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Background Organ transplantation from donors with human immunodeficiency virus (HIV) to recipients with HIV (HIV D+/R+) presents risks of donor-derived infections. Understanding clinical, immunologic, and virologic characteristics of HIV-positive donors is critical for safety. Methods We performed a prospective study of donors with HIV-positive and HIV false-positive (FP) test results within the HIV Organ Policy Equity (HOPE) Act in Action studies of HIV D+/R+ transplantation (ClinicalTrials.gov NCT02602262, NCT03500315, and NCT03734393). We compared clinical characteristics in HIV-positive versus FP donors. We measured CD4 T cells, HIV viral load (VL), drug resistance mutations (DRMs), coreceptor tropism, and serum antiretroviral therapy (ART) detection, using mass spectrometry in HIV-positive donors. Results Between March 2016 and March 2020, 92 donors (58 HIV positive, 34 FP), representing 98.9% of all US HOPE donors during this period, donated 177 organs (131 kidneys and 46 livers). Each year the number of donors increased. The prevalence of hepatitis B (16% vs 0%), syphilis (16% vs 0%), and cytomegalovirus (CMV; 91% vs 58%) was higher in HIV-positive versus FP donors; the prevalences of hepatitis C viremia were similar (2% vs 6%). Most HIV-positive donors (71%) had a known HIV diagnosis, of whom 90% were prescribed ART and 68% had a VL Conclusion The use of HIV-positive donor organs is increasing. HIV DRMs are common, yet resistance that would compromise integrase strand transfer inhibitor–based regimens is rare, which is reassuring regarding safety.

BackgroundNeutralizing monoclonal antibodies (mAb) targeting SARS-CoV-2 decrease hospitalization and death in patients with mild to moderate Covid-19. Yet, their clinical use is limited, and comparative effectiveness is unknown.MethodsWe present the first results of an ongoing, learning health system adaptive platform trial to expand mAb treatment to all eligible patients and evaluate the comparative effectiveness of available mAbs. The trial launched March 10, 2021. Results are reported as of June 25, 2021 due to the U.S. federal decision to pause distribution of bamlanivimab-etesevimab; patient follow-up concluded on July 23, 2021. Patients referred for mAb who met Emergency Use Authorization criteria were provided a random mAb allocation of bamlanivimab, bamlanivimab-etesevimab, or casirivimab-imdevimab with a therapeutic interchange policy. The primary outcome was hospital-free days (days alive and free of hospital) within 28 days, where patients who died were assigned -1 day. The primary analysis was a Bayesian cumulative logistic model of all patients treated at an infusion center or emergency department, adjusting for treatment location, age, sex, and time. Inferiority was defined as a 99% posterior probability of an odds ratio < 1. Equivalence was defined as a 95% posterior probability that the odds ratio is within a given bound.ResultsPrior to trial launch, 3.1% (502) of 16,345 patients who were potentially eligible by an automated electronic health record (EHR) screen received mAb. During the trial period, 23.2% (1,201) of 5,173 EHR-screen eligible patients were treated, a 7.5-fold increase. After including additional referred patients from outside the health system, a total of 1,935 study patients received mAb therapy (128 bamlanivimab, 885 bamlanivimab-etesevimab, 922 casirivimab-imdevimab). Mean age ranged from 55 to 57 years, half were female (range, 53% to 54%), and 17% were Black (range, 12% to 19%). Median hospital–free days were 28 (IQR, 28 to 28) for each mAb group. Hospitalization varied between groups (bamlanivimab, 12.5%; bamlanivimab-etesevimab, 14.7%, casirivimab-imdevimab, 14.3%). Relative to casirivimab-imdevimab, the median adjusted odds ratios were 0.58 (95% credible interval (CI), 0.30 to 1.16) and 0.94 (95% CI, 0.72 to 1.24) for the bamlanivimab and bamlanivimab-etesevimab groups, respectively. These odds ratios yielded 91% and 94% probabilities of inferiority of bamlanivimab versus bamlanivimab-etesevimab and casirivimab-imdevimab respectively, and an 86% probability of equivalence between bamlanivimab-etesevimab and casirivimab-imdevimab, at the prespecified odds ratio bound of 0.25. Twenty-one infusion-related adverse events occurred in 0% (0/128), 1.4% (12/885), and 1.0% (9/922) of patients treated with bamlanivimab, bamlanivimab-etesevimab, and casirivimab-imdevimab, respectively.ConclusionIn non-hospitalized patients with mild to moderate Covid-19, bamlanivimab, compared to bamlanivimab-etesevimab and casirivimab-imdevimab, resulted in 91% and 94% probabilities of inferiority with regards to odds of improvement in hospital-free days within 28 days. There was an 86% probability of equivalence between bamlanivimab-etesevimab and casirivimab-imdevimab at an odds ratio bound of 0.25. However, the trial was unblinded early due to federal distribution decisions, and no mAb met prespecified criteria for statistical inferiority or equivalence. (ClinicalTrials.gov, NCT04790786).

Background Children infected with SARS-CoV-2 are often asymptomatic or have only mild symptoms, leading to underestimation of disease prevalence in symptom-based testing strategies. Objectives This study sought to determine pediatric SARS-CoV-2 disease burden during local mitigation efforts by using antibody testing to compare seroprevalence estimates to cumulative PCR prevalence estimates. Study design In this cross-sectional study, we collected 1142 strict phase and 1196 relaxed phase remnant blood specimens from patients less than 19-years-old in southwestern Pennsylvania (SWPA). Patients were excluded if their residential zip code was outside the region of interest, if they were under 6-months-old, or they had recently received antibody-modifying treatments. Demographic, encounter, and laboratory electronic medical record information was extracted. Samples were tested for SARS-CoV-2 spike protein IgG using an EUA ELISA, and PCR results were recorded from county health department data. Seroprevalence and Clopper-Pearson exact 95% confidence intervals were calculated. Results The observed seroprevalence of SARS-CoV-2 spike protein antibodies in children during strictest mitigation was 0.53% (95% CI 0.19, 1.14) and 0.92% (95% CI 0.46,1.64) during moderately relaxed. Strict and relaxed phase PCR-based prevalence were significantly higher, 2.87% (95% CI 1.95, 4.08) and 3.64 (95% CI 3.01, 4.38), respectively. Conclusions Estimates of pediatric seroprevalence were significantly lower than cumulative PCR prevalence estimates, and less than adult seroprevalence estimates, potentially due to biological, population, or sampling differences. Biological differences in pediatric immune responses to SARS-CoV-2 may make serosurvey interpretation challenging and these differences warrant further study.

We represent a group of investigators funded by the National Institutes of Health (R01AI120938, U01AI134591, U01AI138897) to conduct a prospective multicenter study of the landscape of HIV-infected (HIV+) donors and two prospective multicenter trials comparing outcomes between HIV+ recipients of HIV+ and non-HIV+ donor kidneys and livers. These clinical trials are ongoing (NCT02602262, NCT03500315, NCT03734393).

ObjectivesImmunocompromised patients were excluded from COVID-19 vaccine clinical trials. The objectives of the study were to measure antibody responses, levels, and neutralization capability after COVID-19 vaccination among immunocompromised patients and compare these variables to those of immunocompetent healthcare workers.MethodsThis is an interim analysis of an ongoing observational, prospective cohort study which launched on April 14, 2021 across Western Pennsylvania. Participants were healthy healthcare workers (HCW) and immunocompromised patients who had completed their COVID-19 vaccination series. Individuals with a history of COVID-19 were not eligible. Serum was collected to measure for the presence of IgG against the SARS-CoV-2 Spike protein using a semi-quantitative assay; antibody levels were available for comparisons. A quasi-random subset of patients was selected for pseudovirus neutralization assays. Seropositivity with 95% Clopper-Pearson exact confidence intervals and distribution of antibody levels were measured. To identify risk factors for seronegativity, clinical characteristics were univariately compared between antibody reactive and non-reactive individuals within the immunocompromised group.Results107 HCW and 489 immunocompromised patients were enrolled. Compared to HCWs, seropositivity was significantly lower (pConclusionOur findings demonstrate the heterogeneity of the humoral immune response to COVID-19 vaccines based on underlying immunosuppressive condition and highlight an urgent need to optimize and individualize COVID-19 prevention in these patients. These findings also have implications on public health guidance, particularly given revised Centers for Disease Control and Prevention recommendations permitting vaccinated individuals to abandon masking and social distancing in most settings. Future studies are warranted to determine assessment of cellular immunity, longitudinal measurement of immune responses, and the safety and efficacy of revaccination.

Objectives The primary objective is to evaluate the comparative effectiveness of COVID-19 specific monoclonal antibodies (mABs) with US Food and Drug Administration (FDA) Emergency Use Authorization (EUA), alongside UPMC Health System efforts to increase patient access to these mABs. Trial design Open-label, pragmatic, comparative effectiveness platform trial with response-adaptive randomization Participants We will evaluate patients who meet the eligibility criteria stipulated by the COVID-19 mAB EUAs who receive mABs within the UPMC Health System, including infusion centers and emergency departments. EUA eligibility criteria include patients with mild to moderate COVID-19, <10 days of symptoms, and who are at high risk for progressing to severe COVID-19 and/or hospitalization (elderly, obese, and/or with specific comorbidities). The EUA criteria exclude patients who require oxygen for the treatment of COVID-19 and patients already hospitalized for the treatment of COVID-19. We will use data collected for routine clinical care, including data entered into the electronic medical record and from follow-up calls. Intervention and comparator The interventions are the COVID-19 specific mABs authorized by the EUAs. All aspects of mAB treatment, including eligibility criteria, dosing, and post-infusion monitoring, are as per the EUAs. As a comparative effectiveness trial, all patients receive mAB treatment, and the interventions are compared against each other. When U.S. government mAB policies change (e.g., FDA grants or revokes EUAs), UPMC Health System policies and the evaluated mAB interventions will accordingly change. From November 2020 to February 2021, FDA issued EUAs for three mAB treatments (bamlanivimab; bamlanivimab and etesevimab; and casirivimab and imdevimab), and at trial launch on March 10, 2021 we evaluated all three. Due to a sustained increase in SARS-CoV-2 variants in the United States resistant to bamlanivimab administered alone, on March 24, 2021 the U.S. Government halted distribution of bamlanivimab alone, and UPMC accordingly halted bamlanivimab monotherapy on March 31, 2021. On April 16, 2021, FDA revoked the EUA for bamlanivimab monotherapy. At the time of manuscript submission, we are therefore evaluating the two mAB treatments authorized by EUAs (bamlanivimab and etesevimab; and casirivimab and imdevimab). Main outcomes The primary outcome is total hospital free days (HFD) at 28 days after mAB administration, calculated as 28 minus the number of days during the index stay (if applicable – e.g., for patients admitted to hospital after mAB administration in the emergency department) minus the number of days readmitted during the 28 days after treatment. This composite endpoint captures the number of days from the day of mAB administration to the 28 days thereafter, during which the patient is alive and free of hospitalization. Death within 28 days is recorded as -1 HFD, as the worst outcome. Randomisation We will start with equal allocation. Due to uncertainty in sample size, we will use a Bayesian adaptive design and response adaptive randomization to ensure ability to provide statistical inference despite variable sample size. When mABs are ordered by UPMC physicians as a generic referral order, the order is filled by UPMC pharmacy via therapeutic interchange. OPTIMISE-C19 provides the therapeutic interchange via random allocation. Infusion center operations teams and pharmacists use a mAB assignment application embedded in the electronic medical record to determine the random allocation. Blinding (masking) This trial is open-label. However, outcome assessors conducting follow-up calls at day 28 are blinded to mAB assignment, and investigators are blinded to by-mAB aggregate outcome data until a statistical platform trial conclusion is reached. Numbers to be randomised (sample size) Sample size will be determined by case volume throughout the course of the pandemic, supply of FDA authorized mABs, and by that needed to reach a platform trial conclusion of inferiority, superiority, or futility of a given mAB. The trial will continue as long as more than one mAB type is available under EUA, and their comparative effectiveness is uncertain. Trial Status Protocol Version 1.0, February 24, 2021. Recruitment began March 10, 2021 and is ongoing at the time of manuscript submission. The estimated recruitment end date is February 22, 2022, though the final end date is dependent on how the pandemic evolves, mAB availability, and when final platform trial conclusions are reached. As noted above, due to U.S. Government decisions, UPMC Health System halted bamlanivimab monotherapy on March 31, 2021. Trial registration ClinicalTrials.gov Identifier: NCT04790786. Registered March 10, 2021 Full protocol The full protocol is attached as an additional file, accessible from the Trials website (Additional file 1). In the interest in expediting dissemination of this material, the familiar formatting has been eliminated; this Letter serves as a summary of the key elements of the full protocol.

BackgroundMonoclonal antibody (mAb) treatment may prevent complications of COVID-19. We sought to quantify the impact of bamlanivimab monotherapy on hospitalizations and mortality, as well as Emergency Department (ED) visits without hospitalization, among outpatients at high risk of COVID-19 complications.MethodsWe compared patients receiving mAb to patients who met criteria but did not receive mAb from December 2020 through March 2021. The study population selection used propensity scores to match 1:1 by likelihood to receive mAb. The primary outcome was hospitalization or all-cause mortality within 28 days; the secondary outcome was hospitalization or ED visit without hospitalization within 28 days. Odds ratios (OR) calculation used logistic regression modeling including propensity score and mAb receipt predictors.ResultsThe study population included 234 patients receiving mAb and 234 matched comparator patients not receiving mAb. Patients receiving mAb were less likely to experience hospitalization or mortality (OR 0.31, 95% confidence interval [95%CI] 0.17-0.56, p=0.00001) and hospitalization or ED visit without hospitalization (OR 0.50, 95%CI 0.43-0.83, p=0.007). The impact of mAb was more pronounced in prevention of hospitalization (among all age groups, OR 0.35, 95%CI 0.19-0.66, p=0.001) than mortality or ED visit without hospitalization, and most strongly associated with patients age 65 years and older (primary outcome OR 0.28, 95%CI 0.14-0.56, p=0.0003).ConclusionsBamlanivimab monotherapy was associated with reduction in the composite outcome of hospitalizations and mortality in patients with mild-moderate COVID-19. The benefit may be strongest in preventing hospitalization in patients ages 65 years or older.

Recent case studies have highlighted the fact that certain immunocompromised individuals are at risk for prolonged SARS-CoV-2 replication, intrahost viral evolution of multiply-mutated variants, and poor clinical outcomes. The immunologic determinants of this risk, the duration of infectiousness, and optimal treatment and prevention strategies in immunocompromised hosts are ill defined. Of additional concern is the widespread use of immunosuppressive medications to treat COVID-19, which may enhance and prolong viral replication in the context of immunodeficiency. We outline the rationale for 4 interrelated approaches to usher in an era of evidence-based medicine for optimal management of immunocompromised patients with COVID-19: multicenter pathogenesis and outcomes studies to relate the risk of severe disease to the type and degree of immunodeficiency, studies to evaluate immunologic responses to SARS-CoV-2 vaccines, studies to evaluate the efficacy of monoclonal antibodies for primary prophylaxis, and clinical trials of novel antiviral agents for the treatment of COVID-19.

Background We implemented a preprocedural severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) screening initiative designed to sustain health care during a time when the extent of SARS-CoV-2 infection was unknown. Methods This was a prospective study of patients undergoing procedures at 3 academic hospitals in Pittsburgh, Pennsylvania (April 21–June 11), and 19 community hospitals across Middle/Western Pennsylvania and Southwestern New York (May 1–June 11). Patients at academic hospitals underwent symptom screening ≤7 days preprocedure, then SARS-CoV-2 nasopharyngeal polymerase chain reaction (PCR) testing 1–4 days preprocedure. A subset also underwent day-of-procedure testing. Community hospital patients underwent testing per local protocols. We report SARS-CoV-2 PCR positivity rates, impact, and barriers to testing encountered through June 11. PCR positivity rates of optional preprocedural SARS-CoV-2 testing for 2 consecutive periods following the screening initiative are also reported. Results Of 5881 eligible academic hospital patients, 2415 (41.1%) were tested (April 21–June 11). Lack of interest, distance, self-isolation, and nursing home/incarceration status were barriers. There were 11 PCR-positive patients (10 asymptomatic) among 10 539 patients tested (0.10%; 95% CI, 0.05%–0.19%): 3/2415 (0.12%; 95% CI, 0.02%–0.36%) and 8/8124 (0.10%; 95% CI, 0.04%–0.19%) at academic and community hospitals, respectively. Procedures were performed as scheduled in 40% (4/10) of asymptomatic PCR-positive patients. Positivity increased during subsequent coronavirus disease 2019 (COVID-19) surges: 54/34 948 (0.15%; 95% CI, 0.12%–0.20%) and 101/24 741 (0.41%; 95% CI, 0.33%–0.50%) PCR-positive patients from June 12–September 10 and September 11–December 15, respectively (P Conclusions Implementing preprocedural PCR testing was complex and revealed low infection rates (0.24% overall), which increased during COVID-19 surges. Additional studies are needed to define the COVID-19 prevalence threshold at which universal preprocedural screening is warranted.

Purpose of review Data on the infectious complications of anti-CD19 chimeric antigen receptor-modified T-cell (CAR-T-cell) therapies are scant. The approaches to preventing and managing infections among CAR-T-cell recipients are extrapolated from those of patients with other hematological malignancies. Understanding the incidence and risk factors of infections in these patients will improve clinical outcomes. Recent findings Infections occur in 23-42% of CAR-T-cell recipients and are most frequent in the first month after infusion, declining sharply thereafter. Risk factors include preinfusion (e.g., prior hematopoietic cell transplant, underlying malignancy) and postinfusion variables (e.g., cytokine release syndrome [CRS], neutropenia). Neutropenic fever after CAR-T-cell therapy is nearly universal but is confounded by CRS. The timeline of infections can be divided into preinfusion (because of the preparative regimen); 0-30 days after infusion, when bacterial infections predominate; and 30 days onwards, when respiratory viral infections predominate. Fungal and herpesviridae infections are uncommon. Summary Recent studies have shed light on the epidemiology of infections after CAR-T-cell therapy. Future efforts should focus on identifying modifiable risk factors for infection, defining neutropenic fever in the setting of CRS, determining the benefit of antimold prophylaxis, and identifying the optimal approach to viral monitoring, vaccination, and immunoglobulin replacement.

BACKGROUND HIV-infected (HIV+) donor to HIV+ recipient (HIV D+/R+) transplantation might improve access to transplantation for people living with HIV. However, it remains unknown whether transplant candidates living with HIV will accept the currently unknown risks of HIV D+/R+ transplantation. METHODS We surveyed transplant candidates living with HIV from 9 US transplant centers regarding willingness to accept HIV+ donor organs. RESULTS Among 116 participants, the median age was 55 years, 68% were men, and 78% were African American. Most were willing to accept HIV+ living donor organs (87%), HIV+ deceased donor organs (84%), and increased infectious risk donor organs (70%). Some (30%) were concerned about HIV superinfection; even among these respondents, 71% were willing to accept an HIV D+ organ. Respondents from centers that had already performed a transplant under an HIV D+/R+ transplantation research protocol were more willing to accept HIV+ deceased donor organs (89% vs. 71%, P = 0.04). Respondents who chose not to enroll in an HIV D+/R+ transplantation research protocol were less likely to believe that HIV D+/R+ transplantation was safe (45% vs. 77%, P = 0.02), and that HIV D+ organs would work similar to HIV D- organs (55% vs. 77%, P = 0.04), but more likely to believe they would receive an infection other than HIV from an HIV D+ organ (64% vs. 13%, P < 0.01). CONCLUSIONS Willingness to accept HIV D+ organs among transplant candidates living with HIV does not seem to be a major barrier to HIV D+/R+ transplantation and may increase with growing HIV D+/R+ transplantation experience.

Invasive aspergillosis and mucormycosis are life-threatening infections in solid organ and hematopoietic cell transplant recipients. Despite medical advancements in the care of these patients and the availability of new mold-active drugs, the outcomes remain suboptimal. Therefore, there has been increased interest in the use of combination antifungal therapy, in hopes that leveraging the possible in vitro synergy of these agents will improve the prognosis of invasive mold disease. However, there has been a large disconnect between the results of experimental and clinical investigations, as clinical studies have not unequivocally demonstrated the superiority of combination therapy over monotherapy. This is particularly true for mucormycosis, where the rarity of the condition has made it nearly impossible to prospectively study novel therapeutic strategies. We review the current standard of antifungal therapy and the preclinical and clinical data addressing the merit of combination therapy, and we provide guidance to optimize the management of these mycoses.

To summarize new discoveries in viral pathogenesis and novel therapeutic and prophylactic strategies in organ transplant recipients.For decades, prophylaxis of cytomegalovirus (CMV) has been the standard preventive strategy, but new clinical trials are expected to determine the advantages of preemptive therapy over prophylaxis. Novel anti-CMV agents, such as maribavir and letermovir, are being studied for the treatment of resistant/refractory CMV as alternatives to foscarnet and cidofovir. CMV immune monitoring may offer individualized management plans. Epstein-Barr virus infections in transplant recipients are difficult to prevent and treat, though recent data suggest possible merit to pretransplant rituximab among high-risk transplant recipients. We review the groundbreaking HIV-to-HIV organ transplant trials, which are expected to revolutionize the care of HIV-infected individuals. Finally, we review topical developments in human herpesvirus 8, Zika virus, RNA respiratory viruses, adenovirus, norovirus, and polyoma viruses in organ transplantation.Ongoing trials to optimize CMV prophylaxis and treatment, and outcomes of HIV-to-HIV organ transplantation in the United States, have significant implications to optimize management of these viruses in transplant recipients. Assessment of new antivirals and antiviral strategies, such as adoptive immunotherapy, is warranted for refractory viral infections.

HIV-infected persons who achieve undetectable viral loads on antiretroviral therapy currently have near-normal lifespans. Liver disease is a major cause of non-AIDS-related deaths, and as a result of longer survival, the prevalence of end-stage renal disease in HIV is increasing. HIV-infected persons undergoing organ transplantation generally achieve comparable patient and graft survival rates compared to their HIV-uninfected counterparts, despite a nearly threefold increased risk of acute rejection. However, the ongoing shortage of suitable organs can limit transplantation as an option, and patients with HIV have higher waitlist mortality than others. One way to solve this problem would be to expand the donor pool to include HIV-infected individuals. The results of a South Africa study involving 27 HIV-to-HIV kidney transplants showed promise, with 3- and 5-year patient and graft survival rates similar to those of their HIV-uninfected counterparts. Similarly, individual cases of HIV-to-HIV liver transplantation from the United Kingdom and Switzerland have also shown good results. In the United States, HIV-to-HIV kidney and liver transplants are currently permitted only under a research protocol. Nevertheless, areas of ambiguity exist, including streamlining organ allocation practices, optimizing HIV-infected donor and recipient selection, managing donor-derived transmission of a resistant HIV strain, determining optimal immunosuppressive and antiretroviral regimens, and elucidating the incidence of rejection in HIV-to-HIV solid organ transplant recipients.

BACKGROUND Limited published data exist on outcomes related to heart and/or lung transplantation in human immunodeficiency virus (HIV)-infected individuals. METHODS We conducted a multicenter retrospective study of heart and lung transplantation in HIV-infected patients and describe key transplant- and HIV-related outcomes. RESULTS We identified 29 HIV-infected thoracic transplant recipients (21 heart, 7 lung, and 1 heart and/or lung) across 14 transplant centers from 2000 through 2016. Compared with an International Society for Heart and Lung Transplantation registry cohort, we demonstrated similar 1-, 3-, and 5-year patient and allograft survivals for each organ type with a median follow up of 1,064 (range, 184–3,745) days for heart and 1,540 (range, 116–3,206) days for lung recipients. At 1 year, significant rejection rates were high (62%) for heart transplant recipients (HTRs). Risk factors for rejection were inconclusive, likely because of small numbers, but may be related to cautious early immunosuppression and infrequent use of induction therapy. Pulmonary bacterial infections were high (86%) for lung transplant recipients (LTRs). Median CD4 counts changed from baseline to 1 year from 399 to 411 cells/µl for HTRs and 638 to 280 cells/µl for LTRs. Acquired immunodeficiency syndrome–related events, including infections and malignancies, were rare. Rates of severe renal dysfunction suggest a need to modify nephrotoxic anti-retrovirals and/or immunosuppressants . CONCLUSIONS HIV-infected HTRs and LTRs have similar survival rates to their HIV-uninfected counterparts. Although optimal immunosuppression is not defined, it should be at least as aggressive as that for HIV-uninfected recipients. Such data may help pave the way for the use of hearts and lungs from HIV-infected donors in HIV-infected recipients through HIV Organ Policy Equity Act protocols.

Progressive multifocal leukoencephalopathy (PML) is a life-threatening central nervous system (CNS) disorder, most commonly described in patients infected with the human immunodeficiency virus (HIV). Limited data exist on its natural history and treatment in solid organ transplant (SOT) recipients. A complication of PML is the immune reconstitution inflammatory syndrome (IRIS), which develops after T cell reconstitution and can have severe consequences when it occurs in the CNS. While well described in HIV-infected individuals, its clinical features, diagnosis, and treatment after SOT are largely unknown. We report a case of a kidney transplant recipient who was diagnosed with PML and developed significant worsening of her symptoms upon reduction of immunosuppression. Thallium SPECT showed avid uptake suggestive of lymphoma, but the diagnosis of PML-IRIS was ultimately established by brain biopsy. She survived with nearly complete restoration of her functional status after a prolonged steroid taper.

This new guideline from the AST IDCOP reviews intra-abdominal infections (IAIs), which cause substantial morbidity and mortality among abdominal SOT recipients. Each transplant type carries unique risks for IAI, though peritonitis occurs in all abdominal transplant recipients. Biliary infections, bilomas, and intra-abdominal and intrahepatic abscesses are common after liver transplantation and are associated with the type of biliary anastomosis, the presence of vascular thrombosis or ischemia, and biliary leaks or strictures. IAIs after kidney transplantation include renal and perinephric abscesses and graft-site candidiasis, which is uncommon but may require allograft nephrectomy. Among pancreas transplant recipients, duodenal anastomotic leaks can have catastrophic consequences, and polymicrobial abscesses can lead to graft loss and death. Intestinal transplant recipients are at the highest risk for sepsis, infection due to multidrug-resistant organisms, and death from IAI, as the transplanted intestine is a contaminated, highly immunological, pathogen-rich organ. Source control and antibiotics are the cornerstone of the management of IAIs. Empiric antimicrobial regimens should be tailored to local susceptibility patterns and pathogens with which the patient is known to be colonized, with subsequent optimization once the results of cultures are reported.

Thirty-seven carbapenem-resistant Enterobacteriaceae (CRE)-infected patients were treated with ceftazidime-avibactam. Clinical success and survival rates at 30 days were 59% (22/37) and 76% (28/37), respectively. In 23% (5/22) of clinical successes, CRE infections recurred within 90 days. Microbiologic failure rate was 27% (10/37). Ceftazidime-avibactam resistance was detected in 30% (3/10) of microbiologic failures.

Background Our hospital system created system guidelines to standardize care across 24 hospitals for COVID-19 treatment during the pandemic. Guidelines changed over time. Hydroxychloroquine (HCQ) was unrestricted during phase 1, then restricted by pharmacy outside of a randomized clinical trial (RCT) during phase 2 (excepting those ineligible for RCTs). Methods This was a prospective study to assess system-wide adherence to COVID-19 treatment guidelines, and to evaluate patient outcomes. Results Of 261 patients, median age was 67 years (IQR 56–76); 49% (129/261) were male, and 45% (118/261) required ICU care. Overall, 47% (122/261) were in phase 1; HCQ was offered to 57% (69/122) during this phase. The rate of HCQ prescription in phase 2 decreased significantly to 10% (14/136), (p < 0.001). Adherence to COVID-19 treatment protocol was 97% (135/139) during phase 2. Mortality was similar in both phases (22% vs 28%, p=0.32), as was median length of stay (8 vs 7 days, p=0.3). Overall 66 patients (25%) died in the hospital; neither non-adherence (p=1) to system guidelines nor receipt of HCQ (p=0.17) were risk factors for death. Independent predictors of mortality included: new renal replacement therapy (OR 61, 95%CI 6.7–560, p < 0.001), mechanical ventilation (OR 4.9, 95%CI 2.0–11, p < 0.001), abnormal chest X-ray (OR 4.3, 95%CI 1.4–12.6, p =0.009), history of heart failure (OR 3.9, 95%CI 1.5–11, p=0.006), lack of fever on admission (OR 3.5, 95%CI 1.7 -7.6, p =0.001), receipt of corticosteroids (OR 2.7 95%CI 1.1–6.6, p=0.026) and increased age (OR 1.07 per year, 95%CI 1.04–1.1, p < 0.001). Bacterial pneumonia occurred in 8% (21/261), more commonly in those who died (p=0.02). Black patients had a higher race-specific death rate (308 vs 197) per 1000 than white patients (p< 0.001). Conclusion During the COVID-19 pandemic, our health system guidelines and pharmacy restrictions were successful in delivering consistent care across hospitals. Restriction of HCQ for COVID-19 treatment to RCTs reduced its use in phase two. Non-adherence to systemic guidelines was infrequent, and not associated with adverse outcomes. A COVID-19 treatment team of physicians and pharmacists can effectively coordinate therapy across hospitals in the setting of rapidly changing guidelines. Disclosures J. Ryan Bariola, MD, Infectious Disease Connect (Employee)Mayne Pharma (Advisor or Review Panel member)Merck (Research Grant or Support)

The morbidity and mortality of hematopoietic stem cell and solid organ transplant patients with invasive fungal infections (IFIs) remain high despite an increase in the number of effective antifungal agents. Early diagnosis leading to timely administration of antifungal therapy has been linked to better outcomes. Unfortunately, the diagnosis of IFIs remains challenging. The current gold standard for diagnosis is a combination of histopathology and culture, for which the sensitivity is

Ceftazidime-avibactam and ceftolozane-tazobactam are newly approved agents for the treatment of infections caused by multidrug-resistant Gram-negative bacteria. Resistance to both agents has been described clinically. Susceptibility testing on automated systems is unavailable for either agent. Our objective was to compare the disk diffusion and Etest methods to standard broth microdilution (BMD) methods for testing ceftazidime-avibactam and ceftolozane-tazobactam against a diverse collection of carbapenem-resistant Enterobacteriaceae (CRE) and carbapenem-resistant Pseudomonas aeruginosa (CRP) isolates, respectively. Among 74 ceftazidime-avibactam-susceptible and -resistant CRE isolates, BMD categorical agreement was higher with Etest (96%) than with disk diffusion (72%; P = 0.0003). Twenty-eight percent of ceftazidime-avibactam-susceptible CRE isolates were classified as resistant by disk diffusion. Results were comparable to those obtained with resistance defined genotypically. Among 72 ceftolozane-tazobactam-susceptible and -resistant CRP isolates, the levels of BMD categorical agreement with disk diffusion and Etest were 94% and 96%, respectively; the only errors identified were minor. Our findings demonstrate that Etest measurements of ceftazidime-avibactam and ceftolozane-tazobactam susceptibility correlate closely with standard BMD methods, suggesting a useful role clinically. On the other hand, disk diffusion measurements overcalled CRE resistance to ceftazidime-avibactam. A better understanding of ceftazidime-avibactam interpretive breakpoints is needed before disk diffusion is used routinely in the clinic. Until clinicians and microbiologists understand Etest and disk diffusion performance at their centers, test results should be interpreted cautiously.

Background Data on the use of ceftolozane-tazobactam and emergence of ceftolozane-tazobactam resistance during multidrug resistant (MDR)-Pseudomonas aeruginosa infections are limited. Methods We performed a retrospective study of 21 patients treated with ceftolozane-tazobactam for MDR-P. aeruginosa infections. Whole genome sequencing and quantitative real-time polymerase chain reaction were performed on longitudinal isolates. Results Median age was 58 years; 9 patients (43%) were transplant recipients. Median simplified acute physiology score-II (SAPS-II) was 26. Eighteen (86%) patients were treated for respiratory tract infections; others were treated for bloodstream, complicated intraabdominal infections, or complicated urinary tract infections. Ceftolozane-tazobactam was discontinued in 1 patient (rash). Thirty-day all-cause and attributable mortality rates were 10% (2/21) and 5% (1/21), respectively; corresponding 90-day mortality rates were 48% (10/21) and 19% (4/21). The ceftolozane-tazobactam failure rate was 29% (6/21). SAPS-II score was the sole predictor of failure. Ceftolozane-tazobactam resistance emerged in 3 (14%) patients. Resistance was associated with de novo mutations, rather than acquisition of resistant nosocomial isolates. ampC overexpression and mutations were identified as potential resistance determinants. Conclusions In this small study, ceftolozane-tazobactam was successful in treating 71% of patients with MDR-P. aeruginosa infections, most of whom had pneumonia. The emergence of ceftolozane-tazobactam resistance in 3 patients is worrisome and may be mediated in part by AmpC-related mechanisms. More research on treatment responses and resistance during various types of MDR-P. aeruginosa infections is needed to define ceftolozane-tazobactam's place in the armamentarium.

Background Metagenomic sequencing of respiratory microbial communities may overcome the limitations of culture-based pneumonia diagnostics. Nonetheless, respiratory metagenomics requires high-quality specimens, may miss deep-seated infections and cannot distinguish colonization from infection. Plasma microbial cell-free DNA (mcfDNA) sequencing may offer a noninvasive alternative for culture-independent diagnosis and help refine interpretations of respiratory metagenomics. Methods We obtained concurrent plasma and endo-tracheal aspirate (ETA) samples from 29 mechanically-ventilated patients (15 culture-positive, 11 culture-negative pneumonia, 3 uninfected control patients). We performed plasma mcfDNA sequencing (Karius®Test, Redwood City, CA) and ETA metagenomics (MiNION, Oxford Nanopore Technologies). We compared sequencing results with clinical microbiologic cultures for identified DNA pathogens. Results Uninfected control patients had a negative signal for mcfDNA in plasma and oral bacteria in ETA specimens. In culture-positive pneumonia samples, Karius testing identified a median of 2 pathogens per sample (range 0–10), which were concordant with clinical isolates in 11/15 (73%) cases (figure). In 5/11 (45%) of concordant cases, Karius and MiNION suggested polymicrobial infections with additional pathogens not identified by cultures. In culture-negative cases, Karius detected potential pathogens in 8/11 (73% cases), which matched the species identified in ETA specimens by MiNION. In cases of clinical aspiration, Karius detected more organisms (median 8, range 0–14) per sample mainly consisting of oral origin bacteria compared with cases without history of aspiration (median 1, range 0–6, P = 0.04). Conclusion Metagenomic sequencing in plasma and ETA samples showed good concordance between the blood and lung compartments as well as with culture results in pneumonia patients. Metagenomics revealed potential pathogens missed by cultures in ~75% of culture-negative pneumonias and suggested polymicrobial infections especially in cases with aspiration. Further research is needed to evaluate the clinical utility of real-time metagenomics for pneumonia diagnosis in mechanically ventilated patients. Disclosures All authors: No reported disclosures.

Introduction The association between belatacept, a CD28 costimulation blocker, and invasive mycoses is unclear. Case Report We describe a patient who initiated belatacept 3 years after lung transplantation and developed invasive tracheobronchial aspergillosis, a disease encountered almost exclusively within the first 6 months after transplantation. Conclusions Belatacept may have played a causative role. Until more data are available, belatacept should be used cautiously after lung transplantation.

Background Data on ER and IV POS among organ transplant recipients (OTRs) are limited, and the role of TDM is unclear. Methods Retrospective study of patients (pt) receiving any formulation of POS who had serum troughs checked. Therapeutic was defined as 3 1 mcg/mL. Results We analyzed 88 pt and 340 levels (SUS: 88, ER: 197, IV: 55). Eighty-five pt were OTRs (97%), 73 were lung transplant recipients (LT) (83%), 17 had cystic fibrosis (CF) (19%). POS was used for treatment (70%) (probable aspergillosis (38%), possible aspergillosis (10%), mucormycosis (16%), other mycoses (6%)), prophylaxis (19%), and pre-emptive therapy (14%). POS was given for intolerance of or contraindication to other azoles (47%), salvage therapy (10%), resistance (19%), and failure to achieve therapeutic levels with other azoles (6%). Serum concentration/dose ratios were lower with SUS vs. ER/IV (P < 0.0001) but were similar in ER/IV groups (P = 0.51) (Figure). There was no difference in serum levels between pt receiving ER vs. IV POS at 300 mg once daily (median 1.2 vs. 1.3 mcg/mL, therapeutic 70% vs. 73%, P = 0.57 and >0.99, respectively). 3 pt had levels £ 0.2 mcg/mL on 300 mg ER: 2 had CF and had undergone LT (0.2 and 0 mcg/mL) and 1 had short-gut syndrome (0.1 mcg/mL). Sixty-six percent and 67 % of pt receiving ER or IV POS (300 mg once daily) achieved initial therapeutic levels, respectively; of these, 87% and 83% had median therapeutic follow-up levels, respectively. Serial levels were available for 7 pt whose dose was increased from 300 to 400 mg ER once daily for subtherapeutic levels. 4/7 pt achieved therapeutic levels on 400 vs. 0/7 on 300 mg ER once daily (P = 0.069). Metoclopramide use and CF were associated with subtherapeutic vs. therapeutic levels (25% vs. 4% and 37% vs. 13%, respectively, P = < 0.05). When pt with CF were excluded, neither age nor body mass index were associated with POS levels. CF pt had lower levels than non-CF pt on a dose of 300 mg ER once daily (median 0.8 vs. 1.3 mcg/mL, P = 0.018). Conclusion Therapeutic levels are more reliably achieved with ER & IV POS compared with SUS POS. Serial TDM is unnecessary for most, but is recommended for pt with CF or those on metoclopramide. Dose increases may effectively increase levels. Novel dosing strategies are needed for CF. Disclosures R. K. Shields, Astellas: Received research funding, Research support. Merck: Received research funding, Research support. C. J. Clancy, Merck: Received research funding, Research support. Astellas: Received research funding, Research support. Cidara: Received research funding, Research support. Astellas: Scientific Advisor, Advisory board. Merck: Scientific Advisor, Advisory board. Cidara: Scientific Advisor, Advisory board. Medicines Company: Scientific Advisor, Advisory board.