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Objectives Standard once-daily dosing of ceftriaxone may not lead to adequate antibiotic exposure in all cases of Staphylococcus aureus bacteraemia (SAB). Therefore, we compared clinical effectiveness of empirical antibiotic treatment with flucloxacillin, cefuroxime and ceftriaxone in adult patients with MSSA bacteraemia Methods We analysed data from the Improved Diagnostic Strategies in Staphylococcus aureus bacteraemia (IDISA) study, a multicentre prospective cohort study of adult patients with MSSA bacteraemia. Duration of bacteraemia and 30 day SAB-related mortality were compared between the three groups using multivariable mixed-effects Cox regression analyses. Results In total, 268 patients with MSSA bacteraemia were included in the analyses. Median duration of empirical antibiotic therapy was 3 (IQR 2–3) days in the total study population. Median duration of bacteraemia was 1.0 (IQR 1.0–3.0) day in the flucloxacillin, cefuroxime and ceftriaxone groups. In multivariable analyses, neither ceftriaxone nor cefuroxime was associated with increased duration of bacteraemia compared with flucloxacillin (HR 1.08, 95% CI 0.73–1.60 and HR 1.22, 95% CI 0.88–1.71). In multivariable analysis, neither cefuroxime nor ceftriaxone was associated with higher 30 day SAB-related mortality compared with flucloxacillin [subdistribution HR (sHR) 1.37, 95% CI 0.42–4.52 and sHR 1.93, 95% CI 0.67–5.60]. Conclusions In this study, we could not demonstrate a difference in duration of bacteraemia and 30 day SAB-related mortality between patients with SAB empirically treated with flucloxacillin, cefuroxime or ceftriaxone. Since sample size was limited, it is possible the study was underpowered to find a clinically relevant effect.

BackgroundSeveral studies have suggested that in patients with Staphylococcus aureus bacteremia (SAB) [18F] fluorodeoxyglucose positron emission tomography/computed tomography ([18F]FDG-PET/CT) improves outcome. However, these studies often ignored possible immortal time bias.MethodsProspective multicenter cohort study in 2 university and 5 non-university hospitals, including all patients with SAB. [18F]FDG-PET/CT was performed on clinical indication as part of usual care. Primary outcome was 90-day all-cause mortality. Effect of [18F]FDG-PET/CT was modeled with a Cox proportional hazards model using [18F]FDG-PET/CT as a time-varying variable and corrected for confounders for mortality (age, Charlson score, positive follow-up cultures, septic shock, and endocarditis). Secondary outcome was 90-day infection-related mortality (assessed by adjudication committee) using the same analysis. In a subgroup-analysis, we determined the effect of [18F]FDG-PET/CT in patients with high risk of metastatic infection.ResultsOf 476 patients, 178 (37%) underwent [18F]FDG-PET/CT. Day-90 all-cause mortality was 31% (147 patients), and infection-related mortality was 17% (83 patients). The confounder adjusted hazard ratio (aHR) for all-cause mortality was 0.50 (95% confidence interval [CI]: .34–.74) in patients that underwent [18F]FDG-PET/CT. Adjustment for immortal time bias changed the aHR to 1.00 (95% CI .68–1.48). Likewise, after correction for immortal time bias, [18F]FDG-PET/CT had no effect on infection-related mortality (cause specific aHR 1.30 [95% CI .77–2.21]), on all-cause mortality in patients with high-risk SAB (aHR 1.07 (95% CI .63–1.83) or on infection-related mortality in high-risk SAB (aHR for 1.24 [95% CI .67–2.28]).ConclusionsAfter adjustment for immortal time bias [18F]FDG-PET/CT was not associated with day-90 all-cause or infection-related mortality in patients with SAB.

Summary Background Adults hospitalised to a non-intensive care unit (ICU) ward with moderately severe community-acquired pneumonia are frequently treated with broad-spectrum antibiotics, despite Dutch guidelines recommending narrow-spectrum antibiotics. Therefore, we investigated whether an antibiotic stewardship intervention would reduce the use of broad-spectrum antibiotics in patients with moderately severe community-acquired pneumonia without compromising their safety. Methods In this cross-sectional, stepped-wedge, cluster-randomised, non-inferiority trial (CAP-PACT) done in 12 hospitals in the Netherlands, we enrolled immunocompetent adults (≥18 years) who were admitted to a non-ICU ward and had a working diagnosis of moderately severe community-acquired pneumonia. All participating hospitals started in a control period and every 3 months a block of two hospitals transitioned from the control to the intervention period, with all hospitals eventually ending in the intervention period. The unit of randomisation was the hospital (cluster), and electronic randomisation (by an independent data manager) decided the sequence (the time of intervention) by which hospitals would cross over from the control period to the intervention period. Blinding was not possible. The antimicrobial stewardship intervention was a bundle targeting health-care providers and comprised education, engaging opinion leaders, and prospective audit and feedback of antibiotic use. The co-primary outcomes were broad-spectrum days of therapy per patient, tested by superiority, and 90-day all-cause mortality, tested by non-inferiority with a non-inferiority margin of 3%, and were analysed in the intention-to-treat population, comprising all patients who were enrolled in the control and intervention periods. This trial was prospectively registered at ClinicalTrials.gov , NCT02604628 . Findings Between Nov 1, 2015, and Nov 1, 2017, 5683 patients were assessed for eligibility, of whom 4084 (2235 in the control period and 1849 in the intervention period) were included in the intention-to-treat analysis. The adjusted mean broad-spectrum days of therapy per patient were reduced from 6·5 days in the control period to 4·8 days in the intervention period, yielding an absolute reduction of –1·7 days (95% CI –2·4 to –1·1) and a relative reduction of 26·6% (95% CI 18·0–35·3). Crude 90-day mortality was 10·9% (242 of 2228 died) in the control period and 10·8% (199 of 1841) in the intervention period, yielding an adjusted absolute risk difference of 0·4% (90% CI –2·7 to 2·4), indicating non-inferiority. Interpretation In patients hospitalised with moderately severe community-acquired pneumonia, a multifaceted antibiotic stewardship intervention might safely reduce broad-spectrum antibiotic use. Funding None.

Objectives: Guidelines do not distinguish between 50 mg or 100 mg nitrofurantoin as daily prophylaxis for recurrent urinary tract infection (UTI), although 50 mg might have a better safety profile. Our objective was to compare the effectiveness and safety of both regimens. Methods: Data were retrospectively collected from 84 Dutch GP practices between 2013 and 2020. Nitrofurantoin prescriptions of 100 mg and 50 mg every 24 hours in women were included. Cox proportional hazard regression analysis was used to calculate hazard ratios on first episode of UTI, pyelonephritis and (adverse) events. Patients were followed for the duration of consecutive repeated prescriptions, assuming non-informative right censoring, up to 1 year. Results: Nitrofurantoin prophylaxis was prescribed in 1893 patients. Median lengths of follow up were 90 days (interquartile range (IQR) 37–179 days) for 100 mg (n = 551) and 90 days (IQR 30–146 days) for 50 mg (n = 1342) with few differences in baseline characteristics between populations. Under 100 mg and 50 mg, 82/551 (14.9%) and 199/1342 (14.8%) developed UTI and 46/551 (8.3%) and 81/1342 (6.0%) developed pyelonephritis, respectively. Adjusted HRs of 100 mg versus 50 mg were 1.01 (95% CI 0.78–1.30) on first UTI, 1.37 (95% CI 0.95–1.98) on first pyelonephritis episode, 1.82 (95% CI 1.20–2.74) on first consultation for cough, 2.68 for dyspnoea (95% CI 1.11–6.45) and 2.43 for nausea (95% CI 1.03–5.74). Conclusion: Daily prophylaxis for recurrent UTI with 100 mg instead of 50 mg nitrofurantoin was associated with an equivalent hazard on UTI or pyelonephritis, and a higher hazard on cough, dyspnoea and nausea. We recommend 50 mg nitrofurantoin as daily prophylaxis.

Background The WHO recommends research into non-specific effects of vaccination. For rotavirus vaccines, these have not yet been well established. We studied non-specific effects up to 18 months of age using data from a quasi-experimental before-after study comparing cohorts of rotavirus vaccinated and unvaccinated infants with medical risk conditions. Methods Infants were enrolled at six weeks of age before and after a stepped-wedge implementation of a hospital-based risk-group rotavirus vaccination program. Other infant vaccinations were administered according to the Dutch National Immunization Program and similar in both cohorts. Non-specific effect outcomes were prospectively collected using monthly questionnaires and included acute hospitalization (excluding for acute gastroenteritis), monthly incidence of acute respiratory illness and eczema. We used time-to-event analysis and negative binomial regression to assess the effect of at least one dose of rotavirus vaccination for each of these outcomes. Findings The analysis included 496 rotavirus unvaccinated and 719 vaccinated medical risk infants. In total, 1067 (88%) were premature, 373 (31%) small for gestational age and 201 (17%) had a congenital pathology. The adjusted hazard ratio for first acute hospitalization was 0·91 (95 %CI 0·76;1·16) for rotavirus vaccinated versus unvaccinated infants. Adjusted incidence rate ratio for acute respiratory illness was 1·05 (95 %CI 0·96;1·15) and for eczema 0·89 (95 %CI 0·69;1·15). Conclusion The results suggest no, or minimal non-specific effects from rotavirus vaccination on acute hospitalization, acute respiratory illness or eczema in medical risk infants. Trial registration: as NTR5361 in the Dutch trial registry, www.trialregister.nl .

Background Staphylococcus aureus bacteremia (SAB) is a heterogeneous disease with changing epidemiology due to changing demographics and evolving clinical management. SAB is associated with high mortality, but the current fraction of infection-related mortality is less well quantified. Methods In a multicenter prospective cohort study of consecutive patients with SAB, we determined clinical features of SAB and determined 90-day mortality and risk factors of all-cause and infection-related mortality. Infection-related mortality was based on an adjudication committee evaluation. Results Four hundred ninety patients with SAB were included, with community-acquired (n = 166), health care–associated (n = 163), and hospital-acquired SAB (n = 161). Endocarditis (n = 90, 18.3%), peripheral intravenous catheter infection (n = 80, 16.3%), and septic arthritis (n = 58, 11.8%) were the most frequent diagnoses, but proportions differed for community, health care, and hospital acquisition. One hundred ninety-two patients (39%) had permanent implanted prosthetic material (eg, prosthetic joint, heart valve, pacemaker). Day 90 all-cause mortality was 33% (n = 161), with 60% adjudicated as infection-related, and 90% of infection-related deaths occurring in the first 30 days post-SAB. Infection-related deaths after 30 days were rare and mainly related to endocarditis. Determinants associated with day 90 infection-related mortality were age (odds ratio [OR], 1.09; 95% CI, 1.06–1.11), Charlson comorbidity index (OR, 1.13; 95% CI, 1.01–1.26), septic shock (OR, 9.78; 95% CI, 4.56–20.95), endocarditis (OR, 3.4; 95% CI, 1.75–6.61), and persistent SAB at 48 hours (OR, 2.36; 95% CI, 1.27–4.37). Conclusions Mortality due to S. aureus infection remains high and mainly occurs in the first 30 days, which could guide end points in future studies.

The anti-inflammatory agents dexamethasone (corticosteroid), and tocilizumab and sarilumab (IL6-inhibitors) are effective in the treatment of late COVID-19. Other anti-inflammatory agents, like anakinra (IL1-inhibitor), baricitinib and tofacitinib (JAK-inhibitors) and lenzilumab (GM-CSF-inhibitor) have also shown positive results in late COVID-19. For the treatment of early COVID-19, the inhalation corticosteroid budesonide is regarded as an off-label treatment option. Virus-inhibitors, like remdesivir, molnupiravir and nirmatrelvir/ritonavir decrease the risk of hospitalization and the development of severe COVID-19 by patients with early symptoms. Monoclonal antibodies have shown limited or no efficacy against the omicron-variant of SARS-CoV-2. Fluvoxamine, l-arginine, AT-527 and ensovibep are considered as potential promising new therapies for the treatment of early COVID-19.

Vaccination or recent exposure to infection with SARS-CoV-2 currently grants the vast majority of the population considerable immunity and thereby protection against severe disease. It is yet unknow how long this protection lasts. Continuous changes of the viral genotype and phenotype herein play an important role, in particular the variant-specific alterations of the spike protein. Protection by T-cell immunity seems to be more preserved in the event of changes in the virus as compared to antibody-mediated host defences. Furthermore, the continuous succession of virus variants also directly and indirectly affects the effectiveness of medical treatment. Regarding immune-modulating as well as anti-viral therapy, the viral characteristics of the circulating SARS-CoV-2 variant in combination with the level of host immunity will determine whether their use makes sense, and for which patients. The number of patients needed to treat to prevent a clinically negative outcome herein represents an important figure.

Background We aimed to determine the noninferiority of fosfomycin compared to ciprofloxacin as an oral step-down treatment for Escherichia coli febrile urinary tract infections (fUTIs) in women. Methods This was a double-blind, randomized, controlled trial in 15 Dutch hospitals. Adult women who were receiving 2–5 days of empirical intravenous antimicrobials for E. coli fUTI were assigned to step-down treatment with once-daily 3g fosfomycin or twice-daily 0.5g ciprofloxacin for 10 days of total antibiotic treatment. For the primary end point, clinical cure at days 6–10 post-end of treatment (PET), a noninferiority margin of 10% was chosen. The trial was registered on Trialregister.nl (NTR6449). Results After enrollment of 97 patients between 2017 and 2020, the trial ended prematurely because of the coronavirus disease 2019 pandemic. The primary end point was met in 36 of 48 patients (75.0%) assigned to fosfomycin and 30 of 46 patients (65.2%) assigned to ciprofloxacin (risk difference [RD], 9.6%; 95% confidence interval [CI]: –8.8% to 28.0%). In patients assigned to fosfomycin and ciprofloxacin, microbiological cure at days 6–10 PET occurred in 29 of 37 (78.4%) and 33 of 35 (94.3%; RD, –16.2%; 95% CI: –32.7 to –0.0%). Any gastrointestinal adverse event was reported in 25 of 48 (52.1%) and 14 of 46 (30.4%) patients (RD, 20.8%; 95% CI: 1.6% to 40.0%), respectively. Conclusions Fosfomycin is noninferior to ciprofloxacin as oral step-down treatment for fUTI caused by E. coli in women. Fosfomycin use is associated with more gastrointestinal events. Clinical Trial Registration Trial NL6275 (NTR6449)., Fosfomycin is noninferior to ciprofloxacin regarding clinical cure as a targeted oral step-down treatment for Escherichia colifebrile urinary tract infections in women. Its use could prevent extended hospitalization in cases of resistance, intolerance, or allergies to existing step-down antibiotics.

PurposeAlthough elective surgery is generally safe, some procedures remain associated with an increased risk of complications. Improved preoperative risk stratification and earlier recognition of these complications may ameliorate postoperative recovery and improve long-term outcomes. The perioperative longitudinal study of complications and long-term outcomes (PLUTO) cohort aims to establish a comprehensive biorepository that will facilitate research in this field. In this profile paper, we will discuss its design rationale and opportunities for future studies.ParticipantsPatients undergoing elective intermediate to high-risk non-cardiac surgery are eligible for enrolment. For the first seven postoperative days, participants are subjected to daily bedside visits by dedicated observers, who adjudicate clinical events and perform non-invasive physiological measurements (including handheld spirometry and single-channel electroencephalography). Blood samples and microbiome specimens are collected at preselected time points. Primary study outcomes are the postoperative occurrence of nosocomial infections, major adverse cardiac events, pulmonary complications, acute kidney injury and delirium/acute encephalopathy. Secondary outcomes include mortality and quality of life, as well as the long-term occurrence of psychopathology, cognitive dysfunction and chronic pain.Findings to dateEnrolment of the first participant occurred early 2020. During the inception phase of the project (first 2 years), 431 patients were eligible of whom 297 patients consented to participate (69%). Observed event rate was 42% overall, with the most frequent complication being infection.Future plansThe main purpose of the PLUTO biorepository is to provide a framework for research in the field of perioperative medicine and anaesthesiology, by storing high-quality clinical data and biomaterials for future studies. In addition, PLUTO aims to establish a logistical platform for conducting embedded clinical trials.Trial registration numberNCT05331118.

Objectives Long-term care facilities (LTCFs) may act as a reservoir of ESBL-producing Enterobacterales (ESBL-E) and carbapenemase-producing Enterobacterales (CPE) for hospitals and the general population. In this study, we estimated the prevalence and molecular epidemiology of rectal carriage with ESBL-E and CPE in residents of Dutch LTCFs between March 2018 and December 2018. Methods LTCFs were geographically selected across the country. For each LTCF, a random sample of residents were tested for ESBL-E and CPE in 2018. To identify risk factors for high carriage prevalence and/or individual carriage, characteristics of LTCFs and of a subset of the tested residents were collected. WGS was conducted on isolates from LTCFs with an ESBL-E prevalence of >10% and all CPE isolates to identify institutional clonal transmission. Results A total of 4420 residents of 159 LTCFs were included. The weighted mean ESBL-E prevalence was 8.3% (95% CI: 6.8–10.0) and no CPE were found. In 53 LTCFs (33%), where ESBL-E prevalence was >10%, MLST using WGS (wgMLST) was performed. This included 264 isolates, the majority being Escherichia coli (n = 224) followed by Klebsiella pneumoniae (n = 30). Genetic clusters were identified in more than half (30/53; 57%) of high ESBL-positive LTCFs. Among the E. coli isolates, blaCTX-M-15 (92/224; 41%) and blaCTX-M-27 (40/224; 18%) were the most prevalent ESBL-encoding genes. For K. pneumoniae isolates, the most common was blaCTX-M-15 (23/30; 80%). Conclusions The estimated prevalence of ESBL-E rectal carriage in Dutch LTCFs is 8.3% and resistance is observed mainly in E. coli with predominance of blaCTX-M-15 and blaCTX-M-27. ESBL-E prevalence in LTCFs seems comparable to previously reported prevalence in hospitals and the general population.

Objectives Antibiotic resistance in Gram-negative bacteria has been associated with increased mortality. This was demonstrated mostly for third-generation cephalosporin-resistant (3GC-R) Enterobacterales bacteraemia in international studies. Yet, the burden of resistance specifically in the Netherlands and created by all types of Gram-negative infection has not been quantified. We therefore investigated the attributable mortality of antibiotic resistance in Gram-negative infections in the Netherlands. Methods In eight hospitals, a sample of Gram-negative infections was identified between 2013 and 2016, and separated into resistant and susceptible infection cohorts. Both cohorts were matched 1:1 to non-infected control patients on hospital, length of stay at infection onset, and age. In this parallel matched cohort set-up, 30-day mortality was compared between infected and non-infected patients. The impact of resistance was then assessed by dividing the two separate risk ratios (RRs) for mortality attributable to Gram-negative infection. Results We identified 1,954 Gram-negative infections, of which 1,190 (61%) involved Escherichia coli, 210 (11%) Pseudomonas aeruginosa, and 758 (39%) bacteraemia. Resistant Gram-negatives caused 243 infections (12%; 189 (78%) 3GC-R Enterobacterales, 9 (4%) multidrug-resistant P. aeruginosa, no carbapenemase-producing Enterobacterales). Subsequently, we matched 1,941 non-infected controls. After adjustment, point estimates for RRs comparing mortality between infections and controls were similarly higher than 1 in case of resistant infections and susceptible infections (1.42 (95% confidence interval 0.66-3.09) and 1.32 (1.06-1.65), respectively). By dividing these, the RR reflecting attributable mortality of resistance was calculated as 1.08 (0.48-2.41). Conclusions In the Netherlands, antibiotic resistance did not increase 30-day mortality in Gram-negative infections.

To study whether replacement of nosocomial ampicillin-resistantRetrospective, matched-cohort study.The study included 20 Dutch and Danish hospitals from 2009 to 2014.Within the study period, 63 patients with VRE bacteremia (36 Dutch and 27 Danish) were identified and subsequently matched to 234 patients with ARE bacteremia (130 Dutch and 104 Danish) for hospital, ward, length of hospital stay prior to bacteremia, and age. For all patients, 30-day mortality after bacteremia onset was assessed.The risk ratio (RR) reflecting the impact of vancomycin resistance on 30-day mortality was estimated using Cox regression with further analytic control for confounding factors.The 30-day mortality rates were 27% and 38% for ARE in the Netherlands and Denmark, respectively, and the 30-day mortality rates were 33% and 48% for VRE in these respective countries. The adjusted RR for 30-day mortality for VRE was 1.54 (95% confidence interval, 1.06-2.25). Although appropriate antibiotic therapy was initiated later for VRE than for ARE bacteremia, further analysis did not reveal mediation of the increased mortality risk.Compared to ARE bacteremia, VRE bacteremia was associated with higher 30-day mortality. One explanation for this association would be increased virulence of VRE, although both phenotypes belong to the same well-characterized core genomic lineage. Alternatively, it may be the result of unmeasured confounding.

Immunological phenomena are a minor criteria in the modified Duke Criteria for endocarditis. Given the changes in epidemiology and diagnostics, the added value of determining these phenomena in today's patients with suspected endocarditis is unknown.In a retrospective cohort study of all patients with suspected endocarditis admitted to our hospital and discussed in our endocarditis team, we determined the proportion of patients classified as definite endocarditis because of either positive IgM rheumatoid factor (IgM RF), haematuria, or Roth's spots on ophthalmology consultation. We also determined diagnostic accuracy of each of these immunological phenomena separately and combined.Of 285 patients included, 138 (48%) had definite endocarditis and at least one immunological test was performed in 222 patients (78%). Elevated IgM RF was found in 22 of 126 patients tested (17%), haematuria in 78 of 196 tested (40%) and Roth's spots in six of 120 tested (5%). Eighteen of 138 patients with definite IE (13%) were classified as such because of a positive IgM RF, haematuria or Roth's spots. Haematuria had the highest sensitivity: 50.5% (95% CI 40.4-60.6) and Roth's spots the highest specificity: 98.3% (95% CI 90.8-99.9). The diagnostic accuracy results were robust in a sensitivity analysis aimed at avoiding incorporation bias.Among patients with a clinical suspicion of endocarditis, recommended systematic testing for immunological phenomena helped classify more patients as definite IE and is useful to confirm the diagnosis of endocarditis.

Background Staphylococcus aureus bacteremia (SAB) is in 10% to 20% of cases complicated by infective endocarditis. Clinical prediction scores may select patients with SAB at highest risk for endocarditis, improving the diagnostic process of endocarditis. We compared the accuracy of the Prediction Of Staphylococcus aureus Infective endocarditiseTime to positivity, Iv drug use, Vascular phenomena, preExisting heart condition (POSITIVE), Predicting Risk of Endocarditis Using a Clinical Tool (PREDICT), and VIRSTA scores for classifying the likelihood of endocarditis in patients with SAB. Methods Between August 2017 and September 2019, we enrolled consecutive adult patients with SAB in a prospective cohort study in 7 hospitals in the Netherlands. Using the modified Duke Criteria for definite endocarditis as reference standard, sensitivity, specificity, negative predictive (NPV), and positive predictive values were determined for the POSITIVE, PREDICT, and VIRSTA scores. An NPV of at least 98% was considered safe for excluding endocarditis. Results Of 477 SAB patients enrolled, 33% had community-acquired SAB, 8% had a prosthetic valve, and 11% a cardiac implantable electronic device. Echocardiography was performed in 87% of patients, and 42% received transesophageal echocardiography (TEE). Eighty-seven (18.2%) had definite endocarditis. Sensitivity was 77.6% (65.8%–86.9%), 85.1% (75.8%–91.8%), and 98.9% (95.7%–100%) for the POSITIVE (n = 362), PREDICT, and VIRSTA scores, respectively. NPVs were 92.5% (87.9%–95.8%), 94.5% (90.7%–97.0%), and 99.3% (94.9%–100%). For the POSITIVE, PREDICT, and VIRSTA scores, 44.5%, 50.7%, and 70.9% of patients with SAB, respectively, were classified as at high risk for endocarditis. Conclusions Only the VIRSTA score had an NPV of at least 98%, but at the expense of a high number of patients classified as high risk and thus requiring TEE. Clinical Trials Registration Netherlands Trial Register code 6669.

Purpose:Extraintestinal pathogenic Escherichia coli (ExPEC) are a leading cause of invasive infections in adults. The study aimed to evaluate the incidence of microbiologically confirmed invasive E...

SUMMARY Background In Dutch hospitals a 6-point questionnaire is currently mandatory for risk assessment to identify carriers of multidrug-resistant organisms (MDRO) at the time of hospitalization. Presence of one or more risk factors is followed by pre-emptive isolation and microbiological culturing. Aim We aimed to evaluate the yield of the universal risk assessment in identifying MDRO carriers upon hospitalization. Methods We performed a cross-sectional study using routine healthcare data in a Dutch tertiary hospital between January 1st 2015 and August 1st 2019. MDRO risk assessment upon hospitalization included assessment of: known MDRO carriage, previous hospitalization in another Dutch hospital during an outbreak or a foreign hospital, living in an asylum centre, exposure to livestock farming and household membership of a methicillin-resistant Staphylococcus aureus carrier. Findings 144,051 admissions of 84,485 unique patients were included. In total, 4,480 (3.1%) admissions had a positive MDRO risk assessment. In 1,516 (34%) admissions microbiological screening was performed, of which 341 (23%) yielded MDRO. 81 patients were categorized as new MDRO carriers, as identified through MDRO risk assessment, reflecting 0.06% (95% CI: 0.04%–0.07%) of all admissions and 1.8% (95% CI: 1.4%–2.2%) of those with positive risk assessment. As a result, the number of ‘MDRO risk-assessments needed to perform’ and individual ‘MDRO-questions needed to ask‘ to detect one new MDRO carrier upon hospitalization were 1,778 and 10,420, respectively. Conclusions We conclude that the yield of the current strategy of MDRO risk assessment upon hospitalization is limited and that it needs thorough reconsideration.

Objective Short-course aminoglycosides as adjunctive empirical therapy to β-lactams in patients with a clinical suspicion of sepsis are used to broaden antibiotic susceptibility coverage and to enhance bacterial killing. We quantified the impact of this approach on 30-day mortality in a subset of sepsis patients with a Gram-negative bloodstream infection. Methods From a prospective cohort study conducted in seven hospitals in the Netherlands between June 2013 and November 2015, we selected all patients with Gram-negative bloodstream infection (GN-BSI). Short-course aminoglycoside therapy was defined as tobramycin, gentamicin or amikacin initiated within a 48-hour time window around blood-culture obtainment, and prescribed for a maximum of 2 days. The outcome of interest was 30-day all-cause mortality. Confounders were selected a priori for adjustment using a propensity score analysis with inverse probability weighting. Results A total of 626 individuals with GN-BSI who received β-lactams were included; 156 (24.9%) also received aminoglycosides for a median of 1 day. Patients receiving aminoglycosides more often had septic shock (31/156, 19.9% versus 34/470, 7.2%) and had an eight-fold lower risk of inappropriate treatment (3/156, 1.9% versus 69/470, 14.7%). Thirty-day mortality was 17.3% (27/156) and 13.6% (64/470) for patients receiving and not receiving aminoglycosides, respectively; yielding crude and adjusted odds ratios for 30-day mortality for patients treated with aminoglycosides of 1.33 (95% CI 0.80–2.15) and 1.57 (0.84–2.93), respectively. Conclusions Short-course adjunctive aminoglycoside treatment as part of empirical therapy with β-lactam antibiotics in patients with GN-BSI did not result in improved outcomes, despite better antibiotic coverage of pathogens.

IntroductionThe human gut microbiota is an important reservoir of ESBL-producing Escherichia coli (ESBL-Ec). Community surveillance studies of ESBL-Ec to monitor circulating clones and ESBL genes are logistically challenging and costly.ObjectivesTo evaluate if isolates obtained in routine clinical practice can be used as an alternative to monitor the distribution of clones and ESBL genes circulating in the community.MethodsWGS was performed on 451 Dutch ESBL-Ec isolates (2014–17), including 162 community faeces and 289 urine and blood isolates. We compared proportions of 10 most frequently identified STs, PopPUNK-based sequence clusters (SCs) and ESBL gene subtypes and the degree of similarity using Czekanowski’s proportional similarity index (PSI).ResultsNine out of 10 most prevalent STs and SCs and 8/10 most prevalent ESBL genes in clinical ESBL-Ec were also the most common types in community faeces. The proportions of ST131 (39% versus 23%) and SC131 (40% versus 25%) were higher in clinical isolates than in community faeces (P ConclusionsDistributions of the 10 most prevalent clones and ESBL genes from ESBL-Ec community gut colonization and extra-intestinal infection overlapped in majority, indicating that isolates from routine clinical practice could be used to monitor ESBL-Ec clones and ESBL genes in the community.

Purpose To study the efficacy of lopinavir-ritonavir and hydroxychloroquine in critically ill patients with coronavirus disease 2019 (COVID-19). Methods Critically ill adults with COVID-19 were randomized to receive lopinavir-ritonavir, hydroxychloroquine, combination therapy of lopinavir-ritonavir and hydroxychloroquine or no antiviral therapy (control). The primary endpoint was an ordinal scale of organ support-free days. Analyses used a Bayesian cumulative logistic model and expressed treatment effects as an adjusted odds ratio (OR) where an OR > 1 is favorable. Results We randomized 694 patients to receive lopinavir-ritonavir (n = 255), hydroxychloroquine (n = 50), combination therapy (n = 27) or control (n = 362). The median organ support-free days among patients in lopinavir-ritonavir, hydroxychloroquine, and combination therapy groups was 4 (– 1 to 15), 0 (– 1 to 9) and—1 (– 1 to 7), respectively, compared to 6 (– 1 to 16) in the control group with in-hospital mortality of 88/249 (35%), 17/49 (35%), 13/26 (50%), respectively, compared to 106/353 (30%) in the control group. The three interventions decreased organ support-free days compared to control (OR [95% credible interval]: 0.73 [0.55, 0.99], 0.57 [0.35, 0.83] 0.41 [0.24, 0.72]), yielding posterior probabilities that reached the threshold futility (≥ 99.0%), and high probabilities of harm (98.0%, 99.9% and > 99.9%, respectively). The three interventions reduced hospital survival compared with control (OR [95% CrI]: 0.65 [0.45, 0.95], 0.56 [0.30, 0.89], and 0.36 [0.17, 0.73]), yielding high probabilities of harm (98.5% and 99.4% and 99.8%, respectively). Conclusion Among critically ill patients with COVID-19, lopinavir-ritonavir, hydroxychloroquine, or combination therapy worsened outcomes compared to no antiviral therapy. Supplementary Information The online version contains supplementary material available at 10.1007/s00134-021-06448-5.

Supplemental Digital Content is available in the text., Background: Infants with medical risk conditions are vulnerable to childhood infections including acute gastroenteritis (AGE). To guide prevention programs, we quantified AGE incidence, severity and virus prevalence among medical risk infants in the Netherlands. Methods: This prospective cohort-study was part of the RIVAR-project recruiting infants with prematurity, low birth weight or severe congenital conditions in 13 hospitals. Follow-up included 18 monthly health questionnaires detailing AGE symptoms and healthcare usage. Parents were also instructed to notify when an infant developed AGE, to collect a stool sample and complete a daily severity score (Modified Vesikari Severity). Stool samples were analyzed by real-time polymerase chain reaction for rotavirus, norovirus, adenovirus and astrovirus. Results: Between November 2014 and October 2017, 631 infants participated during 9125 person-months of observation. In total, 559 episodes were identified. The mean AGE incidence rate was 73.5 per 100 person-years (PY) (95% confidence interval: 67.6–79.9) and increased with age [incidence rate: 48.3 (39.8–58.3) vs. 80.2 (73.0–88.1)/100 PY for ages 1–5 vs. 6–18 months, respectively]. Healthcare was attended for 38.1% (213/559) and 26.8% (68/254) were classified as severe based on the Modified Vesikari Severity. Stool samples were obtained from 254 AGE episodes. Norovirus was identified in 65 (25.6%) and rotavirus in 44 (17.7%). Adenovirus and astrovirus together accounted for 8.3% (N = 21). Severe AGE occurred most frequently in rotavirus positive episodes. Conclusion: The observed AGE incidence, severity and healthcare usage among medical risk infants confirms substantial disease burden. Norovirus and rotavirus are the dominant pathogens and severe episodes occurred most frequently in children with rotavirus infection. AGE prevention in medical risk infants should be prioritized.

Objectives: We evaluated the effect of renal function on clinical failure rates of nitrofurantoin, fosfomycin and trimethoprim for the treatment of cystitis in primary care. Methods: Data were retrospectively obtained from 78 Dutch general practitioner (GP) practices between 2013 and 2019. Eligible episodes in patients (>11 years) were those requiring 5 days of nitrofurantoin (NF5), single-dose fosfomycin–trometamol (FT1), 3 days of trimethoprim (TMP3) for uncomplicated cystitis, or 7 days of nitrofurantoin (NF7) or trimethoprim (TMP7) for complicated cystitis. Clinical failure was defined as second antibiotic prescription for cystitis or pyelonephritis within 28 days post-prescription. Mixed effects regression analysis was used, with patient and GP practice as random effects and demography, comorbidity, and cystitis history as fixed effects. Results: Adjusted odds ratios (aORs) for clinical failure per 10mL/min decrease in estimated glomerular filtration rate (eGFR) were 1.05 (95% CI: 1.01–1.09) for NF5 (n = 24,591), 0.96 (95% CI: 0.92–1.01) for FT1 (n = 5359), 0.98 (95% CI: 0.89–1.08) for TMP3 (n = 1064), 1.05 (95% CI: 1.02–1.09) for NF7 (n = 10,628) and 1.02 (95% CI: 0.93–1.14) for TMP7 (n = 831). In uncomplicated cystitis and eGFR ≥60 mL/min, clinical failures occurred in 14.6% (1895/12 980) of NF5-treated, 20.7% (266/1283) of FT1-treated (aOR versus NF5 1.37, 95% CI 1.18–1.59) and 20.8% (66/318) of TMP3-treated patients (aOR 1.42, 95% CI 1.07–1.87 versus NF5). In uncomplicated cystitis and eGFR

Since the 1990s few new antibiotics have become available; during the same period the appearance and spread of bacteria no longer susceptible to first- and second-line antibiotics has accelerated; indeed some bacterial infections have become untreatable with existing antibiotics. Control of antibiotic resistance is multifactorial, and includes restrictive antibiotic use and good infection control. This lecture addresses three aspects of antibiotic resistance, with reference to the Netherlands, that illustrate the complexity of antibiotic resistance epidemiology. Initially selective decontamination of the digestive tract (SDD) was not adopted in the Netherlands because of concern about antibiotic resistance. However, three trials showed that SDD regimens, including four days of systemic cephalosporins, gave better clinical outcomes with no effect on antibiotic-resistant bacteria. Many predictions have been made about the impact of infections with antibiotic-resistant bacteria on human health. However, the situation is complex, because the risk factors for infection with multidrug-resistant bacteria are also risk factors for poor clinical outcome. A study in eight Dutch hospitals estimated the mortality attributable to antibiotic resistance as close to zero. Concern about the emergence of resistance in Staphylococcus aureus has limited the universal use of mupirocin to prevent surgical site infections. However, the risk may have been overstated, and universal decolonization with mupirocin and chlorhexidine has now become standard of care in patients undergoing cardiothoracic or orthopaedic surgery in many Dutch hospitals. Prophylactic antibiotics can improve patient outcomes with acceptable risks of promoting resistance.

Objective: To investigate the incidence, clinical characteristics and outcomes of early hyperbilirubinemia in critically ill patients. Design and Setting: This is a post hoc analysis of a prospective multicenter cohort study. Patients: Patients with measured bilirubin levels within the first 2 days after ICU admission were eligible. Patients with liver cirrhosis were excluded. Endpoints: The primary endpoint was the incidence of early hyperbilirubinemia, defined as bilirubin ≥33 μmol/L within 2 days after ICU admission. Secondary endpoints included clinical characteristics of patients with versus patients without early hyperbilirubinemia, and outcomes up to day 30. Results: Of 4,836 patients, 559 (11.6%) patients had early hyperbilirubinemia. Compared to patients without early hyperbilirubinemia, patients with early hyperbilirubinemia presented with higher severity of illness scores, and higher incidences of sepsis and organ failure. After adjustment for confounding variables, early hyperbilirubinemia remained associated with mortality at day 30 (odds ratio, 1.31 [95%–confidence interval 1.06–1.60]; P = 0.018). Patients with early hyperbilirubinemia and thrombocytopenia (interaction P-value = 0.005) had a higher likelihood of death within 30 days (odds ratio, 2.61 [95%–confidence interval 2.08–3.27]; P < 0.001) than patients with early hyperbilirubinemia and a normal platelet count (odds ratio, 1.09 [95%–confidence interval 0.75–1.55]; P = 0.655). Conclusions: Early hyperbilirubinemia occurs frequently in the critically ill, and these patients present with higher disease severity and more often with sepsis and organ failures. Early hyperbilirubinemia has an association with mortality, albeit this association was only found in patients with concomitant thrombocytopenia.

Background Surveillance is the cornerstone of surgical site infection prevention programs. The validity of the data collection and awareness of vulnerability to inter-rater variation is crucial for correct interpretation and use of surveillance data. The aim of this study was to investigate the reliability and validity of surgical site infection (SSI) surveillance after colorectal surgery in the Netherlands. Methods In this multicentre prospective observational study, seven Dutch hospitals performed SSI surveillance after colorectal surgeries performed in 2018 and/or 2019. When executing the surveillance, a local case assessment was performed to calculate the overall percentage agreement between raters within hospitals. Additionally, two case-vignette assessments were performed to estimate intra-rater and inter-rater reliability by calculating a weighted Cohen’s Kappa and Fleiss’ Kappa coefficient. To estimate the validity, answers of the two case-vignettes questionnaires were compared with the answers of an external medical panel. Results 1111 colorectal surgeries were included in this study with an overall SSI incidence of 8.8% (n = 98). From the local case assessment it was estimated that the overall percent agreement between raters within a hospital was good (mean 95%, range 90–100%). The Cohen’s Kappa estimated for the intra-rater reliability of case-vignette review varied from 0.73 to 1.00, indicating substantial to perfect agreement. The inter-rater reliability within hospitals showed more variation, with Kappa estimates ranging between 0.61 and 0.94. In total, 87.9% of the answers given by the raters were in accordance with the medical panel. Conclusions This study showed that raters were consistent in their SSI-ascertainment (good reliability), but improvements can be made regarding the accuracy (moderate validity). Accuracy of surveillance may be improved by providing regular training, adapting definitions to reduce subjectivity, and by supporting surveillance through automation.

Household transmission studies are useful to quantify SARS-CoV-2 transmission dynamics. We conducted a remote prospective household study to quantify transmission, and the effects of subject characteristics, household characteristics, and implemented infection control measures on transmission. Households with a laboratory-confirmed SARS-CoV-2 index case were enrolled 85% completed sample collection. 200 secondary SARS-CoV-2 infections were detected, yielding a household SAR of 45.7% (95% CI 39.7–51.7%) and per-person SAR of 32.6% (95%CI: 28.1-37.4%). 126 (63%) secondary cases were detected at enrollment. Mild (aRR = 0.57) and asymptomatic index cases (aRR = 0.29) were less likely to transmit SARS-CoV-2, compared to index cases with an acute respiratory illness (p = 0.03 for trend), and child index cases (p = 0.03 for trend). Infection control interventions in households had no significant effect on transmission. We found high SARs with the majority of transmissions occuring early after SARS-CoV-2 introduction into the household. This may explain the futile effect of implemented household measures. Age and symptom status of the index case influence secondary transmission. Remote, digitally-supported study designs with self-sampling are feasible for studying transmission under pandemic restrictions.

Background A causative role of Coxiella burnetii (the causative agent of Q fever) in the pathogenesis of B-cell non-Hodgkin lymphoma (NHL) has been suggested, although supporting studies show conflicting evidence. We assessed whether this association is present by performing a detailed analysis on the risk of mature B-cell NHL after Q fever during and after the largest Q fever outbreak reported worldwide in the entire Dutch population over a 16-year period. Methods We performed an ecological analysis. The incidence of mature B-cell NHL in the entire Dutch population from 2002 until 2017 was studied and modelled with reported acute Q fever cases as the determinant. The adjusted relative risk of NHL after acute Q fever as the primary outcome measure was calculated using a Poisson regression. Results Between January 2002 and December 2017, 266 050 745 person-years were observed, with 61 424 diagnosed with mature B-cell NHL. In total, 4310 persons were diagnosed with acute Q fever, with the highest incidence in 2009. The adjusted relative risk of NHL after acute Q fever was 1.02 (95% CI 0.97–1.06, P = 0.49) and 0.98 (95% CI 0.89–1.07, P = 0.60), 0.99 (95% CI 0.87–1.12, P = 0.85) and 0.98 (95% 0.88–1.08, P = 0.67) for subgroups of diffuse large B-cell lymphoma, follicular lymphoma or B-cell chronic lymphocytic leukaemia, respectively. Modelling with lag times (1–4 years) did not change interpretation. Conclusion We found no evidence for an association between C. burnetii and NHL after studying the risk of mature B-cell NHL after a large Q fever outbreak in Netherlands.

Objectives The efficacy of 13-valent pneumococcal conjugate vaccine (PCV13) in adults to prevent community-acquired pneumonia (CAP) and lower respiratory tract infections (LRTI) not requiring hospitalization is unknown. We determined the effect of PCV13 on CAP, LRTI and antibiotic use in the primary care setting. Methods Community-dwelling immunocompetent adults over 65 years of age were randomized to PCV13 or placebo as part of the double-blind Community-Acquired Pneumonia immunization Trial in Adults (CAPiTA). CAP and LRTI episodes and antibiotic prescription data were extracted from general practitioner information systems of 40 426 individuals. Vaccine efficacy (VE) of PCV13 was determined using Poisson regression with robust standard errors, comparing CAP and non-CAP LRTI episodes, LRTI-specific and total antibiotic prescriptions. Results In all, 20 195 participants received PCV13 and 20 231 received placebo. A total of 1564 and 1659 CAP episodes occurred in the PCV13 and placebo group, respectively; VE 5.5% (95% CI –2.6% to 13.0%). Non-CAP LRTI episodes occurred 7535 and 7817 times in the PCV13 and placebo groups, respectively; VE 3.4% (95% CI –2.0% to 8.5%). A total of 8835 and 9245 LRTI-related antibiotic courses were prescribed in the PCV13 and placebo arms, respectively; VE 4.2% (95% CI –1.0% to 9.1%). Antibiotic courses for any indication were prescribed 43 386 and 43 309 times, respectively; VE –0.4% (–4.9% to 3.9%). Conclusions PCV13 vaccination in the elderly is unlikely to cause a relevant reduction in the incidence of CAP, LRTI, LRTI-related antibiotic use or total antibiotic use in primary care.

Purpose: Sepsis is the most frequent cause of acute kidney injury (AKI). The "Acute Disease Quality Initiative Workgroup" recently proposed new definitions for AKI, classifying it as transient or persistent. We investigated the incidence, mortality, and host response aberrations associated with transient and persistent AKI in sepsis patients., Methods: A total of 1545 patients admitted with sepsis to 2 intensive care units in the Netherlands were stratified according to the presence (defined by any urine or creatinine RIFLE criterion within the first 48 h) and evolution of AKI (with persistent defined as remaining > 48 h). We determined 30-day mortality by logistic regression adjusting for confounding variables and analyzed 16 plasma biomarkers reflecting pathways involved in sepsis pathogenesis (n = 866) and blood leukocyte transcriptomes (n = 392)., Results: AKI occurred in 37.7% of patients, of which 18.4% was transient and 81.6% persistent. On admission, patients with persistent AKI had higher disease severity scores and more frequently had severe (injury or failure) RIFLE AKI stages than transient AKI patients. Persistent AKI, but not transient AKI, was associated with increased mortality by day 30 and up to 1 year. Persistent AKI was associated with enhanced and sustained inflammatory and procoagulant responses during the first 4 days, and a more severe loss of vascular integrity compared with transient AKI. Baseline blood gene expression showed minimal differences with respect to the presence or evolution of AKI., Conclusion: Persistent AKI is independently associated with sepsis mortality, as well as with sustained inflammatory and procoagulant responses, and loss of vascular integrity as compared with transient AKI., peer-reviewed

Background Escherichia coli is the most common cause of bacteremia in high-income countries. To enable the development and implementation of effective prevention strategies, a better understanding of the current epidemiology of invasive E. coli infections is needed. Methods A systematic review of literature published between 1 January 2007 and 31 March 2018 on the burden and epidemiology of E. coli bacteremia in populations that include adults in high-income countries was conducted. Meta-analysis was performed for descriptive purposes. Results During the studied time interval, the estimated incidence rate of E. coli bacteremia was 48 per 100 000 person-years, but this increased considerably with age: rates per 100 000 person-years were >100 in 55-to-75-year-olds and >300 in 75-to-85-year-olds. Overall, E. coli accounted for 27% of documented bacteremia episodes: 18% if hospital acquired, 32% if community-onset healthcare associated, and 33% if community acquired. The estimated case fatality rate was 12%. Approximately 44% of episodes were community acquired, 27% community-onset healthcare associated, and 27% hospital acquired. Urinary tract infection (UTI) was the primary source for 53% of episodes. Conclusions This systematic review confirms the substantial burden of E. coli bacteremia in older adults and justifies the implementation of community-level programs to prevent E. coli bacteremia and ideally UTI in this age group.

SARS-CoV-2 infection is mild in the majority of individuals, but progresses into severe pneumonia in a small proportion of patients. The increased susceptibility to severe disease in the elderly and individuals with co-morbidities argues for an initial defect in anti-viral host defense mechanisms. Long-term boosting of innate immune responses, also termed ‘trained immunity’, by certain live vaccines (BCG, oral polio vaccine, measles) induces heterologous protection against infections, through epigenetic, transcriptional and functional reprogramming of innate immune cells. We propose that induction of trained immunity by whole microorganism vaccines may represent an important tool for reducing susceptibility and severity to SARS-CoV-2., Netea and colleagues argue that we may be able to prevent or decrease the severity of SARS-CoV-2 infection through certain clinically-approved live vaccines that “train” the innate immune system to be broadly vigilant against viral infection.

Selective decontamination of the digestive tract (SDD) is an infection prevention measure for intensive care unit (ICU) patients that was proposed more than 30 years ago, and that is currently considered standard of care in the Netherlands, but only used sporadically in ICUs in other countries. In this narrative review, we first describe the rationale of the individual components of SDD and then review the evidence base for patient-centered outcomes, where we distinguish ICUs with low prevalence of antibiotic resistance from ICUs with moderate–high prevalence of resistance. In settings with low prevalence of antibiotic resistance, SDD has been associated with improved patient outcome in three cluster-randomized studies. These benefits were not confirmed in a large international cluster-randomized study in settings with moderate-to-high prevalence of antibiotic resistance. There is no evidence that SDD increases antibiotic resistance. We end with future directions for research. Electronic supplementary material The online version of this article (10.1007/s00134-019-05883-9) contains supplementary material, which is available to authorized users.

The objective of this study was to determine the value of using SuperPolymyxin™ selective medium (ELITech Group, Puteaux, France) in addition to conventional non-selective inoculation methods in the detection of acquired colistin resistance in a Dutch intensive care unit (ICU) that routinely uses selective decontamination of the digestive tract (SDD). We performed a cross-sectional study with prospective data collection in a tertiary-care ICU. All consecutive surveillance rectal swabs of ICU-patients receiving SDD were included and cultured in an observer-blinded approach using (1) a conventional culture method using non-selective media and (2) SuperPolymyxin™ selective medium. MIC values for colistin of non-intrinsically colistin-resistant Gram-negative isolates were determined with broth microdilution (BMD) using Sensititre™ and colistin resistance was confirmed using BMD according to EUCAST guidelines. One thousand one hundred five rectal swabs of 428 unique ICU-patients were inoculated using both culture methods, yielding 346 and 84 Gram-negative isolates for BMD testing with the conventional method and SuperPolymyxin™ medium, of which 308 and 80 underwent BMD, respectively. The number of identified rectal carriers of isolates with acquired colistin resistance was 3 (0.7%) for the conventional method, 4 (0.9%) for SuperPolymyxin™, and 5 (1.2%) for both methods combined. The number of isolates with acquired colistin resistance was 4 (1.0%) for the conventional method, 8 (2.1%) for SuperPolymyxin™ and 9 (2.3%) for both methods combined. In a surveillance setting of low prevalence of acquired colistin resistance in patients that receive SDD in a Dutch tertiary-care ICU, SuperPolymyxin™ had a higher diagnostic yield than conventional inoculation methods, but the combination of both had the highest diagnostic yield. Electronic supplementary material The online version of this article (10.1007/s10096-019-03718-5) contains supplementary material, which is available to authorized users.

BackgroundAround 15%–20% of children with acute otitis media present with ear discharge due to a spontaneous tear or perforation of the eardrum (AOMd). Current guidance recommends clinicians to consider oral antibiotics as first-line treatment in this condition. The opening in the eardrum however should allow topical antibiotics to enter the middle ear directly. Local administration of antibiotics does not expose children to systemic side effects and may put less selective resistance pressure on bacteria. Evidence on the effectiveness of this approach in children with AOMd is lacking.Methods and analysisA primary care-based, open, individually randomised, controlled, non-inferiority trial. The trial aims to recruit 350 children aged 6 months to 12 years with AOMd and ear pain and/or fever. Participants will be randomised to 7 days of hydrocortisone-bacitracin-colistin eardrops five drops three times daily or amoxicillin oral suspension 50 mg/kg body weight per day, divided over three doses. Parents will keep a daily diary of AOM symptoms, adverse events and complications for 2 weeks. In addition, they will record AOM recurrences, healthcare utilisation and societal costs for 3 months. The primary outcome is the proportion of children without ear pain and fever at day 3. Secondary outcomes include ear pain and fever intensity/severity; days with ear discharge; eardrum perforation at 2 weeks; adverse events during first 2 weeks; costs; and cost effectiveness at 2 weeks and 3 months. The primary analyses will be intention-to-treat and per-protocol analyses will be conducted as well.Ethics and disseminationThe medical research ethics committee Utrecht, The Netherlands has given ethical approval (17-400/G-M). Parents/guardians of participants will provide written informed consent. Study results will be submitted for publication in peer-reviewed medical journals and presented at relevant (inter)national scientific meetings.Trial registration numberThe Netherlands National Trial Register; NTR6723. Date of registration: 27 November 2017.

Rationale: Myocardial injury occurs frequently during sepsis and is independently associated with mortality. However, its etiology remains largely unknown. Objectives: To assess the relative contributions of hyperinflammation, activated coagulation, and endothelial dysfunction to myocardial injury in critically ill patients with sepsis. Methods: We included consecutive patients with sepsis presenting to two tertiary intensive care units in the Netherlands between 2011 and 2013. High-sensitivity cardiac troponin I as well as a wide range of plasma biomarkers related to inflammation, coagulation, and endothelial function were measured. Structural equation modeling was used to construct latent variables representing each of these pathophysiological constructs and to subsequently study their associations with troponin elevation while adjusting for confounders. Results: We analyzed 908 (88%) of 1,037 eligible patients, 553 (61%) of whom had raised high-sensitivity cardiac troponin I levels upon intensive care unit admission. The latent variables included interleukin (IL)-6, IL-8, and IL-1b for inflammation; platelet count, prothrombin time, and protein C for coagulation; and soluble E-selectin, intercellular adhesion molecule-1, and angiopoietin-2 for endothelial function. After adjustment for age and cardiovascular comorbidities, structural equation modeling analysis showed that activated coagulation was independently associated with elevated troponin during sepsis (standardized regression coefficient, 0.551; 95% confidence interval [CI], 0.257-0.845; P,0.001) whereas hyperinflammation and endothelial dysfunction were not (standardized regression coefficient, 20.161; 95% CI, 20.418 to 0.096 and 20.054; 95% CI, 20.168 to 0.060, respectively). Conclusions: Our findings suggest that myocardial injury during sepsis is mediated by systemic activation of coagulation rather than by circulating inflammatory mediators or activation of the endothelium. These findings may guide evaluation of strategies to protect the myocardium during sepsis. Clinical trial registered with clinicaltrials.gov (NCT01905033).

IntroductionReal-world vaccine effectiveness (VE) estimates are essential to identify potential groups at higher risk of break-through infections and to guide policy. We assessed the VE of COVID-19 vaccination against COVID-19 hospitalization, while adjusting and stratifying for patient characteristics.MethodsWe performed a test-negative case-control study in six Dutch hospitals. The study population consisted of adults eligible for COVID-19 vaccination hospitalized between May 1 and June 28 2021 with respiratory symptoms. Cases were defined as patients who tested positive for SARS-CoV-2 by PCR during the first 48 hours of admission or within 14 days prior to hospital admission. Controls were patients tested negative at admission and did not have a positive test during the 2 weeks prior to hospitalization. VE was calculated using multivariable logistic regression, adjusting for calendar week, sex, age, comorbidity and nursing home residency. Subgroup analysis was performed for age, sex and different comorbidities. Secondary endpoints were ICU-admission and mortality.Results379 cases and 255 controls were included of whom 157 (18%) were vaccinated prior to admission. Five cases (1%) and 40 controls (16%) were fully vaccinated (VE: 93%; 95% CI: 81 – 98), and 40 cases (11%) and 70 controls (27%) were partially vaccinated (VE: 70%; 95% CI: 50-82). A strongly protective effect of vaccination was found in all comorbidity subgroups. No ICU-admission or mortality were reported among fully vaccinated cases. Of unvaccinated cases, mortality was 10% and 19% was admitted at the ICUConclusionCOVID-19 vaccination provides a strong protective effect against COVID-19 related hospital admission, in patients with and without comorbidity.