Breakthrough Invasive Fungal Infections on Isavuconazole Prophylaxis and Treatment: What Is Happening in the Real-World Setting?

To the Editor—Invasive fungal infections (IFIs) cause significant morbidity and mortality among immunocompromised hosts (IHs), particularly in those with hematologic malignancy and following stem-cell and solid organ transplantation. Prophylaxis with mold-active antifungals such as voriconazole and posaconazole is widely employed in high-risk populations to decrease IFIs and improve patient outcomes [1, 2]. Breakthrough IFIs due to resistant and atypical fungal pathogens are now increasingly described, however [3].

Isavuconazole is a broad-spectrum triazole antifungal approved by the Food and Drug Administration in 2015 [4] for treatment of invasive aspergillosis and mucormycosis [5, 6]. Although trials (NCT03019939) evaluating isavuconazole as antifungal prophylaxis in IHs are ongoing, it has already been implemented in many clinical settings [1] due to its broad spectrum of activity, ease of dosing, limited need for drug level monitoring, and favorable side effect and drug-drug interaction profile [4].

Little is known about the risk of breakthrough IFI with isavuconazole, particularly in the real-world setting. In a phase I trial of intravenous isavuconazole prophylaxis in acute myeloid leukemia patients, 18% (2/11) of patients in the low-dose arm (200 mg daily after loading) had treatment discontinued due to possible fungal infection [7]. In their 2016 abstract, Dadwal et al evaluated breakthrough IFIs among 131 patients at a single center with hematologic malignancy receiving more than 7 days of isavuconazole for empirical or directed treatment. Six (4.6%) patients developed breakthrough IFI, including 4 cases of proven/probable Aspergillus (unspecified species), 1 case of Rhizopus, and 1 case of Candida novegensis [8]. Another 2017 abstract retrospectively reviewed hematologic malignancy patients (N = 39) at MD Anderson Cancer Center receiving more than 7 days of isavuconazole prophylaxis or treatment, with 10% of patients developing proven/probable breakthrough IFI [9]. Among the 4 microbiologically-confirmed pathogens, 2 were mucormycosis, 1 was Candida parapsilosis, and 1 was Candida guillermondii.

At our institution, we have been selectively using isavuconazole as primary or secondary prophylaxis in patients where voriconazole or posaconazole were contraindicated due to intolerance, need to avoid drug-drug interactions such as QT prolongation, or prior infection with resistant pathogens. Here we outline 5 cases of microbiologically confirmed breakthrough IFI among high-risk hematologic malignancy and organ transplant patients on isavuconazole for prophylaxis and treatment (Table 1). All patients presented with pneumonia, including 2 cases due to Aspergillus nigri group, a nonfumigatus Aspergillus species that exhibits increased minimum inhibitory concentrations to isavuconazole [10]. Additional breakthrough IFI pathogens included Rhizopus spp., Scedosporium apiospermum, and Aspergillus fumigatus. All patients received oral isavuconazole at standard dosing. In 2 cases, isavuconazole levels were measured and demonstrated adequate absorption. All cases were treated with escalation to liposomal amphotericin B with or without a second antifungal agent (triazole or echinocandin). The risk of mortality with breakthrough IFI was high: 3 of 5 died.

Table 1.

Breakthrough Invasive Fungal Infections on Isavuconazole Prophylaxis and Treatment

Age/ Sex	Disease and Transplant Status	Duration of Neutropeniaa	ISA Indication	ISA Duration	ISA Level (mcg/mL)	Breakthrough Infection	Organism Identified	Diagnostic Tests	ISA MIC (mg/L)c	Treatment	Responsed (Cause of Death)
44/F	Pre-B ALL s/p allo-SCT	5 months	Primary prophylaxis	2 months	2.8	Pneumonia	Aspergillus nigri group	Lung FNA: PCRb, septate hyphae on KOH, Aspergillus on path	N/A	L-AMB/VRC to L-AMB	Partial responsee
63/F	Multiple myeloma	8 days	Treatment of pneumonia	4 months	N/A	Pneumonia	Aspergillus nigri group	BAL: PCRb	N/A	L-AMB/VRC to L-AMB/POS	Partial responsee
68/M	Heart transplant Renal transplant	N/A	Secondary IA prophylaxis	4 weeks	2.2	Pneumonia	Rhizopus spp.	Lung FNA: fungal culture	0.5	L-AMB/CAS lobectomy	Death at week 5 (unknown)
65/M	Aplastic anemia s/p allo-SCT	1 month	Primary prophylaxis	13 days	N/A	Pneumonia fungemia	Scedosporium apiospermum	Blood culture	4	L-AMB/CAS to VRC/CAS	Death at week 4 (respiratory failure)
37/M	Relapsed refractory AML	4 months	Primary prophylaxis	5 weeks	N/A	Pneumonia	Aspergillus fumigatus	BAL: fungal culture	0.5	L-AMB/CAS to VRC/CAS	Death at week 7 (refractory AML)

Abbreviations: Allo-SCT, allogeneic stem cell transplant; AML, acute myelogenous leukemia; BAL, bronchoalveolar lavage; CAS, caspofungin; FNA, fine needle aspiration; IA, invasive aspergillosis; ISA, isavuconazole; KOH, potassium hydroxide preparation; L-AMB, liposomal amphotericin B; M/F, male/female; MIC, minimum inhibitory concentrations; N/A, not available; path, pathology; PCR, polymerase chain reaction; POS, posaconazole; VRC, voriconazole.

^aNeutropenia defined as absolute neutrophil count <1000 cells/mm³.

^bFungal PCR with internal transcribed spacer (ITS) primers performed at University of Washington.

^cDetermined using Clinical and Laboratory Standards Institute microtiter dilution [11].

^dResponse to antifungal therapy as defined per Mycoses Study Group consensus criteria [12].

^ePartial response defined as radiologic stabilization (0–25% reduction in diameter of lesion) and resolution of attributable symptoms and signs of disease [12].

Although isavuconazole is an important therapeutic option in the management of IFIs, the epidemiology and microbiology of breakthrough infections on this agent are not well understood. To help guide optimal empirical management in these difficult cases, additional studies are needed to systematically evaluate breakthrough IFIs on isavuconazole given concern for azole-resistant or emerging fungal pathogens.

Note

Potential conflicts of interest. All authors: No reported conflicts of interest. All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Conflicts that the editors consider relevant to the content of the manuscript have been disclosed.