Probable Invasive Fungal Infections Research Articles

#78: Use of Isavuconazonium for Treatment Of Invasive Fungal Infection in Immunocompromised Pediatric Patients

Abstract Background Isavuconazole (ISZ), dosed as the pre-drug isavuconazonium (ISM), is active against a wide variety of clinically important fungal pathogens. ISM is approved for the treatment of invasive aspergillosis and mucormycosis in adults ≥18 years of age. We present our experience with ISM to treat proven or probable fungal infection in immunocompromised pediatric patients. Methods Retrospective review of patients who received ISM at our institution between April 2016 and April 2019, we abstracted demographic information, primary diagnosis, indication for ISM therapy, ISZ serum concentrations if available, and outcomes. Results Of 14 patients who received ISM, 11 were ≤18 years of age (range 6–18 years). Underlying conditions included leukemia (n = 7), lymphoma (n = 1), post BMT (n = 1), diabetes (n = 1), and cardiac transplant (n = 1). Nine (82%) had proven invasive fungal infection (IFI) with aspergillosis (n = 2), zygomycosis (n = 3), mixed aspergillosis and zygomycosis (n = 2), mixed Rhizopus and Scedosporium (n = 1), and pathology only (n = 1) and 2 had probable IFI. Five of these 11 patients received combination ISM and liposomal amphotericin initially and the other 6 received liposomal amphotericin with or without other azoles prior to changing to ISM monotherapy. This was followed by monotherapy with ISM in 10 patients after a mean of 26 days (range 6–63) and continued dual therapy in the one. ISM dosing was 10 mg/kg q8h on days 1 and 2, followed by q24 thereafter, up to a maximum of 372 mg/dose. There were 19 measured ISZ serum concentrations obtained from 8 patients after >1 week of verified inpatient dosing, ranging from 1.0 to 7.5 mg/L, above the MIC in all cases when known. Three (27%) patients died of underlying non-mycological causes, 1 (9%) died of progressive scedosporiosis, and 7 (64%) improved. ISM was well tolerated with no dose-limiting, drug-related toxicities noted. Conclusions ISM is a well-tolerated therapeutic option in pediatric patients at risk for or with invasive mycosis. Only 1 of our 11 patients died from progressive fungal disease.

Filamentous Fungal Infections in a Tertiary Care Setting: Epidemiology and Clinical Outcome

Information on the distribution of filamentous fungal pathogens, which cause potential life-threatening invasive infections mostly in immunocompromised persons, is of great importance. The aim of this study was to evaluate the epidemiology and clinical outcome in patients with infections due to filamentous fungi at the University Hospital of Vienna, Austria. We conducted a retrospective observational study and consecutively included patients of any age with filamentous fungal infections between 2009 and 2017. The classification for probable and proven invasive filamentous fungal infections was based on the European Organization for Research and Treatment of Cancer/Invasive Fungal Infections Cooperative Group (EORTC) criteria or the expert opinion of an experienced clinical mycologist. We included 129 patients (median age: 52 years; 47.3% female) with episodes of 101 proven and probable invasive and 35 localized filamentous fungal infections (16 sinus, 14 eye, one ear, and four deep cutaneous). Aspergillus fumigatus alone accounted for 50.3% of the fungi, which was followed by the Mucorales group (13.7%) and Fusarium spp. (8.5%). Diagnosis was mainly based on culture findings. The lung was the most frequent site of infection. The 30-day and 90-day overall mortality of invasive fungal infections was 30.2% and 42.7%, respectively. We observed a high all-cause mortality among patients with invasive filamentous fungal infections. Prospective data collection in a nationwide registry would be necessary to provide important information on surveillance to clinicians and other decision-makers.

Risk factors for intra-abdominal fungal infection after simultaneous pancreas-kidney transplantation: A single-center retrospective experience.

Data on the risk factors and outcome of intra-abdominal fungal infections (IAFI) following simultaneous pancreas-kidney transplantation (PKT) are scarce. A retrospective monocentric study was conducted on all patients who underwent simultaneous PKT from January 2007 to December 2016. Deep sites positive cultures for fungi during the first post-transplantation year were collected. Clinical, radiological, and microbiological data of proven and probable invasive fungal infections were analysed. Among sixteen PKT patients, 15 were included. Seven patients (47%) developed an invasive fungal infection, exclusively IAFI (six proven, one probable). The proven IAFI included four peritonitis, one pancreatic necrosis with infected hematoma, and one patient with positive preservation fluid only (PF). Candida albicans (n=4) was the most prevalent species (associated with Galactomyces candidus in one case), C glabrata, C dubliniensis, and C krusei were found in one case each. Three patients had either a positive direct examination and/or culture for renal or pancreatic PF and the culture of PF was positive for the same species that caused IAFI. IAFIs were significantly associated with pancreatic graft arterial thrombosis (5/7 vs 0/8, P=.007) and fungal contamination of PF (3/7 vs 0/8, P=.008). Among patients with IAFI, all required an early surgical revision post-transplantation [1-18days] and six had early or delayed pancreatic graft removal. One patient died in the first post-transplant year. IAFI is a common complication in PKT, associated with pancreatic graft thrombosis or fungal contamination of the graft PF, and can sometimes lead to pancreatic detransplantation.

Opportunistic Invasive Fungal Infections Mimicking Progression of Non–Small-Cell Lung Cancer

BackgroundMany studies have shown that invasive pulmonary aspergillosis, cryptococcosis, and mucormycosis can mimic radiographic and clinical features of primary lung cancer. However, more research surveying the incidence and outcomes of these fungal infections among patients with a history of lung cancer is needed. The aim of this study was to describe the occurrence and clinical outcomes of opportunistic invasive fungal infections that can mimic tumors in non–small-cell lung cancer patients. Patients and MethodsPatients seen at Stanford University Medical Center from January 1, 2007, to May 1, 2020, with pulmonary aspergillosis, cryptococcosis, or mucormycosis after non–small-cell lung cancer (NSCLC) diagnosis were reviewed. The European Organization for Research and Treatment of Cancer National Institute of Allergy and Infectious Diseases Mycoses Study Group criteria was used to classify patients with evidence of proven or probable invasive fungal infection within our cohort. ResultsA total of 12 patients with proven or probable invasive mold infection (including 8 cases of aspergillosis) and 1 patient with proven cryptococcosis were identified, without any cases of mucormycosis. Of this cohort, 6 patients (46%) showed radiographic findings that were found to be most consistent with lung cancer by radiologists. Eight cases (62%) were suspected of cancer recurrence or progression by the treatment team on the basis of additional considerations of medical history and clinical symptoms. Most patients had active NSCLC or had a history of recurrence without active NSCLC at the time of fungal discovery (11 patients; 85%). Most patients died without full recovery (7 patients; 54%). ConclusionsInvasive pulmonary aspergillosis and cryptococcosis can often be mistaken as cancer recurrence or progression in patients with a history of NSCLC because of mimicking radiographic and clinical characteristics.

Quantification of 1,3-β-d-glucan by Wako β-glucan assay for rapid exclusion of invasive fungal infections in critical patients: A diagnostic test accuracy study.

Rapid and reliable exclusion of invasive fungal infections (IFI) by markers able to avoid unnecessary empirical antifungal treatment is still a critical unmet clinical need. We investigated the diagnostic performance of a newly available β-d-Glucan (BDG) quantification assay, focusing on the optimisation of the BDG cut-off values for IFI exclusion. BDG results by Wako β-glucan assay (lower limit of detection [LLOD]=2.16pg/mL, positivity≥11pg/mL) on two consecutive serum samples were retrospectively analysed in 170 patients, admitted to haematological wards (N=42), intensive care units (ICUs; N=80), or other wards (N=48), exhibiting clinical signs and/or symptoms suspected for IFI. Only patients with proven IFI (EORTC/MSG criteria) were considered as true positives in the assessment of BDG sensitivity, specificity and predictive values. Patients were diagnosed with no IFI (69.4%), proven IFI (25.3%) or probable IFI (5.3%). Two consecutive BDG values<LLOD performed within a median of 1 (interquartile range: 1-3) day were able to exclude a proven IFI with 100% sensitivity and negative predictive value (primary study goal). Test's specificity improved by using two distinct positivity and negativity cut-offs (7.7pg/mL and LLOD, respectively), but remained suboptimal in ICU patients (50%), as compared to haematological or other patients (93% and 90%, respectively). The classification of Wako's results as negative when<LLOD, and positive when>7.7pg/mL, could be a promising diagnostic approach to confidently rule out an IFI in both ICU and non-ICU patients. The poor specificity in the ICU setting remains a concern, due to the difficulty to interpret positive results in this fragile population.

Incidence of Invasive Fungal Infections in Acute Myeloid Leukemia Without Antifungal Prophylaxis

BackgroundAntifungal prophylaxis during induction for acute myeloid leukemia (AML) varies according to local rates of invasive fungal infections (IFIs). We evaluated fluconazole prophylaxis and no antifungal prophylaxis, as a natural interrupted time-series study to assess survival and infection complications. Patients and MethodsWe identified patients with AML ≥ 18 years old undergoing induction chemotherapy during 2 time periods: period 1, fluconazole prophylaxis from August 1, 2013 to September 30, 2015, and period 2, no prophylaxis from October 1, 2015 to December 31, 2017. The primary outcome was incidence of proven or probable IFI. Secondary outcomes included types of IFIs and 60-day overall survival (OS). IFI was defined by the 2002 European Organization for Research and Treatment of Cancer/Mycoses Study Group Consensus criteria. ResultsOne hundred forty-four patients received induction chemotherapy over the 2 time periods. In the prophylaxis versus no-prophylaxis groups, the rate of proven or probable IFIs was 4 (5%) of 87 versus 12 (21%) of 57 (P = .01). The total number of proven IFIs was 3 (3%) of 87 versus 4 (7%) of 57 (P = .44), whereas probable IFIs were 1 (1%) of 87 versus 8 (14%) of 57 (P < .01). No difference was observed in fungemia. Incidence of IFIs was too low to detect resistance patterns. OS at 60 days was improved in with fluconazole prophylaxis compared with no prophylaxis (hazard ratio, 0.329; 95% confidence interval, 0.12-0.89; P = .028). ConclusionObserved rates of proven or probable IFI were lower in the fluconazole prophylaxis group versus the no-prophylaxis group. Sixty-day OS was higher with fluconazole prophylaxis. Further study is required to evaluate how fluconazole may impart the differences in survival seen in this analysis.

Invasive fungal infections in a pediatric hematology-oncology department: A 16-year retrospective study

Background and Purpose: Invasive fungal infections (IFIs) are a major cause of morbidity and mortality in immunocompromised children. The purpose of our study was to evaluate the incidence of IFIs in pediatric patients with underlying hematologic malignancies and determine the patient characteristics, predisposing factors, diagnosis, treatment efficacy, and outcome of IFIs.Materials and Methods: For the purpose of the study, a retrospective analysis was performed on cases with proven and probable fungal infections from January 2001 to December 2016 (16 years)Results: During this period, 297 children with hematologic malignancies were admitted to the 2nd Pediatric Department of Aristotle University of Thessaloniki, Greece, and 24 cases of IFIs were registered. The most common underlying diseases were acute lymphoblastic leukemia (ALL; n=19,79%), followed by acute myeloid leukemia (AML; n=4, 17%) and non-Hodgkin lymphoma (NHL; n=1,4%). The crude incidence rates of IFIs in ALL, AML, and NHL were 10.5%, 18.2%, and 2.8% respectively. Based on the results, 25% (n=6) and 75% (n=18) of the patients were diagnosed as proven and probable IFI cases, respectively. The lung was the most common site of involvement in 16 (66.7%) cases. Furthermore, Aspergillus and Candida species represented 58.3% and 29.1% of the identified species, respectively. Regarding antifungal treatment, liposomal amphotericin B was the most commonly prescribed therapeutic agent (n=21), followed by voriconazole (n=9), caspofungin (n=3), posaconazole (n=3), micafungin (n=1), and fluconazole (n=1). In addition, 12 children received combined antifungal treatment. The crude mortality rate was obtained as 33.3%.Conclusion: As the findings of the present study indicated, despite the progress in the diagnosis and treatment of IFIs with the use of new antifungal agents, the mortality rate of these infections still remains high.

Antifungal prophylaxis during 7 + 3 induction chemotherapy for acute myeloid leukemia is associated with improved survival, in a setting with low incidence of invasive mold infections.

Invasive fungal infections (IFIs) are a major cause of morbidity and mortality in patients undergoing induction chemotherapy for acute myeloid leukemia (AML). In this patient population, antifungal prophylaxis (AP) has been associated with decreased incidence of IFIs and better survival. However, some centers have not adopted AP during induction chemotherapy for AML, as it is unclear whether AP improves outcomes in settings where the incidence of invasive mold infections is low. We retrospectively assessed the differences in clinical outcomes and resource utilization in patients undergoing 7 + 3 induction chemotherapy for AML, after implementing a policy of AP as part of a dedicated inpatient malignant hematology service (HS) at Rhode Island Hospital. Between January 1, 2007 and April 1, 2019, 56 patients with AML received AP during 7 + 3 induction chemotherapy and 52 patients did not, without significant differences in their baseline characteristics. Use of AP was associated with less proven or probable IFI (0% vs. 6%, P = 0.1) and lower all-cause in-hospital mortality (7% vs. 21%, P < 0.05), without significant increases in resource utilization or toxicities. Empiric and targeted antifungal therapies were more frequently started in the non-AP group (69%) than changed in the AP group (41%, P < 0.005). Having a dedicated inpatient malignant hematology service was also associated with improved outcomes. However, use of AP was associated with better survival (30-day post-induction survival log-rank P < 0.05), prior to the implementation of this clinical service as well, which is suggestive of an independent benefit from AP.

Safety of Isavuconazonium Sulfate in Pediatrics Patients With Hematologic Malignancies and Hematopoietic Cell Transplantation With Invasive Fungal Infections: A Real World Experience.

Primary objective is to evaluate safety of isavuconazonium sulfate (ISA) in pediatrics below 18 years old. Exploratory endpoint includes mortality due to probable and proven invasive fungal infection (IFI) and overall morality in this population. Retrospective review of patients below 18 years receiving ISA for ≥7 days for possible, probable, or proven IFI or prophylaxis between June 2015 and March 2018. Descriptive analysis performed to calculate median, frequency, and percentages. Safety analysis included 18 patients and a subgroup of 11/18 patients were assessed for efficacy. Median age 12.5 years (4 to 17 y), median weight 50.25 kg (19 to 118 kg), 50% male, 77% acute leukemias, 94% hematopoietic cell transplant recipients, 50% matched unrelated donors and 78% in remission. Elevated alanine aminotransferase 3 times baseline within 30 days of ISA occurred in 22% (4/18). No patients had elevated bilirubin or increase in serum creatinine. All-cause mortality at 90 days was 22% (4/18) and 27% (3/11) in patients with probable or proven IFI. Clinical response rates: 14-day: 45% (5/11) partial, 27% (3/11) stable; 30-day: 45% (5/11) partial, 36% (4/11) stable; 90-day: 54% (6/11) had either partial (n=3) or complete (n=3) response to ISA. ISA is safe in pediatric patients for the treatment of IFI. Prospective, randomized controlled trials are warranted to determine efficacy and safety of ISA in pediatric patients with hematologic malignancies and hematopoietic cell transplant.

Breakthrough Invasive Fungal Infections in Patients with Acute Myeloid Leukemia.

We sought to determine the occurrence, risk factors, effect of antifungal prophylaxis, and outcomes of invasive fungal infections (IFIs) in patients with acute myeloid leukemia (AML). We performed a retrospective analysis of all adult patients admitted to the University of Michigan Health System for AML over a 3-year period from 2010 to 2013. We determined comorbidities, hematopoietic cell transplant (HCT) status, antifungal prophylaxis, proven and probable IFI, and outcomes at 12weeks after initiation of appropriate antifungal therapy. Of 333 patients in our cohort, 116 of whom had received a HCT, 98 (29%) developed an IFI. Of the 30 (9%) patients who had a proven or probable IFI, 18 had breakthrough infection while on micafungin (n = 5), voriconazole (n = 4), posaconazole (n = 5), or fluconazole (n = 4). Breakthrough IFIs were due to Aspergillus species (n = 11), other molds (n = 4), and Candida species (n = 3). Factors associated with breakthrough IFI were prolonged severe neutropenia (p = .05) and having received tacrolimus (p = .04). Antifungal therapy was successful in 7 of the 18 (39%) patients with breakthrough IFI and 8 of the 12 (67%) patients with non-breakthrough IFI, p = .13. Mortality at 12weeks was 27%, 5 with breakthrough IFI and 3 with non-breakthrough IFI and was associated with prolonged severe neutropenia, p = .04. Patients with AML remain at risk for IFI despite the use of several different antifungal agents for prophylaxis. Mortality remains high in patients with AML who develop IFI.

Efficacy of posaconazole prophylaxis in acute myeloid leukemia and myelodysplastic syndrome patients treated with hypomethylating agents.

Background:Although many acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS) patients have been treated with hypomethylating agents (HMAs) as a substitute for intensive chemotherapy in recent years, the incidence of invasive fungal infections (IFIs) and the efficacy of posaconazole as antifungal prophylaxis in these patients are not well known to date.Methods:We retrospectively analyzed 280 AML and MDS patients treated with HMAs to identify IFI incidence and posaconazole efficacy as antifungal prophylaxis in these patients.Results:The overall incidence of probable or proven IFIs was 7.9% (22/280 patients): 11.5% in the no-use group (17/148 patients) and 3.8% in the posaconazole group (5/132 patients). Most IFIs occurred during the early cycles of the HMAs (median: 3 cycles; range: 1–8 cycles), especially in patients who had neutropenia or did not respond to HMAs. Posaconazole significantly lowered IFI incidence compared with that in the no-use group in univariate and multivariate analyses. Moreover, patients who had reduced liver function at HMA initiation, were treated with decitabine therapy, and did not respond to HMA chemotherapy were independently associated with a higher IFI risk. In subgroup analysis, posaconazole appeared to be more beneficial for patients with good Eastern Cooperative Oncology Group performance score or liver function at HMA initiation.Conclusion:Thus, in AML and MDS patients receiving HMAs, IFI risk may be high during the early cycles, especially when the underlying disease is not controlled. Posaconazole could represent antifungal prophylaxis in these patients; further studies are needed for its appropriate indications.

Invasive fungal infections in acute myeloid leukemia treated with venetoclax and hypomethylating agents

AbstractThe combination of venetoclax with hypomethylating agents (VEN-HMAs) showed promising activity in newly diagnosed and relapsed/refractory (r/r) acute myeloid leukemia (AML). Treatment with VEN-HMAs results in prolonged cytopenia, thereby exposing patients to invasive fungal infections (IFIs). Here, we retrospectively studied a cohort of 119 AML patients treated with VEN-HMAs and analyzed the occurrence of IFIs, as well as our practice of antifungal prophylaxis, with the aim to identify the nature and risk factors for IFIs and their association with the type of antifungal prophylaxis used. The intended antifungal prophylaxis was micafungin in 38% of patients, azoles in 41% of patients, and none in 21% of patients. Older age was associated with no antifungal prophylaxis or micafungin use and lesser use of azoles (P = .043). We recorded 15 (12.6%) patients who developed probable or proven IFIs, with a median onset of 72 days (range, 35-281) after starting therapy. IFIs were more common among nonresponders compared with responders to VEN-HMA therapy (22% vs 6%, P = .0132) and in r/r compared with newly diagnosed AML (19% vs 5%, P = .0498); however, the antifungal prophylaxis used, patient age, hypomethylating agent schedule, history of prior allogeneic transplant, and initial neutropenia duration did not influence the development of IFIs during therapy. We conclude that the overall risk of IFIs during VEN-HMA therapy is low. The risk of IFIs is higher in nonresponders and in those who were treated in the r/r setting; these patients need reevaluation of their antifungal prophylaxis to minimize the risk of IFIs during therapy.

Single Arm, Single Centre Prospective Study to Assess the Effect of Therapeutic Drug Monitoring (TDM) Based Dosage Adjustment of Posaconazole on the Incidence of Invasive Fungal Infections (IFIs) in AML Patients on Induction Chemotherapy on Posaconazole Prophylaxis

Background: Invasive fungal infections (IFIs) continue to remain a significant cause of morbidity and mortality in AML patients affecting the final outcomes and increasing health care costs. Posaconazole is commonly used as prophylaxis against IFIs due to its broad spectrum of action. The incidence of breakthrough IFIs is particularly high in our setting - one of the several reasons being suboptimal drug levels as we use posaconazole suspension whose absorption is influenced by multiple factors. A breakthrough IFI rate of 51% was seen in a previous study from our centre by Sengar et.al (ASH 2016) and it was seen that sub-optimal drug levels (&lt; 700ng/ml) were associated with a higher rate of breakthrough IFI. This group can benefit from TDM but there are not many studies to guide TDM-based dosing of posaconazole. TDM is expensive and time consuming and the final impact on clinical outcomes has been difficult to estimate. To determine the impact of TDM-based dosing of posaconazole on breakthrough IFI rate, we have undertaken this prospective study. Methods: This prospective, single-arm interventional study included patients 16 years or older undergoing induction chemotherapy for de novo AML with no evidence of IFI at baseline (normal CT chest and normal serum galactomannan ) who have consented for participation (assent and guardian consent were used for those who were &lt; 18 years). Concomitant drugs during induction were recorded everyday. 3 dosing schedules for posaconazole were used based on the drug level : Level 1 - 200mg TDS which was the starting dose in all patients, Level 2 - 200mg QID and Level 3 - 400mg TDS which was the maximum dose. Posaconazole was given with a high fat meal or an aerated drink to improve its absorption. The cut off for day 2 drug level (i.e after atleast 3-4 doses ) was 350ng/ml and the cut-off level at subsequent time points was 700 ng/ml. At any time point, if the patient's drug level was below this cut off, the dose was escalated and a repeat level was sent 5 complete days after the changed dose to allow for re-establishment of the pharmacokinetic equilibrium. A day 2 level was sent for all the patients and the timing of subsequent levels was based on dose escalation. Patients who were continued on the same dose due to adequate drug levels were sampled once in 7 days. QTc interval and liver function tests were monitored for posaconazole toxicity. Posaconazole was continued till the absolute neutrophil count recovered to more than 500 cells/ µl or till the patient was started on an alternative anti-fungal for a proven , possible or probable IFI or empirically at the clinician's discretion for reasons like persistent fever, cough, breathlessness, diarrhoea or vomiting. Relevant imaging and microbiological tests were performed as needed for investigating a suspected IFI. To analyze the primary endpoint chi-square test was used to compare the breakthrough IFI rate with that in a historical cohort from our own centre in which TDM based dosing was not used. Results: A total of 278 samples were collected for drug levels in these 90 patients with a mean of 3.08 (range 1 to 6 samples) per patient . 2 patients were proven to have mixed phenotypic acute leukemia after enrollment and hence were excluded from the analysis. 46 out of 88 patients i.e 52.3% were changed to alternative antifungals. Out of these 46, 13 patients (i.e 28.3%) had proven, probable or possible IFI as per the Revised Definitions of Invasive Fungal Disease from the European Organization for Research and Treatment of Cancer/Invasive Fungal Infections Cooperative Group and the National Institute of Allergy and Infectious Diseases Mycoses Study Group (EORTC/MSG) . The change to alternative antifungals in the remaining 33 out of 46 patients (i.e 71.7%) was empirical due to persistent fever spikes, vomiting or diarrhoea. Thus overall 13 out of 88 patients i.e 14.8% had developed a breakthrough IFI. A similar historical cohort from our own institute, without the TDM based dosing of posaconazole, had a breakthrough IFI rate of 52%. The difference between the breakthrough IFI rate of these 2 cohorts was 37.2% which was statistically significant (p &lt; 0.0001, 95% CI 27.9% to 52.4%). 1 patient had developed grade 3 transaminitis and 1 patient had grade 3 rise in total bilirubin while on posaconazole. Conclusion: TDM-based dose escalation of prophylactic posaconazole in AML patients during induction leads to a significant reduction in the breakthrough IFI rates. Disclosures No relevant conflicts of interest to declare.

1741. Invasive Fungal Infections in Patients with Multiple Myeloma in the Era of Novel Therapies

BackgroundRapid advances in multiple myeloma (MM) therapy have led to improved survival, yet the impact of novel agents on the risk of invasive fungal infection (IFI) is largely unknown. We aim to describe the epidemiology of IFIs in MM patients in the current era of chemotherapy.MethodsWe performed a retrospective chart review of MM patients at Mount Sinai Hospital in New York, NY who entered care between December 2009 and October 2016 and had proven or probable IFI between January 2011 and October 2017. Probable and proven IFIs were defined by revised EORTC/MSG criteria. Descriptive statistics are reported as median (range). We evaluated factors associated with mortality by univariate analysis using Fisher’s exact and Mann–Whitney U tests.Results2,960 MM patients entered care during the study period. We identified 30 episodes of IFI among 29 patients. Median age was 59 (42–80) years and 21 (70%) were men. IFI occurred at a median of 3.7 (0.3–18) years from MM diagnosis. At the time of IFI diagnosis, patients had received a median of 4 (1–12) lines of chemotherapy, 18 (60%) had undergone autologous stem cell transplant (ASCT), and 21 (70%) had progressive disease status. Agents received immediately prior to IFI were immunomodulators (n = 14), proteasome inhibitors (n = 14), conventional chemotherapy (n = 11), monoclonal antibodies (n = 6), checkpoint inhibitors (n = 3) and other (n = 3). Twenty-two (73%) patients received corticosteroids in the prior 30 days. Neutropenia and lymphopenia were present in 12 (40%) and 13 (43%) patients, respectively. There were 9 proven and 21 probable IFIs: invasive aspergillosis (n = 19), candidemia (n = 5), cryptococcosis (n = 3), talaromycosis (n = 1), mucormycosis (n = 1) and other (n = 2). Bacterial and viral respiratory co-infections occurred in 7 and 4 patients, respectively. Eight (27%) patients required ICU admission and 9 (30%) died within 30 days of IFI diagnosis. In univariate analysis, number of lines of chemotherapy (P = 0.05), progressive disease status (P = 0.03), and prior ASCT (P = 0.004) were associated with 30-day mortality.ConclusionIFIs are uncommon in MM patients receiving newer agents but are associated with significant morbidity and mortality. Further study is needed to identify high-risk subgroups that may benefit from antifungal prophylaxis or increased surveillance.Disclosures All authors: No reported disclosures.

1735. Epidemiology of Invasive Fungal Infections During Induction Chemotherapy in Adults With Newly Diagnosed Acute Myeloid Leukemia Without Antifungal Prophylaxis: A Retrospective Cohort Study

BackgroundWhile invasive fungal infections (IFIs) are common in patients with acute myeloid leukemia (AML) undergoing induction chemotherapy, little current data exist on the epidemiology of IFIs in this patient population given widespread use of antifungal prophylaxis. Because our institution does not administer antifungal prophylaxis, we are in a unique position to study the natural history of IFIs in these patients.MethodsWe evaluated the incidence of IFIs using established definitions in adults with AML undergoing induction chemotherapy at Stanford Health Care from 2012 to 2017. We also analyzed incidence of antifungal treatment, impact of IFI diagnosis on survival, and risk factors for IFI development. Patients were followed for up to 12 weeks after beginning induction chemotherapy.ResultsOf 488 patients analyzed, 243 were eligible for inclusion. The median age was 57 (interquartile range 45–65). Men composed 134 (55%) of the patients and 157 (65%) where white. Fifty-four (22%) had antecedent myelodysplastic syndrome; most received a “7 + 3” regimen involving cytarabine and an anthracycline. Thirty-one (13%) developed a proven or probable IFI; 104 (43%) developed a proven, probable, or possible IFI. Most IFIs were due to lower respiratory tract disease. Eighteen identified organisms were Candida, including six C. albicans. Eight organisms were mold, including four Aspergillus isolates (all but one A. fumigatus) and one isolate each of Fusarium solani, Rhizomucor, Rhizopus, and Scedosporium apiospermum/Pseudallescheria boydii. One hundred ninety patients (78%) received antifungals during their initial admission and 99 (46%) of patients surviving their initial admission were discharged on antifungals. Only 66.7% of patients with a proven or probable IFI survived through 12 weeks, compared with 92.2% of those without (P = 0.007). Baseline absolute neutrophil count ≤500 cells/μL and longer duration of neutropenia were significantly associated with development of proven or probable IFIs.ConclusionAmong patients receiving induction chemotherapy for AML, IFIs due to Candida and mold remain frequent absent antifungal prophylaxis and are associated with worse survival. Our findings support the use of antifungal prophylaxis in this patient population.Disclosures All authors: No reported disclosures.

279. Evaluation of β-d-Glucan Utilization in Thailand: Single Academic Center Experience

Backgroundβ-d-glucan (BG) detection was first available in Thailand in 2016 to aid diagnosis of invasive fungal infections (IFIs). Given a paucity of real-world experience of BG use in resource-limited countries, this study was conducted to describe appropriateness of BG testing and sequelae of BG results.MethodsA retrospective study included all patients with at least 1 BG ordered at King Chulalongkorn Memorial Hospital, Bangkok, Thailand during March 2016 to December 2018. Descriptive statistics were used.Results83 patients were tested by BG assay (Fungitell, Associates of Cape Cod, Inc.): 6 with hematopoietic stem cell transplant, 12 with solid-organ transplant, 20 with active cancer receiving chemotherapy, 34 receiving high dose steroids (≥20 mg/day of prednisone for ≥3 weeks) and 11 with other conditions. Seventy-three patients were tested under infectious disease (ID) service’s recommendations. There were 13 and 20 cases of proven and probable IFIs, respectively. Among 13 proven IFIs, there were 11 positive, 1 indeterminate and 1 negative (mucormycosis) BG results. Among 49 cases with positive BG results, 24 were determined to be false-positive results. Median turn-around time for BG results was 16 (IQR: 9–23) days. Due to high turn-around time, only 8 patients were started on antifungal agent(s) and 3 underwent bronchoscopy due to positive BG results. All proven IFI cases were started on antifungal treatment prior to BG availability.ConclusionApproximately 87% of BG use in Thailand was ordered in patients with risk factors for IFIs. This could be due to majority of BG test was recommended by ID specialist. Despite being used in right clinical context, 49% had false-positive BG results. Another barrier of BG use in Thailand was high turn-around time due to small numbers of BG ordered and relative high cost to run the assay. Therefore, the utility of BG for aiding diagnosis or management of fungal infection in our setting is limited.Disclosures All authors: No reported disclosures.

1127. Utilization of Combination Anti-fungal Therapy in Hospitalized Children and Adverse Events

BackgroundCombination antifungal therapy (CAF) is often prescribed to treat invasive fungal infections, despite equivocal data showing benefit. We evaluated number of CAF for treatment of proven, probable and possible invasive fungal infection (IFI) in hospitalized children, associated adverse effects (AE), and use of therapeutic drug monitoring (TDM).MethodsMedical charts of patients ≤ 18 years old that received CAF for ≥72 hours with normal liver function test between 1/1/13 through December 31/18 were reviewed. Patients could be included for multiple episodes of CAF. Data included primary site of IFI, host risk factors, demonstration of fungal elements in tissue/sterile sites, clinical and mycological criteria for IFI (defined by European Organization for Research and Treatment of Cancer/Invasive Fungal Infections Cooperative Group and National Institute of Allergy and Infectious Diseases Mycoses Study Group), CAF regimen, incidence of TDM, and AE.ResultsOverall, 73 episodes of IFI were reviewed [unique patients (n) =60]. The median age was 10 years. Majority (61.6%) of patients were diagnosed with a hematological malignancy (n = 20 acute lymphoblastic leukemia, n = 12 acute myeloid leukemia, n = 5 aplastic anemia). A number of proven, possible, probable IFI were 36, 27 and 20, respectively (Table 1). Most frequent organism isolated in proven IFI was Aspergillus fumigatus (episodes=5, n = 4). Most common primary site of IFI was pulmonary (episodes=32, n = 27). Median days of CAF was 6.8 (range: 3–170). Sixty-six episodes included treatment with a triazole-containing regimen (90%). TDM was conducted in 51 (77%) episodes of triazole-containing regimens. AE were reported in 14 episodes (n = 10) (infusion-related reactions and nephrotoxicity reported in 4 episodes each, electrolyte abnormalities and skin reaction reported in 2 episodes each, and liver dysfunction and hypersensitivity reported in 1 episode each).ConclusionPatients diagnosed with proven or probable IFI received a longer duration of CAF in comparison to possible IFI. Voriconazole was frequently prescribed in combination with either micafungin or liposomal amphotericin B for IFI. Antifungal stewardship opportunities exist to improve TDM and reduce the incidence of AE when prescribing CAF. Disclosures All authors: No reported disclosures

1704. Geotrichum spp. Invasive Infection: Experience From a Third-Level Referral Center in Mexico

Background Geotrichum spp has been recognized as an emergent pathogen that causes invasive infection in immunosuppressed hosts. There is no data in Latin America about invasive Geotrichum spp. infections. Our objective was to describe the epidemiology, clinical characteristics, and outcomes of patients with this infection.MethodsWe conducted a retrospective survey from 2001 to 2018, of all the Geotrichum spp. isolated from clinical samples at our institution. Data on demographic, clinical, laboratory findings, and imaging studies were obtained from medical records. All cases classified as proven or probable invasive fungal infections (IFI) according to the EORTC/MSG criteria were included. Isolates with unavailable clinical information were excluded. Descriptive analysis was made.ResultsWe found 18 patients with a proven/probable Geotrichum spp. IFI. The mean age was 48.5 years and 55.5% were male. The most common predisposing condition was hematological malignancy (55.5%), autoimmune diseases (22.2%) and HIV, chronic granulomatous disease, and solid-organ malignancy in 1 case, respectively. Fifteen (83.3%) received immunosuppressors (cancer chemotherapy or steroids); 27.7% had neutropenia at the time of diagnosis. The most common clinical syndromes were lower respiratory tract infection and persistent fever (83.3%). Chest abnormalities were present in 15/16 CT scans, pulmonary nodules were the most common finding (62.5%). Geotrichum spp. was isolated from bronchoalveolar lavage, 77.7%; blood culture, 22.2%; and peritoneal dyalisis fluid, 5.6%. Seven patients were coinfected with other pathogens: 4 Aspergillus spp., 1 H. parainfluenzae, 1 P. aeruginosa, and 1 E. coli. Fifteen patients received antifungal treatment: 7 amphotericin B, 8 voriconazole, and 1 itraconazole. Among survivors (11), 72.7% received antifungal therapy at discharge: 4 voriconazole and 4 itraconazole. Three patients did not receive any antifungal: 1 was diagnosed postmortem and 2 were considered colonization (both were alive at 30 days). Overall mortality was 38.8%.ConclusionEighteen cases of Geotrichum spp. were found. The majority had lower respiratory tract infection. Despite antifungal therapy 38.8% died. Geotrichum spp. should be recognized as an emerging pathogen in immunosuppressed hosts.Disclosures All authors: No reported disclosures.

2121. Isavuconazole (ISAV) as Primary Anti-Fungal Prophylaxis (PAP) in Patients with Acute Myeloid Leukemia (AML) or Myelodysplastic Syndrome (MDS): An Open-Label, Prospective Study

BackgroundMold-active antifungal prophylaxis (ppx) is recommended in neutropenic patients with newly diagnosed AML or MDS. ISAV is an extended spectrum triazole with superior tolerability, reliability of absorption, fewer drug–drug interactions, lack of QTc prolongation or need for therapeutic drug monitoring, approved for the treatment of invasive aspergillosis (IA) and mucormycosis. NCT03019939 is an investigator-initiated, phase 2 trial of PAP with ISAV in patients with AML/MDS.MethodsTreatment-naïve adult patients with AML or MDS initiating remission-induction chemotherapy (RIC) received ISAV per the dosing recommendations in the United States label until recovery from neutropenia (neutrophils (ANC) ≥ 0.5 × 109/L) and attainment of complete remission (CR), occurrence of proven or probable invasive fungal infection (IFI, EORTC/MSG criteria), or for a maximum of 12 weeks. The primary endpoint was incidence of proven/probable IFI during the study period (up to 30 days from the last dose of ISAV).Results67 patients were enrolled (April 28, 2017 to February 14, 2019) and 60 patients were eligible for assessment (median age 67 years, 57 patients with AML, median ANC on enrollment was 660). Reasons for study completion were achievement of CR with ANC recovery (n = 35), completion of 12 weeks of PAP (n = 9), possible IFI (n = 7), investigator decision (n = 3), death (n = 2, 1 disease progression, 1 cardiac arrest), proven/probable IFI (n = 3), and mild transaminitis, possibly ISAV-related (n = 2). The median durations of neutropenia and ISAV ppx were 33 (7–86) and 31 (7–86) days, respectively. One microbiologically-proven (gluteal abscess due to Candida glabrata) and 2 cases of probable breakthrough IFIs (probable IA with positive galactomannan) occurred (IFI incidence 5%). ISAV trough serum concentrations were available in 31 patients on both day 8 (median 3.74 µg/mL, 2.03–7.65) and day 15 (median 4.10 µg/mL, 2.17–9.25), and were not significantly different.ConclusionISAV is a safe and effective alternative for PAP in patients with newly diagnosed AML/MDS undergoing RIC, with a breakthrough (proven/probable) IFI rate of 5%. ISAV serum levels were adequate in patients with AML/MDS undergoing RIC. Pharmacological features make ISAV attractive for PAP in the era of recently approved or emerging small-molecule AML therapies.Disclosures All authors: No reported disclosures.

1719. Incidence and Characterization of Invasive Fungal Infections (IFIs) in Patients with Chronic Lymphocytic Leukemia (CLL) Treated with Ibrutinib (IBR)

BackgroundIBR is a Bruton’s tyrosine kinase inhibitor, and plays a key role in the treatment of CLL. In randomized clinical trials, <1% of IBR-treated CLL patients developed IFIs. However, several IFIs were reported with real-life use of IBR.MethodsThis is a retrospective observational study of all CLL patients (> 18 years) treated with IBR (2/2014–8/2018) at MD Anderson Cancer Center. We excluded patients with active IFI (proven and probable, EORTC/MSG criteria) at the start of IBR and patients with <6 months of follow-up.ResultsOf the 821 CLL IBR-treated patients, 24 developed probable or proven IFI (2.9%). Of these infections, 21 occurred within 30 days (d) of last IBR dose, while 3 IFIs occurred at 94, 135 and 221 d post IBR, respectively. The majority of patients with IFI were male (83%) with a median age of 66 years at IFI diagnosis. The median prior lines of therapy for CLL was 1 (range 0–7), with 29% receiving IBR as frontline treatment. Five patients had evidence of Richter’s transformation at the time of IFI diagnosis, while two patients had prior stem cell transplant. The average time from start of IBR to diagnosis of IFI was 338 d, with only 7 cases of IFI within the first 3 months of IBR. The majority of IFIs were proven/probable aspergillosis (63%), including 9 cases of Aspergillus fumigatus. The remaining infections consisted of Cryptococcus neoformans (21%), Fusarium spp. (8%), with one case each of candidiasis, histoplasmosis, mucormycosis, and Pneumocystis jiroveci pneumonia. Three patients had evidence of poly-fungal IFI. The sites of infection were pulmonary (88%), blood (13%), CNS (13%), and sinus (8%). Five patients were diagnosed with disseminated IFI, including Cryptococcus spp. (2 cases), Rhizopus spp., Aspergillus spp., and Candida spp. The 42-day mortality rate post IFI diagnosis was 25%.ConclusionWe report the largest single-center cohort of CLL patients on IBR to date. The IFI incidence of 2.9% (24/821) is consistent with most previous reports estimating a 0.5–4% incidence. In contrast to published reports, close to 1/3 of our patients with IFI received IBR as frontline therapy and most IFIs (71%) were diagnosed > 3 months after starting IBR. We are currently conducting a case–control comparison with IBR–treated CLL patients with no infection to uncover risk factors associated with IFIs in these patients.DisclosuresSamuel L. Aitken, PharmD, Melinta Therapeutics: Grant/Research Support, Research Grant; Merck, Sharpe, and Dohme: Advisory Board; Shionogi: Advisory Board.