SCH 56592, Amphotericin B, or Itraconazole Therapy of Experimental Murine Cerebral Phaeohyphomycosis Due to Ramichloridium obovoideum (“ Ramichloridium mackenziei ”)

Abstract

Ramichloridium obovoideum ("Ramichloridium makenziei") is a rare cause of lethal cerebral phaeohyphomycosis. It has been, so far, geographically restricted to the Middle East. BALB/c mice were inoculated with two strains of R. obovoideum intracranially. Therapy with amphotericin B, itraconazole, or the investigational triazole SCH 56592 was conducted for 10 days. Half the mice were monitored for survival and half were killed for determination of the fungal load in brain tissue. Recipients of SCH 56592 had significantly prolonged survival and lower brain fungal burden, and this result was found for mice infected with both of the fungal strains tested. Itraconazole reduced the brain fungal load in mice infected with one strain but not the other, while amphotericin B had no effect on brain fungal concentrations. This study indicates a possible role of SCH 56592 in the treatment of the serious cerebral phaeohyphomycosis due to R. obovoideum.Dematiaceous fungi, the agents of phaeohyphomycosis, cause a variety of clinical syndromes (9). These vary from superficial skin infection to lethal cerebral disease (4,6,8). Several species of the dematiaceous fungi are neurotropic, i.e., have a predilection for central nervous system tissue, causing brain lesions and/or abscesses. These include Cladophialophora bantiana, Wangiella dermatitidis, Chaetomium spp., Exophiala spp., Curvularia spp., Bipolaris spp., and a few other species (1, 2, 4, 5).Ramichloridium obovoideum ("Ramichloridium mackenziei") is a rare cause of cerebral phaeohyphomycosis. It seems to be geographically restricted, as all cases have been reported from the Middle East or natives of the Middle East who lived in other countries (3,7,11). Reported cases have involved both immunocompromised and apparently immunocompetent patients. The infection was lethal for almost all patients with reported cases of infection, despite surgery and, in some cases, antifungal therapy. In the study described here we developed a murine model of infection with R. obovoideum and tested currently available (amphotericin B, itraconazole) and investigational (SCH 56592; Schering-Plough Research Institute Inc., Kenilworth, N.J.) antifungal agents in vitro and in an experimental murine model. MATERIALS AND METHODSPathogen. R. obovoideum ("R. mackenziei") 653 (gift from S. Al-Hedaithy, Riyadh, Saudi Arabia) and 95-1147 (Fungus Testing Laboratory, San Antonio, Tex.) were used for the in vitro testing and the experimental infection of BALB/c nu/ϩ mice. R. obovoideum 653 was also used to establish infection in ICR mice. R. obovoideum strains were grown on potato dextrose agar (PDA) medium plates (BBL, Baltimore Biologics, Cockeysville, Md.) for 14 days at 37°C. Surface growth was washed with sterile 0.85% normal saline and was filtered through layers of sterile glass wool. Homogeneous suspensions of the appropriate conidial concentration were prepared by using hemacytometer counts. The conidial suspension was administered in 0.2 ml for the intravenous inoculations and in 0.06 ml for the int...

First Autochthonous Case of Rhinocladiella mackenziei Cerebral Abscess Outside the Middle East

“…Only a single patient is reported to have survived an R. mackenziei cerebral infection, with pronounced radiological and clinical improvement after switching therapy from a combination of liposomal amphotericin B, flucytosine, and itraconazole to posaconazole (2). This account is supported by in vitro results and data from a murine infection model (1), in which posaconazole prolonged the survival of mice and reduced the brain fungal burdens compared to the survival of and burdens in mice treated with itraconazole and amphotericin B.…”

Fonsecaea pugnacius, a Novel Agent of Disseminated Chromoblastomycosis

“…Agents of cerebral infection mostly cause primary cerebral infection, where neurological symptoms are the first indications of infection and spreading from other sites to the brain takes place unnoticed (38). The main neurotropic agents in the Chaetothyriales are Cladophialophora bantiana (39,40), Rhinocladiella mackenziei (41)(42)(43), and Fonsecaea monophora (17). Exophiala dermatitidis is also neurotropic but tends to cause disseminated infections (44).…”

Effect of Efflux Inhibition on Brain Uptake of Itraconazole in Mice Infected withCryptococcus neoformans

“…Many articles have reported the use of ITC in the treatment of cerebral cryptococcosis (Van Cutsem, 1993) or other brain infections (Al-Abdely et al, 2000;Saulsbury, 2001). Although effective against the pathogens, the efficacy of ITC in the treatment of cerebral infections seems to be limited by its poor brain uptake.…”