Case Commentary: Long-Term Fosmanogepix Use in a Transplant Recipient with Disseminated Aspergillosis Caused by Azole-Resistant Aspergillus calidoustus

ABSTRACT

Aspergillus calidoustus is an emerging, azole-resistant, cryptic Aspergillus species in immunosuppressed patients that often features extrapulmonary involvement and carries high mortality. The case presented by J. F. Camargo, R. Jabr, A. D. Anderson, L. Lekakis, et al. (Antimicrob Agents Chemother 66:e02206-21, 2022, https://doi.org/10.1128/aac.02206-21) describes a transplant recipient with disseminated A. calidoustus infection who was successfully treated with surgical source control, tapering of immunosuppression, and long-term, combination antifungal treatment that included the first-in-class fosmanogepix, which targets fungal mannoprotein trafficking and anchoring.

INTRODUCTION

The case report by Camargo et al. presents a 40-year-old man with a history of allogeneic hematopoietic stem cell transplantation (HSCT) complicated by chronic graft-versus-host disease who developed disseminated infection caused by the multidrug-resistant Aspergillus species Aspergillus calidoustus (1). A. calidoustus was first described in 2008 when clinical and environmental strains previously thought to be Aspergillus ustus were found to be genetically distinct (2); its genome was annotated only recently (3). Like Aspergillus ustus, A. calidoustus typically forms velvety gray to brown colonies with a yellowish reverse color and often a soluble yellow-brown pigment, and it exhibits intrinsic resistance to triazoles in vitro. Phenotypically, A. calidoustus can be distinguished from A. ustus by its ability to grow at 37°C and a positive Ehrlich reaction, which detects indole metabolite production (2).

The number of reported infections caused by A. calidoustus has been increasing. The species gained attention when it was described as the fifth most common species among a large collection of 218 clinical Aspergillus isolates from the Transplant-Associated Infection Surveillance Network (TRANSNET) (4), and it was reported to cause invasive aspergillosis (IA), alongside other cryptic Aspergillus species, in patients with inborn errors of antifungal immunity such as chronic granulomatous disease (5). In the largest multicenter international retrospective study, of 72 cases, of IA caused by species within the Aspergillus section Usti (group, ustus) to date, A. calidoustus was the most frequent causal species (45%) (6). Importantly, mortality was high (58%), 33% of patients had disseminated disease most often involving the skin, soft tissue, and/or brain, and combination antifungal therapy was used in 67% of cases. A total of 80% of patients were transplant recipients (47% HSCT; 33% solid-organ, with lung and heart being most common). Only 8% were neutropenic at the time of IA diagnosis, but 84% were receiving long-term immunosuppressive therapy, with the majority being on corticosteroids and/or calcineurin inhibitors; these clinical features are evident in other retrospective studies (7, 8) and in this case report (1).

Importantly, infections by A. calidoustus (and other Aspergillus cryptic species) often emerge in the setting of mold-active triazole prophylaxis (6, 7, 9–11), as illustrated in the patient who was receiving isavuconazole at IA diagnosis (1). This is consistent with the ability of A. calidoustus to grow in vitro despite high azole concentrations (12, 13). Genome analysis of A. calidoustus has revealed a methionine to valine substitution in one of two Cyp51A-like proteins in a locus thought to be homologous to the methionine at position 220 of the Cyp51A gene in Aspergillus fumigatus, which is involved in azole resistance and may underlie intrinsic azole resistance in A. calidoustus (14). Amphotericin B, echinocandins, and terbinafine show in vitro activity against most, but not all, strains of A. calidoustus (12). Moreover, there is evidence of in vitro activity of certain newer antifungal agents against this organism, including the long-acting echinocandin rezafungin and the pyrimidine synthesis inhibitor olorofim (15, 16). Fosmanogepix, used in this report (1), is a first-in-class N-phosphonooxymethylene prodrug that is converted to manopegix and potently inhibits the fungal Gwt1 enzyme involved in glycosylphosphatidylinositol-mannoprotein biosynthesis and anchoring (17). Fosmanogepix exhibits in vitro activity against multiple Aspergillus species (including A. ustus) and other yeast and mold fungi, has shown efficacy in mouse models of IA caused by A. fumigatus and other invasive mycoses, and is currently being evaluated in a phase 2 clinical trial in patients with invasive infections caused by Aspergillus species and rare molds (NCT04240886) (17–19).

It is difficult to fully attribute the patient’s clinical and radiographic improvement and galactomannan decline to fosmanogepix alone, as multiple therapeutic interventions likely contributed, including surgical source control achieved by iliofemoral thrombectomy and mitral valve vegetectomy, tapering of immunosuppression, and coadministration of liposomal amphotericin B, terbinafine, micafungin, and isavuconazole. Although in vitro Aspergillus susceptibility (MIC) and synergy (checkerboard) testing results can be challenging to correlate to patient IA outcomes, the combination of voriconazole and terbinafine was synergistic against A. calidoustus in vitro and in a Galleria model of infection (20–23), and successful use of isavuconazole with terbinafine was recently reported in another HSCT recipient with A. calidoustus infection (24). Despite these confounding factors, it is notable that long-term fosmanogepix administration was well tolerated and safe, and when it was eventually used as a monotherapy, no clinical relapse or galactomannan level increases were seen (1). The use of serum galactomannan is well established as a surrogate biomarker for monitoring clinical outcomes in IA caused by A. fumigatus (25). This report (1) indicates that serum galactomannan levels, which are typically increased in IA caused by A. calidoustus (6), may also be useful in monitoring treatment responses during A. calidoustus infection, as recently suggested for mice (26).

Growing evidence indicates that certain small-molecule kinase inhibitors may predispose patients to IA. For example, the Bruton tyrosine kinase ibrutinib is implicated in IA with markedly increased incidence when corticosteroids and/or chemotherapeutic agents are coadministered (27, 28). The patient reported by Camargo and colleagues was receiving low-dose prednisone (10 mg daily) and tacrolimus, but also the Janus-associated kinase (JAK) inhibitor ruxolitinib, at the time of IA diagnosis (1). Several JAK inhibitor-associated opportunistic fungal (and other) infections have been reported, including IA (29, 30), and JAK-signal transducer and activator of transcription (STAT) signaling promotes neutrophil oxidative burst in response to Aspergillus (31). Thus, receipt of ruxolitinib in the reported patient may have contributed to his immunosuppressive state and development of IA. Importantly, increased awareness is required by infectious disease experts in recognizing the emerging and expanding roles that novel immune function-targeted biologics play in promoting susceptibility to opportunistic fungal (and other) infections (28, 32).

In summary, this case further highlights the emergence of life-threatening infections by azole-resistant cryptic Aspergillus species in immunosuppressed patients. It also illustrates the complexities and therapeutic challenges associated with the optimal management of patients with breakthrough, often azole-resistant, invasive mold disease, which remains poorly defined (33). The use of fosmanogepix in additional patients and the completion of its phase 2 clinical trial for the treatment of various invasive mold infections will shed more light on the safety, tolerability, extrapulmonary penetration, and efficacy of this novel antifungal.

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