Posaconazole Alone and in Combination with Caspofungin for Treatment of Experimental Exserohilum rostratum Meningoencephalitis: Developing New Strategies for Treatment of Phaeohyphomycosis of the Central Nervous System

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.

Keywords: experimental Exserohilum rostratum meningoencephalitis; posaconazole and caspofungin combination; rabbits.

Figure 1

Inoculum–response studies in experimental E. rostratum meningoencephalitis (ERM), as measured in mean log CFU/g ± SEMs in cerebrum, cerebellum, and spinal cord versus log CFU/inoculum of organism in the immunocompromised rabbit model. Four rabbits were inoculated in each inoculum group. Values are expressed as mean log CFU/g ± SEMs.

Figure 2

Response of Exserohilum rostratum meningitis in persistently neutropenic rabbits to antifungal therapy measured by mean residual tissue fungal burden (log CFU/g) in cerebrum, cerebellum, spinal cord, and paravertebral muscle. There were six rabbits in each treatment group and untreated control rabbits. Values are given as means of log CFU/g± SEMs. *, p < 0.05; **, p < 0.01, ***, p < 0.001, significant decrease in residual fungal burden in rabbits treated with posaconazole at 10 mg/kg/d, 20 mg/kg/d, and in combination with caspofungin in comparison to that of untreated controls (UC).

Figure 3

CSF (1→3)-β-d-glucan levels in rabbits of the experimental Exserohilum rostratum meningitis model in groups of untreated controls (UC), and rabbits receiving oral dose of posaconazole alone and in combination with caspofungin. There were six rabbits in each treatment group and untreated control rabbits. Values are given as mean (1→3)-β-d-glucan levels pg/mL ± SEMs; * p < 0.05.