Alendronate modulates cytokine responses in healthy young individuals after BCG vaccination.

Bacillus Calmette-Guérin (BCG) vaccination induces memory characteristics in innate immune cells and their progenitors, a process called trained immunity mediated by epigenetic and metabolic reprogramming. Cholesterol synthesis plays an amplifying role in trained immunity through mevalonate release. Nitrogen-containing bisphosphonates (N-BPs), such as alendronate, can inhibit cholesterol synthesis. We explored their effects on trained immunity induced by BCG in a placebo-controlled clinical study (NL74082.091.20) in young, healthy individuals. Participants receiving single-dose oral alendronate on the day of BCG vaccination had more neutrophils and plasma cells one month after treatment. Alendronate led to reduced proinflammatory cytokine production by PBMCs stimulated with heterologous bacterial and viral stimuli one month later. Furthermore, the addition of alendronate transcriptionally suppressed multiple immune response pathways in PBMCs upon stimulation. Our findings indicate that N-BPs modulate the long-lasting effects of BCG vaccination on the cytokine production capacity of innate immune cells.

MMR vaccination induces trained immunity via functional and metabolic reprogramming of γδ T cells.

The measles, mumps, and rubella (MMR) vaccine protects against all-cause mortality in children, but the immunological mechanisms mediating these effects are poorly known. We systematically investigated whether MMR can induce long-term functional changes in innate immune cells, a process termed trained immunity, that could at least partially mediate this heterologous protection. In a randomized, placebo-controlled trial, 39 healthy adults received either the MMR vaccine or a placebo. Using single-cell RNA-Seq, we found that MMR caused transcriptomic changes in CD14+ monocytes and NK cells, but most profoundly in γδ T cells. Monocyte function was not altered by MMR vaccination. In contrast, the function of γδ T cells was markedly enhanced by MMR vaccination, with higher production of TNF and IFN-γ, as well as upregulation of cellular metabolic pathways. In conclusion, we describe a trained immunity program characterized by modulation of γδ T cell function induced by MMR vaccination.

Early oral antibiotic switch in Staphylococcus aureus bacteraemia: The Staphylococcus aureus Network Adaptive Platform (SNAP) Trial Early Oral Switch Protocol.

BACKGROUND: Staphylococcus aureus bloodstream infection (bacteraemia) is traditionally treated with at least two weeks of IV antibiotics in adults, 3-7 days in children, and often longer for those with complicated disease. The current practice of treating S. aureus bacteraemia (SAB) with prolonged IV antibiotics (rather than oral antibiotics) is based on historical observational research and expert opinion. Prolonged IV antibiotic therapy has significant disadvantages for patients and healthcare systems, and there is growing interest in whether a switch to oral antibiotics following an initial period of IV therapy is a safe alternative for clinically stable patients. PROTOCOL: The early oral switch (EOS) domain of the S. aureus Network Adaptive Platform (SNAP) trial will assess early switch to oral antibiotics compared with continued IV treatment in clinically stable patients with SAB. The primary endpoint is 90-day all-cause mortality. Hospitalised SAB patients are assessed at platform day 7 +/- 2 (uncomplicated SAB) and day 14 +/-2 (complicated SAB) to determine their eligibility for randomisation to EOS (intervention) or continued IV treatment (current standard of care). DISCUSSION: Recruitment is occurring to the EOS domain of the SNAP trial. As of August 2023, 21% of all SNAP participants had been randomised to the EOS domain, a total of 264 participants across 77 centres, with an aim to recruit at least 1000 participants. We describe challenges and facilitators to enrolment in this domain to aid those planning similar trials.

The impact of BNT162b2 mRNA vaccine on adaptive and innate immune responses.

The mRNA-based BNT162b2 protects against severe disease and mortality caused by SARS-CoV-2 via induction of specific antibody and T-cell responses. Much less is known about its broad effects on immune responses against other pathogens. Here, we investigated the adaptive immune responses induced by BNT162b2 vaccination against various SARS-CoV-2 variants and its effects on the responsiveness of immune cells upon stimulation with heterologous stimuli. BNT162b2 vaccination induced effective humoral and cellular immunity against SARS-CoV-2 that started to wane after six months. We also observed long-term transcriptional changes in immune cells after vaccination. Additionally, vaccination with BNT162b2 modulated innate immune responses as measured by inflammatory cytokine production after stimulation - higher IL-1/IL-6 release and decreased IFN-α production. Altogether, these data expand our knowledge regarding the overall immunological effects of this new class of vaccines and underline the need for additional studies to elucidate their effects on both innate and adaptive immune responses.

Decision-making regarding antibiotic therapy duration: An observational study of multidisciplinary meetings in the intensive care unit.

PURPOSE: Antibiotic therapy is commonly prescribed longer than recommended in intensive care patients (ICU). We aimed to provide insight into the decision-making process on antibiotic therapy duration in the ICU. METHODS: A qualitative study was conducted, involving direct observations of antibiotic decision-making during multidisciplinary meetings in four Dutch ICUs. The study used an observation guide, audio recordings, and detailed field notes to gather information about the discussions on antibiotic therapy duration. We described the participants' roles in the decision-making process and focused on arguments contributing to decision-making. RESULTS: We observed 121 discussions on antibiotic therapy duration in sixty multidisciplinary meetings. 24.8% of discussions led to a decision to stop antibiotics immediately. In 37.2%, a prospective stop date was determined. Arguments for decisions were most often brought forward by intensivists (35.5%) and clinical microbiologists (22.3%). In 28.9% of discussions, multiple healthcare professionals participated equally in the decision. We identified 13 main argument categories. While intensivists mostly used arguments based on clinical status, clinical microbiologists used diagnostic results in the discussion. CONCLUSIONS: Multidisciplinary decision-making regarding the duration of antibiotic therapy is a complex but valuable process, involving different healthcare professionals, using a variety of argument-types to determine the duration of antibiotic therapy. To optimize the decision-making process, structured discussions, involvement of relevant specialties, and clear communication and documentation of the antibiotic plan are recommended.

Routine vaccination for influenza and pneumococcal disease and its effect on COVID-19 in a population of Dutch older adults.

Objectives: Protective heterologous beneficial effects of vaccines have been reported, and in this study we aimed to assess the impact of routine pneumococcal and influenza vaccination on the incidence and symptom duration of COVID-19 in a population of Dutch older adults. Methods: This cohort study is a secondary analysis of the BCG-CORONA-ELDERLY study, a randomised controlled trial on the effect of BCG vaccination on the cumulative incidence of respiratory tract infections requiring medical intervention in adults ≥60 years. The primary outcome was the cumulative incidence of a self-reported positive SARS-CoV-2 PCR test, and was assessed using a Fine-Gray competing risks model adjusted for baseline characteristics at enrolment. We analysed data from November 1st 2020 until the end of the main study in May 2021. Results: Routine vaccination data 2020/2021 were available for 1963/2014 (97.5 %) participants; 44/1963 (2.2 %) were excluded due to COVID-19 before vaccination. 1076/1919 (56.1 %) had received the influenza vaccine and 289/1919 (15.1 %) the pneumococcal vaccine. The cumulative incidence of COVID-19 was 0.030 (95 %CI 0.021-0.041) in those vaccinated against influenza compared to 0.029 (95 %CI 0.019-0.041) in the unvaccinated group (subdistribution hazard ratio (SDHR) 1.018; 95 %CI 0.602-1.721). For pneumococcal vaccination the cumulative incidence was 0.031 (95 %CI 0.015-0.056) for the vaccinated and 0.029 (95 %CI 0.022-0.038) for non-vaccinated individuals (SDHR 0.961; 95 %CI 0.443-2.085). BCG vaccination in the previous year and sex were not significant effect modifiers in the primary analysis. Duration of fever, cough and dyspnoea was also not significantly different between treatment arms. Conclusion: Neither influenza nor pneumococcal vaccination was associated with a lower incidence or shorter duration of COVID-19 symptoms in older adults.

Corrigendum: The impact of circadian rhythm on Bacillus Calmette-Guérin vaccination effects on SARS-CoV-2 infections.

[This corrects the article DOI: 10.3389/fimmu.2023.980711.].

The impact of circadian rhythm on Bacillus Calmette-Guérin vaccination effects on SARS-CoV-2 infections.

Background and objective: A recent study has suggested that circadian rhythm has an important impact on the immunological effects induced by Bacillus Calmette-Guérin (BCG) vaccination. The objective of this study was to evaluate whether the timing of BCG vaccination (morning or afternoon) affects its impact on severe acute respiratory syndrome-coronavirus-2 (SARS-CoV-2) infections and clinically relevant respiratory tract infections (RTIs). Methods: This is a post-hoc analysis of the BCG-CORONA-ELDERLY (NCT04417335) multicenter, placebo-controlled trial, in which participants aged 60 years and older were randomly assigned to vaccination with BCG or placebo, and followed for 12 months. The primary endpoint was the cumulative incidence of SARS-CoV-2 infection. To assess the impact of circadian rhythm on the BCG effects, participants were divided into four groups: vaccinated with either BCG or placebo in the morning (between 9:00h and 11:30h) or in the afternoon (between 14:30h and 18:00h). Results: The subdistribution hazard ratio of SARS-CoV-2 infection in the first six months after vaccination was 2.394 (95% confidence interval [CI], 0.856-6.696) for the morning BCG group and 0.284 (95% CI, 0.055-1.480) for the afternoon BCG group. When comparing those two groups, the interaction hazard ratio was 8.966 (95% CI, 1.366-58.836). In the period from six months until 12 months after vaccination cumulative incidences of SARS-CoV-2 infection were comparable, as well as cumulative incidences of clinically relevant RTI in both periods. Conclusion: Vaccination with BCG in the afternoon offered better protection against SARS-CoV-2 infections than BCG vaccination in the morning in the first six months after vaccination.

Low SARS-CoV-2 Cq values in healthcare workers with symptomatic COVID-19 infections, regardless of symptom severity, The Netherlands, January to August 2022.

We analysed SARS-CoV-2 PCR Cq values from 3,183 healthcare workers who tested positive between January and August 2022. Median Cq values were lower in symptomatic than in asymptomatic HCW. The difference in Cq values between HCW with mild vs moderate/severe symptoms was statistically significant but negligibly small. To prevent nosocomial infections, all symptomatic HCW should be tested irrespective of symptom severity. This information can support decisions on testing and isolation, in the context of ongoing pressure on healthcare systems.

Redefining Staphylococcus aureus bacteremia: A structured approach guiding diagnostic and therapeutic management.

The current duration of therapy in patients with Staphylococcus aureus bacteremia (SAB) is based on differentiating complicated from uncomplicated disease. While this approach allows clinicians and investigators to group SAB patients into broadly similar clinical categories, it fails to account for the intrinsic heterogeneity of SAB. This is due in part to the fact that risk factors for metastatic infection and confirmed metastatic infection are considered as equivalent in most scoring systems. In this viewpoint, we propose a two-step system of categorizing patients with SAB. Initially, patients with SAB would be categorized as 'high risk' or 'low risk' for metastatic infection based upon an initial set of diagnostic procedures. In the second step, patients identified as 'high-risk' would undergo additional diagnostic evaluation. The results of this stepwise diagnostic evaluation would define a 'final clinical diagnosis' to inform an individualized final treatment plan.

How to use quality indicators for antimicrobial stewardship in your hospital: a practical example on outpatient parenteral antimicrobial therapy.

BACKGROUND: Antimicrobial stewardship (AMS) teams are responsible for performing an AMS programme in their hospitals that aims to improve the quality of antibiotic use. Measuring the quality of antimicrobial use is a core task of a stewardship team. Measurement provides insight into the current quality of antibiotic use and allows for the establishment of goals for improvement. Yet, a practical description of how such a quality measurement using quality indicators (QIs) should be performed is lacking. OBJECTIVES: To provide practical guidance on how a stewardship team can use QIs to measure the quality of antibiotic use in their hospital and identify targets for improvement. SOURCES: General principles from implementation science, peer-reviewed publications, and experience from clinicians and researchers with AMS experience. CONTENT: We provide step-by-step guidance on how AMS teams can use QIs to measure the quality of antibiotic use. The principles behind each step are explained and illustrated with the description and results of an audit of patients receiving outpatient parenteral antimicrobial therapy in four Dutch hospitals. IMPLICATIONS: Improving the quality of antibiotic use is impossible without first gaining insight into that quality by performing a measurement with validated QIs. This step-by-step practice example of how to use quality indicators in a hospital will help AMS teams to identify targets for improvement. This enables them to perform their AMS programme more effectively and efficiently.

Activation of cytokine responses by Candida africana.

Candida africana is a fungal pathogen that rarely causes invasive infections, but is mainly isolated from patients with vaginal infections. Vulvovaginal candidiasis is associated with dysregulated inflammatory responses of the host, however, the innate immune responses against C. africana are currently unknown. In this study, we explored the cytokine production of human peripheral blood mononuclear cells (PBMCs) in response to different C. africana isolates (intra-species diversity), and compared it with that induced by other yeasts belonging to the C. albicans species complex such as C. dubliniensis and C. albicans. Candida africana isolates induced both pro- and anti-inflammatory cytokines broadly similar to other Candida species. Candida africana-stimulated PBMCs tended to produce lower Interleukin (IL)-17 and IL-22 levels in comparison with C. albicans, whereas the induction of trained immunity was similar between C. africana and other Candida species. Overall, our results demonstrate that C. africana induces similar innate immune responses as the other Candida species. Therefore, its propensity to cause vulvovaginal infections is not due to an increased capacity to induce cytokine-related immune pathology. Nor is the infrequent occurrence of invasive infection by C. africana explained by a quantitatively different cytokine induction.

Candida africana has been reported to cause vulvovaginal candidiasis. This study shows that C. africana induces broadly similar cytokine production and trained immunity as other Candida species. Its propensity to cause vaginal infections is not due to an enhanced capacity to cause immune dysregulation.

Current Practices and Opportunities for Outpatient Parenteral Antimicrobial Therapy in Hospitals: A National Cross-Sectional Survey.

This nationwide study assessed how outpatient parenteral antimicrobial therapy (OPAT) is organised by Dutch acute care hospitals, the barriers experienced, and how an OPAT program affects the way hospitals organised OPAT care. We systematically developed and administered a survey to all 71 Dutch acute care hospitals between November 2021 and February 2022. Analyses were primarily descriptive and included a comparison between hospitals with and without an OPAT program. Sixty of the 71 hospitals (84.5%) responded. Fifty-five (91.7%) performed OPAT, with a median number of 20.8 (interquartile range [IQR] 10.3-29.7) patients per 100 hospital beds per year. Of these 55 hospitals, 31 (56.4%) had selection criteria for OPAT and 34 (61.8%) had a protocol for laboratory follow-up. Sixteen hospitals (29.1%) offered self-administered OPAT (S-OPAT), with a median percentage of 5.0% of patients (IQR: 2.3%-10.0%) actually performing self-administration. Twenty-five hospitals (45.5%) had an OPAT-related outcome registration. The presence of an OPAT program (22 hospitals, 40.0%) was significantly associated with aspects of well-organised OPAT care. The most commonly experienced barriers to OPAT implementation were a lack of financial, administrative, and IT support and insufficient time of healthcare staff. Concluding, hospital-initiated OPAT is widely available in the Netherlands, but various aspects of well-organised OPAT care can be improved. Implementation of a team-based OPAT program can contribute to such improvements. The observed variation provides leads for further scientific research, guidelines, and practical implementation programs.

[Carbapenems: take it when needed but leave it if you can]. / Carbapenems: inzetten als het moet, vermijden als het kan.

Surveillance data and literature have shown a worldwide increase in infections with resistant bacteria, which has led to increased prescriptions of carbapenems, which in turn has led to increased carbapenem resistance. There is also an increasing use of carbapenems in the Netherlands, a county usually very conservative in antibiotic use. Carbapenem sparing strategies are essential in an attempt to prevent further rise of infections caused by carbapenem resistant bacteria. This article discusses carbapenem sparing strategies with old forgotten antibiotics and novel antibiotics from a Dutch perspective.

Why we prescribe antibiotics for too long in the hospital setting: a systematic scoping review.

BACKGROUND: In daily hospital practice, antibiotic therapy is commonly prescribed for longer than recommended in guidelines. Understanding the key drivers of prescribing behaviour is crucial to generate meaningful interventions to bridge this evidence-to-practice gap. OBJECTIVES: To identify behavioural determinants that might prevent or enable improvements in duration of antibiotic therapy in daily practice. METHODS: We systematically searched PubMed, Embase, PsycINFO and Web of Science for relevant studies that were published between January 2000 and August 2021. All qualitative, quantitative and mixed-method studies in adults in a hospital setting that reported determinants of antibiotic therapy duration were included. RESULTS: Twenty-two papers were included in this review. A first set of studies provided 82 behavioural determinants that shape how health professionals make decisions about duration; most of these were related to individual health professionals' knowledge, skills and cognitions, and to professionals' interactions. A second set of studies provided 17 determinants that point to differences in duration regarding various pathogens, diseases, or patient, professional or hospital department characteristics, but do not explain why or how these differences occur. CONCLUSIONS: Limited literature is available describing a wide range of determinants that influence duration of antibiotic therapy in daily practice. This review provides a stepping stone for the development of stewardship interventions to optimize antibiotic therapy duration, but more research is warranted. Stewardship teams must develop complex improvement interventions to address the wide variety of behavioural determinants, adapted to the specific pathogen, disease, patient, professional and/or hospital department involved.

SARS-CoV-2 RNA in exhaled air of hospitalized COVID-19 patients.

Knowledge about contagiousness is key to accurate management of hospitalized COVID-19 patients. Epidemiological studies suggest that in addition to transmission through droplets, aerogenic SARS-CoV-2 transmission contributes to the spread of infection. However, the presence of virus in exhaled air has not yet been sufficiently demonstrated. In pandemic situations low tech disposable and user-friendly bedside devices are required, while commercially available samplers are unsuitable for application in patients with respiratory distress. We included 49 hospitalized COVID-19 patients and used a disposable modular breath sampler to measure SARS-CoV-2 RNA load in exhaled air samples and compared these to SARS-CoV-2 RNA load of combined nasopharyngeal throat swabs and saliva. Exhaled air sampling using the modular breath sampler has proven feasible in a clinical COVID-19 setting and demonstrated viral detection in 25% of the patients.

An Integral Pharmacokinetic Analysis of Piperacillin and Tazobactam in Plasma and Urine in Critically Ill Patients.

BACKGROUND AND OBJECTIVES: Although dose optimization studies have been performed for piperacillin and tazobactam separately, a combined integral analysis is not yet reported. As piperacillin and tazobactam pharmacokinetics are likely to show correlation, a combined pharmacokinetic model should be preferred to account for this correlation when predicting the exposure. Therefore, the aim of this study was to describe the pharmacokinetics and evaluate different dosing regimens of piperacillin and tazobactam in critically ill patients using an integral population pharmacokinetic model in plasma and urine. METHODS: In this observational study, a total of 39 adult intensive care unit patients receiving piperacillin-tazobactam as part of routine clinical care were included. Piperacillin and tazobactam concentrations in plasma and urine were measured and analyzed using non-linear mixed-effects modeling. Monte Carlo simulations were performed to predict the concentrations for different dosing strategies and different categories of renal function. RESULTS: A combined two-compartment linear pharmacokinetic model for both piperacillin and tazobactam was developed, with an output compartment for the renally excreted fraction. The addition of 24-h urine creatinine clearance significantly improved the model fit. A dose of 12/1.5 g/24 h as a continuous infusion is sufficient to reach a tazobactam concentration above the target (2.89 mg/L) and a piperacillin concentration above the target of 100% f T>1×MIC (minimum inhibitory concentration [MIC] ≤ 16 mg/L). To reach a target of 100% f T>5×MIC with an MIC of 16 mg/L, piperacillin doses of up to 20 g/24 h are inadequate. Potential toxic piperacillin levels were reached in 19.6% and 47.8% of the population with a dose of 12 g/24 h and 20 g/24 h, respectively. CONCLUSIONS: A regular dose of 12/1.5 g/24 h is sufficient in > 90% of the critically ill population to treat infections caused by Escherichia coli and Klebsiella pneumoniae with MICs ≤ 8 mg/L. In case of infections caused by Pseudomonas aeruginosa with an MIC of 16 mg/L, there is a fine line between therapeutic and toxic exposure. Dosing guided by renal function and therapeutic drug monitoring could enhance target attainment in such cases. GOV IDENTIFIER: NCT03738683.

Efficacy of BCG Vaccination Against Respiratory Tract Infections in Older Adults During the Coronavirus Disease 2019 Pandemic.

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.

An Exaggerated Monocyte-Derived Cytokine Response to Candida Hyphae in Patients With Recurrent Vulvovaginal Candidiasis.

BACKGROUND: Recurrent vulvovaginal candidiasis (RVVC) affects up to 8% of women. The immunopathogenesis is poorly understood but it has been suggested that RVVC might be due to dysregulated innate immune response. The aim of this study was to compare cytokine profiles in stimulated primary mononuclear cells (PBMCs) from RVVC and healthy individuals. METHODS: PBMCs isolated from RVVC patients (n = 24) and healthy volunteers (n = 30) were stimulated with unspecific and pathogen-specific antigens. Cytokine production was assessed after 24 hours, 48 hours, and 7 days using ELISA. RESULTS: No significant differences in cytokine production were found in T helper 1 (Th1), Th2, and Th17 immunity in response to both unspecific and pathogen-specific stimulations. Tumor necrosis factor-α (TNF-α) production in response to C. albicans hyphae was significantly higher in patients than controls and within the patient group, a significant positive correlation was found between interleukin-1ß (IL-1ß) and both TNF-α and IL-6. Both IL-1ß/IL-1Ra and TNF-α/IL-10 ratios in Candida hyphae-stimulated PBMCs were significantly higher in patients than controls. CONCLUSIONS: Women affected by RVVC showed increased monocytes-derived cytokine production, which might contribute to an exaggerated vaginal immune response to Candida hyphae. RVVC patients show no defective Th-dependent adaptive immune response upon Candida stimulation.