Central Nervous System Fungal Infections

Meningitis Due to Cryptococcus neoformans: Treatment with Posaconazole

Background: Central nervous system infections caused by Cryptococcus neoformans remain to be opportunistic infections with high mortality in severely immunocompromised patients such as patients with AIDS. Amphotericin B deoxycholate and fluconazole remain to be the drugs of choice; however, in consideration of the intolerance to amphotericin B deoxycholate and the possible resistance to fluconazole, it is necessary to evaluate other azoles, such as posaconazole, that have demonstrated lower adverse events. The objective of this study was to describe the characteristics and clinical and microbiological response of the use of posaconazole in patients with CNS infections caused by C. neoformans.

Methods: We designed a case study that included eight patients diagnosed with AIDS and cryptococcal meningitis. Seven patients were treated with 800 mg of posaconazole orally for 28 days.

Results: During the second week of treatment, a cerebrospinal fluid (CSF) culture was performed and was negative for the development of C. neoformans. The patients showed an improvement in signs and symptoms of impairment of the CNS such as reduction of cephalea, fever, visual disturbances such as double vision, meningism and papilledema, and improved alertness and environmental awareness.

Conclusions: CNS fungal infections usually occur in immunocompromised patients. The use of systemic antifungal agents contributes to the development of fungal resistance. The results of this study suggest that posaconazole is a good alternative in the treatment of fungal CNS infection due to C. neoformans.

Antifungal Therapy Used in Central Nervous System Fungal Infections

Amphotericin B remains an important choice for central nervous system (CNS) fungal infections, although its adverse effects have limited its use, especially nephratoxicity. New formulations of amphotericin B, new azoles and echinocandins have been developed for clinical use in the past decade. However, high mortality is associated with CNS fungal infections, especially those due to filamentous fungi. Mortality risk of cerebral mucormycosis approaches 100% although amphotericin B and neurosurgical intervention are used. Use of voriconazole has improved prognosis of cerebral aspergillosis. However, the mortality risk of the disease remains 70%. The antifungal therapy of minimum of CNS fungal infections due to yeast fungi and endemic fungi, such as Candida spp. Cryptococcus neoformans, Coccidioides immitis, Histoplasma capsulatum, and Blastomyces dermatitidis has been standardized. However, high mortality and increase of CNS fungal infections resistant to standard therapy is waiting for utility of new antifungal options. The treatment of CNS fungal infections due to less common and newly emerging fungi, such as Acremonium species, Fusarium species, Pacilomyces species, Trichoderma species, Trichosporon species, Zygomycetes, and Phaeohyphomectes is challenging and no well-designed studies have been carried out, the available data are based on case reports. In conclusion, the prognosis of CNS fungal infections is not good. Early diagnosis, appropriate use of antifungal agents and management of underlying disease, in combination with neurosurgical intervention may improve the outcome.

Posaconazole: A New Antifungal Weapon

The last twenty years, the incidence of invasive fungal infections (IFI) has risen dramatically due to the prolongation of survival of patients with multiple risk factors for fungal infections. Amphotericin B was for more than 40 years the gold standard for almost all IFI, but toxicity and resistance, especially of new and emerging pathogens remained important issues. Fluconazole and itraconazole have also the same disadvantage of resistance. Voriconazole, a new triazole antifungal has offered an additional option, but the problem of resistant aspergillosis, and zygomycosis remains. Echinocandins (caspofungin, micafungin and anidulafungin) are active only against Candida and Aspergillus spp., but not against Fusarium, Scedosporium and Zygomycetes. Posaconazole is the most recently approved triazole with broad spectrum activity against Candida spp., Aspergillus spp., Cryptococcus neoformans, Zygomycetes, dermatiaceous, dimorphic, and other fungal pathogens. Interestingly, posaconazole is active against Candida spp., resistant to fluconazole and itraconazole, and Aspergillus fumigatus resistant to fluconazole itraconazole, amphotericin B, and voriconazole. The results from clinical trials of posaconazole as salvage treatment are encouraging. Multicenter clinical trials have also established its role in the prophylaxis of (IFI) in the severely immunocompromised patients such as those after hematopoietic stem cell transplantation (HSCT) who developed graft versus host disease (GVHD), as well as the neutropenic patients with an acute myelogenous leukemia (AML) or myelodysplastic syndrome (MDS) after myeloablative chemotherapy. Posaconazole has pharmacokinetic advantages and low side effect profile, which are very important, especially in the seriously ill population.