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ObjectivesAn increasing incidence of positive blood cultures has been reported in several countries. This represents an important challenge for public health due to the large number of hospital admissions with high mortality among these patients. This study aims to characterize the epidemiology and mortality associated with positive blood cultures.Study design and methodsWe performed a nationwide cohort study, identifying all individuals with a blood culture drawn in Denmark from 2010 to 2022. We estimated the incidence of positive blood cultures and 30-day mortality per 100,000 individuals and modeled the case fatality rate (CFR) and population incidences with regression techniques.ResultsWe identified almost 4 million blood cultures drawn during the study period, increasing 64% from 220,757 in 2010 to 362,239 in 2022. During this period, the underlying population increased only 10%, whereas the population of older adults above 85 years increased 3.3 times. The positivity rate was 9.8%, and the most common pathogens were Escherichia coli (29%) and other pathogens associated with urinary tract infection, whereas Staphylococcus aureus accounted for 12%, and Enterococcus faecium for 4.1%. The 30-day CFR was 17% with a small reduction during the study period, with notable differences according to species.ConclusionWe found a substantial rise in blood culture activity and the incidence of positive cultures. This rise is driven by an increasing number of older citizens, which is expected to increase further in the coming years. Considering the high risk of mortality and increasing incidence, a national surveillance of bacteremia is warranted.

Except for a few countries, comprehensive all-cause surveillance for bacteremia is not part of mandatory routine public health surveillance. We argue that time has come to include automated surveillance for bacteremia in the national surveillance systems, and explore diverse approaches and challenges in establishing bacteremia monitoring. Assessed against proposed criteria, surveillance for bacteremia should be given high priority. This is based on severity, burden of illness, health gains obtained by improved treatment and prevention, risk of outbreaks (including health care associated infections), the emergence of antimicrobial drug resistance as well as the changing epidemiology of bacteremia which is seen along with an aging population and advances in medical care. The establishment of comprehensive surveillance for bacteremia was until recently conceived as an insurmountable task. With computerized systems in clinical microbiology, surveillance by real-time data capture has become achievable. This calls for re-addressing the question of including bacteremia among the conditions under mandatory surveillance. Experiences from several countries, including Denmark, show that this is feasible. We propose enhanced international collaboration, legislative action, and funding to address the challenges and opportunities.

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.

IntroductionHerpes virus infections are a major concern after solid organ transplantation and linked to the immune function of the recipient. We aimed to determine the incidence of positive herpes virus (cytomegalovirus (CMV), Epstein-Barr virus (EBV), herpes simplex virus type 1/2 (HSV-1/2), and varicella zoster virus (VZV)) PCR tests during the first year post-transplantation and assess whether a model including immune function pre-transplantation and three months post-transplantation could predict a subsequent positive herpes virus PCR.MethodsAll participants were preemptively screened for CMV, and EBV IgG-negative participants were screened for EBV during the first year post-transplantation. Herpes virus PCR tests for all included herpes viruses (CMV, EBV, HSV-1/2, and VZV) were retrieved from the Danish Microbiology database containing nationwide PCR results from both hospitals and outpatient clinics. Immune function was assessed by whole blood stimulation with A) LPS, B) R848, C) Poly I:C, and D) a blank control. Cytokine concentrations (TNF-α, IL-1β, IL-6, IL-8, IL-10, IL-12p40, IL-17A, IFN-α, and IFN-γ) were measured using Luminex.ResultsWe included 123 liver (54%), kidney (26%), and lung (20%) transplant recipients. The cumulative incidence of positive herpes virus PCR tests was 36.6% (95% CI: 28.1-45.1) during the first year post-transplantation. The final prediction model included recipient age, type of transplantation, CMV serostatus, and change in Poly I:C-induced IL-12p40 from pre-transplantation to three months post-transplantation. The prediction model had an AUC of 77% (95% CI: 61-92). Risk scores were extracted from the prediction model, and the participants were divided into three risk groups. Participants with a risk score 10 (27% of the cohort) had a cumulative incidence of having a positive herpes virus PCR test at 5.8%, 25%, and 73%, respectively (p < 0.001)ConclusionIn conclusion, the incidence of positive herpes virus PCR tests was high, and a risk model including immune function allowed the prediction of positive herpes virus PCR and may be used to identify recipients at higher risk.

ABSTRACT: Objectives: Hospital-associated infections with vancomycin-resistant Enterococcus faecium (VREfm) have increased dramatically in Denmark. A cornerstone in infection control is effective cleaning and disinfection. This study investigated the survival and resuscitation/growth of clinical isolates of E. faecium exposed to the chlorine-releasing disinfectant, sodium dichloroisocyanurate plus detergent (NaDCC Plus). Methods: To assess biocide efficacy, we modified a method developed to characterise the dose-time-response of bacteria to antibiotics. E. faecium isolates (n = 59) were screened in 96-well plates containing 50–1400 ppm free available chlorine. Bacteria were exposed for 10 min, after which the biocide was inactivated with a neutralizer. Cells were collected by centrifugation, new broth added, and after 20–22 h, viability was recorded as growth/no growth. For a subset of strains the impact of shorter biocide exposure times were examined, as was the influence of longer incubation times. Results: E. faecium survived exposure to relatively high concentrations of NaDCC Plus, average 415 ppm of free available chlorine (SD ± 78 ppm), compared to recommended in-use concentration (1000 ppm). “Outbreak” clones did not prove more tolerant to NaDCC Plus compared to other VREfm clones, hospital-associated vancomycin-susceptible E. faecium (VSEfm) or community-associated VSEfm. Shorter exposure time and extended incubation time in broth both significantly increased the concentration needed to eradicate E. faecium, with some isolates surviving higher concentrations than the recommended in-use concentration. Conclusion: Our results indicate that if an exposure time of 10 min is not achieved, the efficacy of the disinfectant will not be sufficient.

Abstract Objective: To identify risk factors associated with methicillin-resistant Staphylococcus aureus (MRSA) colonization in neonatal patients during an MRSA outbreak to minimize future outbreaks. Design: Retrospective case-control study. Setting: Level-IV neonatal intensive care unit (NICU) at Copenhagen University Hospital, Rigshospitalet, Denmark. Patients: Neonates with either MRSA or methicillin-susceptible Staphylococcus aureus (MSSA) Methods: Methicillin-resistant Staphylococcus aureus-positive neonates were matched with those colonized or infected with MSSA in a 1:1 ratio. The control group was selected from clinical samples, whereas MRSA-positive neonates were identified from clinical samples or from screening. A total of 140 characteristics were investigated to identify risk factors associated with MRSA acquisition. The characteristics were categorized into three categories: patient, unit, and microbiological characteristics. Results: Out of 1,102 neonates screened for MRSA, between December 2019 and January 2022, 33 were MRSA positive. They were all colonized with an MRSA outbreak clone (spa type t127) and were included in this study. Four patients (12%) had severe infection. Admission due to respiratory diseases, need for intubation, need for peripheral venous catheters, admission to shared rooms with shared toilets and bath facilities in the aisles, and need for readmission were all correlated with later MRSA colonization (P < 0.05). Conclusion: We identified clinically relevant diseases, procedures, and facilities that predispose patients to potentially life-threatening MRSA infections. A specific MRSA reservoir remains unidentified; however, these findings have contributed to crucial changes in our NICU to reduce the number of MRSA infections and future outbreaks.

Background AWaRe is a tool to categorise and guide antibiotic use. Antibiotics are classified in three groups: Access, Watch and Reserve. The Access group contains first choice antibiotics for 25 of the most common infections. Antibiotics in the Watch and Reserve groups should be restricted to cases that cannot be effectively treated with drugs from the Access group.Objectives The primary aim of this study was to evaluate and adapt the WHO 2019 AWaRe classification for use with antibiotic usage data in Danish hospitals. The secondary aim was to study the usefulness of the abxaware; software package for visualisation and analysis of temporal trends in antibiotic use patterns.Methods We obtained data on purchases of antibiotics in Danish hospitals from January 2015 to July 2021. Sixty-seven unique drugs had been purchased. To better correspond with Danish guidelines, we moved two drugs one AWaRe level upwards. To help aggregate antibiotics according to AWaRe and visualise use patterns, we developed an R package, abxaware.Results After adding two drugs that were not included in the original AWaRe classification nearly all antibiotics (>99%) used in Danish hospitals were covered. The abxaware software package for R is a useful tool to help aggregate, visualise and analyse antibiotic use patterns.Conclusions With minor modifications, we adapted the AWaRe classification to cover most antibiotics used in Danish hospitals and to reflect Danish treatment guidelines. The abxaware package is a useful tool to aggregate and plot antibiotic usage data according to the AWaRe classification and to test for non-random variation in the percentage use of Access antibiotics.

Abstract Background Bacterial and fungal bloodstream infections (BSI) are common after pediatric liver and kidney transplantations and associated with morbidity and mortality. However, knowledge about incidence rates, pathogen composition, and resistance patterns is limited. We aimed to describe the pattern of bacterial and fungal BSI in a cohort of pediatric liver and kidney transplant recipients. Methods A prospective study of 85 pediatric liver and kidney transplant recipients transplanted from 2010 to 2017 with a total of 390 person-years of follow-up. Clinical characteristics and BSI were retrieved from national registries assuring nationwide follow-up for at least 1 year. BSI incidence rates and pathogen composition were investigated and stratified by the time post-transplantation and type of transplanted organ. Results A total of 29 BSI were observed within the first 5 years post-transplantation with 16 different pathogens. The overall incidence rate of first BSI was 1.91 per 100 recipients per month (95% CI, 1.1–3.1) in the first year post-transplantation. The most common pathogens were Enterococcus faecium, Candida albicans, Escherichia coli, and Klebsiella pneumoniae. The pathogen composition depended on the transplanted organ with a higher proportion of BSI with Enterobacterales in kidney transplant recipients than in liver transplant recipients (67% vs. 20%, p = 0.03), while multiple pathogens were detected in the liver transplant recipients. Conclusions BSI were common in pediatric liver and kidney transplant recipients and the pathogen composition differed between liver and kidney transplant recipients. Guidelines for empiric antibiotic therapy should consider the type of transplanted organ as well as the local resistance patterns.

Summary: 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.

ABSTRACT The purpose of this trial was to evaluate the efficacy of a 4-week supplementation of Lactobacillus rhamnosus GG (LGG) in eliminating the gastrointestinal carrier state of vancomycin-resistant Enterococcus faecium (VREfm) in hospitalized adults. The primary outcome of the study was the number of patients with cleared VREfm colonization after the 4-week intervention. Secondary outcomes were clearance of VREfm colonization at weeks 8, 16, and 24, number of VREfm infections (isolated from nonintestinal foci), and changes in fecal microbiome diversity after the intervention. The trial was a multicenter, randomized, double-blind, placebo-controlled trial in hospitalized adult VREfm carriers. Patients were enrolled and randomized to receive 60 billion CFU of LGG daily or placebo for 4 weeks. For a subgroup of patients, rectal swabs for VREfm were collected also at 8, 16, and 24 weeks and analyzed using shotgun metagenomics. Patients ingesting a minimum of 50% of the probiotic during the 4-week intervention were included in subsequent outcome analyses (48 of 81 patients). Twelve of 21 patients in the LGG group (57%) compared to 15 of 27 patients in the placebo group (56%) cleared their VREfm carriage. Eighteen patients completed the entire 24-week intervention with the same minimum compliancy. Of these, almost 90% in both groups cleared their VREfm carriage. We found a statistically significant difference between VREfm clearers and nonclearers regarding metronidazole and vancomycin usage as well as length of hospitalization after inclusion. The microbiome analyses revealed no significant difference in alpha diversity between the LGG and the placebo group. Beta diversity differed between the groups and the different time points. This study did not show an effect of LGG in eradication of VREfm after a 4-week intervention. IMPORTANCE Whereas other studies exploring the effect of L. rhamnosus in clearing VREfm from the intestine included children and adults, with a wider age range, our study consisted of a geriatric patient cohort. The natural clearance of VREfm in this study was almost 60% after 4 weeks, thus much higher than described previously. Also, this study characterizes the microbiome of VREfm patients in detail. This article showed no effect of the probiotic L. rhamnosus in clearing VREfm from the intestine of patients.

BackgroundThe SARS-CoV-2 pandemic has resulted in an unprecedented level of worldwide testing for epidemiologic and diagnostic purposes, and due to the extreme need for tests, the gold-standard Reverse Transcription Polymerase Chain Reaction (RT-PCR) testing capacity has been unable to meet the overall worldwide testing demand. Consequently, although the current literature has shown the sensitivity of rapid antigen tests (RATs) to be inferior to RT-PCR, RATs have been implemented on a large scale without solid data on performance. ObjectiveThis study will compare analytical and clinical sensitivities and specificities of 50 lateral flow– or laboratory-based RATs and 3 strand invasion–based amplification (SIBA)-RT-PCR tests from 30 manufacturers to RT-PCR testing of samples obtained from the deep oropharynx. In addition, the study will compare sensitivities and specificities of the included RATs as well as RT-PCR on clinical samples obtained from the deep oropharynx, the anterior nasal cavity, saliva, the deep nasopharynx, and expired air to RT-PCR on deep oropharyngeal samples. MethodsIn the prospective part of the study, 200 individuals found SARS-CoV-2 positive and 200 individuals found SARS-CoV-2 negative by routine RT-PCR testing will be retested with each RAT, applying RT-PCR as the reference method. In the retrospective part of the study, 304 deep oropharyngeal cavity swabs divided into 4 groups based on RT-PCR quantification cycle (Cq) levels will be tested with each RAT. ResultsThe results will be reported in several papers with different aims. The first paper will report retrospective (analytical sensitivity, overall and stratified into different Cq range groups) and prospective (clinical sensitivity) data for RATs, with RT-PCR as the reference method. The second paper will report results for RAT based on anatomical sampling location. The third paper will compare different anatomical sampling locations by RT-PCR testing. The fourth paper will focus on RATs that rely on central laboratory testing. Tests from 4 different manufacturers will be compared for analytical performance data on retrospective deep oropharyngeal swab samples. The fifth paper will report the results of 4 RATs applied both as professional use and as self-tests. The last paper will report the results from 2 breath tests in the study. A comparison of sensitivity and specificity between RATs will be conducted using the McNemar test for paired samples and the chi-squared test for unpaired samples. Comparison of the positive predictive value (PPV) and negative predictive value (NPV) between RATs will be performed by the bootstrap test, and 95% CIs for sensitivity, specificity, PPV, and NPV will be calculated as bootstrap CIs. ConclusionsThe study will compare the sensitivities of a large number of RATs for SARS-CoV-2 to with those of RT-PCR and will address whether lateral flow–based RATs differ significantly from laboratory-based RATs. The anatomical test locations for both RATs and RT-PCR will also be compared. Trial RegistrationClinicalTrials.gov NCT04913116; https://clinicaltrials.gov/ct2/show/NCT04913116 International Registered Report Identifier (IRRID)DERR1-10.2196/35706

Objectives: The aim of the study was to molecularly characterize third-generation cephalosporin-resistant Klebsiella pneumoniae isolated from bloodstream infections in Denmark in 2018 using whole-genome sequencing (WGS) data, and to compare these isolates to the most common clones detected in 2006 and 2008. Methods: Sixty-two extended-spectrum beta-lactamase (ESBL)/AmpC-producing K. pneumoniae isolates from Danish blood cultures from 2018 were analysed using WGS to obtain multilocus sequence typing (MLST), core genome MLST (cgMLST), resistance profile and phylogeny. These were compared to the most common ESBL K. pneumoniae clones detected in 2006 and 2008. Results: The most common ESBL clone was ST15 CTX-M-15, the DHA-1 enzyme was the most common in AmpC isolates, and the OXA-48-like group was the most common carbapenemase. Thirty-nine different sequence types (STs) were found, with the most frequent being ST14, ST15 and ST37, accounting for 24% of the isolates. The isolates were subdivided into 55 complex types (CTs) of which 49 were singletons, with the most frequent being ST14-CT2080. Two of the CTX-M-15-producing isolates from 2018 belonged to the ST15-CT105/CT3078 clone, which was first detected in 2006. Conclusions: The ESBL/AmpC K. pneumoniae isolates detected in Danish blood cultures belonged to many different types. No dominant clones were circulating in Danish hospitals, but the ST15-CT105/CT3078 CTX-M-15 K. pneumoniae clone was seen 13 years after its first detection.

Abstract 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

IntroductionInfectious spondylodiscitis is a rare infection of the intervertebral disc and the adjacent vertebral bodies that often disseminates and requires long-term antibiotic therapy. Immunologic profiling of patients with infectious spondylodiscitis could allow for a personalized medicine strategy. We aimed to examine the induced immune response in patients with infectious spondylodiscitis during and after antibiotic therapy. Furthermore, we explored potential differences in the induced immune response depending on the causative pathogen and the dissemination of the disease.MethodsThis was a prospective observational cohort study that enrolled patients with infectious spondylodiscitis between February 2018 and August 2020. A blood sample was collected at baseline, after four to six weeks of antibiotic therapy (during antibiotic therapy), and three to seven months after end of antibiotic therapy (post-infection). The induced immune response was assessed using the standardized functional immune assay TruCulture®. We used a panel of three immune cell stimuli (lipopolysaccharide, Resiquimod and polyinosinic:polycytodylic acid) and an unstimulated control. For each stimulus, the induced immune response was assessed by measuring the released concentration of Interleukin (IL)-1β, IL-6, IL-8, IL-10, IL-12p40, IL-17A, Interferon-γ (IFN-γ) and Tumor necrosis factor-α (TNF-α) in pg/mL.ResultsIn total, 49 patients with infectious spondylodiscitis were included. The induced immune responses were generally lower than references at baseline, but the cytokine release increased in patients after treatment with antibiotic therapy. Post-infection, most of the released cytokine concentrations were within the reference range. No significant differences in the induced immune responses based on stratification according to the causative pathogen or dissemination of disease were found.ConclusionWe found lower induced immune responses in patients with infectious spondylodiscitis at baseline. However, post-infection, the immune function normalized, indicating that an underlying immune deficiency is not a prominent factor for spondylodiscitis. We did not find evidence to support the use of induced immune responses as a tool for prediction of the causative pathogen or disease dissemination, and other methods should be explored to guide optimal treatment of patients with infectious spondylodiscitis.

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.

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 (≥102 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]. Keywords: Cystitis, AUC, UTI, Amdinocillin pivoxil, Pivmecillinam, RCT

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.

Abstract 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.

As part of a national surveillance programme initiated in 2004, fungal blood isolates from 2016–2018 underwent species identification and EUCAST susceptibility testing. The epidemiology was described and compared to data from previous years. In 2016–2018, 1454 unique isolates were included. The fungaemia rate was 8.13/100,000 inhabitants compared to 8.64, 9.03, and 8.38 in 2004–2007, 2008–2011, and 2012–2015, respectively. Half of the cases (52.8%) involved patients 60–79 years old and the incidence was highest in males ≥70 years old. Candida albicans accounted for 42.1% of all isolates and Candida glabrata for 32.1%. C. albicans was more frequent in males (p = 0.03) and C. glabrata in females (p = 0.03). During the four periods, the proportion of C. albicans decreased (p < 0.001), and C. glabrata increased (p < 0.001). Consequently, fluconazole susceptibility gradually decreased from 68.5% to 59.0% (p < 0.001). Acquired fluconazole resistance was found in 4.6% Candida isolates in 2016–2018. Acquired echinocandin resistance increased during the four periods 0.0%, 0.6%, 1.7% to 1.5% (p < 0.0001). Sixteen echinocandin-resistant isolates from 2016–2018 harboured well-known FKS resistance-mutations and one echinocandin-resistant C. albicans had an FKS mutation outside the hotspot (P1354P/S) of unknown importance. In C. glabrata specifically, echinocandin resistance was detected in 12/460 (2.6%) in 2016–2018 whereas multidrug-class resistance was rare (1/460 isolates (0.2%)). Since the increase in incidence during 2004–2011, the incidence has stabilised. In contrast, the species distribution has changed gradually over the 15 years, with increased C. glabrata at the expense of C. albicans. The consequent decreased fluconazole susceptibility and the emergence of acquired echinocandin resistance complicates the management of fungaemia and calls for antifungal drug development.

Objectives: TREAT, a decision support system for antimicrobial therapy, was implemented in an acute medical ward. Methods: Patients admitted on suspicion of infection were included in the study. The evaluation of TREAT was done both retrospectively and prospectively. Coverage of empirical antimicrobial treatments was compared to recommendations from TREAT and the optimal use of local guidelines. Results: Five hundred and eleven patients were included, of whom 162 had a microbiologically documented infection. In the retrospective part of the study, TREAT, physician, and guideline antimicrobial coverage rates were 65%, 51%, and 79%, respectively, and in the prospective part, 68%, 62%, and 77%, respectively. TREAT provided lower coverage than local guidelines (p

Objectives: To investigate pivmecillinam´s efficacy in uncomplicated lower urinary tract infection (UTI) caused by Staphylococcus saprophyticus—considered non-susceptible to mecillinam. Methods: Participants with confirmed UTIs caused by S. saprophyticus from four randomized controlled trials, where pivmecillinam was empirically given to females with symptoms of UTIs. The primary outcome was defined as a cumulative clinical effect—symptom resolution during the first eight days of therapy, without a recurrence of UTI symptoms in the long-term follow-up (approximately four weeks). Secondary outcomes included the bacteriological effect—elimination of the causative agent, with or without new uropathogenic bacteria present in the first control urine sample. Significant bacteriuria was defined as ≥103 bacteria/mL. The antibiotic susceptibility testing was done by disc diffusion methodology, according to the European Committee on Antimicrobial Susceptibility Testing (EUCAST). Results: Seventy-four females (18−55 years) were empirically treated with pivmecillinam for UTIs caused by S. saphrophyticus (mean age 25 years; standard deviation (SD) 5.8). The cumulative clinical effect was 53/74 (72%), and the bacteriological effect was 51/59 (86%). Conclusion: Pivmecillinam showed a high clinical and bacteriological effect in UTIs caused by S. saprophyticus in these four clinical trials. The characterization of non-susceptibility for mecillinam regarding the treatment of UTIs caused by this common pathogen may need to be revised.

Bacteraemia is associated with significant morbidity and mortality and timely access to relia-ble information is essential for health care administrators. Therefore, we investigated the complete-ness of bacteraemia registration in the Danish National Patient Registry (DNPR) containing hospital discharge diagnoses and surgical procedures for all non-psychiatric patients. As gold standard we identified bacteraemia patients in three defined areas of Denmark (~2.3 million inhabitants) from 2000 through 2011 by use of blood culture data retrieved from electronic microbiology databases. Diagnoses coded according to the International Classification of Diseases, version 10, and surgical procedure codes were retrieved from the DNPR. The codes were categorized into seven groups, ranked a priori according to the likelihood of bacteraemia. Completeness was analysed by contin-gency tables, for all patients and subgroups. We identified 58,139 bacteraemic episodes in 48,450 patients; 37,740 episodes (64.9%) were covered by one or more discharge diagnoses within the sev-en diagnosis/surgery groups and 18,786 episodes (32.3%) had a code within the highest priority group. Completeness varied substantially according to speciality (from 17.9% for surgical to 36.4% for medical), place of acquisition (from 26.0% for nosocomial to 36.2% for community), and mi-croorganism (from 19.5% for anaerobic Gram-negative bacteria to 36.8% for haemolytic strepto-cocci). The completeness increased from 25.1% in 2000 to 35.1% in 2011. In conclusion, one third of the bacteraemic episodes did not have a relevant diagnosis in the Danish administrative registry recording all non-psychiatric contacts. This source of information should be used cautiously to iden-tify patients with bacteraemia.

In response to a considerable increase in the infections caused by ESBL/AmpC-producing Klebsiella pneumonia in 2008, a multidisciplinary intervention, with a main focus on antimicrobial stewardship, was carried out at one university hospital. Four other hospitals were used as controls. Stringent guidelines for antimicrobial treatment and prophylaxis were disseminated throughout the intervention hospital; cephalosporins were restricted for prophylaxis use only, fluoroquinolones for empiric use in septic shock only, and carbapenems were selected for penicillin-allergic patients, infections due to ESBL/AmpC-producing and other resistant bacteria, in addition to their use in severe sepsis/septic shock. Piperacillin-tazobactam ± gentamicin was recommended for empiric treatments of most febrile conditions. The intervention also included education and guidance on infection control, as well as various other surveillances. Two year follow-up data on the incidence rates of patients with selected bacterial infections, outcomes, and antibiotic consumption were assessed, employing before-and-after analysis and segmented regression analysis of interrupted time series, using the other hospitals as controls. The intervention led to a sustained change in antimicrobial consumption, and the incidence of patients infected with ESBL-producing K. pneumoniae decreased significantly (p

BackgroundThere is limited knowledge of serotypes that cause non-bacteremic pneumococcal pneumonia (NBP). Here we report serotypes, their associated disease potential and coverage of pneumococcal conjugate vaccines (PCV) in adults with NBP and compare these to bacteremic pneumonia (BP).MethodsAdults with pneumonia and Streptococcus pneumoniae isolated from the lower respiratory tract or blood were included 1 year in a population-based design in Denmark. Pneumonia was defined as a new infiltrate on chest radiograph in combination with clinical symptoms or elevated white blood count or plasma C-reactive protein. All isolates were serotyped using type-specific pneumococcal rabbit antisera. All values are medians with interquartile ranges.ResultsThere were 272 cases of NBP and 192 cases of BP. Ninety-nine percent were hospitalized. NBP and BP cases were of comparable age and sex but NBP cases had more respiratory symptoms and less severe disease compared to BP cases. In total, 46 different serotypes were identified. Among NBP cases, 5 serotypes accounted for nearly a third of isolates. PCV10 and -13 types covered 17% (95% confidence interval (CI): 11-23%) and 34% (95% CI: 25-43%) of NBP isolates, respectively. In contrast, the five most frequent serotypes accounted for two-thirds of BP isolates. PCV10 and -13 types covered 39% (95% CI: 30-48%) and 64% (95% CI: 48-79) of BP isolates, respectively. More severe NBP disease was associated with infection with invasive serotypes while there was an inverse relationship for BP.ConclusionsOnly a third of cases of adult non-bacteremic pneumococcal pneumonia would potentially be preventable with the use of PCV13 and just one sixth of cases with the use of PCV10 indicating that PCVs with increased valency are needed to increase vaccine coverage for NBP in adults. PCV13 could potentially prevent two-thirds of adult bacteremic pneumococcal pneumonia.