Treatment, outcomes and characterization of pathogens in urinary tract infections caused by ESBL-producing Enterobacterales: a prospective multicentre study.

OBJECTIVES: Treatment options for urinary tract infections (UTIs) caused by ESBL-producing Enterobacterales are limited. Moreover, evidence to support therapeutic decisions is lacking. This study assessed current treatment strategies and patient and pathogen characteristics in relation to clinical and microbiological outcomes. METHODS: Patients with UTI caused by ESBL-producing Enterobacterales were prospectively recruited by investigators at 15 infectious disease hospital departments. Data were collected on patient characteristics, treatments, clinical and microbiological cure 10-14 days after the end of treatment, and relapse within 3 months. Bacterial isolates were subjected to MIC determination and WGS. RESULTS: In total, 235 patients (107 febrile UTI, 128 lower UTI) caused by Escherichia coli (n = 223) and Klebsiella spp. (n = 12) were included. Clinical and microbiological cure rates were 83% and 64% in febrile UTI, and 79% and 65% in lower UTI. Great variability in treatments was observed, especially in oral therapy for febrile UTI. No difference was seen in clinical outcomes with piperacillin/tazobactam (n = 28) compared with carbapenems (n = 41). Pivmecillinam was frequently used in lower UTI (n = 62), and was also associated with high clinical cure rates when used as initial therapy (10/10) or follow-up (7/8) for febrile UTI. Recurrent infection, diabetes mellitus and urogenital disease were associated (P < 0.05) with clinical failure and relapse. In E. coli, ST131 was significantly associated with relapse, and haemolysin with microbiological failure or relapse. CONCLUSIONS: Antibiotic treatments were highly variable. Patient and pathogen factors were identified as potential determinants of disease presentation and outcomes and may prove useful to guide individualized treatment and follow-up.

Antibiotic use during pregnancy in Sweden: A nationwide utilization study covering 2007-2019.

INTRODUCTION: Antibiotics are often prescribed during pregnancy. Assessing the current state of prenatal antibiotic use is therefore imperative for optimizing prescribing and identifying emerging research priorities. The study aimed to describe recent trends and patterns in antibiotic use during pregnancy among women who gave birth in Sweden, including user characteristics. MATERIAL AND METHODS: Population-based descriptive study using linked nationwide registers. All pregnancies delivered in Sweden from 2007 to 2019 were included. Prevalence of use was defined as the percentage of pregnancies during which at least one prescription forantibiotics was filled. Temporal trends in the prevalence of antibiotic use by calendar year, trimester and weeks of gestation were assessed from time series graphs. RESULTS: Prescriptions for systemic antibiotics were filled in 20.7% of 1 434 431 pregnancies overall, decreasing from 24.7% in 2007 to 18.0% in 2019. Phenoxymethylpenicillin (8.5%), pivmecillinam (6.5%), nitrofurantoin (4.7%), amoxicillin (1.6%) and cefadroxil (1.5%) use were the most prevalent. Their use decreased over the 13-year period, except for pivmecillinam, which increased from 4.0% to 7.4%. Prevalence of use was highest in the second trimester (9.5%), with weekly trends peaking at 13 and 34 weeks of gestation. Compared with non-users, antibiotic users more often belonged to the youngest and oldest age strata, carried multipleton pregnancies, had delivered before, had attained a lower education level and smoked in early pregnancy. A higher body mass index, asthma, chronic renal disease and diabetes mellitus were more prevalent among antibiotic users than among non-users. CONCLUSIONS: Although outpatient antibiotic use during pregnancy in Sweden has been declining, one in five pregnancies was exposed to systemic antibiotics.

Pivmecillinam with Amoxicillin/Clavulanic acid as step down oral therapy in febrile Urinary Tract Infections caused by ESBL-producing Enterobacterales (PACUTI).

BACKGROUND: Oral treatment alternatives for febrile urinary tract infections are limited in the era of increasing antimicrobial resistance. We aim to evaluate if the combination of pivmecillinam and amoxicillin/clavulanic acid is non-inferior to current alternatives for step-down therapy in adult patients with febrile urinary tract infection. METHODS: We plan to perform an investigator-initiated non-inferiority trial. Adult hospitalised patients treated with 1-5 days of intravenous antibiotics for acute febrile urinary tract infection caused by extended spectrum beta-lactamase (ESBL) producing Enterobacterales will be randomised 1:1 to either control (7-10 days of either oral ciprofloxacin 500 mg twice daily or oral trimethoprim-sulfamethoxazole 800 mg/160 mg twice daily or intravenous ertapenem 1 g once daily, depending on sex, drug allergy, glomerular filtration rate and susceptibility testing) or intervention (10 days of pivmecillinam 400 mg three times daily and amoxicillin/clavulanic acid 500/125 mg three times daily). The primary outcome will be clinical cure 10 days (+/- 2 days) after antibiotic treatment completion. Clinical cure is defined as being alive with absence of fever and return to non-infected baseline of urinary tract symptoms without additional antibiotic treatment or re-hospitalisation (for urinary tract infection) based on a centralised allocation-blinded structured telephone interview. We plan to recruit 330 patients to achieve 90% power based on a sample size simulation analysis using a two-group comparison, one-sided alpha of 2.5%, an absolute non-inferiority margin of 10% and expecting 93% clinical cure rate and 10% loss to follow-up. The primary endpoint will be analysed using generalised estimated equations and reported as risk difference for both intention-to-treat and per protocol populations. Patients are planned to be recruited from at least 10 centres in Sweden from 2023 to 2026. DISCUSSION: If the combination of pivmecillinam and amoxicillin/clavulanic acid is found to be non-inferior to the control drugs there are potential benefits in terms of tolerability, frequency of interactions, outpatient treatment, side effects, nosocomial infections and drive for further antimicrobial resistance compared to existing drugs. TRIAL REGISTRATION: NCT05224401. Registered on February 4, 2022.

Antimicrobial resistance of clinical Enterobacterales isolates from urine samples, Germany, 2016 to 2021.

IntroductionEmpirical therapy for the treatment of urinary tract infections should be tailored to the current distribution and susceptibility of potential pathogens to ensure optimal treatment.AimWe aimed to provide an up-to-date overview of the epidemiology and susceptibility of Enterobacterales isolated from urine in Germany.MethodsWe retrospectively analysed antimicrobial susceptibility data from 201,152 urine specimens collected between January 2016 and June 2021 from in- and outpatients. Multiple logistic regression analysis was used to evaluate the association between year of investigation and antibiotic resistance, adjusted for age, sex and species subgroup. Subgroup analyses were performed for midstream urine samples obtained from (i) female outpatients aged 15 to 50 years, (ii) female outpatients older than 50 years and (iii) male outpatients.ResultsResistance rates of less than 20% were observed for nitroxoline (3.9%), fosfomycin (4.6%), nitrofurantoin (11.7%), cefuroxime (13.5%) and ciprofloxacin (14.2%). Resistance to trimethoprim/sulfamethoxazole (SXT) (20.1%), amoxicillin-clavulanic acid (20.5%), trimethoprim (24.2%), pivmecillinam (29.9%) and ampicillin (53.7%) was considerably higher. In the subgroup of outpatient women aged 15-50 years, resistance rates were generally lower. Resistance rates of all antibiotics decreased from 2016 to 2021. Multiple logistic regression revealed the lowest adjusted odds ratio (ORadj) of 0.838 (95% confidence interval (CI): 0.819-0.858; p < 0.001) for pivmecillinam and the highest ORadj of 0.989 (95% CI: 0.972-1.007; p = 0.226) for nitrofurantoin.ConclusionsResistance has generally decreased over the past years, independent of sex, age and causative pathogen. Our data provide an important basis for empirical antibiotic recommendations in various settings and patient collectives.

Antibiotics in the Treatment of Uncomplicated Cystitis: A Google Trends Analysis.

INTRODUCTION: Using Google Trends (GT) data, the trend variations for the most common antibiotics used to treat uncomplicated cystitis were analyzed by time and region since 2004. METHODS: GT was used to create a "line-graph" that shows how interest in a topic in certain locations has grown or decreased over time. The relative search volume, which is displayed on a scale of 0-100, was used to index the search values for specific phrases. Nitrofurantoin (NFN), fosfomycin (FOS), trimethoprim (TMP), pivmecillinam (PIV), and cefadroxil are among the antibiotics recommended by the European Association of Urology (EAU) and the American Urological Association for the treatment of uncomplicated cystitis. Using the "global" inquiry category, the data was searched "worldwide" from 1 February 2004 to 31 December 2021. RESULTS: In the regression analysis, all antibiotics exhibited positive trends (p < 0.05). With a steady rise in popularity, NFN is the most popular antibiotic today. Search trend for cefadroxil stayed nearly stable until 2012, the rate of rise in the last 10 years increased, and cefadroxil is the second most popular antibiotic. In the previous 5 years, there was a decline in interest in TMP. In recent years, there was an increase in the trends for FOS and PIV. CONCLUSION: Clinicians and patients all around the world increasingly use the web to search for antibiotic therapies for uncomplicated cystitis. Antibiotics used to treat uncomplicated cystitis have various trends in different continents throughout the world. The web trends seem to be compatible with daily use.

Pivmecillinam, the paradigm of an antibiotic with low resistance rates in Escherichia coli urine isolates despite high consumption.

OBJECTIVES: Pivmecillinam, the oral version of mecillinam, represents one of the major recommended and used antibiotics for empiric and targeted treatment of urinary tract infections in primary care in Denmark, Norway and Sweden. Mecillinam resistant mutants in Escherichia coli develop easily in vitro, but their fitness cost has been shown to be high. METHODS: We revisited the resistance and consumption data from the monitoring programmes in the three countries and compared pivmecillinam with ciprofloxacin from 2010 to 2020. RESULTS: Mecillinam resistance rates in Escherichia coli remained around 6% in Denmark and Norway relative to a constant consumption in Norway of 1.6-1.8 DID (defined daily doses per 1000 inhabitants per day), and even increasing in Denmark from 1.6 to 2.3 DID. In Sweden resistance was significantly lower at 4% related to the lower consumption of 0.5 DID. For ciprofloxacin, resistance rates fluctuated around 6%-12%, highest in Sweden with the highest consumption (0.8-0.6 DID) and lowest in Denmark (0.55-0.35 DID) and Norway (0.7-0.3 DID), although consumption declined significantly in all three countries. CONCLUSIONS: Pivmecillinam is an example of an antibiotic, which easily develops resistance in vitro, but apparently can be used broadly in primary care without increase in resistance rates.

The efficacy of pivmecillinam in oral step-down treatment in hospitalised patients with E. coli bacteremic urinary tract infection; a single-arm, uncontrolled treatment study.

BACKGROUND: The role of oral beta-lactam antibiotics in treating febrile urinary tract infections (UTI) is not yet definite. Today, fluoroquinolones together with trimethoprim-sulfamethoxazole (TMP-MTX) are considered standard of care and often the only available evidence-based oral treatment for febrile UTI. This study clarifies the efficacy and safety of pivmecillinam (PIV) used as step-down therapy for bacteremic urinary tract infection (UTI). METHODS: A single-arm, uncontrolled treatment trial was conducted in the period September 2017-March 2020. Candidates for inclusion were men and women suffering from E. coli bacteremia due to UTI and were consecutively included in a Norwegian hospital. Exclusion criteria were among others: other ongoing bacterial infection, septic shock, pyonephrosis/abscess and pregnancy. After 3 days of parenteral antibiotic, the treatment was converted to the study drug; oral PIV 400 mg QID for 1 week. Primary endpoint was a combination of three elements; afebrility, no need for retreatment and improvement in self-reported health status. Test Of Cure (TOC) was 1 week post-treatment. Secondary endpoints included among others microbiological efficacy and CRP value < 30 mg/L. RESULTS: Of 476 screened subjects, 53 patients were included. Median age was 67 years, 28 (56%) were women. 50 patients were evaluated for per-protocol analysis. 44 of 50 patients (88%) (95% CI [75.7-95.5]) reached the primary endpoint on TOC. 14 of 48 patients (29.2%) had significant growth (> 103 CFU/mL) of E.coli on TOC. CRP-level was strongly associated to treatment outcome, (OR 0.006 [95% CI 0.00-0.11], p < 0.001). CONCLUSIONS: This trial documents that PIV 400 mg QID given for 1 week following 3 days of parenteral antibiotics, is a suitable treatment option in patients suffering from bacteremic UTI due to E. coli. Randomised clinical trials studying the efficacy of PIV vs standard of care of febrile UTI are warranted. Trial registration The trial was registered at ClinicalTrials.gov under the identifier: NCT03282006 13/09/2017 and approved by The Regional Committees for Medical Research Ethics South East Norway (2015/2384/REK sør-øst) and the Norwegian Medicines Agency (SLV; reference No 16/06018-09; EudraCT No 2016-000984-18) before initiation.

LC-MS/MS methods for determination of unstable pivmecillinam and mecillinam in acidified human plasma: Application to a pharmacokinetic study.

Pivmecillinam, the ester of biologically active antibiotic mecillinam, is an effective oral preparation to treat urinary tract infections. To study pharmacokinetics in humans, LC-MS/MS methods were developed to quantify pivmecillinam and mecillinam in human plasma, respectively. Considering cephalexin as internal standard, analytes were separated on UltimateXB-C18 columns after protein precipitation by acetonitrile. The mobile phase was composed of water containing 0.1% formic acid and methanol. The multiple reactions monitoring transitions of m/z 440.2→167.1, 326.1→167.1, and 348.1→158.1 were selected to inspect pivmecillinam, mecillinam, and the internal standard in positive ion mode. No apparent matrix effect was perceived. Linearities were obtained over calibration ranges of 0.0500-12.0 and 10.0-15,000 ng/mL, respectively. The intraday precisions were below 5.5%, the interday precisions were below 6.1%, and accuracies were within -8.1 to 13.0%. Stability tests were conducted and an acidification step was explored to enhance the stability of pivmecillinam and mecillinam. Further stability was validated under various storage and processing conditions. Both methods were applied to a pharmacokinetic study of pivmecillinam and mecillinam after oral administration of 400 mg pivmecillinam hydrochloride tablets in healthy Chinese subjects.

Prenatal exposure to nitrofurantoin and risk of childhood leukaemia: a registry-based cohort study in four Nordic countries.

BACKGROUND: Studies have suggested increased risks of childhood leukaemia after prenatal exposure to antibiotics, particularly nitrofurantoin. However, these findings may be related to the underlying maternal infection. This multinational study aimed to investigate the association between prenatal nitrofurantoin exposure and childhood leukaemia while accounting for maternal infection. METHODS: In a population-based cohort study of children born in Denmark, Finland, Norway or Sweden from 1997 to 2013, prenatal exposure to nitrofurantoin or pivmecillinam (active comparator) was ascertained from national Prescription Registries. Childhood leukaemia was identified by linkage to national Cancer Registries. Poisson regression was used to estimate incidence rate ratios (IRRs) and incidence rate differences (IRDs) with inverse probability of treatment weights applied to account for confounding. RESULTS: We included 44 091 children prenatally exposed to nitrofurantoin and 247 306 children prenatally exposed to pivmecillinam. The children were followed for 9.3 years on average (standard deviation 4.1). There were 161 cases of childhood leukaemia. The weighted IRR for prenatal nitrofurantoin exposure when compared with pivmecillinam was 1.34 (95% confidence interval 0.88, 2.06), corresponding to an IRD of 15 per million person-years. Higher point estimates were seen for first- and third-trimester exposure. There was no evidence of a dose-response relationship. CONCLUSIONS: Prenatal exposure to nitrofurantoin was not substantially associated with childhood leukaemia, although a slightly elevated IRR with confidence intervals including the null was observed, corresponding to a small absolute risk. The lack of a dose-response relationship and a clear biological mechanism to explain the findings suggests against a causal association.

Different antibiotic regimes in men diagnosed with lower urinary tract infection - a retrospective register-based study.

OBJECTIVE: To compare the proportion of therapy failure, recurrence and complications within 30 days after consultation between men diagnosed with lower urinary tract infection (UTI) treated with narrow-spectrum antibiotics (nitrofurantoin or pivmecillinam) and broad-spectrum antibiotics (fluoroquinolones or trimethoprim or trimethoprim/sulfamethoxazole). DESIGN: A retrospective cohort study based on data derived from electronic medical records between January 2012 and December 2015. SETTING: Primary health care and hospital care in five different counties in Sweden. Patients: A total of 16,555 men aged between 18 and 79 years diagnosed with lower UTI. MAIN OUTCOME MEASURES: Treatment with narrow-spectrum antibiotics was compared with broad-spectrum antibiotics regarding therapy failure, recurrence and complications within 30 days. RESULTS: The median age of included men was 65 IQR (51-72) years. Narrow-spectrum antibiotics were prescribed in 8457 (40%) and broad-spectrum antibiotics in 12,667 (60%) cases, respectively. Therapy failure was registered in 192 (0.9%), recurrence in 1277 (6%) and complications in 121 (0.6%) cases. Therapy failure and recurrence were more common in patients treated with narrow-spectrum antibiotics and trimethoprim (p < 0.001), but no such difference could be detected regarding complications. CONCLUSION: There was no difference in incidence of complications within 30 days between men treated with narrow- or broad-spectrum antibiotics. Patients prescribed broad-spectrum antibiotics had lower odds of reconsultation because of therapy failure and recurrence. From current data, treatment with narrow-spectrum antibiotics seems to be an optimal choice regarding preventing complications when treating men with lower UTI. KEY POINTS Complications such as pyelonephritis and sepsis are uncommon in men diagnosed with lower urinary tract infection treated with antibiotics. There was no difference in incidence of complications among men diagnosed with lower urinary tract infection treated with narrow- or broad-spectrum antibiotics. In spite of higher incidence of therapy failure and recurrence, treatment with narrow-spectrum antibiotics seems to be an optimal choice regarding preventing complications when treating men diagnosed with lower UTI.

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.

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.

Mutational change of CTX-M-15 to CTX-M-127 resulting in mecillinam resistant Escherichia coli during pivmecillinam treatment of a patient.

Pivmecillinam (amdinocillin pivoxil) is the recommended first-choice antibiotic used to treat urinary tract infections (UTIs) in Denmark. The frequency of mutation to mecillinam (MEC) resistance is described as high in vitro; however, treatment of UTI has a good clinical response and prevalence of mecillinam resistance in Escherichia coli remains low despite many years of use. We describe occurrence of in vivo mecillinam resistance in a clinical isolate of ESBL-producing E. coli following pivmecillinam treatment. The identified phenotypic differences in the mecillinam resistant isolate compared with the original mecillinam susceptible isolate were a full-length LPS with O-antigen (O25), mecillinam resistance and a lower MIC for ceftazidime. Regarding genotype, the resistant isolate differed with a mutation in blaCTX-M-15 to blaCTX-M-127 , loss of a part of a plasmid and a genomic island, respectively, and insertion of a transposase in wbbL, causing the rough phenotype. The observed mecillinam resistance is expected to be caused by the mutation in blaCTX-M-15 with additional contribute from the serotype shift. We continue to recommend the use of pivmecillinam as first-line treatment for UTI.

In utero exposure to antibiotics and risk of congenital malformations: a population-based study.

BACKGROUND: Antibiotics are commonly prescribed during pregnancy. Although the safety of most penicillins is well established, some controversy and uncertainty are associated with the use of other commonly prescribed antibiotics. OBJECTIVE: To determine the risk of congenital malformations following first-trimester in utero exposure to 10 commonly prescribed antibiotics in Denmark. MATERIALS AND METHODS: This was a cohort study comprising all singleton liveborn children in Denmark between 2000 and 2015. Data on malformations were collected through 2016. Merging validated and comprehensive populationwide Danish healthcare and civic registries, we merged data on pregnancy, prescription drugs purchases during first trimester and congenital malformations. Using logistic regression, we calculated the odds ratio for congenital malformations (any), major congenital malformations, and cardiac congenital malformations for the 10 most commonly prescribed antibiotics (excluding 4 penicillins that served as control). In the primary analysis, the exposed cohort was compared to a cohort exposed to any of 4 penicillins considered safe during pregnancy (ampicillin, pivampicillin, benzylpenicillin, and phenoxymethylpenicillin). In sensitivity analysis, the exposed cohort was compared to an unexposed cohort. Covariate adjustments were made for maternal age at delivery, year of delivery, parity, pre-pregnancy body mass index, smoking, educational status, employment status, and annual personal income. RESULTS: We found no increased risk of congenital malformations to be related to first-trimester in utero exposure to the 10 most commonly prescribed antibiotics in Denmark compared to a cohort of pregnant women exposed to penicillins that are considered safe during pregnancy. Compared to unexposed pregnancies, small increased risks for major malformations and cardiac malformations were apparent for pivmecillinam (odds ratio, 1.13; confidence interval, 1.06-1.19; and odds ratio, 1.15; confidence interval, 1.04-1.28, respectively), sulfamethizole (odds ratio, 1.15; confidence interval, 1.07-1.24; and odds ratio, 1.22; confidence interval, 1.07-1.39, respectively), and azithromycin (odds ratio, 1.19, confidence interval, 1.03-1.38; and odds ratio, 1.29, confidence interval, 0.99-1.67, respectively). CONCLUSION: In this large populationwide cohort study, we found, with a high degree of precision, no increased risk of congenital malformations following first-trimester exposure to 10 commonly prescribed systemic antibiotics.

Emerging clinical role of pivmecillinam in the treatment of urinary tract infections caused by Extended Spectrum ßeta-lactamase (ESBL) producing Enterobacteriaceae.

BACKGROUND: Extended Spectrum ßeta-lactamase (ESBL)-producing Enterobacteriaceae causing urinary tract infections (UTIs) appear resistant to many common oral agents. There is a growing need to discover new antibiotics to combat with emerging antibiotic resistance problem. Until the discovery of new antimicrobials, we can bring back forgotten antibiotics to our clinical formulary. Pivmecillinam (prodrug of mecillinam), an oral antimicrobial agent is effective against ESBL producing organisms. We analysed the sensitivity rates of ESBL-producing Enterobacteriaceae from urine samples to mecillinam and to document if pivmecillinam is a suitable alternative option in the treatment of UTI. MATERIALS/METHODS: This retrospective study was conducted from September 2015 to September 2017. Data were collected from the pathology information system. Antimicrobial sensitivity testing on ESBL-producing Enterobacteriaceae isolates was carried out by disc diffusion method in accordance with The European Committee on Antimicrobial Susceptibility Testing. RESULTS: A total of 986 ESBL-producing Enterobacteriaceae were tested for mecillinam during the study period. Of 986 organisms, Escherichia coli was the most common organism (889); followed by Klebsiella species (71) and others Enterobacteriaceae (26). Mecillinam sensitivity was found in 96% Escherichia coli (855/889 isolates), 83% Klebsiella species (59/71 isolates) and 88% other Enterobacteriaceae (23/26 isolates). Overall 95% (935/986 isolates) of ESBL-producing urinary isolates were sensitive to mecillinam. CONCLUSIONS: Pivmecillinam appears to be suitable option to treat ESBL-producing Enterobacteriaceae causing uncomplicated UTI. Our results showed low resistance rate to mecillinam. We recommend the use of pivmecillinam in uncomplicated UTIs because of ESBL-producing Enterobacteriaceae. More studies on in vitro activity of mecillinam against ESBL producing organism and its use and clinical outcome should be tried in future.

Treatment duration of pivmecillinam in men, non-pregnant and pregnant women for community-acquired urinary tract infections caused by Escherichia coli: a retrospective Danish cohort study.

OBJECTIVES: To evaluate the importance of treatment duration for therapeutic efficacy of pivmecillinam for community-acquired urinary tract infections (UTIs) caused by Escherichia coli. METHODS: A retrospective cohort study was conducted between 1 January 2010 and 30 September 2016 in adults with community-acquired E. coli bacteriuria, treated empirically with pivmecillinam. Regimens of 3, 5 and 7 days were compared using clinical treatment failure (i.e. redemption of a new antibiotic or hospitalization due to UTI) within 14 and 30 days as outcome. HR and risk difference with 95% CI were estimated for treatment failure. Results were stratified by age (18-50, 51-70, >70 years) and sex. RESULTS: Of the 21864 cases of E. coli UTI that were analysed, 2524 (11.5%) were in men. In 954 cases (4.4%) E. coli produced ESBL and 125 (13.1%) of the cases were in men. The 3 day regimen increased the risk of treatment failure for all groups. The risk differences between the 3 and 5 day regimens were <10% for women, but >10% for men. Comparing the 7 day and 5 day regimens, only women aged >50 years demonstrated an increased risk of treatment failure within 14 days with the 5 day regimen, but not within 30 days. CONCLUSIONS: With the current data, where data on clinical classification of the E. coli UTI were missing, a 5 day treatment with pivmecillinam at 400 mg three times daily seems to be the rational recommendation for lower UTI in men, pregnant women and women >50 years old. A 3 day regimen seems sufficient for non-pregnant women <50 years old.

Prescription of antibiotics for urinary tract infection in general practice in Denmark.

OBJECTIVE: The aim of this study was to describe and characterize the prescription of antibiotics for urinary tract infection (UTI) in general practice in Denmark and to evaluate compliance with current recommendations. DESIGN: National registry-based study Setting: Danish general practice Patients: 267.539 patients who redeemed a prescription for antibiotics with the clinical indication UTI at community pharmacies between July 1st 2012 and June 31st 2013. MAIN OUTCOME MEASURES: Antibiotics prescribed for 1) acute lower UTI, 2) acute upper UTI and 3) recurrent UTI presented as amount of prescriptions, number of treatments per 1000 inhabitants per day (TID) and defined daily doses per 1000 inhabitants per day (DID). RESULTS: A total of 507.532 prescriptions were issued to 267.539 patients during the one year study period, representing 2.35 DID. Acute lower UTI was the most common reason for prescription of antibiotics (89.5%) followed by recurrent UTI (8.4%). The majority of the prescriptions were issued to people above 60 year old (57.6%). Pivmecillinam was the most commonly prescribed antibiotic in acute lower (45.8%) and acute upper (63.3%) UTI. Trimethroprim was the most commonly prescribed antibiotic in recurrent UTI (45.9%). Prescription of quinolones increased with increasing patient-age (p = <.0001). CONCLUSION: Compliance with current Danish recommendations was moderately high. Pivmecillinam is the first line antibiotic for the management of acute lower and upper UTI, and trimethroprim is the first line option of recurrent UTI. A high proportion of the antibiotic prescriptions were issued in the elderly population including a relatively high prescription rate of quinolones. Key points Urinary tract infection (UTI) is a common cause for prescription of antibiotics in general practice Poor compliance in general practice with recommendations for first-line treatment of UTI may increase antibiotic resistance Danish general practitioners are generally compliant with national and regional guidelines for antibiotic treatment of UTI There is high use of antibiotics in the elderly population including a worrisome high use of broad-spectrum antibiotics, such as Quinolones.