Systems-ecology designed bacterial consortium protects from severe Clostridioides difficile infection.

Fecal Microbiota Transplant (FMT) is an emerging therapy that has had remarkable success in treatment and prevention of recurrent Clostridioides difficile infection (rCDI). FMT has recently been associated with adverse outcomes such as inadvertent transfer of antimicrobial resistance, necessitating development of more targeted bacteriotherapies. To address this challenge, we developed a novel systems biology pipeline to identify candidate probiotic strains that would be predicted to interrupt C. difficile pathogenesis. Utilizing metagenomic characterization of human FMT donor samples, we identified those metabolic pathways most associated with successful FMTs and reconstructed the metabolism of encoding species to simulate interactions with C. difficile . This analysis resulted in predictions of high levels of cross-feeding for amino acids in species most associated with FMT success. Guided by these in silico models, we assembled consortia of bacteria with increased amino acid cross-feeding which were then validated in vitro . We subsequently tested the consortia in a murine model of CDI, demonstrating total protection from severe CDI through decreased toxin levels, recovered gut microbiota, and increased intestinal eosinophils. These results support the novel framework that amino acid cross-feeding is likely a critical mechanism in the initial resolution of CDI by FMT. Importantly, we conclude that our predictive platform based on predicted and testable metabolic interactions between the microbiota and C. difficile led to a rationally designed biotherapeutic framework that may be extended to other enteric infections.

Alanyl-glutamine supplementation for Clostridioides difficile infection treatment (ACT): a double-blind randomised controlled trial study protocol.

INTRODUCTION: Clostridioides difficile is the leading cause of healthcare-associated infections in the USA, with an estimated 1 billion dollars in excess cost to the healthcare system annually. C. difficile infection (CDI) has high recurrence rate, up to 25% after first episode and up to 60% for succeeding episodes. Preliminary in vitro and in vivo studies indicate that alanyl-glutamine (AQ) may be beneficial in treating CDI by its effect on restoring intestinal integrity in the epithelial barrier, ameliorating inflammation and decreasing relapse. METHODS AND ANALYSIS: This study is a randomised, placebo-controlled, double-blind, phase II clinical trial. The trial is designed to determine optimal dose and safety of oral AQ at 4, 24 and 44 g doses administered daily for 10 days concurrent with standard treatment of non-severe or severe uncomplicated CDI in persons age 18 and older. The primary outcome of interest is CDI recurrence during 60 days post-treatment follow-up, with the secondary outcome of mortality during 60 days post-treatment follow-up. Exploratory analysis will be done to determine the impact of AQ supplementation on intestinal and systemic inflammation, as well as intestinal microbial and metabolic profiles. ETHICS AND DISSEMINATION: The study has received University of Virginia Institutional Review Board approval (HSR200046, Protocol v9, April 2023). Findings will be disseminated via conference presentations, lectures and peer-reviewed publications. TRIAL REGISTRATION NUMBER: NCT04305769.

Microbiota-Based Live Biotherapeutic RBX2660 for the Reduction of Recurrent Clostridioides difficile Infection in Older Adults With Underlying Comorbidities.

Background: Advanced age and underlying comorbidities are associated with greater rates of recurrence in patients with Clostridioides difficile infection (CDI). Reducing the likelihood of recurrence through treatment with an antimicrobial followed by a microbiota replacement therapy can decrease the burden of this infection and improve patient outcomes. We report the efficacy and safety of RBX2660, a microbiota-based live biotherapeutic, in older adults with recurrent CDI, grouped by comorbidities. Methods: In this post hoc subgroup analysis of the PUNCH CD3 trial, we assessed outcomes in older adults (age ≥65 years) grouped by Charlson Comorbidity Index severity scores at screening (moderate [3-4] and severe [≥5]) and by the presence of underlying cardiac, renal, or gastrointestinal disorders. Results: RBX2660 treatment success rates in older adults with comorbidities were consistent across subgroups and similar to those in the total RBX2660-treated population. A greater percentage of RBX2660-treated older adults remained free of CDI recurrence through 8 weeks following treatment compared with placebo-treated participants in all but 2 subgroups assessed. Across all subgroups, most treatment-emergent adverse events (TEAEs) were mild or moderate in severity and related to a preexisting condition. None of the serious or life-threatening TEAEs that occurred were related to RBX2660 or its administration. Occurrence of TEAEs did not cluster in any subgroup. Conclusions: RBX2660 is efficacious and safe in older adults with recurrent CDI and underlying comorbidities.

Development of telehealth principles and guidelines for older adults: A modified Delphi approach.

The COVID-19 pandemic elevated telehealth as a prevalent care delivery modality for older adults. However, guidelines and best practices for the provision of healthcare via telehealth are lacking. Principles and guidelines are needed to ensure that telehealth is safe, effective, and equitable for older adults. The Collaborative for Telehealth and Aging (C4TA) composed of providers, experts in geriatrics, telehealth, and advocacy, developed principles and guidelines for delivering telehealth to older adults. Using a modified Delphi process, C4TA members identified three principles and 18 guidelines. First, care should be person-centered; telehealth programs should be designed to meet the needs and preferences of older adults by considering their goals, family and caregivers, linguistic characteristics, and readiness and ability to use technology. Second, care should be equitable and accessible; telehealth programs should address individual and systemic barriers to care for older adults by considering issues of equity and access. Third, care should be integrated and coordinated across systems and people; telehealth should limit fragmentation, improve data sharing, increase communication across stakeholders, and address both workforce and financial sustainability. C4TA members have diverse perspectives and expertise but a shared commitment to improving older adults' lives. C4TA's recommendations highlight older adults' needs and create a roadmap for providers and health systems to take actionable steps to reach them. The next steps include developing implementation strategies, documenting current telehealth practices with older adults, and creating a community to support the dissemination, implementation, and evaluation of the recommendations.

Perceptions and Uses of Telehealth in the Care of Older Adults.

Background: Clinicians identify challenges in using telehealth with older adults, yet they continue to use it at high rates. We conducted a nation-wide survey of US clinicians to assess the views and uses of telehealth for older adults (≥65 years old); as well as the perceived advantages and challenges of telehealth and use of age-friendly telehealth practices. Materials/Methods: We distributed an online survey (Wallin Opinion Research) to assess the use of telehealth and clinicians' views on advantages/challenges of telehealth in care of older adults. Respondents were eligible if they were active US clinicians with self-attestation of patient population ≥10% older adults. The survey was distributed through established professional networks. Eligible respondents received a gift card for participation, fulfilled by a third-party vendor. Survey participation was voluntary. Completion of the survey was considered consent to participate. The study was reviewed and determined exempt by the WCG's IRB Affairs Department. SPSS Version-26 was used for descriptive statistics. Results: Approximately 13,300 surveys were distributed and there were 7,246 (55%) respondents. Over half (56%) respondents were licensed independent practitioners. The majority of respondents practiced geriatric medicine (22%) or primary care (9.7%). The most common use was in hospitals (53%), long-term care facilities (47%), and outpatient (47%) settings. The majority of respondents (55%) selected "telehealth improves healthcare for older adults by enhancing engagement between stakeholders" as a top advantage. Fewer primary care clinicians (47%) reported sufficient support in the use of telehealth, as compared with clinicians in geriatrics (62%) or other specialties (60%). A majority (65%) of respondents reported use one or more age-friendly practice (40% often; 25% always). Only 5% of respondents reported that their telehealth program never utilized age-friendly practices. Discussion and Conclusion: Clinicians use telehealth in care of older adults, across clinical roles, sites, and purposes. Our survey results suggest perceived advantages of telehealth outweigh challenges, in care of older adults. This highlights an opportunity for guidance and resources to optimizing telehealth with older adults.

Virtual Daily Rounding for COVID-19 Facility Outbreaks: A Standardized Telehealth-Centered Approach May Reduce Hospital Transfers and Mortality.

Background: Residents of nursing homes are among the most vulnerable to COVID-19. There is no standardized approach for integration with hospitals for outbreak response. Previously, we described collaboration between a hospital and regional facilities. As a component of our COVID-19 Outbreak Response, we describe the impact of virtual daily rounds as an efficient and effective tool for facility outbreak in Central Virginia. Methods: At this facility, 82 (60%) residents were infected. Our team rapidly deployed technology to support staff at the facility. Virtual daily rounds created a systematic approach for patient care. The goals of virtual daily rounds include (1) efficiently facilitating HIPAA-compliant communication between nursing and all licensed independent providers, (2) rapid identification of clinical decline, (3) facilitation of care escalation, (4) facilitating bidirectional transfers, and (5) rapid and efficient identification of patients appropriate for telemedicine pulmonary consultation. Results: The outbreak remained active 6 weeks; 82 of 136 (60%) residents were infected, and 36 (44%) COVID-19 positive residents were seen by telemedicine consultation. Fifty-seven (70%) residents remained in-facility for treatment. Twenty-one residents died (15%); 10 in facility, 11 in hospital. Of those seen in telemedicine consultation, 24 (69%) remained on the treat-in-place protocol with goal-concordant care. These hospitalization and mortality rates are significantly lower than similar outbreaks reported. Discussion and Conclusion: We have since instituted this system at seven other facilities. A model of virtual daily rounding holds promise for decreasing mortality/hospitalization in this vulnerable population through systematically identifying patients most appropriate for telemedicine and cultivating close collaboration between hospitals and nursing homes.

Rapid Telehealth-Centered Response to COVID-19 Outbreaks in Postacute and Long-Term Care Facilities.

Purpose: The vulnerability of postacute and long-term care (PA/LTC) facility residents to COVID-19 has manifested across the world with increasing facility outbreaks associated with high hospitalization and mortality rates. Systematic protocols to guide telehealth-centered interventions in response to COVID-19 outbreaks have yet to be delineated. This article is intended to inform PA/LTC facilities and neighboring health care partners how to collaboratively utilize telehealth-centered strategies to improve outcomes in facility outbreaks. Methods: The University of Virginia rapidly developed a multidisciplinary telehealth-centered COVID-19 facility outbreak strategy in response to a LTC facility outbreak in which 41 (out of 48) facility residents and 7 staff members tested positive. This strategy focused on supporting the facility team remotely using rapidly deployed technologic solutions. Goals included (1) early identification of patients who need their care escalated, (2) monitoring and treating patients deemed safe to remain in the facility, (3) care coordination to facilitate bidirectional transfers between the skilled nursing facility (SNF) and hospital, and (4) daily facility needs assessment related to technology, infection control, and staff well-being. To achieve these goals, a standardized approach centered on daily multidisciplinary virtual rounds and telemedicine consultation was provided. Results: Over a month since the outbreak began, 18 out of 48 (38%) facility residents required hospitalization and 6 (12.5%) died. Eleven facility residents have since returned back to the SNF after recovering from their hospitalization. No staff required hospitalization. Conclusions: Interventions that reduce hospitalizations and mortality are a critical need during the COVID-19 pandemic. The mortality and hospitalization rates seen in this PA/LTC facility outbreak are significantly lower than has been documented in other facility outbreaks. Our multidisciplinary approach centered on telemedicine should be considered as other PA/LTC facilities partner with neighboring health care systems in responding to COVID-19 outbreaks. We have begun replicating these services to additional PA/LTC facilities facing COVID-19 outbreaks.

COVID-19 Collaborative Model for an Academic Hospital and Long-Term Care Facilities.

The COVID-19 pandemic is devastating post-acute and long-term care (PA/LTC). As geriatricians practicing in PA/LTC and a regional academic medical center, we created this program for collaboration between academic medical centers and regional PA/LTC facilities. The mission of the Geriatric Engagement and Resource Integration in Post-Acute and Long-Term Care Facilities (GERI-PaL) program is to support optimal care of residents in PA/LTC facilities during the COVID-19 pandemic. There are 5 main components of our program: (1) Project ECHO; (2) nursing liaisons; (3) infection advisory consultation; (4) telemedicine consultation; and (5) resident social contact remote connections. Implementation of this program has had positive response from our local PA/LTC facilities. A key component of our program is our interprofessional team, which includes physicians and nursing, emergency response, and public health experts. With diverse professional backgrounds, our team members have created a new model for academic medical centers to collaborate with local PA/LTC facilities.

Recommendations for Mandatory Influenza Vaccinations for Health Care Personnel From AMDA's Infection Advisory Subcommittee.

Preventing influenza infections is a national health priority, particularly among geriatric and adults with frailty who reside in post-acute and long-term care (PALTC) settings. Older adults account for more than 70% of deaths from influenza, a reflection of decreased vaccine effectiveness in that age group. Annually vaccinating health care personnel (HCP) working with these patients against influenza is critical to reducing influenza morbidity and mortality among patients. PALTC HCP have the lowest influenza vaccination rate when compared to HCP in other settings. The Advisory Committee on Immunization Practices recommends that all HCP receive an annual influenza vaccination, including those who do not have direct patient care responsibilities. Here, we discuss the importance of influenza vaccination for HCP, detail recommendations for influenza vaccination practice and procedures for PALTC settings, and offer support to PALTC settings and their staff on influenza vaccinations.

Outcomes of a Multidisciplinary Clinic in Evaluating Recurrent Clostridioides difficile Infection Patients for Fecal Microbiota Transplant: A Retrospective Cohort Analysis.

Fecal microbiota transplantation (FMT) has been shown to be an effective treatment for recurrent Clostridioides difficile infections (rCDIs). We assessed the benefits of a multidisciplinary C. difficile clinic for screening FMT eligibility in patients with rCDI. Patients seen at the University of Virginia Complicated C. difficile Clinic (CCDC) underwent comprehensive evaluation for possible FMT. Patients were eligible for FMT if there was history of greater than two episodes of rCDI. Patients were evaluated for the outcome after evaluation in the clinic. A total of 113 patients were evaluated: 77 were eligible for FMT, of which 25 patients did not undergo FMT. The rate of recurrence at three months and all-cause mortality were 4.5% and 7% for patients who received FMT and 16.7% and 12.5% for eligible patients who did not receive FMT. There were 36 patients who were not eligible for FMT, with two or fewer recurrences and a recurrence rate of 8.8% and all-cause mortality of 6%. One in three patients screened for FMT had a nutritional deficiency diagnosed, with zinc deficiency being most common (20%). Additional diagnoses, including inflammatory bowel disease, were made during the evaluation. FMT is a highly effective treatment for rCDI, most notably in patients with multiple recurrences. A systematic approach for evaluating patients with rCDI helps identify patients who benefit most from FMT and those who have other conditions.

A randomized controlled trial of probiotics for Clostridium difficile infection in adults (PICO).

BACKGROUND: Clostridium difficile is the most common cause of hospital-acquired infections, responsible for >450000 infections annually in the USA. Probiotics provide a promising, well-tolerated adjunct therapy to standard C. difficile infection (CDI) treatment regimens, but there is a paucity of data regarding their effectiveness for the treatment of an initial CDI. OBJECTIVES: We conducted a pilot randomized controlled trial of 33 participants from February 2013 to February 2015 to determine the feasibility and health outcomes of adjunct probiotic use in patients with an initial mild to moderate CDI. METHODS: The intervention was a 28 day, once-daily course of a four-strain oral probiotic capsule containing Lactobacillus acidophilus NCFM, Lactobacillus paracasei Lpc-37, Bifidobacterium lactis Bi-07 and B. lactis Bl-04. The control placebo was identical in taste and appearance. Registered at clinicaltrials.gov: trial registration number = NCT01680874. RESULTS: Probiotic adjunct therapy was associated with a significant improvement in diarrhoea outcomes. The primary duration of diarrhoea outcome (0.0 versus 1.0 days; P = 0.039) and two exploratory outcomes, total diarrhoea days (3.5 versus 12.0 days; P = 0.005) and rate of diarrhoea (0.1 versus 0.3 days of diarrhoea/stool diary days submitted; P = 0.009), all decreased in participants with probiotic use compared with placebo. There was no significant difference in the rate of CDI recurrence or functional improvement over time between treatment groups. CONCLUSIONS: Probiotics are a promising adjunct therapy for treatment of an initial CDI and should be further explored in a larger randomized controlled trial.

Pneumococcal Vaccination Guidance for Post-Acute and Long-Term Care Settings: Recommendations From AMDA's Infection Advisory Committee.

Efforts at preventing pneumococcal disease are a national health priority, particularly in older adults and especially in post-acute and long-term care settings The Advisory Committee on Immunization Practices recommends that all adults ≥65 years of age, as well as adults 18-64 years of age with specific risk factors, receive both the recently introduced polysaccharide-protein conjugate vaccine against 13 pneumococcal serotypes as well as the polysaccharide vaccine against 23 pneumococcal serotypes. Nursing facility licensure regulations require facilities to assess the pneumococcal vaccination status of each resident, provide education regarding pneumococcal vaccination, and administer the appropriate pneumococcal vaccine when indicated. Sorting out the indications and timing for 13 pneumococcal serotypes and 23 pneumococcal serotypes administration is complex and presents a significant challenge to healthcare providers. Here, we discuss the importance of pneumococcal vaccination for older adults, detail AMDA-The Society for Post-Acute and Long-Term Care Medicine (The Society)'s recommendations for pneumococcal vaccination practice and procedures, and offer guidance to postacute and long-term care providers supporting the development and effective implementation of pneumococcal vaccine policies.

Probiotics for Clostridium difficile infection in adults (PICO): Study protocol for a double-blind, randomized controlled trial.

BACKGROUND: Clostridium difficile is a pathogen of rapidly increasing public health importance. An estimated quarter of a million Clostridium difficile infections (CDI) occur in the United States annually, at a resultant cost of 14,000 deaths and 1 billion dollars. Clostridium difficile related deaths have risen 400% over the last decade, and current standard antibiotic treatments are only 75 to 85% successful. Besides increasing the risk of antibiotic resistance and side effects, these treatments are very expensive. The most vulnerable population for Clostridium difficile is older adults, who make up approximately half of the cases, but account for 90% of the related deaths. Probiotics may have potential as adjunctive therapeutic agents for CDIs, however, current data is limited. METHODS: This pilot study is a single-site, randomized, placebo-controlled, double-blind, phase two clinical trial. The trial primarily evaluates the effect of four weeks of probiotic therapy in addition to standard of care on Clostridium difficile diarrhea duration and recurrence. Secondary outcomes include effect on fecal cytokines, fecal lactoferrin, and Clostridium difficile toxin density in stool, as well as patient functional status. DISCUSSION: This pilot study will determine the feasibility and effect size to conduct larger randomized controlled trials of probiotic interventions in patients with CDI, to determine the impact of probiotics on the symptoms of CDI. ClinicalTrials.gov Identifier: NCT01680874.

Delirium and other clinical factors with Clostridium difficile infection that predict mortality in hospitalized patients.

BACKGROUND: Clostridium difficile infection (CDI) severity has increased, especially among hospitalized older adults. We evaluated clinical factors to predict mortality after CDI. METHODS: We collected data from inpatients diagnosed with CDI at a U.S. academic medical center (HSR-IRB#13630). We evaluated age, Charlson comorbidity index (CCI), whether patients were admitted from a long-term care facility, whether patients were in an intensive care unit (ICU) at the time of diagnosis, white blood cell count (WBC), blood urea nitrogen (BUN), low body mass index, and delirium as possible predictors. A parsimonious predictive model was chosen using the Akaike information criterion (AIC) and a best subsets model selection algorithm. The area under the receiver operating characteristic curve was used to assess the model's comparative, with the AIC as the selection criterion for all subsets to measure fit and control for overfitting. RESULTS: From the 362 subjects, the selected model included CCI, WBC, BUN, ICU, and delirium. The logistic regression coefficients were converted to a points scale and calibrated so that each unit on the CCI contributed 2 points, ICU admission contributed 5 points, each unit of WBC (natural log scale) contributed 3 points, each unit of BUN contributed 5 points, and delirium contributed 11 points.Our model shows substantial ability to predict short-term mortality in patients hospitalized with CDI. CONCLUSION: Patients who were diagnosed in the ICU and developed delirium are at the highest risk for dying within 30 days of CDI diagnosis.

Quantitative Fecal Lactoferrin as a Biomarker for Severe Clostridium difficile Infection in Hospitalized Patients.

BACKGROUND: The incidence and severity of Clostridium difficile infection (CDI) have increased over the past decade, especially among hospitalized patients. In this study, we determined the value of published criteria for severe CDI in predicting 3 month mortality, as well as the utility of fecal lactoferrin as a biomarker for severe CDI. METHODS: Pilot Year 1 of IRB approved (HSR-IRB# 13630) prospective cohort study of hospitalized patients with CDI at US academic medical center (10/08-4/10). Medical records of hospitalized patients with clinically diagnosed CDI, via toxin assay, were evaluated to objectively define severe CDI based on current guidelines. A stool sample from CDI diagnosis was analyzed for amount of fecal lactoferrin (IBD-SCAN, TechLab, Inc.). Data was analyzed using SPSS for student's t-test and chi-squared, significance p ≤ 0.05. RESULTS: 79 subjects consented and enrolled, mean age was 64 years (standard deviation, sd, 17.2), 48 (61%) female, and average Charlson co-morbidity score was 5.8 (sd 3.8). Subjects with severe CDI were 5 times more likely to die within 3 months of diagnosis (Odds Ratio 5.66 (95% Confidence Interval 2.03-15.79), p=0.001) and had significantly more fecal lactoferrin (580.0 (sd 989.0) vs. 181.7 (sd 244.2) µg/mL, p=0.018), compared to those that did not meet severe CDI criteria. CONCLUSION: In this pilot study, subjects who meet defined criteria for severe CDI had higher mortality and more intestinal inflammation. These preliminary results were, however, underpowered to show a direct association of lactoferrin with mortality. Larger cohort studies are needed to optimize a criterion for severe CDI and evaluate a direct association of lactoferrin and mortality in hospitalized patients with CDI.