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Objectives: Population-based estimates of excess length of stay after hospital-acquired bacteraemia (HAB) are few and prone to time-dependent bias. We investigated the excess length of stay and readmission after HAB. Methods: This population-based cohort study included the North Denmark Region adult population hospitalized for ≥48 hours, from 2006 to 2018. Using a multi-state model with 45 days of follow-up, we estimated adjusted hazard ratios (aHRs) for end of stay and discharge alive. The excess length of stay was defined as the difference in residual length of stay between infected and uninfected patients, estimated using a non-parametric approach with HAB as time-dependent exposure. Confounder effects were estimated using pseudo-value regression. Readmission after HAB was investigated using the Cox regression. Results: We identified 3457 episodes of HAB in 484 291 admissions in 205 962 unique patients. Following HAB, excess length of stay was 6.6 days (95% CI, 6.2–7.1 days) compared with patients at risk. HAB was associated with decreased probability of end of hospital stay (aHR, 0.60; 95% CI, 0.57–0.62) driven by the decreased hazard for discharge alive; the aHRs ranged from 0.30 (95% CI, 0.23–0.40) for bacteraemia stemming from ‘heart and vascular’ source to 0.72 (95% CI, 0.69–0.82) for the ‘urinary tract’. Despite increased post-discharge mortality (aHR, 2.76; 95% CI, 2.38–3.21), HAB was associated with readmission (aHR, 1.42; 95% CI, 1.31–1.53). Conclusion: HAB was associated with considerably excess length of hospital stay compared with hospitalized patients without bacteraemia. Among patients discharged alive, HAB was associated with increased readmission rates.

BACKGROUND: We wish to study disparities in bloodstream infections in migrants and non-migrants by comparing the distribution of pathogens and their resistance patterns in long-term migrants with that in non-migrants in Denmark.METHODS: The study is based on a cohort of migrants, who received residency in Denmark between 1993 and 2015 and a control group of non-migrants. The cohort was linked to a database of bloodstream infections from 2000 to 2015 covering two regions in Denmark. First-time bloodstream infections in individuals ≥18 years of age at the time of sampling were included. We calculated odds ratios adjusted for age, sex, year of sampling, comorbidity, and place of acquisition (hospital- or community-acquired).RESULTS: We identified 4,703 bloodstream infection cases. Family-reunified migrants and refugees had higher odds of Escherichia coli than non-migrants (OR 1.89 95%CI: 1.46-2.44 and OR 1.55 95%CI: 1.25-1.92) and lower odds of Streptococcus pneumoniae (OR 0.38 95%CI: 0.21-0.67 and OR 0.52 95%CI: 0.34-0.81). Differences in pathogen distribution were only prevalent in community-acquired bloodstream infections. Refugees had higher odds of Escherichia coli resistant to piperacillin-tazobactam, ciprofloxacin, and gentamicin compared with non-migrants. Family-reunified migrants had higher odds of Escherichia coli and other Enterobacterales resistant to ciprofloxacin.CONCLUSIONS: Migrants had a higher proportion of community-acquired bloodstream infections with Escherichia coli as well as higher odds of bloodstream infections with resistant Escherichia coli compared with non-migrants. These novel results are relevant for improving migrant health by focussing on preventing and treating infections especially with Escherichia coli such as urinary tract and abdominal infections.

BACKGROUND: Knowledge on hospital-related interventions as risk factors for hospital-acquired bacteraemia (HAB) is sparse.AIM: We aimed to investigate hospital interventions as risk factors for HAB.METHODS: Prospectively through one year, we identified episodes of HAB in a single tertiary hospital. We used a matched incidence density sampled case-control design. Matching on sex and age group, we sampled controls (1:2) from the adult hospital population with ongoing hospitalization for ≥48 h. Using conditional logistic regression, we estimated odds ratios (OR) with 95% confidence intervals (CI). For adjusted ORs (aOR), adjustments were made for length of hospital stay, type and urgency of admission, and Charlson Comorbidity Index score level.FINDINGS: From 15th October 2019 through 14th October 2020, we identified 115 incident episodes of HAB and matched them with 230 controls. HAB patients were more often admitted as 'medicine or emergency surgery'-patients (94% vs 87%) and had a longer hospital stay before inclusion (median days 20 vs 12). They were more frequently categorized as having a 'low level comorbidity' (58% vs 39%) but had higher prevalence of haematologic (15% vs 6%) or metastatic cancer (13% vs 10%). Our estimates for central venous catheters were aOR of 3.46 (95% CI 1.92-6.23), haemodialysis; aOR 5.05 (95% CI 1.41-18.06), immunosuppressive treatment including chemotherapy; aOR of 1.72 (95% CI 1.00-2.96).CONCLUSION: Central venous catheters and haemodialysis were the most prominent risk factors. Immunosuppressive treatment including therapy may play an important role in the development of HAB.

Although a number of comorbidities have been associated with development of bloodstream infection, actual risk factors have not been well defined and quantified in nonselected populations. We sought to quantify population-based risk factors for development of community-onset bloodstream infection (COBSI). Surveillance was conducted among all residents of the Western Interior of British Columbia, Canada, during 2011-2018. Risks were expressed as incidence rate ratios (IRR) with 95% confidence intervals (CI). The annual incidence was 147.1 per 100,000 and older individuals, and males were at overall higher risk. The median Charlson score was 2 (IQR, 0-3), and this was higher among those with healthcare-associated (2; IQR, 1-4) as compared to community-associated (1; IQR, 0-2; P < 0.0001) COBSI. Risk factors for development of COBSI included (IRR; 95% CI): HIV infection (8.89; 5.17-14.27), cancer (6.80; 6.13-7.54), congestive heart failure (4.68; 4.00-5.46), dementia (3.31; 2.82-3.87), diabetes mellitus (3.10; 2.80-3.42), cerebrovascular accident (2.79; 2.34-3.31), renal dysfunction (2.75; 2.33-3.22), chronic lung disease (2.03; 1.79-2.28), peripheral vascular disease (1.68; 1.39-2.01), and rheumatic disease (1.44; 1.14-1.79). Patients with multiple comorbid illnesses were older, more likely to be male, and have healthcare-associated BSI, higher rates of antimicrobial resistance, and different clinical foci of infection. A number of demographic and comorbid conditions significantly increase the risk for development of COBSI.

OBJECTIVES: To investigate bloodstream infection (BSI) related to migrant status by comparing the incidence and mortality in migrants with that in non-migrants.METHODS: In this register-based cohort study we linked a cohort of migrants and non-migrants with a bacteraemia database covering two regions in Denmark. We included first-time BSI between January 2000 and December 2015 in individuals ≥18 years. Migrants were categorized according to status: refugees or family-reunified migrants. Incidence rate ratio and mortality rate ratio were analysed using Poisson regression.RESULTS: We identified 493 080 non-migrants, of which 3405 had BSI, and 80 740 migrants with 576 cases; of the latter, 40 222 were family-reunified migrants with 226 cases and 40 518 were refugees with 350 cases. Refugees had a higher risk of BSI than non-migrants (adjusted IRR 1.19, 95%CI 1.01-1.40). Family-reunified migrants and refugees had a higher risk of Gram-negative BSIs (adjusted IRR 1.23, 95%CI 1.00-1.51 and 1.57, 95%CI 1.32-1.86), respectively, and a lower risk of Gram-positive BSIs (adjusted IRR 0.65, 95%CI 0.51-0.83 and 0.77, 95%CI 0.63-0.95), respectively, compared to non-migrants. Originating from Southeast Asia and the Pacific was associated with an increased risk of BSI compared to non-migrants (adjusted IRR 1.26, 95%CI 1.07-1.49). We found no differences in the adjusted 30-day or 90-day mortality according to migrant status.CONCLUSIONS: Vulnerability towards BSI differs according to migrant status. Refugees had a higher risk of BSI overall. Both refugees and family-reunified migrants had a higher incidence of Gram-negative BSI than non-migrants. Similarly, migrants from Southeast Asia and the Pacific had a higher risk of BSI than non-migrants.

A total of 714 pediatric cases of Staphylococcus aureus bacteremia were identified from 2008 to 2015 in Denmark; 98% were methicillin-susceptible S. aureus (MSSA). Fifteen isolates (2,1%) were Panton-Valentine leucocidin positive (0.17/100,000 children/year) and 87% MSSA. Eight cases (53%) were severe, including all pneumonia cases. Panton-Valentine leucocidin positive Staphylococcus aureus bacteremia is rare in our setting with high MSSA-prevalence. Half of the cases were uncomplicated.

Background Patients with infective endocarditis on the left side of the heart are typically treated with intravenous antibiotic agents for up to 6 weeks. Whether a shift from intravenous to oral antibiotics once the patient is in stable condition would result in efficacy and safety similar to those with continued intravenous treatment is unknown. Methods In a randomized, noninferiority, multicenter trial, we assigned 400 adults in stable condition who had endocarditis on the left side of the heart caused by streptococcus, Enterococcus faecalis, Staphylococcus aureus, or coagulase-negative staphylococci and who were being treated with intravenous antibiotics to continue intravenous treatment (199 patients) or to switch to oral antibiotic treatment (201 patients). In all patients, antibiotic treatment was administered intravenously for at least 10 days. If feasible, patients in the orally treated group were discharged to outpatient treatment. The primary outcome was a composite of all-cause mortality, unplanned cardiac surgery, embolic events, or relapse of bacteremia with the primary pathogen, from the time of randomization until 6 months after antibiotic treatment was completed. Results After randomization, antibiotic treatment was completed after a median of 19 days (interquartile range, 14 to 25) in the intravenously treated group and 17 days (interquartile range, 14 to 25) in the orally treated group (P=0.48). The primary composite outcome occurred in 24 patients (12.1%) in the intravenously treated group and in 18 (9.0%) in the orally treated group (between-group difference, 3.1 percentage points; 95% confidence interval, -3.4 to 9.6; P=0.40), which met noninferiority criteria. Conclusions In patients with endocarditis on the left side of the heart who were in stable condition, changing to oral antibiotic treatment was noninferior to continued intravenous antibiotic treatment. (Funded by the Danish Heart Foundation and others; POET ClinicalTrials.gov number, NCT01375257 .).

In recent decades there has been an increase in knowledge of the distribution, species diversity and growth patterns of bacteria in human chronic infections. This has challenged standard diagnostic methods, which have undergone a development to both increase the accuracy of testing as well as to decrease the occurrence of contamination. In particular, the introduction of new technologies based on molecular techniques into the clinical diagnostic process has increased detection and identification of infectious pathogens. Sampling is the first step in the diagnostic process, making it crucial for obtaining a successful outcome. However, sampling methods have not developed at the same speed as molecular identification. The heterogeneous distribution and potentially small number of pathogenic bacterial cells in chronic infected tissue makes sampling a complicated task, and samples must be collected judiciously and handled with care. Clinical sampling is a step in the diagnostic process that may benefit from innovative methods based on current knowledge of bacteria present in chronic infections. In the present review, we describe and discuss different aspects that complicate sampling of chronic infections. The purpose is to survey representative scientific work investigating the presence and distribution of bacteria in chronic infections in relation to various clinical sampling methods.

Background: Community-acquired bacteremia (CAB) with Escherichia coli may signal occult cancer. This might differ between phylogenetic groups. Methods: We conducted a population-based cohort study in northern Denmark (1994–2013) to examine whether E. coli CAB after age 50 is associated with incident cancer. We followed patients from their bacteremia diagnosis date to identify subsequent gastrointestinal, hepatobiliary, and urinary tract cancer diagnoses. We calculated 1- and 5-year cumulative cancer incidence. We compared the observed incidence with that expected based on national cancer incidence rates, and computed standardized incidence ratios (SIR) at 0– Results: Among 2,735 patients with E. coli CAB, 173 later were diagnosed with cancer. The 1-year cumulative incidence of a gastrointestinal or hepatobiliary tract cancer was 1.9%, and the 0– Conclusions: Gastrointestinal, hepatobiliary, and urinary tract cancer may debut with E. coli CAB. Impact: Owing to the high incidence of E. coli bacteremia, cancers missed at the time of bacteremia diagnosis represent a clinically significant problem.

Antimicrobial resistance in Pseudomonas aeruginosa is a threat to children with cancer. We explored the association between P. aeruginosa resistance and previous antibiotic exposure. All children with cancer and P. aeruginosa bacteremia in 2007 to 2016 in Denmark, a country with an overall resistance rate of ∼3%, were included. Twenty percent (10/49) of isolates from children previously exposed to meropenem were meropenem nonsusceptible. The only significant risk factor of meropenem nonsusceptibility was previous meropenem therapy (P=0.03). On the basis of these results, we suggest that meropenem should be reserved as a last resort for children with febrile neutropenia in countries with low antimicrobial resistance.

OBJECTIVES: To investigate and explore temporal changes in risk factors of community-onset extended-spectrum β-lactamase (ESBL) Escherichia coli and Klebsiella pneumoniae bacteraemia in a region with low antibiotic resistance.METHODS: Population-based case-control study including 223 cases hospitalized with a first-time community-onset ESBL-producing E. coli and K. pneumoniae bacteraemia, 2214 non-ESBL E. coli and K. pneumoniae bacteraemia controls, and 2228 population controls in the North Denmark Region between 2007 and 2017. We used a conditional logistic regression to compute crude and adjusted (age, gender and co-morbidity) odds ratios (aORs) and 95% CIs of risk factors and compared selected risk factors between 2007-2011 and 2016-2017.RESULTS: Several conventional risk factors of ESBL E. coli or K. pneumoniae were identified compared with the population controls. Compared with the non-ESBL controls, use of fluoroquinolones (aOR 3.56, 95% CI 2.52-5.05), three or more admissions within the recent year (aOR 2.18, 95% CI 1.45-3.28), three or more antibiotic prescriptions within 15-365 days before the admission (aOR 2.18, 95% CI 1.53-3.10), male sex (aOR 2.01, 95% CI 1.50-2.69), admission within 1-91 days (aOR 1.84, 95% CI 1.37-2.48) and antibiotic within 15-91 days (aOR 1.82, 95% CI 1.37-2.42) inferred the highest risk. Assessment of temporal dynamics between 2007-2011 and 2016-2017 revealed a slight reduction in risk factors associated with direct health-care contact (e.g. hospital admission).CONCLUSIONS: Recent and frequent hospitalization, and exposure to antibiotics, especially use of fluoroquinolones, appeared to be associated specifically with ESBL production, and focus and interventions should be directed towards these areas. Our results indicated a dissemination of ESBLs into the community.

[Objectives] To assess the impact of ESBL production on mortality and length of hospital stay (LOS) of community-onset infections due to Escherichia coli or Klebsiella pneumoniae., [Methods] A population-based cohort study including all adult patients hospitalized with a first-time community-onset E. coli or K. pneumoniae bacteraemia or urinary tract infection in the North Denmark Region between 2007 and 2017. For each bacterial agent, we computed 1 year Kaplan–Meier survival curves and cumulative incidence functions of LOS, and by use of Cox proportional hazard regression we computed HRs as estimates of 30 day and 1 year mortality rate ratios (MRRs) and LOS among patients with and without ESBL-producing infections., [Results] We included 24 518 cases (among 22350 unique patients), of whom 1018 (4.2%) were infected by an ESBL-producing bacterium. The 30 day cumulative mortality and adjusted MRR (aMRR) in patients with and without ESBL-producing isolates was as follows: E. coli bacteraemia (n = 3831), 15.8% versus 14.0%, aMRR = 1.01 (95% CI = 0.70–1.45); E. coli urinary tract infection (n = 17151), 9.5% versus 8.7%, aMRR = 0.97 (95% CI = 0.75–1.26); K. pneumoniae bacteraemia (n = 734), 0% versus 17.2%, aMRR = not applicable; and K. pneumoniae urinary tract infection (n = 2802), 13.8% versus 10.7%, aMRR = 1.13 (95% CI = 0.73–1.75). The 1 year aMRR remained roughly unchanged. ESBL-producing E. coli bacteraemia was associated with an increased LOS compared with non-ESBL production., [Conclusions] ESBL production was not associated with an increased short- or long-term mortality in community-onset infections due to E. coli or K. pneumoniae, yet ESBL-producing E. coli bacteraemia was associated with an increased LOS., This study was supported by internal funding. B.G.-G. and J.R.-B. receive support for research activities from Plan Nacional de I + D+i 2013–2016 and Instituto de Salud Carlos III, Subdirección General de Redes y Centros de Investigación Cooperativa, Ministerio de Ciencia, Innovación y Universidades, Spanish Network for Research in Infectious Diseases (REIPI RD16/0016/0001), co-financed by the European Development Regional Fund ‘A way to achieve Europe’, Operative programme Intelligent Growth 2014–2020.

Systemic inflammation following curative surgery for colorectal cancer may be associated with increased risk of recurrence. [Correction added on 29 November 2019, after first online publication: text amended for accuracy.] This study investigated whether a clinically suspected infection, for which blood cultures were sent within 30 days after surgery for colorectal cancer, was associated with long-term oncological outcomes.This register-based national cohort study included all Danish residents undergoing surgery with curative intent for colorectal cancer between January 2003 and December 2013. Patients who developed recurrence or died within 180 days after surgery were not included. Associations between blood cultures taken within 30 days after primary surgery and overall survival, disease-free survival and recurrence-free survival were analysed using Cox regression models adjusted for relevant clinical confounders, including demographic data, cancer stage, co-morbidity, blood transfusion, postoperative complications and adjuvant chemotherapy.The study included 21 349 patients, of whom 3390 (15·9 per cent) had blood cultures taken within 30 days after surgery. Median follow-up was 5·6 years. Patients who had blood cultures taken had an increased risk of all-cause mortality (hazard ratio (HR) 1·27, 95 per cent c.i. 1·20 to 1·35; P 0·001), poorer disease-free survival (HR 1·22, 1·16 to 1·29; P 0·001) and higher risk of recurrence (HR 1·15, 1·07 to 1·23; P 0·001) than patients who did not have blood cultures taken.A clinically suspected infection requiring blood cultures within 30 days of surgery for colorectal cancer was associated with poorer oncological outcomes.La inflamación sistémica en el cáncer colorrectal puede asociarse con un aumento del riesgo de recidiva. En este estudio se investigó si la sospecha clínica de infección, en la que se obtuvieron cultivos de sangre periférica durante los primeros 30 días de la cirugía por cáncer colorrectal, se asociaba con los resultados oncológicos a largo plazo. MÉTODOS: Se trata de un estudio de cohortes de un registro de una base de datos nacional, que incluyía todos los sujetos residentes en Dinamarca sometidos a cirugía por cáncer colorrectal con intención curativa desde enero de 2003 a diciembre de 2013. Los pacientes con recidiva o que fallecieron durante los primeros 180 días después de la cirugía fueron excluidos. Se estimaron las asociaciones entre los cultivos de sangre periférica efectuados en los primeros 30 días tras la cirugía primaria y la supervivencia global, supervivencia libre de enfermedad y supervivencia libre de recidiva mediante modelos de regresión de Cox, ajustados por variables clínicas confusoras relevantes (incluyendo datos demográficos, estadio del cáncer, comorbilidad, transfusión de sangre, complicaciones postoperatorias y quimioterapia adyuvante).El estudio incluyó 21.349 pacientes, de los cuales en 3.390 (16%) se habían obtenido cultivos de sangre periférica durante los primeros 30 días tras la cirugía. La mediana de seguimiento fue de 5,6 años. Los pacientes en los que se había obtenido cultivos de sangre periférica presentaron un riesgo aumentado de mortalidad por cualquier causa (cociente de riesgos instantáneos, hazard ratio, HR 1,27, i.c. del 95% 1,20-1,35; P 0.0001), peor supervivencia libre de enfermedad (HR 1,22, i.c. del 95% 1,16-1,29; P 0,0001) y mayor riesgo de recidiva (HR 1,15, i.c. del 95% 1,07-1,23; P 0,0001) que los pacientes en los que no se habían obtenido cultivos. CONCLUSIÓN: La presencia de una infección sospechada clínicamente para la cual se requiere obtener cultivos de sangre periférica en los primeros 30 días tras cirugía por cancer colorrectal se asoció con peores resultados oncológicos.

The Gram-negative bacterium Klebsiella pneumoniae is an opportunistic pathogen, which can cause life-threatening infections such as sepsis. Worldwide, emerging multidrug resistant K. pneumoniae infections are challenging to treat, hence leading to increased mortality. Therefore, understanding the interactions between K. pneumoniae and the immune system is important to develop new treatment options. We characterized ten clinical K. pneumoniae isolates obtained from blood of bacteremia patients. The interaction of the isolates with human serum was investigated to elucidate how K. pneumoniae escapes the host immune system, and how complement activation by K. pneumoniae changed the capsule structure. All K. pneumoniae isolates activated the alternative complement pathway despite serum resistance of seven isolates. One serum sensitive isolate activated two or all three pathways, and this isolate was lysed and had numerous membrane attack complexes in the outer membrane. However, we also found deposition of complement components in the capsule of serum resistant isolates resulting in morphological capsule changes and capsule shedding. These bacteria did not lyse, and no membrane attack complex was observed despite deposition of C5b-9 within the capsule, indicating that the capsule of serum resistant K. pneumoniae isolates is a defense mechanism against complement-mediated lysis.

Background: Data elucidating trends of community-onset extended-spectrum β-lactamase (ESBL)-producing Escherichia coli and Klebsiella pneumoniae infections remain sparse in low prevalence areas. We conducted a population-based study to determine the incidence, temporal trends and co-resistance of community-onset ESBL infections. Methods: We identified all recorded episodes of E. coli and K. pneumoniae bacteraemia and urinary tract infections in adult patients (>15 years) in the North Denmark Region between 2007–2017. Using population-based registries, we obtained information on demographics and place of acquisition, and investigated the standardized incidence rates and temporal trends of community-onset ESBL infections and the associated patterns of co-resistance. Results: A total of 3741 episodes of community-onset ESBL E. coli or K. pneumoniae infections were observed during the study period, with the annual standardized incidence rate increasing from 7.5 to 105 per 100,000 person-years between 2007–2017. The increase was conveyed primarily by a rise in E. coli urinary tract infections shifting from being mainly healthcare-associated to community-acquired. ESBL-producing isolates increased from 0.5 to 4.0% with considerable co-resistance. Conclusion: The proportion of E. coli and K. pneumoniae isolates producing ESBL have increased considerably in the North Denmark Region. The increasing incidence and frequent co-resistance should raise awareness among physicians responsible for empirical antibiotic treatment.

Background: Increasing attention has been given to the risk of infective endocarditis (IE) in patients with certain blood stream infections (BSI). Previous studies have been conducted on selected patient cohorts, yet unselected data are sparse. We aimed to investigate the prevalence of IE in BSIs with bacteria typically associated with IE. Methods: By crosslinking nationwide registries from 2010-2016, we identified patients with BSIs typically associated with IE: Enterococcus faecalis (E. faecalis), Staphylococcus aureus (S. aureus), Streptococcus spp., and coagulase negative staphylococci (CoNS) and examined the concurrent IE prevalence. A trend test was used to examine temporal changes in the prevalence of IE. Findings: In total 60,119, distributed with 15,407, 16,790, and 27,922 BSIs were identified in the periods of 2010-2011, 2012-2013, and 2014-2016, respectively. Patients with E. faecalis had the highest prevalence of IE (16.3%) followed by S. aureus (10.2%), Streptococcus spp. (7.3%), and CoNS (1.6%). Throughout the study period, the prevalence of IE among patients with E. faecalis increased significantly (p=0.003). Male patients had a higher prevalence of IE for all microorganisms investigated compared with females. A significant increase in the prevalence of IE was seen for E. faecalis, Streptococcus spp., and CoNS with increasing age. Interpretation: For E. faecalis BSI, 1 in 6 had IE, for S. aureus BSI 1 in 10 had IE, and for Streptococcus spp. 1 in 14 had IE. Our results suggest that screening for IE seems reasonable in patients with E. faecalis BSI, S. aureus BSI, or Streptococcus spp. BSI. Funding Statement: The authors state: "No funding." Declaration of Interests: Lauge Ostergaard: no competing interest. Niels Eske Bruun: no competing interest. Marianne Voldstedlund: no competing interest. Magnus Arpi: no competing interest. Christian Ostergaard Andersen: no competing interest. Henrik C Schonheyder: no competing interest. Lars Lemming: reports grants from Merck Sharp & Dohme (MSD) outside the submitted work. Flemming Rosenvinge: no competing interest. Nana Valeur: no competing interest. Peter Sogaard: no competing interest. Paal Skytt Andersen: no competing interest. Robert Skov: no competing interest. Ming Chen: no competing interest. Kasper Iversen: no competing interest. Sabine Gill: no competing interest. Trine Kiilerich Lauridsen: no competing interest. Anders Dahl: no competing interest. Louise Bruun Oestergaard: no competing interest. Jonas Agerlund Povlsen: no competing interest. Claus Moser: no competing interest. Henning Bundgaard: no competing interest. Lars Kober: no competing interest. Emil Loldrup Fosbol: no competing interest. Ethics Approval Statement: This study was approved by the Danish Data Protection Agency. Register-based studies do not require ethical approval in Denmark.

Background Increasing attention has been given to patients with blood stream infection (BSI) and the concurrent prevalence of infective endocarditis (IE). However, there exist a gap in knowledge on the prevalence of IE among patients with a left-sided heart valve prosthesis and BSI. Purpose To examine the prevalence between different BSI and IE in patients with a left-sided heart valve prosthesis. Methods By linking Danish nationwide registries, we were able to identify patients with a left-sided prosthetic heart valve and first-time BSI of interest (Enterococcus faecalis, Staphylococcsus aureus, streptococci species (spp.), and coagulase negative staphylococci [CoNS]) in the period of 2010–2016. Concurrent admission for IE was identified from the Danish National Patient Registry in a period of up to 14 days after the BSI. Results A total of 1,465 patients with BSI were included (1,319 patients with an aortic valve prosthesis [82.6% bioprosthetic] and 146 patients with a mitral valve prosthesis [48.6% bioprosthetic]). Among the included patients, 244 had E. faecalis (median age: 78.3 years, 77.0% male), 301 had S. aureus (median age: 76.9 years, 69.1% male), 401 had streptococci spp. (median age: 78.0 years, 69.1% male) and 519 had CoNS (median age: 76.4 years, 64.2% male). The percentage of patients with a diagnosis of IE in relation to the BSI was 44.3%, 33.6%, 34.4%, and 7.9% for E. faecalis, S. aureus, streptococci spp., and CoNS, respectively. No difference in the overall results was seen by type of valve prosthesis, sex, or age group. Percentage of patients with endocarditis Conclusion In patients with a left-sided heart valve prosthesis, IE was diagnosed in almost half of the patients with E. faecalis, in 1/3 with S. aureus or streptococci spp. and in 1 in 12 with CoNS BSI. Future studies may try to explain why some microbes are more likely to cause prosthetic heart valve endocarditis, than others are.

The impact of antibiotic prophylaxis on fecal carriage of ESBL-/AmpC-/carbapenemase-producing Enterobacteriaceae (CPE) was investigated. Patients admitted for elective surgery or diagnostic procedure in a Department of Surgical Gastroenterology (SG) (n= 450) and Orthopedic Surgery (OS) (n= 300) provided a fecal swab at admission and responded to a questionnaire on possible exposures. SG patients received gentamicin/penicillin G (±metronidazole); OS patients received cefuroxime. Two days after surgery a second swab was taken. From SG patients, 6% of first swabs and 9% of second swabs were positive for ESBL-/AmpC-producers. A similar carriage rate was observed in OS patients (6% and 8%, respectively). No CPE were detected. Escherichia coli was the predominant species and blaCTX-M-15 (29% and 22%) and blaCTX-M-14 (11% and 17%) were the most prevalent ESBL genotypes among SG and OS patients. Two different prophylactic antibiotic regimens had no impact on carriage rates. Previous hospitalization and antimicrobial treatment were associated with carriage for SG patients.

Background The recommended duration of antibiotic treatment for uncomplicated Staphylococcus aureus bloodstream infections is 14 days. We compared the outcomes of patients receiving short-course (6–10 days) vs. prolonged-course (11–16 days) antibiotic therapy for S. aureus bacteremia (SAB). Methods 30-day outcome of patients with penicillin (PSSAB, n = 202)) or methicillin-susceptible SAB (MSSAB, n = 203) treated with in vitro active therapy in the range of 6–16 days was analyzed using pooled data from two previously published, observational studies. Individuals were matched 1:1 by nearest neighbor propensity score matching without replacement. Regression analysis was performed to estimate the risk of all-cause mortality within 30 days after the end of antibiotic treatment. Eligible individuals had to have >1 day of follow-up after discontinuation of antimicrobials. Individuals with a diagnosis of endocarditis, bone infection, meningitis or pneumonia were excluded. Results There were 107 well-balanced matched pairs; 58 in the PSSAB and 39 in the MSSAB cohort. For PSSAB, the median duration of therapy was 8 (interquartile range [IQR], 7–10) in the short-course group and 12 days (IQR, 10–13) in the prolonged-course group. For the MSSAB cohort, these numbers were 9 days (IQR, 7–10) and 14 days (IQR, 13–16 days), respectively. No difference in mortality between short-course and prolonged-course treatment was observed (adjusted hazard ratio [aHR], 0.74; 95% confidence interval [CI], .23–2.41) and 1.14; 95% CI, 0.31–4.20), respectively for PSSAB and MSSAB. Conclusion Short courses of antibiotic therapy yielded similar clinical outcomes as prolonged courses of antibiotic therapy for S. aureus bacteremia. The findings warrant a randomized clinical trial to study the safety and efficacy of shortened antimicrobial therapy for the treatment of uncomplicated SAB. Disclosures All authors: No reported disclosures.

BACKGROUND: Candidemia is the most frequent pediatric fungal infection, but incompletely elucidated in population-based settings. We performed a nationwide cohort study including all pediatric patients with candidemia in Denmark from 2004 to 2014 to determine age, incidence, species distribution, underlying diseases, patient management and outcomes.METHODS: All candidemia episodes were identified through the active nationwide fungemia surveillance program. Susceptibility testing followed the EUCAST E.Def 7 (European Committee on Antifungal Susceptibility Testing, Edition Definitive) reference method. χ test, Fisher exact test and Venn diagrams were used for statistical analyses.RESULTS: One hundred fifty-three pediatric patients (≤ 15 years) with 158 candidemia episodes were identified. The overall annual incidence rate was 1.3/100,000 population, higher for neonates (5.7/100,000 live births) and low birth weight neonates (103.8/100,000 live births). From 2004 to 2009 to 2010 to 2014, the proportion of Candida albicans decreased from 74.4% to 64.7%, whereas fluconazole resistance increased from 7.8% to 17.7%. Virtually all patients had at least 1 underlying disease (98.6%) and multimorbidity was common (43.5%, ≥2 underlying diseases). Underlying diseases differed by age with heart malformations and gastrointestinal disease prevalent in children younger than 3 years. The overall 30-days mortality was 10.2% and highest for neonates (17.1%). Mortality increased from 2004 to 2010 to 2014, driven by an increase among older children.CONCLUSION: This first nationwide epidemiologic study of pediatric candidemia confirmed a high incidence among neonates and a substantial burden of comorbidities. Moreover, an increasing proportion of fluconazole resistant nonalbicans species was observed. Our findings underline the importance of choosing correct treatment and continuous surveillance of pediatric candidemia.

AIM: To examine the incidence, clinical presentation and risk factors for neurological sequelae following childhood community-acquired bacterial meningitis (CABM).METHODS: We included all children aged 1 month to 15 years old with CABM in North Denmark Region, 1998-2016. Using medical records, we registered baseline demographics, signs and symptoms at admission, laboratory investigations, and outcome assessed by the Glasgow Outcome Scale (GOS). A GOS score of 1-4 was considered an unfavourable outcome. We used modified Poisson regression to examine predefined risk factors for neurological sequelae among survivors.RESULTS: We identified 88 cases of CABM in 86 patients (45 female) with a median age of 1.4 years (interquartile range 0.7-4.6). Neisseria meningitidis was the most common pathogen (48/88). Neurological sequelae occurred in 23 (27%) as hearing deficits in 13 (15%), cognitive impairment in 10 (12%) and motor or sensory nerve deficits in 8 (9%). Unfavourable outcome was observed in 16 (18%) patients and three (3%) patients died. Abnormalities on cranial imaging remained the only independent risk factor for developing neurological sequelae in adjusted analysis.CONCLUSION: Neurological sequelae following CABM in children remain frequent and abnormal cranial imaging may be an independent risk factor.

Objective To investigate the influence of acetylsalicylic acid (ASA) use on risk and outcome of community-acquired Staphylococcus aureus bacteremia (CA-SAB). Method We used population-based medical databases to identify all patients diagnosed in northern Denmark with first-time CA-SAB and matched population controls from 2000–2011. Categories for ASA users included current users (new or long-term users), former users, and nonusers. The analyses were adjusted for comorbidities, comedication use, and socioeconomic indicators. Results We identified 2638 patients with first-time CA-SAB and 26 379 matched population controls. Compared with nonusers, the adjusted odds ratio (aOR) for CA-SAB was 1.00 (95% confidence interval [CI], 0.88–1.13) for current users, 1.00 (95% CI, 0.86–1.16) for former users, 2.04 (95% CI, 1.42–2.94) for new users, and 0.95 (95% CI, 0.84–1.09) for long-term users. Thirty-day cumulative mortality was 28.0% among current users compared with 21.6% among nonusers, yielding an adjusted hazard rate ratio (aHRR) of 1.02 (95% CI, 0.84–1.25). Compared with nonusers, the aHRR was 1.10 (95% CI, 0.87–1.40) for former users, 0.60 (95% CI, 0.29–1.21) for new users, and 1.06 (95% CI, 0.87–1.31) for long-term users. We observed no difference in the risk or outcome of CA-SAB with increasing ASA dose or by presence of diseases commonly treated with ASA. Conclusions Use of ASA did not seem to influence the risk or outcome of CA-SAB. The apparent increased risk among new users may relate to residual confounding from the circumstances underlying ASA treatment initiation. Our finding of no association remained robust with increasing ASA dose and across multiple patient subsets.

Summary Background At present, reprocessing of sterilizable medical equipment is recommended to be initiated within 6 h after completion of surgery, to ensure that the quality of the instruments does not deteriorate. A literature search showed a lack of evidence for consequences that may occur if medical personnel deviate from the standard 6 h sterilization protocol. Aim To evaluate the 6 h recommendation for reprocessing sterilizable medical equipment by determining whether residual protein increased proportional to holding time before reprocessing was initiated, and likewise whether an increase in corrosion was present on surgical scissors proportional to holding time. Methods Residual protein was identified on surgical instruments contaminated with human blood after different holding times and before washes using the o-phthaldialdehyde (OPA) method. Corrosion was identified on surgical scissors contaminated with human blood after different holding times and after reprocessing using light stereomicroscopy and scanning electron microscopy. Findings Protein residues ranged between 14.0 and 51.9 μg and thus below the accepted threshold of 100 μg per instrument surface. Corrosion corresponding to 0.05% of the surface was identified on 22 of 30 scissors. Pitting corrosion was seen on four of 30 scissors. Conclusion No association was identified between residual protein and holding time, nor between incidence of corrosion and holding time. The study thereby challenges the relevance of upholding the recommendation of a maximum wait of 6 h prior to reprocessing. The findings will potentially have an impact on the organization of reprocessing of surgical instruments in Denmark and internationally.

Follow-up of Oral Antibiotics for Endocarditis This letter describes outcomes of the POET trial at a median follow-up of 3.5 years. The authors found that in patients with endocarditis on the left ...

INTRODUCTION: Staphylococcus aureus bacteremia (SAB) is a high-risk infection and feared complication related to hemodialysis. This study aimed to investigate incidence and risk factors for SAB depending on hemodialysis access type.METHODS: The Danish National Registry on Regular Dialysis and Transplantation was used to identify patients from January 1, 1996 to December 31, 2011 with end-stage kidney disease. Patients were followed until death, the first episode of SAB, or end of study (December 31, 2011). Independent risk factors were assessed by multivariable Poisson regression with time-updated exposure variables.FINDINGS: Total of 9997 patients were included. The initial modality of renal replacement therapy was hemodialysis in 6826 patients and peritoneal dialysis in 2882 patients; 289 patients had preemptive kidney transplantation. SAB occurred in 1278 patients (12.8%). The incidence rate of SAB declined after 90 days and leveled off after 270 days in hemodialysis, peritoneal dialysis, and kidney transplanted. As compared to peritoneal dialysis, the adjusted rate ratio (RR) for SAB was 7.42 (95% CI 5.63-9.79) in uncuffed central venous catheter (CVC), 5.68 (95% CI 4.39-7.36) in cuffed CVC, 4.43 (95% CI 2.10-9.53) in arteriovenous graft, and 3.40 (95% CI 2.79-4.15) in arteriovenous fistula. SAB risk did not differ between uncuffed and cuffed CVC. The risk of SAB was increased during the first three months of renal replacement therapy especially for CVC (RR 11.37 [95% CI7.09-18.22]) compared with peritoneal dialysis. Diabetes mellitus (RR 1.35 [95% CI 1.20-1.51]) and male sex (RR 1.15 [95% CI 1.03-1.29]) were also associated with SAB.DISCUSSION: Patients on hemodialysis had a high incidence rate of SAB, particularly those undergoing hemodialysis via CVC. SAB risk was comparable for cuffed and uncuffed CVC. Diabetes mellitus, male sex, and the first three months in renal replacement therapy were independently associated with SAB.

The role of host genetic variation in the development of complicated Staphylococcus aureus bacteremia (SAB) is poorly understood. We used whole exome sequencing (WES) to examine the cumulative effect of coding variants in each gene on risk of complicated SAB in a discovery sample of 168 SAB cases (84 complicated and 84 uncomplicated, frequency matched by age, sex, and bacterial clonal complex [CC]), and then evaluated the most significantly associated genes in a replication sample of 240 SAB cases (122 complicated and 118 uncomplicated, frequency matched for age, sex, and CC) using targeted sequence capture. In the discovery sample, gene-based analysis using the SKAT-O program identified 334 genes associated with complicated SAB at p, Author summary Complications from bloodstream infection with Staphylococcus aureus (S. aureus) are important causes of hospitalization, significant illness, and death. The causes of these complications are not well understood, but likely involve genetic factors rendering people more susceptible to such infections, differences in the bacteria that cause the infection, and the interactions between them. We examined the parts of the human genome that code for proteins to find variations that were more common in people with complicated S. aureus bacteremia (SAB), and identified one gene, called GLS2, in which variation is more common in complicated SAB cases than uncomplicated cases. Expression of GLS2 is lower in people with SAB than controls and in mouse white blood cells exposed to S. aureus. GLS2 encodes a protein that regulates the metabolism of glutamine, a regulatory process that activates white blood cells. These cells are very important in the immune response to S. aureus infection, and therefore genetic variants that might influence their growth are important potential genetic risk factors for complicated SAB.

Objective To investigate whether the use of systemic glucocorticoids is a risk factor for community-acquired Staphylococcus aureus bacteremia (CA-SAB). Patients and Methods We used population-based medical registries in Northern Denmark to conduct a case-control study including all adults with first-time CA-SAB and matched population controls from January 1, 2000, through December 31, 2011. Glucocorticoid users were categorized as current users (new or long-term use), former users, and nonusers. Using conditional logistic regression, we computed odds ratios (ORs) of CA-SAB according to glucocorticoid exposure, overall and by 90-day prednisolone-equivalent cumulative dose. Results We identified 2638 patients with first-time CA-SAB and 26,379 matched population controls. Current glucocorticoid users experienced considerably increased risk of CA-SAB compared with nonusers (adjusted OR=2.48; 95% CI, 2.12-2.90). The adjusted OR was 2.73 (95% CI, 2.17-3.45) in new users, 2.31 (95% CI, 1.90-2.82) in long-term users, and much lower at 1.33 (95% CI, 0.98-1.81) in former users of glucocorticoids compared with nonusers. The risk of CA-SAB increased with higher 90-day cumulative doses. Compared with nonusers of glucocorticoids, the adjusted OR was 1.32 (95% CI, 1.01-1.72) for persons with a cumulative dose of 150 mg or less, 2.42 (95% CI, 1.76-3.33) for persons whose cumulative dose was greater than 500 to 1000 mg, and 6.25 (95% CI, 4.74-8.23) for persons with a cumulative dose greater than 1000 mg. Conclusion Glucocorticoid use was associated with a substantially increased risk of CA-SAB. The risk increased with higher cumulative dose, revealing a distinct dose-response relation.

OBJECTIVESeasonal variation is a characteristic of many infectious diseases, but relatively little is known about determinants thereof. We studied the impact of place of acquisition and patient characteristics on seasonal variation of bacteremia caused by the 3 most common pathogens.DESIGNSeasonal variation analysis.METHODSIn 3 Danish health regions (2.3 million total inhabitants), patients with bacteremia were identified from 2000 through 2011 using information from laboratory information systems. Analyses were confined to Escherichia coli, Staphylococcus aureus, and Streptococcus pneumoniae. Additional data were obtained from the Danish National Hospital Registry for the construction of admission histories and calculation of the Charlson comorbidity index (CCI). Bacteremias were categorized as community acquired, healthcare associated (HCA), and hospital acquired. We defined multiple subgroups by combining the following characteristics: species, acquisition, age group, gender, CCI level, and location of infection. Assuming a sinusoidal model, seasonal variation was assessed by the peak-to-trough (PTT) ratio with a 95% confidence interval (CI).RESULTSIn total, we included 16,006 E. coli, 6,924 S. aureus, and 4,884 S. pneumoniae bacteremia cases. For E. coli, the seasonal variation was highest for community-acquired cases (PTT ratio, 1.24; 95% CI, 1.17–1.32), was diminished for HCA (PTT ratio, 1.14; 95% CI, 1.04–1.25), and was missing for hospital-acquired cases. No seasonal variation was observed for S. aureus. S. pneumoniae showed high seasonal variation, which did not differ according to acquisition (overall PTT ratio, 3.42; 95% CI, 3.10–3.83).CONCLUSIONSSeasonal variation was mainly related to the species although the place of acquisition was important for E. coli.Infect Control Hosp Epidemiol 2016;37:946–953

Objective Patients with diabetes may experience higher risk of Staphylococcus aureus bacteremia (SAB) than patients without diabetes due to decreased immunity or coexisting morbidities. We investigated the risk of community-acquired (CA) SAB in persons with and without diabetes. Design Using population-based medical databases, we conducted a case–control study of all adults with first-time CA-SAB and matched population controls in Northern Denmark, 2000 – 2011. Methods Based on conditional logistic regression, we computed odds ratios (ORs) of CA-SAB according to diabetes. We further assessed whether the risk of CA-SAB differed according to various diabetes-related characteristics (e.g. duration of diabetes, glycemic control, and presence of diabetes complications). ResultsWe identified 2638 patients with incident CA-SAB, of whom 713 (27.0%) had diabetes, and 26 379 matched population controls (2495 or 9.5% with diabetes). Individuals with diabetes had a substantially increased risk of CA-SAB compared with population controls (adjusted OR = 2.8 (95% confidence interval (CI): 2.5 – 3.1)). Duration of diabetes of ≥10 years and poor glycemic control conferred higher risk estimates, with an adjusted OR = 2.3 (95% CI: 1.9 – 2.7) for diabetes with Hba1c < 7% (< 53 mmol/mol) and an adjusted OR = 5.7 (95% CI: 4.2 – 7.7) for diabetes with Hba1c ≥9% (≥75 mmol/mol). The risk of CA-SAB was particularly high in patient with diabetes complications: adjusted OR = 5.5 (95% CI: 4.2 – 7.2) with presence of microvascular complications and OR = 7.0 (95% CI: 5.4 – 9.0) with combined macro- and microvascular complications. ConclusionsDiabetes is associated with a substantially increased risk of CA-SAB, particularly in patients with diabetes of long duration, poor glycemic control, and diabetes complications.

OBJECTIVE: The objective of this study was to validate a previously published clinical decision rule for predicting a positive blood culture in emergency department (ED) patients with suspected infection on the basis of major and minor criteria and a total score (Shapiro et al., J Emerg Med, 2008; 35:255-264).METHODS: This is a retrospective matched cohort study of adult ED patients with blood cultures obtained from 1 January 2011 through to 31 December 2011. ED patients with blood culture-confirmed bacteremia were matched 1 : 3 with patients with negative cultures. The outcome was 'true bacteremia'. Data on clinical history, comorbid illnesses, physical observations, and laboratory tests were used to evaluate the application of the clinical decision rule. We report the sensitivity, specificity, and area under the curve.RESULTS: Among 1526 patients, 105 (6.9%) patients were classified with true bacteremia. The sensitivity of the prediction rule was 94% (95% confidence interval, 88-98%) and the specificity was 48% (95% confidence interval, 42-53%). The area under the receiver-operating characteristics curve was 0.83.CONCLUSION: The clinical decision rule performed well in our ED setting and is likely to be a useful supplement to clinical judgment.

The predominant indications for revision surgery after total hip (THA) or knee arthroplasty (TKA) are an aseptic failure (AF) and prosthetic joint infection (PJI). Accurate diagnosis is crucial. Therefore, we evaluated prospectively a multidisciplinary diagnostic algorithm including multi-modal radionucleid imaging (RNI) and extended microbiological diagnostics. If the surgeon suspected PJI or AF, revision surgery was performed with multiple samples obtained in parallel for special culture procedures and later molecular analyses. Alternatively, if the underlying cause was not evident, RNI was scheduled comprising 99Tc &ndash, HDP SPECT/CT, 111In-labeled white blood cells combined with 99Tc-nanocoll bone marrow SPECT/CT, and 18F-FDG PET/CT. A multidisciplinary clinical team made a recommendation on the indication for a diagnostic procedure guided by RNI images or revision surgery. A total of 156 patients with 163 arthroplasties were included. Fifty-five patients underwent RNI. In all, 118 revision surgeries were performed in 112 patients: 71 on the indication of AF and 41 revision of PJI. Thirty-four patients were concluded with chronic pain, and revision surgery refrained. The effective median follow-up period was 13 months. A structured approach offered by the algorithm was useful for the clinician in the evaluation of patients with a failing TKA or THA. Surgical revision was possibly obviated in approximately 20% of patients where an explanation or cause of failure was not found. The algorithm served as an effective tool.

Background: Denmark has a high incidence rate of candidaemia. A Nordic study suggested a higher Danish prevalence of haematological malignancies as an underlying reason. This nationwide study ascertained clinical characteristics of Danish candidaemia patients and investigated potential factors contributing to the high incidence and mortality. Methods: Microbiological and clinical data for candidaemia patients in 2010-2011 were retrieved. 30-day mortality was estimated by hazard ratios (HR) with 95% confidence intervals (CI, Cox regression). Results: Data were available for 912/973 candidaemia episodes (93.7%). Intensive care unit (ICU) held the largest share of patients (43.2%). Prevalent host factors were multi-morbidity (≥2 underlying diseases, 74.2%) and gastrointestinal disease (52.5%). Haematological disease was infrequent (7.8%). Risk factors included antibiotic exposure (90.5%), CVC (71.9%) and Candida colonisation (66.7%). 30-day mortality was 43.4%, and 53.6% in ICU. Mortality was lower for patients with recent abdominal surgery (HR 0.70, 95% CI: 0.54-0.92). Conclusion: A substantial prevalence of multi-morbidity and a high 30-day mortality was found. We hypothesise, that an increasing population of severely ill patients with prolonged supportive treatment and microbiological testing may in part explain the high candidaemia incidence in Denmark. Nationwide studies are warranted to clarify this issue. Keywords: Candidaemia, Candida, Epidemiology, Outcome, Mortality

PURPOSE: Data on the systemic dissemination in Staphylococcus aureus bloodstream infection (SAB) remain sparse. We investigated the timing and the sequence of clinical symptoms, diagnostic confirmation, and occurrence of multiple infective foci in relation to three major infective foci.METHODS: From 2006 to 2011, all adult patients with first-time SAB in Cologne and Freiburg, Germany were followed prospectively. The study was restricted to patients with short-term central venous catheter (CVC)-related SAB, vertebral osteomyelitis (VO), and infective endocarditis (IE). The collection date of the first positive blood culture was used as reference point for determining time to onset of clinical symptoms, microbiological findings, imaging results compatible with focal infection, and occurrence of additional infective foci.RESULTS: We included 266 patients with first-time SAB. Among patients with CVC-related SAB, clinical onset, collection of the first positive blood culture, and microbiological confirmation almost coincided. In contrast, among patients with VO or IE, the onset of clinical symptoms most often preceded the collection of the first positive blood culture, and imaging and microbiological confirmation were most frequently obtained subsequent to the SAB diagnosis. CVC-related SAB was infrequently associated with further foci (n = 15/15.5%). Conversely, more than one infective focus was observed in 44 (56.4%) patient with VO and 68 (64.8%) patients with IE.CONCLUSIONS: The sequence of clinical symptoms, diagnostic confirmation, and occurrence of multiple infective foci varied considerably with different infective foci in SAB. Based on these results, we propose a pragmatic and evidence-based terminology for the clinical course of SAB and suggest the terms "portal of entry", "infective focus", "multiple infective foci", and "dominant infective focus".