Effect of COVID-19 vaccination on mortality by COVID-19 and on mortality by other causes, the Netherlands, January 2021-January 2022.

BACKGROUND: We aimed to estimate vaccine effectiveness (VE) against COVID-19 mortality, and to explore whether an increased risk of non-COVID-19 mortality exists in the weeks following a COVID-19 vaccine dose. METHODS: National registries of causes of death, COVID-19 vaccination, specialized health care and long-term care reimbursements were linked by a unique person identifier using data from 1 January 2021 to 31 January 2022. We used Cox regression with calendar time as underlying time scale to, firstly, estimate VE against COVID-19 mortality after primary and first booster vaccination, per month since vaccination and, secondly, estimate risk of non-COVID-19 mortality in the 5 or 8 weeks following a first, second or first booster dose, adjusting for birth year, sex, medical risk group and country of origin. RESULTS: VE against COVID-19 mortality was > 90 % for all age groups two months after completion of the primary series. VE gradually decreased thereafter, to around 80 % at 7-8 months post-primary series for most groups, and around 60 % for elderly receiving a high level of long-term care and for people aged 90+ years. Following a first booster dose, the VE increased to > 85 % in all groups. The risk of non-COVID-19 mortality was lower or similar in the 5 or 8 weeks following a first dose compared to no vaccination, as well as following a second dose compared to one dose and a booster compared to two doses, for all age and long-term care groups. CONCLUSION: At the population level, COVID-19 vaccination greatly reduced the risk of COVID-19 mortality and no increased risk of death from other causes was observed.

Number of COVID-19 hospitalisations averted by vaccination: Estimates for the Netherlands, January 6, 2021 through August 30, 2022.

BACKGROUND: Vaccines against COVID-19 have proven effective in preventing COVID-19 hospitalisation. In this study, we aimed to quantify part of the public health impact of COVID-19 vaccination by estimating the number of averted hospitalisations. We present results from the beginning of the vaccination campaign ('entire period', January 6, 2021) and a subperiod starting at August 2, 2021 ('subperiod') when all adults had the opportunity to complete their primary series, both until August 30, 2022. METHODS: Using calendar-time specific vaccine effectiveness (VE) estimates and vaccine coverage (VC) by round (primary series, first booster and second booster) and the observed number of COVID-19 associated hospitalisations, we estimated the number of averted hospitalisations per age group for the two study periods. From January 25, 2022, when registration of the indication of hospitalisation started, hospitalisations not causally related to COVID-19 were excluded. RESULTS: In the entire period, an estimated 98,170 (95 % confidence interval (CI) 96,123-99,928) hospitalisations were averted, of which 90,753 (95 % CI 88,790-92,531) were in the subperiod, representing 57.0 % and 67.9 % of all estimated hospital admissions. Estimated averted hospitalisations were lowest for 12-49-year-olds and highest for 70-79-year-olds. More admissions were averted in the Delta period (72.3 %) than in the Omicron period (63.4 %). CONCLUSION: COVID-19 vaccination prevented a large number of hospitalisations. Although the counterfactual of having had no vaccinations while maintaining the same public health measures is unrealistic, these findings underline the public health importance of the vaccination campaign to policy makers and the public.

Safe shortening of antibiotic treatment duration for complicated Staphylococcus aureus bacteraemia (SAFE trial): protocol for a randomised, controlled, open-label, non-inferiority trial comparing 4 and 6 weeks of antibiotic treatment.

INTRODUCTION: A major knowledge gap in the treatment of complicated Staphylococcus aureus bacteraemia (SAB) is the optimal duration of antibiotic therapy. Safe shortening of antibiotic therapy has the potential to reduce adverse drug events, length of hospital stay and costs. The objective of the SAFE trial is to evaluate whether 4 weeks of antibiotic therapy is non-inferior to 6 weeks in patients with complicated SAB. METHODS AND ANALYSIS: The SAFE-trial is a multicentre, non-inferiority, open-label, parallel group, randomised controlled trial evaluating 4 versus 6 weeks of antibiotic therapy for complicated SAB. The study is performed in 15 university hospitals and general hospitals in the Netherlands. Eligible patients are adults with methicillin-susceptible SAB with evidence of deep-seated or metastatic infection and/or predictors of complicated SAB. Only patients with a satisfactory clinical response to initial antibiotic treatment are included. Patients with infected prosthetic material or an undrained abscess of 5 cm or more at day 14 of adequate antibiotic treatment are excluded. Primary outcome is success of therapy after 180 days, a combined endpoint of survival without evidence of microbiologically confirmed disease relapse. Assuming a primary endpoint occurrence of 90% in the 6 weeks group, a non-inferiority margin of 7.5% is used. Enrolment of 396 patients in total is required to demonstrate non-inferiority of shorter antibiotic therapy with a power of 80%. Currently, 152 patients are enrolled in the study. ETHICS AND DISSEMINATION: This is the first randomised controlled trial evaluating duration of antibiotic therapy for complicated SAB. Non-inferiority of 4 weeks of treatment would allow shortening of treatment duration in selected patients with complicated SAB. This study is approved by the Medical Ethics Committee VUmc (Amsterdam, the Netherlands) and registered under NL8347 (the Netherlands Trial Register). Results of the study will be published in a peer-reviewed journal. TRIAL REGISTRATION NUMBER: NL8347 (the Netherlands Trial Register).

Comparative effectiveness of ß-lactams for empirical treatment of methicillin-susceptible Staphylococcus aureus bacteraemia: a prospective cohort study.

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.

Rapid syndromic PCR testing in patients with respiratory tract infections reduces time to results and improves microbial yield.

Lack of rapid and comprehensive microbiological diagnosis in patients with community acquired pneumonia (CAP) hampers appropriate antimicrobial therapy. This study evaluates the real-world performance of the BioFire FilmArray Pneumonia panel plus (FAP plus) and explores the feasibility of evaluation in a randomised controlled trial. Patients presenting to hospital with suspected CAP were recruited in a prospective feasibility study. An induced sputum or an endotracheal aspirate was obtained from all participants. The FAP plus turnaround time (TAT) and microbiological yield were compared with standard diagnostic methods (SDs). 96/104 (92%) enrolled patients had a respiratory tract infection (RTI); 72 CAP and 24 other RTIs. Median TAT was shorter for the FAP plus, compared with in-house PCR (2.6 vs 24.1 h, p < 0.001) and sputum cultures (2.6 vs 57.5 h, p < 0.001). The total microbiological yield by the FAP plus was higher compared to SDs (91% (162/179) vs 55% (99/179), p < 0.0001). Haemophilus influenzae, Streptococcus pneumoniae and influenza A virus were the most frequent pathogens. In conclusion, molecular panel testing in adults with CAP was associated with a significant reduction in time to actionable results and increased microbiological yield. The impact on antibiotic use and patient outcome should be assessed in randomised controlled trials.

[Gastric acid suppression and antibiotic resistance; the role of a meta-analysis]. / Maagzuurremming en antibioticaresistentie.

We discuss a meta-analysis that reported on the association between gastric acid suppression and carriage with antibiotic resistant bacteria, with a special focus on the association for carriage with ESBL-producing Gram-negative bacteria in non-hospitalized subjects. Results from a recent population-based study (not included in the meta-analysis) were added to this subgroup of the meta-analysis. The data point to a positive, yet minor, association between gastric acid suppression and carriage with ESBL-producing Gram-negative bacteria in non-hospitalized subjects in the Netherlands.

Impact of time to antibiotic therapy on clinical outcome in patients with bacterial infections in the emergency department: implications for antimicrobial stewardship.

BACKGROUND: Rapid initiation of antibiotic treatment is considered crucial in patients with severe infections such as septic shock and bacterial meningitis, but may not be as important for other infectious syndromes. A better understanding of which patients can tolerate a delay in start of therapy is important for antibiotic stewardship purposes. OBJECTIVES: To explore the existing evidence on the impact of time to antibiotics on clinical outcomes in patients presenting to the emergency department (ED) with bacterial infections of different severity of illness and source of infection. SOURCES: A literature search was performed in the PubMed/MEDLINE database using combined search terms for various infectious syndromes (sepsis/septic shock, bacterial meningitis, lower respiratory tract infections, urinary tract infections, intra-abdominal infections and skin and soft tissue infections), time to antibiotic treatment, and clinical outcome. CONTENT: The literature search generated 8828 hits. After screening titles and abstracts and assessing potentially relevant full-text papers, 60 original articles (four randomized controlled trials, 43 observational studies) were included. Most articles addressed sepsis/septic shock, while few studies evaluated early initiation of therapy in mild to moderate disease. The lack of randomized trials and the risk of confounding factors and biases in observational studies warrant caution in the interpretation of results. We conclude that the literature supports prompt administration of effective antibiotics for septic shock and bacterial meningitis, but there is no clear evidence showing that a delayed start of therapy is associated with worse outcome for less severe infectious syndromes. IMPLICATIONS: For patients presenting with suspected bacterial infections, withholding antibiotic therapy until diagnostic results are available and a diagnosis has been established (e.g. by 4-8 h) seems acceptable in most cases unless septic shock or bacterial meningitis are suspected. This approach promotes the use of ecologically favourable antibiotics in the ED, reducing the risks of side effects and selection of resistance.

Short-course aminoglycosides as adjunctive empirical therapy in patients with Gram-negative bloodstream infection, a cohort study.

OBJECTIVE: Short-course aminoglycosides as adjunctive empirical therapy to ß-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 ß-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 ß-lactam antibiotics in patients with GN-BSI did not result in improved outcomes, despite better antibiotic coverage of pathogens.

The effectiveness of nitrofurantoin, fosfomycin and trimethoprim for the treatment of cystitis in relation to renal function.

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 <60 mL/min, FT1 resulted in 16.0% (39/244) and NF5 in 23.3% clinical failures (110/472), aOR: 0.61, 95% CI: 0.39-0.95). CONCLUSIONS: In eGFR ≥60 mL/min treatment with fosfomycin or trimethoprim for uncomplicated cystitis was associated with more clinical failure than treatment with nitrofurantoin, while in eGFR <60 mL/min nitrofurantoin was associated with more clinical failure than fosfomycin-trometamol. Renal function, if known, should be considered in the clinical decision-making for cystitis treatment.

Optimizing design of research to evaluate antibiotic stewardship interventions: consensus recommendations of a multinational working group.

BACKGROUND: Antimicrobial stewardship interventions and programmes aim to ensure effective treatment while minimizing antimicrobial-associated harms including resistance. Practice in this vital area is undermined by the poor quality of research addressing both what specific antimicrobial use interventions are effective and how antimicrobial use improvement strategies can be implemented into practice. In 2016 we established a working party to identify the key design features that limit translation of existing research into practice and then to make recommendations for how future studies in this field should be optimally designed. The first part of this work has been published as a systematic review. Here we present the working group's final recommendations. METHODS: An international working group for design of antimicrobial stewardship intervention evaluations was convened in response to the fourth call for leading expert network proposals by the Joint Programming Initiative on Antimicrobial Resistance (JPIAMR). The group comprised clinical and academic specialists in antimicrobial stewardship and clinical trial design from six European countries. Group members completed a structured questionnaire to establish the scope of work and key issues to develop ahead of a first face-to-face meeting that (a) identified the need for a comprehensive systematic review of study designs in the literature and (b) prioritized key areas where research design considerations restrict translation of findings into practice. The working group's initial outputs were reviewed by independent advisors and additional expertise was sought in specific clinical areas. At a second face-to-face meeting the working group developed a theoretical framework and specific recommendations to support optimal study design. These were finalized by the working group co-ordinators and agreed by all working group members. RESULTS: We propose a theoretical framework in which consideration of the intervention rationale the intervention setting, intervention features and the intervention aims inform selection and prioritization of outcome measures, whether the research sets out to determine superiority or non-inferiority of the intervention measured by its primary outcome(s), the most appropriate study design (e.g. experimental or quasi- experimental) and the detailed design features. We make 18 specific recommendation in three domains: outcomes, objectives and study design. CONCLUSIONS: Researchers, funders and practitioners will be able to draw on our recommendations to most efficiently evaluate antimicrobial stewardship interventions.

Burden of disease in children with respiratory tract infections in primary care: diary-based cohort study.

BACKGROUND: Respiratory tract infections (RTIs) are a common reason for children to consult in general practice. Antibiotics are often prescribed, in part due to miscommunication between parents and GPs. The duration of specific respiratory symptoms has been widely studied. Less is known about illness-related symptoms and the impact of these symptoms on family life, including parental production loss. Better understanding of the natural course of illness-related symptoms in RTI in children and impact on family life may improve GP-parent communication during RTI consultations. OBJECTIVE: To describe the general impact of RTI on children and parents regarding illness-related symptoms, absenteeism from childcare, school and work, use of health care facilities, and the use of over-the-counter (OTC) medication. METHODS: Prospectively collected diary data from two randomized clinical trials in children with RTI in primary care (n = 149). Duration of symptoms was analysed using survival analysis. RESULTS: Disturbed sleep, decreased intake of food and/or fluid, feeling ill and/or disturbance at play or other daily activities are very common during RTI episodes, with disturbed sleep lasting longest. Fifty-two percent of the children were absent for one or more days from childcare or school, and 28% of mothers and 20% of fathers reported absence from work the first week after GP consultation. Re-consultation occurred in 48% of the children. OTC medication was given frequently, particularly paracetamol and nasal sprays. CONCLUSION: Appreciation of, and communication about the general burden of disease on children and their parents, may improve understanding between GPs and parents consulting with their child.

The quality of studies evaluating antimicrobial stewardship interventions: a systematic review.

BACKGROUND: Antimicrobial stewardship aims to optimize antibiotic use and minimize selection of antimicrobial resistance. The methodological quality of published studies in this field is unknown. AIMS: Our objective was to perform a comprehensive systematic review of antimicrobial stewardship research design and identify features which limit validity and translation of research findings into clinical practice. SOURCES: The following online database was searched: PubMed. STUDY ELIGIBILITY CRITERIA: Studies published between January 1950 and January 2017, evaluating any antimicrobial stewardship intervention in the community or hospital setting, without restriction on study design or outcome. CONTENT: We extracted data on pre-specified design quality features and factors that may influence design choices including (1) clinical setting, (2) age group studied, (3) when the study was conducted, (4) geographical region, and (5) financial support received. The initial search yielded 17 382 articles; 1008 were selected for full-text screening, of which 825 were included. Most studies (675/825, 82%) were non-experimental; 104 (15%) used interrupted time series analysis, 41 (6%) used external controls, and 19 (3%) used both. Studies in the community setting fulfilled a median of five out of 10 quality features (IQR 3-7) and 3 (IQR 2-4) in the hospital setting. Community setting studies (25%, 205/825) were significantly more likely to use randomization (OR 5.9; 95% CI 3.8-9.2), external controls (OR 5.6; 95% CI 3.6-8.5), and multiple centres (OR 10.5; 95% CI 7.1-15.7). From all studies, only 48% (398/825) reported clinical and 23% (190/825) reported microbiological outcomes. Quality did not improve over time. IMPLICATIONS: Overall quality of antimicrobial stewardship studies is low and has not improved over time. Most studies do not report clinical and microbiological outcome data. Studies conducted in the community setting were associated with better quality. These limitations should inform the design of future stewardship evaluations so that a robust evidence base can be built to guide clinical practice.

Relevance of healthcare-associated pneumonia for empirical antibiotic therapy in the Netherlands.

BACKGROUND: There is no consensus whether patients with healthcare-associated pneumonia (HCAP) should be considered as a patient with hospital-acquired pneumonia (HAP) and treated with broad-spectrum antibiotics, or as a patient with community-acquired pneumonia (CAP), and treated with narrow-spectrum antibiotics. HCAP research has focused mostly on the predictive value for non-susceptibility to broad-spectrum antibiotics and multi-drug resistant pathogens, in settings with moderate to high levels of antibiotic resistance. We investigated whether HCAP criteria predicts non-susceptibility to different empirical strategies, including narrow-spectrum antibiotics in the Dutch setting. METHODS: In a post hoc analysis of patients with moderate-severe CAP in seven Dutch hospitals, we compared in vitro antibiotic susceptibilities of definite and possible causative pathogens of CAP and HCAP to amoxicillin and broader antibiotic regimens. In a sensitivity analysis, pathogens with missing susceptibilities were assumed susceptible (best-case scenario) or non-susceptible (worst-case scenario). RESULTS: Among 2,283 patients with moderate-severe CAP, 23.1% (n = 527) were classified as HCAP. Non-susceptibility to amoxicillin ranged from 11.3% (95% CI 9.9-12.8%; best-case) to 14.4% (95% CI 12.8-16.1%; worst-case) in CAP patients and from 16.7% (95% CI 13.8-20.1%; best-case) to 19.7% (95% CI 16.6-23.3%; worst-case) in HCAP patients. The largest reduction in non-susceptibility was achieved by adding ciprofloxacin to amoxicillin treatment in both CAP patients (10% absolute risk reduction) and HCAP patients (11-16% reduction). CONCLUSIONS: In the Netherlands, HCAP criteria predict higher amoxicillin non-susceptibility in patients hospitalized with moderate-severe CAP. Although broadening the antibiotic spectrum of empiric treatment reduced the likelihood of non-susceptibility, absolute reductions of non-susceptibility in HCAP patients were too low to justify the universal use of broad-spectrum empirical therapy.No abstract available.

[A trial to study the effect of influenza vaccination in the elderly: ethical, feasible and badly needed]. / Een trial naar het effect van influenzavaccinatie bij ouderen.

Based on current research, there are no valid reasons to assume that influenza vaccination of people aged 60 and over without any other medical indications, in the context of the national programme of influenza prevention, leads to significant, relevant and cost-effective health benefits. In view of the pressure on health care budgets and the decreasing social willingness to vaccinate, it is of great and urgent importance that the actual effect of influenza vaccination is quantified in a double-blind placebo-controlled randomized trial (RCT) with relevant outcome measures, which does not suffer from the methodological shortcomings of the few previous studies. In order to demonstrate a 10% reduction in hospitalisation for respiratory infections, this RCT should include approximately 100,000 subjects and follow these participants for three years. We consider such a trial feasible in the Dutch situation.

Development of diagnostic prediction tools for bacteraemia caused by third-generation cephalosporin-resistant enterobacteria in suspected bacterial infections: a nested case-control study.

OBJECTIVES: Current guidelines for the empirical antibiotic treatment predict the presence of third-generation cephalosporin-resistant enterobacterial bacteraemia (3GCR-E-Bac) in case of infection only poorly, thereby increasing unnecessary carbapenem use. We aimed to develop diagnostic scoring systems which can better predict the presence of 3GCR-E-Bac. METHODS: A retrospective nested case-control study was performed that included patients ≥18 years of age from eight Dutch hospitals in whom blood cultures were obtained and intravenous antibiotics were initiated. Each patient with 3GCR-E-Bac was matched to four control infection episodes within the same hospital, based on blood-culture date and onset location (community or hospital). Starting from 32 commonly described clinical risk factors at infection onset, selection strategies were used to derive scoring systems for the probability of community- and hospital-onset 3GCR-E-Bac. RESULTS: 3GCR-E-Bac occurred in 90 of 22 506 (0.4%) community-onset infections and in 82 of 8110 (1.0%) hospital-onset infections, and these cases were matched to 360 community-onset and 328 hospital-onset control episodes. The derived community-onset and hospital-onset scoring systems consisted of six and nine predictors, respectively. With selected score cut-offs, the models identified 3GCR-E-Bac with sensitivity equal to existing guidelines (community-onset: 54.3%; hospital-onset: 81.5%). However, they reduced the proportion of patients classified as at risk for 3GCR-E-Bac (i.e. eligible for empirical carbapenem therapy) with 40% (95%CI 21-56%) and 49% (95%CI 39-58%) in, respectively, community-onset and hospital-onset infections. CONCLUSIONS: These prediction scores for 3GCR-E-Bac, specifically geared towards the initiation of empirical antibiotic treatment, may improve the balance between inappropriate antibiotics and carbapenem overuse.