Invasive mold infections in allogeneic hematopoietic cell transplant recipients in 2020: have we made enough progress?

Background Despite progress in diagnostic, prevention and treatment strategies, invasive mold infections (IMI) remain leading cause of mortality in allogeneic hematopoietic cell transplant recipients (allo-HCT-recipients). Methods We describe the incidence, risk factors, and mortality of allo-HCT-recipients with proven/probable IMI in a retrospective single-center 10-year (01.01.2010-01.01.2020) cohort study. Results Among 515 allo-HCT-recipients, 48 (9.3%) patients developed 51 proven/probable IMI: invasive aspergillosis (IA; 34/51, 67%), mucormycosis (9/51, 18%) and other molds (8/51, 15%). Overall 35/51 (68.6%) breakthrough-IMI (bIMI) were identified: 22/35 (62.8%) IA and 13/35 (37.1%) non-IA IMI. One-year IMI cumulative incidence was 7%: 4.9% and 2.1% for IA and non-IA IMI, respectively. Fourteen (29.2 %), 10 (20.8%), and 24 (50.0%) patients were diagnosed during the first 30, 31-180, and >180 days post-HCT, respectively. Risk factors for IMI included: prior allo-HCT (SHR:4.06, p=0.004) and ≥grade-2 acute graft-versus-host disease (aGvHD; SHR: 3.52, p<0.001). All-cause 1-year mortality was 33% (170/515): 48% (23/48) and 31.5% (147/467) for patients with and without IMI (p=0.02). Mortality predictors included: disease relapse (HR:7.47, p<0.001), aGvHD (HR:1.51, p=0.001), CMV-serology-positive recipients (HR:1.47, p=0.03), and IMI (HR:3.94, p<0.001). All-cause 12-week mortality for patients with IMI was 35.4% (17/48): 31.3% (10/32) for IA and 43.8% (7/16) for non-IA IMI (logrank 0.47). At 1-year post-IMI diagnosis, 70.8% (34/48) of patients were dead. Conclusions IA mortality has remained relatively unchanged during the last two decades. More than two thirds of allo-HCT-recipients with IMI die by 1-year post-IMI diagnosis. Dedicated intensified research efforts are required to further improve clinical outcomes.

718. Posaconazole Versus Standard of Care for Treatment of Invasive Mold Infections

Background Invasive mold infections (IMIs) including Aspergillus spp. are a significant cause of morbidity and mortality in immunocompromised patients. Voriconazole is recommended as first line treatment for primary IA. Liposomal amphotericin B and isavuconazole are also recommended alternative therapies. Posaconazole has activity against mold species including those not covered by voriconazole, is available as an IV and oral formulation with a distinct adverse effect profile making it a potential effective alternative for treatment. This study investigated the clinical outcomes of treatment of invasive mold infections (IMIs) with posaconazole compared to standard of care (voriconazole, isavuconazole, liposomal amphotericin B). Methods A retrospective, single center, cohort study was completed to evaluate patients with IMIs treated with posaconazole versus those treated with standard of care therapy. Medication orders for posaconazole or standard of care therapy between January 2012 and December 2020 were identified from a clinical data repository. Only patients with antifungal orders with a listed indication for “treatment of fungal infection” were included. Data collected for each group included baseline demographics, underlying conditions, site of infection, type of mold, therapeutic drug monitoring and classification of IMI. Results A total of 120 patients met inclusion criteria, with 35 patients in the posaconazole group and 85 patients in the SOC group. Baseline characteristics were similar except for increased severe neutropenia in the posaconazole group (p< 0.0001), more probable IMIs in the SOC group (p=0.009) and more possible IMIs in the posaconazole group (p=0.043). In the posaconazole group 37.1% (13/35) of patients were treatment experienced vs. 29.4% (25/85) of patients in the SOC group. More patients achieved a complete/partial response in the SOC group compared to the posaconazole group (p=0.0001) and more patients experienced treatment failure in the posaconazole group (p=0.01). A higher proportion of patients experienced adverse effects in the SOC group compared to the posaconazole group (p=0.0001). Conclusion Posaconazole was not as effective as SOC in treating invasive mold infections but patients experienced comparatively fewer adverse events. Disclosures All Authors: No reported disclosures

708. Evaluation of Fungal Culture versus Bacterial Culture for the Identification of Various Mold Species

Background Invasive mold infections are challenging to diagnose and in part relies on fungal cultures. A large proportion of mold isolates are recovered on routine bacterial cultures in our medical center, thus we sought to define the utility of bacterial versus fungal cultures for isolation of mold from clinical specimens. Methods Routine bacterial and fungal culture results from wound, tissue, body fluid, and respiratory specimens from Jan 2019-Dec 2020 from Keck Medical Center of USC (Los Angeles, CA) were retrospectively reviewed. Cases were excluded if specimens were collected specifically for dermatophyte recovery or for blood culture. Cultures in which mold, including dimorphic fungi, were isolated were included in the evaluation. Results Mold was isolated from 612 specimens from 408 patients, with recovery from 329 bacterial and 450 fungal cultures. Among the 329 bacterial cultures, fungal cultures were not requested in 119 (36.2%) while the remaining 210 had concurrent fungal cultures which recovered mold in 167 cases (79.5%). Of 450 fungal cultures recovering mold, a corresponding bacterial culture was performed in 445, isolating mold in 181 (38.8%) of these cases. Two or more molds were found in 28 fungal cultures and in 5 bacterial cultures. Of positive specimens with both fungal and bacterial cultures performed (n=488), mold was isolated in fungal cultures in 446 (91.4%) and in bacterial cultures in 209 (42.9%) (Table). Yield of molds in 488 specimens with concomitant bacterial and fungal cultures Conclusion Although a significant number of molds are recovered in routine bacterial cultures, over half would be missed without concomitant fungal cultures. Conversely, recovery of clinically relevant mold species was optimal when both bacterial and fungal cultures were requested on a specimen. This may be related to increased specimen sampling and incubation conditions allowing for broader organism recovery. Disclosures All Authors: No reported disclosures

Real-Life Considerations on Antifungal Treatment Combinations for the Management of Invasive Mold Infections after Allogeneic Cell Transplantation

Background: Antifungal combination treatment is frequently administered for invasive mold infections (IMIs) after allogeneic hematopoietic cell transplantation (HCT). Here, we describe the indications, timing, and outcomes of combination antifungal therapy in post-HCT IMI. Methods: A single-center, 10-year, retrospective cohort study including all adult HCT recipients with proven/probable IMI between 1 January 2010 and 1 January 2020 was conducted. Results: During the study period, 515 patients underwent HCT, of whom 47 (9.1%) presented 48 IMI episodes (46 patients with one IMI episode and 1 patient with two separate IMI episodes): 33 invasive aspergillosis (IA) and 15 non-IA IMIs. Almost half (51%) of the patients received at least one course of an antifungal combination (median: 2/patient): 23 (49%), 20 (42%), and 4/47 (9%) patients received pure monotherapy, mixed monotherapy/combination, and pure combination treatment, respectively. Combination treatment was started at a median of 8 (IQR: 2, 19) days post-IMI diagnosis. Antifungal management was complex, with 163 treatment courses prescribed overall, 48/163 (29.4%) concerning antifungals in combination. The clinical reasons motivating the selection of initial combination antifungal therapy included severe IMI (18, 38%), lack of antifungal susceptibility data (14, 30%), lack of pathogen identification (5, 11%), and combination treatment until reaching a therapeutic azole serum level (6, 13%). The most common combination treatments were azole/liposomal amphotericin-B (28%) and liposomal amphotericin-B/echinocandin (21%). Combination treatment was administered cumulatively for a median duration of 28 days (IQR: 7, 47): 14 (IQR: 6, 50) days for IA and 28 (IQR: 21, 34) days for non-IA IMI (p = 0.18). Overall, 12-week mortality was 30%. Mortality was significantly higher among patients receiving ≥ 50% of treatment as combination (logrank = 0.04), especially those with non-IA IMI (logrank = 0.03). Conclusions: Combination antifungal treatment is frequently administered in allogeneic HCT recipients with IMI to improve clinical efficacy, albeit in an inconsistent and variable manner, suggesting a lack of relevant data and guidance, and an urgent need for new studies to improve therapeutic options.

Predictors of Early and Late Mortality for Patients with Hematologic Malignancy and Invasive Mold Disease

Background: Invasive mold infections (IMI) are leading infectious causes of mortality among patients with hematological malignancies. Objectives: To determine the relative contribution of host, disease, and treatment-related factors to patient survival. Methods: An observational, retrospective cohort study reviewing the medical records of patients with hematological malignancy and IMI (2006–2016). Causes of death were classified up to 90 days after diagnosis. Kaplan–Meier and Cox regression analyses were used to determine risk factors for early, late, and overall mortality. Results: Eighty-six patients with IMI were included; 29 (34%) and 41 (47%) died within 6 and 12 weeks of diagnosis, respectively. Death was attributed to IMI in 22 (53.6%) patients, all of whom died within 45 days of diagnosis. Risk factors for early mortality were elevated serum galactomannan, treatment with amphotericin B, IMI progression 3 weeks after diagnosis, and lymphoma undergoing HCT. Late mortality was associated with relapsed/refractory malignancy and elevated serum galactomannan. Conclusions: In this single-center study of patients with IMI, infections were the most frequent causes of death, and time-dependent risk factors for death were identified. These results may help direct risk-assessment and monitoring of patients undergoing treatment of IMI.

Genomic Diversity of Azole-Resistant Aspergillus fumigatus in the United States

Aspergillus fumigatus is one of the most common causes of invasive mold infections in patients with immune deficiencies and has also been reported in patients with severe influenza and severe acute respiratory syndrome coronavirus 2 (SARs-CoV-2). Triazole drugs are the first line of therapy for this infection; however, their efficacy has been compromised by the emergence of azole resistance in A. fumigatus , which was proposed to be selected for by exposure to azole fungicides in the environment [P.

Surveillance practices and air-sampling strategies to address healthcare-associated invasive mold infections in Society for Healthcare Epidemiology of America (SHEA) Research Network hospitals—United States, 2020

With this survey, we investigated healthcare-associated invasive mold infection (HA-IMI) surveillance and air sampling practices in US acute-care hospitals. More than half of surveyed facilities performed HA-IMI surveillance and air sampling. HA-IMI surveillance was more commonly performed in academic versus nonacademic facilities. HA-IMI case definitions and sampling strategies varied widely among respondents.