In vitro antifungal and fungicidal spectra of a new pradimicin derivative, BMS-181184

Abstract

A new pradimicin derivative, BMS-181184, was compared with amphotericin B and fluconazole against 249 strains from 35 fungal species to determine its antifungal spectrum. Antifungal testing was performed by the broth macrodilution reference method recommended by the National Committee for Clinical Laboratory Standards (document M27-P, 1992). BMS-181184 MICs for 97% of the 167 strains of Candida spp., Cryptococcus neoformans, Torulopsis glabrata, and Rhodotorula spp. tested were Յ8 g/ml, with a majority of MICs being 2 to 8 g/ml. Similarly, for Aspergillus fumigatus and 89% of the 26 dermatophytes tested BMS-181184 MICs were Յ8 g/ml. BMS-181184 was fungicidal for the yeasts, dermatophytes, and most strains of A. fumigatus, although the reduction in cell counts was less for A. fumigatus than for the yeasts. BMS-181184 was active against Sporothrix schenckii, dematiaceous fungi, and some members of the non-Aspergillus hyaline hyphomycetes. BMS-181184, however, was not fungicidal against members of the family Dematiaceae. BMS-181184 lacked activity or had poorer activity (MICs, Ն16 g/ml) against Aspergillus niger, Aspergillus flavus, Malassezia furfur, Fusarium spp., Pseudallescheria boydii, Alternaria spp., Curvularia spp., Exserohilum mcginnisii, and the zygomycetes than against yeasts. The activity of BMS-181184 was minimally (twofold or less) affected by changes in testing conditions (pH, inoculum size, temperature, the presence of serum), testing methods (agar versus broth macrodilution), or test media (RPMI 1640, yeast morphology agar, high resolution test medium). Overall, our results indicate that BMS-181184 has a broad antifungal spectrum and that it is fungicidal to yeasts and, to a lesser extent, to filamentous fungi.

Molecular Identification andIn VitroResponse to Antifungal Drugs of Clinical Isolates of Exserohilum

“…are very variable; however, they are scarce and, in general, are from studies performed before the standardization of the procedures for antifungal susceptibility testing for molds (2,5,11,12,16). The high in vitro activity of all the antifungals tested here against Exserohilum is remarkable, although it is unknown how this can be translated to clinical practice.…”

Overview of SPA-S-843 in vitro Activity against Filamentous Fungi

“…In the present study, we compared the in vitro activity of SPA-S-843 and of AmB against filamentous fungi by determining the MICs with the broth macrodilution technique, by adapting the NCCLS reference method for yeasts [21] and according to other studies of filamentous fungi [22,23], and the MFCs by subculturing 0.1 ml from all the MIC tubes with no visible growth onto drugfree SDA plates [25,26]. The results of this study confirm the in vitro antifungal efficacy of this new water-soluble polyene, SPA-S-843.…”

“…The minimum fungicidal concentrations (MFCs) were determined as described later, in accordance with the literature [24,25].…”

“…Afterwards, the colonies were counted, and the MFC was defined in accordance with the decrease in the number of CFU/ml. MFC stands for a 99.99% reduction in the number of CFU of the final inoculum size per milliliter (no growth of colonies on the plates), and MFC 99 stands for a 99% reduction (growth of 10 colonies per plate) [24,25]. The high offscale MFCs were converted to the next-higher concentration.…”

“…The test medium used for the determination of the MFCs was Sabouraud dextrose agar (SDA; Difco Laboratories, Detroit, Mich., USA) [24,25]; the medium was sterilized in an autoclave for 15 min at 121°C.…”