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These updated guidelines from the Infectious Diseases Community of Practice of the American Society of Transplantation review the epidemiology, diagnosis, prevention, and management of infection due to Arenaviruses and West Nile Virus (WNV) in the pre‐ and post‐transplant period. Arenaviruses and WNV have been identified as causes of both donor‐derived and post‐transplant infection. Most data related to these infections have been published in case reports and case series. Transplant recipients may become infected with Arenaviruses if they, or their donors, are exposed to wild rodents or infected pet rodents. Lymphocytic choriomeningitis virus is the most commonly recognized Arenavirus among transplant recipients and should be considered when transplant recipients present with fever, hepatitis, meningitis/encephalitis, and/or multisystem organ failure. WNV is a mosquito‐borne virus, and as such, its incidence varies yearly depending on environmental conditions. WNV in transplant recipients typically presents with fever, myalgias, and rash; approximately one in 40 develop neuroinvasive disease. Due to its morbidity, the Organ Procurement and Transplantation Network recently mandated that transplant centers screen living donors for WNV infection in endemic areas. Little is known about the optimal treatment of Arenaviruses or WNV; reduction in immunosuppression and supportive care are the mainstays of management at present. [ABSTRACT FROM AUTHOR]

Background: Valganciclovir prophylaxis is advocated for lung transplant recipients, but its efficacy is unknown. Methods: Retrospective review was done of 109 donor-positive/recipient-negative lung transplant patients who received alemtuzumab induction and valganciclovir for cytomegalovirus prophylaxis. Results: Median duration of follow-up after transplant was 27 months. Valganciclovir dose reductions (< 900 mg/day or renal-equivalent) were required for 18 patients (17%) due to toxicity, most commonly for neutropenia (n = 15) or gastrointestinal symptoms (n = 2). Of the 109 patients, 34 (31%) had no CMV infections, 45 (41%) had asymptomatic viremia, and 30 (27%) had CMV disease. CMV disease developed off prophylaxis in 10 patients (18%) at a median of 8.7 months after transplant and 2 months after valganciclovir discontinuation. Breakthrough disease occurred during prophylaxis in 10 patients (9%) at a median of 6.7 months. Patients with asymptomatic viremia or no CMV infection received prophylaxis for median 8.6 and 8.7 months, respectively. Risk factors for CMV disease by univariate analysis were increased age (p = 0.01), single-lung transplant (p = 0.03), chronic obstructive pulmonary disease (p = 0.05), reduced-dose valganciclovir (p = 0.001), and less than 6 months of prophylaxis (p = 0.005). By multivariate analysis, advanced age (p = 0.01) and reduced-dose valganciclovir (p = 0.0006) were independent risk factors for CMV disease. CMV disease developed in 4 patients (4%) due to ganciclovir-resistant viruses. CMV-attributable mortality was 5% (5 of 109), including 100% (4 of 4) with ganciclovir-resistant disease. Conclusions: Valganciclovir prophylaxis among donor-positive/recipient-negative lung transplant recipients delayed but did not eliminate CMV disease or CMV-related deaths and was limited by toxicity and ganciclovir-resistance. Our experience suggests that valganciclovir at reduced-doses or for less than 6 months is sub-optimal in preventing CMV disease. [Copyright &y& Elsevier]

Summary: Background: There are few data on the epidemiology and outcomes of influenza infection in recipients of solid-organ transplants. We aimed to establish the outcomes of pandemic influenza A H1N1 and factors leading to severe disease in a cohort of patients who had received transplants. Methods: We did a multicentre cohort study of adults and children who had received organ transplants with microbiological confirmation of influenza A infection from April to December, 2009. Centres were identified through the American Society of Transplantation Influenza Collaborative Study Group. Demographics, clinical presentation, treatment, and outcomes were assessed. Severity of disease was measured by admission to hospital and intensive care units (ICUs). The data were analysed with descriptive statistics. Proportions were compared by use of χ2 tests. We used univariate analysis to identify factors leading to pneumonia, admission to hospital, and admission to an ICU. Multivariate analysis was done by use of a stepwise logistic regression model. We analysed deaths with Kaplan-Meier survival analysis. Findings: We assessed 237 cases of medically attended influenza A H1N1 reported from 26 transplant centres during the study period. Transplant types included kidney, liver, heart, lung, and others. Both adults (154 patients; median age 47 years) and children (83; 9 years) were assessed. Median time from transplant was 3·6 years. 167 (71%) of 237 patients were admitted to hospital. Data on complications were available for 230 patients; 73 (32%) had pneumonia, 37 (16%) were admitted to ICUs, and ten (4%) died. Antiviral treatment was used in 223 (94%) patients (primarily oseltamivir monotherapy). Seven (8%) patients given antiviral drugs within 48 h of symptom onset were admitted to an ICU compared with 28 (22·4%) given antivirals later (p=0·007). Children who received transplants were less likely to present with pneumonia than adults, but rates of admission to hospital and ICU were similar. Interpretation: Influenza A H1N1 caused substantial morbidity in recipients of solid-organ transplants during the 2009–10 pandemic. Starting antiviral therapy early is associated with clinical benefit as measured by need for ICU admission and mechanical ventilation. Funding: None. [Copyright &y& Elsevier]

Abstract: Peptostreptococcus infective endocarditis is rare but associated with high morbidity. We report two cases and evaluate all positive blood cultures for Peptostreptococcus at our institution, followed by a review of the literature. This organism causes a subacute presentation and cardiac valve pathology is a risk factor. Penicillin remains the treatment of choice. [Copyright &y& Elsevier]

Background. Risk factors for Nocardia infection in organ transplant recipients have not been formally assessed in the current era of transplantation. Methods. We performed a matched case-control study (1:2 ratio) between January 1995 and December 2005. Control subjects were matched for transplant type and timing. Univariate matched odds ratios were determined and conditional logistic regression was performed to identify independent risk factors. Clinical and microbiological characteristics of all case patients were reviewed. Results. Among 5126 organ transplant recipients, 35 (0.6%) were identified as having cases of Nocardia infection. The highest frequency was among recipients of lung transplants (18 [3.5%] of 521 patients), followed by recipients of heart (10 [2.5%] of 392), intestinal (2 [1.3%] of 155), kidney (3 [0.2%] of 1717), and liver (2 [0.1%] of 1840) transplants. In a comparison of case patients with 70 matched control subjects, receipt of high-dose steroids (odds ratio, 27; 95% confidence interval, 3.2-235; P=.003) and cytomegalovirus disease (odds ratio, 6.9; 95% confidence interval, 1.02-46; ) P=.047) in the preceding 6 months and a high median calcineurin inhibitor level in the preceding 30 days (odds ratio, 5.8; 95% confidence interval, 1.5-22; P=.012) were found to be independent risk factors for Nocardia infection. The majority of case patients (27 [77%] of 35) had pulmonary disease only. Seven transplant recipients (20%) had disseminated disease. Nocardia nova was the most common species (found in 17 [49%] of the patients), followed by Nocardia farcinica (9 [28%]), Nocardia asteroides (8 [23%]), and Nocardia brasiliensis (1 [3%]). Of the 35 case patients, 24 (69%) were receiving trimethoprim-sulfamethoxazole for Pneumocystis jirovecii pneumonia prophylaxis. Thirty-one case patients (89%) experienced cure of their Nocardia infection. Conclusions. Receipt of high-dose steroids, history of cytomegalovirus disease, and high levels of calcineurin inhibitors are independent risk factors for Nocardia infection in organ transplant recipients. Our study provides insights into the epidemiology of Nocardia infection in the current era, a period in which immunosuppressive and prophylactic regimens have greatly evolved. [ABSTRACT FROM AUTHOR]

Background. Alemtuzumab is being increasingly used for the prevention and/or treatment of acute allograft rejection in organ transplant recipients. We assessed the risks of infection in, to our knowledge, the largest cohort and broadest range of organ transplant recipients yet reported to have received alemtuzumab. Methods. All patients who received alemtuzumab from September 2002 through March 2004, either as induction therapy at the time of transplantation or for the treatment of rejection, were evaluated for the development of an opportunistic infection (OI) until death or for 12 months after receipt of the last dose of alemtuzumab. Results. A total of 547 recipients were included, 65% of whom received alemtuzumab for induction therapy only. Overall, 56 recipients (10%) developed 62 OIs, including cytomegalovirus disease (n = 16), BK virus infection (n = 12), posttransplantation lymphoproliferative disease (n = 5), human herpesvirus 6 infection (n = 1), par- np12 np5 np1 vovirus infection (n = 12), esophageal candidiasis (n = 12), cryptococcosis (n = 2), invasive mold infection (n = 4), Nocardia infection (n = 4), mycobacterial infection (n = 3), Balamuthia mandrillaris infection (n = 1 ), and toxoplasmosis (n = 1). Patients who received alemtuzumab for induction therapy were significantly less likely to develop an OI, compared with patients who received alemtuzumab for rejection therapy (4.5% vs. 21%; P< 001). Independent predictors of the development of an OI were administration of alemtuzumab for rejection therapy (odds ratio [OR], 3.5; 95% confidence interval [CI], 1.8–6.8; P< .001), allograft failure (OR, 2.1; 95% CI, 1.1–4.4; P = .04), and receipt of a lung transplant (OR, 3.7; 95% CI, 1.7–8.0;) or an intestinal transplant (OR, 8.3; 95% CI, 3.5–19.5; P< .001). Conclusions. Patients who received alemtuzumab for the treatment of allograft rejection were significantly more likely to develop an OI, compared with patients who received alemtuzumab for induction therapy only. Such data have implications for new antimicrobial prophylactic strategies. [ABSTRACT FROM AUTHOR]

Purpose: Antimicrobial misuse contributes to antimicrobial resistance in thoracic transplant (TTx) and mechanical circulatory support (MCS) recipients. This study uses a modified Delphi method to define the expected appropriate antimicrobial prescribing for the common clinical scenarios encountered in TTx and MCS recipients., Methods: An online questionnaire on managing 10 common infectious disease syndromes was submitted to a multidisciplinary Delphi panel of 25 experts from various disciplines. Consensus was predefined as 80% agreement for each question. Questions where consensus was not achieved were discussed during live virtual live sessions adapted by an independent process expert., Results: An online survey of 62 questions related to 10 infectious disease syndromes was submitted to the Delphi panel. In the first round of the online questionnaire, consensus on antimicrobial management was reached by 6.5% (4/62). In Round 2 online live discussion, the remaining 58 questions were discussed among the Delphi Panel members using a virtual meeting platform. Consensus was reached among 62% (36/58) of questions. Agreement was not reached regarding the antimicrobial management of the following six clinical syndromes: (1) Burkholderia cepacia pneumonia (duration of therapy); (2) Mycobacterium abscessus (intra-operative antimicrobials); (3) invasive aspergillosis (treatment of culture-negative but positive BAL galactomannan) (duration of therapy); (4) respiratory syncytial virus (duration of antiviral therapy); (5) left ventricular assist device deep infection (initial empirical antimicrobial coverage) and (6) CMV (duration of secondary prophylaxis)., Conclusion: This Delphi panel developed consensus-based recommendations for 10 infectious clinical syndromes seen in TTx and MCS recipients., (© 2024 Wiley Periodicals LLC.)

Invasive aspergillosis (IA) is a rare but fatal disease among liver transplant recipients (LiTRs). We performed a multicenter 1:2 case-control study comparing LiTRs diagnosed with proven/probable IA and controls with no invasive fungal infection. We included 62 IA cases and 124 matched controls. Disseminated infection occurred only in 8 cases (13%). Twelve-week all-cause mortality of IA was 37%. In multivariate analyses, systemic antibiotic usage (adjusted odds ratio [aOR], 4.74; P = .03) and history of pneumonia (aOR, 48.7; P = .01) were identified as independent risk factors associated with the occurrence of IA. Moreover, reoperation (aOR, 5.99; P = .01), systemic antibiotic usage (aOR, 5.03; P = .04), and antimold prophylaxis (aOR, 11.9; P = .02) were identified as independent risk factors associated with the occurrence of early IA. Among IA cases, Aspergillus colonization (adjusted hazard ratio [aHR], 86.9; P < .001), intensive care unit stay (aHR, 3.67; P = .02), disseminated IA (aHR, 8.98; P < .001), and dialysis (aHR, 2.93; P = .001) were identified as independent risk factors associated with 12-week all-cause mortality, while recent receipt of tacrolimus (aHR, 0.11; P = .001) was protective. Mortality among LiTRs with IA remains high in the current era. The identified risk factors and protective factors may be useful for establishing robust targeted antimold prophylactic and appropriate treatment strategies against IA., Competing Interests: Declaration of competing interest The authors of this manuscript have conflicts of interest to disclose as described by the American Journal of Transplantation. J. Hand reports research grant funding from Pfizer, Janssen, Scynexis, and GlaxoSmithKline. D. Neofytos has received research support from MSD and Pfizer and consulting fees from MSD, Pfizer, Basilea, and Gilead. N.J. Mueller is on the scientific advisory board of Takeda MSD, and Pfizer and has received travel support from Biotest. M. Luong is on the Scientific Advisory Board of Takeda and Merck. S. Husain reports grant funding from Merck, Astellas, ScynexisInc, Pulmocide, Ltd, and Gilead Sciences Inc, outside the submitted work. All other authors have no potential conflicts., (Copyright © 2024. Published by Elsevier Inc.)

Background: Antimicrobial resistance (AMR) is undermining modern medicine, a problem compounded by bacterial adaptation to antibiotic pressures. Phages are viruses that infect bacteria. Their diversity and evolvability offer the prospect of their use as a therapeutic solution. Reported are outcomes of customized phage therapy for patients with difficult-to-treat antimicrobial resistant infections., Methods: We retrospectively assessed 12 cases of customized phage therapy from a phage production center. Phages were screened, purified, sequenced, characterized, and Food and Drug Administration-approved via the IND (investigational new drug) compassionate-care route. Outcomes were assessed as favorable or unfavorable by microbiologic and clinical standards. Infections were device-related or systemic. Other experiences such as time to treatment, antibiotic synergy, and immune responses were recorded., Results: Fifty requests for phage therapy were received. Customized phages were generated for 12 patients. After treatment, 42% (5/12) of cases showed bacterial eradication and 58% (7/12) showed clinical improvement, with two-thirds of all cases (66%) showing favorable responses. No major adverse reactions were observed. Antibiotic-phage synergy in vitro was observed in most cases. Immunological neutralization of phages was reported in 5 cases. Several cases were complicated by secondary infections. Complete characterization of the phages (morphology, genomics, and activity) and their production (methods, sterility, and endotoxin tests) are reported., Conclusions: Customized phage production and therapy was safe and yielded favorable clinical or microbiological outcomes in two-thirds of cases. A center or pipeline dedicated to tailoring the phages against a patient's specific AMR bacterial infection may be a viable option where standard treatment has failed., Competing Interests: Potential conflicts of interest. B. W. T. reports grants or contracts, all paid to their institution, from VA Health Services Research & Development; Agency for Healthcare Research and Quality (AHRQ) R18; Craig H. Neilsen Foundation; Genentech; Peptilogics, Inc; AHRQ R01; Center for Innovations in Quality, Effectiveness, and Safety (IQuESt) VA Health Services Research and Development (HSR&D) grant no. CIN 13-413, Bacteriophage to Treat Multidrug-Resistant UTI in Persons with Spinal Cord Injury (5I01RX002595-03); payment to the author for a George Washington ID Board Review Course; support for attending meetings and/or travel from the VA Office of Research and Development and Infectious Diseases Society of America (IDSA); unpaid participation on a Data and Safety Monitoring Board (DSMB) for Cooperative Studies Program #2004 VA. G. A. S. reports grants or contracts unrelated to this work from Adaptive Phage Therapeutics and Phagelux; payment or honoraria for lectures, presentations, speaker’s bureaus, manuscript writing, or educational events from Wayne State University and SUNY Downstate; support for attending meetings and/or travel from Phage Futures, NIH/NIAID, International Committee of Military Medicine, University of Michigan, University of Pittsburgh, and Mayo Alumni Association; a leadership or fiduciary role on the Antimicrobial Resistance Leadership Group and Phagistry. S. A. reports research grants to their institution from Cystic Fibrosis Foundation, Armata Pharmaceuticals, Adaptive Phage Therapeutics, Contrafect, NIAID/NIH, and the National Center for Advancing Translational Sciences (NCATS)/NIH; consulting fees paid to the author from BioMx, and unpaid to the author from Phico; participation as a Medical Advisory Board member for Pherecydes Pharma; a role as an executive committee member for Infection Disease Community of Practice (unpaid) for the American Society of Transplantation and as Chair of the COVID-19 Task Force (unpaid) for the International Society of Heart and Lung Transplantation. S. B. D. reports grants or contracts to the University of California San Francisco (UCSF) from Gilead, Pfizer, F2G, Regeneron, Chan Zuckerberg Biohub, and NIAID/NIH; consulting fees to the author from Genentech and Janssen/J+J; support for travel to speak at IDWeek from the IDSA; patent US20100143379A1 for Mif agonists and antagonist and therapeutic uses thereof; a leadership or fiduciary role on the IDSA Antibacterial Resistance Committee, CADPH HAI Advisory Committee and Antibacterial Resistance Leadership Group Innovations Group, Laboratory Center, Mentorship Committee, Gram Positive Commitee, Immunosuppressed Host Group; payment to the author for clinical events committee/adjudication committee participation from Shinogi, Basilea, and Duke Clinical Research Institute. 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. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

We administered severe acute respiratory syndrome coronavirus-2 viral-specific T cells (VSTs) under emergency investigational new drug applications to 6 immunocompromised patients with persistent coronavirus disease 2019 (COVID-19) and characterized clinical and virologic responses. Three patients had partial responses after failing other therapies but then died. Two patients completely recovered, but the role of VSTs in recovery was unclear due to concomitant use of other antivirals. One patient had not responded to 2 courses of remdesivir and experienced sustained recovery after VST administration. The use of VSTs in immunocompromised patients with persistent COVID-19 requires further study., Competing Interests: Potential conflicts of interest. G. H. reports research grants from AlloVir, Inc, Karius, the National Institutes of Health, and AstraZeneca; consulting fees for serving on the advisory boards of Karius and AstraZeneca; and honoraria from MDOutlook. Y. S. H. is supported by the Hillman Fellowship for Innovative Cancer Research. F. P. S. reports research grants from Ansun, Regeneron, and Merck and serves on the advisory boards for Takeda and Eurofins Viracor. A. M. L. is a cofounder and equity holder in AlloVir, Inc, and Marker Therapeutics and a consultant for AlloVir, Inc. W. L. M. and E. A. are former employees and current stockholders of AlloVir, Inc. M. M. and B. P. are current employees of AlloVir, Inc. J. W. M. is a consultant to Gilead Sciences, Inc; reports grant funding from Gilead Sciences, Inc, to the University of Pittsburgh and compensation from Abound Bio, Inc (unrelated to the current work); and has share options in Infectious Disease Connect, Inc, and Galapagos, NV (unrelated to the current work). All remaining authors: No reported conflicts of interest. 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: Current understanding of severe respiratory syncytial virus (RSV) infections in adults is limited by clinical underrecognition. We compared the prevalence, clinical characteristics, and outcomes of RSV infections vs influenza in adults hospitalized with acute respiratory illnesses (ARIs) in a prospective national surveillance network., Methods: Hospitalized adults who met a standardized ARI case definition were prospectively enrolled across 3 respiratory seasons from hospitals participating across all sites of the US Hospitalized Adult Influenza Vaccine Effectiveness Network (2016-2019). All participants were tested for RSV and influenza using real-time reverse-transcription polymerase chain reaction assay. Multivariable logistic regression was used to test associations between laboratory-confirmed infection and characteristics and clinical outcomes., Results: Among 10 311 hospitalized adults, 6% tested positive for RSV (n = 622), 18.8% for influenza (n = 1940), and 75.1% negative for RSV and influenza (n = 7749). Congestive heart failure (CHF) or chronic obstructive pulmonary disease (COPD) was more frequent with RSV than influenza (CHF: 37.3% vs 28.8%, P < .0001; COPD: 47.6% vs 35.8%, P < .0001). Patients with RSV more frequently had longer admissions (odds ratio [OR], 1.38; 95% confidence interval [CI], 1.06-1.80) for stays >1 week) and mechanical ventilation (OR, 1.45; 95% CI, 1.09-1.93) compared with influenza but not compared with the influenza-negative group (OR, 1.03; 95% CI, .82-1.28 and OR, 1.17; 95% CI, .91-1.49, respectively)., Conclusions: The prevalence of RSV across 3 seasons was considerable. Our findings suggest that those with RSV have worse outcomes compared with influenza and frequently have cardiopulmonary conditions. This study informs future vaccination strategies and underscores a need for RSV surveillance among adults with severe ARI., Competing Interests: Potential conflicts of interest. L. E. L. reports grant support paid to institution from the CDC and funding from Janssen Scientific Affairs paid to institution. E. T. M. reports institutional grant support from the CDC, CDC-Abt Associates, and Merck and grants or contracts unrelated to this work from the NIH, Merck, and FluLab. A. N. M reports a role as member of the Society of Healthcare Epidemiology of America Board of Trustees. F. P. S. reports a research grant paid to institution and unrelated to this work from Ansun and payment to author for honoraria for lectures, presentations, speakers bureaus, manuscript writing, or education events from Janssen. M. J. G. reports institutional grant support or contracts from the CDC; funding from the CDC, CDC-Abt Associates, MedImmune, Janssen, and Pfizer; and a role as co-chair of the Infectious Diseases and Immunization Committee and as chair of the Texas RSV Taskforce for the Texas Pediatric Society, Texas Chapter of American Academy of Pediatrics. A. S. L. reports grants or contracts unrelated to this work from the CDC, Burroughs Wellcome Fund, and National Institute of Allergy and Infectious Diseases (NIAID) and consulting fees from Sanofi and from Roche as a paid member of the baloxavir trial steering committee. R. K. Z. reports a research grant to their university from Sanofi Pasteur. D. B. M. reports consulting fees (advisory group payment to author) from Moderna, Seqirus, Sanofi Pasteur, Novavax, and Valneva and lecture payment to author from Merck and Pfizer. 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. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Background: Acute respiratory infections (ARIs) result in millions of illnesses and hundreds of thousands of hospitalizations annually in the United States. The responsible viruses include influenza, parainfluenza, human metapneumovirus, coronaviruses, respiratory syncytial virus (RSV), and human rhinoviruses. This study estimated the population-based hospitalization burden of those respiratory viruses (RVs) over 4 years, from July 1, 2015 to June 30, 2019, among adults ≥18 years of age for Allegheny County (Pittsburgh), Pennsylvania., Methods: We used population-based statewide hospital discharge data, health system electronic medical record (EMR) data for RV tests, census data, and a published method to calculate burden., Results: Among 26,211 eligible RV tests, 67.6% were negative for any virus. The viruses detected were rhinovirus/enterovirus (2552; 30.1%), influenza A (2,299; 27.1%), RSV (1082; 12.7%), human metapneumovirus (832; 9.8%), parainfluenza (601; 7.1%), influenza B (565; 6.7%), non-SARS-CoV-2 coronavirus (420; 4.9% 1.5 years of data available), and adenovirus (136; 1.6%). Most tests were among female (58%) and White (71%) patients with 60% of patients ≥65 years, 24% 50-64 years, and 16% 18-49 years. The annual burden ranged from 137-174/100,000 population for rhinovirus/enterovirus; 99-182/100,000 for influenza A; and 56-81/100,000 for RSV. Among adults &lt;65 years, rhinovirus/enterovirus hospitalization burden was higher than influenza A; whereas the reverse was true for adults ≥65 years. RV hospitalization burden increased with increasing age., Conclusions: These virus-specific ARI population-based hospital burden estimates showed significant non-influenza burden. These estimates can serve as the basis for several areas of research that are essential for setting funding priorities and guiding public health policy., (© 2022 The Authors. Influenza and Other Respiratory Viruses published by John Wiley & Sons Ltd.)

Background: Therapies for refractory cytomegalovirus infections (with or without resistance [R/R]) in transplant recipients are limited by toxicities. Maribavir has multimodal anti-cytomegalovirus activity through the inhibition of UL97 protein kinase., Methods: In this phase 3, open-label study, hematopoietic-cell and solid-organ transplant recipients with R/R cytomegalovirus were randomized 2:1 to maribavir 400 mg twice daily or investigator-assigned therapy (IAT; valganciclovir/ganciclovir, foscarnet, or cidofovir) for 8 weeks, with 12 weeks of follow-up. The primary endpoint was confirmed cytomegalovirus clearance at end of week 8. The key secondary endpoint was achievement of cytomegalovirus clearance and symptom control at end of week 8, maintained through week 16., Results: 352 patients were randomized (235 maribavir; 117 IAT). Significantly more patients in the maribavir versus IAT group achieved the primary endpoint (55.7% vs 23.9%; adjusted difference [95% confidence interval (CI)]: 32.8% [22.80-42.74]; P < .001) and key secondary endpoint (18.7% vs 10.3%; adjusted difference [95% CI]: 9.5% [2.02-16.88]; P = .01). Rates of treatment-emergent adverse events (TEAEs) were similar between groups (maribavir, 97.4%; IAT, 91.4%). Maribavir was associated with less acute kidney injury versus foscarnet (8.5% vs 21.3%) and neutropenia versus valganciclovir/ganciclovir (9.4% vs 33.9%). Fewer patients discontinued treatment due to TEAEs with maribavir (13.2%) than IAT (31.9%). One patient per group had fatal treatment-related TEAEs., Conclusions: Maribavir was superior to IAT for cytomegalovirus viremia clearance and viremia clearance plus symptom control maintained post-therapy in transplant recipients with R/R cytomegalovirus. Maribavir had fewer treatment discontinuations due to TEAEs than IAT. Clinical Trials Registration. NCT02931539 (SOLSTICE)., Competing Interests: Potential conflicts of interest. R. K. A.: study grant support: AiCuris, Astellas, Chimerix, Merck, Oxford Immunotec, Qiagen, and Takeda/Shire. S. A.: research funding as a scientific expert and site principal investigator: Altona, BioMérieux, Biotest, GlaxoSmithKline, Merck, Merck Sharp & Dohme, Qiagen, Shire, a Takeda company; honoraria for lectures paid to their institution: Biotest, Merck Sharp & Dohme, IQone; support for attending meetings: BioMérieux, Biotest, Quality Control for Molecular Diagnostics; advisory board (unpaid): Quality Control for Molecular Diagnostics. Primary investigator for this study in France. B. D. A.: research funding for work as an investigator: Scynexis, Shire, a Takeda company; research funding to institution for work as an investigator: Astellas, Cidara, F2G, Leadiant; royalties or licenses: UpToDate; consulting fees: Astellas, Scynexis; leadership or fiduciary role: Past President Infectious Diseases Society of America. E. A. B.: research support to their institution: Hologic, Merck, Takeda; scientific medical advisor (unpaid): Merck; Data and Safety Monitoring Board: Amplyx; leadership or fiduciary role: board member (including office holder) American Society of Transplantation. R. F. C.: institutional research grants: AiCuris, Ansun Biopharma, Chimerix, Janssen, Karius, Merck, Novartis, Oxford Immunotec, Pulmotect, Shire, a Takeda company, Viracor; consulting fees: ADMA Biologics, Ansun Biopharma, Janssen, Merck, Molecular Partners, Qiagen, Shire, a Takeda company; honoraria: Genentech, Merck, Oxford Immunotec, Partner Therapeutics, Pulmotect, Shire, a Takeda company; Data Safety Monitoring Board or Advisory Board: Enanta, Duke; stock or stock options: Xenex. C. C.: departmental research funding: Merck, Shire, a Takeda company; consulting fees for advisory board and speaker bureau participation: Merck, Takeda. R. F. D.: departmental research funding: Janssen, Merck, Novartis, Omeros, Roche Diagnostics; consulting fees for advisory boards and speaker bureau participation: Bristol Myers Squibb, Gilead Sciences, Incyte, Jazz Pharmaceuticals, Merck, Omeros, Pfizer, Sanofi Oncology, Sobi, Shire, a Takeda company. D. F. F.: research support for work as an investigator: Astellas, Merck, Nobelpharma, Novavax, Shire, a Takeda company; Data Safety Monitoring Board: Amplyx; advisory boards: Merck, Takeda. N. K.: advisory board and speaker’s fees: Astellas, Biotest, Chiesi, CSL Behring, Merck Sharp & Dohme, Neovii, Novartis Pharma, Sandoz, Sanofi, Shire, a Takeda company. D. K.: consultant: Roche, Sanofi, Takeda; grant/research support: Merck, Qiagen, Roche, Takeda; speaking fee: Astellas. J. M.: consulting fees from Shire/Takeda during the conduct of the study, as well as consulting fees and nonfinancial support from Amgen, Astellas Pharma, Basilea, Cidara, F2G, Schering-Plough, Scynexis; and grants, consulting fees, and nonfinancial support from Bio-Rad, Gilead Sciences, Merck, Pfizer Inc, outside the submitted work; honoraria: Astellas, F2G, Gilead, Pfizer Inc, Merck Sharp & Dohme, Mundipharma. F. M. M.: consultant: AlloVir, Amplyx, Avir, Emcure, F2G, Gilead, Janssen, Kyorin, Merck, Regeneron, ReViral, Symbio, United Medical; investigator and research funding: Ansun, Chimerix, Cidara, Scynexis, Shire, a Takeda company, WHISCON; research funding: AlloVir, Amplyx, F2G, Gilead, Merck, Regeneron. G. A. P.: consulting fees: ADMA Biologics, AlloVir, Amplyx, Astellas, Behring, Cidara, Octapharma, Partner Therapeutics, Shionogi, Shire, a Takeda company, Siemens Healthineers; investigator: Merck, Shire, a Takeda company; honoraria for speaking engagement: Basilea, Merck, Merck Sharp & Dohme Europe. F. P. S.: research support for work as an investigator: Ansun Biopharma, Gilead, Merck, Novartis, Qiagen, Shire, a Takeda company, SlieaGen, WHISCON; travel funding to meetings: Shire, a Takeda company; lecture honoraria: Janssen; consulting fees: Takeda. O. W.: research grants for clinical studies, speaker’s fees, honoraria, and travel expenses: Alexion, Amgen, Astellas, Basilea, Biotest, Bristol Myers Squibb, Chiesi, Correvio, Gilead, Hexal, Janssen, Dr. F. Köhler Chemie, Merck Sharp & Dohme, Novartis, Pfizer, Roche, Sanofi, Takeda, Teva, UCB; unrestricted grant from the Rudolf-Ackermann-Stiftung (Stiftung für Klinische Infektiologie). J. W., A. K. S., and M. F.: employees of and holding stock/stock options in: Takeda Development Center Americas, Inc. 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) 2021. Published by Oxford University Press for the Infectious Diseases Society of America.)

Background: We studied humoral responses after coronavirus disease 2019 (COVID-19) vaccination across varying causes of immunodeficiency., Methods: Prospective study of fully vaccinated immunocompromised adults (solid organ transplant [SOT], hematologic malignancy, solid cancers, autoimmune conditions, human immunodeficiency virus [HIV]) versus nonimmunocompromised healthcare workers (HCWs). The primary outcome was the proportion with a reactive test (seropositive) for immunoglobulin G to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) receptor-binding domain. Secondary outcomes were comparisons of antibody levels and their correlation with pseudovirus neutralization titers. Stepwise logistic regression was used to identify factors associated with seropositivity., Results: A total of 1271 participants enrolled: 1099 immunocompromised and 172 HCW. Compared with HCW (92.4% seropositive), seropositivity was lower among participants with SOT (30.7%), hematological malignancies (50.0%), autoimmune conditions (79.1%), solid tumors (78.7%), and HIV (79.8%) (P < .01). Factors associated with poor seropositivity included age, greater immunosuppression, time since vaccination, anti-CD20 monoclonal antibodies, and vaccination with BNT162b2 (Pfizer) or adenovirus vector vaccines versus messenger RNA (mRNA)-1273 (Moderna). mRNA-1273 was associated with higher antibody levels than BNT162b2 or adenovirus vector vaccines after adjusting for time since vaccination, age, and underlying condition. Antibody levels were strongly correlated with pseudovirus neutralization titers (Spearman r = 0.89, P < .0001), but in seropositive participants with intermediate antibody levels, neutralization titers were significantly lower in immunocompromised individuals versus HCW., Conclusions: Antibody responses to COVID-19 vaccines were lowest among SOT and anti-CD20 monoclonal recipients, and recipients of vaccines other than mRNA-1273. Among those with intermediate antibody levels, pseudovirus neutralization titers were lower in immunocompromised patients than HCWs. Additional SARS-CoV-2 preventive approaches are needed for immunocompromised persons, which may need to be tailored to the cause of immunodeficiency., (© The Author(s) 2022. Published by Oxford University Press for the Infectious Diseases Society of America. All rights reserved. For permissions, e-mail: journals.permissions@oup.com.)

Background: Evidence for vaccine effectiveness (VE) against influenza-associated pneumonia has varied by season, location, and strain. We estimate VE against hospitalization for radiographically identified influenza-associated pneumonia during 2015-2016 to 2017-2018 seasons in the US Hospitalized Adult Influenza Vaccine Effectiveness Network (HAIVEN)., Methods: Among adults aged ≥18 years admitted to 10 US hospitals for acute respiratory illness (ARI), clinician-investigators used keywords from reports of chest imaging performed during 3 days around hospital admission to assign a diagnosis of "definite/probable pneumonia." We used a test-negative design to estimate VE against hospitalization for radiographically identified laboratory-confirmed influenza-associated pneumonia, comparing reverse transcriptase-polymerase chain reaction-confirmed influenza cases with test-negative subjects. Influenza vaccination status was documented in immunization records or self-reported, including date and location. Multivariable logistic regression models were used to adjust for age, site, season, calendar-time, and other factors., Results: Of 4843 adults hospitalized with ARI included in the primary analysis, 266 (5.5%) had "definite/probable pneumonia" and confirmed influenza. Adjusted VE against hospitalization for any radiographically confirmed influenza-associated pneumonia was 38% (95% confidence interval [CI], 17-53%); by type/subtype, it was 74% (95% CI, 52-87%) influenza A (H1N1)pdm09, 25% (95% CI, -15% to 50%) A (H3N2), and 23% (95% CI, -32% to 54%) influenza B. Adjusted VE against intensive care for any influenza was 57% (95% CI, 19-77%)., Conclusions: Influenza vaccination was modestly effective among adults in preventing hospitalizations and the need for intensive care associated with influenza pneumonia. VE was significantly higher against A (H1N1)pdm09 and was low against A (H3N2) and B., (© 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.)

Background: Detailed cytomegalovirus (CMV) kinetics in donor CMV-seropositive, recipient CMV-seronegative (D+/R-) transplant recipients receiving preemptive therapy (PET) have not been fully defined., Methods: The study population consisted of the PET arm of a randomized CMV prevention trial in D+/R- liver transplant recipients. CMV DNA polymerase chain reaction (PCR) assays were performed weekly for 100 days using a sensitive assay. Viral load and clinical parameters were compared for patients with or without high-level increase (defined as higher than the group median log10 increase in viral load from baseline after PET initiation)., Results: Among 79 patients, 93.6% (74/79) developed an increase from baseline viral loads of median 120 IU/mL to 3350 IU/mL; 25.7% (19/74) of the patients had peak levels >10 000 IU/mL. None of the patients with rise in viral load underwent testing for CMV resistance, and viremia resolved with PET with valganciclovir. Patients with high-level increase in viral load had a significantly lower rate of recurrent viremia than those without such increase (16/40 [40%] vs 28/39 [71.8%], respectively; P = .004)., Conclusions: A majority of D+/R- recipients had a marked increase in viral load after initiation of PET before resolution of viremia. This phenomenon is associated with lower rates of subsequent recurrent viremia and does not necessarily imply antiviral resistance., (© 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.)

Background: Risk factors, virological parameters, and outcomes associated with HHV-6 viremia in high-risk donor CMV-seropositive and recipient CMV-seronegative (D+R-) liver transplant recipients in the current era are incompletely defined., Methods: The study population consisted of patients in the preemptive therapy (PET) arm of a randomized, controlled trial of PET versus valganciclovir prophylaxis for CMV prevention in D+R- liver transplant recipients. Weekly blood samples through 100 d in the PET group were tested for HHV-6 viremia using a real-time quantitative polymerase chain reaction. Assessments included virological characteristics and relationship with CMV, risk factors, and impact of HHV-6 viremia with outcomes through 12 mo posttransplant., Results: HHV-6 viremia at any level developed in 42% (40 of 96). Older patient age (P = 0.03), longer hospitalization (P = 0.015), and ICU stay at transplantation (P = 0.029) were significantly associated with high-grade viremia. Concurrent HHV-6 and CMV viremia was associated with earlier onset of HHV-6 viremia (P = 0.004), higher HHV-6 area under the curve (P = 0.043), and higher peak HHV-6 viral load (P = 0.006) versus HHV-6 viremia alone. High-grade viremia was independently associated with biopsy-proven rejection within 12 mo (P = 0.045) posttransplant., Conclusions: Among D+R- liver transplant recipients receiving valganciclovir as PET, high-grade HHV-6 viremia was associated with increased age and critical illness in ICU at time of transplant and was independently associated with allograft rejection., Competing Interests: D.J.W. has received research support form Merck, Chimerix, Shire, Gilead, and Oxford Immnotech. G.M.L. has received research support from Takeda pharmaceutical company. F.P.S. has received research support from Shire, Ansun, and Novartis. A.P.L. has received research support from Merck and Astellas, and consulting support from Helocyte, Inc, Amplyx, Novartis, and AlloVir. The other authors declare no conflicts of interest., (Copyright © 2021 Wolters Kluwer Health, Inc. All rights reserved.)

Adults aged ≥65 years are at increased risk for severe outcomes from COVID-19 and were identified as a priority group to receive the first COVID-19 vaccines approved for use under an Emergency Use Authorization (EUA) in the United States (1-3). In an evaluation at 24 hospitals in 14 states,* the effectiveness of partial or full vaccination † with Pfizer-BioNTech or Moderna vaccines against COVID-19-associated hospitalization was assessed among adults aged ≥65 years. Among 417 hospitalized adults aged ≥65 years (including 187 case-patients and 230 controls), the median age was 73 years, 48% were female, 73% were non-Hispanic White, 17% were non-Hispanic Black, 6% were Hispanic, and 4% lived in a long-term care facility. Adjusted vaccine effectiveness (VE) against COVID-19-associated hospitalization among adults aged ≥65 years was estimated to be 94% (95% confidence interval [CI] = 49%-99%) for full vaccination and 64% (95% CI = 28%-82%) for partial vaccination. These findings are consistent with efficacy determined from clinical trials in the subgroup of adults aged ≥65 years (4,5). This multisite U.S. evaluation under real-world conditions suggests that vaccination provided protection against COVID-19-associated hospitalization among adults aged ≥65 years. Vaccination is a critical tool for reducing severe COVID-19 in groups at high risk., Competing Interests: All authors have completed and submitted the International Committee of Medical Journal Editors form for disclosure of potential conflicts of interest. Christopher J. Lindsell reports grants from National Institutes of Health, U.S. Department of Defense, Marcus Foundation, Endpoint Health, Entegrion, bioMerieux, and Bioscape Digital, outside the submitted work. Jay S. Steingrub reports grants from National Institutes of Health, outside the submitted work. Akram Khan reports grants from United Therapeutics, Actelion Pharmaceuticals, Regeneron, and Reata Pharmaceuticals, outside the submitted work. Samuel M. Brown reports grants from National Institutes of Health, U.S. Department of Defense, Intermountain Research and Medical Foundation, and Janssen, and consulting fees paid to his employer from Faron and Sedana, all outside the submitted work. Ithan D. Peltan reports grants from National Institutes of Health and, outside the submitted work, grants from Asahi Kasei Pharma, Janssen Pharmaceuticals, and Regeneron. Adit A. Ginde reports grants from National Institutes of Health, U.S. Department of Defense and AbbVie, outside the submitted work. Carlos G. Grijalva reports consulting fees from Pfizer, Merck, and Sanofi-Pasteur, grants from Campbell Alliance/Syneos Health, National Institutes of Health, Food and Drug Administration, and Agency for Health Care Research and Quality, outside the submitted work. Michelle N. Gong reports grants from National Institutes of Health, Agency for Healthcare Research and Quality, and consulting fees from Regeneron, Philips Healthcare, all outside the submitted work. Steven Y. Chang reports consulting fees from PureTech Health and speaker fees from La Jolla Pharmaceuticals, both outside the submitted work. Jonathan D. Casey reports grants from National Institutes of Health, outside the submitted work. Todd W. Rice reports grants from National Institutes of Health and Endpoint Health, consulting work for Cumberland Pharmaceuticals, Inc, and Sanofi, Inc., outside the submitted work. Manjusha Gaglani reports grants from CDC-Abt Associates, outside the submitted work. Emily T. Martin reports personal fees from Pfizer and grants from Merck, outside the submitted work. Anurag Malani reports shareholder of Pfizer pharmaceuticals. Arnold S. Monto reports personal fees from Sanofi Pasteur and Seqirus, outside the submitted work. Fernanda P. Silveira reports grants from Shire, Qiagen, Ansun, and Novartis, outside the submitted work. Richard K. Zimmerman reports grants from Sanofi Pasteur, outside the submitted work. Donald B. Middleton reports grants and personal fees from Pfizer and personal fees from Seqirus, Sanofi Pasteur, and GlaxoSmithKline, outside the submitted work. No other potential conflicts of interest were disclosed.

Intravenous (i.v.) minocycline is increasingly used to treat infections caused by multidrug-resistant (MDR) Acinetobacter baumannii Despite its being approved nearly 50 years ago, published information on its pharmacokinetic (PK) profile is limited. This multicenter study examined the PK and probability of pharmacokinetic-pharmacodynamic (PK-PD) target attainment profile of i.v. minocycline in critically ill patients, with suspected or documented infection with Gram-negative bacteria. The PK study population included 55 patients who received a single 200-mg i.v. dose of minocycline. Plasma PK samples were collected predose and 1, 4, 12, 24, 36, and 48 h after initiation of minocycline. Total and unbound minocycline concentrations were determined at each time point. Probabilities of achieving the PK-PD targets associated with stasis and 1-log killing (free area under the curve above the MIC [ f AUC:MIC] of 12 and 18, respectively) in an immunocompetent animal pneumonia infection model of A. baumannii were evaluated. A two-compartment population PK model with zero-order i.v. input and first-order elimination, which estimated a constant fraction unbound (f ub ) for minocycline, best characterized the total and unbound plasma minocycline concentration-time data. The only two covariates retained in the final PK model were body surface area (associated with central volume of distribution) and albumin (associated with f ub ). In the PK-PD probability of target attainment analyses, minocycline 200 mg i.v. every 12 h (Q12H) was predicted to result in a suboptimal PK-PD profile for patients with A. baumannii infections with MIC values of >1 mg/liter. Like all PK-PD profiling studies of this nature, these findings need clinical confirmation., (Copyright © 2021 American Society for Microbiology.)

Background: Isavuconazole is a triazole antifungal available in IV and capsule formulation. Prescribing information states that capsules should not be chewed, crushed, dissolved or opened because the drug was not studied in this manner. However, considering the pharmacokinetics of the capsules, we theorized opening and sprinkling the contents into an enteral feeding tube (EFT) would result in adequate absorption and systemic concentrations of isavuconazole., Objectives: To determine whether patients receiving isavuconazonium sulphate capsules via EFT would achieve clinical blood concentrations of isavuconazole., Methods: Nineteen solid organ and HCT recipients receiving isavuconazole via EFT for prevention or treatment of invasive fungal infection (IFI) were prospectively identified at four academic medical centres in the USA. Patients were included in this evaluation if they received isavuconazole via EFT for at least 5 days and therapeutic drug monitoring (TDM) was performed., Results: TDM was performed after a median of 7 days (range 6-17) following EFT administration and 15 days (range 7-174) of isavuconazole therapy overall. Median isavuconazole concentration was 1.8 μg/mL (range 0.3-5.2). Median isavuconazole concentrations in patients with or without prior IV administration were 1.8 μg/mL (range 0.3-5.2) and 2.2 μg/mL (range 0.8-3.6; P = 0.896), respectively. Concentrations achieved with the EFT route were similar to or greater than the corresponding concentrations via the IV route in six patients who had TDM performed during both routes of administration., Conclusions: It is reasonable to consider opening isavuconazonium sulphate capsules and administering the contents enterally for prevention and treatment of IFI., (© The Author(s) 2020. 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.)

Importance: Despite the use of a cytomegalovirus (CMV) prevention strategy of antiviral prophylaxis for high-risk CMV-seronegative liver transplant recipients with seropositive donors, high rates of delayed-onset postprophylaxis CMV disease occur. An alternate approach, preemptive therapy (initiation of antiviral therapy for early asymptomatic CMV viremia detected by surveillance testing), has not previously been directly compared with antiviral prophylaxis in these patients., Objective: To compare preemptive therapy with antiviral prophylaxis in CMV-seronegative liver transplant recipients with seropositive donors for the prevention of CMV disease., Design, Setting, and Participants: Randomized clinical trial of preemptive therapy vs antiviral prophylaxis in 205 CMV-seronegative liver transplant recipients with seropositive donors aged older than 18 years. The trial was conducted at 6 academic transplant centers in the United States between October 2012 and June 2017, with last follow-up in June 2018., Interventions: Patients were randomized 1:1 to receive either preemptive therapy (valganciclovir, 900 mg, twice daily until 2 consecutive negative tests a week apart) for viremia detected by weekly plasma CMV polymerase chain reaction for 100 days (n = 100) or valganciclovir, 900 mg, daily for 100 days as antiviral prophylaxis (n = 105)., Main Outcomes and Measures: The primary outcome was incidence of CMV disease by 12 months, defined as CMV syndrome (CMV viremia and clinical or laboratory findings) or end-organ disease. Secondary outcomes included acute allograft rejection, opportunistic infections, graft and patient survival, and neutropenia., Results: Among 205 patients who were randomized (mean age, 55 years; 62 women [30%]), all 205 (100%) completed the trial. The incidence of CMV disease was significantly lower with preemptive therapy than antiviral prophylaxis (9% [9/100] vs 19% [20/105]; difference, 10% [95% CI, 0.5% to 19.6%]; P = .04]). The incidence of allograft rejection (28% vs 25%; difference, 3% [95% CI, -9% to 15%]), opportunistic infections (25% vs 27%; difference, 2% [95% CI, -14% to 10%]), graft loss (2% vs 2%; difference, <1% [95% CI, -4% to 4%]), and neutropenia (13% vs 10%; difference, 3% [95% CI, -5% to 12%]) did not differ significantly for the preemptive therapy vs antiviral prophylaxis group, respectively. All-cause mortality at last follow-up was 15% in the preemptive therapy vs 19% in the antiviral prophylaxis group (difference, 4% [95% CI, -14% to 6%]; P = .46)., Conclusions and Relevance: Among CMV-seronegative liver transplant recipients with seropositive donors, the use of preemptive therapy, compared with antiviral prophylaxis, resulted in a lower incidence of CMV disease over 12 months. Further research is needed to replicate these findings and assess long-term outcomes., Trial Registration: ClinicalTrials.gov Identifier: NCT01552369.

Background: Bronchiolitis obliterans syndrome (BOS) is a major limitation in the long-term survival of lung transplant recipients (LTRs). However, the risk factors in the development of BOS remain undetermined. We conducted an international cohort study of LTRs to assess whether Aspergillus colonization with large or small conidia is a risk factor for the development of BOS., Methods: Consecutive LTRs from January 2005 to December 2008 were evaluated. Rates of BOS and associated risk factors were recorded at 4 years. International Society of Heart and Lung Transplantation criteria were used to define fungal and other infections. A Cox proportional-hazards-model was constructed to assess the association between Aspergillus colonization and the development of BOS controlling for confounders., Results: A total of 747 LTRs were included. The cumulative incidence of BOS at 4 years after transplant was 33% (250 of 747). Additionally, 22% of LTRs experienced Aspergillus colonization after transplantation. Aspergillus colonization with either large (hazard ratio [HR] = 0.6, 95% confidence interval [CI] = 0.3-1.2, p = 0.12) or small conidia (HR = 0.9, 95% CI = 0.6-1.4, p = 0.74) was not associated with the development of BOS. Factors associated with increased risk of development of BOS were the male gender (HR = 1.4, 95% CI = 1.1-1.8, p = 0.02) and episodes of acute rejection (1-2 episodes, HR = 1.5, 95% CI = 1.1-2.1, p = 0.014; 3-4 episodes, HR = 1.6, 95% CI = 1.0-2.6, p = 0.036; >4 episodes, HR = 2.2, 95% CI = 1.1-4.3, p = 0.02), whereas tacrolimus use was associated with reduced risk of BOS (HR = 0.6, 95% CI = 0.5-0.9, p = 0.007)., Conclusions: We conclude from this large multicenter cohort of lung transplant patients, that Aspergillus colonization with large or small conidia did not show an association with the development of BOS., (Copyright © 2019 International Society for Heart and Lung Transplantation. Published by Elsevier Inc. All rights reserved.)

Background: Immunosuppressive therapies have led to improved survival for lung transplant (LT) recipients but these therapies can lead to hypogammaglobulinemia (HGG) and potentially an increased risk of infection. Large prospective studies have not been performed to evaluate the impact of HGG on outcomes for LT recipients., Methods: This is a single-center prospective observational study of LT recipients. Pretransplant and posttransplant IgG levels were measured and related to infection, rejection, antibiotic use, and immunosuppression use., Results: One hundred thirty-three LT recipients were prospectively evaluated. Pretransplant IgG values were higher than IgG values at the time of transplant or any time thereafter (all P < 0.0001). Severe HGG (IgG < 400 mg/dL) was highest at the time of transplant (32.4%) while at 3, 6, 9, and 12 months posttransplant the prevalence of severe HGG was 7.4%, 7.5%, 8.9%, and 6.3%, respectively. Severe HGG was associated with 2 or more pneumonias ( P = 0.0006) and increased number of antibiotic courses ( P = 0.003) compared with the subjects without severe HGG. Pretransplant IgG level and less than 30% of pretransplant protective pneumococcal antibody levels were identified as pretransplant risk factors for severe HGG. In multivariate analysis, chronic obstructive pulmonary disease as the underlying disease and the use of basiliximab as the induction agent in conjunction with higher prednisone and mycophenolate dosing were most predictive of severe HGG ( P = 0.005), whereas the combination of age, severe HGG and number of acute steroid courses were most predictive of total days of pneumonia ( P = 0.0001)., Conclusions: Our large prospective study identifies risk factors for severe HGG after LT and demonstrates that LT recipients with severe HGG are at increased risk for recurrent pneumonias and more antibiotic courses.

Purpose of Review: To review and discuss the epidemiology, risk factors, clinical presentation, diagnosis, and treatment of non-tuberculous mycobacteria (NTM) in thoracic transplantation., Recent Findings: Non-tuberculous mycobacteria are ubiquitous but are an uncommon cause of disease after solid organ transplantation. The incidence of infection is higher in thoracic transplant recipients than in abdominal transplant recipients, with most cases seen after lung transplantation. It is associated with increased morbidity and, occasionally, mortality. Infection in the pre-transplant setting can occur in lung transplant candidates, often posing a dilemma regarding transplant listing. Disease manifestations are diverse, and pulmonary disease is the most common. Diagnosis requires a high index of suspicion. Treatment requires a multiple-drug combination and is limited by drug-drug interactions and tolerability. Mycobacterium abscessus is a challenge in lung transplant recipients, due to its intrinsic resistance and propensity to relapse even after prolonged therapy. Mycobacterium chimaera is an emerging pathogen associated with contamination of heater-cooler units and is described to cause disease months after cardiothoracic surgery. NTM infections in thoracic organ transplant recipients are uncommon but are associated with substantial morbidity and mortality. Data from larger multicenter studies is needed to better define the epidemiology of NTM in thoracic transplantation, best treatment options, and the management of infected transplant candidates.

Background: Intravenous colistin is difficult to use because plasma concentrations for antibacterial effect overlap those causing nephrotoxicity, and there is large inter-patient variability in pharmacokinetics. The aim was to develop dosing algorithms for achievement of a clinically desirable average steady-state plasma colistin concentration (C ss,avg ) of 2mg/L., Methods: Plasma concentration-time data from 214 adult critically-ill patients (creatinine clearance 0-236mL/min; 29 receiving renal replacement therapy (RRT)) were subjected to population pharmacokinetic analysis. Development of an algorithm for patients not receiving RRT was based upon the relationship between the dose of colistimethate that would be needed to achieve a desired C ss,avg and creatinine clearance. The increase in colistin clearance when patients were on RRT was determined from the population analysis and guided the supplemental dosing needed. To balance potential antibacterial benefit against risk of nephrotoxicity the algorithms were designed to achieve target attainment rates of >80% for C ss,avg ≥2 and <30% for C ss,avg ≥4mg/L., Results: When algorithm doses were applied back to individual patients not on RRT (including patients prescribed intermittent dialysis on a non-dialysis day), >80% of patients with creatinine clearance <80mL/min achieved C ss,avg ≥2mg/L; but for patients with creatinine clearance ≥80mL/min target attainment was <40%, even with the maximum allowed daily dose of 360mg colistin base activity. For patients receiving RRT, target attainment rates were >80% with the proposed supplemental dosing. In all categories of patients, <30% of patients attained C ss,avg ≥4mg/L., Conclusions: The project has generated clinician-friendly dosing algorithms and pointed to circumstances where intravenous monotherapy may be inadequate., (© The Author 2016. Published by Oxford University Press for the Infectious Diseases Society of America. All rights reserved. For permissions, e-mail: journals.permissions@oup.com.)

Background: The US Food and Drug Administration (FDA) and European Medicines Agency (EMA) have approved updated dose recommendations for intravenous colistin in patients with various degrees of renal function. We assessed the recommendations in relation to their ability to achieve clinically relevant plasma colistin concentrations., Methods: Pharmacokinetic data from 162 adult critically ill patients (creatinine clearance range, 5.4-211 mL/min) were used to determine the average steady-state plasma colistin concentration (Css,avg) that would be achieved if each patient received the FDA or EMA dose. Target attainment rates for FDA- and EMA-approved daily doses to achieve colistin Css,avg of ≥0.5, ≥1, ≥2, and ≥4 mg/L were determined for each creatinine clearance category (≥80 mL/min, 50 to <80 mL/min, 30 to <50 mL/min, and <30 mL/min)., Results: For creatinine clearance <30 mL/min, 100% of patients receiving the EMA dose achieved a colistin Css,avg ≥1 mg/L, but the attainment rate was as low as 53.1% for patients receiving the FDA-approved dose. For colistin Css,avg ≥2 mg/L, the attainment rates were 87.5% with the EMA dose but only 6.3%-34.4% in patients receiving the FDA dose. Differences in attainment rates for a colistin Css,avg of ≥2 mg/L and ≥4 mg/L extended to patients with creatinine clearance 30 to <50 mL/min. For patients with creatinine clearance ≥80 mL/min, only approximately 65%-75% of patients achieved a colistin Css,avg of ≥1 mg/L with either set of recommendations., Conclusions: The study highlights important differences between the FDA- and EMA-approved dose recommendations and informs the setting of clinical breakpoints., Clinical Trials Registration: NCT00235690., (© The Author 2015. Published by Oxford University Press for the Infectious Diseases Society of America. All rights reserved. For permissions, e-mail journals.permissions@oup.com.)

The dematiaceous mold Ochroconis gallopava is increasingly recognized as a human pathogen. Infection is almost always associated with immunosuppression. We describe a case with a unique presentation in a kidney transplant recipient and retrospectively review all 10 cases of O. gallopava at our institution over 18 yr, all in organ transplant recipients. Sixty percent of infections at our institution occurred in the last five yr studied. Infection generally occurred late after transplantation, and pulmonary infection was the most common manifestation. Use of almetuzumab for induction was associated with infection in the first six months post-transplant (p = 0.03). Attributable mortality at six months was 20%. Ochroconis gallopava is a rare but important pathogen in immunosuppressed individuals and organ transplantation is the most common underlying condition. Pulmonary involvement is the most common manifestation among patients with organ transplant. Optimal therapy remains undefined. Prognosis in organ transplant recipients is good if infection is diagnosed prior to dissemination., (© 2011 John Wiley & Sons A/S.)

Background: Early diagnosis and treatment of invasive pulmonary aspergillosis (IPA) improves outcome., Methods: We compared the performance of publicly available pan-Aspergillus, Aspergillus fumigatus-, and Aspergillus terreus-specific real-time polymerase chain reaction (PCR) assays with the Platelia galactomannan (GM) assay in 150 bronchoalveolar lavage (BAL) samples from lung transplant recipients (16 proven/probable IPA, 26 Aspergillus colonization, 11 non-Aspergillus mold colonization, and 97 negative controls)., Results: The sensitivity and specificity of pan-Aspergillus PCR (optimal quantification cycle [Cq], ≤35.0 by receiver operating characteristic analysis) and GM (≥.5) for diagnosing IPA were 100% (95% confidence interval, 79%-100%) and 88% (79%-92%), and 93% (68%-100%) and 89% (82%-93%), respectively. The sensitivity and specificity of A. fumigatus-specific PCR were 85% (55%-89%) and 96% (91%-98%), respectively. A. terreus-specific PCR was positive for the 1 patient with IPA due to this species; specificity was 99% (148 of 149 samples). Aspergillus PCR identified 1 patient with IPA not diagnosed by GM. For BAL samples associated with Aspergillus colonization, the specificity of GM (92%) was higher than that of pan-Aspergillus PCR (50%; P = .003). Among negative control samples, the specificity of pan-Aspergillus PCR (97%) was higher than that of BAL GM (88%; P = .03). Positive results for both BAL PCR and GM testing improved the specificity to 97% with minimal detriment to sensitivity (93%)., Conclusions: A recently developed pan-Aspergillus PCR assay and GM testing of BAL fluid may facilitate the diagnosis of IPA after lung transplantation. A. fumigatus- and A. terreus-specific real-time PCR assays may be useful in rapidly identifying the most common cause of IPA and a species that is intrinsically resistant to amphotericin B, respectively.

Klebsiella pneumoniae carbapenemase (KPC)-producing K. pneumoniae, Escherichia coli, and Serratia marcescens were sequentially identified in a patient who underwent small bowel transplantation. Molecular typing and plasmid analysis suggested that the KPC gene was acquired by E. coli, most likely from K. pneumoniae, and was subsequently transferred to S. marcescens.

Pulmonary viral and fungal infections in solid organ transplant recipients are one of the most common and potentially life-threatening infections. Understanding the strategies used for prophylaxis and prevention of these infections is critical for the health and well-being of transplant recipients. Prophylactic measures range from simple patient education to complex chemoprophylactic interventions; however, a multifaceted approach is most often required. This article focuses on strategies to prevent pulmonary viral and fungal infections in transplant recipients, with an emphasis on recent evidence that may influence practice guidelines.

An outbreak of cephalosporin-resistant Klebsiella pneumoniae occurred in a neonatal intensive care unit in São Paulo, Brazil. Of the 10 pulsotypes identified during the outbreak and follow-up periods, nine produced CTX-M-2 or its new variant CTX-M-59 and one produced SHV-5. bla(CTX-M-2/59) genes were located on closely related plasmids that were transferable.