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Background Isavuconazole (ISA) is an attractive candidate for primary mold-active prophylaxis in high-risk patients with hematologic malignancies or hematopoietic cell transplant (HCT) recipients. However, data supporting the use of ISA for primary prophylaxis in these patients are lacking. Methods We conducted a retrospective review of breakthrough invasive fungal infections (bIFIs) among adult hematologic malignancy patients and HCT recipients who received ≥7 days of ISA primary prophylaxis between 1 September 2016 and 30 September 2018. The incidence of bIFIs in patients receiving ISA was compared to those receiving posaconazole (POS) and voriconazole (VOR) during the same time period. Results One hundred forty-five patients received 197 courses of ISA prophylaxis. Twelve bIFIs (Aspergillus fumigatus [5], Aspergillus species [2], Mucorales [2], Fusarium species [2], and Candida glabrata [1]) occurred, representing 8.3% of patients and 6.1% of courses, after a median duration of 14 days of ISA prophylaxis. All bIFIs occurred during periods of neutropenia. Seven patients (58.3%) died within 42 days of onset of bIFI. In addition, bIFIs complicated 10.2% of ISA, 4.1% of POS, and 1.1% of VOR courses among patients with de novo or relapsed/refractory acute myeloid leukemia during the study period, with invasive pulmonary aspergillosis (IPA) complicating 6.8% of ISA, 1.3% of POS, and zero VOR courses. Conclusions Although ISA has been approved for treatment of invasive Aspergillus and mucormycosis, we observed an increased rate of bIFI, notably IPA, using ISA for primary prophylaxis. These results support the need for further study to determine the role of ISA as primary prophylaxis.

Respiratory virus infections in hematologic stem cell transplant recipients and patients with hematologic malignancies are increasingly recognized as a cause of significant morbidity and mortality. The often overlapping clinical presentation makes molecular diagnostic strategies imperative for rapid diagnosis and to inform understanding of the changing epidemiology of each of the respiratory viruses. Most respiratory virus infections are managed with supportive therapy, although there is effective antiviral therapy for influenza. The primary focus should remain on primary prevention infection control procedures and isolation precautions, avoidance of ill contacts, and vaccination for influenza.

Infection remains an important cause of non-relapse mortality in hematopoietic cell transplant (HCT) recipients. Specific risk for infection is related to prior exposure history (e.g., relapse of latent infection), intensity of the conditioning regimen, immunosuppressive agents utilized, and new exposures in the setting of altered host immune response. Prevention of infection by way of prophylactic and preemptive strategies has been associated with improvement in transplant outcomes over the past few decades.

Cryptococcus species can cause serious life-threatening infection in solid organ transplant recipients by reactivation of prior infection, posttransplant de novo infection, or donor transmission from the transplanted organ. Although previously reported in the literature, the extent of donor-derived cryptococcosis in the United States has not been documented. We analyzed potential donor-derived Cryptococcus transmission events reported to the Organ Procurement and Transplantation Network (OPTN) for investigation by the Ad Hoc Disease Transmission Advisory Committee (DTAC). All reports between 2009 and 2019 in which transmission to recipients was designated proven or probable, or determined to be averted due to implementation of prophylaxis (intervention without disease transmission-"IWDT") were included. During 2009-2019, 58 reports of potential donor-derived cryptococcosis were submitted to DTAC. Among these reports, 12 donors were determined to have resulted in proven or probable transmission to 23/34 (67.6%) recipients. Most of these donors (10/12 [83%]) exhibited central nervous system-related symptoms prior to death and 5/23 (22%) infected recipients died. For 11 different donors, prophylaxis, most often with fluconazole, was administered to 23/35 (65.7%) recipients. Clinicians should maintain awareness of donor-derived cryptococcosis and consider prompt prophylaxis or treatment followed by reporting to OPTN for further investigation.

Hepatitis B virus (HBV) can be transmitted from organ donor to recipient, but details of transmission events are not widely published. The Disease Transmission Advisory Committee (DTAC) evaluated 105 cases of potential donor derived transmission events of HBV between 2009-2017. Proven, probable or possible transmission of HBV occurred in 25 (23.8%) cases. Recipients of liver grafts were most commonly infected (20 of 21 exposed recipients) compared to 9 of 21 exposed non-hepatic recipients. Eleven of 25 donors were HBV core antibody (HBcAb) positive/HBV surface antigen (HBsAg) negative and infected 8/20 recipients. Of the 10 liver recipients and 1 liver-kidney recipient who received organs from these donors: six were not given antiviral prophylaxis, two developed infection after antiviral prophylaxis was discontinued, two developed HBV while on lamivudine prophylaxis, one was on antiviral prophylaxis and did not develop HBV viremia or antigenemia. One recipient of a HBcAb positive/HBsAg negative kidney developed active HBV infection. Unexpected donor-derived transmission of HBV was a rare event in reports to DTAC, but was often detected in the recipient late post-transplant. Six of 11 recipients (54.5%) of a liver from a HBcAb positive donor did not receive prophylaxis; all of these were potentially preventable with the use of anti-viral prophylaxis.

Purpose To provide an updated joint ASCO/Infectious Diseases Society of America (IDSA) guideline on antimicrobial prophylaxis for adult patients with immunosuppression associated with cancer and its treatment. Methods ASCO and IDSA convened an update Expert Panel and conducted a systematic review of relevant studies from May 2011 to November 2016. The guideline recommendations were based on the review of evidence by the Expert Panel. Results Six new or updated meta-analyses and six new primary studies were added to the updated systematic review. Recommendations Antibacterial and antifungal prophylaxis is recommended for patients who are at high risk of infection, including patients who are expected to have profound, protracted neutropenia, which is defined as < 100 neutrophils/µL for > 7 days or other risk factors. Herpes simplex virus–seropositive patients undergoing allogeneic hematopoietic stem-cell transplantation or leukemia induction therapy should receive nucleoside analog-based antiviral prophylaxis, such as acyclovir. Pneumocystis jirovecii prophylaxis is recommended for patients receiving chemotherapy regimens that are associated with a > 3.5% risk for pneumonia as a result of this organism (eg, those with ≥ 20 mg prednisone equivalents daily for ≥ 1 month or on the basis of purine analog usage). Treatment with a nucleoside reverse transcription inhibitor (eg, entecavir or tenofovir) is recommended for patients at high risk of hepatitis B virus reactivation. Recommendations for vaccination and avoidance of prolonged contact with environments that have high concentrations of airborne fungal spores are also provided within the updated guideline. Additional information is available at www.asco.org/supportive-care-guidelines .

Trimethoprim-sulfamethoxazole (TMP-SMX) is the first-line agent for Pneumocystis jiroveci pneumonia (PJP) prophylaxis for solid organ transplant (SOT) recipients because of its efficacy for this indication, extended antimicrobial coverage, and favorable cost. Reported sulfonamide allergy is not uncommon and often results in TMP-SMX avoidance. Desensitization offers an efficacious and cost-effective alternative to TMP-SMX avoidance. Herein, we reviewed our experience with desensitization during the index transplant hospitalization among 52 SOT recipients with history of a non-anaphylactic sulfonamide allergy. Of those enrolled in the desensitization protocol, 92% (48/52) completed the protocol, with nearly 80% (41/52) still on TMP-SMX at 3 months without adverse reaction. Eleven patients discontinued TMP-SMX (7 for allergic reactions and 4 for non-allergic reasons) and switched to pentamidine. A cost savings of $575 per desensitization was calculated based on annual wholesale drug prices, for a total savings of $23 575. Additionally, the protocol did not delay discharge in any patient nor was it associated with any severe allergic reactions. These findings suggest TMP-SMX desensitization is safe and effective in SOT recipients with a history of non-anaphylactic, non-life-threatening sulfonamide hypersensitivity.

Purpose To provide an updated joint ASCO/Infectious Diseases Society of American (IDSA) guideline on outpatient management of fever and neutropenia in patients with cancer. Methods ASCO and IDSA convened an Update Expert Panel and conducted a systematic review of relevant studies. The guideline recommendations were based on the review of evidence by the Expert Panel. Results Six new or updated meta-analyses and six new primary studies were added to the updated systematic review. Recommendation Clinical judgment is recommended when determining which patients are candidates for outpatient management, using clinical criteria or a validated tool such as the Multinational Association of Support Care in Cancer risk index. In addition, psychosocial and logistic considerations are outlined within the guideline. The panel continued to endorse consensus recommendations from the previous version of this guideline that patients with febrile neutropenia receive initial doses of empirical antibacterial therapy within 1 hour of triage and be monitored for ≥ 4 hours before discharge. An oral fluoroquinolone plus amoxicillin/clavulanate (or clindamycin, if penicillin allergic) is recommended as empirical outpatient therapy, unless fluoroquinolone prophylaxis was used before fever developed. Patients who do not defervesce after 2 to 3 days of an initial, empirical, broad-spectrum antibiotic regimen should be re-evaluated and considered as candidates for inpatient treatment. Additional information is available at www.asco.org/supportive-care-guidelines and www.asco.org/guidelineswiki .

Background In the United States, all deceased donors (DD) are evaluated for behavioral risk factors for human immunodeficiency virus (HIV), hepatitis B (HBV), and hepatitis C (HCV) infection during the past 12 months. DD with behavioral risk factors or hemodilution are designated as PHS increased risk donors (IRD). Since 2013, the number of IRD has increased from 13.4% of DD to 27% in 2018. Despite a low residual risk of disease transmission after a negative nucleic acid test for HIV/HBV/HCV, the considerable underutilization of IRD has driven an interest in revising the PHS IRD 2013 guidelines. The objective of this study was to describe the epidemiology of IRD with the goal of guiding policy change and maximize organ use. Methods This is a retrospective cohort study of DD during 2018. Characteristics of IRD were compared with non-IRD. A random 10% sample of IRD was selected for manual review of text narratives and donor questionnaires submitted by organ procurement organizations to determine specific PHS IRD factors. Categorical variables were compared using the χ 2 test and continuous variables were compared using a 2-sample t-test for independent samples. Results Among 10,721 DD in 2018, 2,904 were designated IRD (27.1%) with regional variability noted (Figure). Compared with non-IRD, IRD were younger (median age 35 vs. 45 years, P < 0.001) and more often died from drug intoxication (33.2 vs. 5.6%, P < 0.001). Hemodilution was found in 6.8% of all IRD and was the only factor for IRD designation in 60% of pediatric donors 3 criteria. Conclusion This study represents the most detailed description of PHS IRD factors since the adoption of the new guidelines in 2013. Understanding the prevalence of factors that lead to IRD designation will help inform future policy development, optimize safe DD use, and increase the number of transplants. Disclosures All Authors: No reported Disclosures.

Background Blood stream infection (BSI) during neutropenia is associated with high risk for morbidity and mortality in patients with hematologic malignancies receiving chemotherapy or undergoing hematopoietic cell transplant (HCT). We sought to identify factors associated with increased risk for critical illness (CI) morbidities within 7 days of BSI with index FN following chemotherapy. Methods A prospective ongoing survey among 14 high-volume US cancer centers submitting clinical and microbiologic data from consecutive HM patients with blood stream infection (BSI) during first FN after cytotoxic chemotherapy or HCT. We evaluated factors influencing poor outcomes defined as critical illness (need for pressor support, mechanical ventilation, new pneumonia or new BSI) within 7 days of BSI with index FN. Concordance between antibiotic and BSI isolate was determined by investigator (AZ, AF) interpretation of susceptibility reports provided by each center compared with the initial antimicrobial regimen (IAR) used, for single organism bacteremias only. Results Among 294 FN bacteremic episodes (93 HCT) were 336 bacterial pathogens (48.5% Gram-negative [GN], 46.5% Gram-positive [GP], and 6% anaerobes). Death occurred in 11/294 (4%) and 41/294 (14%) had CI by day 8. At FN presentation, mean MASCC score of those with CI vs. those without was 16.9 vs. 18.6 (P = 0.03) and there was a trend toward higher mean PITT scores for patients with CI by day 8 vs. those without (1.54 vs. 0.82 (P = 0.08)). Among GN bacteremias, 15% developed CI vs. 14.5% in nonviridans group Streptococci (VGS) GP bacteremias, and 10.9% in VGS bacteremias (NS). Among patients with single organism bacteremias (88% of all BSI), mismatch of IAR coverage with isolate susceptibilities occurred in 16.7% (38/227). Among patients whom IAR was active vs. inactive against BSI isolate, 16% vs 14.3%, respectively, developed CI (P = 0.81). Conclusion These data indicate that the MASCC score applied to high-risk inpatients may be a predictor for CI in the first week after bacteremia FN. The PITT shows less correlation with poor outcomes. There was no association between isolate type (GN, GP, or VGS) and CI. Notably there was no association between mismatched BSI susceptibility and antimicrobial spectrum of the IAR and early CI. Disclosures A. G. Freifeld, Merck: Investigator, Research grant. A. Zimmer, Merck: Investigator, Research grant. S. Pergam, Merck: Consultant, Consulting fee. Chimerix: Consultant, Consulting fee. K. V. Rolston, Merck: Investigator, Research grant. JMI Laboratories: Investigator, Research grant. Shionogi (Japan): Investigator, Research grant. S. Shoham, Merck: Investigator and Scientific Advisor, Consulting fee and Grant recipient. Astellas: Investigator, Grant recipient. Shionogi (Japan): Investigator, Grant recipient. Gilead: Investigator, Grant recipient. Shire: Investigator, Grant recipient. T. J. Walsh, Merck: Grant Investigator, Research grant. Atellas: Consultant, Grant Investigator and Scientific Advisor, Consulting fee and Research grant. Gilead: Scientific Advisor, Consulting fee. Allergan: Grant Investigator and Scientific Advisor, Consulting fee and Research grant. Scynexis: Grant Investigator, Research grant. Amplyx: Grant Investigator, Research grant. Shionogi: Scientific Advisor, Consulting fee. J. A. Young, GSK: Investigator, The University of Minnesota is reimbursed for contract costs associated with conducting clinical trials of vaccine. I receive no personal financial benefit. Y. Zhang, Merck: Investigator, Research grant. J. Meza, Merck: Investigator, Research grant.

Background Donor-derived toxoplasmosis (DDT) is a severe and potentially life-threatening infection after solid-organ transplantation (SOT). Serologic testing for Toxoplasma gondii is required for all deceased donors per OPTN policy as of 4/6/17. To assess the impact of universal donor testing and the optimal approach to DDT prevention, we analyzed potential DDT cases reviewed by DTAC. Methods All potential Toxoplasma donor-derived transmission events adjudicated by DTAC from 2008 to 2018 were reviewed. A standardized classification algorithm was used to adjudicate each event as proven, probable, possible, unlikely, excluded or intervention without disease transmission. Results Twenty-eight potential DDT events were reported between 2008 and 2018. Proven or probable (p/p) DDT developed in 16 organ recipients from 15 donors. In the 9 years prior to the new testing requirement (January 2008–March 2017) 11 organ recipients from 10 donors had p/p DDT (0.13 transmissions per 1,000 donors); in the first 21 months of the new testing requirement 5 recipients from 5 donors had p/p DDT (0.27 transmissions per 1,000 donors), rate ratio 2.15; 95% CI 0.577, 6.90;P = 0.18. 10.2% of 18,328 donors tested between April 6, 2017 and December 31, 2018 were Toxoplasma IgG seropositive. Recipient pre-SOT serostatus was unknown in 4 of 5 and negative in 1 case of p/p DDT. Trimethoprim/sulfamethoxazole prophylaxis was either stopped at < 3 months or not used in all 5 cases. Infection was diagnosed a median of 103 days (range 42–153) post-transplant. Four of the 5 recipients died. Conclusion DDT remains a morbid infection in both heart and non-heart recipients. Despite an apparent increase in DDT reporting to DTAC, it is unlikely that the actual incidence of this donor-derived event is increasing. Rather, with universal serologic screening of deceased donors and wider access to molecular diagnostics, DDT is increasingly recognized and diagnosed. To decrease risk for illness and death related to DDT, broader pre-transplant recipient serologic testing and use of prophylaxis or monitoring for high-risk serostatus recipients (Toxoplasma D+/R−) is critical. The optimal duration of prophylaxis is uncertain at this time and warrants further study. Disclosures All authors: No reported disclosures.

Clinical Practice Points Cunninghamella, a relatively infrequent cause of mucormycosis, is associated with aggressive and often fatal disseminated invasive fungal infection in hematopoietic stem cell transplant (HSCT) recipients, in particular those receiving high-dose immune suppression. Polyene-based antifungal agents, such as amphotericin B and its lipid derivatives, are first-line therapy for invasive mucormycosis. Despite currently available treatment approaches, the attributable mortality of mucormycosis remains very high. Our single-center experience suggests that infection with Cunninghamella species portends worse outcomes. The impact of prophylactic approaches (eg, with extended-spectrum azoles such as posaconazole) in preventing this infection in high-risk patients awaits further investigation.

Background Trimethoprim–sulfamethoxazole (TMP-SMX) is first-line for pneumocystis prophylaxis in solid organ transplant (SOT) recipients. TMP-SMX also offers the advantage of urinary tract infection (UTI) prophylaxis (for kidney recipients) and activity against other opportunistic infections. Alternatives for sulfa allergic patients are inferior from the standpoint of pneumocystis protection, activity against other opportunistic infections and cost. Methods In 2013, our SOT program adopted a system-wide protocol for TMP-SMX desensitization during the index transplant hospitalization. Patients with a historical non-anaphylactic allergy were exposed to increasing doses of TMP-SMX and monitored for allergic reaction. If tolerated, they received standard prophylaxis with TMP-SMX. We completed a retrospective chart review of all patients identified for desensitization. We performed a cost analysis to estimate cost savings associated with the protocol. Results Forty-three patients were identified and consented for the desensitization protocol. Thirty-eight (88%) were kidney recipients and the remainder were liver or heart recipients. See Figure 1 for pre-desensitization historical allergies. Thirty-six (84%) did not have an allergic reaction during desensitization; 33 ultimately completed 3 months of TMP-SMX prophylaxis; 7 had non-serious allergic or other reactions either during desensitization or before completing 3 months of prophylaxis (Figure 2). See Table 1 for details of reactions. Based off approximate average wholesale prices for 3 months of standard prophylaxis dosing of TMP-SMX ($65), pentamidine ($600) and nitrofurantoin ($220), we estimated a savings of $755 per kidney recipient, comparing TMP-SMX to an alternative of pentamidine and nitrofurantoin (for UTI prophylaxis for kidney recipients). Conclusion Systematic, protocol-driven TMP-SMX desensitization during index transplant hospitalization is safe and effective in SOT recipients, with resultant cost savings and broader spectrum coverage than second line agents. Table 1 Allergic responses n = 7 Occurred during protocol resulting in discontinuation 4 Occurred during index hospital stay 6 Resulted in higher acuity of care or prolonged admission 0 Hives 2 Other reaction 5 Disclosures L. Strasfeld, Merck: Independent Contractor, Salary

We report a case of disseminated Mycobacterium genavense with pulmonary nodules in a kidney transplant recipient and review the associated literature. Disease caused by M. genavense has been recognized in acquired immunodeficiency syndrome (AIDS) patients since 1990, with subsequent case reports in other immunocompromised host populations. In AIDS patients, pulmonary lesions are an uncommon finding. This is the first report to our knowledge of a human immunodeficiency virus (HIV)-negative patient with pulmonary nodules as a feature of disseminated M. genavense. Diagnosis of M. genavense is often challenging and frequently requires nucleic acid-based identification techniques. Because of limitations in culture and drug susceptibility testing, treatment regimens rely on reported clinical experience. This case report and literature review illustrates a successful approach to the diagnosis and treatment of disseminated M. genavense and summarizes the reports of M. genavense infection in HIV-negative patients.

To determine the predictive value of nasopharyngeal (NP) sample testing for respiratory viruses (RVs) in suspected lower respiratory tract disease, 72 paired NP and bronchoalveolar lavage (BAL) fluid specimen sets, mostly from transplant recipients or patients with hematologic malignancies, were analyzed. Overall, 31.3% of the specimens tested positive for an RV. In 19 sets (26.4%), the NP and BAL fluid specimens were both positive for an RV; in 3 sets (4.2%), the NP specimens were positive but the BAL fluid specimens were negative; and in 3 other sets, the NP specimens were negative but the BAL fluid specimens were positive. The positive and negative predictive values of the NP specimens were 86.4% and 94%, respectively.

Background The empiric initial antibiotic regimen (IAR) for treatment of febrile neutropenia (FN) relies on a knowledge of epidemiology and susceptibility patterns of bacterial bloodstream infections (BSI), especially in high-risk patient populations, i.e., those receiving chemotherapy for hematologic malignancies (HM) or undergoing hematopoietic stem cell transplant (HCT). As the last US national survey of BSI epidemiology in cancer patients was published in 2003, we sought to update these data focusing exclusively on high-risk patients with attention to IARs used and their concordance with susceptibilities of isolated bloodstream pathogens. Methods A prospective ongoing survey among 14 high-volume US cancer centers submitting clinical and microbiologic data from consecutive HM patients with BSI during first FN after cytotoxic chemotherapy or HCT. Concordance between antibiotic and BSI was determined by investigator (AZ, AF) interpretation of susceptibility reports provided by each center compared with IAR used, for single organism bacteremias only. Results Among 294 FN bacteremic episodes (93 HCT), there were 336 bacterial pathogens (48.5% Gram negative [GN] 46.5% Gram positive [GP] and 6% anaerobes), with 88% monomicrobial episodes. E. coli and viridans group Streptococci (VGS) were the most commonly isolated GN and GP, respectively, each accounting for nearly 25% of total organisms identified. IARs included cefepime 61%, piperacillin–tazobactam 24%, and meropenem 8%. Isolates were nonsusceptible to the IAR in 38/227 (17%) of FN episodes. Antibiotic mismatch was more likely to occur with a non-VGS GP (37%) vs. GN (13%) or VGS (2%) P < 0.001. Conclusion This is the first US national survey of high-risk BSI in FN. Although mismatch between BSI and IAR occurs in 17% of FN bacteremia episodes, this is driven primarily by non-VGS GP isolates such as CoNS and MRSA. Currently used IARs, comprised primarily of cefepime and piperacillin–tazobactam, generally provide reliable coverage for GN isolates across the United States (87%) but careful tracking of this rate is essential to identify further erosion of coverage in the current era of antimicrobial resistance. Disclosures A. Zimmer, Merck: Investigator, Research grant. A. G. Freifeld, Merck: Investigator, Research grant. S. Pergam, Merck: Consultant, Consulting fee; Chimerix: Consultant, Consulting fee. K. V. Rolston, Merck: Investigator, Research grant; JMI Laboratories: Investigator, Research grant; Shionogi (Japan): Investigator, Research grant. S. Shoham, Merck: Investigator and Scientific Advisor, Consulting fee and Grant recipient; Astellas: Investigator, Grant recipient; Shionogi (Japan): Investigator, Grant recipient; Gilead: Investigator, Grant recipient; Shire: Investigator, Grant recipient. T. J. Walsh, Merck: Grant Investigator, Research grant; Atellas: Consultant, Grant Investigator and Scientific Advisor, Consulting fee and Research grant; Gilead: Scientific Advisor, Consulting fee; Allergan: Grant Investigator and Scientific Advisor, Consulting fee and Research grant; Scynexis: Grant Investigator, Research grant; Amplyx: Grant Investigator, Research grant; Shionogi: Scientific Advisor, Consulting fee. J. A. Young, GSK: Investigator, The University of Minnesota is reimbursed for contract costs associated with conducting clinical trials of vaccine. I receive no personal financial benefit.. J. Meza, Merck: Investigator, Research grant. Y. Zhang, Merck: Investigator, Research grant.

Background Cryptococcosis is an important fungal complication of solid organ transplantation (SOT); cases occurring within 6 months posttransplant are often severe and sometimes donor derived. Morbidity can be related to delayed recognition of clinical symptoms or lack of communications among the SOT recipient centers. To better understand transmission of Cryptococcus (Crypto) and to identify opportunities for improved identification and communication, all potential donor-derived transmission events (PDDTE) of Crypto reported to OPTN/UNOS ad hoc Disease Transmission Advisory Committee (DTAC) over 10 years were analyzed. Methods All Crypto cases reported to DTAC between January 2008 and December 2017 were reviewed retrospectively as potential donor-derived transmission events (PDDTE). Likelihood of donor-derivation was adjudicated based on recipient and donor data. Results Fourty-six cases of Crypto were reported to DTAC during this period, involving 145 SOT recipients. Of the Proven or Probable donor-derived Crypto cases (n = 9), transmission occurred in 15 recipients; 2 donors each transmitted Crypto to 3 different recipients. Of the Possible cases, 9 recipients were affected. Six recipients with PDDTE Crypto died. Eight recipients received antifungal medications that would prevent transmission of Crypto (classified as intervention without disease transmission). UNOS Region 7 had the highest number donors with 10, with 6 and 7 from Regions 2 and 3, respectively. No cases C. gattii were reported; however, most of the reports to DTAC did not discriminate between C. neoformans and C. gattii. Conclusion This DTAC case series highlights both donor and recipient-derived cryptococcal infections and their potential to have devastating clinical impact. These data also highlight important delays in recognizing Crypto in SOT and in communicating these results to other centers when a PDDTE is possible. Transplant teams should have a high level of suspicion for Crypto in SOT, particularly in those with fever of unknown etiology, pulmonary infiltrates, headaches, and mental status changes. In the future, it may be helpful for transplant center to perform specific testing to discriminate between Cryptococcus species to understand their differential impact in SOT. Disclosures D. F. Florescu, Astellas: Grant Investigator, Grant recipient. C. R. Wolfe, Merck: Scientific Advisor, Consulting fee.

R.K. Avery, F.M. Marty, L. Strasfeld, I. Lee, A. Arrieta, S. Chou, W. Tatarowicz, S. Villano. Oral maribavir for treatment of refractory or resistant cytomegalovirus infections in transplant recipients. Transpl Infect Dis 2010: 12: 489–496. All rights reserved Background. Despite advances in cytomegalovirus (CMV) prophylaxis and therapy, some transplant recipients still develop refractory CMV infections. Maribavir (MBV), an investigational benzimidazole antiviral agent, acts by a mechanism different from that of existing anti-CMV drugs. Previous Phase I and II studies have demonstrated a favorable safety profile for MBV, but its utility in treatment of complex CMV syndromes is unknown. Methods. Between June and December 2008, MBV was released for use under individual emergency investigational new drug applications requested by treating physicians and approved by the US Food and Drug Administration and local institutional review boards. Six patients (5 solid organ transplant recipients and 1 hematopoietic stem cell transplant recipient) who had failed to respond to other therapies and/or had known ganciclovir-resistant CMV were treated with MBV at a starting oral dose of 400 mg twice daily. Results. Patients were treated for a median of 207 days (range, 15–376). Four of 6 patients had no detectable CMV DNAemia within 6 weeks of starting MBV therapy. One patient, who had an initial viral load of 1.8 million copies/mL, developed MBV resistance mutations. One patient, who had low serum levels of MBV, had persistent CMV DNAemia and viruria without developing genotypic or phenotypic resistance to MBV. One patient cleared CMV DNAemia, but died of pneumonia and multiorgan failure. No significant adverse effects attributable to MBV were observed. Conclusions. MBV deserves further systematic evaluation as treatment for CMV infection that is resistant and/or refractory to standard therapies, but its optimal dose, duration of therapy, and use in combinations versus as a single agent have yet to be determined.

The experimental cytomegalovirus UL97 kinase inhibitor maribavir was used to treat 2 cases of infection in which viral mutations that conferred ganciclovir and foscarnet resistance had evolved sequentially. In one case, viral shedding was cleared without evidence of maribavir resistance in an isolate obtained after therapy. In the other case, a high-grade viremia was initially reduced 50-fold but rebounded 2 months later, coincident with the emergence of viral UL97 mutations T409M and H411Y, which confer maribavir resistance. The relatively rapid onset of maribavir resistance probably resulted from incomplete viral suppression in an immunosuppressed host with a high viral load.

Infection is a major complication of hematopoietic cell transplantation. Prolonged neutropenia and graft-versus-host disease are the 2 major complications with an associated risk for infection, and these complications differ according to the graft source. A phase 3, multicenter, randomized trial (Blood and Marrow Transplant Clinical Trials Network [BMT CTN] 0201) of transplantation of bone marrow (BM) versus peripheral blood stem cells (PBSC) from unrelated donors showed no significant differences in 2-year survival between these graft sources. In an effort to provide data regarding whether BM or PBSC could be used as a preferential graft source for transplantation, we report a detailed analysis of the infectious complications for 2 years after transplantation from the BMT CTN 0201 trial. A total of 499 patients in this study had full audits of infection data. A total of 1347 infection episodes of moderate or greater severity were documented in 384 (77%) patients; 201 of 249 (81%) of the evaluable patients had received a BM graft and 183 of 250 (73%) had received a PBSC graft. Of 1347 infection episodes, 373 were severe and 123 were life-threatening and/or fatal; 710 (53%) of these episodes occurred on the BM arm and 637 (47%) on the PBSC arm, resulting in a 2-year cumulative incidence 84.7% (95% confidence interval [CI], 79.6 to 89.8) for BM versus 79.7% (95% CI, 73.9 to 85.5) for PBSC, P = .013. The majority of these episodes, 810 (60%), were due to bacteria, with a 2-year cumulative incidence of 72.1% and 62.9% in BM versus PBSC recipients, respectively (P = .003). The cumulative incidence of bloodstream bacterial infections during the first 100 days was 44.8% (95% CI, 38.5 to 51.1) for BM versus 35.0% (95% CI, 28.9 to 41.1) for PBSC (P = .027). The total infection density (number of infection events/100 patient days at risk) was .67 for BM and .60 for PBSC. The overall infection density for bacterial infections was .4 in both arms; for viral infections, it was .2 in both arms; and for fungal/parasitic infections, it was .04 and .05 for BM and PBSC, respectively. The cumulative incidence of infection before engraftment was 47.9% (95% CI, 41.5 to 53.9) for BM versus 32.8% (95% CI, 27.1 to 38.7) for PBSC (P = .002), possibly related to quicker neutrophil engraftment using PBSC. Infections remain frequent after unrelated donor hematopoietic cell transplantation, particularly after BM grafts.

Background Cytomegalovirus (CMV) infection continues to be a major cause of morbidity in kidney transplant recipients. The CMV donor-positive (D+)/recipient-negative (R−) serostatus pairing poses highest risk for CMV disease. Methods In September 2012, we adopted a CMV matching allocation policy at the centers served by our organ procurement organization, the Pacific Northwest Transplant Bank. CMV serostatus was used as a criterion in determining deceased donor kidney allocation, whereby R− kidney transplant recipients were preferentially paired with a D− organ, and R+ recipients with an R+ organ. We performed a retrospective analysis of CMV-related outcomes for 400 consecutive kidney recipients, 196 prior to (January 1, 2010– August 31, 2012) and 204 following (September 1, 2012–December 3, 2014) implementation of the CMV matching allocation schema at our center. We also looked at waitlist time for patients transplanted during the same period. Results The percentage of D+/R− transplants performed decreased from 17.3% to 2.5% (P Conclusion CMV disease occurred infrequently in our cohort, in the context of 6 months of valganciclovir prophylaxis post-transplant and post-prophylaxis pre-emptive monitoring strategy for our D+/R− recipients. Following implementation of an allocation schema that took CMV serostatus into account, the rate of CMV infection and antiviral treatment decreased significantly. Disclosures L. Strasfeld, Merck: Independent Contractor, Salary

Background Outcomes of CMV infection among HSCT recipients likely vary by patient population and treatment modality. However, data on these outcomes have been reported by relatively few centers. Methods This was a retrospective cohort study of allogenic HSCT recipients age ≥18 years at Oregon Health and Science University Hospital (OHSU) between 2010–2015. During the study period, OHSU standard practice was to preemptively treat CMV-viremic patients (quantitative PCR assay ≥ 200 copies/mL or consecutive PCR assays

Factors associated with serum HCV antibody, HCV RNA level, and HCV genotype were assessed in 557 current and former drug users. Additional assays included HIV antibody, CD4+ lymphocyte counts, HIV viral loads, and hepatitis B markers. Seventy-five percent of subjects were anti-HCV positive, of whom 75% had detectable HCV RNA (median, 5.04 x 10(5) IU/mL; range, 1020-15.7 x 10(6)). On multivariate analysis HCV seropositivity was associated with history of drug injection, HIV seropositivity, and increased age and inversely with drug snorting. Among anti-HCV-positive persons, detectable HCV RNA was independently associated with HIV seropositivity, male gender, and history of injection and inversely associated with hepatitis B surface antigen positivity. Among persons with detectable HCV RNA, higher levels were independently associated with higher HIV viral load, increased age, and genotypes 2a and 2b. These findings demonstrate an association of HCV RNA level with HIV viral load, independent of the level of immunosuppression. However, a substantial degree of the person-to-person variability in the prevalence and level of detectable HCV RNA remains unexplained.

Patients with prior invasive fungal infection (IFI) increasingly proceed to allogeneic hematopoietic cell transplantation (HSCT). However, little is known about the impact of prior IFI on survival. Patients with pre-transplant IFI (cases; n = 825) were compared with controls (n = 10247). A subset analysis assessed outcomes in leukemia patients pre-and post 2001. Cases were older with lower performance status (KPS), more advanced disease, higher likelihood of AML and having received cord blood, reduced intensity conditioning, mold-active fungal prophylaxis and more recently transplanted. Aspergillus spp. and Candida spp. were the most commonly identified pathogens. 68% of patients had primarily pulmonary involvement. Univariate and multivariable analysis demonstrated inferior PFS and overall survival (OS) for cases. At 2 years, cases had higher mortality and shorter PFS with significant increases in non-relapse mortality (NRM) but no difference in relapse. One year probability of post-HSCT IFI was 24% (cases) and 17% (control, P < 0.001). The predominant cause of death was underlying malignancy; infectious death was higher in cases (13% vs 9%). In the subset analysis, patients transplanted before 2001 had increased NRM with inferior OS and PFS compared with later cases. Pre-transplant IFI is associated with lower PFS and OS after allogeneic HSCT but significant survivorship was observed. Consequently, pre-transplant IFI should not be a contraindication to allogeneic HSCT in otherwise suitable candidates. Documented pre-transplant IFI is associated with lower PFS and OS after allogeneic HSCT. However, mortality post transplant is more influenced by advanced disease status than previous IFI. Pre-transplant IFI does not appear to be a contraindication to allogeneic HSCT.

Summary Background Available drugs against cytomegalovirus have adverse effects that compromise their prophylactic use in recipients of allogeneic stem-cell transplants. We assessed the safety, tolerability, and antiviral activity of oral maribavir in such patients. Methods In this placebo-controlled, randomised, double-blind, multicentre phase 3 study, we enrolled adult patients recipient-seropositive or donor-seropositive for cytomegalovirus who had undergone allogeneic stem-cell transplantation. Patients were recruited from 90 centres in Canada, Europe, and the USA. After engraftment, patients were stratified by recipient cytomegalovirus serostatus and conditioning regimen (myeloablative or reduced-intensity) and assigned (2:1) by masked computer-generated randomisation sequence to receive maribavir 100 mg twice daily or placebo for up to 12 weeks, with weekly blood cytomegalovirus surveillance. If the virus was detected, administration of study drug was stopped and pre-emptive anticytomegalovirus treatment started. The primary endpoint was cytomegalovirus disease within 6 months of transplantation. Analysis was by intention-to-treat. This study is registered with ClinicalTrials.gov, NCT00411645. Findings Between December, 2006, and May, 2008, 681 patients were enrolled and assigned to receive maribavir (454) or placebo (227). The incidence of cytomegalovirus disease within 6 months was 20 of 454 (4%) for the maribavir group and 11 of 227 (5%) for the placebo group (OR 0·90; 95% CI 0·42–1·92). During the 100 days following transplantation, cytomegalovirus infection rates as measured by pp65 antigenaemia were lower in the maribavir group (26·4%) than in the placebo group (34·8%; OR 0·67; 0·47–0·95), but not when measured by plasma cytomegalovirus DNA PCR (27·8% vs 30·4%; OR 0·88; 0·62–1·25), nor by initiation of treatment against cytomegalovirus (30·6% vs 37·4%; OR 0·73, 0·52–1·03). Maribavir was well tolerated: most adverse events, including incident acute graft-versus-host disease and neutropenia, affected both groups equally, except for taste disturbance (15% maribavir, 6% placebo). Interpretation Compared with placebo, maribavir prophylaxis did not prevent cytomegalovirus disease when started after engraftment. Cytomegalovirus disease as a primary endpoint might not be sufficient to show improvements in cytomegalovirus prevention in recipients of allogeneic stem-cell transplants in the setting of pre-emptive antiviral treatment. Clinical and virological composite endpoints should be used in future trials. Funding ViroPharma Incorporated.

Respiratory virus infections, such as influenza A, cause significant morbidity in hematopoietic stem cell transplantation (HSCT) recipients. The clinical characteristics and impact of infection with the novel H1N1 virus in this patient population is not yet well defined, however. HSCT recipients diagnosed with proven or probable H1N1 during the 2009 pandemic were identified and charts were retrospectively reviewed with analysis of clinical descriptions, risk factors, diagnosis, treatments, and outcomes. Twenty-seven patients from two medical centers were identified. Fever and cough were the most common presenting symptoms. The incidence of influenza lower respiratory tract infection (LRTI) was 52% (14/27). Compared with patients with LRTI, those with influenza upper respiratory tract infection (URTI) were more likely to have a classic influenza-like syndrome. Compared to patients with URTI, those with LRTI were started on antiviral therapy significantly later after symptom onset (3.0 days vs 6.58 days after onset of symptoms; P = .03; 95% confidence interval [CI], 0.29-6.8). Overall influenza-related 30-day mortality was 22% (6/27), and that in patients with LRTI was 43% (6/14). Chronic steroid use (≥20 mg/day of prednisone equivalent) at the time of presentation was associated with LRTI (P = .006) and mortality (P = .003) on univariate analysis. Five cases were hospital-acquired. In this first season of the novel H1N1 pandemic, infection in HSCT often presented as an atypical severe illness with a high incidence of LRTI and high mortality.

Antiviral drug resistance is an increasing concern in immunocompromised patient populations, where ongoing viral replication and prolonged drug exposure lead to the selection of resistant strains. Rapid diagnosis of resistance can be made by associating characteristic viral mutations with resistance to various drugs as determined by phenotypic assays. Management of drug resistance includes optimization of host factors and drug delivery, selection of alternative therapies based on knowledge of mechanisms of resistance, and the development of new antivirals. This article discusses drug resistance in herpesviruses and hepatitis B.

Solid organ transplant patients are susceptible to rare and unusual dermatoses as a result of their chronic immunosuppression. Trichodysplasia spinulosa (TS) is one such rare clinical entity observed predominantly in immunosuppressed patients with a history of either solid organ transplantation on immunosuppressive therapy or hematologic malignancies treated with chemotherapy. Herein we present 2 cases of TS that were successfully treated with compounded topical cidofovir.