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Background Individuals who are immunocompromised (IC) are at high risk for severe coronavirus disease 2019 (COVID-19). Methods Post hoc analyses of a double-blind trial conducted prior to Omicron (June 2020–April 2021), in hospitalized patients with COVID-19 assessed viral load, clinical outcomes, and safety of casirivimab plus imdevimab (CAS + IMD) versus placebo in IC versus overall study patients. Results Ninety-nine of 1940 (5.1%) patients were IC. IC versus overall patients were more frequently seronegative for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) antibodies (68.7% vs 41.2%) and had higher median baseline viral loads (7.21 vs 6.32 log10 copies/mL). On placebo, IC versus overall patients had slower viral load declines. CAS + IMD reduced viral load in IC and overall patients; least-squares mean difference versus placebo in time-weighted average change from baseline viral load at day 7 was −0.69 (95% confidence interval [CI], −1.25 to −.14) log10 copies/mL for IC patients and −0.31 (95% CI, −.42 to −.20) log10 copies/mL for overall patients. For IC patients, the cumulative incidence of death or mechanical ventilation at day 29 was lower with CAS + IMD (11.0%) versus placebo (17.2%), consistent with overall patients (15.7% CAS + IMD vs 18.3% placebo). IC and overall patients receiving CAS + IMD exhibited similar rates of treatment-emergent adverse events (30.4% and 26.6%, respectively), grade ≥2 hypersensitivity or infusion-related reactions (1.4% and 2.5%), and deaths (8.7% and 12.2%). Conclusions IC patients were more likely to exhibit high viral loads and be seronegative at baseline. For susceptible SARS-CoV-2 variants, CAS + IMD reduced viral load and resulted in fewer death or mechanical ventilation events in IC and overall study patients. There were no new safety findings among IC patients. Clinical Trials Registration. NCT04426695.

Background Pseudomonas aeruginosa (PA) readily acquires genomic mutations and exogenous genetic elements that confer antimicrobial resistance (AMR). With the rise in AMR, there are limited antibiotics available to treat multidrug-resistant (MDR) PA. As such, clinicians have returned to previously used antibiotics. Colistin, sidelined for neurotoxicity and nephrotoxicity, has returned to clinical practice as a viable but suboptimal option for MDR-PA treatment. The most common mechanism of resistance to colistin involves modifications of the lipid A moiety within the bacterial lipopolysaccharide (LPS). Following the identification of a MDR PA isolate, BWH047, we experimentally determined its colistin MIC to be > 1,280 µg/mL and used genomic approaches to identify novel genetic mechanisms of extreme colistin resistance. Methods We created a random, saturated transposon (Tn) insertion library in PA BWH047 using the Himar1 mariner system. After exposure of the library to 640 µg/mL colistin for 10 hours, genomic DNA was harvested, and the Tn insertion sites were sequenced. Insertion sequencing (INSeq) analysis was performed. We identified 27 genes conditionally important for BWH047 growth in the presence of colistin. We selected five initial targets arnC, dedA, wapH, speE2, and bchE and tested their impact on colistin resistance using standard microbroth dilution methods. Results Of our deletion mutants, three showed loss of resistance to colistin. ArnC was chosen as a positive control as its role in colistin resistance in PA is well described. Colistin MICs of BWH047 ΔarnC, ΔdedA, ΔwapH, ΔspeE2, and ΔbchE were determined to be 0.5, 0.5, 1, > 1,280 and > 1280 μg/mL, respectively. Conclusion Here, we used INSeq to identify novel genes involved in extreme colistin resistance. Thus far, we have identified two new candidate genes dedA and wapH, critical for colistin resistance in PA BWH047. Neither gene has been associated with colistin resistance in PA; However, dedA orthologs in Burkholderia thailandenesis and Klebsiella pneumoniae have been shown to be important for colistin resistance. The gene wapH is part of the LPS core oligosaccharide biosynthetic pathway and its discovery hints that additional alterations in the bacterial outer membrane may impact colistin resistance. Disclosures All Authors: No reported disclosures.

Background Cytomegalovirus (CMV) disease is associated with increased morbidity and mortality following solid organ and hematopoietic cell transplantation. Currently, standard of care CMV treatments often have significant myelosuppressive or renal toxicities. Given letermovir’s favorable safety profile when used prophylactically, it may be a safe and efficacious alternative agent for CMV treatment. Methods A proof-of-concept, open-label trial was conducted in patients who lacked effective therapeutic options or presented with baseline organ dysfunction. Participants were eligible for enrollment if they were ≥12 years old and had documented CMV infection refractory to treatment defined as failure to achieve >1 log reduction in CMV viral load (VL) (when VL > 500 IU/mL) or lack of clinical improvement for CMV end-organ disease after ≥14 days of standard CMV treatment. Alternatively, patients with severe myelosuppression and renal dysfunction at baseline or genotypic antiviral resistance were also eligible. Participants were excluded if their current CMV infection developed while receiving letermovir for CMV prophylaxis. Letermovir was administered daily (480 mg PO/IV) for up to 12 weeks, with optional additional 12 weeks of treatment for secondary prophylaxis if clinically indicated. Results Ten patients met eligibility criteria and were enrolled. Reasons for enrollment included ganciclovir resistance (1/10), refractory CMV infection (6/10), renal dysfunction (7/10), and myelosuppression (7/10). The median baseline CMV VL was 1272 IU/ml [interquartile range (IQR); 925, 2546]. Six patients completed the study, three died due to complications of primary disease, and one discontinued due to diarrhea. Five patients (50%) had documented CMV viremia clearance, with a median time to first unquantifiable/undetectable CMV VL of 13 days [IQR; 9,18] and a median treatment duration of 53 days [IQR; 15,84]. Infections and GI disorders were the most common adverse events (AE), none considered related to study drug. No unexpected AE were observed during letermovir treatment. Conclusion Letermovir may be a safe and tolerable alternative for patients with treatment refractory CMV infection or for patients with severe baseline myelosuppression and renal dysfunction. Disclosures Matthew Cheng, MD, AstraZeneca: Honoraria|Cidara Therapeutics: Grant/Research Support|Scynexis Inc.: Grant/Research Support Sandra Burchett, MD, MSc, merck: Grant/Research Support Sarah P. Hammond, MD, F2G: Advisor/Consultant|F2G: Grant/Research Support|GSK: Grant/Research Support|Merck: Grant/Research Support|pfizer: Advisor/Consultant|Scynexis: Grant/Research Support Nicolas C. Issa, MD, AiCuris: Grant/Research Support|Merck: Grant/Research Support Francisco M. Marty, MD, SM, AlloVir: Advisor/Consultant|Amplyx: Advisor/Consultant|Amplyx: Grant/Research Support|Ansun: Grant/Research Support|Avir: Advisor/Consultant|Chimerix: Grant/Research Support|Cidara: Grant/Research Support|F2G: Advisor/Consultant|F2G: Grant/Research Support|Gilead: Grant/Research Support|Janssen: Advisor/Consultant|Kyorin: Advisor/Consultant|Merck: Advisor/Consultant|Merck: Grant/Research Support|Regeneron: Advisor/Consultant|Regeneron: Grant/Research Support|ReViral: Advisor/Consultant|Scynexis: Grant/Research Support|Symbio: Advisor/Consultant|Takeda: Grant/Research Support|United Medical: Advisor/Consultant|WHISCO: Grant/Research Support.

Background There are no antiviral therapies for parainfluenza virus (PIV) infections. DAS181, a sialidase fusion protein, has demonstrated activity in in vitro and in animal models of PIV. Methods Adult immunocompromised patients diagnosed with PIV lower respiratory tract infection (LRTI) who required oxygen supplementation were randomized 2:1 to nebulized DAS181 (4.5 mg/day) or matching placebo for up to 10 days. Randomization was stratified by need for mechanical ventilation (MV) or supplemental oxygen (SO). The primary endpoint was the proportion of patients reaching clinical stability survival (CSS) defined as returning to room air (RTRA), normalization of vital signs for at least 24 hours, and survival up to day 45 from enrollment. Results A total of 111 patients were randomized to DAS181 (n = 74) or placebo (n = 37). CSS was achieved by 45.0% DAS181-treated patients in the SO stratum compared with 31.0% for placebo (P = .15), whereas patients on MV had no benefit from DAS181. The proportion of patients achieving RTRA was numerically higher for SO stratum DAS181 patients (51.7%) compared with placebo (34.5%) at day 28 (P = .17). In a post hoc analysis of solid organ transplant, hematopoietic cell transplantation within 1 year, or chemotherapy within 1 year, more SO stratum patients achieved RTRA on DAS181 (51.8%) compared with placebo (15.8%) by day 28 (P = .012). Conclusions The primary endpoint was not met, but post hoc analysis of the RTRA component suggests DAS181 may have clinical activity in improving oxygenation in select severely immunocompromised patients with PIV LRTI who are not on mechanical ventilation. Clinical Trials Registration. NCT01644877., Immunocompromised adults with severe parainfluenza received nebulized DAS181 or placebo for up to 10 days. The primary endpoint was not met, but a subgroup of severely immunocompromised patients experienced a faster return to room air by day 28 (P = .012).

Clarithromycin (CYP inhibitor) can be used instead of azithromycin for nontuberculous mycobacteria therapy in patients requiring CYP substrates to mitigate rifampin’s CYP induction. We found no differences in adverse events (10/13 vs 14/17; P = .73), drug intolerability (1/5 vs 4/11; P = 1), or 90-day mortality (0/13 vs 1/17; P = 1) in patients receiving clarithromycin vs azithromycin.

BackgroundAntimicrobial resistance (AMR) is a major challenge in the treatment of infections caused by Pseudomonas aeruginosa. Highly drug-resistant infections are disproportionally caused by a small subset of globally distributed P. aeruginosa sequence types (STs), termed “high-risk clones.” We noted that clonal complex (CC) 446 (which includes STs 298 and 446) isolates were repeatedly cultured at 1 medical center and asked whether this lineage might constitute an emerging high-risk clone.MethodsWe searched P. aeruginosa genomes from collections available from several institutions and from a public database for the presence of CC446 isolates. We determined antibacterial susceptibility using microbroth dilution and examined genome sequences to characterize the population structure of CC446 and investigate the genetic basis of AMR.ResultsCC446 was globally distributed over 5 continents. CC446 isolates demonstrated high rates of AMR, with 51.9% (28/54) being multidrug-resistant (MDR) and 53.6% of these (15/28) being extensively drug-resistant (XDR). Phylogenetic analysis revealed that most MDR/XDR isolates belonged to a subclade of ST298 (designated ST298*) of which 100% (21/21) were MDR and 61.9% (13/21) were XDR. XDR ST298* was identified repeatedly and consistently at a single academic medical center from 2001 through 2017. These isolates harbored a large plasmid that carries a novel antibiotic resistance integron.ConclusionsCC446 isolates are globally distributed with multiple occurrences of high AMR. The subclade ST298* is responsible for a prolonged epidemic (≥16 years) of XDR infections at an academic medical center. These findings indicate that CC446 is an emerging high-risk clone deserving further surveillance.

Background Liver tumours observed in rats exposed to micafungin led to a black box warning upon approval in Europe in 2008. Micafungin’s risk for liver carcinogenicity in humans has not been investigated. We sought to describe the risk of fatal hepatocellular carcinoma (HCC) among persons who received micafungin and other parenteral antifungals (PAFs) with up to 12 years of follow-up. Methods We assembled a US multicentre cohort of hospitalized patients who received micafungin or other PAFs between 2005 and 2012. We used propensity score (PS) matching on patient characteristics from electronic medical records to compare rates of HCC mortality identified through the National Death Index though to the end of December 2016. We computed HRs and 95% CIs. Results A total of 40110 patients who received a PAF were identified; 6903 micafungin recipients (87% of those identified) were successfully matched to 16317 comparator PAF users. Ten incident HCC deaths, one in the micafungin-exposed group and nine among comparator PAF users, occurred in 71285 person-years of follow-up. The HCC mortality rate was 0.05 per 1000 person-years in micafungin patients and 0.17 per 1000 person-years in comparator PAF patients. The PS-matched HR for micafungin versus comparator PAF was 0.29 (95% CI 0.04–2.24). Conclusions Both micafungin and comparator PAFs were associated with HCC mortality rates of

Background Candida albicans is the predominant organism causing esophageal candidiasis (EC) and oropharyngel candidiasis (OPC). These infections may arise from subjects colonized with Candida who are predisposed due to illness, debility or a local reduction in host resistance to an overgrowth of their own indigenous flora. Patients with mucocutaneous Candida infections can be treated in the outpatient setting, yet there are limited oral treatment options available for patients who are unresponsive to or who are intolerant to currently available antifungals. Oral ibrexafungerp is an investigational broad-spectrum glucan synthase inhibitor antifungal with activity against Candida species, including azole- and echinocandin-resistant strains. A Phase 3 open-label, single-arm study of ibrexafungerp (FURI; NCT03059992) is ongoing for the treatment of patients intolerant of or with fungal disease refractory to standard antifungal therapy. Table 1. FURI Outcomes in OPC and EC Methods FURI subjects were eligible for enrollment if they had proven or probable severe mucocutaneous candidiasis, invasive candidiasis, invasive aspergillosis, or other fungal diseases with evidence of treatment failure, intolerance, or toxicity related to a currently approved standard-of-care antifungal treatment or if they were unable to receive an approved oral antifungal option (e.g., susceptibility of the organism) and a continued IV antifungal therapy was clinically undesirable or unfeasible. Results An independent Data Review Committee (DRC) provided an assessment of treatment response for 74 subjects enrolled in the FURI study from 22 centers in US, UK and EU treated with ibrexafungerp for mucocutaneous or invasive fungal infections from 2016- 2020. A total 32 subjects (43.2%) had mucocutaneous candidiasis and 24 subjects were diagnosed with OPC or EC. The percent of patients who were determined to have a complete response (CR) or partial response (PR) was 62.5%, stable disease (SD), 20.8%, and progression of disease, 16.7%. Table 1 shows outcomes by EC and OPC as determined by the DRC. Conclusion Analysis of 24 EC and OPC patients from the FURI study indicates that oral ibrexafungerp provides a favorable therapeutic response in patients with challenging mucocutaneous fungal disease and limited treatment options. Disclosures Oliver Cornely, Prof., Actelion (Consultant, Grant/Research Support)Al-Jazeera Pharmaceuticals (Consultant)Allecra Therapeutics (Consultant)Amplyx (Consultant, Grant/Research Support)Astellas (Consultant, Grant/Research Support)Basilea (Consultant, Grant/Research Support)Biocon (Consultant)Biosys (Consultant)Cidara (Consultant, Grant/Research Support)CoRe Consulting (Consultant)Da Volterra (Consultant, Grant/Research Support)DFG (German Research Foundation) (Grant/Research Support)Entasis (Consultant)F2G (Consultant, Grant/Research Support)German Federal Ministry of Research and Education (Grant/Research Support)Gilead (Consultant, Grant/Research Support)Grupo Biotoscana (Consultant)Immunic (Grant/Research Support)IQVIA (Consultant)Janssen (Grant/Research Support)Matinas (Consultant)Medicines Company (Grant/Research Support)MedPace (Consultant, Grant/Research Support)Melinta Therapeutics (Grant/Research Support)Menarini (Consultant)Merck/MSD (Consultant, Grant/Research Support)Molecular Partners (Consultant)MSG-ERC (Consultant)Mylan (Consultant)Nabriva (Consultant)Noxxon (Consultant)Octapharma (Consultant)Paratek (Consultant)Pfizer (Consultant, Grant/Research Support)PSI (Consultant)Roche Diagnostics (Consultant)Scynexis (Consultant, Grant/Research Support)Seres (Consultant)Shionogi (Consultant)Wiley (Blackwell) (Other Financial or Material Support) Philipp Koehler, MD, Ambu GmbH (Consultant, Speaker’s Bureau)Astellas Pharma (Speaker’s Bureau)Euopean Confederation of Medical Mycology (Speaker’s Bureau)German Federal Ministry of Research and Education (Grant/Research Support)Gilead (Consultant, Speaker’s Bureau)MSD (Speaker’s Bureau)Noxxon N.V. (Consultant)Pfizer (Speaker’s Bureau)State of North Rhine-Westphalia, Germany (Grant/Research Support) Riina Rautemaa-Richardson, DDS, PhD, FRCPath, SCYNEXIS, Inc. (Scientific Research Study Investigator) G. Marshall Lyon, MD, SCYNEXIS, Inc. (Scientific Research Study Investigator) Francisco M. Marty, MD, SCYNEXIS, Inc. (Scientific Research Study Investigator) Rachel Miller, MD, SCYNEXIS, Inc. (Scientific Research Study Investigator) Thomas J. Walsh, MD, PhD (hon), Scynexis (Consultant, Grant/Research Support)Shionogi (Consultant, Grant/Research Support) Peter Pappas, MD, Astellas (Grant/Research Support)Cidara (Grant/Research Support, Advisor or Review Panel member)Mayne (Grant/Research Support, Advisor or Review Panel member)Merck (Grant/Research Support)SCYNEXIS, Inc. (Consultant, Grant/Research Support) Todd P. McCarty, MD, Cidara (Grant/Research Support)GenMark (Grant/Research Support, Other Financial or Material Support, Honoraria for Research Presentation)T2 Biosystems (Consultant) Caryn Morse, MD, Chimerix (Scientific Research Study Investigator)Covis Pharma (Scientific Research Study Investigator)Gilead Sciences Inc. (Scientific Research Study Investigator)Ridgeback Biotherapeutics (Scientific Research Study Investigator)Roche (Scientific Research Study Investigator)SCYNEXIS, Inc. (Scientific Research Study Investigator)Theratechnologies (Advisor or Review Panel member)Viiv (Advisor or Review Panel member) Luis Ostrosky-Zeichner, MD, Amplyx (Consultant)Cidara (Consultant)F2G (Consultant)Gilead (Grant/Research Support, Speaker’s Bureau)Pfizer (Scientific Research Study Investigator, Speaker’s Bureau)Scynexis (Grant/Research Support, Scientific Research Study Investigator)Viracor (Consultant) Jürgen Prattes, Dr, AbbVie Inc. (Shareholder)Gilead (Speaker’s Bureau)MSD (Grant/Research Support)Novo Nordisk (Shareholder)Pfizer (Advisor or Review Panel member)Stryker (Shareholder) Andrej Spec, MD, MSCI, SCYNEXIS, Inc. (Consultant, Scientific Research Study Investigator) David Andes, MD, SCYNEXIS, Inc. (Scientific Research Study Investigator) Oliver Witzke, MD, SCYNEXIS, Inc. (Scientific Research Study Investigator) Nkechi Azie, MD, SCYNEXIS, Inc. (Employee, Shareholder) David A. Angulo, MD, SCYNEXIS, Inc. (Employee, Shareholder)

Background Omadacycline is an aminomethylcycline antimicrobial approved by the US Food and Drug Administration in 2018 for community-acquired bacterial pneumonia and acute bacterial skin and skin structure infections. It has in vitro activity against nontuberculous mycobacteria, including Mycobacterium abscessus complex, but clinical data for this indication are lacking. Methods Omadacycline use was reviewed at an 804-bed academic medical center. Patients were included if they received omadacycline for culture-proven M abscessus disease in 2019. Results Four patients received omadacycline for the treatment of culture-positive M abscessus disease in 2019. Two patients had cutaneous disease, 1 had pulmonary disease, and 1 had osteomyelitis and bacteremia. The patients received omadacycline for a median duration of 166 days (range, 104–227) along with a combination of other antimicrobial agents. Omadacycline-containing regimens were associated with a clinical cure in 3 of 4 patients, with 1 patient improving on ongoing treatment. Omadacycline’s tolerability was acceptable for patients with M abscessus disease, with 1 patient discontinuing therapy in month 6 due to nausea. Conclusions Omadacycline is a novel oral option for the treatment of M abscessus disease, for which safe and effective options are needed. Although this case series is promising, further data are required to determine omadacycline’s definitive role in the treatment of M abscessus disease.

We report a case of fulminant Acanthamoeba castellanii encephalitis in a patient with chronic lymphocytic leukemia treated with ibrutinib. The unusually rapid neurologic decline and fatal outcome observed are probably related to alterations in immunologic function associated with inhibition of Bruton tyrosine kinase.

In this multicenter, dose-ranging study of maribavir for the treatment of cytomegalovirus (CMV) infections deemed refractory or resistant to current antivirals, 67% of patients achieved clearance of CMV viremia within 6 weeks, with responses maintained for up to 24 weeks., Background Cytomegalovirus (CMV) infections that are refractory or resistant (RR) to available antivirals ([val]ganciclovir, foscarnet, cidofovir) are associated with higher mortality in transplant patients. Maribavir is active against RR CMV strains. Methods Hematopoietic-cell or solid-organ transplant recipients ≥12 years old with RR CMV infections and plasma CMV deoxyribonucleic acid (DNA) ≥1000 copies/mL were randomized (1:1:1) to twice-daily dose-blinded maribavir 400, 800, or 1200 mg for up to 24 weeks. The primary efficacy endpoint was the proportion of patients with confirmed undetectable plasma CMV DNA within 6 weeks of treatment. Safety analyses included the frequency and severity of treatment-emergent adverse events (TEAEs). Results From July 2012 to December 2014, 120 patients were randomized and treated (40 per dose group): 80/120 (67%) patients achieved undetectable CMV DNA within 6 weeks of treatment (95% confidence interval, 57–75%), with rates of 70%, 63%, and 68%, respectively, for maribavir 400, 800, and 1200 mg twice daily. Recurrent on-treatment CMV infections occurred in 25 patients; 13 developed mutations conferring maribavir resistance. Maribavir was discontinued due to adverse events in 41/120 (34%) patients, and 17/41 discontinued due to CMV infections. During the study, 32 (27%) patients died, 4 due to CMV disease. Dysgeusia was the most common TEAE (78/120; 65%) and led to maribavir discontinuation in 1 patient. Absolute neutrophil counts

Background Remdesivir (RDV) shortens time to recovery time in patients with severe COVID-19. Its effect in patients with moderate COVID-19 remains unclear. Methods We conducted an open-label, phase 3 trial (NCT04252664) involving hospitalized patients with confirmed SARS-CoV-2 infection, evidence of pulmonary infiltrates, and oxygen saturation >94% on room air. Patients were randomly assigned 1:1:1 to receive up to 5d or 10d of RDV with standard of care (SoC), or SoC alone; patients could be discharged prior to completing per-protocol assigned treatment duration. RDV was dosed intravenously at 200 mg on d1, 100 mg daily thereafter. Patients were evaluated daily while hospitalized, and via telephone if discharged. The primary endpoint was clinical status on d11 assessed on a 7-point ordinal scale. Results regarding the primary endpoint are expected to be published before IDWeek 2020; we plan to present d28 results at the meeting. Results In total, 584 patients underwent randomization and started their assigned treatment (191, 5d RDV; 193, 10d RDV; 200, SoC). By d11, ³ 2 point improvement on the ordinal scale occurred in 70% of patients in the 5d arm, 65% in the 10d arm, and 61% in the SoC arm. Patients in the 5d RDV arm were significantly more likely to have an improvement in clinical status than those receiving SoC (odds ratio [OR], 1.65; 95% confidence interval [CI], 1.09–2.48; P=0.017); OR of improvement for the 10d RDV arm compared to SoC was 1.31 (95% CI, 0.88–1.95]; p=0.183). This improvement in the 5-day arm over the SOC arm was noted from d6 through d11. We observed a peak of discharges corresponding with the assigned treatment duration of RDV, with increased discharges at d6 in the 5-day arm and at d11 in the 10-day arm. A worsening of clinical status of ≥ 1 point in the ordinal scale was observed more commonly in the SoC am (n=19, 10%) versus the 5d RDV (n=7, 4%) and 10d RDV (n=9, 5%). Conclusion RDV for up to 5 days was superior to SoC in improving the clinical status of patients with moderate COVID-19 by d11. We will report d28 outcomes at the meeting. Disclosures Francisco M. Marty, MD, Allovir (Consultant)Amplyx (Consultant)Ansun (Scientific Research Study Investigator)Avir (Consultant)Cidara (Scientific Research Study Investigator)F2G (Consultant, Scientific Research Study Investigator)Kyorin (Consultant)Merck (Consultant, Grant/Research Support, Scientific Research Study Investigator)New England Journal of Medicine (Other Financial or Material Support, Honorarium for Video)Regeneron (Consultant, Scientific Research Study Investigator)ReViral (Consultant)Scynexis (Scientific Research Study Investigator)Symbio (Consultant)Takeda (Scientific Research Study Investigator)United Medical (Consultant)WHISCON (Scientific Research Study Investigator) Prashant Malhotra, MD, Gilead Sciences Inc. (Scientific Research Study Investigator) Robert L. Gottlieb, MD, Gilead Sciences Inc. (Scientific Research Study Investigator) Karen T. Tashima, MD, Bristol-Myers Squibb (Research Grant or Support)Gilead Sciences Inc. (Grant/Research Support, Scientific Research Study Investigator)GlaxoSmithKline (Research Grant or Support)Merck (Research Grant or Support)Tibotec (Research Grant or Support)Viiv Healthcare (Research Grant or Support) Massimo Galli, MD, Gilead Sciences Inc. (Grant/Research Support, Scientific Research Study Investigator, Advisor or Review Panel member, Other Financial or Material Support, Personal fees) Louis Yi Ann Chai, MD, Gilead Sciences Inc. (Scientific Research Study Investigator) Devi SenGupta, MD, Gilead Sciences Inc. (Employee, Shareholder) Robert H. Hyland, MD, Gilead Sciences Inc. (Employee, Shareholder) Hongyuan Wang, PhD, Gilead Sciences Inc. (Employee, Shareholder) Lijie Zhong, PhD, Gilead Sciences Inc. (Employee, Shareholder) Huyen Cao, MD, Gilead Sciences Inc. (Employee, Shareholder) Anand Chokkalingam, PhD, Gilead Sciences (Employee) Anu Osinusi, MD, Gilead Sciences (Employee) Diana M. Brainard, MD, Gilead Sciences (Employee) Michael Brown, MD, Gilead Sciences Inc. (Scientific Research Study Investigator) Ane Josune Goikoetxea, MD, Gilead Sciences Inc. (Scientific Research Study Investigator) Mamta Jain, MD, Gilead Sciences Inc. (Scientific Research Study Investigator, Research Grant or Support)GlaxoSmithKline (Advisor or Review Panel member)Janssen (Research Grant or Support)Merck (Research Grant or Support) David Shu Cheong Hui, MD, Gilead Sciences Inc. (Scientific Research Study Investigator) Enos Bernasconi, MD, Gilead Sciences Inc. (Scientific Research Study Investigator) Christoph Spinner, MD, AbbVie (Advisor or Review Panel member, Other Financial or Material Support, Travel)Bristol-Myers Squibb (Grant/Research Support, Advisor or Review Panel member, Other Financial or Material Support, Travel)Gilead Sciences Inc. (Grant/Research Support, Scientific Research Study Investigator, Advisor or Review Panel member, Other Financial or Material Support, Travel)Janssen (Grant/Research Support, Advisor or Review Panel member, Other Financial or Material Support, Travel)MSD (Grant/Research Support, Advisor or Review Panel member, Other Financial or Material Support, Travel)Viiv Healthcare (Grant/Research Support, Advisor or Review Panel member, Other Financial or Material Support, Travel)

Background Rhinosinusitis, malignant otitis externa, and skull base osteomyelitis represent a spectrum of cranial invasive fungal disease (IFD). These syndromes have distinct characteristics, yet they may progress to involve similar structures, resulting in inflammation and invasion of the adjacent internal carotid artery (ICA). Invasive fungal carotiditis can have devastating consequences, including cerebral infarction, subarachnoid hemorrhage, and death. Methods We retrospectively studied all patients diagnosed with cranial IFD and carotid involvement at our institution from 2003 to 2018. We also searched Medline/PubMed for reports of Aspergillus or Mucorales cranial infections with ICA involvement. All cases with mycologic evidence of cranial IFD and radiographic or pathologic evidence of ICA involvement were included. Results We identified 78 cases of invasive fungal carotiditis between 1958 and 2018, including 4 cases at our own institution. Forty-one were caused by Aspergillus and 37 by Mucorales species. Presenting symptoms included vision changes (73%), cranial nerve palsy (69%), and headache (42%). Carotid events included occlusion, aneurysm formation, and vessel rupture. Cerebral infarcts occurred in 50% of cases. Mortality at 6 weeks, 12 weeks, and 2 years was 27%, 41%, and 71% respectively. The median time from symptom onset to death was 150 days for cases due to Aspergillus and 51 days for cases due to Mucorales species. Conclusions Invasive fungal carotiditis is a rare but morbid manifestation of cranial IFD. Early suspicion of IFD and administration of antifungal treatment, vascular imaging, and endovascular interventions should be considered to reduce the high mortality of this disease.

Background Although echinocandins are generally well tolerated, there is little information on the frequency with which renal and hepatic adverse effects occur during use of micafungin or other parenteral antifungal (PAF) agents in clinical practice. Methods MYCOS is a multicentre cohort study of adult and paediatric patients who received micafungin or other PAFs between 2005 and 2012 at seven tertiary care hospitals from six centres in the USA. PAF cohort controls were selected through propensity score (PS) matching to micafungin recipients using clinical characteristics, other treatments, procedures and hospital service where PAF treatment was initiated. Analysis was restricted to patients without chronic liver and kidney conditions at the time of cohort entry. Treatment-emergent hepatic and renal injury was documented by changes in liver enzymes or estimated glomerular filtration rate through 30 days following completion of PAF treatment. Comparisons were quantified using the HR from a proportional hazards analysis. Results There were 2970 micafungin recipients PS matched to 6726 recipients of comparator PAFs. Balance was achieved in all baseline covariates between treatment groups. There were similar rates of hepatic injury (micafungin, 13 events per 100 patients and other PAF, 12 per 100; HR = 0.99; 95% CI 0.86-1.14) and lower rates of renal injury (micafungin, 63 events per 100 patients and other PAF, 65 per 100; HR = 0.93; 95% CI 0.87-0.99) for micafungin recipients versus PAF comparators. Conclusion For a wide spectrum of underlying conditions, we observed no increase in liver injury by micafungin and possibly a reduced risk of renal dysfunction in comparison with other PAF medications.

Face transplantation was performed in a highly sensitized recipient with positive preoperative crossmatch and subsequent antibody-mediated rejection. The recipient was a 45-year-old female with extensive conventional reconstructions after chemical burns over the majority of the body. Residual quality of life and facial functions were poor. Levels of circulating anti-human leukocyte antigen (HLA) antibodies were high, and panel reactive antibody score was 98%. A potential donor was identified; however, with positive T and B cell flow crossmatches. The transplant team proceeded with face transplantation from this donor, under tailored immune suppression and with available salvage options. The operation was successful. Plasmapheresis and induction immune suppression (i.e., thymoglobulin followed by mycophenolate mofetil, tacrolimus, and steroids) were provided. Five days later, there was significant facial swelling, rising anti-HLA antibody titers, and unprecedented evidence of C4d deposits on skin. High doses of steroids and thymoglobulin were provided; however, rejection increased such that by day 19 it was diagnosed grade III in the BANFF scale. After stopping thymoglobulin because of serum sickness, combination therapy of plasmapheresis, eculizumab, bortezomib, and alemtuzumab was provided. HLA antibody levels decreased while swelling and redness improved. At 3 months, there were no longer signs of rejection on biopsy.

Background Candida infections resistant to currently available antifungals are an emerging global threat. Ibrexafungerp is an investigational broad-spectrum glucan synthase inhibitor antifungal with activity against Candida and Aspergillus species, including azole- and echinocandin-resistant strains. A Phase 3 open-label, single-arm study of oral ibrexafungerp (FURI) (Clinicaltrials.gov NCT03059992) is ongoing for the treatment of patients (≥18 years) with fungal diseases who are intolerant of or refractory to standard antifungal therapies. Methods An independent Data Review Committee (DRC) provided an assessment of treatment response for 41 patients. Patients were enrolled in 22 centers from 6 countries. Patients were eligible for enrollment if they had proven or probable, invasive or severe mucocutaneous candidiasis and documented evidence of failure of, intolerance to, or toxicity related to a currently approved standard-of-care antifungal treatment or could not receive approved oral antifungal options (e.g., susceptibility of the organism) and a continued IV antifungal therapy was undesirable or unfeasible. Results The 41 patients assessed had the following infection types: intra-abdominal abscesses, oropharyngeal candidiasis, esophageal candidiasis, candidemia, and others. The DRC adjudicated 23 patients (56%) as achieving complete or partial response, 11 patients (27%) maintaining stable disease, 6 patients (15%) with progression of disease and one case was considered as indeterminate. The efficacy of oral ibrexafungerp by pathogen is shown in Table 1. Ibrexafungerp was well-tolerated with the most common treatment-related adverse events being of gastrointestinal origin. No deaths due to progression of fungal disease were reported. Table 1: Ibrexafungerp Outcomes by Pathogen Conclusion Preliminary analysis of these 41 cases indicate that oral ibrexafungerp provides a favorable therapeutic response in the majority of patients with difficult to treat Candida spp. infections, including those caused by non-albicans Candida species. Disclosures Barbara D. Alexander, MD, MHS, SCYNEXIS, Inc. (Employee, Scientific Research Study Investigator, Research Grant or Support) Oliver Cornely, Prof., Actelion (Grant/Research Support)Actelion (Other Financial or Material Support, Personal fees)Al Jazeera Pharmaceuticals (Consultant)Allecra Therapeutics (Other Financial or Material Support, Personal fees)Amplyx (Other Financial or Material Support, Personal fees)Amplyx (Grant/Research Support)Astellas (Grant/Research Support)Astellas (Other Financial or Material Support, Personal fees)Basilea (Other Financial or Material Support, Personal fees)Basilea (Grant/Research Support)Biosys UK Limited (Other Financial or Material Support, Personal fees)Cidara (Other Financial or Material Support, Personal fees)Cidara (Grant/Research Support)Da Volterra (Grant/Research Support)Da Volterra (Other Financial or Material Support, Personal fees)Entasis (Other Financial or Material Support, Personal fees)F2G (Other Financial or Material Support)F2G (Grant/Research Support)Gilead (Grant/Research Support)Gilead (Other Financial or Material Support, Personal fees)Grupo Biotoscana (Other Financial or Material Support, Personal fees)Janssen Pharmaceuticals (Grant/Research Support)Matinas (Other Financial or Material Support, Personal fees)Medicines Company (Grant/Research Support)MedPace (Grant/Research Support)MedPace (Other Financial or Material Support, Personal fees)Melinta Therapeutics (Grant/Research Support)Menarini Ricerche (Other Financial or Material Support, Personal fees)Merck/MSD (Other Financial or Material Support, Personal fees)Merck/MSD (Grant/Research Support)Mylan Pharmaceuticals (Consultant)Nabriva Therapeutics (Other Financial or Material Support, Personal fees)Octapharma (Other Financial or Material Support, Personal fees)Paratek Pharmaceuticals (Other Financial or Material Support, Personal fees)Pfizer (Other Financial or Material Support, Personal fees)Pfizer (Grant/Research Support)PSI (Other Financial or Material Support, Personal fees)Rempex (Other Financial or Material Support, Personal fees)Roche Diagnostics (Other Financial or Material Support, Personal fees)Scynexis (Other Financial or Material Support, Personal fees)Scynexis (Grant/Research Support)Seres Therapeutics (Other Financial or Material Support, Personal fees)Tetraphase (Other Financial or Material Support, Personal fees) Peter Pappas, MD, SCYNEXIS, Inc. (Consultant, Advisor or Review Panel member, Research Grant or Support) Rachel Miller, MD, SCYNEXIS, Inc. (Scientific Research Study Investigator) Luis Ostrosky-Zeichner, MD, Amplyx (Scientific Research Study Investigator)Astellas (Consultant, Scientific Research Study Investigator, Other Financial or Material Support, Non-branded educational speaking)Biotoscana (Consultant, Other Financial or Material Support, Non-branded educational speaking)Cidara (Consultant, Scientific Research Study Investigator)F2G (Consultant)Gilead (Consultant)Mayne (Consultant)Octapharma (Consultant)Pfizer (Other Financial or Material Support, Non-branded educational speaking)Scynexis (Consultant, Grant/Research Support, Scientific Research Study Investigator)Stendhal (Consultant)Viracor (Consultant) Andrej Spec, MD, SCYNEXIS, Inc. (Scientific Research Study Investigator, Advisor or Review Panel member) Riina Rautemaa-Richardson, DDS, PhD, FRCPath, SCYNEXIS, Inc. (Scientific Research Study Investigator) Robert Krause, MD, SCYNEXIS, Inc. (Scientific Research Study Investigator) Caryn Morse, MD, SCYNEXIS, Inc. (Scientific Research Study Investigator) John W. Sanders, III, MD, SCYNEXIS, Inc. (Scientific Research Study Investigator) David Andes, MD, SCYNEXIS, Inc. (Scientific Research Study Investigator, Advisor or Review Panel member) George Lyon, MD, SCYNEXIS, Inc. (Scientific Research Study Investigator) Francisco M. Marty, MD, Allovir (Consultant)Amplyx (Consultant)Ansun (Scientific Research Study Investigator)Avir (Consultant)Cidara (Scientific Research Study Investigator)F2G (Consultant, Scientific Research Study Investigator)Kyorin (Consultant)Merck (Consultant, Grant/Research Support, Scientific Research Study Investigator)New England Journal of Medicine (Other Financial or Material Support, Honorarium for Video)Regeneron (Consultant, Scientific Research Study Investigator)ReViral (Consultant)Scynexis (Scientific Research Study Investigator)Symbio (Consultant)Takeda (Scientific Research Study Investigator)United Medical (Consultant)WHISCON (Scientific Research Study Investigator) Marisa H. Miceli, MD, FIDSA, SCYNEXIS, Inc. (Advisor or Review Panel member) Thomas F. Patterson, MD, SCYNEXIS, Inc. (Advisor or Review Panel member) Martin Hoenigl, MD, SCYNEXIS, Inc. (Grant/Research Support, Scientific Research Study Investigator, Advisor or Review Panel member) Nkechi Azie, MD, SCYNEXIS, Inc. (Employee, Shareholder) David A. Angulo, MD, SCYNEXIS, Inc. (Employee, Shareholder)

Background Respiratory viruses (RV), including respiratory syncytial virus (RSV), influenza, parainfluenza virus (PIV), and human metapneumovirus (HMPV), frequently lead to serious complications such as lower respiratory tract infections and death in allogeneic hematopoietic cell transplantation (HCT) recipients. We used a large US claims database to compare the total reimbursement (TR), health resource utilization (HRU) and clinical outcomes between HCT patients with and without RV infections (RVI). Methods We used the Decision Resources Group Real World Evidence Data Repository to identify HCT recipients with date of service for the procedure from 1/1/2012-12/31/2017. We estimated the reimbursements from submitted charges using a reimbursement to charge ratio of 0.425. We examined the study outcomes in the year following HCT in patients with and without RVI. We also used a generalized linear model to determine adjusted TR stratified by the presence or absence of any acute or chronic graft-versus-host diseases (GVHD) after adjusting for age, health plan, underlying disease, stem cell source, number of comorbidities, baseline costs, and follow-up time. Results The study included 13,363 patients, representing 22% of HCTs reported to CIBMTR for the study period, of which 1,368 (10%) were coded with an RVI in the year following HCT: 578 (4%) RSV, 687 (5%) influenza, 166 (1%) PIV, and 181 (1%) HMPV. Unadjusted median TR were $132,395 higher for any RVI ($139,439 RSV, $101,963 influenza, $185,041 PIV and $248,029 HMPV) compared to those without RVI (Table 1). Adjusted TR were significantly higher for patients with any RVI compared to patients without that infection (p< .01) with or without GVHD (Figure 1). Patients with any RVI had significantly longer length of stay (LOS) for the HCT hospitalization, readmission rate and LOS after HCT hospitalization compared to patients without RVI (p< 0.05) (Table 2). A significantly higher proportion of patients with any RVI had pneumonia as compared to patients without that infection, irrespective of presence of GVHD (p< .0001). Table 1: Total healthcare reimbursement within one year of undergoing allogeneic HCT for patients with and without respiratory viral infections Figure 1: Adjusted total reimbursements within one year of undergoing allogeneic HCT for patients with and without respiratory viral infections Table 2: Health resource utilization within one year of undergoing allogeneic HCT for patients with and without respiratory viral infections Conclusion Allogeneic HCT patients with RVI have a significantly higher burden of TR, health resource utilization and worse clinical outcomes such as pneumonia during one year of undergoing HCT, regardless of the presence of GVHD. Disclosures Michael G. Ison, MD MS, AlloVir (Consultant) Francisco M. Marty, MD, Allovir (Consultant)Amplyx (Consultant)Ansun (Scientific Research Study Investigator)Avir (Consultant)Cidara (Scientific Research Study Investigator)F2G (Consultant, Scientific Research Study Investigator)Kyorin (Consultant)Merck (Consultant, Grant/Research Support, Scientific Research Study Investigator)New England Journal of Medicine (Other Financial or Material Support, Honorarium for Video)Regeneron (Consultant, Scientific Research Study Investigator)ReViral (Consultant)Scynexis (Scientific Research Study Investigator)Symbio (Consultant)Takeda (Scientific Research Study Investigator)United Medical (Consultant)WHISCON (Scientific Research Study Investigator) Seung Hyun Moon, MD, MPA, AlloVir (Employee, Shareholder) Zhiji Zhang, MS, AlloVir (Independent Contractor) Aastha Chandak, PhD, AlloVir (Independent Contractor)

Background PIV infections are an important cause of morbidity and mortality in IC patients. DAS181, a sialidase fusion protein, has demonstrated activity in preclinical and clinical studies. Methods Adult IC patients diagnosed with PIV LRTI on chest imaging and required SO ≥ 2 L/minute were randomized 2:1 (stratified by mechanical ventilation [MV] at baseline) to nebulized DAS181 (4.5 mg in 3.5 mL/day) or matching placebo for up to 10 days. The primary endpoint was the proportion of patients reaching clinical stability survival (CSS, defined as alive, resolution of SO requirement, and normalization of vital signs) by Day 45. Results From 2014 to 2016, 110 patients were randomized and received study drug (74 DAS181 and 36 placebo). Median age was 57 years (range, 18–85). The majority were hematopoietic cell transplant (HCT) recipients (74), followed by hematological malignancy/solid tumor patients on chemotherapy (29), and lung transplant recipients (7). Day 45 CSS was achieved by 39.2% of DAS181-treated patients compared with 31.4% of placebo (P = 0.29), while the proportion among non-MV patients was 45.0% vs. 31.0% (difference −14.0%, P = 0.15), respectively. Time to CSS in the non-MV stratum was shorter in DAS181-treated patients (figure). Median change in nasopharyngeal PIV viral load by Day 10 and median hospitalization days were −1.44 vs. −0.68 log10 (P = 0.51) and 13.5 vs. 21 days (P = 0.10) for DAS181 and placebo, respectively. Mean absolute increase from baseline FEV1% predicted was 16.82 for DAS181 vs. 2.02 for placebo (P = 0.001). Post-hoc analysis on the probability to return to room air (RTRA) suggested that DAS181 reduced SO need in the non-MV stratum after Day 21 (P = 0.09). HCT recipients within 360 days from transplant had a 40.8% treatment effect on RTRA at Day 28 (P = 0.04) and 36.7% on mortality at Day 45 when compared with placebo (P = 0.06). The rate of adverse events was similar in both treatment groups. Day 45 all-cause mortality was comparable in both groups (32.4% DAS181 vs. 31.4% placebo). Conclusion DAS181 was well tolerated and showed a signal for clinical efficacy in IC patients with PIV LRTI. DAS181 was granted Breakthrough Therapy Designation for the treatment of PIV LRTI in IC patients and a phase 3 trial is being planned. Disclosures R. F. Chemaly, Ansun Biopharma: Consultant and Investigator, Consulting fee and Research grant. R. Moss, Ansun Biopharma: Employee, Salary. F. M. Marty, Ansun Biopharma: Investigator, Research grant. C. R. Wolfe, Ansun Biopharma: Investigator, Research grant. S. J. Lawrence, Ansun Biopharma: Investigator, Research grant. S. Dadwal, Ansun Biopharma: Investigator, Research grant. R. Soave, Ansun Biopharma: Investigator, Research grant. J. Hwang, Ansun Biopharma: Employee, Salary. S. Hawley, Ansun Biopharma: Employee, Salary. R. Routh, Ansun Biopharma: Employee, Salary. J. Ho, Ansun Biopharma: Employee, Salary. G. Wang, Ansun Biopharma: Employee, Salary. N. Chang, Ansun Biopharma: Employee, Salary. M. Boeckh, Ansun Biopharma: Consultant and Investigator, Consulting fee and Research support.

Background Antiviral prophylaxis to prevent PTLD remains controversial, but some data suggest that valganciclovir or ganciclovir ([val]ganciclovir) use in EBV high-risk pediatric renal transplants reduces EBV viremia. We evaluated the impact of [val]ganciclovir on EBV viremia and post-transplant lymphoproliferative disease (PTLD) in pediatric nonrenal SOT recipients. Methods Retrospective study of 100 patients who underwent a first heart, liver, lung, intestine, or multivisceral SOT between November 2013 and November 2016 at Boston Children’s Hospital who survived without re-transplantation for at least 30 days. Data collected included EBV donor/recipient serostatus, donor’s age >2 years-old (to avoid misclassification of EBV risk due to maternal antibody), antiviral use ([val]ganciclovir or acyclovir), time to EBV viremia (>1,000 copies/mL by whole blood PCR), and time to development of PTLD. EBV high-risk patients were those with donor EBV positive [D+]/recipient EBV negative [R–] serologies; intermediate-risk were EBV R+; low risk were EBV D–/R–. Time-to-event analysis using the Kaplan–Meier method was performed and significance (P = 0.05) was evaluated using the log-rank test. Results High (n = 45) or intermediate (n = 27) EBV risk was associated with increased EBV viremia (P = 0.007, table). EBV viremia was significantly decreased in the subgroup of high-risk patients with donors >2 years old who received [val]ganciclovir vs. those who received no antiviral (n = 23, n = 4, P = 0.03, Figure 1). Most PTLD cases (8/9) occurred in the high-risk group (P = 0.03, Figure 2). Overall, patients who received [val]ganciclovir had less PTLD than those who did not (P = 0.03), but this was not significant in the high-risk subgroup (P = 0.14, Figure 3). Conclusion Lower rates of EBV viremia occurred in high EBV risk transplant recipients who received [val]ganciclovir, possibly by preventing primary EBV infection. Recipients with high EBV risk have the highest rate of PTLD. cases=100 EBV Risk Outcome Organ Unknown Low Intermediate High Viremia PTLD Heart 5 8 13 20 18 5 Liver 11 10 18 6 2 Lung 1 1 4 4 6 2 Intestine 1 0 Multivisceral 1 1 Dual organ 3 1 Total 7 21 27 45 43 9 Antiviral No Antiviral 6 6 5 2 Acyclovir 2 1 3 8 7 3 [Val]ganciclovir 5 13 24 31 31 4 Outcome Viremia 2 2 14 25 9 PTLD 1 8 9 Disclosures F. M. Marty, Merck: Consultant and Investigator, Consulting fee, Research support and Speaker honorarium; Astellas: Consultant and Investigator, Consulting fee and Research support; Chimerix: Consultant and Investigator, Consulting fee and Research support; Fate Therapeutics: Consultant, Consulting fee; GlaxoSmithKline: Consultant, Consulting fee; LFB: Consultant, Consulting fee; Roche Molecular Diagnostics: Consultant, Consulting fee; Shire: Consultant and Investigator, Consulting fee and Research support.

Objectives Ethanol is bactericidal against most pathogens implicated in central line-associated bloodstream infections (CLABSIs) and biofilms. Current Infectious Diseases Society of America guidelines cite insufficient evidence to support adjunctive ethanol-lock therapy (ELT) for central venous catheter (CVC) salvage in patients with CLABSI in combination with systemic antimicrobial treatment. We evaluated the safety and potential efficacy of 70% ELT for CLABSI at our institution after implementation of a hospital ELT protocol. Methods We collected data on all patients treated with adjunctive 70% ELT for catheter salvage from September 2009 to September 2011 and assessed clinical outcomes and adverse events associated with ELT. Results Sixty-eight hospitalized patients received 70% ELT for CVC salvage: 45 (66%) met the criteria for CLABSI. Five (11%) had persistent or recurrent bacteraemia triggering CVC removal; 28 (62%) preserved their CVC long term. There were no documented adverse events associated with ELT. Discussion Adjunctive 70% ELT is an inexpensive, well-tolerated option for CVC salvage in patients with CLABSI and warrants further investigation.

Background IA remains a leading cause of morbidity and mortality in immunocompromised children, and our understanding regarding epidemiology and outcomes of IA are limited and based on adult studies. Methods We conducted a retrospective evaluation of cases of proven or probable IA according to the 2008 EORTC/MSG criteria cared for at Boston Children’s Hospital from 2007 to 2019. We collected data including demographics, clinical characteristics, diagnosis modality, antifungal treatment, and survival. Survival curves over one year were estimated using the Kaplan–Meier method and univariate and multivariate Cox modeling was used to evaluate for risk factors for mortality. Results 67 patient cases were identified, 20 (30%) with proven IA and 47 (70%) with probable IA. The mean age at diagnosis was 11.9 years (6 months–28 years). Underlying conditions included hematopoietic-cell transplantation (HCT) in 45%, cancer in 21%, and solid-organ transplantation in 18%. Pulmonary IA was the most common (70.1%) presentation. Diagnostic modalities included positive microbiology alone (18%), fungal PCR alone (1.5%), galactomannan alone (28%), and multiple modalities for the remaining cases (52.5%). 44.8% of patients were neutropenic at diagnosis and 78.5% of patients with malignancies were receiving chemotherapy. Immunosuppressive drugs included glucocorticoids in 34.3%, calcineurin inhibitors in 31.3%, and IMDH inhibitors in 25.3%. Voriconazole was the most common treatment used (72%). Twenty-two (33%) deaths occurred in the cohort attributable to IA (6 of which underwent autopsies and 4 had histopathological confirmation) Most deaths occurred in the BMT patients (15 patients, 45% of deaths). The 6 week mortality was 18% while the 12 week mortality was 25.4%. No antifungal or immunosuppressive regimen had a statistically significant impact on mortality. Conclusion We demonstrate in our >10-year retrospective cohort analysis of immunocompromised hosts that IA is associated with 49% all-cause mortality with particular impact on the BMT population. No protective nor harmful association was also noted with a particular antifungal or immunosuppressive regimen. Disclosures All authors: No reported disclosures.

Background HSV reactivation is a challenging complication of HM and HCT. ACV prophylaxis effectively decreases the incidence of symptomatic HSV episodes, but may contribute to development of ACV-R HSV disease in this population. Outcomes in patients with ACV-R HSV disease remain poorly characterized. Methods We identified adult HM patients and HCT recipients treated at Dana-Farber Cancer Institute who developed clinically significant ACV-R HSV disease between January 1, 2006 and March 1, 2018. HCT recipients typically receive 1 year of ACV prophylaxis after HCT, or longer in those with graft-vs. host disease. Clinical, microbiological and treatment details were collected. Results Nineteen patients had 27 episodes of ACV-R HSV disease during the study. Median age was 50 years (range 31–77); 15 (79%) were men. Fifteen (79%) were allogeneic HCT recipients and 4 (21%) had HM (3 CLL, 1 NHL). Thirteen (68%) had oral ulcers (HSV1), four (21%) had perineal ulcers (3 HSV2, 1 HSV1), one had HSV1 vesicles on the trunk and one had concurrent oral HSV1 and perineal HSV2 ulcers. Three patients had recurrent ACV-R HSV: two had one recurrence each and one had six recurrences. Of 19 first episodes of ACV-R HSV, 15 (79%) were confirmed by culture-based phenotypic resistance testing. Most episodes (20/27, 74%) were treated with foscarnet at clinical diagnosis or after failure of high-dose val-ACV; four of these episodes were also treated with topical cidofovir without success before foscarnet. Three episodes resolved on high-dose val-ACV or IV ACV alone and three were treated with cidofovir or brincidofovir initially. Coinfection was present in 19 episodes (70%), most often bacterial pneumonia or blood stream infection. Twenty-two episodes (81%) resolved completely after a median of 36 days (range 10–88) of treatment. No patient died of HSV disease but five (26%) died before resolution of ACV-R HSV, a median of 25 days (range 1–117) after treatment started. Eight patients died after ACV-R HSV resolved, a median of 111 days (range 27–382) after treatment started. Among HCT recipients, six (37%) died within 12 weeks of diagnosis. Conclusion ACV-R HSV disease is an uncommon complication of HM and allogeneic HCT. While ACV-resistant HSV did not cause death in this cohort, death within 12 weeks of infection was common. Disclosures N. C. Issa, GSK: Investigator, Research grant; Merck: Investigator, Research grant; Akros Pharma: Consultant, Consulting fee. F. M. Marty, Chimerix: Consultant and Investigator, Consulting fee and Research support. S. P. Hammond, Merck: Investigator, Research support.

Background Mycobacterium tuberculosis is a leading cause of morbidity and mortality worldwide. The risk of developing active TB in persons with hematological malignancies is higher than the general population. However, the magnitude and timing of this risk has not been determined in non-endemic settings after HCT. The purpose of this study was to evaluate treatment practices and active TB rates in a cohort of HCT recipients. Methods A retrospective cohort study was performed of all adult patients who underwent HCT at Dana-Farber Cancer Institute between January 2010 and January 2015. Baseline characteristics and laboratory parameters were collected. LTBI diagnostic tests included purified protein derivative (PPD) and interferon-gamma release assays (IGRA). Baseline chest radiography, history of BCG vaccination, and previous LTBI therapy were documented. Institutional guidance recommends that LTBI treatment begins upon discharge or by Day +28 after HCT, whichever is first. Patients were followed until April 2018 for development of active TB. Results In a cohort of 1,288 HCT recipients, 44 (3.4%) had evidence of LTBI, with 43 positive PPD tests and one positive IGRA. Median age was 55 years (range 19–72); 24/44 (54.5%) were male and 28/44 (63.6%) were non-US-born. Nine (20%) patients were treated for LTBI before HCT. Of the remaining 35 patients, 11 (25%) were treated within 3 months of HCT, three (6.8%) initiated treatment later than 3 months post HCT, and 21 (47.7%) did not receive treatment for reasons including death (n = 14, median survival 1.5 years from HCT) and treatment refusal (n = 4). Three patients were lost to follow-up. Among patients who initiated treatment, isoniazid (n = 10) and levofloxacin (n = 4) were used for a median of 145 days (range 7–326). There were no cases of active TB in the whole HCT cohort during the study period, which included a combined 139 person-years of follow-up in 44 patients with LTBI, of which 68 person-years were contributed by untreated individuals. Conclusion These data suggest that TB reactivation does not usually occur very early after HCT. LTBI therapy could be deferred in the immediate post-transplant setting and initiated once patients are clinically stable with a lower risk of synergistic hepatotoxicity. Disclosures S. P. Hammond, Merck: Investigator, Research support

Background Timely diagnosis of IM remains a major challenge in clinical mycology. Because of the lack of specific diagnostic methods for IM and the frequently fulminant nature of this infection, IM-associated mortality remains high. Methods We examined breath volatile metabolite profiles in a neutropenic murine model of IM, using the 3 Mucorales species that most commonly cause human IM - Rhizopus arrhizus var. arrhizus, R. arrhizus var. delemar, and R. microsporus - and for comparison, Aspergillus fumigatus. We infected female balb/c mice (N = 4 per group) treated with cyclophosphamide and cortisone followed by intranasal administration of 106 conidia of each species. 3 days post-infection, we collected breath samples from each mouse via tracheostomy using a flexiVent murine ventilator, examining breath volatile metabolites using thermal desorption gas chromatography/tandem mass spectrometry (GC-MS/MS). We also sampled breath prospectively from five patients eventually diagnosed with proven IM caused by R. microsporus, analyzing breath volatile metabolites using thermal desorption GC-MS/MS. Results Each Mucorales species produced a consistent profile of breath sesquiterpene secondary metabolite VOCs in our murine models, which distinguished these species from each other and from murine invasive aspergillosis (Figure A). These fungi shifted their secondary metabolism significantly in vivo, compared with their previously characterized in vitro metabolism. We found overlapping VOC sesquiterpene metabolites between breath samples from the murine model of R. microsporus infection and 5 of 5 patients with R. microsporus IM, with additional sesquiterpene secondary metabolites detected in patient breath, compared with the murine IM model (Figure B). In one patient with serial breath samples, these sesquiterpenes declined in abundance and disappeared with antifungal therapy, in parallel with clinical improvement (Figure C). Conclusion The three Mucorales species that cause most human IM have distinct breath sesquiterpene profiles that can be used to identify these infections in vivo noninvasively. These profiles distinguish these infections from each other and from aspergillosis, and may be useful in monitoring clinical response to treatment. Disclosures F. M. Marty, Astellas Pharma US: Consultant and Grant Investigator, Consulting fee and Grant recipient; Chimerix: Consultant and Grant Investigator, Consulting fee and Grant recipient; Fate Therapeutics: Scientific Advisor, Consulting fee; Gilead Sciences: Consultant and Grant Investigator, Consulting fee and Grant recipient; LFB: Consultant, Consulting fee; Merck: Consultant, Grant Investigator and Scientific Advisor, Consulting fee and Grant recipient; Roche Molecular Systems: Consultant, Consulting fee; Shire: Consultant and Grant Investigator, Consulting fee and Grant recipient; D. P. Kontoyiannis, Pfizer: Research Contractor, Research support and Speaker honorarium; Astellas: Research Contractor, Research support and Speaker honorarium; Merck: Honorarium, Speaker honorarium; Cidara: Honorarium, Speaker honorarium; Amplyx: Honorarium, Speaker honorarium; F2G: Honorarium, Speaker honorarium

We investigated the prevalence of xenotropic murine leukemia virus-related virus (XMRV) among 293 participants seen at academic hospitals in Boston, Massachusetts. Participants were recruited from the following 5 groups of patients: chronic fatigue syndrome (n = 32), human immunodeficiency virus infection (n = 43), rheumatoid arthritis (n = 97), hematopoietic stem-cell or solid organ transplant (n = 26), or a general cohort of patients presenting for medical care (n = 95). XMRV DNA was not detected in any participant samples. We found no association between XMRV and patients with chronic fatigue syndrome or chronic immunomodulatory conditions.

The most common presentation of dermatophytosis is as a superficial infection characterized by a rash (tinea). In very rare cases, this infection can become invasive, involve deeper dermal structures, and even disseminate. We present a case of biopsy-proven, disseminated dermatophytosis caused by Trichophyton rubrum in a patient with advanced cirrhosis. In addition, we provide a review of the literature.

Background: Candidaemia is often treated with fluconazole in the absence of susceptibility testing. We examined factors associated with candidaemia caused by Candida isolates with reduced susceptibility to fluconazole. Methods: We identified consecutive episodes of candidaemia at two hospitals from 2001 to 2007. Species identification followed CLSI methodology and fluconazole susceptibility was determined by Etest or broth microdilution. Susceptibility to fluconazole was defined as: full susceptibility (MIC ≤ 8 mg/L); and reduced susceptibility (MIC≥ 32 mg/L). Complete resistance was defined as an MIC .32 mg/L. Results: Of 243 episodes of candidaemia, 190 (78%) were fully susceptible to fluconazole and 45 (19%) had reduced susceptibility (of which 27 were fully resistant). Of Candida krusei and Candida glabrata isolates, 100% and 51%, respectively, had reduced susceptibility. Despite the small proportion of Candida albicans (8%), Candida tropicalis (4%) and Candida parapsilosis (4%) with reduced fluconazole susceptibility, these species composed 36% of the reduced-susceptibility group and 48% of the fully resistant group. In multivariate analysis, independent factors associated with reduced fluconazole susceptibility included male sex [odds ratio (OR) 3.2, P,0.01], chronic lung disease (OR 2.7, P ¼0.01), the presence of a central vascular catheter (OR 4.0, P,0.01) and prior exposure to antifungal agents (OR 2.2, P ¼0.04). Conclusions: A significant proportion of candidaemia with reduced fluconazole susceptibility may be caused by C. albicans, C. tropicalis and C. parapsilosis, species usually considered fully susceptible to fluconazole. Thus, identification of these species may not be predictive of fluconazole susceptibility. Other factors that are associated with reduced fluconazole susceptibility may help clinicians choose adequate empirical anti-Candida therapy.

Background Diagnosis of invasive fungal disease (IFD) is challenging, and it remains a significant cause of morbidity and mortality in immunocompromised patients. The (1-->3)-beta-D-glucan (BG) assay may be a useful adjunct, but its diagnostic performance is not well characterized. Methods We retrospectively assessed the diagnostic indices of the BG assay in patients at risk of IFD who had a compatible clinical syndrome for the diagnosis of IFD a week after initial BG testing and at the end of the hospitalization associated with the first BG value. Patients with IFD were classified according to current European Organization for Research and Treatment of Cancer-Mycoses Study Group criteria, independent of BG results. Results A total of 1308 BG assays were performed for 871 patients. One hundred twelve proven or probable IFD cases were diagnosed within 1 week after initial testing, and 116 cases were diagnosed by the end of hospitalization. Sensitivity of an initial BG level 80 pg/mL for IFD at 1 week was 0.64 (95% confidence interval [CI], 0.55-0.73), specificity was 0.84 (95% CI, 0.81-0.86), the positive likelihood ratio was 3.93 (95% CI, 2.94-5.26), and the negative likelihood ratio was 0.43 (95% CI, 0.31-0.59). Albumin, intravenous immunoglobulin, and hemodialysis were associated with elevated BG levels in patients without IFD (odds ratio, 4.78; 95% CI, 2.59-8.80). After excluding patients with these factors, specificity and the positive likelihood ratio of an initial BG level 80 pg/mL increased slightly. Empirical systemic antifungal treatment did not reduce overall BG sensitivity. Sensitivity was slightly lower among patients with hematologic malignancy or stem cell transplantation. Consideration of BG results would have increased the diagnostic certainty to probable in 54% of possible IFD cases. Conclusions BG level appears to be a fair diagnostic adjunct for IFD in patients with appropriate pretest probability and a suggestive clinical syndrome, especially when checked serially in patients not receiving factors associated with an elevated BG level in the absence of IFD.

Invasive fusariosis is an aggressive fungal disease among immunocompromised patients. Mortality remains high in the voriconazole era. Combination therapy should be studied systematically for fusariosis., Background. Invasive fusariosis remains an aggressive, albeit infrequent infection in immunocompromised patients. Methods. We identified all cases of invasive fusariosis between January 2002 and December 2014. We recorded patient characteristics including clinical presentation, treatment, and outcomes at 6 and 12 weeks after diagnosis, as well as species identification and antifungal drug susceptibilities. Results. Fifteen patients were diagnosed with proven (12, 80%) or probable (3, 20%) fusariosis. Median age was 60 years (range, 26–78), and 10 patients were male. Underlying conditions included hematological malignancies (13, 87%), juvenile idiopathic arthritis (1, 7%), and third-degree burns (1, 7%). Five patients underwent hematopoietic stem-cell transplantation before diagnosis. Six patients (40%) received systemic glucocorticoids, and 11 patients (73%) had prolonged neutropenia at the time of diagnosis. Clinical presentations included the following: skin/soft tissue infection (8, 53%), febrile neutropenia (4, 27%), respiratory tract infection (2, 13%), and septic arthritis (1, 7%). Twelve patients were treated with voriconazole: 6 (40%) with voriconazole alone, 4 (27%) with voriconazole and terbinafine, and 2 (13%) with voriconazole, terbinafine, and amphotericin. One patient (7%) was treated with terbinafine alone, and another with micafungin alone. Four patients underwent surgical debridement (4, 27%). Susceptibility testing was performed on 9 isolates; 8 demonstrated voriconazole minimum inhibitory concentrations ≥4 µg/mL. The cumulative probability of survival was 66.7% and 53.3% at 6 and 12 weeks after diagnosis. Conclusions. Mortality associated with invasive fusariosis remains high. Cumulative mortality at our center was lower than previous reports despite elevated voriconazole minimum inhibitory concentrations. Combination therapy should be studied systematically for fusariosis.

Background. Alemtuzumab is an emerging therapy for refractory lymphoproliferative disorders. The associated long-term risks of infection remain poorly defined. Methods. From July 2001 through December 2003, all patients who received alemtuzumab for the treatment of lymphoproliferative disorders at 1 institution underwent a retrospective evaluation to document infectious complications until death or end of follow-up in October 2004. Alemtuzumab recipients who underwent allogeneic hematopoietic stem cell transplantation were compared with a concurrent cohort who also underwent allogeneic hematopoietic stem cell transplantation but did not receive alemtuzumab. Results. Twenty-seven patients were identified (21 with chronic lymphocytic leukemia and 6 with plasma cell disorders). The overall mortality was 37%, with 7 of 10 deaths being related to infection. Significant opportunistic infections occurred in 9 patients (43%) with chronic lymphocytic leukemia, including cytomegalovirus, progressive multifocal leukoencephalopathy, adenovirus, toxoplasmosis, and acanthamaebiasis. Thirty nonopportunistic infections in 22 patients (82%) were also identified. The 3 deaths related to nonopportunistic infections all involved Enterococcus species bacteremia. When compared with a concurrent chronic lymphocytic leukemia cohort that underwent allogeneic hematopoietic stem cell transplantation, alemtuzumab recipients had an incidence of cytomegalovirus reactivation of 66.7% (6 of 9 patients), compared with 37% in the non-alemtuzumab group (10 of 27 patients; P = .15), and an incidence of post-transplant opportunistic infections (excluding herpesviruses) of 44.4% (compared with 29.6% in the non-alemtuzumab group; P = .41). Conclusions. Despite the use of herpesvirus and Pneumocystis pneumonia prophylaxis, serious infectious complications occur in patients receiving alemtuzumab for lymphoproliferative disorders. Infectious complications are more varied and diverse in patients receiving alemtuzumab than has been reported in trials to date.

Background BTK and PI3K inhibitors are increasingly used for treatment in patients with HM. OIs when these agents were used as first line therapy signaled an increased level of immunosuppression beyond what was expected from the mechanism of action of these drugs. The epidemiology of OIs in the setting of BTK and PI3K inhibitor use has not been characterized. Methods We retrospectively studied a cohort of patients with HM who received BTK (ibrutinib, acalabrutinib, spebrutinib) or PI3K (idelalisib, duvelisib, TGR-1202) inhibitors as part of clinical trials at our center between March 2008 and November 2016. Patients were followed up until April 30, 2017. Incident infectious complications were recorded. Cohort baseline characteristics, underlying malignancy, stage of disease, type of therapy and use of antimicrobial prophylaxis were recorded. Results 148 patients who received BTK or PI3K inhibitors as first or second line therapy were included in the study. Median age was 64.5 years, 32% were female, 95.9% had chronic lymphocytic leukemia (CLL), 4.1 % had Non-Hodgkin Lymphoma (NHL). Sixty-three percent received BTK inhibitors and 37% received PI3K inhibitors as first line therapy. Pneumocystis and HSV/VZV prophylaxis were used in 82.4% and 85.8% of patients, respectively. Twenty-seven OIs occurred in 24 patients. The most common OIs were pneumocystosis (7), aspergillosis (5) HSV (3), VZV (3), CMV (2), Cryptococcal meningitis (2), candidiasis (2) and other invasive mold infections (3). Seventy-one patients (48%) had infectious episodes not considered OIs. Median time to onset of OIs after start of therapy was 78 days (range, 6–323). Twelve OIs (8.1 %) occurred after first line therapy with BTK inhibitors, 11 OIs (7.4 %) occurred after first line PI3K inhibitors. Conclusion The use of BTK and PI3K inhibitors as first or second line treatment of CLL or NHL are associated with incident OIs. Clinical awareness of these complications and the use of adequate prophylactic and/or monitoring strategies are essential in preventing serious OIs in this population. Disclosures J. Brown, Pharmacyclics, Janssen, Celgene, Gilead, Infinity, Genentech, and Pfizer, Roche and Sun BioPharma, Janssen, Gilead, Sun BioPharma, and Pfizer: Consultant, Consulting fee; F. Marty, Astellas Pharma US: Consultant and Grant Investigator, Consulting fee and Grant recipient; Chimerix: Consultant and Grant Investigator, Consulting fee and Grant recipient; Fate Therapeutics: Scientific Advisor, Consulting fee; Gilead Sciences: Consultant and Grant Investigator, Consulting fee and Grant recipient; LFB: Consultant, Consulting fee; Merck: Consultant, Grant Investigator and Scientific Advisor, Consulting fee and Grant recipient; Roche Molecular Systems: Consultant, Consulting fee; Shire: Consultant and Grant Investigator, Consulting fee and Grant recipient

Background In a Phase III randomized, double-blind, placebo-controlled study of CMV-seropositive HCT recipients, letermovir prophylaxis significantly reduced the incidence of clinically significant CMV infections (CS-CMVi) through 24 weeks post-HCT. We investigated the impact of letermovir prophylaxis on mortality through Week 48 post-HCT. Methods Adult CMV-seropositive allogeneic HCT recipients with undetectable plasma CMV DNA at screening who could initiate treatment by Week 4 post-HCT were eligible. Subjects stratified by high or low CMV disease risk were randomized 2:1 to letermovir dosed at 480 mg/d (240 mg/d if on cyclosporine) or placebo PO or IV through Week 14 post-HCT. Time to all-cause mortality and non-relapse mortality (defined as death due to any reason other than the indication for HCT) through Week 48 post-HCT are presented using Kaplan–Meier (KM) plots censored at study discontinuation for reasons other than death/non-relapse death or upon study completion. Distribution of time to mortality endpoints was tested by stratified log-rank tests using two-sided P-values. Results This analysis included all 565 patients randomized and treated with ≥1 dose of study drug. Subjects began study drug a median of 9 days post-HCT; 36.5% started post-engraftment. The observed KM event rate for all-cause mortality was lower in the letermovir group (10.6%) than the placebo group (15.5%) at Week 24 post-HCT, and remained lower through Week 48 post-HCT (21.4% vs. 26.2%) (Figure 1). The observed K–M event rate for all-cause mortality in subjects who developed CS-CMVi was also lower in the letermovir group (4.6%) than the placebo group (17.1%) at Week 48 post-HCT. The observed KM event rate for non-relapse mortality was lower in the letermovir group (6.9%) vs. the placebo group (11.2%) at Week 24 post-HCT, and remained lower in the letermovir group (13.9%) than the placebo group (17.5%) through Week 48 post-HCT (Figure 2). Conclusion All-cause and non-relapse mortality were reduced in the letermovir group compared with the placebo group through Week 48 post-HCT (relative risk reduction ~18% and ~21%, respectively). These results are consistent with a clinically meaningful survival benefit for letermovir prophylaxis. Disclosures J. Maertens, MSD: Consultant and Investigator, Consulting fee, Research grant and Speaker honorarium. M. Schmitt, MSD: Consultant and Investigator, Consulting fee. F. M. Marty, Merck & Co., Inc.: Consultant, Grant Investigator and Scientific Advisor, Consulting fee and Grant recipient. P. Ljungman, Merck & Co., Inc.: Consultant and Investigator, Consulting fee, Research grant and Speaker honorarium. R. F. Chemaly, Merck & Co., Inc.: Consultant and Investigator, Consulting fee, Research grant and Speaker honorarium. N. A. Kartsonis, Merck & Co., Inc.: Employee, Salary and stock/stock options. J. Butterton, Merck & Co., Inc.: Employee, Salary and stock, stock options. H. Wan, Merck & Co., Inc.: Employee, Salary and stock, stock options.V. L. Teal, Merck & Co., Inc.: Employee, Salary and Stock/stock options. K. Sarratt, Merck & Co., Inc.: Employee, Salary and stock & stock options. Y. Murata, Merck & Co., Inc.: Employee, Salary and stock and stock options. R. Y. Leavitt, Merck & Co., Inc.: Employee, Salary and stock, stock options. C. Badshah, Merck & Co., Inc.: Employee, Salary and stock, stock options

Mucormycosis is a life-threatening fungal disease in patients with hematological malignancies. The diagnosis of pulmonary mucormycosis is particularly challenging. We describe 3 mucormycosis cases with an uncommon presentation in patients whose cavitary lung disease was attributed to well documented bacterial infection, although evolution and reassessment established mucormycosis as the underlying disease.

• The primary endpoint was Day 42 all-cause mortality in the ITT population. • Success rate (complete or partial) for DRC-assessed overall response at end of therapy (EOT), was a key secondary effi cacy endpoint. − DRC evaluated the overall response based on clinical, mycological, and radiological assessments. • Day 84 all-cause mortality was also assessed. Safety assessments • Adverse events (AEs) were assessed throughout the study for all patients who received at least 1 dose of the study drug. • Other safety assessments included measurement of vital-signs, 12-lead electrocardiograms, clinical laboratory testing (hematology, chemistry, and urinalysis) and physical examinations (including eye examination).