In Vitro Susceptibility
Amphotericin B and other polyenes
Amphotericin B exerts a fungicidal effect on Cryptococcus neoformans [343]. As with Candida spp., the NCCLS method has difficulty distinguishing amphotericin B-resistant isolates from the susceptible ones. However, modifications of this method, such as the use of Antibiotic Medium 3 supplemented to 2% glucose (AM3) instead of the reference RPMI 1640 medium appear useful [427, 1141, 1379, 1382, 1383, 1835]. Shaking the microplates during incubation also appears helpful [1945].
There are also data indicating that minimum fungicidal concentrations (MFCs) may be better predictors of clinical outcome than MICs [1940]. However, these modifications still require validation and standardization. Using E test method instead of NCCLS microdilution methodology may also enhance the detection of amphotericin B-resistant isolates, regardless of the test medium used [1383]. The other method under investigation, flow cytometry, in general yields rapid and correlated results with NCCLS reference method and for amphotericin B and fluconazole [1868].
Variety-related differences in susceptibility patterns have also been observed. Cryptococcus neoformans var. gattii appears less susceptible to amphotericin B and flucytosine than var. neoformans [427]. Defects in sterol isomerase and depletion of ergosterol content in fungal cell membrane may result in emergence of resistance to amphotericin B [7 isomerase in a Cryptococcu…, 1757].
The novel lipid nanosphere-encapsulated amphotericin B formulation, NS-718, generates very low MICs [123, 1071]. Similar to amphotericin B, liposomal nystatin and the parent compound nystatin also show favorable in vitro activity against most Cryptococcus neoformans isolates [385, 1129].
Promisingly, amphotericin B combined with fluconazole, itraconazole, or posaconazole yielded no antagonism in vitro and appeared synergistic for some isolates [187]. In vitro synergy between amphotericin B and flucytosine or rifampin was observed for Cryptococcus neoformans strains isolated from patients who failed to respond to amphotericin B therapy [1939].
Azoles
Azoles, particularly fluconazole and itraconazole, have been shown to have fungistatic effects against most Cryptococcus neoformans isolates [343]. Although most Cryptococcus neoformans strains are susceptible to fluconazole, isolates with high MICs have been detected [1118, 1742, 2451]. Alternative susceptibility testing methods may yield results that differ sharply from the NCCLS reference method. Using Etest instead of the reference microdilution method has resulted in misclassification of a number of susceptible Cryptococcus neoformans isolates as being resistant to fluconazole, itraconazole, and flucytosine [2378]. Colorimetric methods, on the other hand, might interpret some fluconazole- and flucytosine-resistant isolates as susceptible [1367].
Similarly, most of the Cryptococcus neoformans strains are susceptible to itraconazole in vitro [576]. Among the newer azoles, posaconazole (SCH56592) appears most potent on a weight basis, when compared to voriconazole , fluconazole, itraconazole, and ketoconazole [1049, 2472].
Flucytosine
Flucytosine has long been used as part of combination therapy of cryptococcal infections. Resistance may develop during monotherapy [2292]. Use of yeast nitrogen base as the test medium was reported to be very effective in some investigators’ hands in testing flucytosine susceptibility [1770].
Glucan Synthesis Inhibitors
(Echinocandins)
These novel agents have essentially no activity against Cryptococcus neoformans [2226]. In vitro data suggest that activities of amphotericin B and fluconazole against Cryptococcus neoformans may be enhanced by caspofungin [759].
For additional data, go to the N/A(L):Susceptibility Database
In Vivo Efficacy
The most commonly used agents for treatment of cryptococcal infections are amphotericin B, flucytosine, and fluconazole, and particularly amphotericin B and flucytosine in combination. Fluconazole prophylaxis is also in common practice in patients who have recovered from cryptococcal infections. However, clinical failure with fluconazole has been reported [1742]. Fluconazole combined with flucytosine [1471] and triple therapy with amphotericin B, flucytosine, and fluconazole have been reported as effective [1143]. Itraconazole is less effective than fluconazole as maintenance therapy [1992].