Clostridium difficile Colonization and Infection in the Elderly and Associations with the Aging Intestinal Microbiome

The widespread use of antibiotics has led to dramatic increases in the incidence and severity of Clostridium difficile infection (CDI). No group of patients suffers more from CDI than the elderly. Nursing homes (NH) represent the perfect storm of a vulnerable group of frail elders living in confined communities. Nursing home residents suffer from increased morbidity and mortality from CDI and corresponding high rates of C. difficile colonization. Upwards of 40 to 50% of CDI current cases originate from NHs and the prevalence of colonization rates remain high within these facilities, with as many as half of the residents being colonized with C. difficile at any given time. One factor that has become of increasing interest and a target of preventive strategies is the human intestinal microbiome. A healthy, diverse microbiome interacts with the host immune system and contributes to pathogen resistance. In this investigation, we first examine elder specific variables to determine if the associated risks of CDI differ by home living environment (nursing home versus community-dwelling). We then go on explore the relationships of NH environment, frailty, nutritional status, and residents’ age with microbiome composition and potential metabolic function. Finally, we describe the C. difficile colonization patterns among elderly NH residents and the associated risk of colonization based on clinical variables and microbiome determinants. A better understanding of the microbiome’s contribution to C. difficile colonization will provide the basis for informing rational interventions and public health policies to better combat CDI in the nursing home

Proton pump inhibitors and 180-day mortality in the elderly after Clostridium difficile treatment

Background: There is a reported association between proton pump inhibitor (PPI) exposure and increased risk of Clostridium difficile infection (CDI), but less is known about how this class of medications taken during treatment might influence mortality after CDI. Here we examine 180-day mortality rates in a cohort of CDI elders and its association with exposure to PPIs. We conducted a retrospective cohort study of elderly patients ( \u3e 65 years of age) diagnosed and treated for CDI in the years 2014-2016 (n = 874) in the Umass Memorial Health Care system, which represents both academic and community healthcare. Patient characteristics and medication use was extracted from the electronic medical record (EMR) and 6 month mortality data was obtained via the Center for Disease Control National Death Index. A Cox proportional hazards model was used to estimate hazard ratios associated with medication exposures and other relevant variables. Results: Of the 874 elderly adults treated for CDI, 180-day all-cause mortality was 12.4%. Exposure to a PPI was associated with a 55% reduced risk of mortality (adjusted hazard ratio (aHR) 0.45; 95% confidence interval (CI) 0.28-0.72). In our Cox model, increasing age (aHR 1.45; 95% CI 1.14-1.84), those with severe CDI infections (aHR 1.87; 95% CI 1.22-2.88), and those with hospital acquired CDI (aHR 3.01; 95% CI 1.81-4.99) also had increased 180 day mortality risk. There were similar associations noted with both 90 day and 1-year mortality. Conclusion: Use of PPIs during CDI treatment in elderly patients is associated with decreased 180-day mortality. Although use of PPIs has been associated with an increased risk of CDI, it appears to be protective against mortality when used during the treatment phase

All purulence is local - epidemiology and management of skin and soft tissue infections in three urban emergency departments

BACKGROUND: Skin and soft tissue infection (SSTIs) are commonly treated in emergency departments (EDs). While the precise role of antibiotics in treating SSTIs remains unclear, most SSTI patients receive empiric antibiotics, often targeted toward methicillin-resistant Staphylococcus aureus (MRSA). The goal of this study was to assess the efficiency with which ED clinicians targeted empiric therapy against MRSA, and to identify factors that may allow ED clinicians to safely target antibiotic use. METHODS: We performed a retrospective analysis of patient visits for community-acquired SSTIs to three urban, academic EDs in one northeastern US city during the first quarter of 2010. We examined microbiologic patterns among cultured SSTIs, and relationships between clinical and demographic factors and management of SSTIs. RESULTS: Antibiotics were prescribed to 86.1% of all patients. Though S. aureus (60% MRSA) was the most common pathogen cultured, antibiotic susceptibility differed between adult and pediatric patients. Susceptibility of S. aureus from ED SSTIs differed from published local antibiograms, with greater trimethoprim resistance and less fluoroquinolone resistance than seen in S. aureus from all hospital sources. Empiric antibiotics covered the resultant pathogen in 85.3% of cases, though coverage was frequently broader than necessary. CONCLUSIONS: Though S. aureus remained the predominant pathogen in community-acquired SSTIs, ED clinicians did not accurately target therapy toward the causative pathogen. Incomplete local epidemiologic data may contribute to this degree of discordance. Future efforts should seek to identify when antibiotic use can be narrowed or withheld. Local, disease-specific antibiotic resistance patterns should be publicized with the goal of improving antibiotic stewardship

Virtualized Clinical Studies to Assess the Natural History and Impact of Gut Microbiome Modulation in Non-Hospitalized Patients with Mild to Moderate COVID-19 a Randomized, Open-Label, Prospective Study with a Parallel Group Study Evaluating the Physiologic Effects of KB109 on Gut Microbiota Structure and Function: A Structured Summary of a Study Protocol for a Randomized Controlled Study [preprint]

These 2 parallel studies (K031 and K032) aim to evaluate the safety of KB109 in addition to supportive self-care (SSC) compared with SSC alone in outpatients with mild to moderate coronavirus disease 2019 (COVID-19). KB109 is a novel synthetic glycan that was formulated to modulate the gut microbiome composition and metabolic output in order to increase beneficial short-chain fatty acid (SCFA) production in the gut. The K031 study is designed to evaluate the safety of KB109 and characterize its impact on the natural progression of COVID-19 in patients with mild to moderate disease. The K032 study is evaluating the effect of KB109 on the gut microbiota structure and function in this same patient population. Additionally, both studies are evaluating measures of health care utilization, quality of life (QOL), laboratory indices, biomarkers of inflammation, and serological measures of immunity in patients who received SSC alone or with KB109. Noteworthy aspects of these outpatient studies include study design measures aimed at limiting in-person interactions to minimize the risk of infection spread, such as use of online diaries, telemedicine, and at-home sample collection

Deviating from IDSA treatment guidelines for non-purulent skin infections increases the risk of treatment failure in emergency department patients

The Infectious Disease Society of America (IDSA) publishes guidelines regularly for the management of skin and soft tissue infections; however, the extent to which practice patterns follow these guidelines and if this can affect treatment failure rates is unknown. We observed the treatment failure rates from a multicentre retrospective ambulatory cohort of adult emergency department patients treated for a non-purulent skin infection. We used multivariable logistic regression to examine the role of IDSA classification and whether adherence to IDSA guidelines reduced treatment failure. A total of 759 ambulatory patients were included in the cohort with 17.4% failing treatment. Among all patients, 56.0% had received treatments matched to the IDSA guidelines with 29.1% over-treated, and 14.9% under-treated based on the guidelines. After adjustment for age, gender, infection location and medical comorbidities, patients with a moderate infection type had three times increased risk of treatment failure (adjusted risk ratio (aRR) 2.98; 95% confidence interval (CI) 1.15-7.74) and two times increased risk with a severe infection type (aRR 2.27; 95% CI 1.25-4.13) compared with mild infection types. Patients who were under-treated based on IDSA guidelines were over two times more likely to fail treatment (aRR 2.65; 95% CI 1.16-6.05) while over-treatment was not associated with treatment failure. Patients 70 years of age had a 56% increased risk of treatment failure (aRR 1.56; 95% CI 1.04-2.33) compared with those \u3c 70 years. Following the IDSA guidelines for non-purulent SSTIs may reduce the treatment failure rates; however, older adults still carry an increased risk of treatment failure

Alzheimer\u27s Disease Microbiome Is Associated with Dysregulation of the Anti-Inflammatory P-Glycoprotein Pathway

The microbiota-gut-brain axis is a bidirectional communication system that is poorly understood. Alzheimer\u27s disease (AD), the most common cause of dementia, has long been associated with bacterial infections and inflammation-causing immunosenescence. Recent studies examining the intestinal microbiota of AD patients revealed that their microbiome differs from that of subjects without dementia. In this work, we prospectively enrolled 108 nursing home elders and followed each for up to 5 months, collecting longitudinal stool samples from which we performed metagenomic sequencing and in vitro T84 intestinal epithelial cell functional assays for P-glycoprotein (P-gp) expression, a critical mediator of intestinal homeostasis. Our analysis identified clinical parameters as well as numerous microbial taxa and functional genes that act as predictors of AD dementia in comparison to elders without dementia or with other dementia types. We further demonstrate that stool samples from elders with AD can induce lower P-gp expression levels in vitro those samples from elders without dementia or with other dementia types. We also paired functional studies with machine learning approaches to identify bacterial species differentiating the microbiome of AD elders from that of elders without dementia, which in turn are accurate predictors of the loss of dysregulation of the P-gp pathway. We observed that the microbiome of AD elders shows a lower proportion and prevalence of bacteria with the potential to synthesize butyrate, as well as higher abundances of taxa that are known to cause proinflammatory states. Therefore, a potential nexus between the intestinal microbiome and AD is the modulation of intestinal homeostasis by increases in inflammatory, and decreases in anti-inflammatory, microbial metabolism.IMPORTANCE Studies of the intestinal microbiome and AD have demonstrated associations with microbiome composition at the genus level among matched cohorts. We move this body of literature forward by more deeply investigating microbiome composition via metagenomics and by comparing AD patients against those without dementia and with other dementia types. We also exploit machine learning approaches that combine both metagenomic and clinical data. Finally, our functional studies using stool samples from elders demonstrate how the c microbiome of AD elders can affect intestinal health via dysregulation of the P-glycoprotein pathway. P-glycoprotein dysregulation contributes directly to inflammatory disorders of the intestine. Since AD has been long thought to be linked to chronic bacterial infections as a possible etiology, our findings therefore fill a gap in knowledge in the field of AD research by identifying a nexus between the microbiome, loss of intestinal homeostasis, and inflammation that may underlie this neurodegenerative disorder

The high prevalence of Clostridioides difficile among nursing home elders associates with a dysbiotic microbiome

Clostridioides difficile disproportionally affects the elderly living in nursing homes (NHs). Our objective was to explore the prevalence of C. difficile in NH elders, over time and to determine whether the microbiome or other clinical factors are associated with C. difficile colonization. We collected serial stool samples from NH residents. C. difficile prevalence was determined by quantitative polymerase-chain reaction detection of Toxin genes tcdA and tcdB; microbiome composition was determined by shotgun metagenomic sequencing. We used mixed-effect random forest modeling machine to determine bacterial taxa whose abundance is associated with C. difficile prevalence while controlling for clinical covariates including demographics, medications, and past medical history. We enrolled 167 NH elders who contributed 506 stool samples. Of the 123 elders providing multiple samples, 30 (24.4%) elders yielded multiple samples in which C. difficile was detected and 78 (46.7%) had at least one C. difficile positive sample. Elders with C. difficile positive samples were characterized by increased abundances of pathogenic or inflammatory-associated bacterial taxa and by lower abundances of taxa with anti-inflammatory or symbiotic properties. Proton pump inhibitor (PPI) use is associated with lower prevalence of C. difficile (Odds Ratio 0.46; 95%CI, 0.22-0.99) and the abundance of bacterial species with known beneficial effects was higher in PPI users and markedly lower in elders with high C. difficile prevalence.C. difficile is prevalent among NH elders and a dysbiotic gut microbiome associates with C. difficile colonization status. Manipulating the gut microbiome may prove to be a key strategy in the reduction of C. difficile in the NH

Immunization with Cross-Conserved H1N1 Influenza CD4\u3csup\u3e+\u3c/sup\u3e T-Cell Epitopes Lowers Viral Burden in HLA DR3 Transgenic Mice

The emergence of the pandemic H1N1 strain of influenza in 2009 was associated with a unique w-shaped age-related susceptibility curve, with higher incidence of morbidity and mortality among young persons and lower incidence among older persons, also observed during the 1918 influenza pandemic. Pre-existing H1N1 antibodies were not cross-reactive with the prior seasonal vaccine, forcing influenza experts to scramble to develop a new vaccine specific for the pandemic virus. We hypothesized that response to T-cell epitopes that are cross-conserved between pandemic H1N1 and the 2008 seasonal influenza vaccine strains might have contributed to partial protection from clinical illness among older adults, despite the lack of cross-reactive humoral immunity. Using immunoinformatics tools, we previously identified hemagglutinin and neuraminidase epitopes that were highly conserved between seasonal and pandemic H1N1. Here, we validated predicted CD4+ T-cell epitopes for their ability to bind HLA and to stimulate interferon-γ production in peripheral blood mononuclear cells from a cohort of donors presenting with influenza-like illness during the 2009 pandemic and a separate cohort immunized with trivalent influenza vaccine in 2011. A limited-epitope heterologous DNA-prime/peptide-boost vaccine composed of these sequences stimulated immune responses and lowered lung viral loads in HLA DR3 transgenic mice challenged with pandemic 2009 H1N1 influenza. Cross-priming with conserved influenza T-cell epitopes such as these may be critically important to T cell-mediated protection against pandemic H1N1 in the absence of cross-protective antibodies

Oropharyngeal Microbiome Profiled at Admission is Predictive of the Need for Respiratory Support Among COVID-19 Patients [preprint]

The clinical course of infection due to respiratory viruses such as Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV2), the causative agent of Coronavirus Disease 2019 (COVID-19) is thought to be influenced by the community of organisms that colonizes the upper respiratory tract, the oropharyngeal microbiome. In this study, we examined the oropharyngeal microbiome of suspected COVID-19 patients presenting to the Emergency Department and an inpatient COVID-19 unit with symptoms of acute COVID-19. Of 115 enrolled patients, 74 were confirmed COVID-19+ and 50 had symptom duration of 14 days or less; 38 acute COVID-19+ patients (76%) went on to require respiratory support. Although no microbiome features were found to be significantly different between COVID-19+ and COVID-19-patients, when we conducted random forest classification modeling (RFC) to predict the need of respiratory support for the COVID-19+ patients our analysis identified a subset of organisms and metabolic pathways whose relative abundance, when combined with clinical factors (such as age and Body Mass Index), was highly predictive of the need for respiratory support (F1 score 0.857). Microbiome Multivariable Association with Linear Models (MaAsLin2) analysis was then applied to the features identified as predicative of the need for respiratory support by the RFC. This analysis revealed reduced abundance of Prevotella salivae and metabolic pathways associated with lipopolysaccharide and mycolic acid biosynthesis to be the strongest predictors of patients requiring respiratory support. These findings suggest that composition of the oropharyngeal microbiome in COVID-19 may play a role in determining who will suffer from severe disease manifestations. Importance: The microbial community that colonizes the upper airway, the oropharyngeal microbiome, has the potential to affect how patients respond to respiratory viruses such as SARS-CoV2, the causative agent of COVID-19. In this study, we investigated the oropharyngeal microbiome of COVID-19 patients using high throughput DNA sequencing performed on oral swabs. We combined patient characteristics available at intake such as medical comorbidities and age, with measured abundance of bacterial species and metabolic pathways and then trained a machine learning model to determine what features are predicative of patients needing respiratory support in the form of supplemental oxygen or mechanical ventilation. We found that decreased abundance of some bacterial species and increased abundance of pathways associated bacterial products biosynthesis was highly predictive of needing respiratory support. This suggests that the oropharyngeal microbiome affects disease course in COVID-19 and could be targeted for diagnostic purposes to determine who may need oxygen, or therapeutic purposes such as probiotics to prevent severe COVID-19 disease manifestations

Presence of Symptoms 6 Weeks After COVID-19 Among Vaccinated and Unvaccinated US Healthcare Personnel: A Prospective Cohort Study

OBJECTIVES: Although COVID-19 vaccines offer protection against infection and severe disease, there is limited information on the effect of vaccination on prolonged symptoms following COVID-19. Our objective was to determine differences in prevalence of prolonged symptoms 6 weeks after onset of COVID-19 among healthcare personnel (HCP) by vaccination status, and to assess differences in timing of return to work. DESIGN: Cohort analysis of HCP with COVID-19 enrolled in a multicentre vaccine effectiveness study. HCP with COVID-19 between December 2020 and August 2021 were followed up 6 weeks after illness onset. SETTING: Health systems in 12 US states. PARTICIPANTS: HCP participating in a vaccine effectiveness study were eligible for inclusion if they had laboratory-confirmed symptomatic SARS-CoV-2 with mRNA vaccination (symptom onset ≥14 days after two doses) or no prior vaccination. Among 681 eligible participants, 419 (61%) completed a follow-up survey to assess symptoms reported 6 weeks after illness onset. EXPOSURES: Two doses of a COVID-19 mRNA vaccine compared with no COVID-19 vaccine. MAIN OUTCOME MEASURES: Prevalence of symptoms 6 weeks after onset of COVID-19 illness and days to return to work. RESULTS: Among 419 HCP with COVID-19, 298 (71%) reported one or more COVID-like symptoms 6 weeks after illness onset, with a lower prevalence among vaccinated participants compared with unvaccinated participants (60.6% vs 79.1%; adjusted risk ratio 0.70, 95% CI 0.58 to 0.84). Following their illness, vaccinated HCP returned to work a median 2.0 days (95% CI 1.0 to 3.0) sooner than unvaccinated HCP (adjusted HR 1.37, 95% CI 1.04 to 1.79). CONCLUSIONS: Receipt of two doses of a COVID-19 mRNA vaccine among HCP with COVID-19 illness was associated with decreased prevalence of COVID-like symptoms at 6 weeks and earlier return to work