Antifungal Resistance and Predictors of Response in Patients with Hematologic Malignancy

BACKGROUND: Invasive aspergillosis (IA) causes significant morbidity and mortality in patients with hematologic malignancies (HM). Azole resistance has emerged as a therapeutic challenge in managing IA. The aim of this study was to investigate Aspergillus susceptibility to antifungals over the past decade among HM patients, and correlate susceptibility to clinical outcomes. METHODS: All Aspergillusisolates banked from 2002 to 2014 isolated from HM patients with probable/proven IA were tested for antifungal susceptibility. Patients with hematopoietic cell transplant, duplicate and non-viable isolates were excluded. Data were collected on demographics and clinical factors that could affect the treatment response, antifungal susceptibility (MICs/MECs), and treatment response at 14, 30, and 90 days. RESULTS: Forty patients were identified. MICs for amphotericin B slightly increased over the past decade (R = 0.32, P = 0.09), but were stable for voriconazole (R = −0.08, P = 0.61). The MIC50 during the first 3 years (2002–2004) and last 3 years (2012–2014) for amphotericin B were 0.5 and 1 mg/l, and for voriconazole 0.5 and 1. Mean age 56 years, 48% male, 82% had active HM and 45% had received chemotherapy within 14 days of IA. 50% were neutropenic and 30% had circulating blasts. Forty percent were on antifungal prophylaxis. Seventy-five percent of isolates were A. fumigatus. Fourteen responded to treatment (TR) and 26 were non-responders (NTR), and they did not differ in baseline characteristics. However, neutropenia (14% TR vs. 58%, NTR, P < 0.017) and circulating blasts (0% TR vs. 35% NTR, P < 0.02) at 14 days differed. The MIC50 for voriconazole was 0.5 mg/l in both groups, and for amphotericin B was 0.25 in TR vs. 1 mg/l in NTR. Fourteen-day response correlated with 90-day response (R = 0.74, P < 0.01) which validated the use of 14-day response for clinical outcome. All responders on amphotericin B at 14, 30, and 90 days had isolates with MIC < 1, whereas no apparent MIC-response correlation was found for voriconazole. CONCLUSION: Although not statistically significant, a trend of increasing Aspergillus amphotericin B MICs was observed over the past decade. Neutropenia and persistent disease correlated with treatment failure. Clinical response was not affected by the azole or polyene MICs. DISCLOSURES: J. Ito, Astellas: Speaker’s Bureau, Speaker honorarium. S. Dadwal, Merck: Investigator, Research support. GlaxoSmithKline: Investigator, Research support. Ansun Biopharma: Investigator, Research support. Oxford Immunotec: Investigator, Research support. Gilead Sciences: Investigator, Research support