*Purpose: Isavuconazole (ISA) is a broad-spectrum triazole antifungal approved in 2015 for the treatment of invasive aspergillosis and mucormycosis. While it is increasingly used in solid organ transplant (SOT) recipients particularly when other azoles are contraindicated, there are limited data on breakthrough invasive fungal infection (IFI) outcomes in this context. Here, we describe the rate and characteristics of breakthrough IFI among SOT patients receiving ISA treatment and prophylaxis.

*Methods: We retrospectively reviewed University of California, San Francisco inpatient and outpatient pharmacy records from 3/2015-4/2018 to identify adult SOT patients who received ≥7 days of ISA. IFI and response to therapy were defined by EORTC-MSG criteria. Breakthrough IFI was defined as the diagnosis of IFI due to a different organism than originally detected prior to initiation of ISA, or diagnosis of IFI after ≥7 continuous days of ISA use or within 14 days of discontinuing ISA.

*Results: We identified 28 SOT recipients who received ≥7 days of ISA in 29 separate episodes. Of these patients, 15 (53.5%) were lung transplant recipients, 5 (17.9%) liver, 3 (10.7%) kidney, 2 (7.1%) heart, and 3 (10.7%) dual transplant (heart/lung, heart/kidney, liver/kidney). The majority of patients received ISA for empiric or directed treatment of fungal infection, with the remaining 39.3% receiving it for prophylaxis. Median duration of ISA was 57 days (range 7-601). The most common reasons for choosing ISA over other antifungal agents was its broad spectrum including mucormycosis (28.5%), lack of QTc prolongation (21.4%), fewer drug-drug interactions compared to other azoles (14.2%), and intolerance of other azoles (10.7%). Three patients (10.7%) developed proven or probable breakthrough IFI (Table 1). All presented with pulmonary infection, including 2 cases of pulmonary mucormycosis (Rhizopus spp) and a case of Candida empyema. When measured, ISA levels demonstrated adequate absorption (see Table). Mortality with breakthrough IFI was high: 2 of 3 died.

*Conclusions: We demonstrate a 10.7% rate of breakthrough IFI among SOT patients who received ISA. This is similar to recently published rates (12-13%) of ISA breakthrough among hematologic malignancy patients. Further study is needed to characterize risk factors for and epidemiology of ISA breakthrough to help guide optimal ISA use and management of these difficult cases.

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