Experimental Models of Disseminated Scedosporiosis with Cerebral Involvement

Abstract

Scedosporium apiospermum is a soil fungus which can cause severe and often fatal cerebral infections in both immunocompetent patients in the event of near drowning and immunosuppressed patients such as lung transplant recipients. Because of the low susceptibility of this fungus to antifungal drugs, and the low permeability of the blood-brain barrier (BBB), therapeutic drug monitoring is necessary to reach an effective tissue concentration with limited side effects. Indeed, diffusion of the drug in the brain is dependent on several parameters, such as the integrity of the BBB and the activity of efflux pumps. To evaluate drug diffusion, two experimental models were developed in immunocompetent and immunosuppressed rats. Inocula were administered via the penile vein and a clinical scale (0-9) was established, based on weight and clinical and neurologic signs evaluated by the tail suspension test. Cerebral involvement was confirmed by magnetic resonance imaging and histologic examination of brain sections after hematoxylin-eosin-safran or silver staining. Voriconazole or posaconazole was given to the rats at doses ranging from 10 to 75 mg/kg/day via i.v. or oral routes, respectively. Whatever the immune status, the effective doses (defined by a doubling of the survival time and the absence of neurologic sequelae) were 30 mg/kg/day for voriconazole and 50 mg/kg/day for posaconazole. Overall, the results demonstrated that these models may constitute valuable tools for the performance of pharmacokinetic and pharmacodynamic studies for pharmacokinetic-pharmacodynamic modeling.

Trypanosoma brucei CYP51: Essentiality and Targeting Therapy in an Experimental Model

“…A more recently approved delayed-release oral tablet could reduce inter-patient variability and can be taken once daily without the need for food intake to support adequate absorption [73,74]. Data concerning posaconazole diffusion into the brain are limited [75,76], although efficacy when treating invasive cerebral fungal infections have been reported in murine models [77] and clinical cases reports, suggesting that it crosses the blood brain barrier in sufficient quantities to treat cerebral fungal infection and thus possibly treat late stage sleeping sickness [78–80]. The recent results in a phase II clinical trial with posaconazole for Chagas disease have been disappointing [81].…”

Methodologies for in vitro and in vivo evaluation of efficacy of antifungal and antibiofilm agents and surface coatings against fungal biofilms

“…Some examples include the development of a sinusitis infection model 209 , a rat model to study asthma 275 and a guinea pig endophthalmitis model 228 . In addition to Cryptococcus and Aspergillus , model systems for other environmental fungi have also been developed such as a fusariosis model system 276 , a sporotrichosis model system 277 , a mucorales model system 278 279 and a model system for Scedosporium 280 (see Table 1). Efficacy of treatment of these fungal infections is often performed by non-culture based methods, such as qPCR to determine organ fungal burden 281 .…”

Mycetoma Medical Therapy

“…Sc. apiospermum experimental infection in mouse and guinea pig has shown the efficacy of voriconazole and posaconazole [56] – [58] . A high dose of posaconazole was required for efficacy in a murine model of disseminated Sc.…”