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Filip Jansåker,1,2 Jonas Bredtoft Boel,3 Sara Thønnings,1,2 Frederik Boëtius Hertz,3 Katrine Hartung Hansen,2 Niels Frimodt-Møller,2 Jenny Dahl Knudsen1,21Department of Clinical Microbiology, Hvidovre Hospital, University of Copenhagen, 2650 Hvidovre, Denmark; 2Department of Clinical Microbiology, Rigshospitalet, University of Copenhagen, 2100 Copenhagen, Denmark; 3Department of Clinical Microbiology, Herlev and Gentofte Hospital, University of Copenhagen, 2730 Herlev, DenmarkObjectives: 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. Keywords: UTI, ESBL, E. coli, pivmecillinam, nitrofurantoin, cohort

Sara Thønnings,1,2 Filip Jansåker,1,3 Kim Oren Gradel,4,5 Bjarne Styrishave,2 Jenny Dahl Knudsen11Department of Clinical Microbiology, Copenhagen University Hospital, Hvidovre, Denmark; 2Toxicology Laboratory, Analytical BioSciences, Department of Pharmacy, University of Copenhagen, Copenhagen, Denmark; 3Department of Clinical Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark; 4Center for Clinical Epidemiology, Odense University Hospital, Odense, Denmark; 5Research Unit of Clinical Epidemiology, Institute of Clinical Research, University of Southern Denmark, Odense, DenmarkObjectives: On January 18, 2010, a part of the capital region of Denmark shifted the empirical treatment of febrile conditions from cefuroxime to piperacillin/tazobactam. We compare empirical treatment with piperacillin/tazobactam versus cefuroxime for Escherichia coli bacteremia with regard to 14 days mortality, in a low prevalence cohort of Extended-spectrum beta-lactamase-producing E. coli.Methods: From January 18, 2010 to December 31, 2012, we conducted a retrospective cohort study including patients with E. coli bacteremia from six university hospitals in Copenhagen, Denmark. Clinical and laboratory information was obtained from a bacteremia research database, including information on comorbidity, and we used Cox proportional hazard analysis to asses all-cause 14 days mortality.Results: A total of 568 patients receiving either cefuroxime (n=377) or piperacillin/tazobactam (n=191) as empirical therapy were included. In the Cox proportional hazard model, cefuroxime treatment was significantly associated with death (mortality rate ratio 3.95, CI 1.12–13.90). Other variables associated with death were health care related infection (MRR 3.20, CI 1.67–6.15), hospital-acquired infection (MRR 2,17, CI 1.02–4.62), admission at intensive care unit (MRR 20.45, 5.31–78.82), and combination therapy with ciprofloxacin (MRR 2.14, CI 0.98–4.68).Conclusion: Empiric cefuroxime treatment of E. coli bacteremia was significantly associated with higher 14 days mortality in comparison with piperacillin/tazobactam.Keywords: piperacillin/tazobactam, cefuroxime, E. coli, bacteremia, mortality

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 explore the population-based risk factors for genital herpes in women and examine whether genital herpes occurs at higher rates in women diagnosed with cervical neoplasia and common urogenital infections., Methods: An open cohort study consisting of 4,097,075 women ≥15 years of age in Sweden (2002-2018). The outcome was genital herpes diagnosis. The predictor variables were sociodemographic factors (age, educational level, family income, region of residence, and country of origin) and urogenital comorbidities (cervical carcinoma neoplasia, cystitis, vaginosis, and vulvovaginitis) and parity. National registers and primary health care data were used. Cox regression models were used to estimate hazard ratios with 95% confidence intervals. Interactions tests were conducted., Results: A total of 15,727 women received a genital herpes diagnosis in inpatient and outpatient specialist care settings during the study period. Sociodemographic factors and parity were associated with genital herpes. than women without these comorbidities., Conclusions: Genital herpes occurs with higher rates in women of high family income, young age, Swedish origin, co-occurrence of urogenital comorbidities, and nulliparity. The findings can be used by clinicians when encountering women with these risk factors., Competing Interests: The authors have no competing interests to declare., (© 2024 The Author(s).)

Aims: To examine whether vulvovaginal candidiasis (VVC) precedes type 2 diabetes and to quantify the possible time period between VVC and subsequent diabetes., Material and Methods: We conducted a nationwide retrospective primary healthcare study including 1 838 929 women aged 35-65 years in Sweden (2007-2018). Cox regression models were used to examine associations between VVC and type 2 diabetes, while controlling for possible confounders. Propensity-score-weighted analysis was also conducted., Results: The incidence rate of diabetes per 1000 person-years was 3.06 (95% confidence interval [CI] 3.05-3.08) in women without preceding VVC and 4.05 (95% CI 3.86-4.24) in women with preceding VVC. The incidence rate was particularly high in women aged 55 years and older with VVC: 9.56 (95% CI 8.01-11.11). Women with VVC had a hazard ratio (HR) of 1.41 (95% CI 1.28-1.55) for diabetes compared to women without VVC in the multivariable-adjusted model. The corresponding HR was 1.63 (95% CI 1.53-1.74) in propensity-score-weighted analysis. Women with prior VVC also seemed to have a stronger risk of diabetes with older age, particularly after the age of 55 years. The mean (range) time between VVC and subsequent diabetes was 0.57 (0-2) years, depending on the age of the woman., Conclusion: We found temporal associations between VVC and diabetes. The findings demonstrate that the presence of VVC may indicate a future diagnosis of diabetes, especially in women aged 55 years and older. This knowledge could be valuable for clinicians when treating women with VVC., (© 2024 The Author(s). Diabetes, Obesity and Metabolism published by John Wiley & Sons Ltd.)

Objectives: Bacteremia is an acute severe infection with high mortality. Changes in healthcare services and coinfections with SARS-CoV-2 may have affected the mortality for bacteremia during the COVID-19 pandemic, which has been reported for other major diseases. In this study we examine the all-cause bacteremia mortality amidst the COVID-19 pandemic., Methods: A population-based cohort study comprised of laboratory confirmed bacteremia episodes in the Capital Region, Denmark (March 2019-February 2022). Cox proportional hazards models were used to calculate hazard ratios (HR) and 95 % confidence intervals (CI) for all-cause bacteremia mortality associated with the Covid-19 restriction period, a strike period, and coinfection with SARS-CoV-2, adjusted for possible confounders., Results: A total of 14,912 bacteremia episodes were identified in 12,693 patients during the study period. The 30- and 90-day all-cause mortality were 19 % and 27 %, respectively. The fully adjusted HR for 30- and 90-day all-cause mortality associated with the Covid-19 restriction period were 0.91 (95 % CI, 0.84 to 0.99) and 0.90 (95 % CI, 0.84 to 0.96), respectively, compared to the remaining time period. The corresponding HRs associated with SARS-CoV-2 coinfection were 1.29 (95 % CI, 1.11 to 1.50) and 1.36 (95 % CI, 1.20 to 1.55) compared to patients without coinfection. The association between the national nurse strike and all-cause bacteremia mortality was inconclusive., Conclusions: In this large population-based cohort study, a significant reduction in all-cause mortality for bacteremia was observed during the Covid-19 restriction period in Denmark, while coinfection with SARS-CoV-2 seem to be a substantial risk factor for all-cause bacteremia mortality., Competing Interests: All authors affirm that this manuscript is conducted honest, accurate, and transparent. All authors have completed the author submission statement. All authors declare no support from any organization for the submitted work; no financial relationships with any organizations that might have an interest in the submitted work in the previous three years, no other relationships or activities that could appear to have influenced the submitted work., (© 2024 The Authors.)

Patients with bipolar disorder have higher rates of type 2 diabetes (T2D) compared to the general population. Neighbourhood deprivation is associated with T2D and bipolar disorder. The aim of this study was to explore the potential effect of neighbourhood deprivation on incident T2D in patients with bipolar disorder. This nationwide open cohort study (1997-2018) included adults in Sweden ≥20 years with bipolar disorder (90,780 patients) to examine the subsequent risk of T2D. The association between neighbourhood deprivation and T2D was explored using Cox regression analysis, with hazard ratios (HRs) and 95% confidence intervals (95% CIs). All models were conducted in both men and women and adjusted for individual-level sociodemographic factors and comorbidities. Neighbourhood deprivation was significantly associated with T2D in patients with bipolar disorder. The HRs were 1.61 (95% CI 1.40-1.86) for men and 1.83 (1.60-2.10) for women living in high deprivation neighbourhoods compared to those from low deprivation neighbourhoods. After adjustment, these results remained significant: 1.35 (1.17-1.56) in men and 1.39 (1.20-1.60) in women living in high deprivation neighbourhoods. The suggested graded association of higher incident T2D among patients with bipolar disorder, observed when levels of neighbourhood deprivation increased, raises important clinical and public health concerns. The results may help develop a contextual approach to prevention of T2D in patients with bipolar disorder that includes the neighbourhood environment., (© 2023 The Authors. Stress and Health published by John Wiley & Sons Ltd.)

Background: Associations between different cancer types are known. The affirmation of the risk for non-ovarian cancer after ovarian borderline tumors (BOT) is, however, sparse., Aim: To analyze the risk of subsequent or simultaneous cancers in women with BOTs compared with the general female Swedish population., Methods: An open cohort study (1995-2018) was conducted where a diagnosis of BOTs as well as subsequent or simultaneous cancer diagnoses were obtained from the Swedish Cancer Register and matched to the Total Population Register. Each woman with BOT was followed until non-ovarian cancer, death or emigration and could only be included once for the outcome. Standardized incidence ratios (SIRs) with 95% confidence intervals (CIs) for specific non-ovarian cancers were analyzed., Results: The 4998 women with serous and mucinous BOTs were diagnosed during 1995-2018 with a mean age of 55.7 years (SD 16.0) at diagnosis. Compared with the general female population, women with BOTs had increased risks for non-ovarian cancer in colon (SIR = 2.5; 95% CI 2.0-3.1), rectum (SIR = 1.7; 95% CI 1.1-2.5), small intestine (SIR = 5.0; 95% CI 2.3-9.5), cervix (SIR = 2.5; 95% CI 1.4-4.2), endometrium (SIR = 2.4; 95% CI 1.9-3.1), pancreas (SIR = 2.3; 95% CI 1.4-3.5), upper aerodigestive tract (SIR = 2.2; 95% CI 1.2-3.8), lung (SIR = 1.8; 95% CI 1.4-2.3), kidney (SIR = 2.3; 95% CI 1.4-3.7) and bladder (SIR = 1.8; 95% CI 1.1-2.8). Among women with serous BOTs, the risk of thyroid gland cancer (SIR = 3.1; 95% CI 1.2-6.4) was also increased. Lung and pancreas cancer showed increased risks more than 1 year after a diagnosis of BOT., Conclusions: This Swedish population-based study demonstrated an increased risk of multiple malignancies including lung and pancreatic cancers beyond the first year of diagnosis in patients with borderline ovarian tumors (BOTs), suggesting a potential shared etiology., (© 2023. BioMed Central Ltd., part of Springer Nature.)

Objectives: The aim was to explore the association between neighborhood deprivation and all-cause mortality and cause-specific mortalities in patients with schizophrenia and bipolar disorder. A better understanding of this potential relationship may help to identify patients with schizophrenia and bipolar disorder with an increased mortality risk., Methods: This nationwide study included practically all adults (≥30 years) diagnosed with schizophrenia (n = 34,544) and bipolar disorder (n = 64,035) in Sweden (1997-2017). The association between neighborhood deprivation and mortality was explored using Cox regression. All models were conducted in both men and women and adjusted for individual-level sociodemographic factors and comorbidities., Results: There was an association between level of neighborhood deprivation and all-cause mortality in both groups. The adjusted hazard ratios for all-cause mortality associated with high compared to low neighborhood deprivation were 1.18 (95% confidence interval 1.11-1.25) in patients with schizophrenia and 1.33 (1.26-1.41) in patients with bipolar disorder. The two most common mortality causes in both groups were coronary heart disease and cancer. The mortality due to coronary heart disease increased when neighborhood deprivation increased and reached 1.37 (1.18-1.60) in patients with schizophrenia and 1.70 (1.44-2.01) in patients with bipolar disorder living in the most deprived neighborhoods., Conclusions: This study shows that neighborhood deprivation is an important risk factor for all-cause mortality and most cause-specific mortalities among patients with schizophrenia and bipolar disorder. These findings could serve as aid to policymakers when allocating healthcare resources and to clinicians who encounter patients with these conditions in deprived neighborhoods., (© 2023 The Authors. Bipolar Disorders published by John Wiley & Sons Ltd.)

Background: Neighborhood deprivation has been found associated with both type 2 diabetes and lung cancer. The aim of this study was to examine the potential association between neighborhood deprivation and lung cancer incidence or mortality in individuals diagnosed with type 2 diabetes. The results may identify a new risk or prognostic factor for lung cancer in this important subgroup and help develop a more contextual approach to prevention that includes neighborhood environment., Methods and Findings: The study population included adults (n = 613,650) aged ≥ 30 years with type 2 diabetes during 2005 to 2018 in Sweden. Cox regression was used to compute hazard ratios (HRs) and 95% confidence intervals (95% CIs) for incidence or mortality of lung cancer associated with neighborhood deprivation. All models were conducted in both men and women and adjusted for individual-level characteristics (e.g. age, smoking- and alcohol-related comorbidities, sociodemographic factors). The cumulative incidence and mortality for lung cancer were 1.08% (95% CI, 1.06 to 1.11) and 0.93% (0.90 to 0.95), respectively, in the study population during the study period. Neighborhood deprivation was associated with both incidence and mortality of lung cancer in patients with type 2 diabetes independently of the individual-level characteristics. In the fully adjusted models, comparing high- with low-deprivation neighborhoods, the HRs for lung cancer incidence were 1.21 (1.10 to 1.33) in men and 1.08 (0.95 to 1.21) in women. The corresponding HRs for lung cancer mortality were 1.04 (1.00 to 1.07) in men and 0.97 (0.94 to 1.00) in women. Competing risk analyses including cardiovascular mortality attenuated the results., Conclusion: In this large cohort of individuals with type 2 diabetes, we found higher lung cancer incidence and mortality in patients living in areas with high neighborhood deprivation, even after adjusting for individual-level characteristics. These findings may help develop a more contextual approach that includes the neighborhood environment when allocating resources for disease prevention and care in patients with type 2 diabetes. These findings could also help inform clinical care for patients with type 2 diabetes, particularly those living in deprived neighborhoods., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2023 Li et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Sepsis is a severe condition, representing a significant public health concern, especially in the elderly. There is, however, little insight into the potential effects of sociodemographic factors and comorbidities on sepsis incidence and how these factors interact. This was a nationwide open cohort study including individuals (N = 6 746 010) in Sweden ≥ 18 years of age spanning from 1997 to 2018, with 116 175 995 person years of follow-up. The outcome was time to first occurrence of sepsis. The following variables were included in the analysis: sociodemographic factors (age, sex, income, education, marital status, region of residency, and country of origin), severe mental disorders (schizophrenia and bipolar disorders), and Charlson Comorbidity Index. Interaction tests were conducted. A total of 161 558 individuals were diagnosed with sepsis during the study period, corresponding to an incidence rate of 13.9 per 10 000 person years (95% CI: 13.8 - 14.0). The main findings were that male sex, high age, low education, and comorbid conditions were positively associated with sepsis, after adjustments for the other covariates. Being aged 80 years and above yielded a HR of 18.19 (95% CI: 17.84 - 18.55) and the effect of high age was more than twice as high in men than in women. In conclusion, this large nationwide cohort found that several sociodemographic factors and comorbid conditions were independently associated with sepsis and men were more affected by higher age than women. These findings can help improve sepsis awareness and preventive work in risk groups., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2023 The Author(s).)

Background: The experiences of art and music are an essential part of human life and this study aimed to examine the longitudinal association between cultural participation and coronary heart disease., Methods: This was a longitudinal study on a randomly selected representative adult cohort (n = 3296) of the Swedish population. The study period was over 36 years (1982-2017) with three separate eight-year interval measurements of cultural exposure (for example, visiting theatres and museums) starting in 1982/83. The outcome was coronary heart disease during the study period. Marginal structural Cox models with inverse probability weighting were used to account for time-varying weights of the exposure and potential confounders during the follow-up. The associations were also examined through a time-varying Cox proportional hazard regression model., Results: Cultural participation shows a graded association, the higher the exposure the lower the risk of coronary heart disease; the hazard ratio was 0.66 (95% confidence interval, 0.50 to 0.86) for coronary heart disease in participants with the highest level of cultural exposure compared with the lowest level., Conclusion: Although causality cannot be determined due to the remaining risk of residual confounding and bias, the use of marginal structural Cox models with inverse probability weighting strengthens the evidence for a potentially causal association with cardiovascular health, which warrants further studies., (© 2023. The Author(s).)

Objective: This longitudinal study examines a possible causal effect between type 2 diabetes and ischemic heart disease (IHD) by using measurements on four occasions from the Swedish Statistics on Income and Living Conditions (SILC) together with nationwide healthcare registers., Methods: This was a longitudinal study based on a random sample of men and women (n = 2014) from the Swedish population with four measurements in the SILC every eight years. Baseline was 1980/81 and the participants were followed for up to 37 years. The mean age and age range at baseline were 36.5 and 20-59 years, respectively. The study used Marginal Structural Modeling (MSM-Cox) to account for time-varying exposures by implementing inverse probability weighting (IPTW). MSM-Cox with IPTW was compared with Cox proportional hazard modelling., Results: The hazard ratio (HR) for IHD (369 cases) with 95% confidence interval (CI) in participants with type 2 diabetes (11.1%) compared to participants without type 2 diabetes (88.9%) was significantly higher (1.99; CI = 1.15 - 3.44) when using MSM-Cox with IPTW after adjustments for clinical and sociodemographic risk factors. When applying Cox proportional hazard models adjusted for the same variables, the HR was lower and non-significant at 1.34 (CI = 0.94 - 1.98)., Conclusions: This longitudinal study with four measurements assessed a possible causal association between type 2 diabetes and IHD by applying MSM-Cox with IPTW. Although causality cannot be determined due to the remaining risk of residual bias, the results may help to elucidate a potential causal relationship between type 2 diabetes and IHD. Further causal studies on possible underlying mechanisms are, however, needed., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 The Authors. Published by Elsevier B.V. All rights reserved.)

Objectives: To examine the association between cultural attendance and all-cause mortality., Design: A longitudinal cohort study over 36 years (1982-2017) with three 8-year interval measurements of exposure (1982/1983, 1990/1991 and 1998/1999) to cultural attendance and a follow-up period to 31 December 2017., Setting: Sweden., Participants: The study included 3311 randomly selected individuals from the Swedish population with complete data for all three measurements., Primary Outcome Measurements: All-cause mortality during the study period in relation to level of cultural attendance. Cox regression models with time-varying covariates were used to estimate HRs adjusted for potential confounders., Results: The HRs of cultural attendance in the lowest and middle levels compared with the highest level (reference; HR=1) were 1.63 (95% CI 1.34 to 2.00) and 1.25 (95% CI 1.03 to 1.51), respectively., Conclusion: Attending cultural events has a suggested gradient, the lesser cultural exposure the higher all-cause mortality during the follow-up., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2023. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Introduction: Cervical cancer is a major cause of mortality and morbidity. We aimed to estimate the association between sociodemographic factors and cervical neoplasia., Material and Methods: In this Swedish nationwide open cohort study, 4 120 557 women aged ≥15 years at baseline were included between January 1, 2002 and December 31, 2018. The two outcomes were cervical cancer and carcinoma in situ identified in the Swedish Cancer Register. Sociodemographic factors (age, education level, family income level, region of residency, country of origin) were the main predictors. Incidence rates per 10 000 person-years were calculated. Cox regression was used to estimate hazard ratios. Sensitivity analyses were conducted, including parity, urogenital infections, alcohol- and drug-use disorders, and chronic obstructive pulmonary disease (used as a proxy for tobacco abuse)., Results: In 38.9 million person-years of follow-up, 5781 (incidence rate: 1.5, 95% confidence interval [CI] 1.4-1.5) and 62 249 (incidence rate 16.9, 95% CI 15.9-16.1) women were diagnosed with cervical cancer and carcinoma in situ, respectively. Women from Eastern Europe had a hazard ratio of 1.18 (95% CI 1.05-1.33) for cervical cancer compared with Swedish-born women, while women from non-Western regions were inversely associated with cervical cancer and carcinoma in situ. Women with a low education level had a hazard ratio of 1.37 (95% CI 1.29-1.45) for cervical cancer compared with women with a high education level., Conclusions: Women from the Middle East and Africa living in Sweden seem to suffer less from cervical neoplasia, whereas women with low education and women from Eastern Europe seem to suffer more from cervical cancer., (© 2022 The Authors. Acta Obstetricia et Gynecologica Scandinavica published by John Wiley & Sons Ltd on behalf of Nordic Federation of Societies of Obstetrics and Gynecology (NFOG).)

Objectives: We aimed to explore the association between various physiological factors and pyelonephritis in parous women., Methods: Swedish nationwide registers were used to identify 1,073,467 parous women aged 15-50 years. The study period began in 1997 and ended in 2018, or at the first incidence of pyelonephritis, death, or emigration. Cox proportional hazards methods were used to determine hazard ratios (HRs) and 95% confidence intervals (CIs) of pyelonephritis in relation to body mass index (BMI) and body height adjusted for age, parity, and individual-level sociodemographic variables., Results: A total of 21,625 women (2.0%) were diagnosed with pyelonephritis during follow-up. In the fully adjusted model, low BMI (<18.5) was associated with pyelonephritis (HR 1.13, 95% CI 1.06-1.21). Parity and certain sociodemographic characteristics were also independently associated with pyelonephritis. Body height <161 cm was associated with pyelonephritis (HR 1.12, 95% CI 1.09-1.16) in all but the fully adjusted model., Conclusion: Low BMI and body height seem to be associated with uncomplicated pyelonephritis. More research is needed to verify these findings and identify possible mechanisms., (Copyright © 2022 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

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.

The aim was to study the potential effect of neighborhood deprivation on incident and fatal coronary heart disease (CHD) in patients with bipolar disorder. This was a nationwide cohort study which included all adults aged 30 years or older with bipolar disorder (n = 61,114) in Sweden (1997-2017). The association between neighborhood deprivation and the outcomes was explored using Cox regression analysis, with hazard ratios (HRs) and 95% confidence intervals (CIs). Patients with bipolar disorder living in neighborhoods with high or moderate levels of deprivation were compared with those living in neighborhoods with low deprivation scores. There was an association between level of neighborhood deprivation and incident and fatal CHD among patients with bipolar disorder. The HRs were 1.24 (95% CI 1.07-1.44) for men and 1.31 (1.13-1.51) for women for incident CHD among patients with bipolar disorder living in high deprivation neighborhoods compared to those from low deprivation neighborhoods, after adjustments for potential confounders. The corresponding HR for fatal CHD were 1.35 (1.22-1.49) in men and 1.30 (1.19-1.41) in women living in high deprivation neighborhoods. Increased incident and fatal CHD among patients with bipolar disorder living in deprived neighborhoods raises important clinical and public health concerns., (© 2022. The Author(s).)

Background: Cervical cancer is a major cause of mortality and morbidity in women worldwide. This study aimed to estimate the association between common urogenital infections and cervical neoplasia., Methods: A multi-register national cohort study of 4,120,557 women aged ≥15 years (2002-2018) was conducted. The outcomes were cervical cancer and carcinoma in situ (Swedish Cancer Register). The main predictors were urogenital infections-(urinary) cystitis, (bacterial) vaginosis, (candida) vulvovaginitis. Incidence rates per 10,000 person-years were calculated (using the European Standard Population). Cox regression was used to estimate hazard ratios (HR) while adjusting for possible confounders-other genital infections (e.g., cervicitis, salpingitis, urogenital herpes), parity, and sociodemographic factors., Findings: In 39·0 million person-years of follow-up, the incidence rate for cervical cancer was 1·2 (95% CI 1·1-1·2) per 10,000 person-years and the figure for cervical carcinoma in situ was more than tenfold higher. The fully adjusted HRs for cervical cancer were 1·31 (95% CI 1·15 and 1·48) and 1·22 (95% CI 1·16 and 1·29) for vaginosis and cystitis, respectively. Vaginosis showed a gradient association to carcinoma in situ. Vulvovaginitis was inversely associated with cervical cancer, but not significantly related with carcinoma in situ in the fully adjusted model. A temporal association with cervical cancer was observed for vaginosis and vulvovaginitis (inversely) but not for cystitis., Interpretation: In this large nationwide cohort of women, medically attended common urogenital infections were independently associated with cervical neoplasia, but cystitis was not temporally associated with cervical neoplasia. These findings could be used to increase focus on preventive measures, HPV-vaccination programmes, HPV-analyses- and cervical cancer screening, especially in women suffering from vaginosis. Future studies on the causal mechanism are warranted before generalized public health recommendations can be made., Funding: Region Skåne, Tore Nilsons Stiftelse, and Swedish Society of Medicine., Competing Interests: The authors have nothing to disclose., (© 2022 The Author(s).)

Objective: This study aimed to estimate the association between potential risk factors and common vaginal infections using nationwide primary health care and other national registers., Methods: 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., Results: 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)., Conclusion: This study presents novel risk factors associated with medically attended vaginal infections. Women from non-Western countries seem to develop these conditions disproportionately., Competing Interests: Declaration of Competing Interest The authors have nothing to disclose., (Copyright © 2022 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

In this nationwide cohort of one million fertile women, BMI, height, and parity only had minor but statistically significant effects on the risk of uncomplicated cystitis. The results indicate that underweight women and certain sociodemographic groups might have higher risks, which could have underlying explanations that need further studying., (© 2022. The Author(s).)

Background: Antibiotics are commonly prescribed for outpatient management of cystitis. Previous evidence suggests that certain factors likely beyond the infection seem to influence the choice of antimicrobial treatment. However, studies on the specific antibiotic treatments for cystitis are lacking. This study aimed to explore the antibiotic treatments for cystitis using nationwide primary healthcare data and investigate if factors beyond the infection could be associated with fluoroquinolone treatment., Methods: This nationwide follow-up cohort study consisted of 352,507 women with cystitis. The primary aim was to investigate what specific classes of antibiotics were redeemed by patients within five days from the cystitis diagnosis. Each patient could only be included once. Logistic regression models were also used to examine the relationship between fluoroquinolone (FQ) treatment, parity, and sociodemographic factors., Results: In total, 192,065 antibiotic prescriptions were redeemed. Pivmecillinam (58.4%) followed by nitrofurantoin (22.2%), trimethoprim (12.0%), fluoroquinolone (5.6%), and cephalosporins (1.5%) were the most redeemed antibiotics. Sociodemographic factors were weakly associated with fluoroquinolone treatment; young age was inversely associated with fluoroquinolone treatment. Parity and cervical cancer history were not associated with fluoroquinolone treatment. The proportion of fluoroquinolone and trimethoprim treatments decreased over time, while pivmecillinam and nitrofurantoin increased., Conclusions: The treatment trends of antibiotics redeemed within five days from a cystitis diagnosis were similar to the national surveillance program of these antibiotics (not diagnosis linked). Fluoroquinolones were weakly associated with sociodemographic factors, which likely is only of historical relevance.

Objectives: Urinary incontinence (UI) is a very common condition in the primary healthcare settings. Few studies have investigated whether sociodemographic factors are related to UI. This nationwide study aimed to investigate whether there is a relationship between sociodemographic factors and UI in women., Methods: A nationwide open cohort study included 2,044,065 women aged 15-50 years. Several national population-based (Sweden) databases including nationwide primary healthcare data were used. The outcome was the time to the first event of any UI diagnosis during the study period (1997-2018). Cox regression models were used to test for associations between individual sociodemographic factors and UI., Results: The study identified 44,250 UI events. These corresponded to 2.16% of the study population and an incidence rate (IR) per 1000 person-years of 1.85 (95% CI 1.84-1.87). In the fully adjusted model, a high age, low education level, and being born outside of Sweden were independently associated with a higher UI risk, while rural living was associated with a lower risk. The income level did not seem to have a large impact. Most notably, women born in the Middle East/North Africa and Latin America/Caribbean had a substantially higher risk of UI with HRs of 2.41 (95% CI 2.33-2.49) and 2.30 (95% CI 2.17-2.43), respectively. Parity was strongly and independently associated with UI., Conclusion: This study presents novel risk factors associated with UI. The findings provide new knowledge concerning the burden of this disease among women, which could be used to provide more equal healthcare for these patients in the future. Previous research allied with these findings suggests using a comprehensive approach targeting health disparities.

Background: Uncomplicated cystitis is one of the most common reasons for antibiotic treatment in otherwise healthy women. Nationwide studies on antibiotic treatment for this infection and in relation to factors beyond the infection itself have hitherto not been available., Methods: This was a nationwide open cohort study consisting of 352,507 women aged 15-50 years with uncomplicated cystitis (2006-2018). The outcome was a redeemed antibiotic prescription within five days from the cystitis diagnosis. Logistic regression models were used to examine the relationship between the outcome and the predictor variables., Results: This study identified 192,065 redeemed treatments (54.5%). Several sociodemographic variables were associated with antibiotic treatment. For example, women with the lowest income had an odds ratio (OR) of 1.26 (95% CI 1.23-1.28) compared to those with the highest income. History of cervical cancer and high parity were also associated with lower treatment rates., Conclusion: This study presents novel factors beyond the infection which seem to affect the antibiotic treatment for uncomplicated cystitis in women. Future studies to investigate possible mechanisms are warranted in order to properly use our findings. This may help healthcare workers and planners to provide a more equal treatment plan for this common infection, which may reduce misuse of antibiotics, decrease costs and improve efforts against antibiotic resistance.

This study explored all-cause mortality of bacteremia diagnosed during a 60-day non-physician healthcare worker strike in 2008. A significant change, with 5.0% (95% confidence interval [CI] 1.2-8.7%, P < .01) absolute risk increase, was seen in 90-day mortality during the strike (n = 598) compared with the rest of the study period 2000-2015 (n = 75 647)., (© The Author(s) 2020. Published by Oxford University Press for the Infectious Diseases Society of America. All rights reserved. For permissions, e-mail: journals.permissions@oup.com.)

Objective: To study the relationship between sociodemographic factors and pyelonephritis., Methods: A nationwide open cohort study consisting of 2,052,873 women (76.2% Swedish-born) aged 15-50 years was conducted (1997-2018). The outcome was the first event of acute uncomplicated pyelonephritis diagnosed in primary healthcare settings in relation to the sociodemographic factors. Cox regression models were used in the analyses., Results: The study identified 40,724 cases. In the fully adjusted model, women from non-Western countries had a higher risk of pyelonephritis compared to Swedish-born women. Women from Latin America/the Caribbean had the highest risk (Hazard ratio = 1.60; 95% CI 1.49-1.72), followed by Eastern Europe (HR = 1.26; 95% CI 1.21-1.32) and the Middle East/North Africa (HR = 1.25; 95% CI 1.19-1.30). Low education, low income, urban living, and young age were also associated with higher risks of pyelonephritis., Conclusion: This study presents novel risk factors associated with pyelonephritis. Women from non-Western countries and with low socioeconomic status might disproportionately suffer from this serious infection. This might be due to biological predispositions and the fact that immigrant women do not acquire the same level of health or might receive less healthcare compared to native women, even in the presence of universal healthcare., (Copyright © 2021 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Introduction: Bacteraemia is a frequent infectious condition that strongly affects morbidity and mortality. The incidence is increasing worldwide. This study explores all-cause 30-day mortality after bacteraemia in two out of Denmark's five healthcare regions with approximately 2.4 million inhabitants., Methods: Clinically significant bacteraemia episodes ( n = 55,257) were identified from a geographically well-defined background population between 2000 and 2014, drawing on population-based data regarding bacterial species and vital status. All-cause 30-day mortality was assessed in relation to bacteraemia episodes, number of patients with analysed blood cultures and the background population., Results: We observed a decreasing trend of all-cause 30-day mortality between 2000 and 2014, both in relation to the number of bacteraemia episodes and the background population. Mortality decreased from 22.7% of the bacteraemia episodes in 2000 to 17.4% in 2014 (annual IRR [95% CI]: 0.983 [0.979-0.987]). In relation to the background population, there were 41 deaths per 100,000 inhabitants in 2000, decreasing to 39 in 2014 (annual IRR [95% CI]: 0.988 [0.982-0.993]). Numbers of inhabitants, bacteraemia episodes, and analysed persons having BCs increased during the period., Conclusions: All-cause 30-day mortality in patients with bacteraemia decreased significantly over a 15-year period.

Background: 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., Methods: 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., Findings: 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., Interpretation: 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., Funding: The Primary Healthcare Management and ALF funding (Region Skåne, Sweden) and the Swedish Research Council., Competing Interests: The authors have nothing to disclose., (© 2021 The Author(s).)

Background: People who inject drugs (PWID) have increased risk of acquiring blood-transmitted chronic viral infections such as Hepatitis B (HBV), Hepatitis C (HCV) and Human Immunodeficiency Virus (HIV) as well as increased risk of acquiring bacterial infections. We aimed to identify and describe bacteraemic episodes, their recurrence rates, predictive and prognostic factors amongst hospitalised PWID., Methods: In this retrospective cohort study, we included 257 hospitalised PWID during 2000-2006 with follow up at the Department of Infectious Diseases, Hvidovre Hospital, Denmark. Data collection included comorbidity (HBV-, HCV-, HIV-, and psychiatric comorbidities), social information (contact to an addiction treatment centre, homelessness), opioid substitution treatment (OST), treatment completion and microbiology findings. There was a 10-years follow-up regarding mortality., Results: The study identified 257 patients classified as PWID. Of these, 58 (22.6%) had at least one episode of bacteraemia during their first hospital admission. Recurrence was found in 29 (50.0%) of the bacteraemia cases. Staphylococcus aureus was the dominant microorganism of both first and recurrent episodes with 24 (41.4%) and nine (31.4%) of cases, respectively. A psychiatric diagnose was significantly associated with a lower risk of bacteraemia in the multivariate analysis (OR: 0.29, [95%CI: 0.11-0.77], P = 0.01). Mortality was significantly higher in patients with bacteraemia (17.2% vs. 3.0%, P < 0.01, OR: 6.67 [95%CI: 2.33-20], P < 0.01)., Conclusions: In hospitalised PWID, bacteraemia was found in 22.6% and was associated with at higher mortality. The most common microorganism of bacteraemia was S. aureus. Psychiatric comorbidity was significantly associated with a lower risk of bacteraemia.

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 bla CTX-M-15 to bla CTX-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 bla CTX-M-15 with additional contribute from the serotype shift. We continue to recommend the use of pivmecillinam as first-line treatment for UTI., (© 2019 The Authors. MicrobiologyOpen published by John Wiley & Sons Ltd.)

The worldwide increase in infections caused by extended-spectrum beta-lactamase- (ESBL) and AmpC-producing Enterobacteriaceae (ESBL-E) is a concern. Surveillance is extensive in Europe, North America, and Asia. Yet, there is no summarizing surveillance in Africa. This study aimed to perform a preliminary investigation on the prevalence of ESBL-E in the northeastern part of Nigeria. However, of the 60 samples collected, we were able to culture 15 Escherichia coli and 7 Klebsiella spp. only. In the collection of clinical hospital samples, we found eight of 15 E. coli isolates to be ESBL (53%) and two out of seven Klebsiella spp. to be ESBL/AmpC (29%). Due to the limitations of this study, our findings cannot take a broad view on the prevalence of ESBL-E, in Nigeria and other parts of Africa. Yet, to know which genes encode ESBL in Nigeria, and to know exact prevalence of every ESBL gene would be of importance., (© 2019 The Authors. MicrobiologyOpen published by John Wiley & Sons Ltd.)

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., (© The Author(s) 2019. Published by Oxford University Press on behalf of the British Society for Antimicrobial Chemotherapy. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Background: To investigate if a 5-day course pivmecillinam (amdinocillin pivoxil) 400 mg three times daily is superior to a 3-day course in women with uncomplicated urinary tract infection (UTI)., Methods: A randomised, double-blind, placebo-controlled trial conducted at nine primary care centres in Denmark. 368 women (18-70 years) with symptoms compatible with UTI were randomised to blinded therapy of 5 days [5d] or 3 days followed by 2 days of placebo [3d] from May 2015 to November 2017. Clinical data were assessed using a validated questionnaire at inclusion (day-0), daily the following 7 days and once again within the 2nd to 6th week after intervention. Bacteriological data were collected prior to intervention and twice between day 7 and 42. Main clinical endpoints were days to symptom resolution within 7 days after inclusion and proportions with clinical success at the end of intervention. Main bacteriological endpoint was proportion of participants with significant reduction of bacteriuria (≥ 10 2 CFU/mL) in 1st control urine sample. ClinicalTrialsRegister.eu: 2014-001321-32., Findings: 180 (5d) and 188 (3d) participants were included in the study (mean age: 35.4 [5d] and 34.9 [3d]). Of these, 125 (70% [5d]) and 122 (66% [3d]) had a positive baseline urine culture. Forty-four participants were lost to follow-up, leaving 161 [5d] and 163 [3d] participants for analysis, respectively. Mean time to symptom resolution was 2.91 (SD 1.46; [5d]) days and 2.94 (SD 1.42; [3d]) days (P = .894). Clinical success at the end of treatment occurred for 117 of 153 (76%) receiving the 5d-course and for 115 of 157 (73%) receiving the 3d course (difference 3.2% [95% CI -7.1% - 13.5%]; P = .601). Bacteriological success was seen in 92 of 104 (88%) participants given the 5d course and in 86 of 99 (87%) given the 3d course (difference 1.6% [95% CI -8.4%-11.6%]; P = .895)., Interpretations: A 5-day course of pivmecillinam was not superior to a 3-day course in clinical or bacteriological outcomes for UTI., Primary Funding Source: The Danish Regions [no. 14/217].

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 ≥10 3 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.

Background: Uncomplicated lower urinary tract infections (LUTI) are very common, and presumably around 200,000 female patients are treated for this annually in Denmark. The current Danish national clinical practice guidelines recommend pivmecillinam as a first-line drug (i.e., 400 mg t.i.d. for 3 days). Pivmecillinam is also one of the first-line drugs recommended in the international guidelines for LUTIs (i.e., 400 mg b.i.d. for 5 days). The international recommended duration is based on evidence saying that a 7-day regimen is better than a 3-day regimen. However, no data says that a 5-day regimen is superior to a 3-day regimen. With this study we aim to identify and to compare the efficacy of pivmecillinam 400 mg t.i.d in a 3-day respectively 5-day regimen, against community acquired uncomplicated LUTI, i.e., in women at the age of 18-70 year old., Method/design: The general practitioner will at consultation give a suitable patient the opportunity to participate in the study. If the patient will give her consent, a double-blinded kit (i.e., the antibiotic with/without placebo, questionnaires and self-urinary samples) will be given to the patient. We aim for 161 evaluable patients in each arm., Discussion: Pivmecillinam is an excellent choice against urinary tract infections and we believe this study will fill in the gaps and strengthen the evidence on the treatment against one of the most common infections in our society. Thus, aiming to provide a more rational and ecological beneficial antimicrobial therapy., Trial Registration: EudraCTno.: 2014-001321-32 .

Objectives: 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., Methods: 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., Results: 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%)., Conclusions: Pivmecillinam was proven bacteriologically and clinically effective for treatment of lower UTIs caused by ESBL-producing Enterobacteriaceae.