Ravuconazole Research Articles

In Vitro Survey of Triazole Cross-Resistance among More than 700 Clinical Isolates of Aspergillus Species

Few data exist to describe in vitro patterns of cross-resistance among large collections of clinical Aspergillus isolates, including those of species other than Aspergillus fumigatus. We examined 771 Aspergillus spp. clinical isolates collected from 2000 to 2006 as part of a global antifungal surveillance program (553 A. fumigatus, 76 A. flavus, 59 A. niger, 35 A. terreus, and 24 A. versicolor isolates and 24 isolates of other Aspergillus species). Antifungal susceptibility testing was performed by the Clinical and Laboratory Standards Institute (CLSI) M38-A broth dilution method with itraconazole (ITR), posaconazole (POS), ravuconazole (RAV), and voriconazole (VOR). We examined the potential for cross-resistance by using measures of correlation overall and by species. For most Aspergillus isolates (from 88% of isolates for ITR to 98% of isolates for VOR and POS), MICs of each triazole were < or = 1 microg/ml. When all 771 isolates were examined, there were statistically significant correlations for all six triazole-triazole pairs. For A. fumigatus, the strongest correlations seen were those between VOR and RAV MICs (r = 0.7) and ITR and POS MICs (r = 0.4). Similarly, for A. flavus, only VOR and RAV MICs and ITR and POS MICs demonstrated statistically significant positive correlations. We have demonstrated correlations among triazole MICs for Aspergillus, which for the most common species (A. fumigatus and A. flavus) were strongest between VOR and RAV MICs and ITR and POS MICs. However, Aspergillus species for which MICs of VOR or POS were >2 microg/ml remain extremely rare (<1% of isolates).

Evaluation of microdilution and disk diffusion methods for antifungal susceptibility testing of dermatophytes

A total of 63 dermatophyte strains belonging to 6 species (Trichophyton rubrum (16), T. mentagrophytes (16), T. tonsurans (20), T. violaceum (2), Microsporum canis (7), and Epidermophyton floccosum (2)) were tested for their in vitro susceptibility to a range of antifungal drugs using disk diffusion and Clinical Laboratory Standards Institute M38-A (CLSI, formerly NCCLS) broth microdilution methods. The antifungals used were ciclopirox (CIC), terbinafine (TER), griseofulvin (GRE), fluconazole (FLC), itraconazole (ITR), posaconazole (POS), and ravuconazole (RAV). In the broth microdilution assay terbinafine was found to have the highest activity followed by ravuconazole, posaconazole, ciclopirox, itraconazole, griseofulvin and fluconazole. In the disk diffusion assay terbinafine produced the largest inhibition zone diameters (IZDs) on Dermasel agar media followed by ravuconazole, griseofulvin, posaconazole, and itraconazole. A significant correlation was not observed between the minimum inhibitory concentrations (MICs) and IZDs, but some correlations were observed for POS, RAV, and TER (correlation coefficients r=-0.507, -0.249, -0.267, P<0.05, respectively). MICs obtained by the microdilution method with ITR and GRE did not correlate with IZDs obtained in disk diffusion assays in this study. The ciclopirox (20 microg/disk) and fluconazole (25 microg/disk) did not produce well defined inhibition zone diameters on Dermasel agar medium.

Effects of several antifungal drug combinations against clinical and environmental isolates of Cryptococcus neoformans from China.

The in vitro interactions of caspofungin (CSP) with terbinafine (TRB) and ravuconazole (RVC) with 5-fluorocytosine (5-FC) were tested against 82 clinical and environmental isolates of Cryptococcus neoformans from China. The interaction of CSP with TRB proved synergistic against those isolates with a CSP MIC < or =2 microg ml-1 (5% of the isolates), additive against 42% of the isolates and indifferent against 53%. The effects of RVC with 5-FC were synergistic, additive or indifferent against 8%, 26% and 67% of the isolates, respectively. No antagonistic effects were found among any of the drugs. The combinations of CSP with TRB and RVC with 5-FC may display beneficial effects in a strain-dependent manner, while in no case showed antagonistic effects. These data might be of use to design safer and more efficient treatments for patients with cryptococcosis and warrant further evaluation.

Novel effect of voriconazole on conidiation of Aspergillus species

Our previous studies of Aspergillus fumigatus showed that colonies that grew in the presence of voriconazole (VCZ) were characteristically white without pigmentation. We therefore investigated the effect of various triazoles on conidiation and pigmentation in four commonly isolated Aspergillus species and the results were compared with those obtained for polyene and echinocandin classes of antifungal drugs. Aspergillus cultures were grown on Sabouraud dextrose agar containing subinhibitory concentrations of the antifungal drugs; fungal colonies that grew in the presence of drug were examined microscopically for conidiation and the number of conidia per fungal colony was determined by haemocytometry. Voriconazole at 0.125–0.5 mg/l inhibited conidiation in A. fumigatus, Aspergillus flavus, Aspergillus niger and Aspergillus nidulans producing white colonies. The effect of voriconazole was concentration dependent and greater than 99% inhibition of conidiation was obtained in A. flavus at 0.5 mg/l. When the white colonies were subcultured on drug-free medium, they readily produced conidia and pigmentation indicating that the effect is reversible. Other triazoles such as itraconazole (ITZ) and posaconazole (PCZ) were poor inhibitors of conidiation. On the other hand, ravuconazole (RCZ) with structural similarity to voriconazole inhibited conidiation in A. fumigatus and A. flavus, but not in A. niger and A. nidulans. Amphotericin B (AMB), nystatin (NYS), caspofungin (CFG) and micafungin (MFG) showed no effect on conidiation. Varying ability among the triazoles to inhibit conidiation in Aspergillus species suggests that the mechanism of action may be unrelated to the well-known inhibition of P450-dependent 14α-sterol demethylase, and perhaps is due to direct or indirect effect on the formation of conidia.

In vitro interactions of licensed and novel antifungal drugs against Fusarium spp

We have studied the in vitro interactions of amphotericin B (AMB) with terbinafine (TBF), itraconazole, voriconazole (VCZ), albaconazole, and ravuconazole (RVZ), as well as TBF combined with the same azoles, against 11 isolates of Fusarium spp. using the fractional inhibitory concentration index. The highest percentage of synergistic interactions was observed for the combinations AMB-RVZ, TBF-VCZ, and TBF-RCZ.