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Objectives: The COVID-19 pandemic increases healthcare worker (HCW) absenteeism. The bacillus Calmette-Gue?rin (BCG) vaccine may provide non-specific protection against respiratory infections through enhancement of trained immunity. We investigated the impact of BCG vaccination on HCW absenteeism during the COVID-19 pandemic. Methods: HCWs exposed to COVID-19 patients in nine Dutch hospitals were randomized to BCG vaccine or placebo in a 1:1 ratio, and followed for one year using a mobile phone application. The primary endpoint was the self-reported number of days of unplanned absenteeism for any reason. Secondary endpoints included documented COVID-19, acute respiratory symptoms or fever. This was an investigator-funded study, registered at ClinicalTrials.gov (NCT03987919). Results: In March/April 2020, 1511 HCWs were enrolled. The median duration of follow-up was 357 person-days (interquartile range [IQR], 351 to 361). Unplanned absenteeism for any reason was observed in 2.8% of planned working days in the BCG group and 2.7% in the placebo group (adjusted relative risk 0.94; 95% credible interval, 0.78-1.15). Cumulative incidences of documented COVID-19 were 14.2% in the BCG and 15.2% in the placebo group (adjusted hazard ratio (aHR) 0.94; 95% confidence interval (CI), 0.72-1.24). First episodes of self-reported acute respiratory symptoms or fever occurred in 490 (66.2%) and 443 (60.2%) participants, respectively (aHR: 1.13; 95% CI, 0.99-1.28). Thirty-one serious adverse events were reported (13 after BCG, 18 after placebo), none considered related to study medication.Conclusions: During the COVID-19 pandemic, BCG-vaccination of HCW exposed to COVID-19 patients did not reduce unplanned absenteeism nor documented COVID-19. (C) 2022 The Author(s). Published by Elsevier Ltd on behalf of European Society of Clinical Microbiology and Infectious Diseases.

Objective To compare the effectiveness of five versus seven days of nitrofurantoin treatment for urinary tract infection (UTI) in diabetic women. Methods Data were collected retrospectively from Dutch general practitioners between 2013 and 2020. Nitrofurantoin prescriptions with a duration of five (5DN) or seven days (7DN) in women with diabetes were included. Inverse propensity weighting (IPW) was performed to calculate adjusted risk differences (RD) for treatment failure within 28 days. Secondary outcomes were 14-day treatment failure, severe treatment failure, and 28-day treatment failure in defined risk groups. Results Nitrofurantoin was prescribed in 6866 episodes, 3247 (47,3%) episodes with 5DN and 3619 (52,7%) episodes with 7DN. Patients in the 7DN group had more co-morbidities, more diabetes-related complications and were more insulin-dependent. There were 517/3247 (15.9%) failures in the 5DN group versus 520/3619 (14.4%) in the 7DN group. The adjusted RD for failure within 28 days was 1.4% (95% CI -0.6 to 3.4). Conclusion We found no clinically significant difference in treatment failure in diabetic women with UTI treated either five or seven days with nitrofurantoin within 28 days. A 5-day treatment should be considered to reduce cumulative nitrofurantoin exposure in DM patients.

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.

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.

October 31, 2022

June 16, 2020

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September 19, 2022

Background Older age is associated with increased severity and death from respiratory infections, including coronavirus disease 2019 (COVID-19). The tuberculosis BCG vaccine may provide heterologous protection against nontuberculous infections and has been proposed as a potential preventive strategy against COVID-19. Methods In this multicenter, placebo-controlled trial, we randomly assigned older adults (aged ≥60 years; n = 2014) to intracutaneous vaccination with BCG vaccine (n = 1008) or placebo (n = 1006). The primary end point was the cumulative incidence of respiratory tract infections (RTIs) that required medical intervention, during 12 months of follow-up. Secondary end points included the incidence of COVID-19, and the effect of BCG vaccination on the cellular and humoral immune responses. Results The cumulative incidence of RTIs requiring medical intervention was 0.029 in the BCG-vaccinated group and 0.024 in the control group (subdistribution hazard ratio, 1.26 [98.2% confidence interval, .65–2.44]). In the BCG vaccine and placebo groups, 51 and 48 individuals, respectively tested positive for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) with polymerase chain reaction (subdistribution hazard ratio, 1.053 [95% confidence interval, .71–1.56]). No difference was observed in the frequency of adverse events. BCG vaccination was associated with enhanced cytokine responses after influenza, and also partially associated after SARS-CoV-2 stimulation. In patients diagnosed with COVID-19, antibody responses after infection were significantly stronger if the volunteers had previously received BCG vaccine. Conclusions BCG vaccination had no effect on the incidence of RTIs, including SARS-CoV-2 infection, in older adult volunteers. However, it improved cytokine responses stimulated by influenza and SARS-CoV-2 and induced stronger antibody titers after COVID-19 infection. Clinical trials registration EU Clinical Trials Register 2020-001591-15 ClinicalTrials.gov NCT04417335.

BackgroundBacillus Calmette-Guerin (BCG) vaccination has been hypothesised to reduce SARS-CoV-2 infection, severity, and/or duration via trained immunity induction.MethodsHealthcare workers (HCWs) in 9 Dutch hospitals were randomised to BCG or placebo vaccination (1:1) in March/April 2020 and followed for one year. They reported daily symptoms, SARS-CoV-2 test results, and healthcare-seeking behaviour via a smartphone application, and donated blood for SARS-CoV-2 serology at two time points.Results1,511 HCWs were randomised and 1,309 analysed (665 BCG and 644 placebo). Of the 298 infections detected during the trial, 74 were detected by serology only. The SARS-CoV-2 incidence rates were 0.25 and 0.26 per person-year in the BCG and placebo groups, respectively (incidence rate ratio=0.95; 95% confidence interval 0.76-1.21; p=0.732). Only three participants required hospitalisation for COVID-19. The proportions of participants with asymptomatic, mild, or mild-to-moderate infections, and the mean infection durations, did not differ between randomisation groups. Unadjusted and adjusted logistic regression and Cox proportional hazards models showed no differences between BCG and placebo vaccination for any of these outcomes either. The percentage of participants with seroconversion (7.8% versus 2.8%; p=0.006) and mean anti-S1 antibody concentration (13.1 versus 4.3 IU/ml; p=0.023) were higher in the BCG than placebo group at 3 months but not at 6 or 12 months post-vaccination.ConclusionsBCG vaccination of HCWs did not reduce SARS-CoV-2 infections nor infection duration or severity (on a scale from asymptomatic to moderate). In the first 3 months after vaccination, BCG vaccination may enhance SARS-CoV-2 antibody production during SARS-CoV-2 infection.

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.

Chronic pancreatitis (CP) is an inflammatory disease that may be complicated by abdominal pain, pancreatic dysfunction, nutritional deficiencies, and diminished bone density. Importantly, it is also associated with a substantially impaired quality of life and reduced life expectancy. This may partly be explained by suboptimal treatment, in particular the long-term management of this chronic condition, despite several national and international guidelines. Standardization of care through a structured implementation of guideline recommendations may improve the level of care and lower the complication rate of these patients. Therefore, the aim of the present study is to evaluate to what extent patient education and standardization of care, through the implementation of an evidence-based integrated management algorithm, improve quality of life and reduce pain severity in patients with CP.The COMBO trial is a nationwide stepped-wedge cluster-randomized controlled trial. In a stepwise manner, 26 centers, clustered in 6 health regions, cross-over from current practice to care according to an evidence-based integrated management algorithm. During the current practice phase, study participants are recruited and followed longitudinally through questionnaires. Individual patients contribute data to both study periods. Co-primary study endpoints consist of quality of life (assessed by the PANQOLI score) and level of pain (assessed by the Izbicki questionnaire). Secondary outcomes include process measure outcomes, clinical outcomes (e.g., pancreatic function, nutritional status, bone health, interventions, medication use), utilization of healthcare resources, (in) direct costs, and the level of social participation. Standard follow-up is 35 months from the start of the trial.This is the first stepped-wedge cluster-randomized controlled trial to investigate whether an evidence-based integrated therapeutic approach improves quality of life and pain severity in patients with CP as compared with current practice.ISRCTN, ISRCTN13042622. Registered on 5 September 2020.

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.

Objectives We assessed the prognostic value of phase I IgG titres during treatment and follow-up of chronic Q fever. Methods We performed a retrospective cohort study to analyse the course of phase I IgG titres in chronic Q fever. We used a multivariable time-varying Cox regression to assess our primary (first disease-related event) and secondary (therapy failure) outcomes. In a second analysis, we evaluated serological characteristics after 1 year of therapy (fourfold decrease in phase I IgG titre, absence of phase II IgM and reaching phase I IgG titre of ≤1:1024) with multivariable Cox regression. Results In total, 337 patients that were treated for proven (n = 284, 84.3%) or probable (n = 53, 15.7%) chronic Q fever were included. Complications occurred in 190 (56.4%), disease-related mortality in 71 (21.1%) and therapy failure in 142 (42.1%) patients. The course of phase I IgG titres was not associated with first disease-related event (HR 1.00, 95% CI 0.86–1.15) or therapy failure (HR 1.02, 95% CI 0.91–1.15). Similar results were found for the serological characteristics for the primary (HR 0.97, 95% CI 0.62–1.51; HR 1.12, 95% CI 0.66–1.90; HR 0.99, 95% CI 0.57–1.69, respectively) and secondary outcomes (HR 0.86, 95% CI 0.57–1.29; HR 1.37, 95% CI 0.86–2.18; HR 0.80, 95% CI 0.48–1.34, respectively). Discussion Coxiella burnetii serology does not reliably predict disease-related events or therapy failure during treatment and follow-up of chronic Q fever. Alternative markers for disease management are needed, but, for now, management should be based on clinical factors, PCR results, and imaging results.

Objectives There is a global increase in infections caused by Gram-negative bacteria. The majority of research is on bacteremic Gram-negative infections (GNI), leaving a knowledge gap on the burden of non-bacteremic GNI. Our aim is to describe characteristics and determine the burden of bacteremic and non-bacteremic GNI in hospitalized patients in the Netherlands. Methods We conducted a prospective cohort study of patients in eight hospitals with microbiologically confirmed GNI, between June 2013 and November 2015. In each hospital the first five adults meeting the eligibility criteria per week were enrolled. We estimated the national incidence and mortality of GNI by combining the cohort data with a national surveillance database for antimicrobial resistance. Results 1,954 patients with GNI were included of which 758 (39%) were bloodstream infections (BSI). 243 GNI (12%) involved multi-drug resistant pathogens. 30-day mortality rate was 11.1% (n = 217) Estimated national incidences of non-bacteremic GNI and bacteremic GNI in hospitalized adults were 74 (95% CI 58 – 89) and 86 (95% CI 72–100) per 100,000 person years, yielding estimated annual numbers of 30-day all-cause mortality deaths of 1,528 (95% CI 1,102–1,954) for bacteremic and 982 (95% CI 688 – 1,276) for non-bacteremic GNI. Conclusion GNI form a large mortality burden in a low-resistance country. A third of the associated mortality occurs after non-bacteremic GNI.

Streptococcus pneumoniae is the most frequent pathogen in community-acquired pneumonia and also causes invasive diseases like bacteremia and meningitis. Young children and elderly are especially at risk for pneumococcal diseases and are, therefore, eligible for pneumococcal vaccination in most countries. This reviews provides an overview of the current epidemiology of pneumococcal infections, history and evidence of available pneumococcal polysaccharide and conjugate vaccines, and current recommendations.

Background: Acute Myeloid Leukemia (AML) and high-risk Myelodysplastic Syndrome (MDS) patients frequently receive antibiotics (ABX) for febrile neutropenia (prophylaxis or empirical treatment) or for suspected or documented bacterial infections. ABX affect the composition of the human intestinal microbiome and the resulting dysbiosis can have important consequences for patients including Clostridioides difficile infections (CDI). The reported cumulative incidence of CDI in patients with AML varies from 9 to 24% in the first 120 days following the start of induction chemotherapy and from 8 to 31% after allogeneic Hematopoietic Stem Cell Transplant (allo-HSCT). In patients undergoing allo-HSCT, acute Graft-versus-Host Disease (GvHD) and GvHD-related mortality are other important complications associated with intestinal dysbiosis, as shown in experimental studies in mice and retrospective analyses in humans. DAV132 is a microbiome protective therapy that can be administered concomitantly with oral or intravenous ABX. It has been primarily developed for adsorbing antibiotic residues in the distal ileum and colon in order to preserve the integrity of the gut microbiome, without impacting antimicrobial pharmacokinetics. Randomized clinical trials conducted to date, both in heathy volunteers and in patients, showed that DAV132 adsorbed residues of ABX in the colon and protected the intestinal microbiome from the dysbiosis induced by ABX while preserving their bioavailability. In addition, DAV132 was safely used in hospitalized patients receiving (multiple) concomitant drugs. Study Design and Methods: MICROCARE is a multicenter, randomized, placebo-controlled, parallel-arm phase 3 clinical trial. A total of 900 patients (randomized 1:1 to either DAV132 or placebo) are planned to be enrolled in approximately 80 study sites worldwide. The primary objective of this study is to evaluate the efficacy of DAV132 in preventing CDI in patients with newly diagnosed AML or high-risk MDS treated with intensive chemotherapy. In addition, the study aims to determine whether the protection of the intestinal microbiome with DAV132 can reduce the incidence of colonization with multidrug-resistant bacteria, bacteremia, and acute GvHD, and improve the long-term outcomes of transplanted patients. Randomization will be stratified by (i) site, and (ii) use of ABX within 30 days before inclusion and/or history of CDI. During the cycle of induction chemotherapy, DAV132 will be administered to patients every day until neutrophil recovery, regardless of the administration of ABX treatment. After neutrophil recovery and up to day 120, DAV132 will be administered every time an ABX treatment is given, for the length of the ABX treatment plus 2 days. The primary analysis of this study is the comparison of the time to CDI between DAV132 patients versus placebo patients up to 120 days after randomization. This will be analyzed using the cause-specific Cox proportional hazards model, whereby time to CDI is the outcome of interest, and mortality will be considered as competing event. In the primary outcome, a cause-specific Cox model will be used assuming that the impact of DAV132 on mortality is negligible; this will be confirmed in a secondary analysis. Secondary and exploratory endpoints include the rate of patients with ABX-associated diarrhea, the rate of patients with a gut colonization by resistant bacteria or a bloodstream infection, the diversity of the gut microbiome, the incidence of acute GvHD and overall survival. Two interim analyses will be performed at approximately 35 and 50 CDI events. Study status: Recruitment of patients in the study is starting in multiple countries in Europe. A first patient has been randomized in July 2021. Topics: Microbiome; CDI; GvHD; Dysbiosis; Antibiotics Disclosure: This work is supported by the IMI Joint Undertaking (JU) (grant 115523), Combatting Bacterial Resistance in Europe, with resources including financial contribution from the EU's Seventh Framework Programme and in-kind contributions from Da Volterra, a company part of the European Federation of Pharmaceutical Industries and Associations (EFPIA). Disclosures Vehreschild: 3M: Research Funding; Astellas Pharma: Consultancy, Research Funding, Speakers Bureau; Biontech: Research Funding; Da Volterra: Consultancy, Research Funding, Speakers Bureau; Evonik: Research Funding; Gilead Sciences: Consultancy, Research Funding, Speakers Bureau; Glycom: Research Funding; Immunic AG: Consultancy, Research Funding, Speakers Bureau; MaaT Pharma: Consultancy, Research Funding; Merck/MSD: Consultancy, Research Funding, Speakers Bureau; Organobalance: Consultancy, Research Funding, Speakers Bureau; Roche: Consultancy, Research Funding, Speakers Bureau; Seres Therapeutics: Research Funding; Takeda Pharmaceutical: Research Funding; Alb Fils Kliniken GmbH: Consultancy, Speakers Bureau; Arderypharm: Consultancy, Speakers Bureau; Basilea: Consultancy, Speakers Bureau; Bio-Mérieux: Consultancy, Speakers Bureau; Farmak International Holding GmbH: Consultancy, Honoraria, Speakers Bureau; Ferring: Consultancy, Speakers Bureau; Pfizer: Consultancy, Speakers Bureau; SocraTec R&D GmbH: Consultancy, Speakers Bureau. Dane: Da Volterra: Consultancy. Mentré: Da Volterra: Consultancy. Burdet: Da Volterra: Consultancy; Mylan: Consultancy. Sablier-Gallis: Da Volterra: Current Employment, Current holder of individual stocks in a privately-held company. Andremont: Da Volterra: Consultancy, Current holder of individual stocks in a privately-held company, Honoraria. de Gunzburg: Da Volterra: Consultancy, Current holder of individual stocks in a privately-held company. Buffet: Da Volterra: Current Employment. Wilcox: Da Volterra: Consultancy, Research Funding. Cornely: Amplyx, Basilea, BMBF, Cidara, DZIF, EU-DG RTD (101037867), F2G, Gilead, Matinas, MedPace, MSD, Mundipharma, Octapharma, Pfizer, Scynexis: Other: Grants or Contracts. Bonten: Merck/MSD: Research Funding; Janssen Vaccines: Consultancy, Speakers Bureau; OM Pharma: Consultancy, Speakers Bureau; Pfizer: Consultancy, Speakers Bureau; Takeda: Consultancy, Research Funding. Vitry: Da Volterra: Current Employment.

This review focuses on the evidence base for guideline recommendations on the diagnosis, the optimal choice, timing and duration of empirical antibiotic therapy, and the use of microbiological tests for patients hospitalized with community-acquired pneumonia (CAP): issues for which guidelines are frequently used as a quick reference. Furthermore, we will discuss possibilities for future research in these topics.Many national and international guideline recommendations, even on critical elements of CAP management, are based on low-to-moderate quality evidence.The diagnosis and management of CAP has hardly changed for decades. The recommendation to cover atypical pathogens in all hospitalized CAP patients is based on observational studies only and is challenged by two recent trials. The following years, improved diagnostic testing, radiologically by low-dose Computed Tomography or ultrasound and/or microbiologically by point-of-care multiplex PCR, has the potential to largely influence the choice and start of antibiotic therapy in hospitalized CAP patients. Rapid microbiological testing will hopefully improve antibiotic de-escalation or early pathogen-directed therapy, both potent ways of reducing broad-spectrum antibiotic use. Current guideline recommendations on the timing and duration of antibiotic therapy are based on limited evidence, but will be hard to improve.

Introduction: The safety of de-escalation of empirical antimicrobial therapy is largely based on observational data, with many reporting protective effects on mortality. As there is no plausible biological explanation for this phenomenon, it is most probably caused by confounding by indication. Areas covered: We evaluate the methodology used in observational studies on the effects of de-escalation of antimicrobial therapy on mortality. We extended the search for a recent systematic review and identified 52 observational studies. The heterogeneity in study populations was large. Only 19 (36.5%) studies adjusted for confounders and four (8%) adjusted for clinical stability during admission, all as a fixed variable. All studies had methodological limitations, most importantly the lack of adjustment for clinical stability, causing bias toward a protective effect. Expert opinion: The methodology used in studies evaluating the effects of de-escalation on mortality requires improvement. We depicted all potential confounders in a directed acyclic graph to illustrate all associations between exposure (de-escalation) and outcome (mortality). Clinical stability is an important confounder in this association and should be modeled as a time-varying variable. We recommend to include de-escalation as time-varying exposure and use inverse-probability-of-treatment weighted marginal structural models to properly adjust for time-varying confounders.

[Background] The possibility of bloodstream infections caused by third-generation cephalosporin-resistant Enterobacterales (3GC-R-BSI) leads to a trade-off between empiric inappropriate treatment (IAT) and unnecessary carbapenem use (UCU). Accurately predicting 3GC-R-BSI could reduce IAT and UCU. We externally validate 2 previously derived prediction rules for community-onset (CO) and hospital-onset (HO) suspected bloodstream infections., [Methods] In 33 hospitals in 13 countries we prospectively enrolled 200 patients per hospital in whom blood cultures were obtained and intravenous antibiotics with coverage for Enterobacterales were empirically started. Cases were defined as 3GC-R-BSI or 3GC-R gram-negative infection (3GC-R-GNI) (analysis 2); all other outcomes served as a comparator. Model discrimination and calibration were assessed. Impact on carbapenem use was assessed at several cutoff points., [Results] 4650 CO infection episodes were included and the prevalence of 3GC-R-BSI was 2.1% (n = 97). IAT occurred in 69 of 97 (71.1%) 3GC-R-BSI and UCU in 398 of 4553 non–3GC-R-BSI patients (8.7%). Model calibration was good, and the AUC was .79 (95% CI, .75–.83) for 3GC-R-BSI. The prediction rule potentially reduced IAT to 62% (60/97) while keeping UCU comparable at 8.4% or could reduce UCU to 6.3% (287/4553) while keeping IAT equal. IAT and UCU in all 3GC-R-GNIs (analysis 2) improved at similar percentages. 1683 HO infection episodes were included and the prevalence of 3GC-R-BSI was 4.9% (n = 83). Here model calibration was insufficient., [Conclusions] A prediction rule for CO 3GC-R infection was validated in an international cohort and could improve empirical antibiotic use. Validation of the HO rule yielded suboptimal performance., J. R.-B. receives funds for research 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 Program Intelligent Growth 2014-2020.

Background It is unknown whether nitrofurantoin 50 mg normal-release every 6 h (NF50) and nitrofurantoin 100 mg extended-release every 12 h (NF100) are equally effective for treating cystitis in primary care. In the Netherlands, GP prescription of either option largely depends on pharmacy procurement, rather than on patient-related factors. Methods GP data between January 2013 and July 2018 were retrospectively collected. Inclusion criteria were the use of nitrofurantoin for uncomplicated cystitis, complicated cystitis or cystitis in pregnancy. Criteria for early and late failure were a second antibiotic prescription for cystitis or pyelonephritis within 14 and 28 days post-prescription, respectively. Crude and confounder-adjusted (CA) risk differences (RDs) were estimated using linear regression. Instrumental variable analysis and CA instrumental variable analysis used GP practice proportion of NF50 versus NF100 use as the instrumental variable. Results For uncomplicated cystitis (n=46855), treatment with NF50 and NF100 resulted in late failure in 9.7% and 9.6%, respectively. The CA RD, instrumental variable RD and CA instrumental variable RD were 0.2% (95% CI=−0.5 to 0.8), −0.7% (95% CI=−1.7 to 0.3) and 0.0% (95% CI=−0.9 to 1.0), respectively. In complicated cystitis (n=10767), late failure occurred in 10.9% and 11.1% after using NF50 and NF100, respectively [CA RD=0.5% (95% CI=−1.2 to 1.8), instrumental variable RD=−0.8% (95% CI=−3.4 to 1.8) and CA instrumental variable RD=−0.3% (95% CI=−3.0 to 2.4)]. For cystitis in pregnancy (n=1087), NF50 and NF100 resulted in late failure in 13.4% and 7.8%, respectively [CA RD=−5.4% (95% CI=−10.0 to −1.4), instrumental variable RD=−8.9% (95% CI=−16.0 to −1.8) and CA instrumental variable RD=−8.9% (95% CI=−16.0 to −1.7)]. No differences were observed in early failure. Conclusions In patients with cystitis in pregnancy, NF100 was associated with a lower incidence of late clinical failure compared with NF50. We found no differences in clinical failure between NF50 and NF100 for uncomplicated and complicated cystitis.

Background We conducted a post-hoc analysis of a double blind, randomized, placebo-controlled trial of 13-valent pneumococcal conjugate vaccine (PCV13) among adults aged 65 years or older to assess public health impact. Methods For all outcomes, we included all randomized subjects, using a modified intention-to-treat (mITT) approach to determine vaccine efficacy (VE), vaccine preventable disease incidence (VPDI) defined as control minus vaccinated group incidence, and numbers needed to vaccinate (NNV) (based on a five-year duration of protection). Results Results are reported for, in order, clinical, adjudicated (clinical plus radiologic infiltrate determined by committee), pneumococcal, and vaccine-type pneumococcal (VT-Sp) community-acquired pneumonia; invasive pneumococcal disease (IPD) and VT-IPD. VEs (95% CI) for all hospital episodes were 8.1% (−0.6%, 16.1%), 6.7% (−4.1%, 16.3%), 22.2% (2.0%, 38.3%), 37.5% (14.3%, 54.5%), 49.3% (23.2%, 66.5%), and 75.8% (47.6%, 88.8%). VPDIs per 100,000 person-years of observation (PYOs) were 72, 37, 25, 25, 20, and 15 with NNVs of 277, 535, 816, 798, 1016, and 1342. For clinical CAP, PCV13 was associated with a reduction of 909 (−115, 2013) hospital days per 100,000 PYOs translating to a reduction over 5 years of one hospital day for every 22 people vaccinated. When comparing at-risk persons (defined by self-report of diabetes, chronic lung disease, or other underlying conditions) to not at-risk persons, VEs were similar or lower, but because baseline incidences were higher the VPDIs were approximately 2–10 times higher and NNVs 50–90% lower. Conclusion A public health analysis of pneumonia and IPD outcomes in a randomized controlled trial found substantial burden reduction following adult PCV13 immunization implemented in a setting with an ongoing infant PCV7-PCV10 program. VPDIs were higher among at-risk adults. Funding The original study and the current analysis were funded by Pfizer.

ObjectiveTo determine the cost-effectiveness of selective digestive decontamination (SDD) as compared to selective oropharyngeal decontamination (SOD) in intensive care units (ICUs) with low levels of antimicrobial resistance.DesignPost-hoc analysis of a previously performed individual patient data meta-analysis of two cluster-randomised cross-over trials.Setting24 ICUs in the Netherlands.Participants12 952 ICU patients who were treated with ≥1 dose of SDD (n=6720) or SOD (n=6232).InterventionsSDD versus SOD.Primary and secondary outcome measuresThe incremental cost-effectiveness ratio (ICER; ie, costs to prevent one in-hospital death) was calculated by comparing differences in direct healthcare costs and in-hospital mortality of patients treated with SDD versus SOD. A willingness-to-pay curve was plotted to reflect the probability of cost-effectiveness of SDD for a range of different values of maximum costs per prevented in-hospital death.ResultsThe ICER resulting from the fixed-effect meta-analysis, adjusted for clustering and differences in baseline characteristics, showed that SDD significantly reduced in-hospital mortality (adjusted absolute risk reduction 0.0195, 95% CI 0.0050 to 0.0338) with no difference in costs (adjusted cost difference €62 in favour of SDD, 95% CI –€1079 to €935). Thus, SDD yielded significantly lower in-hospital mortality and comparable costs as compared with SOD. At a willingness-to-pay value of €33 633 per one prevented in-hospital death, SDD had a probability of 90.0% to be cost-effective as compared with SOD.ConclusionIn Dutch ICUs, SDD has a very high probability of cost-effectiveness as compared to SOD. These data support the implementation of SDD in settings with low levels of antimicrobial resistance.

In response to Theilacker et al. we explain that we consider the point estimate as well as the confidence bounds in our interpretation of the study results and do not treat confidence intervals as a dichotomous signal. We refute that the proposed calculation of vaccine preventable disease incidence is more valuable than calculation of vaccine efficacy. Finally we remain at our conclusion that 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.

BackgroundObservational studies have demonstrated that de-escalation of antimicrobial therapy is independently associated with lower mortality. This most probably results from confounding by indication. Reaching clinical stability is associated with the decision to de-escalate and with survival. However, studies rarely adjust for this confounder. We quantified the potential confounding effect of clinical stability on the estimated impact of de-escalation on mortality in patients with community-acquired pneumonia.MethodsData were used from the Community-Acquired Pneumonia immunization Trial in Adults (CAPiTA). The primary outcome was 30-day mortality. We performed Cox proportional-hazards regression with de-escalation as time-dependent variable and adjusted for baseline characteristics using propensity scores. The potential impact of unmeasured confounding was quantified through simulating a variable representing clinical stability on day three, using data on prevalence and associations with mortality from the literature.ResultsOf 1,536 included patients, 257 (16.7%) were de-escalated, 123 (8.0%) were escalated and in 1156 (75.3%) the antibiotic spectrum remained unchanged. The adjusted hazard ratio of de-escalation for 30-day mortality (compared to patients with unchanged coverage), without adjustment for clinical stability, was 0.36 (95%CI: 0.18-0.73). If 90% to 100% of de-escalated patients were clinically stable on day three, the fully adjusted hazard ratio would be 0.53 (95%CI: 0.26-1.08) to 0.90 (95%CI: 0.42-1.91), respectively. The simulated confounder was substantially stronger than any of the baseline confounders in our dataset.ConclusionsWith plausible, literature-based assumptions, clinical stability is a very strong confounder for the effects of de-escalation. Quantification of effects of de-escalation on patient outcomes without proper adjustment for clinical stability results in strong negative bias. As a result, the safety of de-escalation remains to be determined.

The Community-Acquired Pneumonia Immunization Trial in Adults (CAPiTA) demonstrated the efficacy of 13-valent pneumococcal conjugate vaccine (PCV13) in preventing vaccine-type community-acquired pneumonia and vaccine-type invasive pneumococcal disease in elderly subjects. We examined the cost-effectiveness of PCV13 vaccination in the Netherlands. Using a Markov-type model, incremental cost-effectiveness ratios (ICER) of PCV13 vaccination in different age- and risk-groups for pneumococcal disease were evaluated using a societal perspective. Estimates of quality-adjusted life-years (QALYs), costs, vaccine efficacy and epidemiological data were based on the CAPiTA study and other prospective studies. The base-case was PCV13 vaccination of adults aged 65–74 years compared to no vaccination, assuming no net indirect effects in base-case due to paediatric 10-valent pneumococcal conjugate vaccine use. Analyses for age- and risk-group specific vaccination strategies and for different levels of hypothetical herd effects from a paediatric PCV programme were also conducted. The ICER for base-case was €8650 per QALY (95% CI 5750–17 100). Vaccination of high-risk individuals aged 65–74 years was cost-saving and extension to medium-risk individuals aged 65–74 years yielded an ICER of €2900. Further extension to include medium- and high-risk individuals aged ≥18 years yielded an ICER of €3100. PCV13 vaccination is highly cost-effective in the Netherlands. The transferability of our results to other countries depends upon vaccination strategies already implemented in those countries., Vaccinating the elderly with 13-valent pneumococcal conjugate vaccine is highly cost-effective http://ow.ly/NVeui

Admission glucose levels do not improve discrimination of current severity scores in community-acquired pneumonia http://ow.ly/Dyrz30f7Bwi

Objective. To evaluate the effectiveness of the Epley maneuver compared with vestibular rehabilitation on patientreported symptom relief and conversion of the Dix-Hallpike from positive to negative in patients with posterior benign paroxysmal positional vertigo (p-BPPV). Data Sources. PubMed, Embase, and the Cochrane Library. Review Methods. A systematic search was conducted. Studies reporting original study data were included. Relevance and risk of bias (RoB) of the selected articles were assessed. Studies with low relevance, high RoB, or both were excluded. For outcomes of interest, absolute risk differences and their 95% confidence intervals (CIs) were extracted. Results. A total of 373 unique studies were retrieved. Five of these satisfied the eligibility criteria. One study with low RoB and 3 studies with moderate RoB showed that the Epley maneuver is more effective than vestibular rehabilitation at 1-week follow-up with regard to patient-reported symptom relief and conversion of the Dix-Hallpike maneuver from positive to negative (risk differences range from 10% [95% CI, 30-47] to 55% [95% CI, 35-71]). There is inconsistent evidence for the effectiveness of the Epley maneuver compared with vestibular rehabilitation at 1-month follow-up. Most studies suggest that the Epley maneuver and vestibular rehabilitation are equally effective at 1-month follow-up. Conclusion. The Epley maneuver is more effective in treating p-BPPV than vestibular rehabilitation at 1-week follow-up. There is inconsistent evidence for the effectiveness of the Epley maneuver compared with vestibular rehabilitation at 1-month follow-up.

Background To determine the cost-effectiveness of strategies of preferred antibiotic treatment with beta-lactam/macrolide combination or fluoroquinolone monotherapy compared to beta-lactam monotherapy. Methods Costs and effects were estimated using data from a cluster-randomized cross-over trial of antibiotic treatment strategies, primarily from the reduced third payer perspective (i.e. hospital admission costs). Cost-minimization analysis (CMA) and cost-effectiveness analysis (CEA) were performed using linear mixed models. CMA results were expressed as difference in costs per patient. CEA results were expressed as incremental cost-effectiveness ratios (ICER) showing additional costs per prevented death. Results A total of 2,283 patients were included. Crude average costs within 90 days from the reduced third payer perspective were €4,294, €4,392, and €4,002 per patient for the beta-lactam monotherapy, beta-lactam/macrolide combination, and fluoroquinolone monotherapy strategy, respectively. CMA results were €106 (95% CI €-697 to €754) for the beta-lactam/macrolide combination strategy and €-278 (95%CI €-991 to €396) for the fluoroquinolone monotherapy strategy, both compared to the beta-lactam monotherapy strategy. The ICER was not statistically significantly different between the strategies. Other perspectives yielded similar results. Conclusions There were no significant differences in cost-effectiveness of strategies of preferred antibiotic treatment of CAP on non-ICU wards with either beta-lactam monotherapy, beta-lactam/macrolide combination therapy, or fluoroquinolone monotherapy. Trial registration The trial was registered with ClinicalTrials.gov, number NCT01660204, on May 2nd, 2012. Electronic supplementary material The online version of this article (doi:10.1186/s12879-016-2179-6) contains supplementary material, which is available to authorized users.

Background We aimed to evaluate health status and associated factors in community-dwelling elderly in the Netherlands. Methods Participants from a placebo-controlled double-blind randomized controlled trial conducted in the Netherlands were invited at the time of enrolment to participate in this study. Data were collected on comorbidities, socio-demographic background and health status, using EQ-5D-3L instrument. EQ-5D-3L summary index values (EQ-5D-indices) was derived using Dutch tariff. Regression analysis was conducted to identify factors associated with EQ-5D-indices and visual analogue scale (EQ-VAS). Results 48,634 elderly (≥65 years) were included. The most frequently reported complaint was pain/discomfort (29.4%), but for the elder elderly (i.e. ≥85 years) it was mobility (52.9%). The proportion of persons reporting (multiple) problems increased with age from 31.5% for 65–69 years old subjects to 65.9% for elder elderly. The mean EQ-5D-indices and EQ-VAS decreased with age from 0.94 and 84, respectively in those 65 to 69 years old to 0.86 and 76, respectively, in ≥85 years old subjects. Increasing age, female gender, low education, geographic factors and comorbidities were associated with impaired health status. Conclusions Within community-dwelling elderly large differences in health status exist. Impairment increases rapidly with age, but health status is also associated with socio-demographic variables and comorbidities. Trial registration ClinicalTrials.gov, NCT00812084. Electronic supplementary material The online version of this article (doi:10.1186/s12955-016-0577-5) contains supplementary material, which is available to authorized users.