Abstract
Phaeohyphomycosis of the central nervous system (CNS) is a life-threatening infection associated with severe morbidity. New approaches to treatment of CNS phaeohyphomycosis are critically needed. We therefore studied posaconazole with or without caspofungin for treatment of experimental CNS phaeohyphomycosis caused by Exserohilum rostratum. Each clinical isolate of E. rostratum isolate was inoculated intracisternally with 1.0 × 106 microconidia to fully anesthetized New Zealand White rabbits. Profound persistent neutropenia and immunosuppression were established and maintained using cytarabine and methylprednisolone, respectively. Study groups consisted of posaconazole suspension administered as oral formulation at 10 (PSC10) or 20 (PSC20) mg/kg, caspofungin (CFG) at 2 mg/kg intravenously (IV), combinations of PSC10+CFG or PSC20+CFG, and untreated controls (UC). Posaconazole produced a significant reduction of residual fungal burden of E. rostratum in cerebrum, cerebellum, spinal cord, and paravertebral muscle (p < 0.01), in comparison to UC. The combination of PSC10+CFG and PSC20+CFG achieved full clearance of residual fungal burden from cerebrum, while only PSC20+CFG treated rabbits demonstrated clearance from cerebellum, spinal cord, and paravertebral muscle (p < 0.01). These data correlated with the significant reduction of CSF (1→3)-β-d-glucan levels in rabbits treated with PSC20 and PSC20+CFG in comparison to those of UC (p < 0.05). Posaconazole alone or in combination with caspofungin demonstrated significant antifungal efficacy in the treatment of experimental E. rostratum meningoencephalitis and warrants further study for treatment of CNS phaeohyphomycosis.
Highlights
Phaeohyphomycosis of the central nervous system (CNS) is a life-threatening infection associated with severe morbidity and high mortality [1,2,3,4,5,6]
Posaconazole produced a significant reduction of residual fungal burden of E. rostratum in cerebrum, cerebellum, spinal cord, and paravertebral muscle (p < 0.01) in comparison to untreated controls (UC)
This study found that posaconazole alone or in combination with caspofungin demonstrated significant antifungal efficacy in the treatment of experimental E. rostratum meningoencephalitis in persistently neutropenic immunocompromised rabbits
Summary
Phaeohyphomycosis of the central nervous system (CNS) is a life-threatening infection associated with severe morbidity and high mortality [1,2,3,4,5,6]. J. Fungi 2020, 6, 33 phaeohyphomycosis, Exserohilum rostratum has been found to be especially virulent as a CNS pathogen following the administration of contaminated methylprednisolone, resulting in meningoradiculitis, brain abscesses, ensuing neurologic deficits, and death [7,8]. Posaconazole is cited as a potential treatment option for the management of CNS phaeohyphomycosis [9], it is not well defined or supported by preclinical in vivo or clinical data for this indication. While voriconazole or liposomal amphotericin B may be effective in some patients, mortality and morbidity remains high and toxicity from either agent may be dose limiting
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