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Antimicrobial Agents and Chemotherapy, May 2001, p. 1355-1359, Vol. 45, No. 5
0066-4804/01/$04.00+0   DOI: 10.1128/AAC.45.5.1355-1359.2001
Copyright © 2001, American Society for Microbiology. All rights reserved.

Interactions of Posaconazole and Flucytosine against Cryptococcus neoformans

Francesco Barchiesi,1,* Anna Maria Schimizzi,1 Laura K. Najvar,2 Rosie Bocanegra,2 Francesca Caselli,1 Simona Di Cesare,1 Daniele Giannini,1 Luigi Falconi Di Francesco,1 Andrea Giacometti,1 Flavia Carle,3 Giorgio Scalise,1 and John R. Graybill2

Istituto di Malattie Infettive e Medicina Pubblica1 and Centro Interdipartimentale di Epidemiologia, Biostatistica e Informatica Medica,3 Università degli Studi di Ancona, Ancona, Italy; and University of Texas Health Science Center at San Antonio and Audie Murphy Veterans Administration Hospital, San Antonio, Texas2

Received 16 October 2000/Returned for modification 27 November 2000/Accepted 5 February 2001

A checkerboard methodology, based on standardized methods proposed by the National Committee for Clinical Laboratory Standards for broth microdilution antifungal susceptibility testing, was applied to study the in vitro interactions of flucytosine (FC) and posaconazole (SCH 56592) (FC-SCH) against 15 isolates of Cryptococcus neoformans. Synergy, defined as a fractional inhibitory concentration (FIC) index of <0.50, was observed for 33% of the isolates tested. When synergy was not achieved, there was still a decrease in the MIC of one or both drugs when they were used in combination. Antagonism, defined as a FIC of >4.0, was not observed. The in vitro efficacy of combined therapy was confirmed by quantitative determination of the CFU of C. neoformans 486, an isolate against which the FC-SCH association yielded a synergistic interaction. To investigate the potential beneficial effects of this combination therapy in vivo, we established two experimental murine models of cryptococcosis by intracranial or intravenous injection of cells of C. neoformans 486. At 1 day postinfection, the mice were randomized into different treatment groups. One group each received each drug alone, and one group received the drugs in combination. While combination therapy was not found to be significantly more effective than each single drug in terms of survival, tissue burden experiments confirmed the potentiation of antifungal activity with the combination. Our study demonstrates that SCH and FC combined are significantly more active than either drug alone against C. neoformans in vitro as well in vivo. These findings suggest that this therapeutic approach could be useful in the treatment of cryptococcal infections.

* Corresponding author. Mailing address: Istituto di Malattie Infettive e Medicina Pubblica, Azienda Ospedaliera Umberto I°, Via Conca-Torrette, 60020, Ancona, Italy. Phone: 39. 71. 5963467. Fax: 39. 71. 5963468. E-mail: cmalinf{at}popcsi.unian.it.

Antimicrobial Agents and Chemotherapy, May 2001, p. 1355-1359, Vol. 45, No. 5
0066-4804/01/$04.00+0   DOI: 10.1128/AAC.45.5.1355-1359.2001
Copyright © 2001, American Society for Microbiology. All rights reserved.


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