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Usual Susceptibility Patterns for Cryptococcus spp.
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 [1180, 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 Susceptibility Database
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].
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References
123. Arikan, S., and J. H. Rex. 2000. NS-718. Current Opinion in Anti-infective Investigational Drugs Journal. 2:413-415.
187. Barchiesi, F., A. M. Schimizzi, F. Caselli, A. Novelli, S. Fallani, D. Giannini, D. Arzeni, S. Di Cesare, L. F. Di Francesco, M. Fortuna, A. Giacometti, F. Carle, T. Mazzei, and G. Scalise. 2000. Interactions between triazoles and amphotericin B against Cryptococcus neoformans. Antimicrob. Agents Chemother. 44:2435-2441.
343. Burgess, D. S., and R. W. Hastings. 2000. A comparison of dynamic characteristics of fluconazole, itraconazole, and amphotericin B against Cryptococcus neoformans using time-kill methodology. Diagn Microbiol Infect Dis. 38:87-93.
385. Carrillo-Munoz, A. J., G. Quindos, C. Tur, M. T. Ruesga, Y. Miranda, O. del Valle, P. A. Cossum, and T. L. Wallace. 1999. In vitro antifungal activity of liposomal nystatin in comparison with nystatin, amphotericin B cholesteryl sulphate, liposomal amphotericin B, amphotericin B lipid complex, amphotericin B desoxycholate, fluconazole and itraconazole. J Antimicrob Chemother. 44:397-401.
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1382. Lozano-Chiu, M., M. A. Ghannoum, P. Belanger, and J. H. Rex. 1997. Effect of Media on Detection of Amphotericin B (AmB)-Resistant Cryptococcus neoformans. 97th General Meeting of the American Society for Microbiology, Abstract No. C-251.
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1945. Rodriguez-Tudela, J. L., F. Martin-Diez, M. Cuenca-Estrella, L. Rodero, Y. Carpintero, and B. Gorgojo. 2000. Influence of shaking on antifungal susceptibility testing of Cryptococcus neoformans: a comparison of the NCCLS standard M27A medium, buffered yeast nitrogen base, and RPMI-2% glucose. Antimicrob. Agents Chemother. 44:400-404.
1992. Saag, M. S., G. A. Cloud, J. R. Graybill, J. D. Sobel, C. U. Tuazon, P. C. Johnson, W. J. Fessel, B. L. Moskovitz, B. Wiesinger, D. Cosmatos, L. Riser, C. Thomas, R. Hafner, and W. E. Dismukes. 1999. A comparison of itraconazole versus fluconazole as maintenance therapy for AIDS-associated cryptococcal meningitis. Clin Infect Dis. 28:291-296.
2226. Tawara, S., F. Ikeda, K. Maki, Y. Morishita, K. Otomo, N. Teratani, T. Goto, M. Tomishima, H. Ohki, A. Yamada, K. Kawabata, H. Takasugi, K. Sakane, H. Tanaka, F. Matsumo, and S. Kuwahara. 2000. In vitro activities of a new lipopeptide antifungal agent, FK463, against a variety of clinically important fungi. Antimicrob. Agents Chemother. 44:57-62.
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2378. Warnock, D. W., E. M. Johnson, and T. R. F. Rogers. 1998. Multi-centre evaluation of the Etest method for antifungal drug susceptibility testing of Candida spp. and Cryptococcus neoformans. J Antimicrob Chemother. 42:321-331.
2451. Witt, M. D., R. J. Lewis, R. A. Larsen, E. N. Milefchik, M. A. E. Leal, R. H. Haubrich, J. A. Richie, J. E. Edwards, Jr., and M. A. Ghannoum. 1996. Identification of patients with acute AIDS-associated cryptococcal meningitis who can be effectively treated with fluconazole: The role of antifungal susceptibility testing. Clin. Infect. Dis. 22:322-328.
2472. Yildiran, S. T., M. A. Saracli, A. W. Fothergill, and M. G. Rinaldi. 2000. In vitro susceptibility of environmental Cryptococcus neoformans variety neoformans isolates from Turkey to six antifungal agents, including Posaconazole and voriconazole. Eur. J. Clin. Microbiol. Infect. Dis. 19:317-319.
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