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Carolyn D Alonso,1,2 Monica V Mahoney3 1Department of Medicine, Division of Infectious Diseases, Beth Israel Deaconess Medical Center, Boston, MA, USA; 2Harvard Medical School, Boston, MA, USA; 3Department of Pharmacy, Beth Israel Deaconess Medical Center, Boston, MA, USA Abstract: Clostridium difficile infection (CDI) is a leading nosocomial disease estimated to cause nearly half a million cases in the United States annually. Recurrent CDI (rCDI) affects ~25% of patients after completion of standard of care therapy and is associated with substantial health care costs and a negative impact on patient’s overall markers of quality of life. Bezlotoxumab is the first of its kind monoclonal antibody directed against C. difficile toxin B and indicated for prevention of rCDI in at-risk patients. For the present review, we assessed English-language studies evaluating the clinical efficacy, safety, and pharmacokinetics of bezlotoxumab in humans. Relevant studies were obtained through PubMed, Embase, Cochrane database library, Web of Science, and clinicaltrials.gov. Overall, bezlotoxumab demonstrated a 40% relative reduction rate (absolute rate reduction of ~10%) and a number needed to treat of 10 patients with a favorable safety profile. Special populations, including the elderly, immunocompromised, and patients with end-stage renal disease were evaluated in post hoc analyses with a similarly favorable reduction in rCDI. This review presents and interprets the most recent safety data and the clinical application of bezlotoxumab, highlighting specific high-risk patient populations. Keywords: MK-6072, MDX-1388, Clostridium difficile monoclonal antibody, Clostridioides difficile, bezlotoxumab, Zinplava

Clostridioides difficile infection (CDI) is a well-known cause of hospital-acquired infectious diarrhea in developed countries, though it has not been a top priority in the healthcare policies of developing countries. In the last decade, several studies have reported a wide range of CDI rates between 1.3% and 96% in developing nations, raising the concern that this could represent a healthcare threat for these nations. This review defines developing countries as those with a human development index (HDI) below 0.8. We aim to report the available literature on CDI epidemiology, diagnostics, management, and prevention in developing countries. We identify limitations for CDI diagnosis and management, such as limited access to CDI tests and unavailable oral vancomycin formulation, and identify opportunities to enhance CDI care, such as increased molecular test capabilities and creative solutions for CDI. We also discuss infection prevention strategies, including antimicrobial stewardship programs and opportunities emerging from the COVID-19 pandemic, which could impact CDI care.

Purpose: Kidney transplantation has a survival benefit for people with human immunodeficiency virus (HIV) and end-stage kidney disease, however increased rates of rejection remain an issue. Questions remain regarding the impact of induction immunosuppression therapy and antiretroviral (ARV) choice on long-term outcomes., Methods: We performed a multicenter retrospective analysis of outcomes in recipients with HIV who received kidneys from donors without HIV transplanted between 2004 and 2019. The association between induction and ARV regimens and long-term outcomes including rejection, graft, and recipient survival over 5 years was investigated using Cox regression modeling., Results: Seventy-eight kidney transplants (KT) performed in 77 recipients at five US transplant centers were included, with median follow up of 7.1 (4.3-10.7) years. Overall recipient and graft survival were 83% and 67%, respectively. Rejection occurred in 37% (29/78). Recipients with rejection were more likely to be younger, recipients of deceased donor organs, and Black. Receipt of rabbit anti-thymocyte globulin (rATG) induction without protease-inhibitor (PI)-based ARVs was associated with 83% lower risk of rejection (adjusted hazard ratio (aHR) 0.17 (95% CI 0.05-0.63), p =.007) and a non-statistically significantly lower risk of graft failure (aHR 0.18 (0.03-1.16), p =.07) when compared to those who received other induction and ARV combinations., Conclusions: In this multicenter retrospective study, we found a trend toward lower rejection and improved graft survival among those who received both rATG for induction and PI-sparing ARVs., (© 2024 Takeda Development Center Americas, Inc. Transplant Infectious Disease published by Wiley Periodicals LLC.)

Background: Antibiotic use is a major risk factor for recurrent Clostridioides difficile infection (CDI) due to the associated disruption in gut microbiota. Fecal microbiota, live-jslm (REBYOTA®; RBL, previously RBX2660), is the first microbiota-based live biotherapeutic approved by the US Food and Drug Administration to prevent recurrent CDI in adults following standard-of-care antibiotic treatment. To investigate the impact of non-CDI antibiotics on the durability of RBL, a subgroup analysis was conducted on PUNCH™ Open-Label study participants who received non-CDI antibiotics during the period between RBL administration and up to 2 years after., Methods: Participants in PUNCH™ Open-Label who received non-CDI antibiotics after RBL administration were included in this subgroup analysis. Treatment response was defined as the absence of CDI diarrhea needing retreatment at the last evaluable time point (8 weeks, 6 months, 1 year, or 2 years) after RBL administration., Results: Among participants from PUNCH™ Open-Label, 43 received non-CDI antibiotics after RBL administration but before CDI recurrence as evaluated over a 2-year period. Across all evaluable time points, 86% (37/43) of participants had a treatment response regardless of when non-CDI antibiotic exposure occurred. Treatment response was sustained for a median 470 days (IQR, 212-648) from the first day of non-CDI antibiotic use. Most participants (5/6) with CDI recurrences received a high-risk antibiotic., Conclusions: RBL remained efficacious in participants with a history of recurrent CDI after subsequent non-CDI antibiotic exposure., Clinical Trials Registration: NCT02589847 (https://clinicaltrials.gov/study/NCT02589847)., Competing Interests: Potential conflicts of interest. K. R. R. served as a consultant and speaker for Ferring Pharmaceuticals and received research funding (paid to her institution) from Merck & Co, Inc, and AstraZeneca. A. J. G.-L. received prior research funding paid to her institution from Cidara Therapeutics, Paratek Pharmaceuticals, Merck, and Seres Therapeutics and served as a consultant for Ferring Pharmaceuticals and Innoviva Specialty Therapeutics. Y. G. has served as a consultant for Ferring Pharmaceuticals, Seres Therapeutics, and Vedanta and as a principal investigator for Vedanta and has received honoraria for speaking for Ferring and Seres. C. D. A. received prior research funding from Merck paid to her institution; served in an advisory role to Cidara Therapeutics, AiCuris, Merck, DSM-Firmenich, and Pfizer; and received honoraria for speaking from the Academy for Continued Healthcare Learning, American Society of Health System Pharmacists, and Clinical Care Options. B. G. is an employee of Rebiotix Inc, a Ferring Company. M. R. B. is an employee of Ferring Pharmaceuticals. X. T. and V. P. were employees of Ferring Pharmaceuticals at the time of the analysis. C. V. C. has served as a consultant for Ferring Pharmaceuticals and Seres Therapeutics. A. M. S. received prior research funding paid to his institution from Paratek Pharmaceuticals; serves on the advisory board of Bio-K+; has served as a consultant for Ferring Pharmaceuticals; and has received honoraria for speaking from the American Society of Health System Pharmacist, MJH Life Sciences, and Academy for Continued Healthcare Learning., (© The Author(s) 2024. Published by Oxford University Press on behalf of Infectious Diseases Society of America.)

Solid organ transplant recipients (SOTRs) frequently receive adjunctive glucocorticoid therapy (AGT) for Pneumocystis jirovecii pneumonia (PJP). This multicenter cohort of SOTRs with PJP admitted to 20 transplant centers in Canada, the United States, Europe, and Australia, was examined for whether AGT was associated with a lower rate of all-cause intensive care unit (ICU) admission, 90-day death, or a composite outcome (ICU admission or death). Of 172 SOTRs with PJP (median [IQR] age: 60 (51.5-67.0) years; 58 female [33.7%]), the ICU admission and death rates were 43.4%, and 20.8%, respectively. AGT was not associated with a reduced risk of ICU admission (adjusted odds ratio [aOR] [95% CI]: 0.49 [0.21-1.12]), death (aOR [95% CI]: 0.80 [0.30-2.17]), or the composite outcome (aOR [95% CI]: 0.97 [0.71-1.31]) in the propensity score-adjusted analysis. AGT was not significantly associated with at least 1 unit of the respiratory portion of the Sequential Organ Failure Assessment score improvement by day 5 (12/37 [32.4%] vs 39/111 [35.1%]; P = .78). We did not observe significant associations between AGT and ICU admission or death in SOTRs with PJP. Our findings should prompt a reevaluation of routine AGT administration in posttransplant PJP treatment and highlight the need for interventional studies., (Crown Copyright © 2023. Published by Elsevier Inc. All rights reserved.)

Bloodstream infections (BSIs) account for 18% of bacterial infections in the first year after solid organ transplantation (SOT). Enterococcus accounts for up to 20% of BSIs in this population, with vancomycin-resistant enterococcus (VRE) posing a particular risk. This is a retrospective, case-control study of adult liver and kidney transplant recipients between 01/01/2016 and 06/30/2021 that characterizes the epidemiology and outcomes of enterococcal BSIs in liver and kidney transplantations at a single institution. Subjects with an enterococcal BSI within the first 6 months post-transplant were compared to those with non-enterococcal BSIs in the same period. We identified 26 subjects with enterococcal BSIs and 28 controls with non-enterococcal BSIs (n = 54; 10.3%). Cases were mostly liver transplant recipients (n = 20; 77%) with a median MELD at transplant of 33 (range 14-43); controls included 14 KT recipients (50%). Groups differed significantly (all p < .05) by factors including perioperative transfusion requirements, need for reoperation, and number of interventions post-transplant. Cases had a median time of 25.5 days to infection and controls 100.5 days (p < .0001). There were no differences in 1-year mortality between the groups. Enterococcus faecium was the predominant species of Enterococcus (n = 23; 88.5%), with a majority (91.3%) of the isolates being VRE. In our liver and kidney transplants, enterococcal BSIs occurred early among liver transplant recipients. The high incidence of VRE among E. faecium isolates in this population warrants further investigation into the optimal approach to empiric antimicrobials for bacteremia in the early post-transplant period., (© 2024 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Background: Immunosuppression in solid organ transplantation (SOT) increases the risk of Epstein-Barr virus (EBV) DNAemia, which may herald development of posttransplant lymphoproliferative disease (PTLD). Few studies have characterized the incidence, risk factors, and clinical impact of EBV DNAemia in adult SOT recipients (SOTR)., Methods: A single-center, retrospective review of adult (≥18 years) SOTR between 01 January 2015 and 31 December 2019 was conducted. Patients were stratified by the primary study endpoint of development of EBV DNAemia (whole blood EBV DNA PCR > 200 copies/mL). Secondary endpoints included development of PTLD, reduction in immunosuppression (RIS), use of pre-emptive therapy, and all-cause mortality., Results: Among 442 adult SOTR, the predominant transplant organs were the kidney (258, 58%) and liver (141, 31.9%). EBV serostatus in most subjects (430, 97%) was classified as intermediate risk (R+). Eight subjects (2%) were high risk (donor (D+/R-), and 4 (1%) were low risk (D-/R-). The overall incidence of EBV DNAemia was 4.1% (18/442) with a median time to detection of 14 months (range 3-60). The highest proportion of DNAemia was observed in D+/R- subjects (37.5%; p < 0.001). Development of PTLD was significantly associated with EBV DNAemia and occurred in 3/18 patients with DNAemia (16.7%) vs. 3/424 (0.7%) without DNAemia ( p < 0.001). All patients with PTLD were managed with RIS and rituximab., Conclusion: We observed that EBV D+/R- serostatus and development of sustained EBV DNAemia were high risk features associated with subsequent development of PTLD in our cohort of adult SOTR., Competing Interests: CDA has received research funding from Merck (paid to BIDMC) and has served in an advisory role to Cidara Therapeutics, AiCuris, and Merck. The authors declare that they have no conflicts of interest., (Copyright © 2024 Sara W. Dong et al.)

Background: SARS-CoV-2 infection in solid organ transplant (SOT) recipients is associated with high morbidity and mortality. Tixagevimab/cilgavimab monoclonal antibodies were previously authorized for pre-exposure prophylaxis for immunocompromised individuals. We aimed to determine if tixagevimab/cilgavimab could prevent breakthrough SARS-CoV-2 infection in SOT recipients., Material and Methods: We conducted a prospective single-center study of SOT recipients who received tixagevimab/cilgavimab compared with those who did not. Demographics, type of transplant, immunosuppression regimen, COVID-19 vaccination status, and tixagevimab/cilgavimab administration data were collected. Participants were interviewed for 6 months or until they tested positive for SARS-CoV-2, whichever came first. Kaplan-Meier SARS-CoV-2-free survival curves were created based on the tixagevimab/cilgavimab administration date and SARS-CoV-2 infection. The log-rank test was used for comparison. Univariate and multivariate Cox regression models were constructed., Results: The study cohort included 323 patients. Two hundred forty-eight received tixagevimab/cilgavimab, and 75 did not (control). COVID-19 vaccination rate was higher among tixagevimab/cilgavimab recipients than nontixagevimab/cilgavimab recipients (99.6% vs 92.0%; P < .001). Twenty-six patients in the tixagevimab/cilgavimab group (10.5%) and 23 in the control group (30.7%) tested positive for SARS-CoV-2 infection (P < .001). In a multivariate analysis, receipt of tixagevimab/cilgavimab and duration from transplant were both associated with reduced risk of SARS-CoV-2 infection (hazard ratio 0.431; 95% CI 0.224-0.828 and hazard ratio 0.917; 95% CI 0.861-0.978, respectively)., Conclusion: During the study period, SOT recipients who received tixagevimab/cilgavimab had a significantly lower rate of SARS-CoV-2 infection. There were no differences in symptom frequency, illness severity, hospitalization rate, or treatment of SARS-CoV-2 infection., Competing Interests: Declaration of Competing Interest Martha Pavlakis received research support from Transplant Genomics, CareDx. Consulting fees from Moderna, Merck & Co, Inc. and Vertex Pharmaceuticals. Carolyn D. Alonso received research support: Merck & Co, Inc. Advisory boards: Cidara Therapeutics, Merck, AiCuris. Honoraria for presentations: American Society of Healthcare Pharmacists, Academy for Continued Healthcare Learning. Michael Curry received research support from Mallinckrodt, Sonic Incytes. Consulting fees from Mallinckrodt, Sonic Incytes, Albireo, Alexion., (Copyright © 2023 Elsevier Inc. All rights reserved.)

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.)

Background: Clostridioides difficile infection (CDI) immune response is influenced by the innate and adaptive (humoral) immune systems. Our prior research found attenuated humoral responses to C difficile in immunocompromised hosts (ICHs) with CDI. We sought to evaluate whether the innate immune response to CDI was influenced by ICH status., Methods: We conducted a prospective study of hospitalized adults with CDI (acute diarrhea, positive C difficile stool nucleic acid amplification testing [NAAT], and decision to treat), with and without immunosuppression and measured a panel of cytokines (granulocyte colony-stimulating factor [G-CSF], interleukin [IL]-10, IL-15, IL-1β, IL-4, IL-6, IL-8, and tumor necrosis factor-α) in blood and stool at CDI diagnosis. Results were compared with measurements from a cohort of asymptomatic carrier patients (ASCs) (NAAT positive, without diarrhea) with and without immunocompromise., Results: One hundred twenty-three subjects (42 ICHs, 50 non-ICHs, 31 ASCs) were included. Median values for blood and stool cytokines were similar in ICH versus non-ICH CDI subjects. In blood, G-CSF, IL-10, IL-15, IL-6, and IL-8 were higher in both groups of CDI subjects versus the ASC cohort ( P < .05). In stool, IL-1β and IL-8 were higher in both groups of CDI subjects versus the ASC cohort ( P < .05). Median stool concentrations of IL-1β demonstrated significant differences between the groups (ICHs, 10.97 pg/mL; non-ICHs, 9.71 pg/mL; and ASCs, 0.56 pg/mL) ( P < .0001)., Conclusions: In this small exploratory analysis, ICH status did not significantly impact blood and fecal patterns of cytokines in humans at the diagnosis of CDI, suggesting that the innate immune response to C difficile may be conserved in immunocompromised patients., Competing Interests: Potential conflicts of interest. J. V.-G. receives partial salary support from an unrestricted research grant from Milky Way Life Sciences to Beth Israel Deaconess Medical Center (BIDMC). C. P. K. has acted as a paid consultant to Artugen, Facile Therapeutics, Ferring, First Light Biosciences, Finch, Milky Way Life Sciences, Pfizer, RVAC Medicines, Seres, Summit, and Vedanta and has received grant support from Milky Way Life Sciences and Pfizer. K. W. G. has received grant support paid to the University of Houston from Acurx, Summit, Paratek Pharmaceuticals, and Seres Health. C. D. A. has received research funding from Merck (paid to BIDMC) and has served in an advisory role to Cidara Therapeutics, AiCuris, and Merck. All other authors report no conflicts of interest., (© The Author(s) 2023. Published by Oxford University Press on behalf of Infectious Diseases Society of America.)

Background: Despite advances in the understanding and diagnosis of Clostridioides difficile infection (CDI), clinical distinction within the colonization-infection continuum remains an unmet need., Methods: By measuring stool cytokines and antitoxin antibodies in well-characterized cohorts of CDI (diarrhea, nucleic acid amplification test [NAAT] positive), non-CDI diarrhea (NCD; diarrhea, NAAT negative), asymptomatic carriers (ASC; no diarrhea, NAAT positive) and hospital controls (CON; no diarrhea, NAAT negative), we aim to discover novel biological markers to distinguish between these cohorts. We also explore the relationship of these stool cytokines and antitoxin antibody with stool toxin concentrations and disease severity., Results: Stool interleukin (IL) 1β, stool immunoglobulin A (IgA), and immunoglobulin G (IgG) anti-toxin A had higher (P < .0001) concentrations in CDI (n = 120) vs ASC (n = 43), whereas toxins A, B, and fecal calprotectin did not. Areas under the receiver operating characteristic curve (ROC-AUCs) for IL-1β, IgA, and IgG anti-toxin A were 0.88, 0.83, and 0.83, respectively. A multipredictor model including IL-1β and IgA anti-toxin A achieved an ROC-AUC of 0.93. Stool IL-1β concentrations were higher in CDI compared to NCD (n = 75) (P < .0001) and NCD + ASC+ CON (CON, n = 75) (P < .0001), with ROC-AUCs of 0.83 and 0.86, respectively. Stool IL-1β had positive correlations with toxins A (ρA = +0.55) and B (ρB = +0.49) in CDI (P < .0001) but not in ASC (P > .05)., Conclusions: Stool concentrations of the inflammasome pathway, proinflammatory cytokine IL-1β, can accurately differentiate CDI from asymptomatic carriage and NCD, making it a promising biomarker for CDI diagnosis. Significant positive correlations exist between stool toxins and stool IL-1β in CDI but not in asymptomatic carriers., Competing Interests: Potential conflicts of interest. C. D. A. has received grant support from Merck (investigator-initiated award, paid to institution); consulting fees for advisory board from Cidara Therapeutics, Merck, and Prime Meridian Group (on behalf of AiCuris); and honoraria for presentations from the American Society of Healthcare Pharmacists. A. B. reports being an employee of bioMérieux. M. M. reports being an employee of bioMérieux and a holder of patent (Susceptibility to C. difficile infection and Fecal Immunoglobulins; bioMérieux). C. P. K. has acted as a paid consultant to Artugen, Facile Therapeutics, Ferring, First Light Biosciences, Finch, Janssen (J&J), Milky Way Life Sciences, Pfizer, Seres, Summit, RVAC Medicines, and Vedanta; has received grant support from Milky Way Life Sciences; reports participation on a data and safety monitoring board or advisory board from Finch Therapeutics (payments to self); has served as Secretary (unpaid) for the Society for the Study of Celiac Disease; and holds stock or stock options from First Light. K. W. G. has received grant support paid to the University of Houston from Acurx, Summit, Paratek Pharmaceuticals, Tetraphase Pharmaceuticals, and Seres Health, and reports consulting fees from Acurx and Summit Pharmaceuticals. 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) 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.)

Ultrasensitive, quantitative Clostridioides difficile stool toxin measurement demonstrated significantly higher concentrations of toxins A and B in patients infected with the North American pulsed-field gel electrophoresis type 1/ribotype 027 (NAP-1/027) strain compared with other strains, providing in vivo confirmation of the in vitro association between NAP-1/027 and elevated toxin production., Competing Interests: Potential conflicts of interest . C. D. A. has received grant support from Merck (investigator-initiated award, paid to their institution) and an NIH Loan Repayment Award, outside the submitted work. C. P. K. reports stock ownership options with First Light; has served as an investigator for a Pfizer-sponsored research study; has served as an investigator for a Merck-sponsored research study; has served as an investigator for a Janssen-sponsored research study; has acted as a paid consultant to Artugen (scientific advisor on clinical and clinical research aspects of Clostridioides difficile infection [CDI]), Facile Therapeutics (scientific advisor on clinical and clinical research aspects of CDI), Ferring (scientific advisor on clinical and clinical research aspects of CDI), First Light Biosciences (scientific advisor on clinical and clinical research aspects of diagnosis of CDI), Finch (scientific advisor on clinical and clinical research aspects of CDI), Janssen (J&J) (scientific advisor on clinical and research aspects of CDI), Matrivax (scientific advisor on C. difficile vaccine development), Merck (scientific advisor on clinical and research aspects of CDI), Seres, Pfizer (scientific advisor on C. difficile vaccine development), and Vedanta (scientific advisor on clinical and clinical research aspects of CDI). K. W. G. has received grant support from Acurx, Paratek, Summit, and Tetraphase Pharmaceuticals (research grants paid to the university) and has received consulting fees from Acurx and Summit Pharmaceuticals. M. M., A. F., A. L., and A. B. are employees of bioMérieux. 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) 2022. Published by Oxford University Press on behalf of the Infectious Diseases Society of America. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

The eye and the kidney share structural and developmental similarities on a cellular and clinical level, and they are often affected by the same disease processes. Performing an eye exam to look for signs of conditions such as hypertension and diabetes can provide a helpful window into the health of the kidney. Patients with kidney transplants (KT) are a unique population that require close monitoring. These patients are maintained on a number of immunosuppressive medications and may face complications such as medication side effects, infections, and graft rejection. Patients with KT are at higher risk of both infectious and noninfectious eye conditions related to underlying systemic disease or use of immunosuppressive medications. Screening for eye conditions is important because preserving visual function is integral to quality of life, and also because the eye exam can help with early detection and treatment of systemic conditions. Here we describe some of the common eye findings and conditions in patients with KT. We recommend that patients with KT receive annual eye exams, and we hope that the information provided here can help nephrologists become more familiar with eye findings and identify situations where a referral to ophthalmology is warranted., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Background: Stool toxin concentrations may impact Clostridioides difficile infection (CDI) severity and outcomes. We correlated fecal C difficile toxin concentrations, measured by an ultrasensitive and quantitative assay, with CDI baseline severity, attributable outcomes, and recurrence., Methods: We enrolled 615 hospitalized adults (≥18 years) with CDI (acute diarrhea, positive stool nucleic acid amplification testing, and decision to treat). Baseline stool toxin A and B concentrations were measured by single molecule array. Subjects were classified by baseline CDI severity (4 scoring methods) and outcomes within 40 days (death, intensive care unit stay, colectomy, and recurrence)., Results: Among 615 patients (median, 68.0 years), in all scoring systems, subjects with severe baseline disease had higher stool toxin A+B concentrations than those without (P < .01). Nineteen subjects (3.1%) had a severe outcome primarily attributed to CDI (group 1). This group had higher median toxin A+B (14 303 pg/mL [interquartile range, 416.0, 141 967]) than subjects in whom CDI only contributed to the outcome (group 2, 163.2 pg/mL [0.0, 8423.3]), subjects with severe outcome unrelated to CDI (group 3, 158.6 pg/mL [0.0, 1795.2]), or no severe outcome (group 4, 209.5 pg/mL [0.0, 8566.3]) (P = .003). Group 1 was more likely to have detectable toxin (94.7%) than groups 2-4 (60.5%-66.1%) (P = .02). Individuals with recurrence had higher toxin A+B (2266.8 pg/mL [188.8, 29411]) than those without (154.0 pg/mL [0.0, 5864.3]) (P < .001) and higher rates of detectable toxin (85.7% versus 64.0%, P = .004)., Conclusions: In CDI patients, ultrasensitive stool toxin detection and concentration correlated with severe baseline disease, severe CDI-attributable outcomes, and recurrence, confirming the contribution of toxin quantity to disease presentation and clinical course., (© The Author(s) 2021. Published by Oxford University Press for the Infectious Diseases Society of America. All rights reserved. For permissions, e-mail: journals.permissions@oup.com.)

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.)

There are no studies comparing the prognosis for mature T-cell lymphoma (TCL) in people with HIV (PWH) to people without HIV (PWoH) and to AIDS-defining B-cell lymphomas (A-BCLs) in the modern antiretroviral therapy era. North American AIDS Cohort Collaboration on Research and Design and Comprehensive Oncology Measures for Peripheral T-cell Lymphoma Treatment are cohorts that enroll patients diagnosed with HIV and TCL, respectively. In our study, 52, 64, 101, 500, and 246 PWH with histologic confirmation of TCL, primary central nervous system lymphoma, Burkitt's lymphoma, diffuse large B-cell lymphoma (DLBCL), and Hodgkin's lymphoma (HL), respectively, and 450 TCLs without HIV were eligible for analysis. At the time of TCL diagnosis, anaplastic large-cell lymphoma (ALCL) was the most common TCL subtype within PWH. Although PWH with TCL diagnosed between 1996 and 2009 experienced a low 5-year survival probability at 0.23 (95% confidence interval [CI]: 0.13, 0.41), we observed a marked improvement in their survival when diagnosed between 2010 and 2016 (0.69; 95% CI: 0.48, 1; P = .04) in contrast to TCLs among PWoH (0.45; 95% CI: 0.41, 0.51; P = .53). Similarly, PWH with ALCLs diagnosed between 1996 and 2009 were associated with a conspicuously inferior 5-year survival probability (0.17; 95% CI: 0.07, 0.42) and consistently lagged behind A-BCL subtypes such as Burkitt's (0.43; 95% CI:0.33, 0.57; P = .09) and DLBCL (0.17; 95% CI: 0.06, 0.46; P = .11) and behind HL (0.57; 95% CI: 0.50, 0.65; P < .0001). Despite a small number, those diagnosed between 2010 and 2016 experienced a remarkable improvement in survival (0.67; 95% CI: 0.3, 1) in comparison with PWoH (0.76; 95% CI: 0.66, 0.87; P = .58). Thus, our analysis confirms improved overall survival for aggressive B- and T-cell malignancies among PWH in the last decade., (© 2022 by The American Society of Hematology. Licensed under Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0), permitting only noncommercial, nonderivative use with attribution. All other rights reserved.)

Objectives: To evaluate the safety and efficacy of cidofovir for the treatment of double-stranded DNA (dsDNA) viral infections following allogeneic haematopoietic cell transplant (HCT)., Methods: This was a retrospective multicentre cohort study including adult HCT recipients who received ≥1 dose of IV-administered cidofovir for any dsDNA viral infection from 2006 to 2019. The objectives were to describe the rate of and risk factors for nephrotoxicity and virological response by the end of treatment (EOT)., Results: We included 165 patients from nine centres. Cidofovir was administered at 5 mg/kg/week (N = 115; 69.7%), 1 mg/kg/week (18; 10.9%), 3 mg/kg/week (12; 7.3%) or 1 mg/kg three times/week (11; 6.7%). Cidofovir was administered for adenovirus, cytomegalovirus (CMV) and BK virus infection in 75 (45.5%), 64 (38.8%) and 51 (30.9%) patients, respectively. Among 158 patients with renal function data at baseline and EOT, 40 (25.3%) developed nephrotoxicity. In multivariable analyses, age (OR 1.04; P = 0.05), weight (OR 1.05; P = 0.01), CMV infection (OR 3.6; P = 0.02), liposomal amphotericin B (OR 8.06; P = 0.05) and IV voriconazole/posaconazole (OR 13.0; P = 0.003) were predictors of nephrotoxicity. Creatinine concentration was significantly higher at EOT (1.16 ± 0.95 mg/dL) compared with baseline (0.91 ± 0.39 mg/dL; P < 0.001), but improved by 2 weeks (0.91 ± 0.84 mg/dL; P = 0.007) and 4 weeks (0.96 ± 0.89 mg/dL; P = 0.03) post-EOT. Median viral load significantly declined for patients with adenovirus DNAaemia by EOT (P < 0.0001) and for patients with CMV DNAaemia by EOT + 4 weeks (P = 0.003), but not for patients with BK virus DNAaemia., Conclusions: One in four HCT recipients treated with IV cidofovir developed largely reversible nephrotoxicity. Careful selection of patients and close follow-up of renal function may minimize toxicity., (© The Author(s) 2021. Published by Oxford University Press on behalf of the British Society for Antimicrobial Chemotherapy. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Clostridioides difficile infection (CDI) is caused by Toxins A and B, secreted from pathogenic strains of C. difficle. This infection can vary greatly in symptom severity and in clinical presentation. Current assays used to diagnose CDI may lack the required sensitivity to detect the exotoxins circulating in blood. The ultrasensitive single molecule array (Simoa) assay was modified to separately detect toxin A and toxin B in serum with a limit of detection at the low picogram level. When applied to a diverse cohort, Simoa was unable to detect toxins A or B in serum from patients with CDI, including many classified as having severe disease. The detection of toxin may be limited by the inference of antitoxin antibodies circulating in serum. This result does not support the hypothesis that toxemia occurs in C. difficile infection, conflicting with the findings of other published reports., (© 2020. Springer Science+Business Media, LLC, part of Springer Nature.)

Background: The humoral immune response to Clostridioides difficile toxins in C difficile infection (CDI) is incompletely characterized in immunocompromised hosts (ICHs)., Methods: We conducted a prospective study of hospitalized adults with CDI, with and without immunosuppression (hematologic malignancy, active solid tumor, solid organ or stem cell transplant, inflammatory bowel disease, autoimmune disease, congenital or acquired immunodeficiency, asplenia, chronic receipt of high-dose steroids, or receipt of immunosuppressing medications within 12 months). Serum and stool antibody concentrations of immunoglobulin (Ig)M, IgG, and IgA to C difficile toxins A and B at treatment days 0, 3, and 10-14 were compared., Results: Ninety-eight subjects (47 ICH; 51 non-ICH) were enrolled. Baseline serum antitoxin A and B antibody levels were similar. At day 3, ICHs demonstrated lower serum levels of antitoxin A IgG, antitoxin A IgA, and antitoxin B IgA (all P < .05). At day 10-14, lower antitoxin A IgG concentrations were observed in ICHs (ICH, 21 enzyme-linked immunosorbent assay [ELISA] units; interquartile range [IQR], 16.4-44.6) compared with non-ICH subjects (49.0 ELISA units; IQR, 21.5-103; P = .045). In stool, we observed lower concentrations of antitoxin B IgA antibodies at baseline and at day 3 for ICH subjects, with a notable difference in concentrations of antitoxin B IgA at day 3 (ICH, 6.7 ELISA units [IQR, 1.9-13.9] compared with non-ICH, 18.1 ELISA units [IQR, 4.9-31.7]; P = .003)., Conclusions: The ICHs with CDI demonstrated lower levels of C difficile antitoxin antibodies in serum and stool during early CDI therapy compared with non-ICHs. These data provide insight into the humoral response to CDI in ICHs., (© The Author(s) 2021. Published by Oxford University Press on behalf of Infectious Diseases Society of America.)

Patients who have hematologic malignancies are at high risk for infections but vaccinations may be effective prophylaxis. The increased infection risk derives from immune defects secondary to malignancy, the classic example being CLL, and chemotherapies and immunotherapy used to treat the malignancies. Therapy of hematologic malignancies is being revolutionized by introduction of novel targeted agents and immunomodulatory medications, improving the survival of patients. At the same time those agents uniquely change the infection risk and response to immunizations. This review will summarize current vaccine recommendations for patients with hematologic malignancies including patients who undergo hematopoietic cell transplant., (Copyright © 2020. Published by Elsevier Ltd.)

Importance: Control of the global COVID-19 pandemic will require the development and deployment of safe and effective vaccines., Objective: To evaluate the immunogenicity of the Ad26.COV2.S vaccine (Janssen/Johnson & Johnson) in humans, including the kinetics, magnitude, and phenotype of SARS-CoV-2 spike-specific humoral and cellular immune responses., Design, Setting, and Participants: Twenty-five participants were enrolled from July 29, 2020, to August 7, 2020, and the follow-up for this day 71 interim analysis was completed on October 3, 2020; follow-up to assess durability will continue for 2 years. This study was conducted at a single clinical site in Boston, Massachusetts, as part of a randomized, double-blind, placebo-controlled phase 1 clinical trial of Ad26.COV2.S., Interventions: Participants were randomized to receive 1 or 2 intramuscular injections with 5 × 1010 viral particles or 1 × 1011 viral particles of Ad26.COV2.S vaccine or placebo administered on day 1 and day 57 (5 participants in each group)., Main Outcomes and Measures: Humoral immune responses included binding and neutralizing antibody responses at multiple time points following immunization. Cellular immune responses included immunospot-based and intracellular cytokine staining assays to measure T-cell responses., Results: Twenty-five participants were randomized (median age, 42; age range, 22-52; 52% women, 44% male, 4% undifferentiated), and all completed the trial through the day 71 interim end point. Binding and neutralizing antibodies emerged rapidly by day 8 after initial immunization in 90% and 25% of vaccine recipients, respectively. By day 57, binding and neutralizing antibodies were detected in 100% of vaccine recipients after a single immunization. On day 71, the geometric mean titers of spike-specific binding antibodies were 2432 to 5729 and the geometric mean titers of neutralizing antibodies were 242 to 449 in the vaccinated groups. A variety of antibody subclasses, Fc receptor binding properties, and antiviral functions were induced. CD4+ and CD8+ T-cell responses were induced., Conclusion and Relevance: In this phase 1 study, a single immunization with Ad26.COV2.S induced rapid binding and neutralization antibody responses as well as cellular immune responses. Two phase 3 clinical trials are currently underway to determine the efficacy of the Ad26.COV2.S vaccine., Trial Registration: ClinicalTrials.gov Identifier: NCT04436276.

Background: To optimize utility of laboratory testing for Clostridiodes difficile infection (CDI), the 2017 Infectious Diseases Society of America-Society for Healthcare Epidemiology of America (IDSA-SHEA) clinical practice guidelines recommend excluding patients from stool testing for C. difficile if they have received laxatives within the preceding 48 hours. Sparse data support this recommendation., Methods: Patients with new-onset diarrhea (≥3 bowel movements in any 24-hour period in the 48 hours before stool collection) and a positive stool C. difficile nucleic acid amplification test were enrolled. Laxative use within 48 hours before stool testing, severity of illness (defined by 4 distinct scoring methods), and clinical outcomes were recorded., Results: 209 patients with CDI were studied, 65 of whom had received laxatives. There were no significant differences in the proportion of patients meeting severe CDI criteria by 4 severity scoring methods in patients receiving versus not receiving laxatives (66.2% vs 56.3%, respectively; P = .224) by IDSA-SHEA, the primary scoring system. Similar rates of serious outcomes attributable to CDI, including death, intensive care unit admission, and colectomy, were observed in the laxative and no laxative groups., Conclusions: Our study found similar rates of severe CDI and serious CDI-attributable clinical outcomes in CDI-diagnosed patients who did or did not receive laxatives. Precluding recent laxative users from CDI testing, as proposed by the IDSA-SHEA guideline, carries a potential for harm due to delayed diagnosis and treatment., (© The Author(s) 2019. Published by Oxford University Press for the Infectious Diseases Society of America. All rights reserved. For permissions, e-mail: journals.permissions@oup.com.)

Clostridioides (formerly Clostridium) difficile is responsible for a substantial burden of nosocomial infection. Recurrent C. difficile infection (rCDI) remains a concern due to its high morbidity, mortality, and cost. Despite the updated 2017 IDSA C. difficile treatment guidelines, there remains a lack of well-studied preventive control measures and treatment modalities for rCDI. There are ongoing efforts to develop novel therapies, such as new antibiotics with a lesser impact on gut microbiota and more targeted therapies, such as bacteriotherapy. This mini review highlights key rCDI management updates, preventive measures and ongoing research on novel treatment strategies including bacteriotherapy., Competing Interests: Declaration of competing interest Monica V. Mahoney was on the advisory board of Tetraphase Pharmaceuticals Inc. and Spero Therapeutics; received speaker fees from Tetraphase Pharmaceuticals Inc., and research funding from Merck. Ciaran P. Kelly was a scientific advisor for Artugen, Facile Therapeutics, Finch, Merck and Vedanta; received speaker fees from Merck and research grants (to BIDMC) from the National Institutes of Health (NIAIDR01AI116596, R01AI132711, U19 AI 109776), Institut Merieux and Merck. Carolyn D. Alonso was a scientific advisor for Merck and Roche. Dr. Alonso has received research funding from Merck and has NIH Loan Repayment Funding through the National Institute of Allergy and Infectious Diseases (NIAID). Dr. Alonso has been involved in research studies funded by Astellas and Vedanta Biosciences. The other authors do not have any conflicts of interest associated with this publication., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

Controlling norovirus transmission in units with immunocompromised patients is challenging. We present a cluster of norovirus cases that occurred on a stem-cell transplant unit and the prevention efforts that were implemented to limit the outbreak. Protocols developed to control this cluster may provide a model for other facilities.

Recurrent Clostridioides (formerly Clostridium) difficile infection (rCDI) is common, and patients who have had one recurrence are more likely to have multiple recurrences. Frequent recurrences have been associated with increased morbidity and mortality, high healthcare costs, and lower quality of life. In this review, we compare the efficacy of interventions designed to prevent rCDI. We performed a systematic review of the English literature, including randomized controlled trials (RCTs) that evaluated rCDI as an outcome. Studies were included irrespective of patient demographics, disease severity, type of intervention, comparator used, or time-point of outcome evaluation. We performed a comprehensive literature search with the assistance of a research librarian. Two reviewers independently extracted data and assessed risk of bias. Our search yielded 38 RCTs (8,102 participants). Nineteen RCTs (3,743 subjects) evaluated antibiotics, eight fecal microbiota transplantation (FMT) (582 subjects), three monoclonal antibodies (MAbs) (2,805 subjects), and eight probiotics, prebiotics, or non-antibiotic polymers (972 subjects). The antibiotic and FMT therapies that demonstrated efficacy in rCDI prevention included: fidaxomicin (when compared to a ten-day vancomycin course) and FMT administered by nasogastric tube (when compared to a fourteen-day vancomycin course and a fourteen-day vancomycin course plus bowel lavage). Actoxumab (MAb against C. difficile toxin A; CDA1) plus bezlotoxumab (MAb against C. difficile toxin B; CDB1) in combination or bezlotoxumab alone appeared to be more effective in preventing rCDI compared to actoxumab alone. Of the prebiotics, probiotics, and nonantibiotic polymers, oligofructose, Saccharomyces boulardii, and the nontoxigenic C. difficile strain M3 were the most efficacious for rCDI prevention. Thirty-eight RCTs (>8,000 participants) evaluating treatment modalities for CDI were examined for efficacy in prevention of rCDI. Several CDI-specific antibiotics, FMT modalities, monoclonal antibodies, and various prebiotics and probiotics demonstrated a reduction in risk of rCDI with the greatest risk reduction observed with FMT and monoclonal antibody therapy. It is notable that the comparators in these studies were very different from one another and the relative risk reduction of rCDI may not be directly comparable from one study to the next., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

Palivizumab has been used to treat respiratory syncytial virus (RSV)-infected hematologic malignancy patients at our institution based on limited published data. We conducted this retrospective study to evaluate clinical outcomes and mortality rates of RSV-infected hematologic malignancy patients from 2007 to 2016. A total of 67 patients (19 received palivizumab and 47 received supportive care) were identified. Palivizumab-treated patients had a significantly higher proportion of underlying ischemic heart disease, graft-versus-host-disease, hypogammaglobulinemia, and concomitant pulmonary infections. There were no significant differences in mortality rates or readmission rates between the two groups. The estimated odds ratio for death in patients receiving palivizumab after adjusting for propensity scores and covariates were 0.12 ([0.01, 1.32], p = .08) and 0.09 ([0.01, 1.03], p = .05) respectively. After adjustment for factors associated with severity of illness, there was no difference in mortality among patients treated with palivizumab.

Background: Infections with adenoviruses (ADVs) can result in considerable mortality and morbidity in solid organ transplant (SOT) recipients. Standard therapy for ADV infections in transplant recipients is not established. At our institution, intravenous cidofovir and immunoglobulin have been used to treat disseminated or invasive ADV in SOT and hematopoietic stem cell transplant recipients., Methods: A retrospective case series of SOT recipients treated with cidofovir and intravenous immunoglobulin was performed., Results: Five SOT recipients (four renal and one heart transplant) with adenovirus infection were treated successfully with cidofovir and immunoglobulin. Cidofovir was discontinued after the first negative ADV viral load and resolution of clinical symptoms, given the concern for nephrotoxicity in renal transplant recipients. Renal tubular acidosis type 2 and iritis were observed in two patients receiving therapy., Conclusion: Symptom resolution and a single negative ADV viral load may be indicators for cidofovir discontinuation., (© 2018 Pharmacotherapy Publications, Inc.)

Clostridium difficile, an anaerobic gram-positive, spore-forming bacillus, has become the most common cause of nosocomial infectious diarrhea, and is associated with increased mortality in all populations. Patients who have received solid organ transplants (SOT) are at increased risk of Clostridium difficile infection (CDI) and CDI recurrence (rCDI). This may be related to chronic immunosuppression, frequent antibiotic exposure, and increased or prolonged hospitalizations. Increased morbidity and mortality from CDI is well-described in SOT patients. Conventional treatments for index and recurrent CDI include vancomycin and fidaxomicin. Fecal microbiota transplantation has emerged as an effective and safe alternative for treating rCDI in the general population. Reports of its safety in certain immunocompromised populations, such as those with inflammatory bowel disease, appear reassuring, but outcomes among SOT patients are less well known. Here, we summarize the experiences published to date on the treatment of rCDI with FMT in SOT patient, and also describe our detailed FMT protocol and experience in treating a series of SOT patients with rCDI. In addition to reporting the safety and efficacy of our FMT experience, we also discuss the diagnostic challenges and considerations in this population of solid organ transplant recipients., (© 2018 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Objective: To review the pharmacology, pharmacokinetics, efficacy, safety, and place in therapy of bezlotoxumab (BEZ), a novel monoclonal antibody against Clostridium difficile toxin B., Data Sources: A PubMed search was conducted for data between 1946 and April 2017 using MeSH terms bezlotoxumab, MK-6072, or MDX-1388 alone and the terms Clostridium difficile combined with monoclonal antibody or antitoxin., Study Selection and Data Extraction: The literature search was limited to English-language studies that described clinical efficacy, safety, and pharmacokinetics in humans and animals. Abstracts featuring prepublished data were also evaluated for inclusion., Data Synthesis: BEZ is indicated for adult patients receiving standard-of-care (SoC) antibiotics for C difficile infection (CDI) to prevent future recurrence. Two phase III trials-MODIFY I (n = 1452) and MODIFY II (n = 1203)-demonstrated a 40% relative reduction in recurrent CDI (rCDI) with BEZ compared with placebo (16.5% vs 26.6%, P < 0.0001). The most common adverse drug events associated with BEZ were mild to moderate infusion-related reactions (10.3%)., Conclusions: In patients treated with SoC antibiotics, BEZ is effective in decreasing rCDI. BEZ has no apparent effect on treatment of an initial CDI episode. In light of increasing rates of CDI, BEZ is a promising option for preventing recurrent episodes. The greatest benefit has been demonstrated in high-risk patients, though the targeted patient population is yet to be defined.

Background: Clostridium difficile infection (CDI) is the leading cause of health-care associated infectious diarrhea. The aim of this study was to evaluate the epidemiology and risk factors for CDI in the 100 days following umbilical cord blood transplantation (UCBT) at three Boston hospitals., Methods: We performed a multicenter, retrospective, case-cohort study of 226 UCBT recipients at Beth Israel Deaconess Medical Center, Massachusetts General Hospital, and Dana Farber/Brigham and Women's Cancer Center from 2003 to 2012. CDI was defined as diarrhea (≥3 unformed bowel movements for at least 2 days) plus a positive stool test for toxinogenic C. difficile and not attributed to any other cause., Results: Among 226 UCBT recipients, 22 patients (9.7%) developed CDI within the first 100 days of transplant (corresponding to an infection rate of 10.8 cases per 10 000 person-days). The 100-day and 1-year rates were stable across the time period and between institutions. UCBT recipients with CDI were more likely than non-CDI patients to be older, with higher body mass indices, and to have received an antipseudomonal penicillin agent. In a time-dependent case-cohort analysis of the risk factors associated with CDI in the first 100 days after UCBT, bacterial infection after UCBT was the strongest risk factor for CDI (hazard ratio 2.8; 95% confidence interval 1.08-7.24; P=.03), after adjustment for transplant variables including antibiotic exposure., Conclusion: This study verifies the previously reported risk factors for CDI including older age and antibiotic exposure and identifies a novel association between bacterial infections and risk for CDI., (© 2017 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Severe Clostridium difficile infection is associated with a high rate of mortality; however, the optimal treatment for severe- complicated infection remains uncertain for patients who are not candidates for surgical intervention. Thus, we sought to evaluate the benefit of adjunctive tigecycline in this patient population using a retrospective cohort adjusted for propensity to receive tigecycline. We found that patients who received tigecycline had similar outcomes to those who did not, although the small sample size limited power to adjust for comorbidities and severity of illness.

Background: Clostridium difficile infection (CDI) is a significant complication of allogeneic hematopoietic stem cell transplantation (allo-HSCT). Our primary objective was to determine risk factors for the development of CDI during the first year following allo-HSCT., Methods: A matched case-control study nested in a cohort of allo-HSCT at a single hospital in Montréal, Québec, Canada, was conducted from 2002 through 2011., Results: Sixty-five of 760 patients who underwent allo-HSCT between 2002 and 2011 developed CDI, representing an incidence of 8.6%. We selected 123 controls matched for year of transplant for risk factor analyses. In the multivariable analysis, receipt of trimethoprim-sulfamethoxazole (TMP-SMX) prior to transplantation (adjusted odds ratio [aOR] 0.07, 95% confidence interval [CI] 0.02-0.27), mucositis (aOR 5.90, 95% CI 2.08-16.72), and reactivation of cytomegalovirus (CMV) (aOR 6.17, 95% CI 2.17-17.57) and of other Herpesviridae viruses (aOR 3.04, 95% CI 1.13-8.16) were the variables that remained statistically associated with CDI. High-risk antibiotic use in the late post-transplant period (aOR 7.63, 95% CI 2.14-27.22) was associated with development of late CDI., Conclusion: This study revealed reactivation of CMV and other Herpesviridae viruses as novel risk factors for CDI. Administration of TMP-SMX prior to transplantation was independently associated with a decreased risk of CDI. Early and late CDI after HSCT may have distinct risk factors., (© 2016 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Objectives: The objective of this study was to determine our institution's compliance with 2010 Society for Healthcare Epidemiology of America and IDSA Clostridium difficile infection (CDI) treatment guidelines and their respective outcomes., Methods: We collected clinical parameters, laboratory values, antibiotic therapy and clinical outcomes from the electronic medical records for all patients hospitalized at our institution with a diagnosis of CDI from December 2012 to November 2013. We specifically evaluated whether SHEA-IDSA treatment guidelines were followed and evaluated the associations between guideline adherence and severe outcomes including mortality., Results: We identified 230 patients with CDI meeting inclusion criteria during the study period. Of these, 124 (54%) were appropriately treated, 46 (20%) were under-treated and 60 (26%) were over-treated. All-cause 90 day mortality was 17.4% overall; 43.5% in the under-treated group versus 12.9% in those appropriately treated (P < 0.0001) and 10.9% in those appropriately treated plus over-treated (P < 0.0001). Similarly, 90 day mortality attributed to CDI was 21.7% in those under-treated versus 8.9% in those appropriately treated (P = 0.03) and 8.2% in those either appropriately treated or over-treated (P = 0.015). Severe-complicated CDI occurred in 46 patients. In this subgroup, there was a non-significant trend towards increased mortality in under-treated patients (56.7%) compared with appropriately treated patients (37.5%, P = 0.35). Under-treatment was also associated with a higher rate of CDI-related ICU transfer (17.4% versus 4.8% in those appropriately treated, P = 0.023)., Conclusions: Adherence to CDI treatment guidelines is associated with improved outcomes especially in those with severe disease. Increased emphasis on provision of appropriate, guideline-based CDI treatment appears warranted., (© The Author 2016. Published by Oxford University Press on behalf of the British Society for Antimicrobial Chemotherapy. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.)

Sparganosis is a parasitic infection caused by Spirometra spp. and often presents as a subcutaneous swelling, most commonly noticed in the abdominal wall or extremities. Amphibians such as frogs ingest infected copepods (crustaceans that have ingested coracidia, i.e., Spirometra spp. embryos) and serve as a secondary intermediate host. Complete surgical excision is recommended for definitive diagnosis and treatment. Granulomatous inflammation is the most common histologic finding. Although dissemination can occur, most cases are localized. Serum enzyme-linked immunosorbent assay (ELISA) has been suggested as a potential surveillance tool. Medical therapy with antiparasitic agents, such as praziquantel, is not typically recommended but may be effective at high doses. Preventing recurrence thus depends on adequate surgical removal of the parasite. We report a case of a breast mass caused by sparganosis infection in a Chinese female whose likely exposure was due to frog consumption. The diagnosis was confirmed on surgical excision and no systemic antiparasitic therapy was required., (© The American Society of Tropical Medicine and Hygiene.)

Clostridium difficile infection (CDI) is increasingly prevalent, dangerous and challenging to prevent and manage. Despite intense national and international attention the incidence of primary and of recurrent CDI (PCDI and RCDI, respectively) have risen rapidly throughout the past decade. Of major concern is the increase in cases of RCDI resulting in substantial morbidity, morality and economic burden. RCDI management remains challenging as there is no uniformly effective therapy, no firm consensus on optimal treatment, and reliable data regarding RCDI-specific treatment options is scant. Novel therapeutic strategies are critically needed to rapidly, accurately, and effectively identify and treat patients with, or at-risk for, RCDI. In this review we consider the factors implicated in the epidemiology, pathogenesis and clinical presentation of RCDI, evaluate current management options for RCDI and explore novel and emerging therapies., (Copyright © 2015 Elsevier Ltd. All rights reserved.)

Background: Human granulocytic anaplasmosis (HGA) is an acute nonspecific febrile illness caused by the bacterium Anaplasma phagocytophilum. Although usually transmitted via tick bite, HGA may rarely also be acquired through transfusion. HGA during pregnancy may pose significant gestational risks due to altered maternal immune status and the potential for perinatal transmission., Case Report: A pregnant 34-year-old Massachusetts woman with β-thalassemia trait was diagnosed at 32 weeks of gestation with transfusion-associated HGA (TAHGA) after receiving nine leukoreduced red blood cell transfusions. She was successfully treated with rifampin therapy and gave birth to a healthy child who tested negative for HGA after delivery. An implicated blood donor was subsequently identified through physician collaboration with the regional American Red Cross and Massachusetts Department of Public Health., Discussion: This is the 11th reported case of HGA in pregnancy and is at least the sixth known case in which leukoreduction did not prevent TAHGA. As seen in this case, nonspecific symptomatology of variable onset can impede diagnosis and treatment. This may increase risk of poor outcomes in maternal HGA patients. Cases of TAHGA, although currently uncommon, may increase as the incidence of HGA in certain parts of the country increases., Conclusion: Heightened cross-institutional awareness of the potential risk of TAHGA is warranted. Clinicians need to consider transfusion-associated infections when fever occurs in a transfusion recipient. This case provides additional evidence that leukoreduction does not obviate risk of A. phagocytophilum contamination of donated blood components., (© 2014 AABB.)

Patients undergoing solid organ and stem cell transplantation are at increased risk of Clostridium difficile infection (CDI) compared with nontransplant patients. CDI may be associated with significant morbidity in this population including prolonged hospitalization, increased hospital charges, and complications in the transplanted organ. A combination of host factors, including both B-cell and T-cell immunosuppression, in addition to traditional risk factors for CDI such as broad-spectrum antibacterial exposure, are likely to contribute to the elevated risk in this population. This article addresses the current epidemiology and risk factors for CDI in transplant recipients, the downstream complications following this infection, and current management strategies, with an emphasis on novel approaches for primary and recurrent disease including fecal microbiota transplantation.

Infection with the dematiaceous environmental fungus Exophiala, an emerging pathogen in immunocompromised individuals, poses a diagnostic and therapeutic challenge. Herein, we report the first Exophiala dermatitidis fungemia case, to our knowledge, in an allogeneic hematopoietic stem cell transplant patient with graft-versus-host disease, expanding the clinical setting where Exophiala species mycosis should be suspected., (© 2014 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

We sought to describe the epidemiology of Clostridium difficile infection (CDI) among adult recipients of autologous hematopoietic stem cell transplantation (auto-HSCT) within the first year after HSCT in centers with variable epidemiology of hypertoxigenic strains. A multicenter, retrospective nested case-control study was conducted among 873 auto-HSCT recipients at Johns Hopkins Hospital (JHH) and Hôpital Maisonneuve-Rosemont (HMR) between January 2003 and December 2008. Despite center differences in the prevalence of NAP-1 strains during the study period (21% to 43% at JHH versus 80% to 84% in HMR), the 1-year incidence of CDI was similar in the 2 hospitals (6.2% at JHH versus 5.7% at HMR). The median time to infection was 11 days (interquartile range, 1 to 27 days). In case-control analyses, grade ≥2 mucositis (odds ratio [OR], 3.00; P = .02) and receipt of a fourth-generation cephalosporin (OR, 2.76; P = .04) were identified as predictors for CDI. Mucositis was the strongest predictor of risk for CDI in multivariate analysis (adjusted OR, 2.77; P = .03). CDI is a common and early complication of auto-HSCT. Treatment-related gastrointestinal mucosal damage, along with the potentially modifiable risk of antimicrobial exposure, influence the risk for CDI early after auto-HSCT., (Copyright © 2013 American Society for Blood and Marrow Transplantation. Published by Elsevier Inc. All rights reserved.)

Purpose of Review: To review the most recent data regarding the epidemiology, risks factors, and outcomes among hematopoietic stem cell transplant recipients with Clostridium difficile infection (CDI)., Recent Findings: With the emergence of an epidemic strain of C. difficile known as NAP1 in the early 2000s, rates of this infection have escalated globally. Hematopoietic stem cell transplant recipients appear to be one of the most vulnerable populations for the development of CDI. Traditional risk factors for CDI including antimicrobial exposure and older age are likely only a piece of the overall risk profile, with recent study results also emphasizing other factors such as transplant type, conditioning regimen, and graft-versus-host disease (GVHD). The relationship between CDI and subsequent development of GVHD, particularly of the gastrointestinal tract, is of specific interest. A bidirectional relationship of association has been highlighted in a number of recent studies and underscores the need for further prospective studies to address the potential indirect effects of alloreactivity induced by CDI., Summary: CDI has emerged as one of the most common infections in the early transplant period. Recent studies have begun to address the epidemiology of disease, risk factors for, and outcomes after infection in the stem cell transplant. However, more research is needed to unravel the observed relationship between CDI and GVHD.

Background: The epidemiology of invasive mold infections (IMI) in transplant recipients differs based on geography, hosts, preventative strategies, and methods of diagnosis., Methods: We conducted a retrospective observational study to evaluate the epidemiology of proven and probable IMI, using prior definitions, among all adult hematopoietic stem cell transplant (HSCT) and solid organ transplant (SOT) recipients in the era of "classic" culture-based diagnostics (2000-2009). Epidemiology was evaluated before and after an initiative was begun to increase bronchoscopy in HSCT recipients after 2005., Results: In total, 106 patients with one IMI were identified. Invasive aspergillosis (IA) was the most common IMI (69; 65.1%), followed by mucormycosis (9; 8.5%). The overall rate of IMI (and IA) was 3.5% (2.5%) in allogeneic HSCT recipients. The overall incidence for IMI among lung, kidney, liver, and heart transplant recipients was 49, 2, 11, and 10 per 1000 person-years, respectively. The observed rate of IMI among human leukocyte antigen-matched unrelated and haploidentical HSCT recipients increased from 0.6% annually to 3.0% after bronchoscopy initiation (P < 0.05). The 12-week mortality among allogeneic HSCT, liver, kidney, heart, and lung recipients with IMI was 52.4%, 47.1%, 27.8%, 16.7%, and 9.5%, respectively. Among allogeneic HSCT (odds ratio [OR]: 0.07, P = 0.007) and SOT (OR: 0.22, P = 0.05) recipients with IA, normal platelet count was associated with improved survival. Male gender (OR: 14.4, P = 0.007) and elevated bilirubin (OR: 5.7, P = 0.04) were significant predictors of mortality for allogeneic HSCT and SOT recipients with IA, respectively., Conclusions: During the era of culture-based diagnostics, observed rates of IMI were low among all transplants except lung transplant recipients, with relatively higher mortality rates. Diagnostic aggressiveness and host variables impact the reported incidence and outcome of IMI and likely account for institutional variability in multicenter studies. Definitions to standardize diagnoses among SOT recipients are needed., (© 2013 John Wiley & Sons A/S.)

Background: We sought to describe the epidemiology and risk factors for Clostridium difficile infection (CDI) among kidney transplant recipients (KTR) between 1 January 2008 and 31 December 2010., Methods: A single-institution retrospective study was conducted among all adult KTR with CDI, defined as a positive test for C. difficile by a cell cytotoxic assay for C. difficile toxin A or B or polymerase chain reaction test for toxigenic C. difficile., Results: Among 603 kidney transplants performed between 1 January 2008 and 31 December 2010, 37 (6.1%) patients developed CDI: 12 (of 128; 9.4%) high-risk (blood group incompatible and/or anti-human leukocyte antigen donor-specific antibodies) vs. 25 (of 475; 5.3%, P = 0.08) standard-risk patients. The overall rate of CDI increased from 3.7% in 2008 to 9.4% in 2010 (P = 0.05). The median time to CDI diagnosis was 9 days, with 27 (73.0%) patients developing CDI within the first 30 days after their transplant, and 14 (51.8%) developing CDI within 7 days. A case-control analysis of 37 CDI cases and 74 matched controls demonstrated the following predictors for CDI among KTR: vancomycin-resistant Enterococcus colonization before transplant (odds ratio [OR]: 3.6, P = 0.03), receipt of an organ from Centers for Disease Control high-risk donor (OR: 5.9, P = 0.006), and administration of high-risk antibiotics within 30 days post transplant (OR: 6.6, P = 0.001)., Conclusions: CDI remains a common early complication in KTR, with rates steadily increasing during the study period. Host and transplant-related factors and exposure to antibiotics appeared to significantly impact the risk for CDI among KTR., (© 2012 John Wiley & Sons A/S.)

Background. Clostridium difficile is the leading cause of infectious diarrhea among hospitalized patients and is a major concern for patients undergoing hematopoietic stem cell transplantation (HSCT). Risk factors and the natural history of C. difficile infection (CDI) are poorly understood in this population. Methods. We performed a retrospective nested case-control study to describe the epidemiology, timing, and risk factors for CDI among adult patients who received HSCTs at our center from January 2003 through December 2008. Results. The overall 1-year incidence of CDI was 9.2% among HSCTs performed (n = 999). The median time to diagnosis of CDI was short among both autologous and allogeneic HSCT recipients (6.5 days and 33 days, respectively). Risk factors for CDI in allogeneic HSCT recipients included receipt of chemotherapy prior to conditioning for HSCT, broad-spectrum antimicrobial use, and acute graft-versus-host disease (GVHD; adjusted odds ratio [AOR], 4.45; 95% confidence interval [CI], 1.54-12.84; P = .006). There was a strong relationship between early CDI and subsequent development of gastrointestinal tract GVHD in the year following allogeneic HSCT (P < .001). Gastrointestinal GVHD was also strongly associated with an increased risk for recurrent CDI (AOR, 4.23 [95% CI, 1.20-14.86]; P = .02). Conclusions. These results highlight the high incidence and early timing of CDI after HSCT. Early timing, coupled with the noted risk of pretransplant chemotherapy, suggests that the natural history of disease in some patients may involve colonization prior to HSCT. A potentially important interplay between CDI and GVHD involving the gastrointestinal tract was observed.