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Purpose: Monotherapy with vancomycin or daptomycin remains guideline-based care for methicillin-resistant Staphylococcus aureus bacteremia (MRSA-B) despite concerns regarding efficacy. Limited data support potential benefit of combination therapy with ceftaroline as initial therapy. We present an assessment of outcomes of patients initiated on early combination therapy for MRSA-B., Methods: This was a single-center, retrospective study of adult patients admitted with MRSA-B between July 1, 2017 and April 31, 2023. During this period, there was a change in institutional practice from routine administration of monotherapy to initial combination therapy for most patients with MRSA-B. Combination therapy included vancomycin or daptomycin plus ceftaroline within 72 h of index blood culture and monotherapy was vancomycin or daptomycin alone. The primary outcome was a composite of persistent bacteremia, 30-day all-cause mortality, and 30-day bacteremia recurrence. Time to microbiological cure and safety outcomes were assessed. All outcomes were assessed using propensity score-weighted logistic regression., Results: Of 213 patients included, 118 received monotherapy (115 vancomycin, 3 daptomycin) and 95 received combination therapy with ceftaroline (76 vancomycin, 19 daptomycin). The mean time from MRSA-positive molecular diagnostic blood culture result to combination therapy was 12.1 h. There was no difference between groups for the primary composite outcome (OR 1.58, 95% CI 0.60, 4.18). Time to microbiological cure was longer with combination therapy (mean difference 1.50 days, 95% CI 0.60, 2.41). Adverse event rates were similar in both groups., Conclusions: Early initiation of ceftaroline-based combination therapy did not improve outcomes for patients with MRSA-B in comparison to monotherapy therapy., Competing Interests: Declarations. Ethics approval and consent to participate: The research protocol received an Exempt approval by the Institutional Review Board (IRB) for Health Sciences Research at the University of Virginia. Consent for publication: Not applicable. Competing interests: The authors declare no competing interests., (© 2025. The Author(s).)

Clostridioides difficile is a leading cause of healthcare associated infection and an unacceptably high proportion of patients with C. difficile infection die despite conventional antibiotic treatment. Host-directed immunotherapy has been proposed as an ideal treatment modality for C. difficile infection to mitigate the underlying toxin-mediated pathogenic immune response while sparing protective gut microbes. Interleukin-23 monoclonal antibody inhibitors are used extensively to control pro-inflammatory Th17 immune pathways in psoriasis and inflammatory bowel disease that are similarly important during C. difficile infection. We used a large retrospective electronic health record database to test the hypothesis that hospitalized patients with C. difficile infection who are on anti-IL-23 treatment will have improved survival compared to patients without anti-IL-23. 9,301 anti-IL-23 patients had significantly lower probability of all-cause death within 30 days (0.54%) compared with 1:1 propensity-matched control patients (3.1%). IL-23 inhibition is a promising adjunct to C. difficile treatment and further clinical trials repositioning anti-IL-23 monoclonal antibodies from psoriasis and inflammatory bowel disease to C. difficile infection are warranted.

Clostridioides difficile infection (CDI) recurs in one of five patients. Monoclonal antibodies targeting the virulence factor TcdB reduce disease recurrence, suggesting that an inadequate anti-TcdB response to CDI leads to recurrence. In patients with CDI, we discovered that IL-33 measured at diagnosis predicts future recurrence, leading us to test the role of IL-33 signaling in the induction of humoral immunity during CDI. Using a mouse recurrence model, IL-33 was demonstrated to be integral for anti-TcdB antibody production. IL-33 acted via ST2+ ILC2 cells, facilitating germinal center T follicular helper (GC-Tfh) cell generation of antibodies. IL-33 protection from reinfection was antibody-dependent, as μMT KO mice and mice treated with anti-CD20 mAb were not protected. These findings demonstrate the critical role of IL-33 in generating humoral immunity to prevent recurrent CDI.

Background: Clostridioides difficile infection results in life-threatening short-term outcomes and the potential for subsequent recurrent infection. Predicting these outcomes at diagnosis, when important clinical decisions need to be made, has proven to be a difficult task., Methods: 52 clinical features from existing models or the literature were collected retrospectively within ±48 h of diagnosis among 1660 inpatient infections. A modified desirability of outcome ranking (DOOR) was designed to encompass clinically-important severe events attributable to the acute infection (intensive care transfer due to sepsis, shock, colectomy/ileostomy, mortality) and/or 60-day recurrence. A deep neural network was constructed and interpreted using SHapley Additive exPlanations (SHAP). High-importance features were used to train a reduced, shallow network and performance was compared to existing conventional models (7 severity, 7 recurrence; after summing DOOR probabilities to align with conventional binary outputs) using area under the ROC curve (AUROC) and DeLong tests., Findings: The full (52-feature) model achieved an out-of-sample AUROC 0.823 for severity and 0.678 for recurrence. SHAP identified 13 unique, highly-important features (age, hypotension, initial treatment, onset, PCR cycle threshold, number of prior episodes, antibiotic exposure, fever, hypotension, pressors, leukocytosis, creatinine, lactate) that were used to train a reduced model, which performed similarly to the full model (severity AUROC difference P = 0.130; recurrence P = 0.426) and significantly better than the top severity model (reduced model predicting severity 0.837, ATLAS 0.749; P = 0.001). The reduced model also outperformed the top recurrence model, but this was not statistically-significant (reduced model recurrence AUROC 0.653, IDSA Recurrence Risk Criteria 0.595; P = 0.196). The final, reduced model was deployed as a web application with real-time SHAP explanations., Interpretation: Our final model outperformed existing severity and recurrence models; however, it requires external validation. A DOOR output allows specific clinical questions to be asked with explainable predictions that can be feasibly implemented with limited computing resources., Funding: National Institutes of Health-Institute of Allergy and Infectious Diseases., Competing Interests: Declaration of interests This work was funded by National Institutes of Health (K23AI163368 to G.R.M., R01-AI152477 and -AI124214 (to W.A.P.), 5T32AI055432-20 to R.H.B) and National Center for Advancing Translational Science (UL1TR003015, KL2TR003016 to G.R.M.). W. A. Petri is a consultant for TechLab Inc., a company that manufactures diagnostic tests for C. difficile toxins. All other authors report no conflicts of interest relevant to this article., (Copyright © 2024 The Author(s). Published by Elsevier B.V. All rights reserved.)

Healthcare-associated infections (HAIs) due to multi-drug resistant organisms (MDROs) are a significant burden to the healthcare system. Patients are sometimes already infected at the time of admission to the hospital (referred to as "importation"), and additional patients might get infected in the hospital through transmission ("nosocomial infection"). Since many of these importation and nosocomial infection cases may present no symptoms (i.e., "asymptomatic"), rapidly identifying them is difficult since testing is limited and incurs significant delays. Although there has been a lot of work on examining the utility of both mathematical models of transmission and machine learning for identifying patients at risk of MDRO infections in recent years, these methods have limited performance and suffer from different drawbacks: Transmission modeling-based methods do not make full use of rich data contained in electronic health records (EHR), while machine learning-based methods typically lack information about mechanistic processes. In this work, we propose NEURABM, a new framework which integrates both neural networks and agent-based models (ABM) to combine the advantages of both modeling-based and machine learning-based methods. NEURABM simultaneously learns a neural network model for patient-level prediction of importation, as well as the ABM model which is used for identifying infections. Our results demonstrate that NEURABM identifies importation and nosocomial infection cases more accurately than existing methods.

Objective: To evaluate the economic costs of reducing the University of Virginia Hospital's present "3-negative" policy, which continues methicillin-resistant Staphylococcus aureus (MRSA) contact precautions until patients receive 3 consecutive negative test results, to either 2 or 1 negative., Design: Cost-effective analysis., Settings: The University of Virginia Hospital., Patients: The study included data from 41,216 patients from 2015 to 2019., Methods: We developed a model for MRSA transmission in the University of Virginia Hospital, accounting for both environmental contamination and interactions between patients and providers, which were derived from electronic health record (EHR) data. The model was fit to MRSA incidence over the study period under the current 3-negative clearance policy. A counterfactual simulation was used to estimate outcomes and costs for 2- and 1-negative policies compared with the current 3-negative policy., Results: Our findings suggest that 2-negative and 1-negative policies would have led to 6 (95% CI, -30 to 44; P < .001) and 17 (95% CI, -23 to 59; -10.1% to 25.8%; P < .001) more MRSA cases, respectively, at the hospital over the study period. Overall, the 1-negative policy has statistically significantly lower costs ($628,452; 95% CI, $513,592-$752,148) annually ( P < .001) in US dollars, inflation-adjusted for 2023) than the 2-negative policy ($687,946; 95% CI, $562,522-$812,662) and 3-negative ($702,823; 95% CI, $577,277-$846,605)., Conclusions: A single negative MRSA nares PCR test may provide sufficient evidence to discontinue MRSA contact precautions, and it may be the most cost-effective option.

Late anti-toxin-B humoral immunity acquired after treatment is important for preventing recurrent Clostridioides difficile infection. We prospectively-measured anti-toxin-B IgG and neutralization titers at diagnosis as potential early predictors of recurrence. High anti-toxin-B-IgG/neutralizing antibodies were associated with short-lasting protection within 6-weeks, however, no difference in recurrence risk was observed by 90-days post-infection., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: William A. Petri Jr is a consultant for TechLab, a company that makes diagnostics for C. difficile. The other authors declare no conflicts of interest., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Objectives: Clostridioides difficile infection (CDI) is characterized by neutrophilia in blood, with a high leukocyte count accompanying severe infection. In this study, we characterized peripheral blood neutrophil activation and maturity in CDI by (i) developing a method to phenotype stored neutrophils for disease-related developmental alterations and (ii) assessing neutrophil-associated biomarkers., Methods: We stored fixed leukocytes from blood collected within 24 h of diagnosis from a cohort of hospitalized patients with acute CDI. Additional study cohorts included recurrent CDI patients at time of and two months after FMT therapy and a control healthy cohort. We assessed levels of neutrophil surface markers CD66b, CD11b, CD16 and CD10 by flow cytometry. Plasma neutrophil elastase and lipocalin-2 were measured using ELISA, while G-CSF, GM-CSF and cytokines were measured using O-link Proteomic technology., Results: CD66b + neutrophil abundance assessed by flow cytometry correlated well with complete blood counts, establishing that neutrophils in stored blood are sufficiently well-preserved for phenotyping by flow cytometry. Neutrophil abundance was significantly increased in CDI patients compared to healthy controls. Emergency granulopoiesis in acute CDI patients was evidenced by lower neutrophil surface expression of CD10, CD11b and CD16. CD10 + staining of neutrophils started to recover within 3-7 days of CDI treatment. Neutrophil activation and degranulation were higher in acute CDI as assessed by plasma neutrophil elastase and lipocalin-2. Biomarker levels in immunocompetent subjects were associated with recurrence and fatal outcomes., Conclusions: Neutrophil activation and emergency granulopoiesis characterize the early immune response in acute CDI, with plasma degranulation biomarkers predictive of disease severity., Competing Interests: Declaration of competing interest WAP has a conflict of interest in that he is a consultant for TechLab, Inc, which makes diagnostic tests for C. difficile infection. The other authors have no conflicts of interest to disclose., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Objective: We sought to validate available tools for predicting recurrent C. difficile infection (CDI) including recurrence risk scores (by Larrainzar-Coghen, Reveles, D'Agostino, Cobo, and Eyre et al ) alongside consensus guidelines risk criteria, the leading severity score (ATLAS), and PCR cycle threshold (as marker of fecal organism burden) using electronic medical records., Design: Retrospective cohort study validating previously described tools., Setting: Tertiary care academic hospital., Patients: Hospitalized adult patients with CDI at University of Virginia Medical Center., Methods: Risk scores were calculated within ±48 hours of index CDI diagnosis using a large retrospective cohort of 1,519 inpatient infections spanning 7 years and compared using area under the receiver operating characteristic curve (AUROC) and the DeLong test. Recurrent CDI events (defined as a repeat positive test or symptom relapse within 60 days requiring retreatment) were confirmed by clinician chart review., Results: Reveles et al tool achieved the highest AUROC of 0.523 (and 0.537 among a subcohort of 1,230 patients with their first occurrence of CDI), which was not substantially better than other tools including the current IDSA/SHEA C. difficile guidelines or PCR cycle threshold (AUROC: 0.564), regardless of prior infection history., Conclusions: All tools performed poorly for predicting recurrent C. difficile infection (AUROC range: 0.488-0.564), especially among patients with a prior history of infection (AUROC range: 0.436-0.591). Future studies may benefit from considering novel biomarkers and/or higher-dimensional models that could augment or replace existing tools that underperform.

Clostridioides difficile infection (CDI) is responsible for around 300,000 hospitalizations yearly in the United States, with the associated monetary cost being billions of dollars. Gut microbiome dysbiosis is known to be important to CDI. To the best of our knowledge, metatranscriptomics (MT) has only been used to characterize gut microbiome composition and function in one prior study involving CDI patients. Therefore, we utilized MT to investigate differences in active community diversity and composition between CDI+ ( n  = 20) and CDI- ( n  = 19) samples with respect to microbial taxa and expressed genes. No significant (Kruskal-Wallis, p  > 0.05) differences were detected for richness or evenness based on CDI status. However, clustering based on CDI status was significant for both active microbial taxa and expressed genes datasets (PERMANOVA, p  ≤ 0.05). Furthermore, differential feature analysis revealed greater expression of the opportunistic pathogens Enterocloster bolteae and Ruminococcus gnavus in CDI+ compared to CDI- samples. When only fungal sequences were considered, the family Saccharomycetaceae expressed more genes in CDI-, while 31 other fungal taxa were identified as significantly (Kruskal-Wallis p  ≤ 0.05, log(LDA) ≥ 2) associated with CDI+. We also detected a variety of genes and pathways that differed significantly (Kruskal-Wallis p  ≤ 0.05, log(LDA) ≥ 2) based on CDI status. Notably, differential genes associated with biofilm formation were expressed by C. difficile . This provides evidence of another possible contributor to C. difficile 's resistance to antibiotics and frequent recurrence in vivo . Furthermore, the greater number of CDI+ associated fungal taxa constitute additional evidence that the mycobiome is important to CDI pathogenesis. Future work will focus on establishing if C. difficile is actively producing biofilms during infection and if any specific fungal taxa are particularly influential in CDI., Competing Interests: JC, JL, JW and RL was employed by Wright Labs LLC. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Chen See, Leister, Wright, Kruse, Khedekar, Besch, Kumamoto, Madden, Stewart and Lamendella.)

Purpose: Monotherapy with vancomycin or daptomycin remains guideline-based care for methicillin-resistant Staphylococcus aureus bacteremia (MRSA-B) despite concerns regarding efficacy. Limited data support potential benefit of combination therapy with ceftaroline as initial therapy. We present an assessment of outcomes of patients initiated on early combination therapy for MRSA-B., Methods: This was a single-center, retrospective study of adult patients admitted with MRSA-B between July 1, 2017 and April 31, 2023. During this period, there was a change in institutional practice from routine administration of monotherapy to initial combination therapy for most patients with MRSA-B. Combination therapy included vancomycin or daptomycin plus ceftaroline within 72 hours of index blood culture and monotherapy was vancomycin or daptomycin alone. The primary outcome was a composite of persistent bacteremia, 30-day all-cause mortality, and 30-day bacteremia recurrence. Time to microbiological cure and safety outcomes were assessed. All outcomes were assessed using propensity score-weighted logistic regression., Results: Of 213 patients included, 118 received monotherapy (115 vancomycin, 3 daptomycin) and 95 received combination therapy with ceftaroline (76 vancomycin, 19 daptomycin). The mean time from MRSA-positive molecular diagnostic blood culture result to combination therapy was 12.1 hours. There was no difference between groups for the primary composite outcome (OR 1.58, 95% CI 0.60, 4.18). Time to microbiological cure was longer with combination therapy (mean difference 1.50 days, 95% CI 0.60, 2.41). Adverse event rates were similar in both groups., Conclusions: Early initiation of ceftaroline-based combination therapy did not improve outcomes for patients with MRSA-B in comparison to monotherapy therapy., Competing Interests: Declarations Competing Interests The authors declare that they have no competing interests.

Objective: Evaluate potential risk factors for severe coronavirus disease 2019 (COVID-19) among health care workers (HCWs) at the University of Virginia Medical Center in Charlottesville, Virginia., Methods: We conducted a retrospective manual chart review of data from HCWs who were diagnosed with COVID-19 from March 2020 to March 2021. Using data from patient medical histories, we ascertained risk factors for COVID-19-related emergency department encounter, hospitalization, or death., Results: We had 634 patients in total, and 9.8% had a severe COVID-19-related outcome. A history of deep vein thrombosis/pulmonary embolism/stroke (odds ratio, 19.6; 95% confidence interval, 5.11 to 94.7), as well as asthma, chronic lung disease, diabetes, or current immunocompromised status, was associated with increased adjusted odds of COVID-19-related emergency department encounter/hospitalization/death., Conclusions: A preexisting history of deep vein thrombosis/pulmonary embolism/stroke is a novel risk factor for poor COVID-19 outcomes among a cohort of HCWs., Competing Interests: Conflict of interest: L.F.O. reports that she has an immediate family member who is employed by and has stock/stock options in PLX Pharma. L.F.O. does not have any personal or direct financial stakes in PLX Pharma. G.R.M., D.S., D.C.C., and J.C.E. do not report any conflicts of interest., (Copyright © 2023 American College of Occupational and Environmental Medicine.)

Traditional clinical models for predicting recurrent Clostridioides difficile infection do not perform well, likely owing to the complex host-pathogen interactions involved. Accurate risk stratification using novel biomarkers could help prevent recurrence by improving underutilization of effective therapies (i.e., fecal transplant, fidaxomicin, bezlotoxumab). We used a biorepository of 257 hospitalized patients with 24 features collected at diagnosis, including 17 plasma cytokines, total/neutralizing anti-toxin B IgG, stool toxins, and PCR cycle threshold ( C T ) (a proxy for stool organism burden). The best set of predictors for recurrent infection was selected by Bayesian model averaging for inclusion in a final Bayesian logistic regression model. We then used a large PCR-only data set to confirm the finding that PCR C T predicts recurrence-free survival using Cox proportional hazards regression. The top model-averaged features were (probabilities of >0.05, greatest to least): interleukin 6 (IL-6), PCR C T , endothelial growth factor, IL-8, eotaxin, IL-10, hepatocyte growth factor, and IL-4. The accuracy of the final model was 0.88. Among 1,660 cases with PCR-only data, cycle threshold was significantly associated with recurrence-free survival (hazard ratio, 0.95; P <  0.005). Certain biomarkers associated with C. difficile infection severity were especially important for predicting recurrence; PCR C T and markers of type 2 immunity (endothelial growth factor [EGF], eotaxin) emerged as positive predictors of recurrence, while type 17 immune markers (IL-6, IL-8) were negative predictors. In addition to novel serum biomarkers (particularly, IL-6, EGF, and IL-8), the readily available PCR C T may be critical to augment underperforming clinical models for C. difficile recurrence.

Clostridioides difficile is the leading health care-associated pathogen, leading to substantial morbidity and mortality; however, there is no widely accepted model to predict C. difficile infection severity. Most currently available models perform poorly or were calibrated to predict outcomes that are not clinically relevant. We sought to validate six of the leading risk models (Age Treatment Leukocyte Albumin Serum Creatinine (ATLAS), C. difficile Disease (CDD), Zar, Hensgens, Shivashankar, and C. difficile Severity Score (CDSS)), guideline severity criteria, and PCR cycle threshold for predicting C. difficile-attributable severe outcomes (inpatient mortality, colectomy/ileostomy, or intensive care due to sepsis). Models were calculated using electronic data available within ±48 h of diagnosis (unavailable laboratory measurements assigned zero points), calibrated using a large retrospective cohort of 3,327 inpatient infections spanning 10 years, and compared using receiver operating characteristic (ROC) and precision-recall curves. ATLAS achieved the highest area under the ROC curve (AuROC) of 0.781, significantly better than the next best performing model (Zar 0.745; 95% confidence interval of AuROC difference 0.0094-0.6222; P =  0.008), and highest area under the precision-recall curve of 0.232. Current IDSA/SHEA severity criteria demonstrated moderate performance (AuROC 0.738) and PCR cycle threshold performed the worst (0.531). The overall predictive value for all models was low, with a maximum positive predictive value of 37.9% (ATLAS cutoff ≥9). No clinical model performed well on external validation, but ATLAS did outperform other models for predicting clinically relevant C. difficile - attributable outcomes at diagnosis. Novel markers should be pursued to augment or replace underperforming clinical-only models.

This case series and propensity-matched cohort study on the use of tigecycline in Clostridioides difficile infection (CDI) evaluated the effect of tigecycline on 30-day mortality. Adjusted for ATLAS Score, hypotension, treatment time period, and serum lactate, tigecycline did not significantly improve 30-day mortality (odds ratio: 0.89; 95% confidence interval: 0.25-3.12; P =  0.853). A randomized controlled trial is needed to determine efficacy and safety of tigecycline in severe or refractory CDI.

The COVID-19 pandemic caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is an unprecedented event requiring frequent adaptation to changing clinical circumstances. Convalescent immune plasma (CIP) is a promising treatment that can be mobilized rapidly in a pandemic setting. We tested whether administration of SARS-CoV-2 CIP at hospital admission could reduce the rate of ICU transfer or 28-day mortality or alter levels of specific antibody responses before and after CIP infusion. In a single-arm phase II study, patients >18 years-old with respiratory symptoms with confirmed COVID-19 infection who were admitted to a non-ICU bed were administered two units of CIP within 72 h of admission. Levels of SARS-CoV-2 detected by PCR in the respiratory tract and circulating anti-SARS-CoV-2 antibody titers were sequentially measured before and after CIP transfusion. Twenty-nine patients were transfused high titer CIP and 48 contemporaneous comparable controls were identified. All classes of antibodies to the three SARS-CoV-2 target proteins were significantly increased at days 7 and 14 post-transfusion compared with baseline ( P  < 0.01). Anti-nucleocapsid IgA levels were reduced at day 28, suggesting that the initial rise may have been due to the contribution of CIP. The groups were well-balanced, without statistically significant differences in demographics or co-morbidities or use of remdesivir or dexamethasone. In participants transfused with CIP, the rate of ICU transfer was 13.8% compared to 27.1% for controls with a hazard ratio 0.506 (95% CI 0.165-1.554), and 28-day mortality was 6.9% compared to 10.4% for controls, hazard ratio 0.640 (95% CI 0.124-3.298). IMPORTANCE Transfusion of high-titer CIP to non-critically ill patients early after admission with COVID-19 respiratory disease was associated with significantly increased anti-SARS-CoV-2 specific antibodies (compared to baseline) and a non-significant reduction in ICU transfer and death (compared to controls). This prospective phase II trial provides a suggestion that the antiviral effects of CIP from early in the COVID-19 pandemic may delay progression to critical illness and death in specific patient populations. This study informs the optimal timing and potential population of use for CIP in COVID-19, particularly in settings without access to other interventions, or in planning for future coronavirus pandemics.

Background: The incidence of Clostridioides difficile infection (CDI) has increased over the past 2 decades and is considered an urgent threat by the Centers for Disease Control and Prevention. Hypervirulent strains such as ribotype 027, which possess genes for the additional toxin C. difficile binary toxin (CDT), are contributing to increased morbidity and mortality., Methods: We retrospectively tested stool from 215 CDI patients for CDT by enzyme-linked immunosorbent assay (ELISA). Stratifying patients by CDT status, we assessed if disease severity and clinical outcomes correlated with CDT positivity. Additionally, we completed quantitative PCR (PCR) DNA extracted from patient stool to detect cdtB gene. Lastly, we performed 16 S rRNA gene sequencing to examine if CDT-positive samples had an altered fecal microbiota., Results: We found that patients with CdtB, the pore-forming component of CDT, detected in their stool by ELISA, were more likely to have severe disease with higher 90-day mortality. CDT-positive patients also had higher C. difficile bacterial burden and white blood cell counts. There was no significant difference in gut microbiome diversity between CDT-positive and -negative patients., Conclusions: Patients with fecal samples that were positive for CDT had increased disease severity and worse clinical outcomes. Utilization of PCR and testing for C. difficile toxins A and B may not reveal the entire picture when diagnosing CDI; detection of CDT-expressing strains is valuable in identifying patients at risk of more severe disease., (© The Author(s) 2022. Published by Oxford University Press on behalf of Infectious Diseases Society of America.)

Rationale: The COVID-19 pandemic caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is an unprecedented event requiring rapid adaptation to changing clinical circumstances. Convalescent immune plasma (CIP) is a promising treatment that can be mobilized rapidly in a pandemic setting., Objectives: We tested whether administration of SARS-CoV-2 CIP at hospital admission could reduce the rate of ICU transfer or 28 day mortality., Methods: In a single-arm phase II study, patients >18 years-old with respiratory symptoms documented with COVID-19 infection who were admitted to a non-ICU bed were administered two units of CIP within 72 hours of admission. Detection of respiratory tract SARS-CoV-2 by polymerase chain reaction and circulating anti-SARS-CoV-2 antibody titers were measured before and at time points after CIP transfusion., Measurements and Main Results: Twenty-nine patients were transfused CIP and forty-eight contemporaneous controls were identified with comparable baseline characteristics. Levels of anti-SARS-CoV-2 IgG, IgM, and IgA anti-spike, anti-receptor-binding domain, and anti-nucleocapsid significantly increased from baseline to post-transfusion for all proteins tested. In patients transfused with CIP, the rate of ICU transfer was 13.8% compared to 27.1% for controls with a hazard ratio 0.506 (95% CI 0.165-1.554), and 28-day mortality was 6.9% compared to 10.4% for controls, hazard ratio 0.640 (95% CI 0.124-3.298)., Conclusions: Transfusion of high-titer CIP to patients early after admission with COVID-19 respiratory disease was associated with reduced ICU transfer and 28-day mortality but was not statistically significant. Follow up randomized trials may inform the use of CIP for COVID-19 or future coronavirus pandemics.

Background: Proper hand hygiene (HH) practices have been shown to reduce healthcare-acquired infections. Several potential challenges in low-income countries might limit the feasibility of effective HH, including preexisting knowledge gaps and staffing., Aim: We sought to evaluate the feasibility of the implementation of effective HH practice at a teaching hospital in Rwanda., Methods: We conducted a prospective quality improvement project in the intensive care unit (ICU) at the Kigali University Teaching Hospital. We collected data before and after an intervention focused on HH adherence as defined by the World Health Organization '5 Moments for Hand Hygiene' and assuring availability of HH supplies. Pre-intervention data were collected throughout July 2019, and HH measures were implemented in August 2019. Post-implementation data were collected following a 3-month wash-in., Results: In total, 902 HH observations were performed to assess pre-intervention adherence and 903 observations post-intervention adherence. Overall, HH adherence increased from 25% (222 of 902 moments) before intervention to 75% (677 of 903 moments) after intervention ( P < 0.001). Improvement was seen among all health professionals (nurses: 19-74%, residents: 23-74%, consultants: 29-76%)., Conclusions: Effective HH measures are feasible in an ICU in a low-income country. Ensuring availability of supplies and training appears key to effective HH practices., Competing Interests: The authors report no conflicts of interest. This work was supported by the UVA Global Infectious Diseases Institute, National Institutes of Health Center for Advancing Translational Science (UL1TR003015/KL2TR003016), and National Institute Of Allergy And Infectious Diseases (K23AI163368).

Background: Clostridioides difficile is the leading health care-associated pathogen, but clinicians lack a test that can reliably differentiate colonization from infection. Health care costs attributed to C. difficile are substantial, but the economic burden associated with C. difficile false positives is poorly understood., Methods: A propensity score matching model for cost per hospitalization was developed to estimate the costs of both true infection and false positives. Predictors of C. difficile positivity used to estimate the propensity score were age, Charlson comorbidity index, white cell count, and creatinine. We used polymerase chain reaction (PCR) cycle threshold to identify and compare 3 groups: (1) true infection, (2) C. difficile colonization, and (3) C. difficile negative., Results: A positive test was associated with $3018 higher unadjusted hospital cost. Among the 3 comparisons made with propensity-matched negative controls (all positives [+$179; P = .934], true positives [-$1892; P = .100], and colonized positives), only colonization was associated with significantly increased (+$3418; P = .012) cost. Differences in lengths of stay (all positives 0 days, P = .126; true 0 days, P = .919; colonized 1 day, P = .019) appeared to underly cost differences., Conclusions: In the first C. difficile cost analysis to utilize PCR cycle threshold to differentiate colonization, we found high propensity-matched hospital costs associated with colonized but not true positives. This unexpected finding may be due to misdiagnosis of non- C. difficile diarrhea or unadjusted factors associated with colonization., (© The Author(s) 2020. Published by Oxford University Press on behalf of Infectious Diseases Society of America.)

There is a pressing need for biomarker-based models to predict mortality from and recurrence of Clostridioides difficile infection (CDI). Risk stratification would enable targeted interventions such as fecal microbiota transplant, antitoxin antibodies, and colectomy for those at highest risk. Because severity of CDI is associated with the immune response, we immune profiled patients at the time of diagnosis. The levels of 17 cytokines in plasma were measured in 341 CDI inpatients. The primary outcome of interest was 90-day mortality. Increased tumor necrosis factor alpha (TNF-α), interleukin 6 (IL-6), C-C motif chemokine ligand 5 (CCL-5), suppression of tumorigenicity 2 receptor (sST-2), IL-8, and IL-15 predicted mortality by univariate analysis. After adjusting for demographics and clinical characteristics, the mortality risk (as indicated by the hazard ratio [HR]) was higher for patients in the top 25th percentile for TNF-α (HR = 8.35, P = 0.005) and IL-8 (HR = 4.45, P = 0.01) and lower for CCL-5 (HR = 0.18, P  ≤ 0.008). A logistic regression risk prediction model was developed and had an area under the receiver operating characteristic curve (AUC) of 0.91 for 90-day mortality and 0.77 for 90-day recurrence. While limited by being single site and retrospective, our work resulted in a model with a substantially greater predictive ability than white blood cell count. In conclusion, immune profiling demonstrated differences between patients in their response to CDI, offering the promise for precision medicine individualized treatment. IMPORTANCE Clostridioides difficile infection is the most common health care-associated infection in the United States with more than 20% patients experiencing symptomatic recurrence. The complex nature of host-bacterium interactions makes it difficult to predict the course of the disease based solely on clinical parameters. In the present study, we built a robust prediction model using representative plasma biomarkers and clinical parameters for 90-day all-cause mortality. Risk prediction based on immune biomarkers and clinical variables may contribute to treatment selection for patients as well as provide insight into the role of immune system in C. difficile pathogenesis., (Copyright © 2020 Abhyankar et al.)

Background: Overtesting and overdiagnosis of Clostridioides difficile infection are suspected to be common. Reducing inappropriate testing through interventions designed to promote evidence-based diagnostic testing (ie, diagnostic stewardship) may improve C. difficile test utilization. However, the safety of these interventions is not well understood despite the potential risk for missed or delayed diagnoses., Methods: This retrospective case-control study examined the outcomes of patients admitted to the University of Virginia Medical Center following introduction of a computerized clinical decision support tool without hard-stops designed to reduce inappropriate tests. Outcomes were compared between patients with a prevented C. difficile nucleic acid amplification test and those with a negative result. Chart reviews were performed for patients with a subsequent positive within 7 days, as well as those patients who received C. difficile -active antibiotics after implementation of the computerized clinical decision support tool., Results: Multivariate analysis of 637 cases (490 negative, 147 prevented) showed that a prevented test was not significantly associated with the primary composite outcome (inpatient mortality or intensive care unit transfer) compared with a negative test (adjusted odds ratio, 0.912; P  = .747). Fifty-four of 147 (37%) prevented tests were followed by a completed test within 7 days; 11 of these results were positive, resulting in a potential delay in diagnosis. Individual case reviews found that either clinical changes warranted the delay in testing or no adverse events occurred attributable to C. difficile infection. C. difficile treatment without a positive test was not identified., Conclusions: Diagnostic stewardship of C. difficile testing using computerized clinical decision support may be both safe and effective for reducing inappropriate inpatient testing., (© The Author(s) 2020. Published by Oxford University Press on behalf of Infectious Diseases Society of America.)

We report a case of Entamoeba histolytica infection in a young man who presented with cerebral infarction and shortly after admission developed bloody diarrhea with fever. A rapid diagnosis of severe E. histolytica colitis was established through the use of a multiplex polymerase chain reaction enteropathogen stool panel. This result was unexpected in a patient native to the United States without known risk factors for amebiasis and negative stool microscopy examination for ova and parasites. Rapid diagnosis allowed prompt initiation of appropriate anti-amebic therapy and ultimately a good outcome in a condition that otherwise carries high morbidity and fatality.

We report a case of human immunodeficiency virus (HIV)-associated vacuolar encephalomyelopathy with progressive central nervous system dysfunction and corresponding vacuolar degeneration of the spinal cord, cranial nerves, and brain, the anatomic extent of which has not previously been described., (Published by Oxford University Press on behalf of Infectious Diseases Society of America 2019.)

Background: We report a case of prosthetic hip joint infection in a heart transplant recipient due to Anaerobiospirillum succiniciproducens, a genus of spiral-shaped curved anaerobic gram-negative rod which colonizes the gastrointestinal tract of cats and dogs. Invasive infections in humans are rare and typically occur in immunocompromised hosts., Case Presentation: A 65-year-old male dog breeder with a history of rheumatoid arthritis, bilateral hip arthroplasties, and non-ischemic cardiomyopathy with a heart transplant 10 years ago presented with a three month history of progressive left hip pain and frank purulence on hip aspiration. He underwent irrigation and debridement of the left hip and one-stage revision with hardware exchange. Although gram stain and culture from synovial fluid and intraoperative cultures were initially negative, anaerobic cultures from tissue specimens later grew a spiral-shaped gram-negative rod, identified as Anaerobiospirillum spp. by 16S rRNA gene sequencing. The patient was treated with ceftriaxone 2 g daily for 6 weeks with a good response to treatment. A similar organism was unable to be isolated from culture of 2 of the patient's dogs, however, they were thought to be the most likely source of his infection., Conclusion: Anaerobiospirillum spp. should be considered in immunocompromised patients with exposure to dogs or cats who present with bacteremia, gastrointestinal infection, pyomyositis, or prosthetic joint infections, especially in cases of culture-negative or with anaerobic culture growth.

BACKGROUND Clostridioides difficile infection (CDI) is a frequent complication of solid organ transplantation, especially in the early post-transplantation period. Overdiagnosis of CDI is likely common in hospitals using nucleic acid amplification testing (NAAT), potentially leading to unnecessary iatrogenesis and cost. Recently, multiple studies have shown that computerized clinical decision support (CCDS)-based interventions can significantly reduce inappropriate C. difficile testing and healthcare facility-onset CDI events across hospitals and health systems. We aimed to determine if a CCDS-based intervention could reduce C. difficile testing and surveillance infection events among recent solid organ transplant recipients, a population at high risk for CDI. We also sought to determine the safety of the CCDS intervention. MATERIAL AND METHODS Quasi-experimental census-adjusted interrupted time-series analyses were performed retrospectively to examine testing and CDI events pre- and post-intervention. Mortality and readmissions rates were also examined. RESULTS A significant 33% relative reduction in tests and a nonsignificant trend towards fewer CDI events were observed following the intervention, without significant differences in mortality or 30-day readmission. A review of patients with positive C. difficile NAATs after prevented tests revealed no specific adverse events attributable to a possible delay in CDI diagnosis. CONCLUSIONS CCDS may be a helpful and safe adjunctive strategy to reduce unnecessary testing in accordance with guideline recommendations among solid organ transplant recipients.

Copper-impregnated surfaces and linens have been shown to reduce infections and multidrug-resistant organism (MDRO) acquisition in healthcare settings. However, retrospective analyses of copper linen deployment at a 40-bed long-term acute-care hospital demonstrated no significant reduction in incidences of healthcare facility-onset Clostridium difficile infection or MDRO acquisition.

Purpose of Review: Chlorhexidine gluconate (CHG) and mupirocin are increasingly used for Staphylococcus aureus decolonization to prevent healthcare-associated infections; however, increased use of these agents has led to concerns for growing resistance and reduced efficacy. In this review, we describe current understanding of reduced susceptibility to CHG and mupirocin in S. aureus and their potential clinical implications., Recent Findings: While emergence of S. aureus tolerant or resistant to topical antimicrobial agents used for decolonization is well described, the clinical impact of reduced susceptibility is not clear. Important challenges are that standardized methods of resistance testing and interpretation are not established, and the risk for selection for co- or cross-resistance using universal, as opposed to targeted decolonization, is unclear. Evidence continues to support S. aureus decolonization in certain patient groups, although further studies are needed to determine the long-term impact of CHG and mupirocin resistance on efficacy. Strategies to mitigate further development of reduced susceptibility and the consequences of selection pressures through universal decolonization on resistance will benefit from further investigation.

We hypothesized that a computerized clinical decision support tool for Clostridium difficile testing would reduce unnecessary inpatient tests, resulting in fewer laboratory-identified events. Census-adjusted interrupted time-series analyses demonstrated significant reductions of 41% fewer tests and 31% fewer hospital-onset C. difficile infection laboratory-identified events following this intervention.Infect Control Hosp Epidemiol 2018;39:737-740.

Pseudo-atrial flutter is an EKG artifact that mimics a true atrial flutter. We report a case of pseudo-atrial flutter in a 67-year-old male with quadriplegia and ventilator dependence due to amyotrophic lateral sclerosis (ALS) who was hospitalized for respite care. Ihe pseudo-atrial flutterwas found to be due to percussions from a built-in chest wall percussion device in a hospital mattress used for chest physiotherapy.

Mechanical stimulation of osteoblasts activates many cellular mechanisms including the release of ATP. Binding of ATP to purinergic receptors is key to load-induced osteogenesis. Osteoblasts also respond to fluid shear stress (FSS) with increased actin stress fiber formation (ASFF) that we postulate is in response to activation of the P2Y2 receptor (P2Y2R). Furthermore, we predict that ASFF increases cell stiffness and reduces the sensitivity to further mechanical stimulation. We found that small interfering RNA (siRNA) suppression of P2Y2R attenuated ASFF in response to FSS and ATP treatment. In addition, RhoA GTPase was activated within 15 min after the onset of FSS or ATP treatment and mediated ASFF following P2Y2R activation via the Rho kinase (ROCK)1/LIM kinase 2/cofilin pathway. We also observed that ASFF in response to FSS or ATP treatment increased the cell stiffness and was prevented by knocking down P2Y2R. Finally, we confirmed that the enhanced cell stiffness and ASFF in response to RhoA GTPase activation during FSS drastically reduced the mechanosensitivity of the osteoblasts based on the intracellular Ca(2+) concentration ([Ca(2+)]i) response to consecutive bouts of FSS. These data suggest that osteoblasts can regulate their mechanosensitivity to continued load through P2Y2R activation of the RhoA GTPase signaling cascade, leading to ASFF and increased cell stiffness., (Copyright © 2014 the American Physiological Society.)