The prevalence of urinary tract infections (UTIs) caused by extended-spectrum β-lactamase (ESBL)-producing Enterobacteriaceae is increasing and the therapeutic options are limited, especially in primary care. Recent indications have suggested pivmecillinam to be a suitable option. Here, we evaluated the clinical and bacteriological effects of pivmecillinam in UTIs caused by ESBL-producing Enterobacteriaceae. We carried out a prospective follow-up of 39 patients diagnosed with UTI caused by ESBL-producing Enterobacteriaceae, initiated on pivmecillinam. The patients were from general practice (n = 29) or admitted to hospitals (n = 10) in the Copenhagen area, Denmark (n = 30) or Halland, Sweden (n = 9). Both patients and physicians were asked to complete a questionnaire on the pretreatment signs and symptoms. Patients were asked to send in two more urine samples for culture examination, together with questionnaires for clinical effect, 2-6 and 10-20 days, respectively, after end of treatment. Of the 39 patients included, 30 received a treatment regimen of 400 mg of pivmecillinam three times a day and 9 received 200 mg three times a day. All isolates were susceptible to mecillinam. The bacteriological cure rate was 79% (31/39); 80% (24/30) and 78% (7/9) for 400 and 200 mg three times a day, respectively. Relapse, i.e. ESBL-producing bacteria in the second control urine after previous bacteriological cure, was seen in five patients. Clinical cure was evaluable in 19 patients; 16 had a clinical effect (84%). Pivmecillinam was proven bacteriologically and clinically effective for treatment of lower UTIs caused by ESBL-producing Enterobacteriaceae.

Symptoms suggestive of uncomplicated cystitis constitutes one of the most common reasons to seek health care in otherwise healthy women. Previous studies regarding the relationship between sociodemographic factors and uncomplicated cystitis are limited, mainly because of the lack of nationwide population-based data from primary healthcare settings, where most uncomplicated cystitis are diagnosed. A Swedish nation-wide open cohort study consisting of 2 044 065 females who were 15–50 years of age during the study period (1997–2018) was conducted. The outcome was first event uncomplicated cystitis diagnosed in primary health care rather than an assessment of the "true" incidence, which is not feasible in nationwide datasets. Cox regression models were used in the statistical analyses. The study identified 546 076 first events of uncomplicated cystitis (26•7% of the study population), corresponding to an incidence rate per 100 person-years of 2•91 (95% CI 2•90–2•91). In fully adjusted models, rural living was associated with lower risks of uncomplicated cystitis (Hazard ratio, HR, 0•67; 95% CI, 0•66–0•68) compared to urban living, while both Middle Eastern/North African (HR, 1•15; 95% CI, 1•14–1•16) and Latin American/Caribbean (HR, 1•24; 95% CI, 1•22–1•27) women had higher risks compared to Swedish women. Low education and low income were also associated with higher risks compared to high education and high income. This study presents novel risk factors associated with uncomplicated cystitis in women. The findings may help health care workers in the treatment of women with symptoms of uncomplicated cystitis. The Primary Healthcare Management and ALF funding (Region Skåne, Sweden) and the Swedish Research Council.

Mecillinam for the treatment of acute pyelonephritis and bacteremia caused by Enterobacteriaceae: a literature review Filip Jansåker,1,2 Niels Frimodt-Møller,3 Thomas L Benfield,2,4 Jenny Dahl Knudsen1,3 1Department of Clinical Microbiology, Hvidovre Hospital, University of Copenhagen, Hvidovre, Denmark; 2Department of Clinical Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark; 3Department of Clinical Microbiology, Rigshospitalet, University of Copenhagen, Copenhagen, Denmark; 4Department of Infectious Diseases, Hvidovre Hospital, University of Copenhagen, Hvidovre, Denmark Purpose: The pharmacokinetic properties of mecillinam (MEC) for urinary tract infections are excellent, and the resistance rate in Enterobacteriaceae is low compared to other recommended antibiotics. The oral prodrug pivmecillinam (P-MEC) has been used successfully as first choice for cystitis in the Nordic countries for many years. Norwegian and Danish guidelines also recommend P-MEC for acute uncomplicated pyelonephritis (AUP) and intravenous (IV) MEC for suspected urosepsis (only in Denmark). Here, we wish to present an updated investigation on the clinical data behind these recommendations together with sparse but more current clinical data.Methods: Prospective clinical trials evaluating MEC as monotherapy or in polytherapy with one other beta-lactam (mostly ampicillin [AMP]) for pyelonephritis or bacteremia were reviewed. Outcomes of primary interest were clinical and bacteriological success and relapse, respectively. Search databases used were PubMed, Cochrane Library, and Embase.Results: Twelve clinical studies (1979–2015) were included in this integrated literature review. Clinical success was seen in 38/51 (75%) patients treated with MEC as monotherapy and in 152/164 (93%) patients treated with MEC and one other beta-lactam. Bacteriological success was seen in 35/47 (74%) and 117/167 (70%) patients treated with MEC alone and with one other beta-lactam, respectively. In complicated infections, bacteriological success was much lower. Clinical relapse rate was not well described. Several uropathogenic bacteremia cases were treated successfully with MEC alone (ie, 10/15 [67%] and 13/15 [87%] for clinical and bacteriological success, respectively) or with one other beta-lactam (ie, 57/65 [88%] and 53/63 [84%] for clinical and bacteriological success, respectively). However, data on bacteremia are very sparse. Adverse reactions were few and mild (73/406 [18%]) and primarily seen when AMP was co-administered (69/73 [95%]). No serious adverse reactions were reported.Conclusion: IV MEC or oral P-MEC for 14 days may be suitable for the treatment of AUP and pediatric pyelonephritis. Randomized controlled trials using a single standardized dose of P-MEC compared to other current recommendations are warranted. Similarly, more evidence is required before MEC should be recommended for bacteremia or sepsis due to Enterobacteriaceae. Keywords: pyelonephritis, mecillinam, review, pivmecillinam, amdinocillin

Objectives: To compare the therapeutic effect of pivmecillinam and other common oral antibiotics for community-acquired urinary tract infections (UTIs) caused by Extended Spectrum Beta-Lactamase (ESBL)- or non-ESBL-producing Escherichia coli.
Methods: Retrospective cohort study from 2010 to mid-2016 with data from the regional Laboratory Database and three national databases on antibiotic prescriptions, hospital admission, and mortality, respectively. Primary care patients (≥18 years) empirically treated for UTI caused by non-ESBL- or ESBL-producing E. coli (non-ESBL and ESBL E. coli) were included. Seven antibiotics, commonly used empirically for UTI, were investigated. Treatment failure measured as the redemption of a new antibiotic prescription or admission to hospital due to UTI. Cox proportional hazard ratios and adjusted risk differences along with 95% confidence intervals were calculated for 14 and 30 days, respectively. Results: Thirty-six thousand two hundred and ninety-three (95.7%) and 1624 (4.3%) cases were included in the non-ESBL and ESBL groups, respectively. Male sex, high age, ESBL production, and resistance to empirical therapy were found to independently increase the risk of treatment failure. Compared to pivmecillinam, ciprofloxacin had significantly lower treatment failure for non-ESBL E. coli, but significantly higher treatment failure in ESBL E. coli. There was no significant difference between nitrofurantoin and pivmecillinam. Conclusion: All antibiotics seem to have a higher risk of treatment failure for UTI caused by ESBL-producing E. coli as compared to non-ESBL-producing E. coli. At present, nitrofurantoin and pivmecillinam seem to be the most relevant orally available therapies for E. coli UTI. Local resistance data should guide which of the two that should be the contemporary first-line option.

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.

This study aimed to estimate the association between potential risk factors and common vaginal infections using nationwide primary health care and other national registers. An open cohort study consisting of 2,357,711 women aged 15 years to 50 years (2001 to 2018) was conducted in Sweden. The outcomes were first event of vulvovaginal candidiasis (VVC) and bacterial vaginosis (BV) in relation to sociodemographic factors. Cox regression models were used. Sensitivity analyses including diabetes mellitus, contraceptive use, and cervical cancer were conducted. The incidence rates per 1,000 person-years for VVC and BV were 3.3 (95% confidence interval [CI] 3.2-3.3) and 3.4 (95% CI 3.4-3.4), respectively. In the fully adjusted model, sociodemographic factors were significantly associated with both outcomes. Compared with Swedish-born women, women from Middle East/North Africa had the highest risk of VVC (hazard ratio [HR] 2.77, 95% CI, 2.72-2.83), followed by Africa (excluding North Africa) (HR 2.53, 95% CI, 2.45-2.61), and Latin America and the Caribbean (HR 2.18, 95% CI, 2.09-2.27). For BV, women from Latin America and the Caribbean had the highest risk (HR 1.83, 95% CI, 1.75-1.92). This study presents novel risk factors associated with medically attended vaginal infections. Women from non-Western countries seem to develop these conditions disproportionately.