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. 2006 Sep;50(9):3011-8.
doi: 10.1128/AAC.00254-06.

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, Gabrijela Ergovic, Natasa Marsic, Mihael Skerlev, Joachim Mittendorf, Ulrich Geschke, Axel Schmidt, Wolfgang Schoenfeld
Affiliations

In vitro activity and in vivo efficacy of icofungipen (PLD-118), a novel oral antifungal agent, against the pathogenic yeast Candida albicans

Andreja Hasenoehrl et al. Antimicrob Agents Chemother. 2006 Sep.

Abstract

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 degrees C using an inoculum of 50 to 100 CFU/well. The MICs for 69 Candida albicans strains ranged from 4 to 32 microg/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.

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Figures

FIG. 1.
FIG. 1.
Efficacy of icofungipen in the C. albicans lethal infection model in mice. Ten animals per group were infected with 106 yeasts (ATCC 200498) intravenously 30 min prior to the first dosing and treated with icofungipen orally b.i.d. at indicated dosages for 4 days. MIC of icofungipen, 1 μg/ml. All treated groups showed significant survival in comparison to controls (P values of at least <0.002, calculated according to survival curves and a chi-square test).
FIG. 2.
FIG. 2.
Efficacy of icofungipen (ICO) and FLC in the lethal C. albicans infection model in mice. Mice were infected with FLC-susceptible (FLC-S; MIC, ≤4 mg/liter) and FLC-resistant (FLC-R; MIC, ≥64 mg/liter) strains. Cumulative survival is shown for the two isolate and treatment groups. Each treatment arm represents the survival data from infection experiments with 27 different clinical isolates; group size was 5 mice per strain (total number of mice per treatment arm, 135). Icofungipen (10 mg/kg twice daily) and FLC (2 mg/kg/day) were given orally twice daily for 4 days. n.s., not significant. P values were calculated according to survival curves and a chi-square test.
FIG. 3.
FIG. 3.
Efficacy of icofungipen in a lethal systemic C. albicans (ATCC 200498) infection in rats. Icofungipen was given at 1, 2.5, and 5 mg/kg orally b.i.d. for 5 days (days 0 to 4), with intravenous infection of C. albicans at day 0. Rats (n = 10 per treatment arm) were observed for up to 40 days, and no further changes in survival in the treated groups were observed (data not shown). All treated groups showed significant survival in comparison to controls (P values of at least <0.02, calculated according to survival curves and a chi-square test).
FIG. 4.
FIG. 4.
Efficacy of a single oral dose of icofungipen in rats with a lethal systemic C. albicans (ATCC 200498) infection (n = 5). Icofungipen was given 30 min after the intravenous inoculation of C. albicans (5 × 106 CFU).
FIG. 5.
FIG. 5.
Influence of l-isoleucine on the in vivo efficacy of icofungipen in the C. albicans (ATCC 200498) mouse infection model. CFW1 mice (n = 10) were infected intravenously and treated orally b.i.d. for 4 days. Icofungipen was given alone or was mixed prior to the dosing with an equimolar amount of l-isoleucine. Differences between the icofungipen- and icofungipen-plus-isoleucine-treated animals were not statistically significant, as calculated according to survival curves and a chi-square test.
FIG. 6.
FIG. 6.
Influence of l-isoleucine on the in vivo efficacy of icofungipen in the C. albicans (ATCC 200498) rat infection model. Rats (n = 10) were infected intravenously and treated orally b.i.d. for 4 days. Icofungipen was given alone or mixed prior to the dosing with an equimolar amount of l-isoleucine.
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