Pliva Pharmaceutical Company has announced the development of PLD-118, a novel antifungal compound which demonstrates in vitro activity against many strains of the yeast, "Candida," including those that have become resistant to one of the most frequently prescribed drugs, fluconazole.

PLD-118, which has yet to be given a generic name, constitutes an entirely unique class of antifungal drugs. Derived from a naturally occurring beta-amino acid, cispentacin, PLD-118 is accumulated intracellularly by susceptible fungi. It then works by inhibiting the action of isoleucyl-tRNA synthetase, an enzyme vital to fungal protein synthesis and hence, fungal cell growth. This dual mechanism of action is entirely different from currently prescribed antifungal medications as well as other investigational drugs.

Systemic and cutaneous fungal infections remain a challenge to the medical community in this era of HIV and hospital-acquired infections. Yet, few novel classes effective against yeast infections have been discovered. Treatment is based mainly on the use of azoles, polyenes, and the newly introduced echinocandins -- the latter two are only available intravenously and the former group is facing drug resistance.

Data from in vitro assays, in vivo animal studies, and Phase I clinical trial of this investigational new antifungal will be presented at the 41st Interscience Conference on Antimicrobial Agents and Chemotherapy (ICAAC), the American Society for Microbiology's Annual Meeting on Infectious Diseases.

These data reveal PLD-118 to be potentially safe, well-tolerated, and active against a broad spectrum of yeasts, including "Candida albicans" and non-albicans species, such as "C. glabrata," "C. krusei," and "C. tropicalis."

Currently, the most commonly prescribed class of antifungal compounds are the azoles (fluconazole, clotrimazole, ketoconazole, and itraconazole). However, the rise of the AIDS epidemic, and the use of potent antibiotic and chemotherapeutic agents has led to increasing numbers of intensive care and immunocompromised patients with azole-resistent systemic fungal infections. This is especially significant because "Candida albicans" is now the fourth most common type of pathogen identified in hospital-acquired infections.

In vitro, PLD-118 reduced the growth of "Candida" species, including "C. albicans" strains and non-albicans "Candida" species that are resistant to azole antifungals. In vivo, studies of PLD-118 in mice and rats have also demonstrated the compound to be highly active; depending on dose, up to 100% of animals survived an otherwise lethal dose of "C. albicans" administered intravenously. This includes data from experiments where 100% of non-treated controls and 89% of animals infected with fluconazole-resistant strains and subsequently treated with fluconazole died.

Due to its unique mechanism of action, PLD-118 demonstrates no cross-resistance to existing antifungal classes. It has a high bioavailability with low plasma protein binding. PLD-118 is distributed homogeneously throughout animal tissues and is excreted via the kidneys almost entirely unchanged, thus, is unlikely to contribute to drug-drug interactions. In humans, peak plasma concentrations are reached within approximately 1 hour of administration (slightly longer if taken with a meal), and the mean half-life is 6 to 7 hours.

In animal and Phase I human trials, PLD-118 appears to be safe and well tolerated. In the first human study conducted on PLD-118, there were only 8 adverse events reported -- all of which were categorized as mild to moderate, pointing to PLD-118 as potentially safe with minimal side effect potential.