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Antimicrobial Agents and Chemotherapy, September 2006, p. 3011-3018, Vol. 50, No. 9
0066-4804/06/$08.00+0     doi:10.1128/AAC.00254-06
Copyright © 2006, American Society for Microbiology. All Rights Reserved.

In Vitro Activity and In Vivo Efficacy of Icofungipen (PLD-118), a Novel Oral Antifungal Agent, against the Pathogenic Yeast Candida albicans

Andreja Hasenoehrl,1 Tatjana Galic,1 Gabrijela Ergovic,1 Natasa Marsic,1 Mihael Skerlev,2 Joachim Mittendorf,3 Ulrich Geschke,3 Axel Schmidt,4 and Wolfgang Schoenfeld1*

GlaxoSmithKline Research Centre Zagreb Ltd., Zagreb, Croatia,1 University of Zagreb Medical School, Department of Dermatology and Venerology, Zagreb, Croatia,2 Bayer AG, Pharma Research, Wuppertal, Germany,3 Bayer HealthCare AG, Monheim, Germany4

Received 1 March 2006/ Returned for modification 5 April 2006/ Accepted 1 July 2006

Icofungipen (PLD-118) is the representative of a novel class of antifungals, beta amino acids, active against Candida species. It has been taken through phase II clinical trials. The compound actively accumulates in yeast, competitively inhibiting isoleucyl-tRNA synthetase and consequently disrupting protein biosynthesis. As a result, in vitro activity can be studied only in chemically defined growth media without free amino acids that would compete with the uptake of the compound. The MIC of icofungipen was reproducibly measured in a microdilution assay using yeast nitrogen base medium at pH 6 to 7 after 24 h of incubation at 30 to 37°C using an inoculum of 50 to 100 CFU/well. The MICs for 69 Candida albicans strains ranged from 4 to 32 µg/ml. This modest in vitro activity contrasts with the strong in vivo efficacy in C. albicans infection. This was demonstrated in a lethal model of C. albicans infection in mice and rats in which icofungipen showed dose-dependent protection at oral doses of 10 to 20 mg/kg of body weight per day in mice and 2 to 10 mg/kg/day in rats. The in vivo efficacy was also demonstrated against C. albicans isolates with low susceptibility to fluconazole, indicating activity against azole-resistant strains. The efficacy of icofungipen in mice and rats was not influenced by concomitant administration of equimolar amounts of L-isoleucine, which was shown to antagonize its antifungal activity in vitro. Icofungipen shows nearly complete oral bioavailability in a variety of species, and its in vivo efficacy indicates its potential for the oral treatment of yeast infections.

* Corresponding author. Present address: EUCODIS GmbH, Brunnerstrasse 59, A-1230 Vienna, Austria. Phone: 43 1 86634 9240. Fax: 43 1 86634 449. E-mail: schoenfeld{at}eucodis.com.

Antimicrobial Agents and Chemotherapy, September 2006, p. 3011-3018, Vol. 50, No. 9
0066-4804/06/$08.00+0     doi:10.1128/AAC.00254-06
Copyright © 2006, American Society for Microbiology. All Rights Reserved.





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