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Background: Clostridioides difficile infection (CDI) may be misdiagnosed if testing is performed in the absence of signs or symptoms of disease. This study sought to support appropriate testing by estimating the impact of signs, symptoms, and healthcare exposures on pre-test likelihood of CDI., Methods: A panel of fifteen experts in infectious diseases participated in a modified UCLA/RAND Delphi study to estimate likelihood of CDI. Consensus, defined as agreement by >70% of panelists, was assessed via a REDCap survey. Items without consensus were discussed in a virtual meeting followed by a second survey., Results: All fifteen panelists completed both surveys (100% response rate). In the initial survey, consensus was present on 6 of 15 (40%) items related to risk of CDI. After panel discussion and clarification of questions, consensus (>70% agreement) was reached on all remaining items in the second survey. Antibiotics were identified as the primary risk factor for CDI and grouped into three categories: high-risk (likelihood ratio [LR] 7, 93% agreement among panelists in first survey), low-risk (LR 3, 87% agreement in first survey), and minimal-risk (LR 1, 71% agreement in first survey). Other major factors included new or unexplained severe diarrhea (e.g., ≥ 10 liquid bowel movements per day; LR 5, 100% agreement in second survey) and severe immunosuppression (LR 5, 87% agreement in second survey)., Conclusion: Infectious disease experts concurred on the importance of signs, symptoms, and healthcare exposures for diagnosing CDI. The resulting risk estimates can be used by clinicians to optimize CDI testing and treatment., Competing Interests: All authors report no conflicts of interest related to this article. The findings and conclusions in this manuscript are those of the authors and do not necessarily represent the official position of the U.S. Centers for Disease Control and Prevention., (© The Author(s) 2024.)

Background: The 2021 update to the Infectious Diseases Society of America Clostridioides difficile infection (CDI) guidelines recommended fidaxomicin as the preferred treatment over vancomycin for patients with initial and recurrent CDI. Few studies have examined how treatment patterns and clinical outcomes of hospitalized CDI patients changed after the postguideline update or contemporary real-world outcomes of fidaxomicin vs vancomycin., Methods: This retrospective, observational study used the PINC AI Healthcare Database on adult patients who received CDI treatment between 1/2020 and 6/2021 (pre period) and between 10/2021 and 9/2022 (post period). We examined treatment patterns of fidaxomicin, vancomycin, and metronidazole, as well as clinical and health care resource use outcomes of patients treated exclusively with fidaxomicin vs vancomycin, using nearest-neighbor propensity matching and hierarchical regression methods. As a sensitivity analysis, we repeated the fidaxomicin vs vancomycin comparisons among patients with recurrent and nonrecurrent index infections., Results: A total of 45 049 patients with CDI from 779 US hospitals met initial inclusion criteria. Comparing the pre vs post periods, the proportion of patients treated with fidaxomicin increased from 5.9% to 13.7% ( P < .001), vancomycin use decreased from 87.9% to 82.9% ( P < .001), and metronidazole use decreased from 21.6% to 17.2% ( P < .001). When comparing fidaxomicin vs vancomycin in the post period, fidaxomicin was associated with lower CDI recurrence (6.1% vs 10.2%; P < .001) and higher sustained clinical response (91.7% vs 87.8%; P < .001). Ninety-day postdischarge costs were not significantly different between groups. A sensitivity analyses showed similar findings., Conclusions: Since the 2021 guideline update, fidaxomicin use has increased significantly but could be further utilized given its association with better clinical outcomes and no increase in postdischarge costs., Competing Interests: Potential conflicts of interest. E.R.D. has received relevant research support through grants from Theriva Biologics, Ferring, Pfizer, and AstraZeneca. E.R.D. has also received consulting fees from Merck & Co., Inc. (Rahway, NJ, USA), Seres, Ferring, AstraZeneca, Abbott, Pfizer, Summit, GSK, and Recursion. Q.L. was an employee of Merck Sharp & Dohme LLC, a subsidiary of Merck & Co., Inc. (Rahway, NJ, USA), at the time this study was conducted but is currently a full-time employee of Takeda. E.N.O., V.T., and F.S. are employees of Merck Sharp & Dohme LLC, a subsidiary of Merck & Co., Inc. (Rahway, NJ, USA). B.H.N.'s company, OptiStatim, LLC, has received consulting fees from Merck & Co., Inc. (Rahway, NJ, USA)., (© The Author(s) 2024. Published by Oxford University Press on behalf of Infectious Diseases Society of America.)

Background: Clostridioides difficile infection (CDI) causes substantial mortality and healthcare burden. We assessed the detoxified toxin-A/B PF-06425090 vaccine for primary CDI prevention., Methods: This phase 3 observer-blinded study randomized (1:1) ≥50-year-olds at increased CDI risk (N=17,535) to receive 3 PF-06425090 or placebo doses (0,1,6-months). Primary endpoints were first CDI episode (≥3 unformed stools within 24 hours; central laboratory-confirmed toxin A/B positive) ≥14 days post-dose 3 (PD3; first primary) and post-dose 2 (PD2; second primary). CDI duration, need for CDI-related medical attention (secondary endpoints), and antibiotic use (post hoc analysis) PD3 were evaluated. Tolerability/safety was assessed., Results: The primary endpoint was not met (17 PF-06425090 and 25 placebo recipients had first CDI episode ≥14 days PD3 [vaccine efficacy (VE)=31.0% (96.4%CI: -38.7%-66.6%)]; 24 PF-06425090 and 34 placebo recipients had first CDI episode ≥14 days PD2 [VE=28.6% (-28.4%-61.0%)]). Median CDI duration was lower with PF-06425090 (1 day) versus placebo (4 days; 2-sided nominal P=0.02). Of participants with first CDI episode, 0 PF-06425090 and 11 placebo recipients sought CDI-related medical attention (post hoc analysis estimated VE=100% [95%CI: 59.6%-100.0%]) and 0 PF-06425090 and 10 placebo recipients required antibiotic treatment (VE=100% [54.8%-100.0%]). Local reactions were more frequent in PF-06425090 recipients and systemic events were generally similar between groups; most were mild-to-moderate. AE rates were similar between groups., Conclusions: Three PF-06425090 doses were safe and well-tolerated. Although the primary endpoint was not met, PF-06425090 reduced symptom duration, CDI requiring medical attention, and CDI-directed antibiotic treatment, highlighting its potential to reduce CDI-associated healthcare burden. NCT03090191., (© The Author(s) 2024. Published by Oxford University Press on behalf of Infectious Diseases Society of America.)

Objective: To evaluate the safety and efficacy of fecal microbiota, live-jslm (RBL; REBYOTA) - the first single-dose, broad consortia microbiota-based live biotherapeutic approved by the United States (US) Food and Drug Administration for preventing recurrent Clostridioides difficile infection (rCDI) in adults following standard-of-care (SOC) antibiotic treatment., Design: PUNCH CD3-OLS was a prospective, phase 3, open-label study, conducted across the US and Canada. Participants were aged ≥18 years with documented rCDI and confirmed use of SOC antibiotics. Participants with comorbidities including inflammatory bowel disease and mild-to-moderate immunocompromising conditions could be enrolled. A single dose of RBL was rectally administered within 24-72h of antibiotic completion. The primary endpoint was the number of participants with RBL- or administration-related treatment-emergent adverse events (TEAEs). Secondary endpoints included treatment success and sustained clinical response, at 8 weeks and 6 months after RBL administration, respectively., Results: Overall, 793 participants were enrolled, of whom 697 received RBL. TEAEs through 8 weeks after administration were reported by 47.3% of participants; most events were mild or moderate gastrointestinal disorders. Serious TEAEs were reported by 3.9% of participants. The treatment success rate at 8 weeks was 73.8%; in participants who achieved treatment success, the sustained clinical response rate at 6 months was 91.0%. Safety and efficacy rates were similar across demographic and baseline characteristic subgroups., Conclusions: RBL was safe and efficacious in participants with rCDI and common comorbidities. This is the largest microbiota-based live biotherapeutic study to date and findings support use of RBL to prevent rCDI in a broad patient population., Clinical Trial Registration: The study is registered at ClinicalTrials.gov (NCT03931941)., (© The Author(s) 2024. Published by Oxford University Press on behalf of Infectious Diseases Society of America.)

Gastrointestinal colonization by Clostridioides difficile is common in healthcare settings and ranges in clinical presentation from asymptomatic carriage to lethal C. difficile infection (CDI). We used a systems biology approach to investigate why patients colonized with C. difficile have a range of outcomes. Microbiota-humanization of germ-free mice with fecal samples from toxigenic C. difficile carriers revealed a spectrum of virulence among clade 1 lineages and identified commensal Blautia associated with markers of non-pathogenic colonization. Using gnotobiotic mice engrafted with defined human microbiota, we observed strain-specific CDI severity across clade 1 strains. Yet, mice engrafted with a higher diversity community were protected from severe disease across all strains without suppression of C. difficile colonization. These results indicate that when colonization resistance has been breached without overt infection, commensals can attenuate a diversity of virulent strains without inhibiting pathogen colonization, providing insight into determinants of stable C. difficile carriage.

Background: Exposure to antibiotics predisposes to dysbiosis and Clostridioides difficile infection (CDI) that can be severe, recurrent (rCDI), and life-threatening. Nonselective drugs that treat CDI and perpetuate dysbiosis are associated with rCDI, in part due to loss of microbiome-derived secondary bile acid (SBA) production. Ridinilazole is a highly selective drug designed to treat CDI and prevent rCDI., Methods: In this phase 3 superiority trial, adults with CDI, confirmed with a stool toxin test, were randomized to receive 10 days of ridinilazole (200 mg twice daily) or vancomycin (125 mg 4 times daily). The primary endpoint was sustained clinical response (SCR), defined as clinical response and no rCDI through 30 days after end of treatment. Secondary endpoints included rCDI and change in relative abundance of SBAs., Results: Ridinilazole and vancomycin achieved an SCR rate of 73% versus 70.7%, respectively, a treatment difference of 2.2% (95% CI: -4.2%, 8.6%). Ridinilazole resulted in a 53% reduction in recurrence compared with vancomycin (8.1% vs 17.3%; 95% CI: -14.1%, -4.5%; P = .0002). Subgroup analyses revealed consistent ridinilazole benefit for reduction in rCDI across subgroups. Ridinilazole preserved microbiota diversity, increased SBAs, and did not increase the resistome. Conversely, vancomycin worsened CDI-associated dysbiosis, decreased SBAs, increased Proteobacteria abundance (∼3.5-fold), and increased the resistome., Conclusions: Although ridinilazole did not meet superiority in SCR, ridinilazole greatly reduced rCDI and preserved microbiome diversity and SBAs compared with vancomycin. These findings suggest that treatment of CDI with ridinilazole results in an earlier recovery of gut microbiome health. Clinical Trials Registration.Ri-CoDIFy 1 and 2: NCT03595553 and NCT03595566., Competing Interests: Potential conflicts of interest. K. W. G. received grants paid to his institution from Acurx, Paratek, Cidara, Therapeutics, and Seres Health. P. C. O. received faculty grant/research support from Merck, Sharp and Dohme, Deinove Pharmaceuticals, Summit Pharmaceuticals, Melinta Pharmaceuticals, the National Institutes of Health (NIH) National Institute of Allergy and Infectious Diseases (NIAID), Kieberg Foundation, and Napo Pharmaceutical; is a consultant to Napo Pharmaceutical, Ferring Pharmaceutical, Summit Pharmaceutical, SNIPR Biome Company, Haleon, and SNIPR; received payment for speaking from Colegio Mexicano de Medicina Interna; participated on a Scientific Advisory Board for Napo Pharmaceuticals; and has stock or stock options from Moderna, Pfizer, Haleon, Biontech, GSK, Novavax, AstraZeneca, Beam, and Johnson & Johnson. T. L. attended advisory board meetings for Summit, Inc, and received payments for the conduct of clinical trials for Seres Therapeutics, Finch Therapeutics, and Rebiotix/Ferring. E. D. and D. J. were employees of Summit, Inc, and owned stock options in Summit Therapeutics (parent company) at the time of manuscript submission. J. G. M. is a part-time employee and owns stock options in Summit, Inc. E. R. D. has received grants paid to his institution from Theriva Biologics and Ferring and consulting fees from Pfizer, Merck, Seres, Abbott, AstraZeneca, Summit, GSK, and Ferring. M. W. has received consulting fees from AiCuris, Bayer, Crestone, Da Volterra, Deinove, EnteroBiotix, The European Tissue Symposium, Ferring, GSK, Menarini, Merck, Nestlé, Paion, Paratek, Pfizer, Phico Therapeutics, Qpex Biopharma, Seres, Surface Skins, Summit, Tillotts, Vaxxilon/Idorsia, and Vedanta; lecture fees from GSK, Merck, Pfizer, Seres, and Tillotts; and grant support from Almirall, Da Volterra, EnteroBiotix, GSK, Merck, MicroPharm, Nabriva, Paratek, Pfizer, Seres, Summit, The European Tissue Symposium, and Tillotts. J. L., B. Y. C., J. S., L. S., and F. C. are employees of Summit, Inc, and own Summit stock options. All other authors report no potential conflicts. All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Conflicts that the editors consider relevant to the content of the manuscript have been disclosed., (© The Author(s) 2024. Published by Oxford University Press on behalf of Infectious Diseases Society of America.)

Using a life tables approach with 2011-2017 claims data, we calculated lifetime risks of Clostridioides difficile infection (CDI) beginning at age 18 years. The lifetime CDI risk rates were 32% in female patients insured by Medicaid, 10% in commercially insured male patients, and almost 40% in females with end-stage renal disease.

Background: Urinary tract infections (UTI) affect approximately 250 million people annually worldwide. Patients often experience a cycle of antimicrobial treatment and recurrent UTI (rUTI) that is thought to be facilitated by a gut reservoir of uropathogenic Escherichia coli (UPEC)., Methods: 125 patients with UTI caused by an antibiotic-resistant organism (ARO) were enrolled from July 2016 to May 2019 in a longitudinal, multi-center cohort study. Multivariate statistical models were used to assess the relationship between uropathogen colonization and recurrent UTI (rUTI), controlling for clinical characteristics. 644 stool samples and 895 UPEC isolates were interrogated for taxonomic composition, antimicrobial resistance genes, and phenotypic resistance. Cohort UTI gut microbiome profiles were compared against published healthy and UTI reference microbiomes, as well as assessed within-cohort for timepoint- and recurrence-specific differences., Findings: Risk of rUTI was not independently associated with clinical characteristics. The UTI gut microbiome was distinct from healthy reference microbiomes in both taxonomic composition and antimicrobial resistance gene (ARG) burden, with 11 differentially abundant taxa at the genus level. rUTI and non-rUTI gut microbiomes in the cohort did not generally differ, but gut microbiomes from urinary tract colonized patients were elevated in E. coli abundance 7-14 days post-antimicrobial treatment. Corresponding UPEC gut isolates from urinary tract colonizing lineages showed elevated phenotypic resistance against 11 of 23 tested drugs compared to non-colonizing lineages., Interpretation: The gut microbiome is implicated in UPEC urinary tract colonization during rUTI, serving as an ARG-enriched reservoir for UPEC. UPEC can asymptomatically colonize the gut and urinary tract, and post-antimicrobial blooms of gut E. coli among urinary tract colonized patients suggest that cross-habitat migration of UPEC is an important mechanism of rUTI. Thus, treatment duration and UPEC populations in both the urinary and gastrointestinal tract should be considered in treating rUTI and developing novel therapeutics., Funding: This work was supported in part by awards from the U.S. Centers for Disease Control and Prevention Epicenter Prevention Program (grant U54CK000482; principal investigator, V.J.F.); to J.H.K. from the Longer Life Foundation (an RGA/Washington University partnership), the National Center for Advancing Translational Sciences (grants KL2TR002346 and UL1TR002345), and the National Institute of Allergy and Infectious Diseases (NIAID) (grant K23A1137321) of the National Institutes of Health (NIH); and to G.D. from NIAID (grant R01AI123394) and the Eunice Kennedy Shriver National Institute of Child Health and Human Development (grant R01HD092414) of NIH. R.T.'s research was funded by the Deutsche Forschungsgemeinschaft (DFG; German Research Foundation; grant 402733540). REDCap is Supported by Clinical and Translational Science Award (CTSA) Grant UL1 TR002345 and Siteman Comprehensive Cancer Center and NCI Cancer Center Support Grant P30 CA091842. The content is solely the responsibility of the authors and does not necessarily represent the official views of the funding agencies., Competing Interests: E.R.D. reports grants from Theriva Biologics, trial enrollment support and consulting fees from Ferring, and consulting fees from Seres. V.F. reports grants from The Foundation for Barnes-Jewish Hospital, grants from Doris Duke Charitable Foundation, grants from NIH/NCATS (project numbers KL2TR002346, UL1TR002345), and royalties/licenses from Elsevier (Goldman-Cecil Medicine, 2-Volume Set, 27e). She has served various roles at the Infectious Diseases Society of America (Board of Directors 2017–2020, IDSA Leadership Institute 2018–2022, Editor-in-Chief Search Committee Chair of the Open Forum Infectious Disease Journal 2022). Her spouse is a consultant and former Senior Vice President/Chief Medical Officer at Cigna/Express-Scripts. M.A.O. reports consulting fees from Pfizer. C.A.B. reports paid roles as editor at the Journal of Clinical Microbiology, and unpaid roles with the Clinical and Laboratory Standards Institute. She has served as Chief Clinical Officer at Pattern Bioscience since 2022 and holds shares. All other authors declare no conflict of interests., (© 2024 The Authors.)

Clostridioides difficile infection (CDI) is a major cause of healthcare-associated diarrhea, despite the widespread implementation of contact precautions for patients with CDI. Here, we investigate strain contamination in a hospital setting and the genomic determinants of disease outcomes. Across two wards over 6 months, we selectively cultured C. difficile from patients ( n = 384) and their environments. Whole-genome sequencing (WGS) of 146 isolates revealed that most C. difficile isolates were from clade 1 (131/146, 89.7%), while only one isolate of the hypervirulent ST1 was recovered. Of culture-positive admissions ( n = 79), 19 (24%) patients were colonized with toxigenic C. difficile on admission to the hospital. We defined 25 strain networks at ≤2 core gene single nucleotide polymorphisms; two of these networks contain strains from different patients. Strain networks were temporally linked ( P < 0.0001). To understand the genomic correlates of the disease, we conducted WGS on an additional cohort of C. difficile ( n = 102 isolates) from the same hospital and confirmed that clade 1 isolates are responsible for most CDI cases. We found that while toxigenic C. difficile isolates are associated with the presence of cdtR , nontoxigenic isolates have an increased abundance of prophages. Our pangenomic analysis of clade 1 isolates suggests that while toxin genes ( tcdABER and cdtR ) were associated with CDI symptoms, they are dispensable for patient colonization. These data indicate that toxigenic and nontoxigenic C. difficile contamination persist in a hospital setting and highlight further investigation into how accessory genomic repertoires contribute to C. difficile colonization and disease., Importance: Clostridioides difficile infection remains a leading cause of hospital-associated diarrhea, despite increased antibiotic stewardship and transmission prevention strategies. This suggests a changing genomic landscape of C. difficile . Our study provides insight into the nature of prevalent C. difficile strains in a hospital setting and transmission patterns among carriers. Longitudinal sampling of surfaces and patient stool revealed that both toxigenic and nontoxigenic strains of C. difficile clade 1 dominate these two wards. Moreover, quantification of transmission in carriers of these clade 1 isolates underscores the need to revisit infection prevention measures in this patient group. We identified unique genetic signatures associated with virulence in this clade. Our data highlight the complexities of preventing transmission of this pathogen in a hospital setting and the need to investigate the mechanisms of in vivo persistence and virulence of prevalent lineages in the host gut microbiome., Competing Interests: The authors declare no conflict of interest.

Importance: Nucleic acid amplification tests (NAATs) are frequently used in Clostridioides difficile research and diagnostic testing, but the effect of freezing specimens on C. difficile NAAT performance is not well characterized. This study evaluated the concordance of NAAT results between fresh and frozen specimens (fecal and rectal swabs) and found it to be very good to excellent. The results indicate that frozen fecal and rectal swab specimens may be used for C. difficile NAAT testing in research when fresh specimens are not available., Competing Interests: R.E.D., T.H., K.A.R., E.S., Z.H.I., C.C., and J.H.K. report no conflicts. C-A.D.B. is an employee of Pattern Bioscience. M.A.O. reports consulting fees from Pfizer. R.E.D. reports research support from Biomerieux. E.R.D. reports grants or contracts from Theriva Biologics and Ferring, and consulting fees from Pfizer, Glaxo-Smith Kline, Merck, Seres, Ferring, Summit, Abbott, and AztraZeneca.

Introduction: Clostridioides difficile infection (CDI) causes symptoms of varying severity and negatively impacts patients' health-related quality of life (HRQL). Despite antibiotic treatment, recurrence of CDI (rCDI) is common and imposes clinical and economic burdens on patients. Fecal microbiota, live-jslm (REBYOTA [RBL]) is newly approved in the USA for prevention of rCDI following antibiotic treatments. We analyzed efficacy and HRQL impact of RBL vs. placebo in patients at first rCDI using data from the phase 3 randomized, double-blind placebo-controlled clinical trial, PUNCH CD3., Methods: This post hoc analysis included patients at first rCDI fromPUNCH CD3. Treatment success (i.e., absence of diarrhea within 8 weeks post-treatment) was analyzed adjusting for baseline patient characteristics. HRQL was measured using the Clostridioides difficile Quality of Life Survey (Cdiff32); absolute scores and change from baseline in total and domain (physical, mental, and social) scores were summarized and compared between arms. Analyses were conducted for the trial's blinded phase only., Results: Among 86 eligible patients (32.8% of the overall trial population, RBL 53 [61.6%], placebo 33 [38.4%]), RBL-treated patients had significantly lower odds of recurrence (i.e., greater probability of treatment success) at week 8 vs. placebo (odds ratio 0.35 [95% confidence interval 0.13, 0.98]). Probability of treatment success at week 8 was 81% for RBL and 60% for placebo, representing 21% absolute and 35% relative increases for RBL (crude proportions 79.2% vs. 60.6%; relative risk 0.53, p = 0.06). Additionally, RBL was associated with significantly higher Cdiff32 total (change score difference 13.5 [standard deviation 5.7], p < 0.05) and mental domain (16.2 [6.0], p < 0.01) scores vs. placebo from baseline to week 8., Conclusion: Compared to placebo, RBL demonstrated a significantly higher treatment success in preventing further rCDI and enhanced HRQL among patients at first recurrence, establishing RBL as an effective treatment to prevent further recurrences in these patients., Trial Registration: ClinicalTrials.gov Identifier NCT03244644., (© 2024. The Author(s).)

Objective: We compared the individual-level risk of hospital-onset infections with multidrug-resistant organisms (MDROs) in hospitalized patients prior to and during the coronavirus disease 2019 (COVID-19) pandemic. We also quantified the effects of COVID-19 diagnoses and intrahospital COVID-19 burden on subsequent MDRO infection risk., Design: Multicenter, retrospective, cohort study., Setting: Patient admission and clinical data were collected from 4 hospitals in the St. Louis area., Patients: Data were collected for patients admitted between January 2017 and August 2020, discharged no later than September 2020, and hospitalized ≥48 hours., Methods: Mixed-effects logistic regression models were fit to the data to estimate patients' individual-level risk of infection with MDRO pathogens of interest during hospitalization. Adjusted odds ratios were derived from regression models to quantify the effects of the COVID-19 period, COVID-19 diagnosis, and hospital-level COVID-19 burden on individual-level hospital-onset MDRO infection probabilities., Results: We calculated adjusted odds ratios for COVID-19-era hospital-onset Acinetobacter spp., P. aeruginosa and Enterobacteriaceae spp infections. Probabilities increased 2.64 (95% confidence interval [CI], 1.22-5.73) times, 1.44 (95% CI, 1.03-2.02) times, and 1.25 (95% CI, 1.00-1.58) times relative to the prepandemic period, respectively. COVID-19 patients were 4.18 (95% CI, 1.98-8.81) times more likely to acquire hospital-onset MDRO S. aureus infections., Conclusions: Our results support the growing body of evidence indicating that the COVID-19 pandemic has increased hospital-onset MDRO infections.

In this retrospective cohort from 3 Missouri hospitals from January 2017 to August 2020, hospital-onset Clostridioides difficile infections were more common during the severe acute respiratory syndrome coronavirus 2 pandemic at the tertiary care hospital. Risk factors associated with hospital-onset C difficile infection included the year of hospitalization, age, high-risk antibiotic use, acid-reducing medications, chronic comorbidities, and severe acute respiratory syndrome coronavirus 2 infection., (Copyright © 2023 Association for Professionals in Infection Control and Epidemiology, Inc. Published by Elsevier Inc. All rights reserved.)

Background: Despite improvements in prevention and treatment, severe coronavirus disease 2019 (COVID-19) is associated with high mortality. Phosphoinositide 3-kinase (PI3K) pathways contribute to cytokine and cell-mediated lung inflammation. We conducted a randomized, placebo-controlled, double-blind pilot trial to determine the feasibility, safety, and preliminary activity of duvelisib, a PI3Kδγ inhibitor, for the treatment of COVID-19 critical illness., Methods: We enrolled adults aged ≥18 years with a primary diagnosis of COVID-19 with hypoxic respiratory failure, shock, and/or new cardiac disease, without improvement after at least 48 hours of corticosteroid. Participants received duvelisib (25 mg) or placebo for up to 10 days. Participants had daily semi-quantitative viral load measurements performed. Dose modifications were protocol driven due to adverse events (AEs) or logarithmic change in viral load. The primary endpoint was 28-day overall survival (OS). Secondary endpoints included hospital and intensive care unit length of stay, 60-day OS, and duration of critical care interventions. Safety endpoints included viral kinetics and AEs. Exploratory endpoints included serial cytokine measurements and cytometric analysis., Results: Fifteen patients were treated in the duvelisib cohort, and 13 in the placebo cohort. OS at 28 days was 67% (95% confidence interval [CI], 38%-88%) compared to 62% (95% CI, 32%-86%) for placebo ( P = .544). Sixty-day OS was 60% versus 46%, respectively (hazard ratio, 0.66 [95% CI, .22-1.96]; P = .454). Other secondary outcomes were comparable. Duvelisib was associated with lower inflammatory cytokines., Conclusions: In this pilot study, duvelisib did not significantly improve 28-day OS compared to placebo for severe COVID-19. Duvelisib appeared safe in this critically ill population and was associated with reduction in cytokines implicated in COVID-19 and acute respiratory distress syndrome, supporting further investigation., Clinical Trials Registration: NCT04372602., Competing Interests: Potential conflicts of interest. J. P. reports employment with Verastem Oncology Inc. All other authors report no potential conflicts., (© The Author(s) 2023. Published by Oxford University Press on behalf of Infectious Diseases Society of America.)

Since the initial publication of A Compendium of Strategies to Prevent Healthcare-Associated Infections in Acute Care Hospitals in 2008, the prevention of healthcare-associated infections (HAIs) has continued to be a national priority. Progress in healthcare epidemiology, infection prevention, antimicrobial stewardship, and implementation science research has led to improvements in our understanding of effective strategies for HAI prevention. Despite these advances, HAIs continue to affect ∼1 of every 31 hospitalized patients, leading to substantial morbidity, mortality, and excess healthcare expenditures, and persistent gaps remain between what is recommended and what is practiced.The widespread impact of the coronavirus disease 2019 (COVID-19) pandemic on HAI outcomes in acute-care hospitals has further highlighted the essential role of infection prevention programs and the critical importance of prioritizing efforts that can be sustained even in the face of resource requirements from COVID-19 and future infectious diseases crises.The Compendium: 2022 Updates document provides acute-care hospitals with up-to-date, practical expert guidance to assist in prioritizing and implementing HAI prevention efforts. It is the product of a highly collaborative effort led by the Society for Healthcare Epidemiology of America (SHEA), the Infectious Disease Society of America (IDSA), the Association for Professionals in Infection Control and Epidemiology (APIC), the American Hospital Association (AHA), and The Joint Commission, with major contributions from representatives of organizations and societies with content expertise, including the Centers for Disease Control and Prevention (CDC), the Pediatric Infectious Disease Society (PIDS), the Society for Critical Care Medicine (SCCM), the Society for Hospital Medicine (SHM), the Surgical Infection Society (SIS), and others.

Objective: To determine the relationship between severe acute respiratory syndrome coronavirus 2 infection, hospital-acquired infections (HAIs), and mortality., Design: Retrospective cohort., Setting: Three St. Louis, MO hospitals., Patients: Adults admitted ≥48 hours from January 1, 2017 to August 31, 2020., Methods: Hospital-acquired infections were defined as those occurring ≥48 hours after admission and were based on positive urine, respiratory, and blood cultures. Poisson interrupted time series compared mortality trajectory before (beginning January 1, 2017) and during the first 6 months of the pandemic. Multivariable logistic regression models were fitted to identify risk factors for mortality in patients with an HAI before and during the pandemic. A time-to-event analysis considered time to death and discharge by fitting Cox proportional hazards models., Results: Among 6,447 admissions with subsequent HAIs, patients were predominantly White (67.9%), with more females (50.9% vs 46.1%, P  = .02), having slightly lower body mass index (28 vs 29, P  = .001), and more having private insurance (50.6% vs 45.7%, P  = .01) in the pre-pandemic period. In the pre-pandemic era, there were 1,000 (17.6%) patient deaths, whereas there were 160 deaths (21.3%, P  = .01) during the pandemic. A total of 53 (42.1%) coronavirus disease 2019 (COVID-19) patients died having an HAI. Age and comorbidities increased the risk of death in patients with COVID-19 and an HAI. During the pandemic, Black patients with an HAI and COVID-19 were more likely to die than White patients with an HAI and COVID-19., Conclusions: In three Midwestern hospitals, patients with concurrent HAIs and COVID-19 were more likely to die if they were Black, elderly, and had certain chronic comorbidities., Competing Interests: All authors report no potential conflicts of interest., (© The Author(s) 2023.)

Background: Although increased occurrence of septicemia in persons with Clostridioides difficile infection (CDI) has been reported, incidence rates and risk of septicemia and urinary tract infection (UTI) after CDI are unclear., Methods: The first episode of CDI was identified using 2011-2017 MarketScan and CMS Medicare data and CDI cases categorized by standard surveillance definitions. Uninfected persons were frequency matched 4:1 to cases by the CDI case surveillance definition. Multivariable Cox proportional hazards models were used to identify risk factors for septicemia and UTI within 90 days of CDI onset, accounting for the competing risk of death in the Medicare population., Results: The incidence of septicemia was highest after hospital-onset CDI in the Medicare, younger commercial, and younger Medicaid populations (25.5%, 15.7%, and 19.5%, respectively) and lowest in those with community-associated CDI (3.8%, 4.3%, and 8.3%, respectively). In contrast, the incidence of UTI was highest in those with other healthcare facility onset CDI in all 3 populations (32.1%, 24.2%, and 18.1%, respectively). Hospital-onset CDI was associated with highest risk of septicemia compared with uninfected controls in all 3 populations. In the younger populations, risk of septicemia was more uniform across the CDI surveillance definitions. The risk of UTI was significantly higher in all CDI surveillance categories compared to uninfected controls, and among CDI cases it was lowest in those with community-associated CDI., Conclusions: The incidence of septicemia is high after CDI, particularly after hospital-onset infection. Additional preventive measures are needed to reduce infectious complications of CDI., Competing Interests: Potential conflicts of interest. The sponsor participated in study design, interpretation of the data, and final review of the manuscript. MAO reports personal fees from Pfizer for consulting work. ERD reports receipt of grant funding from Pfizer, Synthetic Biologics, and Ferring in the past 36 months and personal fees from Ferring, Rebiotix, Summit, Merck, Pfizer, and Seres. HY is an employee of Pfizer, Inc. and has stock or stock options for Pfizer. DS reports stock or stock options from AbbVie, Inc., and Bristol-Myers Squibb. Conflicts that the editors consider relevant to the content of the manuscript have been disclosed., (© The Author(s) 2023. Published by Oxford University Press on behalf of Infectious Diseases Society of America.)

Background: Recurrence of Clostridioides difficile infection (rCDI) is common, prolonging disease morbidity and leading to poor quality of life. We evaluated disease-specific health-related quality of life (HRQL) in patients with rCDI treated with fecal microbiota, live-jslm (REBYOTA [RBL]; Rebiotix) versus placebo., Methods: This was a secondary analysis of a randomized, double-blind, placebo-controlled phase 3 study (PUNCH CD3). The disease-specific Clostridioides difficile Quality of Life Survey (Cdiff32) was administered at baseline and at weeks 1, 4, and 8. Changes in Cdiff32 total and domain (physical, mental, social) scores from baseline to week 8 were compared between RBL and placebo and for responders and nonresponders., Results: Findings were analyzed in a total of 185 patients (RBL, n = 128 [69.2%]; placebo, n = 57 [30.8%]) with available Cdiff32 data. Patients from both arms showed significant improvements in Cdiff32 scores relative to baseline across all outcomes and at all time points (all P < .001); RBL-treated patients showed significantly greater improvements in mental domain than those receiving placebo. In adjusted analyses, RBL-treated patients showed greater improvements than placebo in total score and physical and mental domains (all P < .05). Similar improvement in mental domain was observed among responders, while nonresponders showed numerical improvements with RBL but not placebo., Conclusions: In a phase 3 double-blinded clinical trial, RBL-treated patients reported more substantial and sustained disease-specific HRQL improvements than placebo-treated patients., Clinical Trials Registration: ClinicalTrials.gov NCT03244644 (https://clinicaltrials.gov/ct2/show/NCT03244644)., Competing Interests: Potential conflict of interest. A. G. is an employee of Ferring Pharmaceuticals. A. H. and L. L. B. are employees of Rebiotix, a Ferring Company. M. Y., V. G. H., M. F., and H. W. are employees of Analysis Group, which received payment from Ferring Pharmaceuticals for participation in this research. G. S. T. is an employee of GST Micro and a consultant for Ferring Pharmaceuticals, Spero, and Taro Pharmaceuticals. K. W. G. is an employee of the University of Houston College of Pharmacy and a consultant for Ferring Pharmaceuticals and has received research grants from Acurx, Summit, Paratek Pharmaceuticals, and Seres Health. E. R. D. is an employee of Washington University School of Medicine; is a consultant for and Ferring, Pfizer, Abbott, Merck, Seres, and Summit; has received research grants from Ferring, Pfizer, and Synthetic Biologics; and is a member of the advisory board for Rebiotix. P. F. is an employee of Yale University School of Medicine; a consultant for Ferring Pharmaceuticals/Rebiotix, Seres Therapeutics, and Merck and Co; a member of the speakers’ bureau for Ferring Pharmaceuticals/Rebiotix; and an advisory board member for Ferring Pharmaceuticals/Rebiotix, Seres Therapeutics, and Takeda Pharmaceuticals., (© The Author(s) 2023. Published by Oxford University Press on behalf of Infectious Diseases Society of America.)

In a US adult population aged <65 years, attributable costs due to Clostridioides difficile infection (CDI) were highest in persons with hospital onset and lowest in those with community-associated CDI treated outside a hospital. The economic burden of CDI in younger adults underscores the need for additional CDI-preventive strategies., Competing Interests: Potential conflicts of interest. M. A. O. reports personal fees from Pfizer for consulting work. H. Y. is an employee of Pfizer. E. R. D. reports receipt of grant funding from Pfizer, Synthetic Biologics, and Ferring in the past 36 months and personal fees from Ferring, Rebiotix, Summit, Merck, Pfizer, and Seres. All other authors report no potential conflicts., (© The Author(s) 2023. Published by Oxford University Press on behalf of Infectious Diseases Society of America.)

With the approval and development of narrow-spectrum antibiotics for the treatment of Clostridioides difficile infection (CDI), the primary endpoint for treatment success of CDI antibiotic treatment trials has shifted from treatment response at end of therapy to sustained response 30 days after completed therapy. The current definition of a successful response to treatment (three or fewer unformed bowel movements [UBMs] per day for 1-2 days) has not been validated, does not reflect CDI management, and could impair assessments for successful treatment at 30 days. We propose new definitions to optimise trial design to assess sustained response. Primarily, we suggest that the initial response at the end of treatment be defined as (1) three or fewer UBMs per day, (2) a reduction in UBMs of more than 50% per day, (3) a decrease in stool volume of more than 75% for those with ostomy, or (4) attainment of bowel movements of Bristol Stool Form Scale types 1-4, on average, by day 2 after completion of primary CDI therapy (ie, assessed on day 11 and day 12 of a 10-day treatment course) and following an investigator determination that CDI treatment can be ceased., Competing Interests: Declaration of interests AMS is supported by career development awards from the US Veteran Affairs and Institute for Translational Medicine, serves on an advisory board for Recursion Pharmaceuticals, and has accepted honoraria from the American Society of Healthcare Pharmacists and the Academy for Continued Healthcare Learning. CDA has been supported by an investigator-initiated grant from Merck; serves on advisory boards for Cidara Therapeutics, Merck, and AiCuris; and has accepted honoraria from the American Society of Healthcare Pharmacists and the Academy for Continued Healthcare Learning. OAC has grants from Amplyx, Basilea, German Federal Ministry of Education and Research, Cidara, German Center for Infection Research, Commission's Directorate-General for Research and Innovation (101037867), F2G, Gilead, Matinas, MedPace, Merck Sharp & Dohme, Mundipharma, Octapharma, Pfizer, and Scynexis, has accepted consulting fees from AbbVie, Amplyx, Biocon, Biosys, Cidara, Da Volterra, Gilead, IQVIA, Janssen, Matinas, MedPace, Menarini, Molecular Partners, Mycoses Study Group Education & Research Consortium, Noxxon, Octapharma, Pardes, Pfizer, Pharmaceutical Security Institute, Scynexis, and Seres Therapeutics; has accepted speakernhonoraria from Abbot, AbbVie, Al-Jazeera Pharmaceuticals, Astellas, Gilead, Grupo Biotoscana/United Medical/Knight, Hikma, MedScape, MedUpdate, Merck/MSD, Mylan, Noscendo, Pfizer, and Shionogi; has served as an expert witness for Cidara; has participated on advisory boards for Actelion, Allecra, Cidara, Entasis, IQVIA, Janssen, MedPace, Paratek, PSI, Pulmocide, Shionogi, and the Prime Meridian Group; has filed for a patent with the German Patent and Trade Mark Office (Geschlossene Inkubationssysteme mit verbessertem Atemwegszugang für Untersuchungsvorrichtungen, DE 10 2021 113 007.7); has stock in CoRe Consulting; and has non-financial interests in the European Confederation of Medical Mycology, International Society for Human and Animal Mycology, Mycoses Study Group Education & Research Consortium, and Wiley Publishing. KWG is funded by investigator-initiated awards from Summit Therapeutics, Acurx, Paratek, and Seres Therapeutics. DNG has grants from the US Centers for Disease Control and Prevention and US Veteran Affairs, a licensing agreement with Destiny Pharma, and has accepted consulting fees from Destiny Pharma. SJ is funded by grants from Paratek and Destiny Pharma, has accepted consulting fees from Bio-K+, Acurx, Ferring Pharmaceuticals, and Summit Therapeutics, and serves on the data safety monitoring board for Pfizer. SAK is funded by the Crohn's and Colitis Foundation, the Mooney Family Initiative for Translational and Clinical Studies in Rare Diseases Translational Research Program, Cures Within Reach, and the National Institute of Allergy and Infectious Diseases; has accepted consulting fees from Guidepoint; has accepted honoraria from the Louisiana Academy of Nutrition & Diabetics and Boston IBD; has accepted travel support from the Crohn's and Colitis and Helmsley Foundations; serves on the Peggy Lillis Foundation advisory board; and holds Eli Lilly stock. CPK has grant funding from Milky Way Life Sciences, Pfizer, National Institutes of Health (NIH), Merck, and Takeda Pharmaceuticals; has accepted consulting fees from Artugen, Facile Therapeutics, Ferring Pharmaceuticals, Finch Therapeutics, Pfizer, Milky Way Life Sciences, RVAC Medicines, Seres Therapeutics, and Summit Therapeutics; has a patent with Quanterix; serves on the advisory board for Finch Therapeutics; is secretary for the Foundation for Celiac Disease Outcome Measures; and has stock in First Light and Cour Pharmaceuticals. CRK has grant funding from the NIH; has accepted consulting fees from Sebela Pharmaceuticals; and has accepted speakers honoraria from the American College of Gastroenterology. LKK has research funding from Merck. TL has accepted funding from Summit, Crestone, MGB Biopharma, Actelion, Cubist/Merck, Seres Therapeutics, and Vedanta Biosciences; and has accepted consulting fees from MGB Biopharma and Seres Therapeutics. MJGTV has received grants from MSD, Heel, Biontech, and Roche; has accepted consulting fees from MaaT, Tillots, MSD/Merck, FAV00B, Dr Regenold, Roche, and EUMEDICA; and has accepted honoraria from Merck/MSD, 3M, Ferring Pharmaceuticals, Astellas, Uniklinik Karlsruhe, Uniklinik Köln, Akademia für Infektionsmedizin, Klinikum Essen, Pfizer, Universitätsklinikum Heidelberg, Uniklinik Frankfurt, Landesärztekammer Hessen, Janssen, Institut Merieux, Forum für medizinische Fortildung, Universitätsklinikum Freburg, Berliner Dialy Seminar, Zertifikatskurs PTA im Krankenhaus, Falk Foundation, St Johannes Hospital, DiaLog Service, CED Service, Ärtzekammer Niedersachsen, St Josef Hospital, Limbach Grupe SE, SUMIT OZFORD, EUMDEICA Kit Kongress, Tillots Pharma, Helios Lkiniken, Lahn-Dill-Kliniken, and Gilead. MHW has research support from Almirall, Da Volterra, EnteroBiotix, GlaxoSmithKline (GSK), Merck, MicroPharm, Nabriva, Paratek, Pfizer, Seres Therapeutics, Summit Therapeutics, The European Tissue Symposium, Tillotts, IMI2 (EU Horizon 2020), and EFPIA partners; has accepted consulting fees from AiCuris, Bayer, Crestone, Da Volterra, Deinove, Destiny Pharma, EnteroBiotix, The European Tissue Symposium, Ferring, GSK, Menarini, Merck, Nestlé, Paion, Paratek, Pfizer, Phico Therapeutics, Qpex Biopharma, Seres, Surface Skins, Summit, Tillotts, and Vaxxilon/Idorsia; and has accepted speakers honoraria from Merck, Pfizer, Seres, and Tillotts. ERD is funded by grants from Synthetic Biologics and Ferring Pharmaceuticals and has accepted consulting fees from Pfizer, Merck, Ferring Pharmaceuticals, Abbott, GSK, Seres Therapeutics, and Summit Therapeutics. All other authors declare no competing interests., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

Objective: Few data are available to quantify the Clostridioides difficile infection (CDI) burden in US adults depending on Medicaid insurance status; thus, we sought to contribute to this body of information., Methods: Retrospective cohort study to identify adults with codes for CDI from 2011 to 2017 in MarketScan commercial and Medicaid databases (for those aged 25-64 years) and the CMS Medicare database (for those aged ≥65 years). CDI was categorized as healthcare-facility-associated (HCA-CDI) and community-associated CDI (CA-CDI). CDI incidence rates were compared by year, insurer, and age group., Results: The overall CDI incidence in the elderly was 3.1-fold higher in persons insured by Medicare plus Medicaid than in those insured by Medicare only (1,935 vs 618 per 100,000 person years (PY)), and the CDI incidence was 2.7-fold higher in younger adults with Medicaid compared to commercial insurance (195 vs 73 per 100,000 PY). From 2011 to 2017, HCA-CDI rates declined in the younger Medicaid population (124.0 to 95.2 per 100,000 PY; P < .001) but were stable in those commercially insured (25.9 to 24.8 per 100,000 PY; P = .33). In the elderly HCA-CDI rates declined from 2011 to 2017 in the Medicare-only population (403 to 318 per 100,000 PY; P < .001) and the Medicare plus Medicaid population (1,770 to 1,163 per 100,000 PY; P < .002). Persons with chronic medical conditions and those with immunocompromising conditions insured by Medicaid had 2.8- and 2.7-fold higher CDI incidence compared to the commercially insured population, respectively. The incidence of CDI was lowest in Medicaid and commercially insured younger adults without chronic medical or immunosuppressive conditions (67.5 and 45.6 per 100,000 PY, respectively)., Conclusions: Although HCA-CDI incidence decreased from 2011 to 2017 in elderly and younger adults insured by Medicaid, the burden of CDI remains much higher in low-income adults insured by Medicaid.

Introduction: Up to 35% of patients with a first episode of Clostridioides difficile infection (CDI) develop recurrent CDI (rCDI), and of those, up to 65% experience multiple recurrences. A systematic literature review (SLR) was conducted to review and summarize the economic impact of rCDI in the United States of America., Methods: English-language publications reporting real-world healthcare resource utilization (HRU) and/or direct medical costs associated with rCDI in the USA were searched in MEDLINE, MEDLINE In-Process, Embase, and the Cochrane Library databases over the past 10 years (2012-2022), as well as in selected scientific conferences that publish research on rCDI and its economic burden over the past 3 years (2019-2022). HRU and costs identified through the SLR were synthesized to estimate annual rCDI-attributable direct medical costs to inform the economic impact of rCDI from a US third-party payer's perspective., Results: A total of 661 publications were retrieved, and 31 of them met all selection criteria. Substantial variability was found across these publications in terms of data source, patient population, sample size, definition of rCDI, follow-up period, outcomes reported, analytic approach, and methods to adjudicate rCDI-attributable costs. Only one study reported rCDI-attributable costs over 12 months. Synthesizing across the relevant publications using a component-based cost approach, the per-patient per-year rCDI-attributable direct medical cost was estimated to range from $67,837 to $82,268., Conclusions: While real-world studies on economic impact of rCDI in the USA suggested a high-cost burden, inconsistency in methodologies and results reporting warranted a component-based cost synthesis approach to estimate the annual medical cost burden of rCDI. Utilizing available literature, we estimated the average annual rCDI-attributable medical costs to allow for consistent economic assessments of rCDI and identify the budget impact on US payers., (© 2023. The Author(s).)

An isolate of Morganella morganii (MMOR1) that tested susceptible to 3 rd /4 th -generation cephalosporins and intermediate to meropenem was characterized as positive for NDM and IMP carbapenemases by NG-Test CARBA 5. Our objective was to further investigate this result, given the inconsistent susceptibility profile and unusual epidemiological profile for our region. The MMOR1 isolate was retested for antimicrobial susceptibilities and characterized for carbapenemase production. MMOR1 tested susceptible to ceftazidime, ceftriaxone, cefepime, aztreonam, and ertapenem, and intermediate to meropenem and imipenem. The isolate tested positive by carbapenem inactivation method (CIM) and CIM+EDTA (eCIM) testing, indicating metallo-β-lactamase production. The isolate tested negative for all carbapenemase genes on Xpert Carba-R, but positive for IMP on repeat testing of NG-Test CARBA 5. Whole-genome sequencing revealed MMOR1 contained bla IMP-27 , but no other carbapenemase genes. Additional testing with NG-Test CARBA 5 revealed a false-positive NDM band when the assay was overloaded with test inoculum. Supplementary isolates were tested with an overloaded inoculum ( n  = 6 M. morganii; n  = 1 P. mirabilis; n  = 1 IMP-27-producing P. rettgeri ; n  = 1 K. pneumoniae), and two non-carbapenemase-producing carbapenem non-susceptible M. morganii also generated a false-positive NDM band; though, this was not universal among this species. A dual IMP+/NDM+ M. morganii is an unusual result that should prompt additional investigation, especially in nonendemic regions and when the susceptibility profile is incompatible. IMP-27 is not detected by Xpert Carba-R but is variably detected by NG-Test CARBA 5. The microorganism inoculum used for NG-Test CARBA 5 must be carefully controlled for accurate results. n  = 1 K. pneumoniae), and two non-carbapenemase-producing carbapenem non-susceptible M. morganii also generated a false-positive NDM band; though, this was not universal among this species. A dual IMP+/NDM+ M. morganii is an unusual result that should prompt additional investigation, especially in nonendemic regions and when the susceptibility profile is incompatible. IMP-27 is not detected by Xpert Carba-R but is variably detected by NG-Test CARBA 5. The microorganism inoculum used for NG-Test CARBA 5 must be carefully controlled for accurate results. IMPORTANCE The detection of carbapenemase-producing carbapenem-resistant Enterobacterales (CP-CRE) is an important function of the clinical microbiology laboratory, where positive identifications have immediate implications for infection control and surveillance strategies in the inpatient setting and can inform appropriate selection of therapy among the various novel anti-CP-CRE agents. NG-Test CARBA 5 is a relatively new lateral flow assay used for detection of carbapenemases in CP-CRE. Here, we describe the characterization of a Morganella morganii isolate that generated a false-positive NDM carbapenemase detection by this assay, and perform bacterial test inoculum experiments with additional isolates to further investigate a cause of false-positive results using the NG-Test CARBA 5. While a lateral flow assay like the NG-Test CARBA 5 is a very desirable test format for clinical laboratories, there are pitfalls to avoid when performing this test and interpreting results, including recognizing an overloaded test assay, which could lead to false-positive results., Competing Interests: The authors declare a conflict of interest. N.J.T. has equity in the startup company BioAmp Diagnostics. E.R.D. is a consultant for Abbott. M.A.W. and C.-A.D.B. are employees of Pattern Bioscience. C.-A.D.B. has received research support from bioMérieux, Cepheid, Luminex, and BioFire Diagnostics. C.-A.D.B. is a consultant for Cepheid and Pattern Bioscience. M.L.Y. has received research funding from bioMérieux. M.L.Y. serves as an advisory board member for Shionogi, Inc. M.L.Y. has received editorial fees from ASM, personal fees from IVD Logix, and travel fees from AACC and ACLPS.

Background: Microbiota-based treatments reduce the incidence of recurrent Clostridioides difficile infections (rCDIs), but prospectively collected safety data needed to broaden patient access and protect public health have been limited., Objectives: We provide cumulative safety data from five prospective clinical trials evaluating fecal microbiota, live-jslm (RBL) - the first microbiota-based live biotherapeutic product approved by the US Food and Drug Administration - for preventing rCDI in adults., Design: Integrated safety analysis includes three phase II trials (PUNCH CD, PUNCH CD2, PUNCH Open-Label) and two phase III trials (PUNCH CD3, PUNCH CD3-OLS) of RBL., Methods: Trial participants were at least 18 years of age with documented rCDI who completed standard-of-care antibiotic therapy before treatment with RBL. Assigned study treatment regimen was one or two doses of RBL (or placebo) administered rectally, depending on the trial design. In four of the five trials, participants with CDI recurrence within 8 weeks after RBL or placebo administration were eligible for treatment with open-label RBL. Treatment-emergent adverse events (TEAEs) were recorded for at least 6 months following last study treatment; in PUNCH CD2 and PUNCH Open-Label trials, TEAEs and serious TEAEs were collected through 12 and 24 months, respectively., Results: Among the five trials, 978 participants received at least one dose of RBL (assigned treatment or after recurrence) and 83 participants received placebo only. TEAEs were reported in 60.2% of Placebo Only participants and 66.4% of RBL Only participants. Only abdominal pain, nausea, and flatulence were significantly higher in the RBL Only group compared with the Placebo Only group. Most TEAEs were mild or moderate in severity and were most frequently related to preexisting conditions. There were no reported infections for which the causative pathogen was traced to RBL. Potentially life-threatening TEAEs were infrequent (3.0% of participants)., Conclusion: Across five clinical trials, RBL was well tolerated in adults with rCDI. In aggregate, these data consistently demonstrated the safety of RBL., Competing Interests: The authors declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: CL received grants from Rebiotix Inc., a Ferring Company, Seres Therapeutics, and Summit Therapeutics for clinical trials. TL received grants from Rebiotix Inc, Seres Therapeutics, Summit Therapeutics and Finch Therapeutics. RO and ERD serve on the Rebiotix Physician Advisory Board. ERD received grants from Synthetic Biologics and Pfizer, and is a consultant for Pfizer, Merck, Seres Therapeutics, Summit Therapeutics, Ferring Pharmaceuticals and Abbott. PF is a consultant/advisory board member and speaker for Ferring Pharmaceuticals, Seres Therapeutics, and Takeda Pharmaceuticals and consultant for Merck & Co., Inc. LB, BG, and AH are employees of Rebiotix Inc., a Ferring Company. SK is a consultant/advisory board member for Ferring Pharmaceuticals, Takeda Pharmaceuticals, Niche Pharmaceuticals, and Immuron Ltd., (© The Author(s), 2023.)

We analyzed our challenging experience with a randomized controlled trial of misoprostol for prevention of recurrent C. difficile. Despite careful prescreening and thoughtful protocol modifications to facilitate enrollment, we closed the study early after enrolling just 7 participants over 3 years. We share lessons learned, noting the importance of feasibility studies, inclusion of biomarker outcomes, and dissemination of such findings to inform future research design and implementation successes., Competing Interests: Declaration of competing interest S.K.M.: Research funding from Finch Therapeutics. E.R.D: Research funding provided by Ferring, Synthetic Biologics, and Pfizer; Consultant for Summit, Seres, Abbott, Pfizer, Merck, Ferring., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

Studies comparing the impact of the COVID-19 pandemic on diagnostic microbiology culture yields and antimicrobial resistance proportions in low-to-middle-income and high-income countries are lacking. A retrospective study using blood, respiratory, and urine microbiology data from a community hospital in India and two community hospitals (Hospitals A and B) in St. Louis, MO, USA was performed. We compared the proportion of cultures positive for selected multi-drug-resistant organisms (MDROs) listed on the WHO's priority pathogen list both before the COVID-19 pandemic (January 2017-December 2019) and early in the COVID-19 pandemic (April 2020-October 2020). The proportion of blood cultures contaminated with coagulase-negative Staphylococcus (CONS) was significantly higher during the pandemic in all three hospitals. In the Indian hospital, the proportion of carbapenem-resistant (CR) Klebsiella pneumoniae in respiratory cultures was significantly higher during the pandemic period, as was the proportion of CR Escherichia coli in urine cultures. In the US hospitals, the proportion of methicillin-resistant Staphylococcus aureus in blood cultures was significantly higher during the pandemic period in Hospital A, while no significant increase in the proportion of Gram-negative MDROs was observed. Continuity of antimicrobial stewardship activities and better infection prevention measures are critical to optimize outcomes and minimize the burden of antimicrobial resistance among COVID-19 patients.

Background: Although hospital-onset Clostridioides difficile infection (CDI) is associated with significant healthcare costs, the economic burden of CDI with onset in other facilities or the community has not been well studied., Methods: Incident CDI cases were identified using 2011-2017 Medicare fee-for-service data. Controls were randomly selected in a 4:1 ratio matching to the CDI case surveillance definition. Inverse probability of exposure weights were used to balance on measured confounders. One-, 3-, and 5-year cumulative costs attributable to CDI were computed using a 3-part estimator (parametric survival model and pair of 2-part models predicting costs separately in intervals where death did and did not occur)., Results: A total of 60 492 CDI cases were frequency-matched to 241 968 controls. One-, 3-, and 5-year adjusted attributable costs were highest for hospital-onset CDI at $14 257, $18 953, and $21 792, respectively, compared with hospitalized controls and lowest for community-associated CDI compared with community controls at $1013, $3161, and $6454, respectively. Adjusted 1-, 3-, and 5-year costs attributable to community-onset healthcare facility-associated CDI were $8222, $13 066, and $16 329 and for other healthcare facility-onset CDI were $5345, $6764, and $7125, respectively., Conclusions: Economic costs attributable to CDI in elderly persons were highest for hospital-onset and community-onset healthcare facility-associated CDI. Although lower, attributable costs due to CDI were significantly higher in cases with CDI onset in the community or other healthcare facility than for comparable persons without CDI. Additional strategies to prevent CDI in the elderly are needed to reduce morbidity and healthcare expenditures., Competing Interests: Potential conflicts of interest. M. A. O. reports receipt of grant funding from Pfizer and personal fees from Pfizer for consulting work. E. R. D. reports receipt of grant funding from Pfizer, Synthetic Biologics, and Ferring and personal fees from Ferring, Rebiotix, Summit, Merck, Pfizer, and Seres. H. Y. is an employee of Pfizer, and has stock or stock options for Pfizer. D. S. reports stock or stock options from AbbVie, Inc, and Bristol-Myers Squibb. The remaining author reports no potential conflicts. All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Conflicts that the editors consider relevant to the content of the manuscript have been disclosed., (© The Author(s) 2022. Published by Oxford University Press on behalf of Infectious Diseases Society of America. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Background: Clostridioides difficile is the most common cause of healthcare-associated infections in the United States. It is unknown whether universal gown and glove use in intensive care units (ICUs) decreases acquisition of C. difficile., Methods: This was a secondary analysis of a cluster-randomized trial in 20 medical and surgical ICUs in 20 US hospitals from 4 January 2012 to 4 October 2012. After a baseline period, ICUs were randomized to standard practice for glove and gown use versus the intervention of all healthcare workers being required to wear gloves and gowns for all patient contact and when entering any patient room (contact precautions). The primary outcome was acquisition of toxigenic C. difficile determined by surveillance cultures collected on admission and discharge from the ICU., Results: A total of 21 845 patients had both admission and discharge perianal swabs cultured for toxigenic C. difficile. On admission, 9.43% (2060/21 845) of patients were colonized with toxigenic C. difficile. No significant difference was observed in the rate of toxigenic C. difficile acquisition with universal gown and glove use. Differences in acquisition rates in the study period compared with the baseline period in control ICUs were 1.49 per 100 patient-days versus 1.68 per 100 patient-days in universal gown and glove ICUs (rate difference, -0.28; generalized linear mixed model, P = .091)., Conclusions: Glove and gown use for all patient contact in medical and surgical ICUs did not result in a reduction in the acquisition of C. difficile compared with usual care., Clinical Trials Registration: NCT01318213., Competing Interests: Potential conflicts of interest. E. R. D. reports grants or contracts from Synthetic Biologics, Ferring, and Pfizer, outside of the submitted work, and consulting fees from Seres, Merck, Pfizer, Abbott, and Ferring. S. L. reports grants/contracts to their institution under the CDC Prevention Epicenters and Broad Agency Agreement mechanisms in the broad field of infection prevention and healthcare epidemiology from the Centers for Disease Control and Prevention and a contract for Maryland hospital collaboratives on C. difficile and COVID-19 prevention from the Maryland Department of Health, all outside of the submitted work. T. H. reports grants or contracts paid to their institution from Synthetic Biologics, Inc, and CDC Epicenters, both outside of the submitted work. D. J. M. reports grants or contracts unrelated to this work from the National Institutes of Health, CDC, and Veterans Affairs Health Services Research and Development; reimbursement for travel from IDWeek and the Society for Healthcare Epidemiology of America (SHEA); and unpaid positions as Chair of the IDWeek SHEA Committee and as lead of the SHEA Diagnostic Stewardship Taskforce. All other authors report no potential conflicts. All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Conflicts that the editors consider relevant to the content of the manuscript have been disclosed., (Published by Oxford University Press on behalf of Infectious Diseases Society of America 2022.)

Introduction: Effective treatments for recurrent Clostridioides difficile infection (rCDI) are urgently needed. RBX2660 is an investigational microbiota-based live biotherapeutic to reduce CDI recurrence following standard-of-care antibiotic treatment in individuals with rCDI. Here we report the final safety data through 24 months of follow-up as well as final efficacy data, reflecting alignment of the pre-specified statistical analysis plan definitions with the data presented., Methods: The PUNCH CD2 clinical trial was a prospective, multicenter, randomized, double-blinded, placebo-controlled, three-arm phase 2b study conducted to evaluate the efficacy and safety of RBX2660 for the reduction of rCDI compared to placebo. Eligible patients were at least 18 years of age and had at least three episodes of CDI and at least two rounds of standard antibiotic treatment or had at least two episodes of severe CDI resulting in hospitalization. Patients were randomized 1:1:1 to group A, two doses of RBX2660; group B, two doses of placebo; or group C, one dose of RBX2660 and one dose of placebo; all administered 7 ± 2 days apart. Treatment success was prevention of recurrence, defined as absence of diarrhea and no re-treatment for CDI any time after the first dose until 8 weeks after the second dose of the study treatment. Safety was assessed by reports of adverse events and symptoms. The final efficacy and safety are reported for data available through 24 months., Results: For the primary endpoint, treatment success at 8 weeks, 56.8% (25/45) of participants who received one dose of RBX2660 + one dose of placebo, 55.6% (25/45) of participants who received two doses of RBX2660, and 43.2% (19/44) of participants who received two doses of placebo in the final intention-to-treat (ITT) population were responders (both p = 0.2 vs placebo). In the per-protocol population, 87.5% (21/24) of participants who received one dose of RBX2660 + one dose of placebo and 58.1% (18/31) of those who received two doses of placebo had treatment success (p = 0.017; treatment difference, 29.4 [95% CI 7.6, 51.3]); 75.0% (21/28) of participants in the PP population who received two doses of RBX2660 were responders (p = 0.17 vs placebo). The safety profile of RBX2660, whether delivered as one or two doses, was similar to the placebo group., Conclusion: While the phase 2b PUNCH CD2 clinical trial did not meet its pre-defined primary endpoint of treatment success at 8 weeks after two doses of RBX2660 vs two doses of placebo, clinically meaningful data were obtained to justify proceeding with the single dose regimen in the phase 3 clinical trial, PUNCH CD3, now complete. To date, the cumulative data for RBX2660 demonstrate consistent efficacy and safety outcomes for reduction of CDI recurrence in adults., Clinical Trial Registration: ClinicalTrials.gov: NCT02299570., (© 2022. The Author(s).)

Objective: To use interrupted time-series analyses to investigate the impact of the coronavirus disease 2019 (COVID-19) pandemic on healthcare-associated infections (HAIs). We hypothesized that the pandemic would be associated with higher rates of HAIs after adjustment for confounders., Design: We conducted a cross-sectional study of HAIs in 3 hospitals in Missouri from January 1, 2017, through August 31, 2020, using interrupted time-series analysis with 2 counterfactual scenarios., Setting: The study was conducted at 1 large quaternary-care referral hospital and 2 community hospitals., Participants: All adults ≥18 years of age hospitalized at a study hospital for ≥48 hours were included in the study., Results: In total, 254,792 admissions for ≥48 hours occurred during the study period. The average age of these patients was 57.6 (±19.0) years, and 141,107 (55.6%) were female. At hospital 1, 78 CLABSIs, 33 CAUTIs, and 88 VAEs were documented during the pandemic period. Hospital 2 had 13 CLABSIs, 6 CAUTIs, and 17 VAEs. Hospital 3 recorded 11 CLABSIs, 8 CAUTIs, and 11 VAEs. Point estimates for hypothetical excess HAIs suggested an increase in all infection types across facilities, except for CLABSIs and CAUTIs at hospital 1 under the "no pandemic" scenario., Conclusions: The COVID-19 era was associated with increases in CLABSIs, CAUTIs, and VAEs at 3 hospitals in Missouri, with variations in significance by hospital and infection type. Continued vigilance in maintaining optimal infection prevention practices to minimize HAIs is warranted., (© The Author(s) 2023.)

Prevention of hazardous drug exposure is essential in averting unnecessary health risks to health care workers (HCW). To address the risk to HCWs when handling hazardous drugs, engineering controls can be utilized to reduce the exposure. A closed system transfer device (CSTD) was introduced for hazardous drugs administration in 6 oncology wards; this new CSTD was associated with a significant increase in CLABSI rates., (© 2023 The Authors.)

The prevalence of extended-spectrum beta-lactamases (ESBLs) among clinical isolates of Escherichia coli has been increasing, with this spread driven by ESBL-encoding plasmids. However, the epidemiology of ESBL-disseminating plasmids remains understudied, obscuring the roles of individual plasmid lineages in ESBL spread. To address this, we performed an in-depth genomic investigation of 149 clinical ESBL-like E. coli isolates from a tertiary care hospital. We obtained high-quality assemblies for 446 plasmids, revealing an extensive map of plasmid sharing that crosses time, space, and bacterial sequence type boundaries. Through a sequence-based network, we identified specific plasmid lineages that are responsible for the dissemination of major ESBLs. Notably, we demonstrate that IncF plasmids separate into 2 distinct lineages that are enriched for different ESBLs and occupy distinct host ranges. Our work provides a detailed picture of plasmid-mediated spread of ESBLs, demonstrating the extensive sequence diversity within identified lineages, while highlighting the genetic elements that underlie the persistence of these plasmids within the clinical E. coli population. IMPORTANCE The increasing incidence of nosocomial infections with extended-spectrum beta-lactamase (ESBL)-producing Escherichia coli represents a significant threat to public health, given the limited treatment options available for such infections. The rapid ESBL spread is suggested to be driven by localization of the resistance genes on conjugative plasmids. Here, we identify the contributions of different plasmid lineages in the nosocomial spread of ESBLs. We provide further support for plasmid-mediated spread of ESBLs but demonstrate that some ESBL genes rely on dissemination through plasmids more than the others. We identify key plasmid lineages that are enriched in major ESBL genes and highlight the encoded genetic elements that facilitate the transmission and stable maintenance of these plasmid groups within the clinical E. coli population. Overall, our work provides valuable insight into the dissemination of ESBLs through plasmids, furthering our understating of factors underlying the increased prevalence of these genes in nosocomial settings.

Background: The 2017 Infectious Diseases Society of America/Society for Healthcare Epidemiology of America (IDSA/SHEA) Clostridium (Clostridioides) difficile infection (CDI) guideline update recommended treatment with fidaxomicin or vancomycin for CDI. We aimed to examine outpatient CDI treatment utilization before and after the guideline update and compare clinical outcomes associated with fidaxomicin versus vancomycin use., Methods: A pre-post study design was employed using Medicare data. CDI treatment utilization and clinical outcomes (4- and 8-week sustained response, CDI recurrence) were compared between patients indexed from April-September 2017 (preguideline period) and those indexed from April-September 2018 (postguideline period). Clinical outcomes associated with fidaxomicin versus vancomycin were compared using propensity score-matched analyses., Results: From the pre- to postguideline period, metronidazole use decreased (initial CDI: 81.2% to 53.5%; recurrent CDI: 49.7% to 27.6%) while vancomycin (initial CDI: 17.9% to 44.9%; recurrent CDI: 48.1% to 66.4%) and fidaxomicin (initial CDI: 0.87% to 1.63%; recurrent CDI: 2.2% to 6.0%) use increased significantly ( P < .001 for all). However, clinical outcomes did not improve. In propensity score-matched analyses, fidaxomicin versus vancomycin users had 4-week sustained response rates that were higher by 13.5% (95% confidence interval [CI], 4.0%-22.9%; P = .0058) and 30.0% (95% CI, 16.8%-44.3%; P = .0002) in initial and recurrent CDI cohorts, respectively. Recurrence rates were numerically lower for fidaxomicin in both cohorts., Conclusions: Vancomycin use increased and metronidazole use decreased after the 2017 guideline update. Fidaxomicin use increased but remained low. Improved outcomes associated with fidaxomicin relative to vancomycin suggest benefits from its greater use in Medicare patients., Competing Interests: Potential conflicts of interest. ERD reports research funding from Ferring and Pfizer, and serving as a consultant for Merck, Pfizer, Seres, and Summit. JTP and SKB are employees of COVIA Health Solutions, a consulting firm with clients in the biotechnology/pharmaceutical sector. BCS has served as a consultant for COVIA Health Solutions. ENO and KD are current employees of Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Rahway, NJ, and may own stock and/or stock options in Merck & Co., Inc., Rahway, NJ, USA. JAD reports research funding from Humana, Janssen, Merck, NIH, PAN Foundation, Regeneron, and Sanofi, and serving as an advisory board member or consultant for AbbVie, Acadia, Allergan, Catabasis, Janssen, Merck, Otsuka, and Takeda. All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Conflicts that the editors consider relevant to the content of the manuscript have been disclosed. All other authors have no potential conflict of interests to declare., (© The Author(s) 2022. Published by Oxford University Press on behalf of Infectious Diseases Society of America.)

Large-scale genomic studies have identified within-host adaptation as a hallmark of bacterial infections. However, the impact of physiological, metabolic, and immunological differences between distinct niches on the pathoadaptation of opportunistic pathogens remains elusive. Here, we profile the within-host adaptation and evolutionary trajectories of 976 isolates representing 119 lineages of uropathogenic Escherichia coli (UPEC) sampled longitudinally from both the gastrointestinal and urinary tracts of 123 patients with urinary tract infections. We show that lineages persisting in both niches within a patient exhibit increased allelic diversity. Habitat-specific selection results in niche-specific adaptive mutations and genes, putatively mediating fitness in either environment. Within-lineage inter-habitat genomic plasticity mediated by mobile genetic elements (MGEs) provides the opportunistic pathogen with a mechanism to adapt to the physiological conditions of either habitat, and reduced MGE richness is associated with recurrence in gut-adapted UPEC lineages. Collectively, our results establish niche-specific adaptation as a driver of UPEC within-host evolution., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2022 Elsevier Inc. All rights reserved.)

The Practice Guidelines Committee of the American Society for Transplantation and Cellular Therapy partnered with its Transplant Infectious Disease Special Interest Group to update its 2009 compendium-style infectious disease guidelines for hematopoietic cell transplantation (HCT). A completely new approach was taken with the goal of better serving clinical providers by publishing each standalone topic in the infectious disease series as a concise format of frequently asked questions (FAQ), tables, and figures. Adult and pediatric infectious disease and HCT content experts developed and then answered FAQs and finalized topics with harmonized recommendations that were made by assigning an A through E strength of recommendation paired with a level of supporting evidence graded I through III. This fifth guideline in the series focuses on Clostridioides difficile infection with FAQs that address the prevalence, incidence, clinical features, colonization versus infection, clinical complications, diagnostic considerations, pharmacological therapies for episodic or recurrent infection, and the roles of prophylactic antibiotics, probiotics, and fecal microbiota transplantation., (Copyright © 2022 The American Society for Transplantation and Cellular Therapy. Published by Elsevier Inc. All rights reserved.)

Antibiotics are deployed against bacterial pathogens, but their targeting of conserved microbial processes means they also collaterally perturb the commensal microbiome. To understand acute and persistent effects of antibiotics on the gut microbiota of healthy adult volunteers, we quantify microbiome dynamics before, during, and 6 months after exposure to 4 commonly used antibiotic regimens. We observe an acute decrease in species richness and culturable bacteria after antibiotics, with most healthy adult microbiomes returning to pre-treatment species richness after 2 months, but with an altered taxonomy, resistome, and metabolic output, as well as an increased antibiotic resistance burden. Azithromycin delays the recovery of species richness, resulting in greater compositional distance. A subset of volunteers experience a persistent reduction in microbiome diversity after antibiotics and share compositional similarities with patients hospitalized in intensive care units. These results improve our quantitative understanding of the impact of antibiotics on commensal microbiome dynamics, resilience, and recovery., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2022 The Author(s). Published by Elsevier Inc. All rights reserved.)

Background: Effective treatment options for recurrent Clostridioides difficile infection (rCDI) are limited, with high recurrence rates associated with the current standard of care. Herein we report results from an open-label Phase 2 trial to evaluate the safety, efficacy, and durability of RBX2660-a standardized microbiota-based investigational live biotherapeutic-and a closely-matched historical control cohort., Methods: This prospective, multicenter, open-label Phase 2 study enrolled patients who had experienced either ≥ 2 recurrences of CDI, treated by standard-of-care antibiotic therapy, after a primary CDI episode, or ≥ 2 episodes of severe CDI requiring hospitalization. Participants received up to 2 doses of RBX2660 rectally administered with doses 7 days apart. Treatment success was defined as the absence of CDI diarrhea without the need for retreatment for 8 weeks after completing study treatment. A historical control group with matched inclusion and exclusion criteria was identified from a retrospective chart review of participants treated with standard-of-care antibiotics for recurrent CDI who matched key criteria for the study. The primary objective was to compare treatment success of RBX2660 to the historical control group. A key secondary outcome was the safety profile of RBX2660, including adverse events and CDI occurrence through 24 months after treatment. In addition, fecal samples from RBX2660-treated participants were sequenced to evaluate microbiome composition and functional changes from before to after treatment., Results: In this Phase 2 open-label clinical trial, RBX2660 demonstrated a 78.9% (112/142) treatment success rate compared to a 30.7% (23/75) for the historical control group (p < 0.0001; Chi-square test). Post-hoc analysis indicated that 91% (88/97) of evaluable RBX2660 responders remained CDI occurrence-free to 24 months after treatment demonstrating durability. RBX2660 was well-tolerated with mostly mild to moderate adverse events. The composition and diversity of RBX2660 responders' fecal microbiome significantly changed from before to after treatment to become more similar to RBX2660, and these changes were durable to 24 months after treatment., Conclusions: In this Phase 2 trial, RBX2660 was safe and effective for reducing rCDI recurrence as compared to a historical control group. Microbiome changes are consistent with restorative changes implicated in resisting C. difficile recurrence. Clinical Trials Registration NCT02589847 (10/28/2015)., (© 2022. The Author(s).)

Background: Hospitalized patients with diarrhea who have a negative Clostridoides difficile (C. difficile) test are not routinely evaluated for alternative causes of infectious diarrhea. This study assessed for potential infectious causes of diarrhea in hospitalized patients with an order for repeat C. difficile toxin enzyme immunoassay (tEIA) testing after an initial tEIA test was negative., Methods: For patients age ≥18 years who had a second C. difficile tEIA test ordered within 96 h after a negative tEIA test, remnant fecal specimens from the first (negative) tEIA test were evaluated using the BioFire FilmArray Gastrointestinal Panel PCR, C. difficile toxigenic culture, and culture on a blood agar plate (BAP) to identify other potential causes of infectious diarrhea. Growth of organisms on the BAP was also used to assess potential disruptions in the gastrointestinal microbiota., Results: Among 84 remnant specimens, toxigenic C. difficile was identified in 9 (11%) by culture or PCR, while potential alternative causes of infectious diarrhea, including norovirus, rotavirus, enteropathogenic Escherichia coli, and Salmonella, were identified in 11 specimens (13%) by PCR. For the majority of patients, no infectious cause of diarrhea was identified, but 84% exhibited disrupted gastrointestinal microbiota, which may contribute to diarrhea., Conclusions: When a hospitalized patient has a negative C. difficile tEIA test but continues to have diarrhea, alternative infectious and noninfectious causes of diarrhea should be considered. If the patient has clinical signs and symptoms suggestive of infection or risk factors for gastrointestinal infection, laboratory testing for other etiologic agents may be appropriate., (© American Association for Clinical Chemistry 2021. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Objective: Alteration of the colonic microbiota following antimicrobial exposure allows colonization by antimicrobial-resistant organisms (AROs). Ingestion of a probiotic, such as Lactobacillus rhamnosus GG (LGG), could prevent colonization or infection with AROs by promoting healthy colonic microbiota. The purpose of this trial was to determine the effect of LGG administration on ARO colonization in hospitalized patients receiving antibiotics., Design: Prospective, double-blinded, randomized controlled trial of LGG versus placebo among patients receiving broad-spectrum antibiotics., Setting: Tertiary care center., Patients: In total, 88 inpatients receiving broad-spectrum antibiotics were enrolled., Intervention: Patients were randomized to receive 1 capsule containing 1×1010 cells of LGG twice daily (n = 44) or placebo (n = 44), stratified by ward type. Stool or rectal-swab specimens were collected for culture at enrollment, during admission, and at discharge. Using selective media, specimens were cultured for Clostridioides difficile, vancomycin-resistant Enterococcus spp (VRE), and antibiotic-resistant gram-negative bacteria. The primary outcome was any ARO acquisition. Secondary outcomes included loss of any ARO if colonized at enrollment, and acquisition or loss of individual ARO., Results: ARO colonization prevalence at study enrollment was similar (LGG 39% vs placebo 39%). We detected no difference in any ARO acquisition (LGG 30% vs placebo 33%; OR,1.19; 95% CI, 0.38-3.75) nor for any individual ARO acquisition. There was no difference in the loss of any ARO (LGG 18% vs placebo 24%; OR, 1.44; 95% CI, 0.27-7.68) nor for any individual ARO., Conclusion: LGG administration neither prevented acquisition of ARO nor accelerated loss of ARO colonization.

Clostridioides difficile infection (CDI) imposes a substantial burden on the health care system in the United States. Understanding the biological basis for the spectrum of C. difficile -related disease manifestations is imperative to improving treatment and prevention of CDI. Here, we investigate the correlates of asymptomatic C. difficile colonization using a multi-omics approach. We compared the fecal microbiome and metabolome profiles of patients with CDI versus asymptomatically colonized patients, integrating clinical and pathogen factors into our analysis. We found that CDI patients were more likely to be colonized by strains with the binary toxin (CDT) locus or strains of ribotype 027, which are often hypervirulent. We find that microbiomes of asymptomatically colonized patients are significantly enriched for species in the class Clostridia relative to those of symptomatic patients. Relative to CDI microbiomes, asymptomatically colonized patient microbiomes were enriched with sucrose degradation pathways encoded by commensal Clostridia, in addition to glycoside hydrolases putatively involved in starch and sucrose degradation. Fecal metabolomics corroborates the carbohydrate degradation signature: we identify carbohydrate compounds enriched in asymptomatically colonized patients relative to CDI patients. Further, we reveal that across C. difficile isolates, the carbohydrates sucrose, rhamnose, and lactulose do not serve as robust growth substrates in vitro, consistent with their enriched detection in our metagenomic and metabolite profiling of asymptomatically colonized individuals. We conclude that pathogen genetic variation may be strongly related to disease outcome. More interestingly, we hypothesize that in asymptomatically colonized individuals, carbohydrate metabolism by other commensal Clostridia may prevent CDI by inhibiting C. difficile proliferation. These insights into C. difficile colonization and putative commensal competition suggest novel avenues to develop probiotic or prebiotic therapeutics against CDI., Competing Interests: SF, JR, TH, KR, EN, CB, JH, GD No competing interests declared, ED E.R.D. has received research support from Synthetic Biologics, Pfizer and Ferring, and has been a consultant for Summit, Merck, Ferring, Pfizer and Seres Therapeutics, all unrelated to this study, (© 2022, Fishbein et al.)

Purpose of Review: To describe the current state of literature on modeling risk of incident and recurrent Clostridioides difficile infection (iCDI and rCDI), to underscore limitations, and to propose a path forward for future research., Recent Findings: There are many published risk factors and models for both iCDI and rCDI. The approaches include scores with a limited list of variables designed to be used at the bedside, but more recently have also included automated tools that take advantage of the entire electronic health record. Recent attempts to externally validate scores have met with mixed success., Summary: For iCDI, the performance largely hinges on the incidence, which even for hospitalized patients can be low (often <1%). Most scores fail to achieve high accuracy and/or are not externally validated. A challenge in predicting rCDI is the significant overlap with risk factors for iCDI, reducing the discriminatory ability of models. Automated electronic health record-based tools show promise but portability to other centers is challenging. Future studies should include external validation and consider biomarkers to augment performance., (Copyright © 2021 Wolters Kluwer Health, Inc. All rights reserved.)

Introduction: Drive line infections (DLIs) are common complications of left ventricular assist devices (LVADs). Data on use of suppression antibiotic therapy are limited., Methods: We performed a retrospective review of 451 patients who underwent LVAD placement from January 2009 to May 2015. First superficial DLIs were included for analysis. We examined factors associated with the use of chronic suppressive antibiotics (CSAs) therapy. Cox proportional hazards models were performed to identify factors associated with DLI relapse with the same organism as the initial DLI., Results: A total of 69 patients developed a superficial DLI within a median of 195 (interquartile range [IQR] 98-348) days of LVAD insertion. The median age was 57 years, 87% were males, and 74% were White. Gram positive bacteria caused 61% of infections, with Staphylococcus aureus being the most common (35%). Forty-three (62%) patients received suppressive antibiotic therapy. Relapse DLI occurred in 29 (42%) patients. Independent risk factors for relapse infection in multivariable analysis were sepsis (aHR 5.94 [CI 1.42-24.92]), and MRSA DLI (aHR 4.19 [CI 1.37-12.79]). There was no difference in the proportion of patients with relapse among those who were treated with antibiotic suppression therapy versus not (44% vs. 38%, p = 0.64), although relapse occurred at a later time in those who received suppression (185 vs. 69 days, p < 0.01)., Conclusion: CSA therapy was associated with delayed time to DLI relapse but no significant difference in the proportion of patients with relapse. A prospective study is needed to examine the effect of suppression on relapse rates., (© 2021 Wiley Periodicals LLC.)