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.

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.

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.

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.

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.

Antibiotic prescription and clinical management of common infections among general practitioners in Latvia, Lithuania, and Sweden: a pilot survey with a simple protocol.

Comparative information on diagnosis-related antibiotic prescribing patterns are scarce from primary care within and between countries. To describe and compare antibiotic prescription and routine management of infections in primary care in Latvia (LV), Lithuania (LT) and two study sites in Sweden (SE), a cross-sectional observational study on patients who consulted due to sypmtoms compatible with infection was undetraken. Infection and treatment was detected and recorded by physicians only. Data was collected from altogether 8786 consecutive patients with infections in the three countries. Although the overall proportion of patients receiving an antibiotic prescription was similar in all three countries (LV and LT 42%, SE 38%), there were differences in the rate of prescription between the countries depending on the respective diagnoses. While penicillins dominated among prescriptions (LV 58%, LT 67%, SE 70%), phenoxymethylpenicillin was most commonly prescribed in Sweden (57% of all penicillins), while it was amoxicillin with or without clavulanic acid in Latvia (99%) and Lithuania (85%) respectively. Pivmecillinam and flucloxacillin, which accounted for 29% of penicillins in Sweden, were available neither in Latvia nor in Lithuania. The applied methodology was simple, and provided useful information on differences in treatment of common infections in ambulatory care in the absence of available computerized diagnosis-prescription data. Despite some limitations, the method can be used for assessment of intention to treat and compliance to treatment guidelines and benchmarking locally, nationally, or internationally, just as the point prevalence surveys (PPS) protocols have been used in hospitals all over Europe.

Inadequate adherence to Swedish guidelines for uncomplicated lower urinary tract infections among adults in general practice.

In a primary care study of urinary tract infections (UTIs) performed 2008 in Uppsala County, Sweden, 43% of the patients were culture negative. In order to investigate the background to the observed overdiagnosis of UTI, study invitations were sent to the previously included patients. A total of 256 patients (88% women) approved to participate. Patient charts and recorded laboratory data were reviewed. Two or more of the cardinal symptoms were reported in 53% of the women and in 19% of the men. A dipstick test was performed in 93% of the consultations. The highest positive predicted values in women had a positive nitrite test (95%, 95% CI 87; 99) and dysuria in combination with urgency (81%, 95% CI 72; 88). Seventy-one percent of the women who fulfilled the symptom criteria received an antibiotic prescription directly, 87% of these had a positive culture. The drug of choice was pivmecillinam for women (51%) and quinolones (50%) for men. The treatment duration was too long for the women; 68% were treated for ≥7 days. In conclusion, the adherence to national guidelines/recommendations was inadequate. To reduce the selection of multiresistant bacteria, an improvement of the use of diagnostic criteria/tools and antibiotic drugs in primary care is necessary.

Characteristics of gram-negative urinary tract infections caused by extended spectrum beta lactamases: pivmecillinam as a treatment option within South Dublin, Ireland.

BACKGROUND: The prevalence of urinary tract infections (UTIs) caused by extended-spectrum ß-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. This pilot study aimed to assess the viability of pivmecillinam as a therapeutic option in a Dublin cohort of mixed community and healthcare origin. METHODS: A prospective measurement of mean and fractional inhibitory concentrations of antibiotic use in 95 patients diagnosed with UTI caused by ESBL-producing Enterobacteriaceae was carried out. 36 % patients were from general practice, 40 % were admitted to hospital within south Dublin, and 25 % samples arose from nursing homes. EUCAST breakpoints were used to determine if an isolate was sensitive or resistant to antibiotic agents. RESULTS: Sixty-nine percent of patients (N = 66) with urinary ESBL isolates were female. The mean age of females was 66 years compared with a mean age of 74 years for males. Thirty-six percent of isolates originated from primary care, hospital inpatients (26 %), and nursing homes (24 %). The vast majority of ESBL isolates were E. coli (80 %). The E tests for mecillinam and co-amoxiclav had concentration ranges from 0.16 mg/L up to 256 mg/L. The mean inhibitory concentration (MIC) of mecillinam ranged from 0.25 to 256 mg/L, while co-amoxiclav MICs ranged from 6 to 256 mg/L. The percentage of isolates resistant to mecillinam and co-amoxiclav was found to be 5.26 and 94.74 % respectively. CONCLUSIONS: This is the first study exploring the use of pivmecillinam in an Irish cohort and has demonstrated that its use in conjunction with or without co-amoxiclav is an appropriate and useful treatment for urinary tract infections caused by ESBL-producing organisms.

In vitro susceptibility to mecillinam of Escherichia coli strains isolated from the urine of pregnant women.

OBJECTIVES: Pivmecillinam is a safe beta-lactam for use in pregnancy. It has been widely used for the treatment of lower urinary tract infections (UTIs) in the Nordic countries where its efficacy, minor impact on the microbiota, and low level of resistance among the Escherichia coli strains have been proven. However, susceptibility data related to E. coli involved in asymptomatic bacteriuria and lower UTIs in pregnant women is lacking. We aimed to support the 2015 recommendations issued by the French Infectious Diseases Society (SPILF) on gestational UTI, with a particular focus on pivmecillinam. MATERIAL AND METHODS: Antimicrobial susceptibility testing was performed by 12 hospitals with a maternity department on 235 E. coli strains isolated from the urine of pregnant women. Susceptibility to mecillinam was tested by disk diffusion method using the 2015 recommendations of the antibiogram committee of the French microbiology society (CA-SFM). RESULTS: Global susceptibility to mecillinam was 86.4%. Susceptibility to mecillinam was 96.5% for strains susceptible to amoxicillin-clavulanic acid and 38.7% for resistant strains. All six extended-spectrum beta-lactamase-producing E. coli strains were susceptible to mecillinam. CONCLUSION: Given the efficacy and safety of pivmecillinam during pregnancy, it may be used for the documented treatment of asymptomatic bacteriuria and acute cystitis in pregnant women. It also represents an alternative for the treatment of multidrug-resistant bacterial infections.

Epidemiological factors associated with ESBL- and non ESBL-producing E. coli causing urinary tract infection in general practice.

The purpose of the study was to evaluate how use of antibiotics precedes the presence of ESBL-producing E.coli in general practice. The authors performed a triple-case-control study where three case groups were individually compared to a single control group of uninfected individuals. Urine samples were prospectively collected and retrospective statistical analyses were done. This study included 98 cases with urinary tract infection (UTI) caused by ESBL-producing E. coli, 174 with antibiotic-resistant (non-ESBL) E. coli, 177 with susceptible E. coli and 200 with culture negative urine samples. Case groups had significantly higher use of antibiotics than the control group within 30 days before infection (p < 0.0001). The ESBL group had significantly more hospital admissions than the other case groups (p < 0.05). Hospital admission was an independent risk factor for community onset UTI by ESBL-producing E. coli. Exposure to antibiotics was a risk factor for UTI with E. coli, while prior antibiotic usage was not an indisputable predictor for infection with ESBL-producing E.coli in general practice.

General practitioners do not systematically adhere to regional recommendations on treatment of uncomplicated urinary tract infections.

INTRODUCTION: Uncomplicated urinary tract infection (uUTI) is a common reason for seeing a GP. In Denmark, it is debated if sulfamethizole or pivmecillinam should be recommended for empirical treatment of uUTIs. We evaluated sulfamethizole and pivmecillinam use in the five Danish regions from 2007 to 2011 and explored if the choice of antibiotic in primary care was in accordance with the regional recommendations for uUTI. MATERIAL AND METHODS: Regional drug use data on pivmecillinam and sulfamethizole from 2007 to 2011 were retrieved from the Registry of Medicinal Product Statistics. Regional recommendations from the same period were identified. We calculated differences in consumption based on defined daily doses per 1,000 inhabitants per day (DID) of pivmecillinam and sulfamethizole between the five regions, and intraregional developments. RESULTS: Four regions had recommendations on uUTI in 2011. From 2007 to 2009, sulfamethizole was the only antibiotic recommended. Pivmecillinam was recommended along with sulfametizole in one of four regions from 2010, which increased to two regions in 2011. During the five-year period, sulfamethizole consumption decreased in all regions. The absolute decrease ranged from 0.4 to 0.6 DID. Pivmecillinam consumption increased steadily; the absolute increase ranged from 1.5 to 2.5 DID. During the whole period, the total pivmecillinam consumption was higher than the total sulfamethizole consumption. CONCLUSION: Pivmecillinam dominated the treatment of uUTIs, whereas sulfamethizole prevailed in the regional recommendations, which suggests a lack of adherence to regional recommendations. FUNDING: not relevant. TRIAL REGISTRATION: not relevant.

Mecillinam resistance and outcome of pivmecillinam treatment in uncomplicated lower urinary tract infection in women.

Pivmecillinam (PIV) is a first-line antimicrobial for treatment of lower urinary tract infection in women (LUTIW). Mecillinam, the active substance of PIV, is bactericidal mainly against gram-negative uropathogens, whereas gram-positive species are considered intrinsically resistant. However, successful treatment of LUTIW caused by Staphylococcus saprophyticus has been reported, but more rarely for other gram-positive species. The aim of this study was to compare clinical and bacteriological outcome of PIV vs placebo treatment among uropathogens with special focus on mecillinam-resistant isolates. We analysed data from a prospective, multicentre, placebo-controlled, primary health care, therapy study performed in Sweden in 1995­1998 that included 1143 women with symptoms suggestive of LUTIW. Urine cultures were collected and symptoms registered at inclusion and at follow-up visits. Overall, the efficacy of PIV was superior to that of placebo. Clinical and bacteriological outcomes of PIV treatment were similar for S. saprophyticus, Escherichia coli as for most other uropathogens irrespective of their susceptibility to mecillinam. However, the occurrence of enterococci increased nearly fivefold shortly post PIV treatment, although with mild symptoms and a high spontaneous eradication. As susceptibility to mecillinam in vitro did not predict bacteriological and clinical outcome of PIV treatment, we suggest that the present breakpoints for mecillinam should be revised.