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Background: Plasma microbial cell-free DNA (mcfDNA) sequencing can establish the etiology of multiple infectious syndromes by identifying microbial DNA in plasma. However, data are needed to define the clinical scenarios where this tool offers the highest clinical benefit., Methods: We conducted a prospective multicenter observational study that evaluated the impact of plasma mcfDNA sequencing compared with usual care testing among adults with hematologic malignancies. This is a secondary analysis of an expanded cohort that evaluated the clinical utility of plasma mcfDNA sequencing across prespecified and adjudicated outcomes. We examined the percentage of participants for whom plasma mcfDNA sequencing identified a probable cause of pneumonia or clinically relevant nonpneumonia infection. We then assessed potential changes in antimicrobial therapy based on plasma mcfDNA sequencing results and the potential for early mcfDNA testing to avoid bronchoscopy and its associated adverse events., Results: Of 223 participants, at least 1 microbial detection by plasma mcfDNA sequencing was adjudicated as a probable cause of pneumonia in 57 (25.6%) and a clinically relevant nonpneumonia infection in 88 (39.5%). A probable cause of pneumonia was exclusively identified by plasma mcfDNA sequencing in 23 (10.3%) participants. Antimicrobial therapy would have changed for 41 (18.4%) participants had plasma mcfDNA results been available in real time. Among the 57 participants with a probable cause of pneumonia identified by plasma mcfDNA sequencing, bronchoscopy identified no additional probable cause of pneumonia in 52 (91.2%)., Conclusions: Plasma mcfDNA sequencing could improve management of both pneumonia and other concurrent infections in immunocompromised patients with suspected pneumonia., Competing Interests: Potential conflicts of interest. Deng B. Madut reports receiving consulting fees from Karius. Roy F. Chemaly reports being a scientific advisor or consultant for ADMA Biologics, Pulmotec, Janssen, Merck/MSD, Partner Therapeutics, Takeda, Shinoigi, Genentech, Astellas, Adagio Therapeutics, Oxford Immunotec, Qiagen, Karius, Moderna, and Ansun Pharmaceuticals and received research grants paid to his institution from NIH/NCI, Merck/MSD, Karius, AiCuris, Ansun Pharmaceuticals, Takeda, Genentech, Oxford Immunotec, Freestyle, and Eurofins-Viracor. Sanjeet Dadwal reports research grants paid to his institution from Karius, Merck, Gilead, Ansun Biopharma, Allovir. He has served on advisory boards for Merck, Takeda, Allovir, and Aseptiscope, Inc. He is on speakers’ bureaus of Merck, Astellas, and Takeda and holds stock options in Aseptiscope, Inc. Joshua A. Hill reports research grants paid to his institution from Karius and consulting for Karius. He reports no other relevant conflicts of interest. Yeon Joo Lee has served as an investigator for Astellas, Karius, AiCuris, and Scynexis and has received research grant support from Merck & Co. Inc. Ghady Haidar is a recipient of research grants from Allovir, Karius, and AstraZeneca and also serves on the scientific advisory boards of Karius and AstraZeneca. Alfred Luk reports no relevant conflicts of interest. Alexander Drelick reports no relevant conflicts of interest. Peter V. Chin-Hong reports no relevant conflicts of interest. Esther Benamu reports no relevant conflicts of interest. Fareed Khawaja reports an honorarium from Medscape and research support from Eurofins-Viracor. Deepa Nanayakkara reports no relevant conflicts of interest. Genovefa A. Papanicolaou reports research support from MSD and Takeda/Shire and consulting and other fees from AlloVir, Amplyx, SLC Behring, Cidara, MSD, Takeda, and Octapharma. Catherine Butkus Small reports research grant support from NIH, GlaxoSmithKline, ViiV, Abbott, Merck, Gilead, Chimerix, Shire/Takeda, Schering-Plough, Ablynx, Janssen, Ansun Biopharma, and Karyopharm Therapeutics. Monica Fung reports research grant support from NIH. Michelle A. Barron reports no relevant conflicts of interest. Thomas Davis reports no relevant conflicts of interest. Micah T. McClain reports being a consultant for UpToDate and a co-inventor of patents on Methods to Detect and Treat Acute Respiratory Infections. Eileen K. Maziarz reports no relevant conflicts of interest. Armando D. Bedoya reports no relevant conflicts of interest. Daniel L. Gilstrap reports no relevant conflicts of interest. Jamie L. Todd reports advisory board participation for Sanofi, Natera, Theravance, and Altavant Sciences (now Enzyvant Therapeutics), in addition to grants to the institution from Boehringer-Ingelheim, AstraZeneca, and CareDx. Christina E. Barkauskas reports no relevant conflicts of interest. Madeleine R. Heldman reports receiving consulting fees from Karius and Medacorp. Robert Bigelow reports stock holdings in Merck, Johnson & Johnson, COVIDien, Pfizer, Sanofi, McKesson, and Viatris and consulting fees from Elixir. Jeffrey D. Leimberger reports no relevant conflicts of interest. Ephraim L. Tsalik reports personal fees from Biomeme, stock options in Danaher, and being an employee of Danaher Corp. Olivia Wolf reports no relevant conflicts of interest. Mona Mughar reports being an employee of Karius Inc., Redwood City, California, and may own stock options. Constance Lau reports being an employee of Karius Inc., Redwood City, California, and may own stock options. Nicholas Noll reports being an employee of Karius Inc., Redwood City, California, and may own stock options. Desiree Hollemon reports being a former employee of Karius Inc., Redwood City, California. Radha Duttagupta reports being a former employee of Karius Inc., Redwood City, California. Daniel S. Lupu reports being an employee of Karius Inc., Redwood City, California, and may own stock options. Sivan Bercovici reports being an employee of Karius Inc., Redwood City, California, and may own stock options. Bradley A. Perkins reports being an employee of Karius Inc., Redwood City, California, and may own stock options. Timothy A. Blauwkamp reports being an employee of Karius Inc., Redwood City, California, and may own stock options. Vance G. Fowler Jr. reports personal fees from Novartis, Debiopharm, Genentech, Achaogen, Affinium, Medicines Co., MedImmune, Bayer, Basilea, Affinergy, Janssen, Contrafect, Regeneron, Destiny, Amphliphi Biosciences, Integrated Biotherapeutics, C3J, Armata, Valanbio, Akagera, Aridis, and Roche; grants from NIH, MedImmune, Allergan, Pfizer, Advanced Liquid Logics, Theravance, Novartis, Merck, Medical Biosurfaces, Locus, Affinergy, Contrafect, Karius, Genentech, Regeneron, Deep Blue, Basilea, and Janssen; royalties from UpToDate; stock options from Valanbio and ArcBio; honoraria from the Infectious Diseases Society of America for his service as Associate Editor of Clinical Infectious Diseases; and a pending patent on sepsis diagnostics. Thomas L. Holland reports being an advisor and consultant to Aridis, Basilea Pharmaceutica, Karius, and Lysovant and royalties from UpToDate. Stephen P. Bergin reports being a consultant to C3J Therapeutics., (© The Author(s) 2024. Published by Oxford University Press on behalf of Infectious Diseases Society of America.)

We evaluated use of maribavir (MBV) for treatment of 15 episodes of refractory/resistant cytomegalovirus infection in 13 solid organ transplant recipients. Treatment failure due to treatment-emergent MBV resistance or early virological recurrence after MBV discontinuation occurred in 7 (47%) episodes. Sustained viral clearance was achieved in 6 (40%) episodes., Competing Interests: Potential conflicts of interest. All authors: No reported conflicts., (© The Author(s) 2024. Published by Oxford University Press on behalf of Infectious Diseases Society of America.)

Competing Interests: Potential conflicts of interest. All authors: No reported conflicts.

Mollicute infections, caused by Mycoplasma and Ureaplasma species, are serious complications after lung transplantation; however, understanding of the epidemiology and outcomes of these infections remains limited. We conducted a single-center retrospective study of 1156 consecutive lung transplants performed from 2010-2019. We used log-binomial regression to identify risk factors for infection and analyzed clinical management and outcomes. In total, 27 (2.3%) recipients developed mollicute infection. Donor characteristics independently associated with recipient infection were age ≤40 years (prevalence rate ratio [PRR] 2.6, 95% CI 1.0-6.9), White race (PRR 3.1, 95% CI 1.1-8.8), and purulent secretions on donor bronchoscopy (PRR 2.3, 95% CI 1.1-5.0). Median time to diagnosis was 16 days posttransplant (IQR: 11-26 days). Mollicute-infected recipients were significantly more likely to require prolonged ventilatory support (66.7% vs 21.4%), undergo dialysis (44.4% vs 6.3%), and remain hospitalized ≥30 days (70.4% vs 27.4%) after transplant. One-year posttransplant mortality in mollicute-infected recipients was 12/27 (44%), compared to 148/1129 (13%) in those without infection (P <.0001). Hyperammonemia syndrome occurred in 5/27 (19%) mollicute-infected recipients, of whom 3 (60%) died within 10 weeks posttransplant. This study highlights the morbidity and mortality associated with mollicute infection after lung transplantation and the need for better screening and management protocols., Competing Interests: Disclosure The authors of this manuscript have no conflicts of interest to disclose as described by the American Journal of Transplantation., (Copyright © 2023 American Society of Transplantation & American Society of Transplant Surgeons. Published by Elsevier Inc. All rights reserved.)

Background: Pneumonia is a common cause of morbidity and mortality, yet a causative pathogen is identified in a minority of cases. Plasma microbial cell-free DNA sequencing may improve diagnostic yield in immunocompromised patients with pneumonia., Methods: In this prospective, multicenter, observational study of immunocompromised adults undergoing bronchoscopy to establish a pneumonia etiology, plasma microbial cell-free DNA sequencing was compared to standardized usual care testing. Pneumonia etiology was adjudicated by a blinded independent committee. The primary outcome, additive diagnostic value, was assessed in the Per Protocol population (patients with complete testing results and no major protocol deviations) and defined as the percent of patients with an etiology of pneumonia exclusively identified by plasma microbial cell-free DNA sequencing. Clinical additive diagnostic value was assessed in the Per Protocol subgroup with negative usual care testing., Results: Of 257 patients, 173 met Per Protocol criteria. A pneumonia etiology was identified by usual care in 52/173 (30.1%), plasma microbial cell-free DNA sequencing in 49/173 (28.3%) and the combination of both in 73/173 (42.2%) patients. Plasma microbial cell-free DNA sequencing exclusively identified an etiology of pneumonia in 21/173 patients (additive diagnostic value 12.1%, 95% confidence interval [CI], 7.7% to 18.0%, P < .001). In the Per Protocol subgroup with negative usual care testing, plasma microbial cell-free DNA sequencing identified a pneumonia etiology in 21/121 patients (clinical additive diagnostic value 17.4%, 95% CI, 11.1% to 25.3%)., Conclusions: Non-invasive plasma microbial cell-free DNA sequencing significantly increased diagnostic yield in immunocompromised patients with pneumonia undergoing bronchoscopy and extensive microbiologic and molecular testing., Clinical Trials Registration: NCT04047719., Competing Interests: Potential conflicts of interest. S. P. B. reports being a consultant to C3J Therapeutics. R. F. C. reports being a scientific advisor or consultant for ADMA Biologics, Pulmotec, Janssen, Merck/MSD, Partner Therapeutics, Takeda, Shinoigi, Genentech, Astellas, Adagio Therapeutics, Oxford Immunotec, Qiagen, Karius, and Ansun Pharmaceuticals and received research grants paid to his institution from National Institutes of Health (NIH)/National Cancer Institute (NCI), Merck/Merck, Sharp & Dohme (MSD), Karius, AiCuris, Ansun Pharmaceuticals, Takeda, Genentech, Oxford Immunotec, Freestyle, and Eurofins-Viracor, and reports payment or honoraria as a speaker for Qiagen and Viracor-Eurofins. S. D. reports research grants paid to his institution from Karius, Merck, Gilead, Ansun Biopharma, Allovir, Geovax. He has served on advisory boards of Merck, Takeda, Allovir, and Aseptiscope, Inc. He is on speaker's bureau of Merck, Astellas and Takeda, and reports payment or honoraria from Viracor for educational event at ID week 2022 and from MJH for cytomegalovirus (CMV) symposium at American Society of Hematology (ASH) 2022. He has stock options in Aseptiscope, Inc, Matinas Biopharma, and Cidara Therapeutics. He reports consulting fees from Merck and Allovir; support for attending meetings and/or travel from American Society of Transplantation and Cellular Therapy—Tandem 2022 and 2023 (registration credit), ID week 2022—Infectious Diseases Society of America (IDSA) (partial support—airfare), and Immunocompromised Host Society (ICHS) 2022 (air fare and hotel expenses); Patent # 9416395, Assigned to City of Hope. Inventors—Markus Kalkum, Karine Bagramyan, Diana Diaz-Arevalo, James I. Ito, Sanjeet S. Dadwal (assigned to City of Hope) and US Provisional Patent Application no. 63/067,855: Inventors—Markus Kalkum, Daniel Roeth, Sanjeet S. Dadwal (assigned to City of Hope); a role as Chair of Transplant Infectious Disease Special Interest Group of American Society of Transplant and Cellular Therapy (ASTCT). J. A. H. reports research grants paid to his institution from Karius and consulting for Karius and support for travel to advisory board meeting from Karius. Y. J. L. has served as an investigator for Astellas, Karius, AiCuris, and Scynexis and has received research grant support from Merck & Co Inc. G. H. is a recipient of research grants from Allovir, Karius, and AstraZeneca and also serves on the scientific advisory boards of and receives consulting fees from Karius and AstraZeneca, and reports grants or contracts from NIH; payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events from MDOutlook, PeerView Medical Education, International AIDS Society. A. L. reports consulting fees from Karius. F. K. reports honorarium from Medscape and research support from Eurofins-Viracor. G. A. P. reports research support from MSD and Takeda/Shire and consulting and other fees from AlloVir, Amplyx, SLC Behring, Cidara, MSD, Takeda and Octapharma. C. B. S. reports research grant support from NIH, GlaxoSmithKline, ViiV, Abbott, Merck, Gilead, Chimerix, Shire/Takeda, Schering-Plough, Ablynx, Janssen, Ansun Biopharma, and Karyopharm Therapeutics; participation on Janssen Respiratory Viruses Advisory Board and Merck Scientific Input Engagement (SIE) Panel for Molnupirivir. M. F. reports research grant support from NIH, and research funding (UCSF PI Fung) from Scynexis and Vatic, Ltd. M. T. M. reports being a consultant for UpToDate and Karius and a co-inventor of patents on Methods to Detect and Treat Acute Respiratory Infections. E. K. M. reports consulting fees from Karius Inc as a Clinical Events Committee member/reviewer—received payments as clinical adjudicator for another Karius project. D. B. M. reports consulting fees from Karius Inc.. A. D. B . reports payment or honoraria from Novartis for lecture on Sepsis Watch, AI program developed at Duke. J. L. T. reports advisory board participation for Sanofi, Natera, Theravance and Altavant Sciences (now Enzyvant Therapeutics) in addition to grants to the institution from Boehringer-Ingelheim, AstraZeneca, Sanofi, NIH, Cystic Fibrosis Foundation and CareDx; and consulting fees from Sanofi. C. E. B. reports grants or contracts from American Lung Association and NIH (National Heart, Lung, and Blood Institute [NHLBI] and National Institute of Allergy and Infectious Diseases [NIAID] funded projects—not related to this project); participation as member of a Data and Safety Monitoring Board (DSMB) for VASSPR—an ICU-based trial with no relationship to this project. R. B. reports stock holdings in Merck, Johnson & Johnson, COVIDien, Pfizer, Sanofi, McKesson, and Viatris and consulting fees from Elixir. E. L. T. reports personal fees from Biomeme and Predigen, stock options in Danaher, and being an employee of Danaher Corp. O, W. reports support for attending meetings and/or travel from Karius (as Clinical Events Classification [CEC] Project Leader initiated and attended meetings with Karius for the PICKUP study); a role as CEC Project Leader coordinated CEC committee meetings within Duke Clinical Research Institute (DCRI) for the PICKUP trial. M. M. reports being an employee of Karius Inc, Redwood City, California, and may own stock options. D. H. reports being a former employee of Karius Inc, Redwood City, California, and a patent issued for related work while at Karius as employee (WO-2020106987-A1—Detection and Prediction of Infectious Disease). R. D. reports being a former employee of Karius Inc, Redwood City, California, and is owner of Karius stock options. D. S. L. reports being an employee of Karius Inc, Redwood City, California, and may own stock options. S. B. reports being an employee of Karius Inc, Redwood City, California, and may own stock options, and reports support for attending meetings and/or travel and patents planned, issued, or pending with Karius Inc. B, A. P. reports being an employee of Karius Inc, Redwood City, California, patents planned, issued or pending with Karius Inc, and may own stock options. T. A. B. reports being an employee of and having a leadership or fiduciary role with Karius Inc, Redwood City, California, and may own stock options. V. G. F. reports personal fees from Novartis, Debiopharm, Genentech, Achaogen, Affinium, Medicines Co., MedImmune, Bayer, Basilea, Affinergy, Janssen, Contrafect, Regeneron, Destiny, Amphliphi Biosciences, Integrated Biotherapeutics; C3J, Armata, Valanbio; Akagera, Aridis, Roche, grants from NIH, MedImmune, Allergan, Pfizer, Advanced Liquid Logics, Theravance, Novartis, Merck; Medical Biosurfaces; Locus; Affinergy; Contrafect; Karius; Genentech, Regeneron, Deep Blue, Basilea, Janssen; royalties from UpToDate, stock options from Valanbio and ArcBio, honoraria from IDSA for his service as Associate Editor of Clinical Infectious Diseases, and a patent sepsis diagnostics pending. T. L. H. reports being an advisor and consultant to Aridis, Basilea Pharmaceutica, Karius, and Lysovant; royalties from UpToDate; reports grants or contracts with Karius (adjudication committee) and with NIH; reports consulting fees from Pfizer and Affinivax; participation on DSMB for platform trial for SNAP Trial; and on advisory board for Basilea. 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) 2023. Published by Oxford University Press on behalf of Infectious Diseases Society of America.)

Background: Hepatitis C virus (HCV) nucleic acid amplification test (NAAT)-positive donors have increased the organ pool. Direct-acting antivirals (DAAs) have led to high rates of treatment success and sustained virologic response (SVR) in recipients with donor-derived HCV infection without significant adverse effects, although variability remains in the timing and duration of antivirals., Methods: This retrospective study analyzed all adult HCV-NAAT-negative transplant recipients who received an organ from HCV-NAAT-positive donors from November 24, 2018, to March 31, 2022, at Duke University Medical Center with protocolized delay of DAA initiation until after hospital discharge, with at least 180-d follow-up on all patients. Transplant and HCV-related outcomes were analyzed., Results: Two hundred eleven transplants (111 kidneys, 41 livers, 34 hearts, and 25 lungs) were performed from HCV-NAAT-positive donors to HCV-NAAT-negative recipients. Ninety percent of recipients became viremic within 7 d posttransplant. Ninety-nine percent of recipients were initiated on pangenotypic DAAs in the outpatient setting a median of 52 d posttransplant, most commonly with 12-wk courses of sofosbuvir-velpatasvir (lungs) and glecaprevir-pibrentasvir (heart, kidney, and liver). Ninety-seven percent of recipients had SVR after a first-line DAA; all ultimately achieved SVR at 12 wk after subsequent treatment courses. The median peak HCV RNA for all organ systems was 2 436 512 IU/mL; the median time from antiviral to undetectable RNA was 48 d, although differences were noted between organ groups. No patient deaths or graft losses were directly attributable to HCV infection., Conclusions: One hundred percent of transplant recipients of HCV-NAAT-positive organs ultimately developed SVR without significant adverse effects when HCV antivirals were initiated in the outpatient setting after transplant hospitalization, suggesting that this real-world treatment pathway is a viable option., Competing Interests: The authors declare no funding or conflicts of interest., (Copyright © 2023 The Author(s). Transplantation Direct. Published by Wolters Kluwer Health, Inc.)

Introduction: Heart transplant (HT) recipients with prior exposure to cytomegalovirus (CMV R+) are considered intermediate risk for CMV-related complications. Consensus guidelines allow for either universal prophylaxis (UP) or preemptive therapy (PET) (serial CMV testing) approaches to CMV prevention in such patients. Whether an optimal approach to mitigate CMV related risks exists in this setting remains uncertain. We therefore assessed the utility of PET as compared to UP in CMV R+ HT recipients., Methods: Retrospective analysis of all CMV R+ HT recipients from 6 U.S. centers between 2010 and 2018 was performed. The primary outcome was the development of CMV DNAemia or end-organ disease resulting in the initiation/escalation of anti-CMV therapy. The secondary outcome was CMV-related hospitalization. Additional outcomes included incidence of acute cellular rejection (ACR) ≥ grade 2R, death, cardiac allograft vasculopathy (CAV), and leukopenia., Results: Of 563 CMV R+ HT recipients, 344 (61.1%) received UP. PET was associated with increased risk for the primary (adjusted HR 3.95, 95% CI: 2.65-5.88, p < .001) and secondary (adjusted HR 3.19, 95% CI: 1.47-6.94, p = .004) outcomes, and with increased ACR ≥ grade 2R (PET 59.4% vs. UP 34.4%, p < .001). Incidence of detectable CAV was similar at 1 year (PET 8.2% vs. UP 9.5%, p = .698). UP was associated with increased incidence of leukopenia within 6 months post-HT (PET 34.7% vs. UP 43.6%, p = .036)., Conclusion: The use of a PET CMV prophylaxis strategy in intermediate risk HT recipients associated with increased risk of CMV infection and CMV-related hospitalization, and may associate with worse post-HT graft outcomes., (© 2023 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Nontuberculous mycobacteria are emerging pathogens, yet data on the epidemiology and management of extrapulmonary nontuberculous mycobacteria infections in orthotopic heart transplantation (OHT) and ventricular assist device (VAD) recipients are scarce. We retrospectively reviewed records of OHT and VAD recipients who underwent cardiac surgery at our hospital and developed Mycobacterium abscessus complex (MABC) infection from 2013 to 2016 during a hospital outbreak of MABC linked to heater-cooler units. We analyzed patient characteristics, medical and surgical management, and long-term outcomes. Ten OHT patients and 7 patients with VAD developed extrapulmonary M. abscessus subspecies abscessus infection. The median time from presumed inoculation during cardiac surgery to the first positive culture was 106 days in OHT and 29 days in VAD recipients. The most common sites of positive cultures were blood (n = 12), sternum/mediastinum (n = 8), and the VAD driveline exit site (n = 7). The 14 patients diagnosed when alive received combination antimicrobial therapy for a median of 21 weeks, developed 28 antibiotic-related adverse events, and underwent 27 surgeries. Only 8 (47%) patients survived longer than 12 weeks after diagnosis, including 2 patients with VAD who experienced long-term survival after an explantation of infected VADs and OHT. Despite aggressive medical and surgical management, OHT and VAD patients with MABC infection experienced substantial morbidity and mortality., (Copyright © 2023 American Society of Transplantation & American Society of Transplant Surgeons. Published by Elsevier Inc. All rights reserved.)

Background: Rising antimicrobial resistance rates may impact the efficacy of empirical antibiotic treatment for febrile neutropenia in high-risk cancer patients. Lacking contemporary data about the epidemiology, antibiotic resistance patterns, and clinical outcomes from bloodstream infections (BSIs) in US cancer patients, it is unclear if current guidelines remain relevant., Methods: In a cross-sectional study, 14 US cancer centers prospectively identified BSIs in high-risk febrile neutropenic (FN) patients, including those receiving chemotherapy for hematologic malignancies or hematopoietic stem cell transplantation., Results: Among 389 organisms causing BSI in 343 patients, there was an equal distribution of gram-negative (GN) and gram-positive (GP) bacteria, with variability across centers. Cefepime and piperacillin-tazobactam were the most commonly prescribed empirical antibiotics for FN, at 62% and 23%, respectively; a GP-directed agent was empirically included in nearly half of all FN episodes within the first 24 hours. Susceptibility to fluoroquinolones, cefepime, piperacillin-tazobactam, and carbapenems was 49%, 84%, 88%, and 96%, respectively, among GN isolates. Critical illness (CrI), defined as a new requirement for mechanical ventilation, vasopressor, or death within 30 days, occurred in 15% and did not correlate with fluoroquinolone prophylaxis, organism type, initial antibiotics, or adequacy of coverage. Only severity of illness at presentation, signified by a Pitt bacteremia score ≥2, predicted for critical illness within 30 days. Mortality was 4% by day 7 and 10% overall., Conclusions: In accordance with US guidelines, cefepime or piperacillin-tazobactam remain effective agents or empirical treatment for high-risk cancer patients with FN who are stable at presentation, maintaining high GN pathogen susceptibility and yielding excellent outcomes., (© The Author(s) 2022. Published by Oxford University Press on behalf of Infectious Diseases Society of America.)

Background: Cytomegalovirus (CMV) infection is common following thoracic organ transplantation and causes substantial morbidity and mortality. Letermovir is a novel antiviral agent used off-label in this population for CMV prevention. Our goal was to understand patterns of letermovir use and effectiveness when applied for CMV prophylaxis after thoracic transplantation., Methods: We retrospectively evaluated letermovir use among thoracic transplant recipients at an academic transplant center who initiated letermovir from January 2018 to October2019 for CMV prophylaxis. We analyzed indication, timing, and duration of prophylaxis; tolerability; and occurrence of breakthrough CMV DNAemia and disease., Results: Forty-two episodes of letermovir prophylaxis occurred in 41 patients, including 37 lung and 4 heart transplant recipients. Primary prophylaxis (26/42, 61.9%) was utilized mainly due to myelosuppression (25/26, 96.2%) and was initiated a median of 315 days post-transplant (interquartile range [IQR] 125-1139 days). Sixteen episodes of secondary prophylaxis (16/42, 38.1%) were initiated a median of 695 days post-transplant (IQR 537-1156 days) due to myelosuppression (10/16, 62.5%) or prior CMV resistance (6/16, 37.5%). Median duration of letermovir prophylaxis was 282 days (IQR 131-433 days). Adverse effects required letermovir cessation in 5/42 (11.9%) episodes. Only one episode (2.4%) was complicated by clinically significant breakthrough CMV infection. Transient low-level CMV DNAemia (<450 IU/ml) occurred in 15 episodes (35.7%) but did not require letermovir cessation., Conclusions: Letermovir was well tolerated and effective during extended prophylactic courses with only one case of breakthrough CMV infection in this cohort of thoracic transplant recipients. Further prospective trials of letermovir prophylaxis in this population are warranted., (Copyright © 2022 International Society for Heart and Lung Transplantation. Published by Elsevier Inc. All rights reserved.)

Introduction: Coccidioidomycosis is a fungal infection endemic in the southwestern United States (US). Primary pulmonary coccidioidomycosis (PPC) is a leading cause of community-acquired pneumonia (CAP) in this region, although its diagnosis is often delayed, leading to lag in antifungal treatment and subsequent morbidity. The impact of early empiric antifungal therapy as part of treatment for CAP in endemic areas on clinical outcomes is unknown., Methods: Phase IV randomized, double-blind, placebo-controlled trial in individuals aged 18 years or older with CAP who met all eligibility criteria in Coccidioides endemic regions in the US. Eligible participants with CAP were randomized to receive either fluconazole (400 mg daily) or matching placebo for 42 days and were subsequently monitored for clinical resolution of their illness., Objectives: The primary objective was to assess the clinical response of early empiric antifungal therapy with fluconazole through Day 22 in subjects with PPC who were adherent to the study intervention. Secondary objectives included: assessments of the impact of early empiric antifungal therapy with fluconazole through Day 22 and 43 in subjects with PPC regardless of adherence, comparisons of the clinical response and its individual components over time by treatment group in subjects with PPC, assessments of days lost from work or school, hospitalization, and all-cause mortality., Discussion: This trial was halted early due to slow enrollment (72 participants in one year, 33 received fluconazole and 39 received placebo). Of those enrolled, eight (11%) met the study definition of PPC. The study design and challenges are discussed., Competing Interests: Julia A. Messina, MD, MHS, MSc: Nothing to report. Eileen K. Maziarz, MD: Nothing to report. John Galgiani, MD: Nothing to report. Jonathan T. Truong, MD: Nothing to report. Aung K. Htoo, MD: Nothing to report. Arash Heidari, MD: Nothing to report. Royce H. Johnson, MD: Nothing to report. Aneesh T. Narang, MD: Nothing to report. Fabria M. Donovan, MD, PhD: Nothing to report. Marion Ewell, ScD: Nothing to report. Antonino Catanzaro, MD: Nothing to report. George R. Thompson III, MD: Nothing to report. Neil M. Ampel, MD: Nothing to report. John R. Perfect, MD: reports research grants and consultation from the following: Astellas, Pfizer, Merck, Amplyx, Scynexis, Matinas, F2G, Appili and Minnetronix. Susanna Naggie, MD, MHS: Nothing to report. Emmanuel B. Walter, MD, MPH: has served as an investigator for clinical trials funded by Moderna and Pfizer., (© 2021 Published by Elsevier Inc.)

Background: We recently mitigated a clonal outbreak of hospital-acquired Mycobacterium abscessus complex (MABC), which included a large cluster of adult patients who developed invasive infection after exposure to heater-cooler units during cardiac surgery. Recent studies have detailed Mycobacterium chimaera infections acquired during cardiac surgery; however, little is known about the epidemiology and clinical courses of cardiac surgery patients with invasive MABC infection., Methods: We retrospectively collected clinical data on all patients who underwent cardiac surgery at our hospital and subsequently had positive cultures for MABC from 2013 through 2016. Patients with ventricular assist devices or heart transplants were excluded. We analyzed patient characteristics, antimicrobial therapy, surgical interventions, and clinical outcomes., Results: Ten cardiac surgery patients developed invasive, extrapulmonary infection from M. abscessus subspecies abscessus in an outbreak setting. Median time from presumed inoculation in the operating room to first positive culture was 53 days (interquartile range [IQR], 38-139 days). Disseminated infection was common, and the most frequent culture-positive sites were mediastinum (n = 7) and blood (n = 7). Patients received a median of 24 weeks (IQR, 5-33 weeks) of combination antimicrobial therapy that included multiple intravenous agents. Six patients required antibiotic changes due to adverse events attributed to amikacin, linezolid, or tigecycline. Eight patients underwent surgical management, and 6 patients required multiple sternal debridements. Eight patients died within 2 years of diagnosis, including 4 deaths directly attributable to MABC infection., Conclusions: Despite aggressive medical and surgical management, invasive MABC infection after cardiac surgery caused substantial morbidity and mortality. New treatment strategies are needed, and compliance with infection prevention guidelines remains critical., (© The Author(s) 2020. Published by Oxford University Press for the Infectious Diseases Society of America. All rights reserved. For permissions, e-mail: journals.permissions@oup.com.)

Background: Lung transplant recipients commonly develop invasive fungal infections (IFIs), but the most effective strategies to prevent IFIs following lung transplantation are not known., Methods: We prospectively collected clinical data on all patients who underwent lung transplantation at a tertiary care academic hospital from January 2007-October 2014. Standard antifungal prophylaxis consisted of aerosolized amphotericin B lipid complex during the transplant hospitalization. For the first 180 days after transplant, we analyzed prevalence rates and timing of IFIs, risk factors for IFIs, and data from IFIs that broke through prophylaxis., Results: In total, 156 of 815 lung transplant recipients developed IFIs (prevalence rate, 19.1 IFIs per 100 surgeries, 95% confidence interval [CI] 16.4-21.8%). The prevalence rate of invasive candidiasis (IC) was 11.4% (95% CI 9.2-13.6%), and the rate of non-Candida IFIs was 8.8% (95% CI 6.9-10.8%). First episodes of IC occurred a median of 31 days (interquartile range [IQR] 16-56 days) after transplant, while non-Candida IFIs occurred later, at a median of 86 days (IQR 40-121 days) after transplant. Of 169 IFI episodes, 121 (72%) occurred in the absence of recent antifungal prophylaxis; however, IC and non-Candida breakthrough IFIs were observed, most often representing failures of micafungin (n = 16) and aerosolized amphotericin B (n = 24) prophylaxis, respectively., Conclusions: Lung transplant recipients at our hospital had high rates of IFIs, despite receiving prophylaxis with aerosolized amphotericin B lipid complex during the transplant hospitalization. These data suggest benefit in providing systemic antifungal prophylaxis targeting Candida for up to 90 days after transplant and extending mold-active prophylaxis for up to 180 days after surgery., (© 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.)

Treatment options for drug-resistant cytomegalovirus (CMV) are limited. Letermovir is a novel antiviral recently approved for CMV prophylaxis following hematopoietic cell transplantation, but its efficacy in other settings is unknown. We recently used letermovir for salvage treatment in four solid organ transplant recipients with ganciclovir-resistant CMV retinitis. All patients improved clinically without known adverse drug events. However, three patients failed to maintain virologic suppression, including two patients who developed genotypically confirmed resistance to letermovir while on therapy., (Copyright © 2019 American Society for Microbiology.)

Background: Nontuberculous mycobacteria (NTM) commonly colonize municipal water supplies and cause healthcare-associated outbreaks. We investigated a biphasic outbreak of Mycobacterium abscessus at a tertiary care hospital., Methods: Case patients had recent hospital exposure and laboratory-confirmed colonization or infection with M. abscessus from January 2013 through December 2015. We conducted a multidisciplinary epidemiologic, field, and laboratory investigation., Results: The incidence rate of M. abscessus increased from 0.7 cases per 10000 patient-days during the baseline period (January 2013-July 2013) to 3.0 cases per 10000 patient-days during phase 1 of the outbreak (August 2013-May 2014) (incidence rate ratio, 4.6 [95% confidence interval, 2.3-8.8]; P < .001). Thirty-six of 71 (51%) phase 1 cases were lung transplant patients with positive respiratory cultures. We eliminated tap water exposure to the aerodigestive tract among high-risk patients, and the incidence rate decreased to baseline. Twelve of 24 (50%) phase 2 (December 2014-June 2015) cases occurred in cardiac surgery patients with invasive infections. Phase 2 resolved after we implemented an intensified disinfection protocol and used sterile water for heater-cooler units of cardiopulmonary bypass machines. Molecular fingerprinting of clinical isolates identified 2 clonal strains of M. abscessus; 1 clone was isolated from water sources at a new hospital addition. We made several water engineering interventions to improve water flow and increase disinfectant levels., Conclusions: We investigated and mitigated a 2-phase clonal outbreak of M. abscessus linked to hospital tap water. Healthcare facilities with endemic NTM should consider similar tap water avoidance and engineering strategies to decrease risk of NTM infection., (© The Author 2017. Published by Oxford University Press for the Infectious Diseases Society of America. All rights reserved. For permissions, e-mail: journals.permissions@oup.com.)

We report 2 cases of disseminated cryptococcosis with central nervous system involvement in patients with chronic lymphoid malignancies occurring within 1 month of starting on ibrutinib. Characteristically, in both cases, no inflammation was seen in the cerebrospinal fluid. Central nervous system mycoses should be considered as a potential complication of ibrutinib.

Cryptococcosis is an invasive mycosis caused by pathogenic encapsulated yeasts in the genus Cryptococcus. Cryptococcus gained prominence as a pathogen capable of widespread disease outbreaks in vulnerable populations. We have gained insight into the pathobiology of Cryptococcus, including the yeast' s capacity to adapt to environmental pressures, exploit new geographic environments, and cause disease in both immunocompromised and apparently immunocompetent hosts. Inexpensive, point-of-care testing makes diagnosis more feasible than ever. The associated worldwide burden and mortality remains unacceptably high. Novel screening strategies and preemptive therapy offer promise at making a sustained and much needed impact on this sugar-coated opportunistic mycosis., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Scedosporium apiospermum is an increasingly appreciated pathogen in immunosuppressed patients. We present a case of S. apiospermum endocarditis in a 70-year-old male who had undergone orthotopic heart transplant. Echocardiogram demonstrated a 1.4 cm tricuspid valve vegetation. He underwent valve replacement, complicated by fatal massive post-operative haemorrhage. Valve cultures grew S. apiospermum. To our knowledge, our case is the first reported instance of endocarditis caused by S. apiospermum in a recipient of a cardiac transplant.