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.

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.

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.

Acute cystitis in men- a nationwide study from primary care: antibiotic prescriptions, risk factors, and complications.

BACKGROUND: Research on acute cystitis in men is scarce and treatment guidelines differ between countries. Improved antibiotic stewardship is needed. AIM: To analyse antibiotic prescriptions and outcomes of Norwegian men diagnosed with cystitis in primary care. DESIGN & SETTING: A nationwide retrospective study was undertaken in primary care in Norway. METHOD: We identified all episodes of acute cystitis in men diagnosed in Norwegian primary care during 2012-2019. Choice of antibiotic (from the Norwegian Prescription Database), treatment failure, re-prescription, and complications were stratified by age, calendar year, and risk factors. We used logistic regression to explore predefined risk factors (diabetes, prostate cancer, benign prostate hyperplasia [BPH], urinary retention, and any cancer) with complications (pyelonephritis, prostatitis, and hospitalisation) and re-prescriptions. Linear regression was used to explore time trends. RESULTS: In total, 108 994 individuals contributed 148 635 episodes. Narrow-spectrum antibiotics were first-choice treatment in 71.0% of the episodes (52.5% of all prescriptions were pivmecillinam). More than 75% of the episodes with narrow-spectrum versus 82.2% of broad-spectrum treatment did not lead to any re-prescription or complication. Complications occurred in 1.8% of all episodes (0.5% prostatitis, 0.7% pyelonephritis, and 0.7% hospitalisation). BPH was associated with increased risk of complications and re-prescription. Diabetes was associated with a lower risk of re-prescriptions. Prostate cancer and urinary retention were associated with a lower risk of both complications and re-prescriptions. CONCLUSION: Our results support narrow-spectrum antibiotics as first-line treatment. Risk factor analyses warrants further investigation.

The Risk of Pyelonephritis Following Uncomplicated Cystitis: A Nationwide Primary Healthcare Study.

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.

Reducing antibiotic use in uncomplicated urinary tract infections in adult women: a systematic review and individual participant data meta-analysis.

BACKGROUND: Randomised controlled trials (RCTs) investigated analgesics, herbal formulations, delayed prescription of antibiotics, and placebo to prevent overprescription of antibiotics in women with uncomplicated urinary tract infections (uUTI). OBJECTIVES: To estimate the effect of these strategies and to identify symptoms, signs, or other factors that indicate a benefit from these strategies. DATA SOURCES: MEDLINE, EMBASE, Web of Science, LILACS, Cochrane Database of Systematic Reviews and of Controlled Trials, and ClinicalTrials. STUDY ELIGIBILITY CRITERIA, PARTICIPANTS AND INTERVENTIONS: RCTs investigating any strategies to reduce antibiotics vs. immediate antibiotics in adult women with uUTI in primary care. METHODS: We extracted individual participant data (IPD) if available, otherwise aggregate data (AD). Bayesian random-effects meta-analysis of the AD was used for pairwise comparisons. Candidate moderators and prognostic indicators of treatment effects were investigated using generalised linear mixed models based on IPD. RESULTS: We analysed IPD of 3524 patients from eight RCTs and AD of 78 patients. Non-antibiotic strategies increased the rates of incomplete recovery (OR 3.0; 95% credible interval (CrI), 1.7-5.5; Bayesian p-value (pB) = 0.0017; τ = 0.6), subsequent antibiotic treatment (OR 3.5; 95% CrI, 2.1-5.8; pB = 0.0003) and pyelonephritis (OR 5.6; 95% CrI, 2.3-13.9; pB = 0.0003). Conversely, they decreased overall antibiotic use by 63%. Patients positive for urinary erythrocytes and urine culture were at increased risk for incomplete recovery (OR 4.7; 95% CrI, 2.1-10.8; pB = 0.0010), but no difference was apparent where both were negative (OR 0.8; 95% CrI, 0.3-2.0; pB = 0.667). In patients treated using non-antibiotic strategies, urinary erythrocytes and positive urine culture were independent prognostic indicators for subsequent antibiotic treatment and pyelonephritis. CONCLUSIONS: Compared to immediate antibiotics, non-antibiotic strategies reduce overall antibiotic use but result in poorer clinical outcomes. The presence of erythrocytes and tests to confirm bacteria in urine could be used to target antibiotic prescribing.

Treatment of uncomplicated UTI in males: a systematic review of the literature.

BACKGROUND: Urinary tract infections (UTIs) affect around 20% of the male population in their lifetime. The incidence of UTIs in men in the community is 0.9-2.4 cases per 1000 aged <55 years and 7.7 per 1000 aged ≥85 years. AIM: To evaluate the outcomes of randomised controlled trials (RCTs) comparing the effectiveness of different antimicrobial treatments and durations for uncomplicated UTIs in adult males in outpatient settings. METHOD: A systematic literature review of RCTs of adult male patients with an uncomplicated UTI treated with oral antimicrobials in any outpatient setting. The outcomes were symptom resolution within 2 weeks of starting treatment, duration until symptom resolution, clinical cure, bacteriological cure, and frequency of adverse events. RESULTS: From the 1052 abstracts screened, three provided sufficient information on outcomes. One study compared trimethoprim-sulfamethoxazole for 14 days (21 males) with 42 days (21 males). Fluoroquinolones were compared in the two other RCTs: lomefloxacin (10 males) with norfloxacin (11 males), and ciprofloxacin for 7 days (19 males) and 14 days (19 males). Combining the results from the three RCTs shows that for 75% males with a UTI (76/101) bacteriological cure was reported at the end of the study. Of the 59 patients receiving a fluoroquinolone, 57 (97%) reported bacteriological and clinical cure within 2 weeks after treatment. CONCLUSION: The evidence available is insufficient to make any recommendations in relation to type and duration of antimicrobial treatment for male UTIs. Sufficiently powered RCTs are needed to identify best treatment type and duration for male UTIs in primary care.

Antibiotic switch after treatment with UTI antibiotics in male patients.

Background: There is a lack of evidence on treatment of urinary tract infections (UTIs) in male patients in a primary care setting, and whether narrow-spectrum antibiotics are safe and effective.Objectives: To explore antibiotic switch rates after treatment with UTI antibiotics in men over the last 11 years.Material: We analysed data from the Norwegian Prescription Database (NorPD). Men ≥16 years receiving cefalexin, ciprofloxacin, cotrimoxazole, nitrofurantoin, ofloxacin, pivmecillinam or trimethoprim during the period 2008-2018 were included. Antibiotic switch was defined as being prescribed a different antibiotic drug appropriate for UTI within 14 days after initial treatment. We calculated rates of antibiotic switch and corresponding odds ratios for each antibiotic drug.Results: Seven hundred twenty-six thousand and ninety-six (726,096) prescriptions to 429,807 men were defined as possible UTI episodes. Fluoroquinolones, pivmecillinam and cotrimoxazole were most frequently prescribed. Forty-nine thousand five hundred and thirty-one (49,531) (6.8%) of the treatments resulted in antibiotic switch. Compared to cotrimoxazole, the risk of antibiotic switch was higher for pivmecillinam (OR: 2.46; 95% CI, 2.39-2.53) and trimethoprim (OR: 2.12; 95% CI, 2.04-2.20), and lower for fluoroquinolones (OR: 0.40; 95% CI, 0.39-0.42) and cefalexin (OR: 0.28; 95% CI, 0.26-0.30). Treatment duration of ≥7 days and age of ≥50 years were associated with an increased risk of antibiotic switch.Conclusion: Fluoroquinolones and cefalexin were associated with lower antibiotic switch rates than the recommended UTI antibiotics (pivmecillinam, nitrofurantoin and trimethoprim). However, the rates of antibiotic switch following treatment of male patients with first-line empirical UTI antibiotics are relatively low, indicating that the current guidelines are safe.

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).

Strategies to reduce antibiotic use in women with uncomplicated urinary tract infection in primary care: protocol of a systematic review and meta-analysis including individual patient data.

INTRODUCTION: Uncomplicated urinary tract infection (UTI) in women is a common reason to present in general practice and is usually treated with antibiotics to reduce symptom severity and duration. Results of recent clinical trials indicate that non-antibiotic treatment approaches can also be effective. However, it remains unclear which patients would benefit from antibiotic treatment and which can effectively and safely be treated without antibiotics. This systematic review and meta-analysis aims to estimate the effect of treatment strategies to reduce antibiotic use in comparison with immediate antibiotic treatment and to identify prognostic factors and moderators of treatment effects. A further aim is to identify subgroups of patients benefiting from a specific therapy. METHODS AND ANALYSIS: A systematic literature search will be performed to identify randomised controlled trials which investigated the effect of treatment strategies to reduce antibiotic use in female adults with uncomplicated UTI compared with immediate antibiotic treatment. Therefore, the primary outcome of the meta-analysis is incomplete recovery. Anonymised individual patient data (IPD) will be collected. Aggregate data will be used for pairwise comparisons of treatment strategies using meta-analysis models with random effects accounting for potential between-study heterogeneity. Potential effect moderators will be explored in meta-regressions. For IPD, generalised linear mixed models will be used, which may be adjusted for baseline characteristics. Interactions of baseline variables with treatment effects will be explored. These models will be used to assess direct comparisons of treatment, but might be extended to networks. ETHICS AND DISSEMINATION: The local institutional review and ethics board judged the project a secondary analysis of existing anonymous data which meet the criteria for waiver of ethics review. Dissemination of the results will be via published scientific papers and presentations. Key messages will be promoted for example, via social media or press releases. PROSPERO REGISTRATION NUMBER: CRD42019125804.

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.