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Background Pneumonia is the most common infectious cause of morbidity and excess mortality complicating hematopoietic cell transplantation (HCT) and treatment of hematologic malignancy. Standard bronchoscopic and noninvasive microbiologic testing identify causative pathogens in less than half of cases. The Karius Test, a plasma next-generation sequencing assay of microbial cell-free DNA, may improve diagnostic yield in these patients. Methods Patients with active hematologic malignancy or recent HCT undergoing bronchoscopy for suspected pneumonia were prospectively enrolled in this observational study conducted at 10 United States medical centers. A panel of expert clinicians blinded to Karius Test results reviewed a standardized panel of microbiologic and molecular testing from bronchoalveolar lavage and blood samples for bacterial and fungal testing, nasopharyngeal swab for respiratory viral testing, imaging results, clinical documentation, and any additional microbiologic or molecular testing collected per usual standard of care to adjudicate a probable cause of pneumonia. The panel then adjudicated whether a probable cause of pneumonia or other clinically relevant infection was identified by the Karius Test. Results Between January 3, 2020 and February 4, 2022, 257 patients were enrolled. A planned interim analysis of the first 69 sequentially enrolled patients in the per protocol population was conducted. An adjudicated probable cause of pneumonia was identified by standard care in 18/69 (26%) patients. The Karius Test identified an adjudicated probable cause of pneumonia in 10/51 (20%) patients when no cause of pneumonia was identified by standard care testing. The combination of standard care and the Karius Test together identified a probable cause of pneumonia in 28/69 (41%) patients. At least one additional pathogen adjudicated as a probable cause of pneumonia was identified by the Karius Test in 6/18 (33%) of patients with positive standard care testing. Conclusion The Karius Test notably increased the probability of identifying a pathogenic cause of pneumonia among immunocompromised patients undergoing bronchoscopy. The additive diagnostic value of the Karius Test may significantly enhance management of this common condition. Disclosures Roy F. Chemaly, MD/MPH, Karius: Advisor/Consultant|Karius: Grant/Research Support Radha Duttagupta, PhD, Karius Inc: Stocks/Bonds Sanjeet S. Dadwal, MD, FACP, FIDSA, AlloVir: Advisor/Consultant|AlloVir: Grant/Research Support|Ansun Biopharma: Grant/Research Support|Aseptiscope: Advisor/Consultant|Aseptiscope: Stocks/Bonds|Astellas: Speaker's Bureau|Cidara: Advisor/Consultant|Gilead: Grant/Research Support|Karius: Grant/Research Support|Merck: Advisor/Consultant|Merck: Grant/Research Support|Merck: Speaker's Bureau|Takeda: Speaker's Bureau Joshua A. Hill, MD, Allovir: Advisor/Consultant|Allovir: Grant/Research Support|Covance/CSL: Advisor/Consultant|CRISPR: Advisor/Consultant|Deverra: Grant/Research Support|Gilead: Grant/Research Support|Karius: Advisor/Consultant|Karius: Grant/Research Support|Merck: Grant/Research Support|Octapharma: Advisor/Consultant|OptumHealth: Advisor/Consultant|Oxford Immunotec: Grant/Research Support|Pfizer: Advisor/Consultant|Symbio: Advisor/Consultant|Takeda: Advisor/Consultant Ghady Haidar, MD, Karius, Allovir, and AstraZeneca: Grant/Research Support Alfred Luk, MD, Karius: Grant/Research Support Jamie Todd, MD, Altavant Sciences: Advisor/Consultant|AstraZeneca: Grant/Research Support|Boehringer Ingelheim: Grant/Research Support|CareDx: Grant/Research Support|Cellarity: Advisor/Consultant|Natera: Advisor/Consultant Genovefa Papanicolaou, MD, AlloVir: Board Member|AlloVir: Serve as member of DSMC|Amplyx: Board Member|Amplyx: Serve as member of DSMC|Astellas: Advisor/Consultant|Cidara: Advisor/Consultant|CSL Behring: Advisor/Consultant|Merck: Advisor/Consultant|Merck: Grant/Research Support|Merck: Investigator for Merck|MSD: Advisor/Consultant|Octapharma: Advisor/Consultant|Octapharma: Board Member|Octapharma: Serve as EAC member|Partners RX: Advisor/Consultant|SymBio: Advisor/Consultant|Takeda: Advisor/Consultant|Takeda: Grant/Research Support|Takeda: Investigator for Takeda|Vera: Board Member|Vera: Serve as member of DSMC Elena Nemirovich-Danchenko, MD PhD, Karius: Stocks/Bonds Mona Mughar, BS, Karius: Stocks/Bonds Sudeb Dalai, MD, Karius: Stocks/Bonds Sudeb Dalai, MD, Karius: Stocks/Bonds Yuen Cho, MS, CLS(CA-DPH), Karius: Stocks/Bonds Asim A. Ahmed, MD, Karius: Employee|Karius: Stocks/Bonds Desiree Hollemon, MSN, MPH, Karius: Stocks/Bonds David K. Hong, MD, Janssen Pharmaceutical Companies of Johnson & Johnson: Employee|Vir Biotechnology: Employee|Vir Biotechnology: Stocks/Bonds Marla Lay Vaughn, BS, MT(ASCP), Karius: Employee|Karius: Stocks/Bonds Tim Blauwkamp, PhD, Karius: Board Member|Karius: Ownership Interest Zivjena Vucetic, MD, Karius: Stocks/Bonds Rina Romano, BS, Karius Inc: Stocks/Bonds|Karius Inc: Stocks/Bonds Rina Romano, BS, Karius Inc: Stocks/Bonds|Karius Inc: Stocks/Bonds Rina Romano, BS, Karius Inc: Stocks/Bonds|Karius Inc: Stocks/Bonds Vance G. Fowler, Jr, MD, MHS, Affinergy: Grant/Research Support|Affinergy: Honoraria|Affinium: Honoraria|Amphliphi Biosciences: Honoraria|ArcBio: Stocks/Bonds|Basilea: Grant/Research Support|Basilea: Honoraria|Bayer: Honoraria|C3J: Honoraria|Cerexa/Forest/Actavis/Allergan: Grant/Research Support|Contrafect: Grant/Research Support|Contrafect: Honoraria|Cubist/Merck: Grant/Research Support|Debiopharm: Grant/Research Support|Deep Blue: Grant/Research Support|Destiny: Honoraria|Genentech: Grant/Research Support|Genentech: Honoraria|Integrated Biotherapeutics: Honoraria|Janssen: Grant/Research Support|Janssen: Honoraria|Karius: Grant/Research Support|Medicines Co.: Honoraria|MedImmune: Grant/Research Support|MedImmune: Honoraria|NIH: Grant/Research Support|Novartis: Grant/Research Support|Novartis: Honoraria|Pfizer: Grant/Research Support|Regeneron: Grant/Research Support|Regeneron: Honoraria|Sepsis diagnostics: Sepsis diagnostics patent pending|UpToDate: Royalties|Valanbio: Stocks/Bonds Thomas L. Holland, MD, Aridis: Advisor/Consultant|Lysovant: Advisor/Consultant.

Dimorphic endemic fungi exist as mold and yeast forms at room and body temperature within the host, respectively. Primary infection can arise from new environmental exposure and less frequently through organ transplantation. Reactivation of latent infection can occur when immunosuppression is introduced or intensified. Transplant and immunocompromised hosts (ICH) represent important populations at risk for complicated and disseminated forms of endemic mycoses (EM). Diagnosis is challenging as immunosuppression contributes to insidious clinical presentations resulting in diagnostic and treatment delays. Herein, we present updated diagnosis and prevention strategies for EM in the potential organ donor, transplant candidate and recipient, and ICH. Several EM have previously been considered as restricted to a limited geographical area; however, factors such as global warming, changing precipitation patterns, and increased travel are actively expanding the geographical distribution of endemic fungi. Serological testing, often used in the immunocompetent host, has significant limitations in transplant recipients and ICH. Fungal molecular methods have emerged as an important complementary diagnostic strategy for EM but would benefit from greater standardization and wider availability. High clinical suspicion and a multipronged diagnostic approach are recommended for timely diagnosis and prevention of complications. In ICH, combining diagnostic methods increases diagnostic yield for EM. Immunosuppression-specific risk assessment, laboratory monitoring, and targeted antifungal prophylaxis are pivotal to reduce EM burden. The use of molecular methods for early diagnosis and the role of newer azoles and immunomodulation in the management of EM require further investigation.

Clostridioides difficile infection (CDI) is a common complication in the hematopoietic stem cell transplantation (HSCT) and hematologic malignancy (HM) population. CDI is associated with increased hospital length of stay, health care and societal costs, morbidity, and mortality. Identifying strategies for secondary prevention of CDI is of extreme importance in the HSCT/HM population. In this study, our primary objective was to evaluate the effectiveness and safety of an oral vancomycin prophylaxis (OVP) protocol for secondary prevention of CDI in a retrospective cohort of adult autologous/allogeneic HSCT recipients and patients with HM who did not undergo HSCT with a first CDI episode treated with concomitant broad-spectrum antibiotics (BSA). Patients were diagnosed and treated for CDI as inpatients and/or outpatients and were divided into 2 groups based on a preprotocol versus postprotocol analysis: the OVP group, comprising patients who received planned monotherapy with oral vancomycin 125 mg every 6 hours for 14 days for a first episode of CDI and subsequently received OVP posttreatment and a no OVP (NOVP) group, comprising patients who received planned monotherapy with oral vancomycin 125 mg every 6 hours for 14 days for a first episode of CDI and subsequently did not receive OVP posttreatment. OVP was defined as vancomycin 125 mg every 12 hours for up to 7 days after BSA discontinuation. The primary endpoint was recurrent CDI (rCDI), defined as symptoms of loose stools/diarrhea with high clinical suspicion for CDI prompting empiric therapy within 60 days of completion of treatment/prophylaxis for the first CDI episode. The incidence of vancomycin-resistant enterococcal (VRE) infection and 60-day mortality were also compared between the 2 groups. Multivariate logistic regression was created from associated variables to identify independent associations with rCDI. A total of 50 patients were included, 21 in the OVP group (42%) and 29 in the NOVP group (58%). The mean patient age was 58 years, and the cohort was 60% male and 86% Caucasian. HSCT was performed in 60% of the patients, and 76% of CDI cases were diagnosed during hospitalization. The rate of rCDI was significantly lower in the OVP group compared with the NOVP group (5% [1 of 21] versus 35% [10 of 29]; P= .016), with no subsequent increase in VRE infection rate (14% [3 of 21] versus 10% [3 of 29]; P = .686). By multivariable logistic regression, rCDI was inversely associated with OVP (odds ratio [OR], .14; 95% confidence interval [CI], .007 to .994; P = .049) and directly associated with outpatient CDI diagnosis (OR, 8.72; 95% CI, 1.816 to 49.158; P = .007). No between-group differences were found in 60-day mortality (10% [2 of 21] for OVP versus 7% [2 of 29] for NOVP; P > 0.999). OVP appears to be safe and effective for secondary prevention of CDI in the HSCT/HM population. Prospective trials are needed to validate the effectiveness of OVP in this vulnerable population to prevent rCDI.

Chagas disease (CD) is the third most common parasitic infection globally and can cause cardiac and gastrointestinal complications. Around 300,000 carriers of CD live in the U.S., with about 3000 of those in Colorado. We described our experience in diagnosing CD at a Colorado teaching hospital to revise screening eligibility criteria. From 2006 to 2020, we reviewed Trypanosoma cruzi (TC) IgG serology results for 1156 patients in our institution. We identified 23 patients (1.99%) who had a positive test. A total of 14/23 (60%) of positive serologies never had confirmatory testing, and 7 of them were lost to follow up. Confirmatory testing, performed in 9 patients, resulted in being positive in 3. One additional case of CD was identified by positive tissue pathology. All four confirmed cases were among patients born in Latin America. While most of the testing for CD at our institution is part of the pretransplant screening, no confirmed cases of CD derived from this strategy. Exposure risk in this population is not always documented, and initial positive results from screening are not always confirmed. The lack of standardized screening protocols for CD in our institution contributes to underdiagnosis locally and in health systems nationwide. Given a large number of individuals in the U.S. with chronic CD, improved screening is warranted.

Background Standard testing fails to identify a pathogen in most patients with febrile neutropenia (FN). We evaluated the ability of the Karius microbial cell-free DNA sequencing test (KT) to identify infectious etiologies of FN and its impact on antimicrobial management. Methods This prospective study (ClinicalTrials.gov; NCT02912117) enrolled and analyzed 55 patients with FN. Up to 5 blood samples were collected per subject within 24 hours of fever onset (T1) and every 2 to 3 days. KT results were compared with blood culture (BC) and standard microbiological testing (SMT) results. Results Positive agreement was defined as KT identification of ≥1 isolate also detected by BC. At T1, positive and negative agreement were 90% (9/10) and 31% (14/45), respectively; 61% of KT detections were polymicrobial. Clinical adjudication by 3 independent infectious diseases specialists categorized Karius results as: unlikely to cause FN (N = 0); definite (N = 12): KT identified ≥1 organism also found by SMT within 7 days; probable (N = 19): KT result was compatible with a clinical diagnosis; possible (N = 10): KT result was consistent with infection but not considered a common cause of FN. Definite, probable, and possible cases were deemed true positives. Following adjudication, KT sensitivity and specificity were 85% (41/48) and 100% (14/14), respectively. Calculated time to diagnosis was generally shorter with KT (87%). Adjudicators determined real-time KT results could have allowed early optimization of antimicrobials in 47% of patients, by addition of antibacterials (20%) (mostly against anaerobes [12.7%]), antivirals (14.5%), and/or antifungals (3.6%); and antimicrobial narrowing in 27.3% of cases. Clinical Trials Registration NCT02912117 Conclusion KT shows promise in the diagnosis and treatment optimization of FN.

We present a case of Cryptococcus neoformans pericarditis in a cardiac transplant recipient. This article reviews the diagnosis, treatment, and complications of cryptococcosis specifically in transplant patients. While pericarditis is a rare manifestation of Cryptococcus infection, this case highlights that cryptococcosis should be considered in the differential diagnosis for solid organ transplant and immunocompromised patients presenting with pericardial effusions.

The recognition of the role of complement and Janus kinase (JAK)-dependent cytokines in the pathogenesis of inflammatory and immune-mediated disorders has revolutionized the treatment of a myriad of rheumatological and inflammatory diseases. C5 inhibitors and Janus kinase inhibitors have emerged as attractive therapeutic options. Because of the blockage of immune pathways, these targeted therapies carry an increased risk of infection. This article reviews the mechanism of action and the approved and off-label indications of the agents with most clinical experience within this drug classes. It discusses the associated risks of infection, proposing screening, prevention, and risk mitigation strategies.

Solid organ demand far exceeds organ supply. Strategies to increase the donor pool include the liberalization of selection criteria without increasing the risk of unexpected donor-derived infection (DDI), a rare complication of transplantation carrying high morbidity and mortality. We review the challenging aspects in the prevention of DDI, focusing on the complexities of data sharing and efficient communication and the role infectious diseases specialists play in the process.Advances in donor screening, transmission recognition and reporting allow for a better estimation of the risk of DDI. However, there is great variability in the frequency and methods with which organ procurement organizations report transmission events.Moreover, the Scientific Registry of Transplant Recipients provides limited donor and recipient outcome infectious diseases related data. Infectious disease contribution to the allocation process has been found to improve organ donation efficiency and communication between involved parties. Although communication gaps are strongly associated with infection transmission (relative risk 2.36%, confidence interval 1.48-3.78), effective communication minimizes or prevents infection in transplant recipients (X(1) 13.13, P = 0.0003).Prospective research is still required to define optimal screening protocols and further prevent transmission of infection. A holistic approach is likely to result in enhanced transplantation safety. Toward this goal, development of standards of investigation; improvement in reporting and data sharing; and strategies ensuring coordinated and rapid communication among parties involved in the allocation process need to be pursued.

Cytomegalovirus (CMV) is a DNA virus of the Herpesviridae family and is estimated to affect 15%-30% of high-risk solid organ transplant recipients. Typical manifestations of CMV end-organ disease in this population include colitis, esophagitis, and pneumonitis, and myocarditis is a rarely reported manifestation. We describe two cases of CMV myocarditis in solid organ transplant recipients and review the literature regarding previously published cases of CMV myocarditis.

The risk of toxoplasmosis in high-risk cardiac transplant recipients is well recognized prompting universal donor and candidate screening with administration of targeted post-transplant chemoprophylaxis in high-risk (D+/R-) cardiac transplant patients. In contrast, until recently, there have been neither well-defined recommendations nor consensus regarding toxoplasmosis preventive strategies among non-cardiac solid organ transplant recipients. We report 3 cases of post-transplant toxoplasmosis in non-cardiac transplant recipients (one lung and two liver); all 3 infections presumed to be donor-derived. Not surprisingly, pre-transplant Toxoplasma serology was negative in all the patients. None of the patients were on trimethoprim-sulfamethoxazole (TMP-SMX) prophylaxis at the time of diagnosis of toxoplasmosis. The median time from transplant to onset of infection was 90 days (range: 30-120 days). Clinical presentations included cerebral (n = 1) and disseminated infections (n = 2). Two of the 3 patients, both with disseminated infection died (mortality ~ 67%).

Background Multidrug-resistant (MDR) and extensively drug-resistant (XDR) gram-negative bacteria may be transmitted from organ donors to solid organ transplant recipients and are associated with poor outcomes post-transplant. Methods We reported the prevalence of MDR/XDR gram-negative respiratory colonization among 702 deceased organ donors in the New York City area from 2011 to 2014 and performed chart reviews for a subset of recipients to determine whether donor respiratory culture results were predictive of subsequent recipient infection or used to guide post-transplant antimicrobial therapy. Results Fifty donors (7% of the cohort) had MDR or XDR gram-negative bacteria isolated from endotracheal aspirate or bronchoalveolar lavage culture. Organs from these 50 donors were transplanted into 120 recipients; chart review was performed for 89 of these recipients (38 kidney, 32 liver, 11 heart, 6 kidney/pancreas, 1 liver/kidney, 1 lung). None of the 89 recipients of organs from donors with MDR/XDR gram-negative respiratory colonization were reported to have a donor-derived infection post-transplant, and chart review for the 88 non-lung recipients indicated that peri-transplant antibiotics were not adjusted specifically for donor respiratory culture results. Conclusion These results suggest that donor respiratory culture results are not predictive of post-transplant infection in non-lung recipients and are unlikely to impact post-transplant management.

Infection with Scedosporium species is associated with a significant morbidity and mortality and is becoming increasingly common, especially in immunocompromised patients. We describe the presentation and successful management of an immunocompromised patient with Scedosporium apiospermum infection of the upper urinary tract system, a rare disease manifestation. The current literature on urinary tract scedosporiosis is further reviewed with emphasis on treatment options and limitations of current antifungal therapy.

Staphylococcus aureusbacteraemia (SAB) remains a complex disease with a high associated morbidity and mortality, especially when it is able to establish an occult nidus safe from antimicrobial eradication. Without rapid identification and intervention, the nidus can cause persistent relapse of disease, morbidity and mortality. Having a high clinical suspicion for the foci of occult S. aureus is important, and awareness of potential sites of infection is critical and can be life-saving. We present a unique case of a 65-year-old man with end-stage renal disease receiving haemodialysis who developed septic shock from SAB. Despite 18 days of appropriate antibiotics, the patient had persistent high-grade bacteraemia until his gall bladder was ultimately percutaneously drained. The day after drainage, he cleared his blood cultures, although he ultimately passed away as he decided to transition his care to focus on comfort measures.

Background The present review is part of the ESCMID Study Group for Infections in Compromised Hosts (ESGICH) Consensus Document on the safety of targeted and biological therapies. Aims To review, from an Infectious Diseases perspective, the safety profile of agents targeting interleukins, immunoglobulins and complement factors and to suggest preventive recommendations. Sources Computer-based MEDLINE searches with MeSH terms pertaining to each agent or therapeutic family. Content Patients receiving interleukin-1 (IL-1) -targeted (anakinra, canakinumab or rilonacept) or IL-5-targeted (mepolizumab) agents have a moderate risk of infection and no specific prevention strategies are recommended. The use of IL-6/IL-6 receptor-targeted agents (tocilizumab and siltuximab) is associated with a risk increase similar to that observed with anti-tumour necrosis factor-α agents. IL-12/23-targeted agents (ustekinumab) do not seem to pose a meaningful risk of infection, although screening for latent tuberculosis infection may be considered and antiviral prophylaxis should be given to hepatitis B surface antigen-positive patients. Therapy with IL-17-targeted agents (secukinumab, brodalumab and ixekizumab) may result in the development of mild-to-moderate mucocutaneous candidiasis. Pre-treatment screening for Strongyloides stercoralis and other geohelminths should be considered in patients who come from areas where these are endemic who are receiving IgE-targeted agents (omalizumab). C5-targeted agents (eculizumab) are associated with a markedly increased risk of infection due to encapsulated bacteria, particularly Neisseria spp. Meningococcal vaccination and chemoprophylaxis must be administered 2–4 weeks before initiating eculizumab. Patients with high-risk behaviours and their partners should also be screened for gonococcal infection. Implications Preventive strategies are particularly encouraged to minimize the occurrence of neisserial infection associated with eculizumab.

Eculizumab inhibits complement effector functions and has significantly impacted the treatment of paroxysmal nocturnal hemoglobinuria and atypical hemolytic uremic syndrome. However, the risks of potentially life-threatening infections, notably with Neisseria spp. in addition to its cost, are major challenges in clinical practice. In this review, we characterize and summarize the infectious complications reported with the use of eculizumab in the context of its typical and expanding indications.Use of eculizumab is rapidly extending to the fields of transplantation and neurology. Eculizumab has been primarily associated with an increased risk of meningococcal infections. Immunization against its commonest serotypes (ABCWY) is now possible with the advent of the meningococcal B vaccine. A combined ABCWY vaccine is underway. Preventive strategies against breakthrough Neisseria infections should also include chemoprophylaxis. Less is known about the association of eculizumab with other infections as recently reported. Surrogate markers of complement blockade, notably CH50, and eculizumab efficacy may help in the risk assessment of infection.Eculizumab has opened new horizons in the treatment of complement-mediated disorders. Prophylactic and immunization strategies against the risk of Nesseria spp. infections are sound and feasible. The use of eculizumab is expanding beyond complement-mediated diseases to transplantation and neurological disorders. Further research is needed to better define and stratify the risk of infection and prevention strategies in patients with the latter indications.

Background: Cytomegalovirus (CMV) infection remains an important cause of morbidity and cost following umbilical cord blood transplantation (UCBT). While the introduction of letermovir represents a novel approach to CMV prophylaxis, optimal CMV management strategies remain controversial. An intensive strategy to prevent CMV disease including one week of pre-transplant ganciclovir followed by high-dose acyclovir or high-dose valacyclovir through day 100 reduced post-transplant CMV reactivation (Milano et al, Blood 2011), but this approach is costly and potentially challenging to administer. Insurance approval for outpatient high-dose valacyclovir is variable, and the pill burden of high-dose acyclovir for post-transplant patients may be unmanageable. A recent study demonstrates that the removal of pre-transplant ganciclovir does not decrease CMV reactivation rates (Hill et al, BBMT 2018). At our center we have attempted to implement the high intensity strategy described above, but for patients who are unable to obtain high-dose valacyclovir at hospital discharge, we have transitioned to standard dose 800 mg acyclovir twice daily. Additionally, in November 2016, we discontinued pre-transplant ganciclovir. To examine the efficacy of these approaches, we compared CMV outcomes among these patients. Methods: All consecutive adult CMV seropositive (CMV R+) patients who received their first double UCBT from December 2009 to January 2018 were reviewed. Patients were excluded if they had initial CMV reactivation prior to day 0 or after day 100, graft failure, death or relapse before day 100, or participated in a CMV prophylaxis trial. Starting the day of transplant, CMV R+ patients received either valacyclovir 2 grams orally 3 times daily or acyclovir 500 mg/m2 intravenously every 8 hours until able to tolerate oral medication. At hospital discharge, patients for whom valacyclovir was authorized by insurance received valacyclovir 2 grams orally 3 times daily through day 100. All others received acyclovir 800 mg orally twice a day through day 100. No patients received anti-thymocyte globulin with conditioning. All patients transplanted prior to November 2016 received pre-transplant ganciclovir, after which pre-transplant ganciclovir was discontinued. CMV reactivation was defined as any detectable PCR positive whole blood sample (checked twice weekly through day 100). Thresholds for treatment with ganciclovir or foscarnet evolved over time, but required high initial copies levels, persistent or rising DNAemia, or evidence of end-organ involvement. Acute graft-versus-host-disease (aGVHD) treatment was based on institutional guidelines and uniform for all patients. Results: Demographics of the 101 patients studied are provided in table 1. Forty-one patients received prophylaxis with high-dose valacyclovir until post-transplant discharge only (median 23 days) and 60 received valacyclovir through day 100. Between day 0 and day 100, fewer patients in the high-dose valacyclovir group (n= 20, 36%) had CMV reactivation compared to those in the acyclovir group (n= 23, 57%), p= 0.025 (figure 1). Nine patients (9%) in the acyclovir group and 6 (6%) in valacyclovir group received CMV directed treatment (p= 0.1). Patients who did or did not received pre-transplant ganciclovir had similar rates of CMV reactivation (p= 0.55 in acyclovir arm, p= 0.15 in valacylcovir arm). Overall survival (p= 0.64), neutrophil and platelet engraftment time, and incidence of grade 2-3 (p= 0.7) and grade 3-4 aGVHD (p= 0.3) were comparable between groups. Conclusions: High-dose valacyclovir through day 100 post-transplant as compared to through the day of hospital discharge post-transplant reduced CMV reactivation rates. While threshold for treatment will vary according to institutional protocol, high-dose valacyclovir through day 100 likely reduces treatment episodes. One week of pre-transplant ganciclovir does not reduce CMV reactivation rates. These data provide important baselines for future comparisons of outcomes following letermovir prophylaxis in this population. Disclosures Haverkos: Viracta Therapeutics: Membership on an entity's Board of Directors or advisory committees.

Background Standard microbiological testing (MT) fails to identify a pathogen in most chemotherapy recipients with febrile neutropenia (FN), who therefore receive prolonged empiric courses of broad-spectrum antimicrobials (AM). We evaluated the ability of the Karius next-generation sequencing plasma test (KT) to identify infectious etiologies of NF and its impact on AM management. Methods This prospective, observational study enrolled 57 patients with ≤500 neutrophils/mm3. Samples were collected within 24 hours of fever onset (T0) and every 2–3 days. Cell-free plasma DNA was prepared and sequenced in a CLIA/CAP laboratory, human reads excluded, and remaining sequences aligned to a curated pathogen database that includes bacteria, viruses, fungi and parasites. Positive agreement (PA) was defined as KT identification of ≥1 isolate also seen by blood culture (BC). Discordant results were adjudicated by 3 infectious disease specialists as: Definite: KT identified ≥1 organism also seen by MT± 7 days of enrollment; Probable: KT result was a likely cause of NF compatible with clinical diagnosis; Possible: KT result was consistent with an infection but not a common cause of NF. Results 56 results (55 subjects) with valid KT and BC results were analyzed. Compared with BC, KT had a PA of 90% (9/10) and negative agreement of 31% (14/45). KT identified >1 organism in 61% (25/41) of the cases. Definite (13), Probable (24) and Possible (4) cases were classified as True Positives. Using clinical adjudication, KT had a sensitivity of 98% (41/42) and specificity of 100% (14/14). The committee would have changed AM therapy 68% (27/40) of the time, had the KT results been available in real-time (~T52–100h). In 8/19 cases (42%) vancomycin would have been discontinued; in 6/27 cases (22%) and in 5/27 cases (19%), anaerobic coverage or antivirals would have been added earlier. Serial analysis of a Pneumocystis jirovecii infection indicated that earlier diagnosis and treatment may have prevented morbidity and eventual ICU transfer. Conclusion The absence of infectious etiology in NF often leads to broad AM therapy or delay of targeted treatment. Given its sensitivity and ability to detect a breadth of pathogens, the KT can provide useful data for diagnosis and management of NF and may allow for optimization of AM therapy. Disclosures H. Seng, Karius, Inc.: Employee, Salary. R. Aquino, Karius, Inc.: Employee, Salary. D. Hollemon, Karius: Employee, Salary. D. Hong, Karius, Inc.: Employee, Salary. T. Blauwkamp, Karius, Inc.: Board Member, Employee and Shareholder, Salary. M. Kertesz, Karius Inc.: Board Member, Employee and Shareholder, Salary. L. Blair, Karius: Employee, Salary. S. Zompi, Karius, Inc.: Employee, Salary.

Background Blood cultures (BC) fail to detect a pathogen in most patients with neutropenic fever (NF). We examined the performance of the Karius next generation sequencing plasma test (plasma NGS) compared with that of BC in chemotherapy-induced NF. Methods Patients 18 years or older with absolute neutrophil count 7 days were enrolled at the time of BC collection (T0) due to fever. Plasma samples were collected at T0 and twice weekly until neutrophil recovery or discharge. Samples were shipped to the Karius CLIA/CAP laboratory (Redwood City, CA) where cell-free plasma was prepared, DNA extracted, and NGS performed. After removing human reads, remaining sequences were aligned to a curated pathogen database. Organisms present at a significance- level above a predefined threshold were reported. T0 BC and plasma NGS results were compared, excluding organisms (eg, viruses) not recoverable by BC. Positive agreement was defined as plasma NGS identification of at least one isolate seen on BC. Plasma NGS+/BC- results underwent adjudication by 3 infectious diseases specialists. Diagnosis was Definite if microbiology confirmed NGS result within 7 days of enrollment; Probable if clinical, radiologic, and laboratory data were compatible with plasma NGS test result; and otherwise Indeterminate. Results The first 18 patients were evaluated. At the time of enrollment, 6 patients were on antibiotics and 3 were on antifungals. There were 4 positive BC (each monomicrobial) at T0 and all were concordant with plasma NGS. The plasma NGS test identified additional organisms in 2 of the BC+ patients with surgical abdomen. Compared with BC, plasma NGS positive agreement was 100% (4/4) with lack of agreement in 43% (6/14). All 8 NGS+/BC- cases were deemed Probable by adjudication. These included patients with single or mixed organisms in patients with enterocolitis or severe mucositis. In one sample, Aspergillus fumigatus was detected in a patient with new lung nodules. Conclusion The etiologic diagnosis of NF is frequently unknown, leading to broad antibiotics and sometimes delay of targeted treatment. Plasma NGS may provide useful data for managing NF given its ability to detect a breadth of pathogens even when patients are pretreated with antibiotics. Disclosures H. Seng, Karius, Inc: Employee, Salary; D. Hollemon, Karius, Inc: Employee, Salary; D. Hong, Karius, Inc.: Collaborator, Research support and Salary T. A. Blawkamp, Karius Inc.: Board Member and Employee, Salary; M. Kertesz, Karius Inc.: Board Member and Employee, Salary

Staphylococcus aureusbacteraemia (SAB) remains a complex disease with a high associated morbidity and mortality, especially when it is able to establish an occult nidus safe from antimicrobial eradication. Without rapid identification and intervention, the nidus can cause persistent relapse of disease, morbidity and mortality. Having a high clinical suspicion for the foci of occult S. aureus is important, and awareness of potential sites of infection is critical and can be life-saving.We present a unique case of a 65-year-old man with end-stage renal disease receiving haemodialysis who developed septic shock from SAB. Despite 18 days of appropriate antibiotics, the patient had persistent high-grade bacteraemia until his gall bladder was ultimately percutaneously drained. The day after drainage, he cleared his blood cultures, although he ultimately passed away as he decided to transition his care to focus on comfort measures.