Abstract Background Coccidioidomycosis is a significant cause of morbidity and mortality in solid organ transplant (SOT) recipients. Although existing guidelines address some aspects of pre- and post-transplant testing, prophylaxis, and monitoring, in many cases best practices are unknown, particularly for regions with variable Coccidioides endemicity such as California. This study aims to understand existing coccidioidomycosis prevention strategies at California transplant centers. Methods We designed a web-based survey that inquired about California transplant centers’ protocols for pre-transplant coccidioidomycosis testing, post-transplant prophylaxis, and post-transplant monitoring. The Organ Procurement and Transplantation Network website was used to identify adult transplant centers in California that performed at least one SOT in 2023. Primarily pediatric centers were excluded. A transplant infectious disease or transplant physician from each center was invited to complete the survey on behalf of their institution. Results Eight out of 15 California transplant centers, representing 68.9% of the total SOT volume for 2023, completed the survey by the time of this report. Types of SOTs performed by the centers are shown in Table 1. All centers had at least one coccidioidomycosis protocol. Many centers had protocols that applied to multiple SOT types; no center had different protocols for the different abdominal transplant types. Details of the seven prophylaxis protocols for abdominal transplants are provided in Table 2. No center recommended Coccidioides-directed prophylaxis for all recipients. Conclusion All transplant centers that responded to the survey had at least one coccidioidomycosis protocol, but not all had protocols that applied to all transplant types, and the amount of detail provided by the protocols varied widely. All centers provided some guidance about prophylaxis for recipients from endemic areas, and the majority recommended indefinite prophylaxis for those who were seropositive pre-transplant. Fewer centers provided guidance addressing recipients’ personal history of coccidioidomycosis or donor status. Further research is needed to clarify best practices for reducing coccidioidomycosis after SOT so that approaches can be better standardized. Disclosures Catherine DeVoe, MD, AN2 Therapeutics: Grant/Research Support Alan Koff, MBBS, Astra Zeneca: Clinical trial support to institution Joanna M. Schaenman, MD, PhD, FAST, Eurofins Viracor: Honoraria|F2G: Grant/Research Support|MedCure: Advisor/Consultant|Moderna: Clinical trial support to institution|OneLegacy: Advisor/Consultant

Abstract Secondary bacterial pneumonia (2°BP) is associated with significant morbidity following respiratory viral infection, yet remains incompletely understood. In a prospective cohort of 112 critically ill adults intubated for COVID-19, we comparatively assess longitudinal airway microbiome dynamics and the pulmonary transcriptome of patients who developed 2°BP versus controls who did not. We find that 2°BP is significantly associated with both mortality and corticosteroid treatment. The pulmonary microbiome in 2°BP is characterized by increased bacterial RNA mass and dominance of culture-confirmed pathogens, detectable days prior to 2°BP clinical diagnosis, and frequently also present in nasal swabs. Assessment of the pulmonary transcriptome reveals suppressed TNFα signaling in patients with 2°BP, and sensitivity analyses suggest this finding is mediated by corticosteroid treatment. Further, we find that increased bacterial RNA mass correlates with reduced expression of innate and adaptive immunity genes in both 2°BP patients and controls. Taken together, our findings provide fresh insights into the microbial dynamics and host immune features of COVID-19-associated 2°BP, and suggest that suppressed immune signaling, potentially mediated by corticosteroid treatment, permits expansion of opportunistic bacterial pathogens.

Background:This study characterizes the clinical utility and validity of the Karius test (KT), a plasma microbial cell-free DNA sequencing platform, as an infection surveillance tool among hematopoietic stem cell transplant (HCT) recipients, including monitoring for cytomegalovirus (CMV) and detecting infections relative to standard microbiologic testing (SMT). Methods:A prospective, observational cohort study was performed among adult HCT recipients as inpatients and outpatients. Serial KTs were performed starting with 1 sample within 14 days before HCT, then weekly from 7-63 days posttransplant then monthly from 3-12 months post-HCT. Diagnostic performance of KT versus CMV polymerase chain reaction was evaluated with positive percent agreement and negative percent agreement. Infectious events (<12 months post-HCT) were extracted from medical records. For infectious events without positive SMT, 2 clinicians adjudicated KT results to determine if any detections were a probable cause. Difference in time from KT pathogen detection and infection onset was calculated. Results:Of the 70 participants, mean age was 49.9 years. For CMV surveillance, positive percent agreement was 100% and negative percent agreement was 90%. There was strong correlation between CMV DNA and KT molecules per microliter (r 2: 0.84, P < .001). Of the 32 SMT+/KT+ infectious events, KT identified 26 earlier than SMT (median: -12 days) and an additional 5 diagnostically difficult pathogens identified by KT but not SMT. Conclusions:KT detected CMV with high accuracy and correlation with quantitative polymerase chain reaction. Among infectious events, KT demonstrated additive clinical utility by detecting pathogens earlier than SMT and those not detected by SMT.

TO THE EDITOR—Cytomegalovirus (CMV) infection remains a frequent cause of morbidity and mortality among stem-cell and solid organ transplant recipients, with devastating complications including graft failure and death [1, 2]. Limitations of existing anti-CMV agents such as valganciclovir, ganciclovir, foscarnet, and cidofovir include toxicity (bone marrow suppression, renal failure, electrolyte disturbances), route of administration, and potential for resistance [1, 2]. Maribavir is an oral benzimidazole nucleoside inhibiting viral kinase UL97 that was Food and Drug Administration– approved in November 2021 for refractory/resistant posttransplant CMV infection [3]. In the SOLSTICE phase 3 trial of maribavir compared to investigator-assigned therapy, maribavir demonstrated superior viral clearance at week 8 (55.7% vs 23.9%, P< .0001) and fewer side effects such as neutropenia (9.4% vs 22.4%) and kidney injury (8.5% vs 9.5%) [4]. However, recurrence after treatment discontinuation occurred in 50% of initial responders [3, 4]. Additionally, treatment-emergent UL97 mutations conferring reduced maribavir susceptibility, including some conferring cross-resistance to ganciclovir/valganciclovir, occurred frequently (up to 25% of enrolled subjects) in both SOLSTICE and prior phase 2 studies [3–7]. Outside of clinical trial settings, little is known about outcomes of maribavir therapy. Here, we present 2 transplant recipients receiving maribavir who developed breakthrough CMV infection, including 1 with resistance.

Ceftolozane-tazobactam (C/T) has been shown to be a safe and effective alternative for the treatment of difficult to treat infections due to Pseudomonas aeruginosa (PA) in the general nonimmunocompromised population. However, the experience of this agent in immunosuppressed neutropenic patients is very limited.

Two molecular phenotypes of the acute respiratory distress syndrome (ARDS) with substantially different clinical trajectories have been identified. Classification as "hyperinflammatory" or "hypoinflammatory" depends on systemic biomarker profiling. Differences in the biology underlying these phenotypes at the site of injury, the lung, are unknown. We analyze tracheal aspirate transcriptomes from 46 mechanically ventilated subjects to assess differences in lung inflammation and repair between ARDS phenotypes. We then integrate these results with metatranscriptomic sequencing, single cell RNA sequencing, and plasma proteomics to identify distinct features of each ARDS phenotype. We also compare phenotype-specific differences in gene expression to experimental models of acute lung injury and use an in silico analysis to identify candidate treatments for each phenotype. We find that hyperinflammatory ARDS is associated with increased integrated stress response and interferon gamma signaling, distinct immune cell polarization, and differences in microbial community composition in TA. These findings demonstrate that each phenotype has distinct respiratory tract biology that may be relevant to developing effective therapies for ARDS.

Objective: To evaluate broad-spectrum intravenous antibiotic use before and after the implementation of a revised febrile neutropenia management algorithm in a population of adults with hematologic malignancies. Design: Quasi-experimental study. Setting and population: Patients admitted between 2014 and 2018 to the Adult Malignant Hematology service of an acute-care hospital in the United States. Methods: Aggregate data for adult malignant hematology service were obtained for population-level antibiotic use: days of therapy (DOT), C. difficile infections, bacterial bloodstream infections, intensive care unit (ICU) length of stay, and in-hospital mortality. All rates are reported per 1,000 patient days before the implementation of an febrile neutropenia management algorithm (July 2014-May 2016) and after the intervention (June 2016-December 2018). These data were compared using interrupted time series analysis. Results: In total, 2,014 patients comprised 6,788 encounters and 89,612 patient days during the study period. Broad-spectrum intravenous (IV) antibiotic use decreased by 5.7% with immediate reductions in meropenem and vancomycin use by 22 (P = .02) and 15 (P = .001) DOT per 1,000 patient days, respectively. Bacterial bloodstream infection rates significantly increased following algorithm implementation. No differences were observed in the use of other antibiotics or safety outcomes including C. difficile infection, ICU length of stay, and in-hospital mortality. Conclusions: Reductions in vancomycin and meropenem were observed following the implementation of a more stringent febrile neutropenia management algorithm, without evidence of adverse outcomes. Successful implementation occurred through a collaborative effort and continues to be a core reinforcement strategy at our institution. Future studies evaluating patient-level data may identify further stewardship opportunities in this population.

Objective: We compared the rates of hospital-onset secondary bacterial infections in patients with coronavirus disease 2019 (COVID-19) with rates in patients with influenza and controls, and we investigated reports of increased incidence of Enterococcus infections in patients with COVID-19. Design: Retrospective cohort study. Setting: An academic quaternary-care hospital in San Francisco, California. Patients: Patients admitted between October 1, 2019, and October 1, 2020, with a positive SARS-CoV-2 PCR (N = 314) or influenza PCR (N = 82) within 2 weeks of admission were compared with inpatients without positive SARS-CoV-2 or influenza tests during the study period (N = 14,332). Methods: National Healthcare Safety Network definitions were used to identify infection-related ventilator-associated complications (IVACs), probable ventilator-associated pneumonia (PVAP), bloodstream infections (BSIs), and catheter-associated urinary tract infections (CAUTIs). A multiple logistic regression model was used to control for likely confounders. Results: COVID-19 patients had significantly higher rates of IVAC and PVAP compared to controls, with adjusted odds ratios of 4.7 (95% confidence interval [CI], 1.7-13.9) and 10.4 (95 % CI, 2.1-52.1), respectively. COVID-19 patients had higher incidence of BSI due to Enterococcus but not BSI generally, and whole-genome sequencing of Enterococcus isolates demonstrated that nosocomial transmission did not explain the increased rate. Subanalyses of patients admitted to the intensive care unit and patients who required mechanical ventilation revealed similar findings. Conclusions: COVID-19 is associated with an increased risk of IVAC, PVAP, and Enterococcus BSI compared with hospitalized controls, which is not fully explained by factors such as immunosuppressive treatments and duration of mechanical ventilation. The mechanism underlying increased rates of Enterococcus BSI in COVID-19 patients requires further investigation.

The immunological features that distinguish COVID-19-associated acute respiratory distress syndrome (ARDS) from other causes of ARDS are incompletely understood. Here, we report the results of comparative lower respiratory tract transcriptional profiling of tracheal aspirate from 52 critically ill patients with ARDS from COVID-19 or from other etiologies, as well as controls without ARDS. In contrast to a "cytokine storm," we observe reduced proinflammatory gene expression in COVID-19 ARDS when compared to ARDS due to other causes. COVID-19 ARDS is characterized by a dysregulated host response with increased PTEN signaling and elevated expression of genes with non-canonical roles in inflammation and immunity. In silico analysis of gene expression identifies several candidate drugs that may modulate gene expression in COVID-19 ARDS, including dexamethasone and granulocyte colony stimulating factor. Compared to ARDS due to other types of viral pneumonia, COVID-19 is characterized by impaired interferon-stimulated gene (ISG) expression. The relationship between SARS-CoV-2 viral load and expression of ISGs is decoupled in patients with COVID-19 ARDS when compared to patients with mild COVID-19. In summary, assessment of host gene expression in the lower airways of patients reveals distinct immunological features of COVID-19 ARDS.

Secondary bacterial infections, including ventilator-associated pneumonia (VAP), lead to worse clinical outcomes and increased mortality following viral respiratory infections including in patients with coronavirus disease 2019 (COVID-19). Using a combination of tracheal aspirate bulk and single-cell RNA sequencing (scRNA-seq) we assessed lower respiratory tract immune responses and microbiome dynamics in 28 COVID-19 patients, 15 of whom developed VAP, and eight critically ill uninfected controls. Two days before VAP onset we observed a transcriptional signature of bacterial infection. Two weeks prior to VAP onset, following intubation, we observed a striking impairment in immune signaling in COVID-19 patients who developed VAP. Longitudinal metatranscriptomic analysis revealed disruption of lung microbiome community composition in patients with VAP, providing a connection between dysregulated immune signaling and outgrowth of opportunistic pathogens. These findings suggest that COVID-19 patients who develop VAP have impaired antibacterial immune defense detectable weeks before secondary infection onset.

We performed comparative lower respiratory tract transcriptional profiling of 52 critically ill patients with the acute respiratory distress syndrome (ARDS) from COVID-19 or from other etiologies, as well as controls without ARDS. In contrast to a cytokine storm, we observed reduced proinflammatory gene expression in COVID-19 ARDS when compared to ARDS due to other causes. COVID-19 ARDS was characterized by a dysregulated host response with increased PTEN signaling and elevated expression of genes with non-canonical roles in inflammation and immunity that were predicted to be modulated by dexamethasone and granulocyte colony stimulating factor. Compared to ARDS due to other types of viral pneumonia, COVID-19 was characterized by impaired interferon-stimulated gene expression (ISG). We found that the relationship between SARS-CoV-2 viral load and expression of ISGs was decoupled in patients with COVID-19 ARDS when compared to patients with mild COVID-19. In summary, assessment of host gene expression in the lower airways of patients with COVID-19 ARDS did not demonstrate cytokine storm but instead revealed a unique and dysregulated host response predicted to be modified by dexamethasone.

Immunosuppressed patients such as solid organ transplant and hematologic malignancy patients appear to be at increased risk for morbidity and mortality due to coronavirus disease 2019 (COVID-19) caused by SARS coronavirus 2 (SARS-CoV-2). Convalescent plasma, a method of passive immunization that has been applied to prior viral pandemics, holds promise as a potential treatment for COVID-19. Immunocompromised patients may experience more benefit from convalescent plasma given underlying deficits in B and T cell immunity as well as contraindications to antiviral and immunomodulatory therapy. We describe our institutional experience with four immunosuppressed patients (two kidney transplant recipients, one lung transplant recipient, and one chronic myelogenous leukemia patient) treated with COVID-19 convalescent plasma through the Expanded Access Program (NCT04338360). All patients clinically improved after administration (two fully recovered and two discharged to skilled nursing facilities) and none experienced a transfusion reaction. We also report the characteristics of convalescent plasma product from a local blood center including positive SARS-CoV-2 IgG and negative SARS-CoV-2 PCR in all samples tested. This preliminary evidence suggest that convalescent plasma may be safe among immunosuppressed patients with COVID-19 and emphasizes the need for further data on the efficacy of convalescent plasma as either primary or adjunctive therapy for COVID-19.

The coronavirus disease 2019 (COVID-19) pandemic caused by SARS coronavirus 2 (SARS-CoV-2) has caused significant morbidity and mortality for patients and stressed healthcare systems worldwide. The clinical features, disease course, and serologic response of COVID-19 among immunosuppressed patients such as solid organ transplant (SOT) recipients, who are at presumed risk for more severe disease, are not well characterized. We describe our institutional experience with COVID-19 among 10 SOT patients, including the clinical presentation, treatment modalities, and outcomes of 7 renal transplant recipients, 1 liver transplant recipient, 1 heart transplant recipient, and 1 lung transplant recipient. In addition, we report the serologic response in SOT recipients, documenting a positive IgG response in all 7 hospitalized patients. We also review the existing literature on COVID-19 in SOT recipients to consolidate the current knowledge on COVID-19 in the SOT population for the transplant community.

Abstract Background Febrile neutropenia (FN) is a common complication of cancer therapy and often necessitates prolonged antibiotic treatment. Antibiotic de-escalation can be challenging given tenuous clinical status. Furthermore, a microbiological or clinical etiology is identified in a minority of FN patients. In 2016 we implemented several evidence-based strategies to guide antibiotic use in high-risk FN patients including specifying vancomycin use indications, minimizing carbapenem escalation in stable patients with ongoing fevers, and defining antibiotic durations regardless of neutrophil count. The study objective was to characterize and evaluate our experience implementing these strategies on antibiotic use and clinical outcomes. Methods Interrupted time series analysis of all admissions to the Malignant Hematology service at the University of California, San Francisco between June 2014 and December 2018. The primary outcome was monthly days of therapy (DOT) per 1,000 patient-days of broad-spectrum IV antibiotics (aztreonam, cefepime, piperacillin–tazobactam, meropenem, and vancomycin). Secondary outcomes included DOT/1,000 patient-days for each IV antibiotic, incidence rates of bloodstream infections (BSI) and C. difficile infections (CDI), and in-hospital all-cause mortality. A segmented regression analysis was conducted to evaluate the impact of the FN management algorithm implementation on antibiotic use and clinical outcomes. Summary statistics and time series scatter plots were used to visualize the trends and outliers. Results 2319 unique patients with 6,788 encounters were included. The median (IQR) age was 59 (46–68) years and 60% were male. Regression results and time series plots are shown in Table 1 and Figures 1–3. Conclusion Implementation of an evidence-based FN management algorithm led to decreased vancomycin and meropenem use without a statistically significant impact on overall antibiotic use, CDI rates, or mortality.While BSI rates fluctuated in the 2 months post-implementation, rates returned to baseline thereafter. A multidisciplinary effort facilitated successful implementation of this stewardship project. This collaboration remains essential to addressing future antimicrobial management strategies in this population. Disclosures All authors: No reported disclosures.

Introduction: Patients with acute neurologic injury such as aneurysmal subarachnoid hemorrhage (aSAH) are at risk of central fever and infections. Fever has been found to independently increase morbidity and mortality. These patients are at risk of exposure to antibiotic overuse, resistant infections, and extensive fever work-ups as central fever remains a diagnosis of exclusion. Methods: We included 28 patients who underwent treatment for aSAH at the University of California, San Francisco’s Neurointensive Care Units from 2012-2016. We retrospectively reviewed their fever curves, with every 2 seconds temperature data, and used strict CDC infection criteria to delineate between central and infectious fever. For every patient, we extracted one or multiple 12-hours-fever-windows (FW) for a total of 289 FW. We then extracted 40 features in either time or frequency domain such as signal skewness, kurtosis, and variance for each FW, and trained a Random Forest model to classify between central and infectious fever. Our model was trained and cross-validated using 19 patients and tested using the remaining 9 patients. Results: Our initial machine learning model shows a cross-validated ROC AUC score of 0.825 ± 0.150, and a testing ROC AUC score of 0.75 on 30% test patients. Conclusion: These preliminary results suggest that there are combinations of characteristics or patterns that can differentiate between central and infectious fever through a machine learning model. To our knowledge, this has never been done before. Our next steps include the development of a more robust features matrix and the use of other machine learning models such as the Recurrent Neural Network (RNN). If this machine learning model can effectively identify central versus infectious fevers, we can optimize antibiotic stewardship, tailor the work up and treatment of this critically ill population and open the door for prospective central fever and temperature management research.

Abstract Background Fluoroquinolone (FQ) prophylaxis for high-risk neutropenic patients has been shown to reduce rates of febrile neutropenia and is standard at many centers. For patients who cannot receive a FQ, oral third-generation cephalosporins (OTGCs) are often used as an alternative; however, this strategy is not well studied. We sought to compare clinically-relevant outcomes in patients receiving FQ vs. OTGC prophylaxis. Methods This was a retrospective cohort study of adults who were admitted to the Malignant Hematology service at the University of California, San Francisco between December 2012 and June 2018 and received >48 hours of an OTGC (cefdinir or cefpodoxime) or an FQ (levofloxacin) for neutropenic prophylaxis. For each OTGC patient, an FQ patient was randomly selected from the same admission year. Exclusion criteria were fever on admission, receipt of systemic antibiotics prior to or during the prophylaxis period, diagnosis of acute promyelocytic leukemia, and crossover. A multivariable logistic regression analysis adjusting for age, QTc, Charlson Comorbidity Index, underlying diagnosis, receipt of stem cell transplant (SCT), and duration of neutropenia was used to compare the groups with respect to a primary composite outcome of 30-day in-hospital mortality, intensive care unit (ICU) admission, and bacteremia. Results Of 520 patients screened, 173 (33.3%) were included in the study; 76 of these received an OTGC and 97 received an FQ. Hematologic diagnoses included multiple myeloma (38.2%), acute myeloid leukemia (29.5%), acute lymphoblastic leukemia (8.7%), B-cell lymphoma (12.7%), aplastic anemia (2.9%), and others (3.5%). During admission, 9.2% underwent allogeneic SCT and 28.3% underwent autologous SCT. Outcomes are shown in Table 1. Conclusion Prophylaxis with an OTGC rather than a FQ was not associated with worse outcomes in this pragmatic evaluation of a heterogeneous group of patients with hematologic malignancies. In this multivariable model, neutropenia lasting more than 7 days was the only consistent predictor of failure across outcomes, suggesting that degree of immunosuppression is a much more significant driver of poor outcomes in this population than is prophylaxis choice. Further evaluation of the role of prophylaxis is needed. Disclosures All authors: No reported disclosures.

Abstract Background Isavuconazole (ISA) is a novel triazole antifungal approved for treating invasive aspergillosis and mucormycosis. While ISA is increasingly used for prophylaxis in hematologic malignancy patients when other azoles are contraindicated, there are currently limited data on breakthrough invasive fungal infection (IFI) rates in this context. Methods We retrospectively reviewed inpatient and outpatient pharmacy records from March 2015 to April 2018 to identify adult patients with hematologic malignancy who received at least 7 days of ISA for prophylaxis. Breakthrough IFI was defined by EORTC-MSG criteria. Results We identified 73 hematologic malignancy patients who received ISA; 29 received at least 7 days ISA for prophylaxis in 33 separate episodes. Of these patients, 52% had acute myeloid leukemia, 14% had acute promyelocytic leukemia, 10% had myelodysplastic syndrome, and 21% had another malignancy. Eighty-six percent of patients were neutropenic (median duration 24 days; range 2–213). Median duration of ISA prophylaxis was 61 days (range 8–635). The most common reason for choosing ISA over other antifungal agents was QTc prolongation (45%), followed by intolerance of other antifungals (27%) and drug-drug interactions with other azoles (21%). Four patients (12%) developed proven or probable breakthrough IFI (Table 1). Among patients with breakthrough IFI, mortality was 50% at 12 weeks. Table 1. Characteristics of Breakthrough IFI Among Hematologic Malignancy Patients Receiving ISA Prophylaxis Age/Gender Disease IFI site Organism Diagnostic Test ANCNadir Neutropenia Duration (days) Duration ISA (days) Outcome (12 weeks) 32M AML Lung Aspergillus fumigatus BAL: fungal culture <10 118 38 Death 65M Aplastic anemia Blood, lung Scedosporium apiospermum Blood culture <100 14 13 Death 44F ALL Lung Aspergillus nigri Lung FNA: PCR, path 0 143 52 Partial response 63F AML Lung Unknown* Lung FNA negative 110 90 73 Partial response *Probable IFI; other threecases were proven. Conclusion We demonstrate a 12% rate of breakthrough IFI among hematologic malignancy patients on ISA prophylaxis, similar to published rates (10–15%) on posaconazole prophylaxis. Further study is needed to characterize risk factors for and epidemiology of ISA breakthrough. Disclosures S. B. Doernberg, Genentech: Consultant, Consulting fee. Actelion: Consultant, Consulting fee.

The effect of vaccination on severity of subsequent COVID-19 in patients with hematologic malignancies (HMs) is unknown. In this single-center retrospective cohort study, we found no difference in severity of COVID-19 disease in vaccinated (n = 16) versus unvaccinated (n = 54) HM patients using an adjusted multiple logistic regression model. Recent anti-B-cell therapy was associated with more severe illness.