for treatment failure of pivmecillinam in community-acquired urinary tract infections (ca-UTIs) caused by ESBL-producing Escherichia coli. Eighty-nine ESBL-producing E. coli isolated from women suffering from ca-UTIs were included. The susceptibilities to mecillinam were determined using MIC gradient strip. Whole genome sequencing was performed on a MiSeq platform, and genome assembly was performed using SPAdes v3.11.0. Neither mecillinam MICs nor ESBL genotypes were associated with treatment outcome of patients treated with pivmecillinam. Specific STs, however, showed significant differences in treatment outcome. Patients infected with ST131 were more likely to experience treatment failure compared to patients infected with non-ST131 (p 0.02) when adjusted for pivmecillinam dose, mecillinam MIC and severity of infection. Patients infected with ST69 were more often successfully treated compared to patients infected with non-ST69 (p 0.04). Patients infected with blaCTX-M-15 ST131 strains were more likely to experience treatment failure than those infected with non-blaCTX-M-15 ST131 strains (p 0.02). The results suggest that specific STs are associated with the clinical efficacy of pivmecillinam. Further studies with a larger number of strains, including a larger number of mecillinam resistant strains, are needed to confirm these results.

Pivmecillinam for Uncomplicated Lower Urinary Tract Infections Caused by Staphylococcus saprophyticus-Cumulative Observational Data from Four Recent Clinical Studies.

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.

Bacteriology in uncomplicated urinary tract infections in Norwegian general practice from 2001-2015.

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.