Paradoxical worsening on olorofim in patients undergoing treatment for invasive fungal diseases.

OBJECTIVES

Paradoxical reactions to appropriate antimicrobial therapy are seldom reported in systemic fungal diseases. Olorofim (formerly F901318) is an orally available first-in-class antifungal and exhibits in vitro killing. Recently, an open-label, single-arm phase IIb study (NCT03583164) enrolling patients with invasive fungal diseases for which there were limited or no other treatment options was completed. During the conduct of this trial, several investigators noted a transient worsening of disease in a subset of treated patients despite subsequent improvement, and we aimed to describe these patients in detail to assist clinicians prescribing olorofim treatment.

METHODS

Detailed methods and results of the phase 2b trial have been previously described, and a subsequent managed access programme used the same rules as the phase 2b study for enrolment (combined N = 470). Briefly, patients with hyaline moulds, thermally dimorphic fungi, or other fungi requiring sponsor approval were enrolled and given olorofim therapy. A paradoxical reaction was defined as worsening clinical or radiological findings following initiation of treatment (olorofim) in the absence of evidence for underlying disease worsening/relapse or the presence of an alternative diagnosis after initiation of treatment.

RESULTS

Case review identified six patients meeting criteria, and 4/6 were immunocompetent. The timing of paradoxical responses was variable and ranged from days to months following initiation of olorofim. All patients were maintained on olorofim and paradoxical reactions resolved without specific intervention, and all patients exhibited a subsequent successful response to therapy.

CONCLUSIONS

Paradoxical reactions to appropriate antimicrobial therapy are infrequently observed in systemic fungal diseases. Similar responses are seen in the treatment of both tuberculosis (worsening of lymphadenitis) and leprosy (reversal reactions), suggesting a similar pathophysiologic mechanism may be responsible given the overlapping immune response between mycobacterial and fungal pathogens. Awareness of this potential syndrome is essential during the treatment of patients with olorofim therapy.