Recent developments in pradimicin-benanomicin and triazole antibiotics.
Fungal infections are on the rise as the number of patients with compromised immune systems continues to increase. The need for safer and more effective antifungals has resulted in the search for novel drug classes and for modifications to existing classes, with the aim of enhancing their antifungal spectra and potency. In this review, two classes of antifungals are discussed: the pradimicin-benanomicin antibiotics and the newer triazole derivatives. These have activity against Candida spp., Cryptococcus neoformans and Aspergillus spp., as well as variable activity against other less commonly encountered fungi including Pneumocystis carinii. Pradimicins-benanomicins are generally fungicidal, whereas the newer azoles appear to be selectively fungicidal to Cryptococcus neoformans and Aspergillus spp. Pradimicin-benanomicin acts by binding to mannan and alters membrane integrity. One water-soluble pradimicin candidate, BMS-181184, has been selected for clinical development. The triazoles act by inhibiting cytochrome P450 sterol 14a-demethylase. Four triazoles either currently in clinical development (voriconazole and D0870) or being considered as clinical candidates (ER-30346 and Sch 56592) will be discussed. The antifungal spectra, pharmacokinetic and toxicologic data in animals, and efficacy results in experimental infection models will be reviewed for BMS-181184 and the four newer triazoles. Results from the early clinical trials for voriconazole and D0870 will also be discussed.
Bristol-Myers Squibb Pharmaceutical Research Institute, Wallingford, Connecticut 06492-7660, USA.
J C
JC
Fung-Tomc
D P
DP
Bonner