Microbiota-based markers predictive of development of Clostridioides difficile infection

Antibiotic-induced modulation of the intestinal microbiota can lead to Clostridioides difficile infection (CDI), which is associated with considerable morbidity, mortality, and healthcare costs globally. Therefore, identification of markers predictive of CDI could substantially contribute to guiding therapy and decreasing the infection burden. Here, we analyze the intestinal microbiota of hospitalized patients at increased CDI risk in a prospective, 90-day cohort-study before and after antibiotic treatment and at diarrhea onset. We show that patients developing CDI already exhibit significantly lower diversity before antibiotic treat ment and a distinct microbiota enriched in Enterococcus and depleted of Ruminococcus, Blautia, Prevotella and Bifidobacterium compared to non-CDI patients. We find that antibiotic treatment-induced dysbiosis is class-specific with beta-lactams further increasing enter ococcal abundance. Our findings, validated in an independent prospective patient cohort developing CDI, can be exploited to enrich for high-risk patients in prospective clinical trials, and to develop predictive microbiota-based diagnostics for management of patients at risk for CDI

Impact of antimicrobial de-escalation on mortality: a literature review of study methodology and recommendations for observational studies

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

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

Five versus seven days of nitrofurantoin for urinary tract infections in women with diabetes: a retrospective cohort study

Objective: To compare the effectiveness of 5 versus 7 days of nitrofurantoin treatment for urinary tract infection (UTI) in women with diabetes. Methods: Data were collected retrospectively from Dutch general practitioners between 2013 and 2020. Nitrofurantoin prescriptions with a duration of 5 days (5DN) or 7 days (7DN) in women with diabetes were included. Inverse propensity weighting 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 women with diabetes with UTI treated with either 5DN or 7DN within 28 days. A 5-day treatment should be considered to reduce cumulative nitrofurantoin exposure in DM patients

Higher-valency pneumococcal conjugate vaccines in older adults, taking into account indirect effects from childhood vaccination: a cost-effectiveness study for the Netherlands

Background: New 15- and 20-valent pneumococcal vaccines (PCV15, PCV20) are available for both children and adults, while PCV21 for adults is in development. However, their cost-effectiveness for older adults, taking into account indirect protection and serotype replacement from a switch to PCV15 and PCV20 in childhood vaccination, remains unexamined. Methods: We used a static model for the Netherlands to assess the cost-effectiveness of different strategies with 23-valent pneumococcal polysaccharide vaccine (PPV23), PCV15, PCV20, and PCV21 for a 65-year-old cohort from a societal perspective, over a 15-year time horizon. Childhood vaccination was varied from PCV10 to PCV13, PCV15, and PCV20. Indirect protection was assumed to reduce the incidence of vaccine serotypes in older adults by 80% (except for serotype 3, no effect), completely offset by an increase in non-vaccine serotype incidence due to serotype replacement. Results: Indirect effects from childhood vaccination reduced the cost-effectiveness of vaccination of older adults, depending on the serotype overlap between the vaccines. With PCV10, PCV13, or PCV15 in children, PCV20 was more effective and less costly for older adults than PPV23 and PCV15. PCV20 costs approximately €10,000 per quality-adjusted life year (QALY) gained compared to no pneumococcal vaccination, which falls below the conventional Dutch €20,000/QALY gained threshold. However, with PCV20 in children, PCV20 was no longer considered cost-effective for older adults, costing €22,550/QALY gained. As indirect effects progressed over time, the cost-effectiveness of PCV20 for older adults further diminished for newly vaccinated cohorts. PPV23 was more cost-effective than PCV20 for cohorts vaccinated 3 years after the switch to PCV20 in children. PCV21 offered the most QALY gains, and its cost-effectiveness was minimally affected by indirect effects due to its coverage of 11 different serotypes compared to PCV20. Conclusions: For long-term cost-effectiveness in the Netherlands, the pneumococcal vaccine for older adults should either include invasive serotypes not covered by childhood vaccination or become more affordable than its current pricing for individual use

Microbiota-based markers predictive of development of Clostridioides difficile infection

Antibiotic-induced modulation of the intestinal microbiota can lead to Clostridioides difficile infection (CDI), which is associated with considerable morbidity, mortality, and healthcare-costs globally. Therefore, identification of markers predictive of CDI could substantially contribute to guiding therapy and decreasing the infection burden. Here, we analyze the intestinal microbiota of hospitalized patients at increased CDI risk in a prospective, 90-day cohort-study before and after antibiotic treatment and at diarrhea onset. We show that patients developing CDI already exhibit significantly lower diversity before antibiotic treatment and a distinct microbiota enriched in Enterococcus and depleted of Ruminococcus, Blautia, Prevotella and Bifidobacterium compared to non-CDI patients. We find that antibiotic treatment-induced dysbiosis is class-specific with beta-lactams further increasing enterococcal abundance. Our findings, validated in an independent prospective patient cohort developing CDI, can be exploited to enrich for high-risk patients in prospective clinical trials, and to develop predictive microbiota-based diagnostics for management of patients at risk for CDI

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

Positive impact of [18F]FDG-PET/CT on mortality in patients with Staphylococcus aureus bacteremia explained by immortal time bias

BACKGROUND: Several 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. METHODS: Prospective 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. RESULTS: Of 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]). CONCLUSIONS: After 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

The impact of Bacillus Calmette-Guérin vaccination on antibody response after COVID-19 vaccination

Earlier studies showed that BCG vaccination improves antibody responses of subsequent vaccinations. Similarly, in older volunteers we found an increased IgG receptor-binding domain (RBD) concentration after SARS-CoV-2 infection if they were recently vaccinated with BCG. This study aims to assess the effect of BCG on the serum antibody concentrations induced by COVID-19 vaccination in a population of adults older than 60 years. Serum was collected from 1,555 participants of the BCG-CORONA-ELDERLY trial a year after BCG or placebo, and we analyzed the anti-SARS-CoV-2 antibody concentrations using a fluorescent-microsphere-based multiplex immunoassay. Individuals who received the full primary COVID-19 vaccination series before serum collection and did not test positive for SARS-CoV-2 between inclusion and serum collection were included in analyses (n = 945). We found that BCG vaccination before first COVID-19 vaccine (median 347 days [IQR 329-359]) did not significantly impact the IgG RBD concentration after COVID-19 vaccination in an older European population