Results Obtained with Various Antifungal Susceptibility Testing Methods Do Not Predict Early Clinical Outcome in Patients with Cryptococcosis

Abstract

The in vitro susceptibilities of Cryptococcus neoformans isolates from consecutive human immunodeficiency virus-positive and -negative patients to the antifungal agents fluconazole, amphotericin B, and flucytosine were determined by different techniques, including the CLSI method, Etest, and broth microdilution in yeast nitrogen base (YNB) medium, during a multicenter prospective study in France. The relationship between the in vitro data and the clinical outcome 2 weeks after the initiation of antifungal therapy was assessed. In addition, the correlation between the strain serotype and the in vitro activities of the antifungals was determined, and the susceptibility results obtained with the different techniques were also compared. Thirty-seven patients received a combination of amphotericin B with flucytosine as first-line therapy, 22 were treated with amphotericin B alone, and 15 received fluconazole alone. Whatever the antifungal tested, there was no trend toward higher MICs for strains isolated from patients who failed to respond to a given therapy compared to those from patients who did not with either the CLSI method, Etest, or broth microdilution in YNB medium. The MICs obtained by the CLSI or Etest method were significantly lower for serotype D strains than for serotype A strains for both fluconazole and amphotericin B, while flucytosine MICs were not different according to serotype. These findings suggest that the in vitro antifungal susceptibility of C. neoformans, as determined with the techniques used, is not able to predict the early clinical outcome in patients with cryptococcosis.

Correlation of Genotype and In Vitro Susceptibilities of Cryptococcus gattii Strains from the Pacific Northwest of the United States

“…Clearly, there are differences between the subtypes, and these differences need to be further explored. (1,8). The authors of these manuscripts reached opposite conclusions, with one study stating that among AIDS patients high fluconazole MICs may be predictive for patients who will not respond to fluconazole therapy (1), and the other study stating that among HIV-positive and -negative patients treated with fluconazole alone, there was no correlation between MICs and clinical success or failure (8).…”

Cryptococcus neoformans-Cryptococcus gattii Species Complex: an International Study of Wild-Type Susceptibility Endpoint Distributions and Epidemiological Cutoff Values for Fluconazole, Itraconazole, Posaconazole, and Voriconazole

“…While CBPs predict clinical outcome of therapy, the role of the ECV is to detect emerging resistance or those non-WT strains with reduced susceptibility (due to mutations) to the agent being evaluated. Attempts to correlate in vitro fluconazole results with clinical outcome have not been successful (15,55) and, to our knowledge, have not been reported for the other three triazoles. Therefore, CBPs for either C. neoformans or C. gatti infections versus any antifungal agent are not available due to the paucity of data on PK/PD and clinical outcomes compared to MICs.…”

“…The more geographically restricted C. gattii (serotypes B and C) causes infections among immunocompromised as well as nonimmunocompromised patients, and the infections are more difficult to treat (27,38). Irrespective of the species, cryptococcal disease is associated with high mortality rates (Ն12.7%) (15,17,38). Using molecular methodologies, eight major molecular types have been identified among the four serotypes and their hybrids (4,6,8,25,31,51).…”

PI3K signaling of autophagy is required for starvation tolerance and virulenceof Cryptococcus neoformans

“…These analyses, used to predict antifungal resistance during clinical infections, were conducted under nutrient-replete conditions as recommended by the National Committee for Clinical Laboratory Standards (45,46). Unfortunately, cryptococcal fungal MICs have shown a remarkable inability to predict clinical endpoints (47), which could be partly due to differences in antifungal resistance within differing nutrient environments.…”