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Invasive fungal diseases (IFDs) have become major causes of morbidity and mortality among highly immunocompromised patients. Authoritative consensus criteria to diagnose IFD have been useful in establishing eligibility criteria for antifungal trials. There is an important need for generation of consensus definitions of outcomes of IFD that will form a standard for evaluating treatment success and failure in clinical trials. Therefore, an expert international panel consisting of the Mycoses Study Group and the European Organization for Research and Treatment of Cancer was convened to propose guidelines for assessing treatment responses in clinical trials of IFDs and for defining study outcomes. Major fungal diseases that are discussed include invasive disease due to Candida species, Aspergillus species and other molds, Cryptococcus neoformans, Histoplasma capsulatum, and Coccidioides immitis. We also discuss potential pitfalls in assessing outcome, such as conflicting clinical, radiological, and/or mycological data and gaps in knowledge.

Objectives: The therapeutic efficacy of caspofungin alone and in combination with amphotericin B deoxycholate was evaluated in treatment of murine coccidioidomycosis., Methods: Survival and tissue burdens of the spleens and livers were used as antifungal response markers. In a monotherapy study, caspofungin was injected intraperitoneally at 0.1, 0.2, 0.5, 1 and 5 mg/kg per day on days 2 through 15. Amphotericin B deoxycholate was given at 0.1, 0.2 and 0.5 mg/kg intravenously and 1 and 5 mg/kg intraperitoneally three times per week for 2 weeks. In a combination therapy study, amphotericin B deoxycholate at 0.1 mg/kg was administered intravenously three times per week for 2 weeks, respectively, with and without caspofungin intraperitoneally given at 0.1, 0.5 and 5 mg/kg daily on days 2 through 15 post-infection., Results: The study shows that caspofungin and amphotericin B deoxycholate at > or =0.5 and > or =0.1 mg/kg, respectively, were significant in both prolongation of survival and reduction of the tissue fungal burdens of mice compared with controls. No sterilization of either organ was observed with caspofungin doses. In combination therapy, any combination of caspofungin (0.1, 0.5 and 5 mg/kg) with amphotericin B deoxycholate (0.1 mg/kg) improved the period of survival and significantly reduced spleen and liver counts compared with controls., Conclusions: This study indicates that caspofungin has efficacy against systemic coccidioidomycosis in a murine model given in combination with amphotericin B deoxycholate.

The difficulties in managing this potentially horrific disease, with its myriad manifestations, are immense, because host factors dramatically impact outcome. Coccidioidomycosis should warrant great respect among clinicians, because, even with dramatic improvements in therapies, outcomes remain poor. Although there have been outstanding successes with these new therapies, tragic losses after years of immense patient suffering still occur. Coccidioidomycosis is a geographically restricted fungus but is one that inflicts tremendous suffering on affected patients. In addition, because of travel and the influx of susceptible hosts, dramatic increases in patients at risk for infection are seen throughout the southwest United States. The extended-spectrum azoles, such as posaconazole and voriconazole, may prove to be more efficacious in the treatment of coccidioidomycosis than prior agents, including amphotericin B, fluconazole, and itraconazole. Additional resources are needed to conduct randomised, controlled clinical trials for the treatment of this disease.

Background: Disseminated coccidioidomycosis (which is caused by the endemic fungi of the genus Coccidioides) can be a life-threatening systemic fungal infection. Although conventional antifungal therapies have activity against Coccidioides, the disease can be refractory to standard therapies. Drug-associated toxicities also may limit the clinical utility of the standard antifungal drugs. In addition, relapses in patients with disseminated coccidioidomycosis are common, making long-term management of this disease challenging., Methods: We report the outcomes of 6 patients with coccidioidomycosis who were treated with posaconazole salvage therapy after treatment with conventional antifungal therapies failed to produce sustained clinical improvement. Patients were administered posaconazole oral suspension 800 mg/day in divided doses as part of an open-label clinical trial. A modified version of the Mycoses Study Group Coccidioides scoring system was used to evaluate the burden of disease. Posaconazole therapy resulted in rapid clinical improvements in the signs and symptoms of coccidioidomycosis., Results: At the end of therapy, 5 of 6 patients had successful outcomes. Posaconazole was well tolerated despite long-term administration (1-2 years), and 2 patients continued to receive posaconazole maintenance therapy at the time of writing., Conclusions: The successful outcomes observed in this case series suggest that posaconazole is an effective therapy for coccidioidomycosis.

The therapeutic efficacy of three lipid formulations of amphotericin B was compared with that of conventional amphotericin B in treatment of murine coccidioidomycosis. All treatments prolonged survival compared with the no-treatment group (P < 0.0001). Although conventional amphotericin B was more active than lipid formulations on reducing quantitative fungal load on a milligram-per-kilogram basis (P < 0.003 to 0.0002), the lipid preparations could be administered at higher doses, sterilizing liver and spleen tissues. The efficacies of the lipid preparations were similar in this murine model of coccidioidomycosis.

Posaconazole (SCH 56592) was tested against 25 strains of Coccidioides immitis to determine their in vitro susceptibilities. The geometric mean 48-h MIC of posaconazole (POSA) was 0.5 microg/ml, the MIC range was 0.25 to 1 microg/ml, and the MIC at which 50% of the isolates tested are inhibited (MIC50) and the MIC90 were 0.5 and 1 microg/ml, respectively. The geometric mean 48-h MIC of itraconazole (ITRA) was 0.23 microg/ml, the MIC range was 0.125 to 0.5 microg/ml, and the MIC50 and MIC90 were both 0.25 microg/ml. Two strains of C. immitis were selected for in vivo studies on the basis of the POSA 48-h MICs for the isolates. POSA orally administered at 0.01, 0.1, 0.5, 1, 5, and 10 mg/kg of body weight/day was compared with ITRA administered at 10 and 30 mg/kg three times a day. The spleens and livers of mice that died or survived to day 50 were removed to measure the fungal burdens. Mice had >or=90% survival when they were treated with >or=0.5 mg of POSA per kg or 30 mg of ITRA per kg. Cultures of whole spleens and livers from mice treated with 10 mg of POSA per kg showed >or=70% sterilization. No sterilization of whole spleens and livers from mice treated with ITRA was seen. POSA displayed potent in vivo activity against the two strains of C. immitis tested.

Presents a letter to the editor in response to a case study about patients treated with posaconazole.