In Vivo Efficacy of Olorofim against Systemic Scedosporiosis and Lomentosporiosis

Abstract

Clinically relevant members of the Scedosporium/Pseudallescheria species complex and Lomentospora prolificans are generally resistant against currently available systemic antifungal agents in vitro, and infection due to these species is difficult to treat. We studied the in vivo efficacy of a new fungicidal agent, olorofim (formerly F901318), against scedosporiosis and lomentosporiosis in neutropenic animals. Cyclophosphamide-immunosuppressed CD-1 mice infected by Scedosporium apiospermum, Pseudallescheria boydii (Scedosporium boydii), and Lomentospora prolificans were treated by intraperitoneal administration of olorofim (15 mg/kg of body weight every 8 h for 9 days). The efficacy of olorofim treatment was assessed by the survival rate at 10 days postinfection, levels of serum (1-3)-β-d-glucan (BG), histopathology, and fungal burdens of kidneys 3 days postinfection. Olorofim therapy significantly improved survival compared to that of the untreated controls; 80%, 100%, and 100% of treated mice survived infection by Scedosporium apiospermum, Pseudallescheria boydii, and Lomentospora prolificans, respectively, while less than 20% of the control mice (phosphate-buffered saline [PBS] treated) survived at 10 days postinfection. In the olorofim-treated neutropenic CD-1 mice infected with any of the three species, serum BG levels were significantly suppressed and fungal DNA detected in the target organs was significantly lower than in controls. Furthermore, histopathology of kidneys revealed no or only a few lesions with hyphal elements in the olorofim-treated mice, while numerous fungal hyphae were present in control mice. These results indicate olorofim to be a promising therapeutic agent for systemic scedosporiosis/lomentosporiosis, devastating emerging fungal infections that are difficult to treat with currently available antifungals.

Keywords: F901318; Lomentospora prolificans; Pseudallescheria boydii; Scedosporium apiospermum; lomentosporiosis; neutropenia; olorofim; scedosporiosis.

FIG 1

Efficacy of olorofim against S. apiospermum in CD-1 mice. CD-1 mice were treated for 9 days with either 15 mg/kg olorofim or PBS every 8 h via intraperitoneal administration, starting 6 h postinfection (intravenous [i.v.]) with 1 × 10⁴ conidia/mouse S. apiospermum (DI-17-07). Animals were randomized into groups of 17. (A) The survival rate of mice (n = 10) was monitored for 10 days. (B) On day 3 postinfection, blood samples were collected from olorofim-treated and untreated mice (n = 3) to measure (1-3)-β-d-glucan (BG) in serum samples. ***, P ≤ 0.001. (C) In addition, on day 3 postinfection, kidneys were harvested (n = 4) and fungal burdens estimated by quantification of fungal DNA using qPCR. ****, P ≤ 0.0001. Error bars show standard deviations.

FIG 2

Efficacy of olorofim against P. boydii in CD-1 mice. The CD-1 mice were treated for 9 days with either 15 mg/kg olorofim or PBS every 8 h via intraperitoneal administration, starting 6 h postinfection (i.v.) with 1 × 10⁴ conidia/mouse P. boydii (DI-17-11). Animals were randomized into groups of 17. (A) The survival rate of mice (n = 10) was monitored for 10 days. (B) On day 3 postinfection, blood samples were collected from olorofim-treated and untreated mice (n = 3) to measure (1-3)-β-d-glucan (BG) in serum samples. ***, P ≤ 0.001. (C) In addition, on day 3 postinfection, kidneys (n = 4) were harvested and fungal burdens estimated by quantification of fungal DNA using qPCR. ****, P ≤ 0.0001. Error bars show standard deviations.

FIG 3

Efficacy of olorofim against L. prolificans in CD-1 mice. The CD-1 mice were treated for 9 days with either 15 mg/kg olorofim or PBS every 8 h via intraperitoneal administration, starting 6 h postinfection (i.v.) with 1 × 10⁴ conidia/mouse L. prolificans (DI-17-14). Animals were randomized into groups of 17. (A) The survival rate of mice (n = 10) was monitored for 10 days. (B) On day 3 postinfection, blood samples were collected from olorofim-treated and untreated mice (n = 3) to measure (1-3)-β-d-glucan (BG) in serum samples. ****, P ≤ 0.0001. (C) In addition, on day 3 postinfection, kidneys (n = 4) were harvested and fungal burdens estimated by quantification of fungal DNA using qPCR. **, P ≤ 0.01. Error bars show standard deviations.

FIG 4

Representative sections of GMS-stained kidneys of CD-1 mice infected with Lomentospora prolificans. Histopathology sections of kidneys in CD-1 mice at day 3 postinfection showed numerous fungal elements throughout the organ in control group mice infected with any of the three etiological agents of scedosporiosis/lomentosporiosis. However, only a few lesions with hyphal elements were observed in the animals that received olorofim therapy.