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Background The aminoglycoside apramycin has been proposed as a drug candidate for the treatment of critical Gram-negative systemic infections. However, the potential of apramycin in the treatment of drug-resistant bloodstream infections (BSIs) has not yet been assessed. Methods The resistance gene annotations of 40 888 blood-culture isolates were analysed. In vitro profiling of apramycin comprised cell-free translation assays, broth microdilution, and frequency of resistance determination. The efficacy of apramycin was studied in a mouse peritonitis model for a total of nine Escherichia coli and Klebsiella pneumoniae isolates. Results Genotypic aminoglycoside resistance was identified in 87.8% of all 6973 carbapenem-resistant Enterobacterales blood-culture isolates, colistin resistance was shown in 46.4% and apramycin in 2.1%. Apramycin activity against methylated ribosomes was > 100-fold higher than that for other aminoglycosides. Frequencies of resistance were < 10-9 at 8 × minimum inhibitory concentration (MIC). Tentative epidemiological cut-offs (TECOFFs) were determined as 8 µg/mL for E. coli and 4 µg/mL for K. pneumoniae. A single dose of 5 to 13 mg/kg resulted in a 1-log colony-forming unit (CFU) reduction in the blood and peritoneum. Two doses of 80 mg/kg resulted in an exposure that resembles the AUC observed for a single 30 mg/kg dose in humans and led to complete eradication of carbapenem- and aminoglycoside-resistant bacteraemia. Conclusion Encouraging coverage and potent in vivo efficacy against a selection of highly drug-resistant Enterobacterales isolates in the mouse peritonitis model warrants the conduct of clinical studies to validate apramycin as a drug candidate for the prophylaxis and treatment of BSI., Niels Frimodt-Møller, Diarmaid Hughes, Carina Vingsbo Lundberg and Sven N. Hobbie share senior authorship

Background: Population-based studies have shown an increased risk of dementia after infections, but weaker links were reported for autoimmune diseases. Evidence is scarce for whether the links may be modified by the dementia or exposure subtype. Objective: We aimed to investigate the association between infections and/or autoimmune diseases and rates of major types of dementias in the short- and long terms. Methods: Nationwide nested case-control study of dementia cases (65+ years) diagnosed in Denmark 2016–2020 and dementia-free controls. Exposures were hospital-diagnosed infections and autoimmune diseases in the preceding 35 years. Two groups of dementia cases were those diagnosed in memory clinics (MC) and those diagnosed outside memory clinics (non-memory clinic cases, NMC). Results: In total, 26,738 individuals were MC and 12,534 were NMC cases. Following any infection, the incidence rate ratio (IRR) for MC cases was 1.23 (95% CI 1.20–1.27) and 1.70 for NMC cases (1.62–1.76). Long-term increased rates were seen for vascular dementia and NMC cases. IRRs for autoimmune diseases were overall statistically insignificant. Conclusions: Cases with vascular dementia and not Alzheimer’s disease, and a subgroup of cases identified with poorer health have increased long-term risk following infections. Autoimmune diseases were not associated with any type of dementia. Notably increased risks (attributed to the short term) and for NMC cases may indicate that immunosenescence rather than de novo infection explains the links. Future focus on such groups and on the role of vascular pathology will explain the infection-dementia links, especially in the long term., Background: Population-based studies have shown an increased risk of dementia after infections, but weaker links were reported for autoimmune diseases. Evidence is scarce for whether the links may be modified by the dementia or exposure subtype. Objective: We aimed to investigate the association between infections and/or autoimmune diseases and rates of major types of dementias in the short- and long terms. Methods: Nationwide nested case-control study of dementia cases (65+ years) diagnosed in Denmark 2016–2020 and dementia-free controls. Exposures were hospital-diagnosed infections and autoimmune diseases in the preceding 35 years. Two groups of dementia cases were those diagnosed in memory clinics (MC) and those diagnosed outside memory clinics (non-memory clinic cases, NMC). Results: In total, 26,738 individuals were MC and 12,534 were NMC cases. Following any infection, the incidence rate ratio (IRR) for MC cases was 1.23 (95% CI 1.20–1.27) and 1.70 for NMC cases (1.62–1.76). Long-term increased rates were seen for vascular dementia and NMC cases. IRRs for autoimmune diseases were overall statistically insignificant. Conclusions: Cases with vascular dementia and not Alzheimer’s disease, and a subgroup of cases identified with poorer health have increased long-term risk following infections. Autoimmune diseases were not associated with any type of dementia. Notably increased risks (attributed to the short term) and for NMC cases may indicate that immunosenescence rather than de novo infection explains the links. Future focus on such groups and on the role of vascular pathology will explain the infection-dementia links, especially in the long term.

Objective To evaluate the implementation of switch from intravenous-to-oral antibiotic therapy with amoxicillin in neonates with early-onset infection (EOI). Design, setting and patients A population-based multicentre cohort study. All term-born neonates with EOI were prospectively included between 1 December 2018 to 30 November 2020. Intervention Intravenous-to-oral switch antibiotic therapy in clinically stable neonates. Main outcome measures The primary outcome was readmission due to infection. Secondary outcomes were days of hospitalisation and antibiotic use in the pre-implementation versus post implementation period. Results During 2 years, 835 neonates commenced antibiotics for EOI (1.5% (95% CI 1.4% to 1.6%)) of all term live births). Of those, 554 (66%) underwent a full course of treatment. There were 23 episodes of culture-proven infection (0.42 per 1000 term live births (95% CI 0.27 to 0.63)). A total of 478 of 531 (90%) neonates with probable infection underwent switch therapy. None was readmitted due to infection. The median duration of hospitalisation was 3.0 days (IQR 2.5–3.5) and 7.4 days (IQR 7.0–7.5) in the switch and intravenous therapy groups, respectively. According to antibiotic surveillance data, 1.2% underwent a full course of treatment following implementation of oral switch therapy (2019–2020), compared with 1.2% before (2017–2018). Conclusion In clinical practice, switch therapy was safe and used in 9 of 10 neonates with probable EOI. Knowledge of the safety of antibiotic de-escalation is important as home-based oral therapy ameliorates the treatment burden for neonates, caregivers and healthcare systems. Despite the ease of oral administration, implementation of switch therapy did not increase the overall use of antibiotics., Objective: To evaluate the implementation of switch from intravenous-to-oral antibiotic therapy with amoxicillin in neonates with early-onset infection (EOI). Design, setting and patients: A population-based multicentre cohort study. All term-born neonates with EOI were prospectively included between 1 December 2018 to 30 November 2020. Intervention: Intravenous-to-oral switch antibiotic therapy in clinically stable neonates. Main outcome measures: The primary outcome was readmission due to infection. Secondary outcomes were days of hospitalisation and antibiotic use in the pre-implementation versus post implementation period. Results: During 2 years, 835 neonates commenced antibiotics for EOI (1.5% (95% CI 1.4% to 1.6%)) of all term live births). Of those, 554 (66%) underwent a full course of treatment. There were 23 episodes of culture-proven infection (0.42 per 1000 term live births (95% CI 0.27 to 0.63)). A total of 478 of 531 (90%) neonates with probable infection underwent switch therapy. None was readmitted due to infection. The median duration of hospitalisation was 3.0 days (IQR 2.5-3.5) and 7.4 days (IQR 7.0-7.5) in the switch and intravenous therapy groups, respectively. According to antibiotic surveillance data, 1.2% underwent a full course of treatment following implementation of oral switch therapy (2019-2020), compared with 1.2% before (2017-2018). Conclusion: In clinical practice, switch therapy was safe and used in 9 of 10 neonates with probable EOI. Knowledge of the safety of antibiotic de-escalation is important as home-based oral therapy ameliorates the treatment burden for neonates, caregivers and healthcare systems. Despite the ease of oral administration, implementation of switch therapy did not increase the overall use of antibiotics.

This study aimed to investigate the role played by pets as reservoirs of Escherichia coli strains causing human urinary tract infections (UTIs) in household contacts. Among 119 patients with community-acquired E. coli UTIs, we recruited 19 patients who lived with a dog or a cat. Fecal swabs from the household pet(s) were screened by antimicrobial selective culture to detect E. coli displaying the resistance profile of the human strain causing UTI. Two dogs shed E. coli isolates indistinguishable from the UTI strain by pulsed-field gel electrophoresis. Ten months later, new feces from these dogs and their owners were screened selectively and quantitatively for the presence of the UTI strain, followed by core-genome phylogenetic analysis of all isolates. In one pair, the resistance phenotype of the UTI strain occurred more frequently in human (108 CFU/g) than in canine feces (104 CFU/g), and human fecal isolates were more similar (2–7 SNPs) to the UTI strain than canine isolates (83–86 SNPs). In the other pair, isolates genetically related to the UTI strain (23–40 SNPs) were only detected in canine feces (105 CFU/g). These results show that dogs can be long-term carriers of E. coli strains causing UTIs in human household contacts.

Objectives: It is unknown whether invasive procedures are associated with brain abscess. Methods: Nationwide, population-based, matched case–control study of patients with culture verified brain abscess in Denmark from 1989 to 2016. Exposure was invasive procedures 0–6 months before study inclusion. Results: We identified 435 patients and 3909 controls. The level of comorbidity was higher among patients with brain abscess than among controls. A total of 48 cases (11%) had one or more invasive procedures 0–6 months before study inclusion (adjusted odds ratios (aOR) of 3.6 (95% confidence interval (CI): 2.5–5.1), a population attributable fractions of 8% (95% CI: 7–9)). In primary care, ear, nose and throat (ENT) procedures were associated with brain abscess (aOR of 4.0 (95% CI: 2.0–8.0)), but gastrointestinal endoscopies were not (aOR of 1.0 (95% CI: 0.3–3.2)). No bronchoscopies were performed in primary care. In the hospital-based setting, ENT procedures, bronchoscopies and gastrointestinal endoscopies were associated with an increased risk of brain abscess (aOR of 14.5 (95% CI: 4.8–43.8), 20.3 (95% CI: 3.8–110.1) and 3.4 (95% CI: 2.0–5.6), respectively). Conclusions: The association between invasive procedures and brain abscess was more pronounced in the hospital-based setting than in primary care.

Importance: Systemic inflammation has been suggested to explain reported associations between infections and dementia. Associations between autoimmune diseases and dementia also suggest a role for peripheral systemic inflammation. Objective: To investigate the associations of infections and autoimmune diseases with subsequent dementia incidence and to explore potential shared signals presented by the immune system in the 2 conditions. Design, Setting, and Participants: This nationwide, population-based, registry-based cohort study was conducted between 1978 and 2018 (40-year study period). All Danish residents born 1928 to 1953, alive and in Denmark on January 1, 1978, and at age 65 years were included. Persons with prior registered dementia and those with HIV infections were excluded. Data were analyzed between May 2022 and January 2023. Exposures: Hospital-diagnosed infections and autoimmune diseases. Main Outcomes and Measures: All-cause dementia, defined as the date of a first registered dementia diagnosis after age 65 years in the registries. Poisson regression with person-years at risk as an offset variable was used to analyze time to first dementia diagnosis. Results: A total of 1493896 individuals (763987 women [51%]) were followed for 14093303 person-years (677147 [45%] with infections, 127721 [9%] with autoimmune diseases, and 75543 [5%] with dementia). Among individuals with infections, 343504 (51%) were men, whereas among those with autoimmune diseases, 77466 (61%) were women. The dementia incidence rate ratio (IRR) following any infection was 1.49 (95% CI, 1.47-1.52) and increased along with increasing numbers of infections in a dose-dependent manner. Dementia rates were increased for all infection sites in the short term, but not always in the long term. The dementia IRR following any autoimmune disease was 1.04 (95% CI, 1.01-1.06), but no dose-dependent increase was observed, and only a few autoimmune conditions showed increased IRRs for dementia.

INTRODUCTION: Urinary tract infections (UTIs) are associated with 25-40% of antibiotics consumed in primary care and are, therefore, driving antibiotic resistance. The worldwide increase in antibiotic resistance especially in Escherichia coli has complicated the treatment choices for UTIs and absence of effective oral antibiotics may lead to increasing need for more effective treatments.AREAS COVERED: In this review we focus on the importance of the correct diagnosis of UTI as based on proof of urinary pathogens in the urine and discuss diagnostic measures including microscopy, dipstick, and culture. Antibiotic treatment can often await diagnostic measures with pain relief such as ibuprofen. The risk of an uncomplicated UTI leading to pyelonephritis is low (1-2%) and presence of bacteria in the bladder leaves some time for the immune system to react. Three antibiotics are recommended as based on their activity, and low propensity to select for resistance, i.e. nitrofurantoin, fosfomycin, and pivmecillinam, and in general, 3-5 days of treatment will suffice.EXPERT OPINION: Understanding the usual benign course of uUTIs can help reduce antibiotic treatment in many cases, e.g. starting treatment by pain relief and awaiting the course of infection without antibiotics. Better rapid tests in primary care are urgently needed to enforce such policies.

Background It is unknown whether patients diagnosed with brain abscess have an increased risk of psychiatric disorders. Methods In this nationwide, population-based matched cohort study from Denmark, we compared the incidence of psychiatric disorders, use of psychiatric hospitals, and receipt of psychiatric medications between patients diagnosed with brain abscess and individuals from the general population, matched on date of birth, sex, and residential area. Results We included 435 patients diagnosed with brain abscess and 3909 individuals in the comparison cohort: 61% were male and median age was 54 years. Patients diagnosed with brain abscess were more likely to suffer from comorbidity. The risk of a hospital diagnosis of psychiatric disorders was increased the first 5 years of observation. In the subpopulation, who had never been in contact with psychiatric hospitals or received psychiatric medication before study inclusion, the risk of developing psychiatric disorders was close to that of the background population, especially when we excluded dementia from this outcome. There was a substantial increase in the receipt of anxiolytics and antidepressants. The difference in the proportion of individuals who received anxiolytics and antidepressants increased from 4% (95% confidence interval [CI], 0%–7%) and 2% (95% CI, −1% to 5%) 2 years before study inclusion to 17% (95% CI, 12%–21%) and 11% (95% CI, 7%–16%) in the year after study inclusion. Conclusions Patients with brain abscess without prior psychiatric disorders or receipt of psychiatric medicine are not at increased risk psychiatric disorders diagnosed in psychiatric hospitals, but they have an increased receipt of psychiatric medication., Background: It is unknown whether patients diagnosed with brain abscess have an increased risk of psychiatric disorders. Methods: In this nationwide, population-based matched cohort study from Denmark, we compared the incidence of psychiatric disorders, use of psychiatric hospitals, and receipt of psychiatric medications between patients diagnosed with brain abscess and individuals from the general population, matched on date of birth, sex, and residential area. Results: We included 435 patients diagnosed with brain abscess and 3909 individuals in the comparison cohort: 61% were male and median age was 54 years. Patients diagnosed with brain abscess were more likely to suffer from comorbidity. The risk of a hospital diagnosis of psychiatric disorders was increased the first 5 years of observation. In the subpopulation, who had never been in contact with psychiatric hospitals or received psychiatric medication before study inclusion, the risk of developing psychiatric disorders was close to that of the background population, especially when we excluded dementia from this outcome. There was a substantial increase in the receipt of anxiolytics and antidepressants. The difference in the proportion of individuals who received anxiolytics and antidepressants increased from 4% (95% confidence interval [CI], 0%-7%) and 2% (95% CI, -1% to 5%) 2 years before study inclusion to 17% (95% CI, 12%-21%) and 11% (95% CI, 7%-16%) in the year after study inclusion. Conclusions: Patients with brain abscess without prior psychiatric disorders or receipt of psychiatric medicine are not at increased risk psychiatric disorders diagnosed in psychiatric hospitals, but they have an increased receipt of psychiatric medication.

Antimicrobial resistance threatens infectious disease management outcomes, especially in developing countries. In this study, the occurrence of resistant coagulase-negative staphylococci (rCoNS) and antibiotic residues in urine samples of 401 healthy individuals from Korle-Gonno (KG) and Dodowa (DDW) in Ghana was investigated. MALDI-ToF/MS with gram-staining techniques detected and identified the CoNS. SPE-LC-MS/MS detected and quantified nine commonly used antibiotics in the samples. The results showed 63 CoNS isolates detected in 47 (12%) samples, with S. haemolyticus (78%) and S. epidermidis (8%) being predominant. Most of the isolates (95%) were resistant to at least one antibiotic, with the highest resistance observed against sulphamethoxazole (87%). Resistance profiles in samples from DDW and KG were largely comparable, but with some differences. For instance, DDW isolates were more resistant to gentamicin (p = 0.0244), trimethoprim (p = 0.0045), and cefoxitin (p = 0.0078), whereas KG isolates were more resistant to erythromycin (p = 0.0356). Although the volunteers had not knowingly consumed antibiotics two weeks before sampling, antibiotic residues, ranging between 1.44–17000 ng mL−1 were identified in 22% of urine samples. Samples with antibiotic residues were likely to also contain rCoNS (89%). The most frequent antibiotics detected were tetracycline (63%) and ciprofloxacin (54%). Healthy individuals could thus be reservoirs of antibiotic residues and rCoNS at the community level.

BACKGROUND: Brain abscesses are frequently caused by oral cavity bacteria, but whether dental status and invasive dental procedures are important risk factors is unknown. METHODS: A nationwide, population-based, case-control study examined the association between dentist's visits and invasive dental procedures and risk of brain abscess caused by oral cavity bacteria from 1989 through 2016. Date of brain abscess diagnosis was considered the index date. Using risk-set sampling, 10 population controls per case were individually matched by age, sex, and residential area. Conditional logistic regression was used to compute odds ratios with 95% confidence intervals (CIs), adjusted for comorbidity. RESULTS: We identified 362 patients with culture-proven brain abscess caused by oral cavity bacteria. The median age was 53 years (interquartile range, 39-65 years) and 220 (61%) were male. Invasive dental procedures within 6 months before the index date was observed in 21 of 362 (6%) patients with brain abscess and 179 of 3257 (5%) population controls (adjusted odds ratio [aOR], 1.07 [95% CI, .67-1.70]). Two hundred thirteen of 362 (59%) patients with brain abscess had visited their dentist within 1 year before the index date compared with 1944 of 3257 (60%) of population controls (aOR, 0.99 [95% CI, .77-1.26]). Using no dentist's visits as reference, we observed aORs of 0.95 (95% CI, .64-1.40) for 1-2 visits within 3 years of the index date and 1.01 (95% CI, .76-1.35) for 3 or more visits. CONCLUSIONS: Recent invasive dental procedures and number of dentist's visits were not associated with culture-verified brain abscess caused by oral cavity bacteria.

Here, we present a longitudinal shotgun sequencing metagenomics study of 16 healthy, Danish women in the reproductive age. The aim of the study was to investigate whether lactobacilli, orally consumed, had any impact on the vaginal microbiome and its functional potential. The 16 women aged 19–45 years were recruited from Copenhagen, Denmark. One baseline vaginal sample (Day 0) and two study samples (Days 25–30 and Days 55–60, respectively), were sampled. The vaginal samples were analyzed by shotgun metagenomics. We detected 26 species in the vaginal microbiota of the 16 women, of which six belonged to the Lactobacillus genus. We observed three vaginal microbiome clusters mainly dominated by Gardnerella vaginalis, Lactobacillus iners, or Lactobacillus crispatus. The oral probiotic had no detectable effect on either the composition or the functional potential of the vaginal microbiota. Most of the study subjects (11 out of 16 women) exhibited only minor changes in the vaginal microbiome during the treatment with probiotics. Any compositional changes could not be associated to the probiotic treatment. Future studies may benefit from an increased number of participants, and administration of the probiotics during conditions with bacterial imbalance (e.g., during/after antibiotic treatment) or the use of different Lactobacillus spp. known to colonize the vagina.