In vitro activities of voriconazole, posaconazole, and fluconazole against 4,169 clinical isolates of Candida spp. and Cryptococcus neoformans collected during 2001 and 2002 in the ARTEMIS global antifungal surveillance program

We examined the in vitro activities of voriconazole, posaconazole, and fluconazole against 3,932 isolates of Candida spp. and 237 isolates of Cryptococcus neoformans obtained from over 100 medical centers worldwide during 2001 and 2002. The MICs of the antifungal drugs were determined by broth microdilution tests performed according to the National Committee for Clinical Laboratory Standards (NCCLS) methods using RPMI 1640 as the test medium. Voriconazole and posaconazole were very active against Candida spp. (97-98% susceptible at MICs < or =1 microg/ml) and C. neoformans (98-100% susceptible at MICs < or =1 microg/mL). C. albicans (MIC90, 0.015-0.03 microg/ml) was the most susceptible species of Candida to both agents and C. glabrata (MIC90, 1-2 microg/mL) was the least susceptible. Both voriconazole and posaconazole were more active than fluconazole against all Candida spp. and C. neoformans. These results provide further evidence for the increased spectrum and potency of the new triazoles against a large and geographically diverse collection of opportunistic fungal pathogens.     

In vitro activities of posaconazole, fluconazole, itraconazole, voriconazole, and amphotericin B against a large collection of clinically important molds and yeasts

The in vitro activity of the novel triazole antifungal agent posaconazole (Noxafil; SCH 56592) was assessed in 45 laboratories against approximately 19,000 clinically important strains of yeasts and molds. The activity of posaconazole was compared with those of itraconazole, fluconazole, voriconazole, and amphotericin B against subsets of the isolates. Strains were tested utilizing Clinical and Laboratory Standards Institute broth microdilution methods using RPMI 1640 medium (except for amphotericin B, which was frequently tested in antibiotic medium 3). MICs were determined at the recommended endpoints and time intervals. Against all fungi in the database (22,850 MICs), the MIC(50) and MIC(90) values for posaconazole were 0.063 microg/ml and 1 mug/ml, respectively. MIC(90) values against all yeasts (18,351 MICs) and molds (4,499 MICs) were both 1 mug/ml. In comparative studies against subsets of the isolates, posaconazole was more active than, or within 1 dilution of, the comparator drugs itraconazole, fluconazole, voriconazole, and amphotericin B against approximately 7,000 isolates of Candida and Cryptococcus spp. Against all molds (1,702 MICs, including 1,423 MICs for Aspergillus isolates), posaconazole was more active than or equal to the comparator drugs in almost every category. Posaconazole was active against isolates of Candida and Aspergillus spp. that exhibit resistance to fluconazole, voriconazole, and amphotericin B and was much more active than the other triazoles against zygomycetes. Posaconazole exhibited potent antifungal activity against a wide variety of clinically important fungal pathogens and was frequently more active than other azoles and amphotericin B.     

Head-to-head comparison of the activities of currently available antifungal agents against 3,378 Spanish clinical isolates of yeasts and filamentous fungi

We have compared the activities of posaconazole and other currently available antifungal agents against a collection of 3,378 clinical isolates of yeasts and filamentous fungi. A total of 1,997 clinical isolates of Candida spp., 359 of other yeast species, 697 strains of Aspergillus spp., and 325 nondermatophyte non-Aspergillus spp. were included. The average geometric means of the MICs of agents that were tested against Candida spp. were 0.23 microg/ml for amphotericin B, 0.29 microg/ml for flucytosine, 0.97 microg/ml for fluconazole, 0.07 microg/ml for itraconazole, 0.04 microg/ml for voriconazole, 0.15 microg/ml for caspofungin, and 0.03 microg/ml for posaconazole. Voriconazole and posaconazole were active in vitro against the majority of isolates, with resistance to fluconazole and itraconazole, and against Cryptococcus neoformans and other Basidiomycota yeasts. Posaconazole was the most active of antifungal agents tested against Aspergillus spp., with an average geometric mean of 0.10 microg/ml. It was active against Paecilomyces spp., Penicillium spp., Scedosporium apiospermum, and some black fungi, such as Alternaria spp. Multiresistant filamentous fungi, such as Scedosporium prolificans, Scopulariopsis brevicaulis, and Fusarium solani, were also resistant to voriconazole, caspofungin, and posaconazole. Amphotericin B and posaconazole were found to be active against most of the Mucorales strains tested. Posaconazole and currently available antifungal agents exhibit a potent activity in vitro against the majority of pathogenic fungal species.     

In vitro activities of caspofungin compared with those of fluconazole and itraconazole against 3,959 clinical isolates of Candida spp., including 157 fluconazole-resistant isolates

Caspofungin is an echinocandin antifungal agent with broad-spectrum activity against Candida and Aspergillus spp. The in vitro activities of caspofungin against 3,959 isolates of Candida spp. obtained from over 95 different medical centers worldwide were compared with those of fluconazole and itraconazole. The MICs of the antifungal drugs were determined by broth microdilution tests performed according to the NCCLS method using RPMI 1640 as the test medium. Caspofungin was very active against Candida spp. (MIC at which 90% of the isolates were inhibited [MIC(90)], 1 micro g/ml; 96% of MICs were < or =2 micro g/ml). Candida albicans, C. dubliniensis, C. tropicalis, and C. glabrata were the most susceptible species of Candida (MIC(90), 0.25 to 0.5 micro g/ml), and C. guilliermondii was the least susceptible (MIC(90), >8 micro g/ml). Caspofungin was very active against Candida spp., exhibiting high-level resistance to fluconazole and itraconazole (99% of MICs were < or =1 micro g/ml). These results provide further evidence for the spectrum and potency of caspofungin activity against a large and geographically diverse collection of clinically important isolates of Candida spp.     

In vitro activities of ravuconazole and voriconazole compared with those of four approved systemic antifungal agents against 6,970 clinical isolates of Candida spp

The in vitro activities of ravuconazole and voriconazole were compared with those of amphotericin B, flucytosine (5FC), itraconazole, and fluconazole against 6,970 isolates of Candida spp. obtained from over 200 medical centers worldwide. Both ravuconazole and voriconazole were very active against all Candida spp. (MIC at which 90% of the isolates tested are inhibited [MIC(90)], 0.25 microg/ml; 98% of MICs were < or 1 microg/ml); however, a decrease in the activities of both of these agents was noted among isolates that were susceptible-dose dependent (fluconazole MIC, 16 to 32 microg/ml) and resistant (MIC, > or = 64 microg/ml) to fluconazole. Candida albicans was the most susceptible species (MIC(90) of both ravuconazole and voriconazole, 0.03 microg/ml), and C. glabrata was the least susceptible species (MIC(90), 1 to 2 microg/ml). Ravuconazole and voriconazole were each more active in vitro than amphotericin B, 5FC, itraconazole, and fluconazole against all Candida spp. and were the only agents with good in vitro activity against C. krusei. These results provide further evidence for the spectrum and potency of ravuconazole and voriconazole against a large and geographically diverse collection of Candida spp.     

Trends in frequency and in vitro susceptibilities to antifungal agents,including voriconazole and anidulafungin,of Candida bloodstream isolates. Results from a six-year study (1996-2001)

The frequency of isolation and antifungal susceptibility patterns to established and two new antifungal agents were determined for 218 Candida spp isolates causing bloodstream infection from 1996 to 2001. Overall, 41.7% of the candidemias were due to C. albicans, followed by C. parapsilosis (22%), C. tropicalis (16.1%), C. glabrata (11.9%), C. krusei (6%) and miscellaneous Candida spp (2.3%). Isolates of C. albicans C. parapsilosis and C. tropicalis (80% of isolates) were highly susceptible to fluconazole (94 to 100% at /= 32 microg/ml).     

Antifungal susceptibilities of clinical isolates of Candida species, Cryptococcus neoformans, and Aspergillus species from Taiwan: surveillance of multicenter antimicrobial resistance in Taiwan program data from 2003

The susceptibilities of nonduplicate isolates to six antifungal agents were determined for 391 blood isolates of seven Candida species, 70 clinical isolates (from blood or cerebrospinal fluid) of Cryptococcus neoformans, and 96 clinical isolates of four Aspergillus species, which were collected in seven different hospitals in Taiwan (as part of the 2003 program of the study group Surveillance of Multicenter Antimicrobial Resistance in Taiwan). All isolates of Candida species other than C. glabrata and C. krusei were susceptible to fluconazole. Among the 59 C. glabrata isolates, 16 (27%) were not susceptible to fluconazole, and all were dose-dependently susceptible or resistant to itraconazole. For three (5.1%) C. glabrata isolates, voriconazole MICs were 2 to 4 microg/ml, and for all other Candida species isolates, voriconazole MICs were /=2 microg/ml were 100% (3 isolates) for C. krusei, 11% (23 of 207 isolates) for Candida albicans, 3.0% (2 of 67 isolates) for Candida tropicalis, 20% (12 of 59 isolates) for C. glabrata, and 0% for both Candida parapsilosis and Candida lusitaniae. For three (4%) Cryptococcus neoformans isolates, fluconazole MICs were >/=16 microg/ml, and two (3%) isolates were not inhibited by 1 mug of amphotericin B/ml. For four (4.2%) of the Aspergillus isolates, itraconazole MICs were 8 microg/ml. Aspergillus flavus was less susceptible to amphotericin B, with the MICs at which 50% (1 microg/ml) and 90% (2 microg/ml) nsrsid417869\delrsid7301351 of isolates were inhibited being twofold greater than those for Aspergillus fumigatus and Aspergillus niger. All Aspergillus isolates were inhibited by 相似文献   

Trends in antifungal drug susceptibility of Cryptococcus neoformans isolates in the United States: 1992 to 1994 and 1996 to 1998

The antifungal drug susceptibilities of two collections of Cryptococcus neoformans isolates obtained through active laboratory-based surveillance from 1992 to 1994 (368 isolates) and 1996 to 1998 (364 isolates) were determined. The MICs of fluconazole, itraconazole, and flucytosine were determined by the National Committee for Clinical Laboratory Standards broth microdilution method; amphotericin B MICs were determined by the E-test. Our results showed that the MIC ranges, the MICs at which 50% of isolates are inhibited (MIC(50)s), and the MIC(90)s of these four antifungal agents did not change from 1992 to 1998. In addition, very small numbers of isolates showed elevated MICs suggestive of in vitro resistance. The MICs of amphotericin B were elevated (>or=2 microg/ml) for 2 isolates, and the MICs of flucytosine were elevated (>or=32 microg/ml) for 14 isolates. Among the azoles, the fluconazole MIC was elevated (>or=64 microg/ml) for 8 isolates and the itraconazole MIC (>or=1 microg/ml) was elevated for 45 isolates. Analysis of 172 serial isolates from 71 patients showed little change in the fluconazole MIC over time. For isolates from 58 patients (82% of serial cases) there was either no change or a twofold change in the fluconazole MIC. In contrast, for isolates from seven patients (12% of serial cases) the increase in the MIC was at least fourfold. For isolates from another patient there was a 32-fold decrease in the fluconazole MIC over a 1-month period. We conclude that in vitro resistance to antifungal agents remains uncommon in C. neoformans and has not significantly changed with time during the past decade.     

In vitro activities of new and conventional antifungal agents against clinical Scedosporium isolates.

The susceptibilities of 13 clinical isolates of Scedosporium apiospermum and 55 clinical isolates of S. prolificans to new and conventional drugs belonging to three different classes of antifungal agents, the azoles (miconazole, itraconazole, voriconazole, UR-9825, posaconazole), the polyenes (amphotericin B, nystatin and liposomal nystatin), and allylamines (terbinafine), were studied by use of proposed standard M38-P of NCCLS. Low growth-inhibitory antifungal activities were found in vitro for most of the drugs tested against S. prolificans isolates, with the MICs at which 90% of isolates are inhibited (MIC(90)s) being >8 microg/ml; the MIC(90)s of voriconazole and UR-9825, however, were 4 microg/ml. S. apiospermum isolates were more susceptible in vitro, with the highest activity exhibited by voriconazole (MIC(90)s, 0.5 microg/ml), followed by miconazole (MIC(90)s, 1 microg/ml), UR-9825 and posaconazole (MIC(90)s, 2 microg/ml), and itraconazole (MIC(90)s, 4 microg/ml). The MICs of terbinafine, amphotericin B, and the two formulations of nystatin (for which no statistically significant differences in antifungal activities were found for the two species) for S. apiospermum isolates were high. Cross-resistance was observed among all the azoles except posaconazole and among all the polyenes except the lipid formulation. A distribution analysis was performed with the MICs of each drug and for each species. Bimodal and skewed MIC distributions were obtained, and cutoffs indicating the borders of different MIC subpopulations of the distributions were determined on the basis of the normal plot technique. These cutoffs were in many cases reproducible between 48 and 72 h.     

Antifungal activities of posaconazole, ravuconazole, and voriconazole compared to those of itraconazole and amphotericin B against 239 clinical isolates of Aspergillus spp. and other filamentous fungi: report from SENTRY Antimicrobial Surveillance Program, 2000

Posaconazole, ravuconazole, and voriconazole are new triazole derivatives that possess potent, broad-spectrum antifungal activity. We evaluated the in vitro activity of these investigational triazoles compared with that of itraconazole and amphotericin B against 239 clinical isolates of filamentous fungi from the SENTRY Program, including Aspergillus spp. (198 isolates), Fusarium spp. (7 isolates), Penicillium spp. (19 isolates), Rhizopus spp. (4 isolates), Mucor spp. (2 isolates), and miscellaneous species (9 isolates). The isolates were obtained from 16 different medical centers in the United States and Canada between January and December 2000. In vitro susceptibility testing was performed using the microdilution broth method outlined in the National Committee for Clinical Laboratory Standards M38-P document. Overall, posaconazole was the most active compound, inhibiting 94% of isolates at a MIC of < or = 1 microg/ml, followed by voriconazole (91%), amphotericin B (89%), ravuconazole (88%), and itraconazole (70%). All three new triazoles demonstrated excellent activity (MIC, < or = 1 microg/ml) against Aspergillus spp. (114 Aspergillus fumigatus, 22 Aspergillus niger, 13 Aspergillus flavus, 9 Aspergillus versicolor, 8 Aspergillus terreus, and 32 Aspergillus spp.): posaconazole (98%), voriconazole (98%), ravuconazole (92%), amphotericin B (89%), and itraconazole (72%). None of the triazoles were active against Fusarium spp. (MIC at which 50% of the isolates tested were inhibited [MIC(50)], >8 microg/ml) or Mucor spp. (MIC(50), >8 microg/ml). Posaconazole and ravuconazole were more active than voriconazole against Rhizopus spp. (MIC(50), 1 to 2 microg/ml versus >8 microg/ml, respectively). Based on these results, all three new triazoles exhibited promising activity against Aspergillus spp. and other less commonly encountered isolates of filamentous fungi. The clinical value of these in vitro data remains to be seen, and in vitro-in vivo correlation is needed for both new and established antifungal agents. Surveillance efforts should be expanded in order to monitor the spectrum of filamentous fungal pathogens and their in vitro susceptibility as these new antifungal agents are introduced into clinical use.     

In vitro activities of the new antifungal triazole SCH 56592 against common and emerging yeast pathogens

A broth microdilution method performed in accordance with the National Committee for Clinical Laboratory Standards guidelines was used to compare the in vitro activity of the new antifungal triazole SCH 56592 (SCH) to that of fluconazole (FLC), itraconazole (ITC), and ketoconazole (KETO) against 257 clinical yeast isolates. They included 220 isolates belonging to 12 different species of Candida, 15 isolates each of Cryptococcus neoformans and Saccharomyces cerevisiae, and seven isolates of Rhodotorula rubra. The MICs of SCH at which 50% (MIC(50)) and 90% (MIC(90)) of the isolates were inhibited were 0.06 and 2.0 microg/ml, respectively. In general, SCH was considerably more active than FLC (MIC(50) and MIC(90) of 1.0 and 64 microg/ml, respectively) and slightly more active than either ITC (MIC(50) and MIC(90) of 0.25 and 2.0 microg/ml, respectively) and KETO (MIC(50) and MIC(90) of 0.125 and 4.0 microg/ml, respectively). Our in vitro data suggest that SCH has significant potential for clinical development.     

In vitro activity of a new semisynthetic echinocandin, LY-303366, against systemic isolates of Candida species, Cryptococcus neoformans, Blastomyces dermatitidis, and Aspergillus species.

The in vitro activities of LY-303366, a new semisynthetic echinocandin, and comparators amphotericin B, 5-fluorocytosine, fluconazole, and ketoconazole against 205 systemic isolates of Candida species, Cryptococcus neoformans, Blastomyces dermatitidis, and Aspergillus species were determined. LY-303366 had MICs of < or = 0.32 microg/ml for all Candida albicans (n = 99), Candida glabrata (n = 18), and Candida tropicalis (n = 10) isolates tested. LY-303366 was also active against Aspergillus species (minimum effective concentration at which 90% of the isolates are inhibited, 0.02 microg/ml) (n = 20), was less active against Candida parapsilosis (MIC at which 90% of the isolates are inhibited [MIC90], 5.12 microg/ml) (n = 10), and was inactive against C. neoformans (MIC90, >10.24 microg/ml) (n = 15) and B. dermatitidis (MIC90, 16 microg/ml) (n = 29).     

In vitro susceptibilities of clinical yeast isolates to a new echinocandin derivative, LY303366, and other antifungal agents.

LY303366 is a new semisynthetic echinocandin derivative with potent, broad-spectrum fungicidal activity. We investigated the in vitro activity of LY303366, amphotericin B, flucytosine (5FC), fluconazole, and itraconazole against 435 clinical yeast isolates (413 Candida and 22 Saccharomyces cerevisiae isolates) obtained from over 30 different medical centers. MICs for all five antifungal agents were determined by the National Committee for Clinical Laboratory Standards method with RPMI 1640 test medium. LY303366 was also tested in antibiotic medium 3 as specified by the manufacturer. Overall, LY303366 was quite active against all of the yeast isolates when tested in RPMI 1640 (MIC at which 90% of the isolates are inhibited [MIC90], 1.0 microg/ml) but appeared to be considerably more potent when tested in antibiotic medium 3 (MIC90, 0.03 microg/ml). When tested in antibiotic medium 3, LY303366 was 16- to >2,000-fold more active than itraconazole, fluconazole, amphotericin B, or 5FC against all species except Candida parapsilosis. When tested in RPMI 1640, LY303366 was comparable to amphotericin B and itraconazole and more active than fluconazole and 5FC. All of the isolates for which fluconazole and itraconazole had elevated MICs (> or = 128 and > or = 2.0 microg/ml, respectively) were inhibited by < or = 0.007 microg of LY303366/ml when tested in antibiotic medium 3 and < or = 0.5 microg/ml when tested in RPMI 1640. Based on these studies, LY303366 has promising antifungal activity and warrants further in vitro and in vivo investigation.     

Testing of the in vitro susceptibilities of Madurella mycetomatis to six antifungal agents by using the Sensititre system in comparison with a viability-based 2,3-bis(2-methoxy-4-nitro-5-sulfophenyl)-5- [(phenylamino)carbonyl]-2H-tetrazolium hydroxide (XTT) assay and a modified NCCLS method

The in vitro susceptibilities of 36 clinical isolates of Madurella mycetomatis, the prime agent of eumycetoma in Africa, to ketoconazole, itraconazole, fluconazole, voriconazole, amphotericin B, and flucytosine were determined by the Sensititre YeastOne system. This system appeared to be a rapid and easy test, and by use of hyphal suspensions it generated results comparable to those of a modified NCCLS method. After 10 days of incubation, the antifungal activities of ketoconazole (MIC at which 90% of isolates were inhibited [MIC90], 0.125 microg/ml), itraconazole (MIC90, 0.064 microg/ml), and voriconazole (MIC90, 0.125 microg/ml) appeared superior to those of fluconazole (MIC90, 128 microg/ml) and amphotericin B (MIC90, 1 microg/ml), with MICs in the clinically relevant range. All isolates were resistant to flucytosine (all MICs above 64 microg/ml). Based on the relatively broad range of MICs obtained for the antifungal agents, routine testing of M. mycetomatis isolates for susceptibility to antifungal agents seems to be relevant to adequate therapeutic management.     

Antifungal activity of posaconazole compared with fluconazole and amphotericin B against yeasts from oropharyngeal candidiasis and other infections

OBJECTIVES: The in vitro antifungal activity of posaconazole was compared with that of fluconazole and amphotericin B. Materials and methods: A microdilution method (M27-A2) was used with 331 clinical yeast isolates. RESULTS: The geometric mean MICs of posaconazole, fluconazole and amphotericin B were 0.16, 0.91 and 0.15 mg/L, respectively. Posaconazole was markedly more active than fluconazole and was active against 9/11 fluconazole-resistant Candida albicans, and five Candida glabrata had an MIC of posaconazole of 16 mg/L. CONCLUSIONS: These data indicate that posaconazole is a potentially effective antifungal agent for the treatment of mycoses caused by yeasts.     

In vitro activity of E1210, a novel antifungal, against clinically important yeasts and molds

E1210 is a new antifungal compound with a novel mechanism of action and broad spectrum of antifungal activity. We investigated the in vitro antifungal activities of E1210 compared to those of fluconazole, itraconazole, voriconazole, amphotericin B, and micafungin against clinical fungal isolates. E1210 showed potent activities against most Candida spp. (MIC(90) of ≤0.008 to 0.06 μg/ml), except for Candida krusei (MICs of 2 to >32 μg/ml). E1210 showed equally potent activities against fluconazole-resistant and fluconazole-susceptible Candida strains. E1210 also had potent activities against various filamentous fungi, including Aspergillus fumigatus (MIC(90) of 0.13 μg/ml). E1210 was also active against Fusarium solani and some black molds. Of note, E1210 showed the greatest activities against Pseudallescheria boydii (MICs of 0.03 to 0.13 μg/ml), Scedosporium prolificans (MIC of 0.03 μg/ml), and Paecilomyces lilacinus (MICs of 0.06 μg/ml) among the compounds tested. The antifungal action of E1210 was fungistatic, but E1210 showed no trailing growth of Candida albicans, which has often been observed with fluconazole. In a cytotoxicity assay using human HK-2 cells, E1210 showed toxicity as low as that of fluconazole. Based on these results, E1210 is likely to be a promising antifungal agent for the treatment of invasive fungal infections.     

In vitro activities of a new lipopeptide antifungal agent, FK463, against a variety of clinically important fungi

The in vitro antifungal activity and spectrum of FK463 were compared with those of amphotericin B, fluconazole, and itraconazole by using a broth microdilution method specified by National Committee for Clinical Laboratory Standards document M27-A (National Committee for Clinical Laboratory Standards, Wayne, Pa., 1997). FK463 exhibited broad-spectrum activity against clinically important pathogens including Candida species (MIC range, <==0.0039 to 2 microg/ml) and Aspergillus species (MIC range, <==0.0039 to 0.0313 microg/ml), and its MICs for such fungi were lower than those of the other antifungal agents tested. FK463 was also potently active against azole-resistant Candida albicans as well as azole-susceptible strains, and there was no cross-resistance with azoles. FK463 showed fungicidal activity against C. albicans, i.e., a 99% reduction in viability after a 24-h exposure at concentrations above 0.0156 microg/ml. The minimum fungicidal concentration (MFC) assays indicated that FK463 was fungicidal against most isolates of Candida species. In contrast, the MFCs of FK463 for A. fumigatus isolates were much higher than the MICs, indicating that its action is fungistatic against this species. FK463 had no activity against Cryptococcus neoformans, Trichosporon species, or Fusarium solani. Neither the test medium (kind and pH) nor the inoculum size greatly affected the MICs of FK463, while the addition of 4% human serum albumin increased the MICs for Candida species and A. fumigatus more than 32 times. Results from preclinical in vitro evaluations performed thus far indicate that FK463 should be a potent parenteral antifungal agent.     

In vitro activities of ravuconazole (BMS-207147) against 541 clinical isolates of Cryptococcus neoformans

The in vitro activities of the new triazole, ravuconazole (BMS-207147), were compared to those of fluconazole and itraconazole against 541 clinical isolates of Cryptococcus neoformans. Isolates were obtained from cerebrospinal fluid (396), blood (116), and miscellaneous clinical specimens (29). Overall, ravuconazole (MIC at which 90% of the isolates are inhibited [MIC(90)], 0.25 microg/ml) was more active than either itraconazole (MIC(90), 0.5 microg/ml) or fluconazole (MIC(90), 8 microg/ml). Among the isolates inhibited by > or =16 microg of fluconazole/ml, 90.2% were inhibited by < or =1 microg of ravuconazole/ml. On the basis of our findings and the favorable pharmacokinetic properties of ravuconazole, we suggest that ravuconazole may be useful for the treatment of infectious diseases due to C. neoformans and that further clinical studies to confirm these promising in vitro results are warranted.     

In Vitro and In Vivo Activities of CS-758 (R-120758), a New Triazole Antifungal Agent

The activity of CS-758 (R-120758), a new triazole antifungal agent, was evaluated and compared with those of fluconazole, itraconazole, and amphotericin B in vitro and with those of fluconazole and itraconazole in vivo. CS-758 exhibited potent in vitro activity against clinically important fungi. The activity of CS-758 against Candida spp. was superior to that of fluconazole and comparable or superior to those of itraconazole and amphotericin B. CS-758 retained potent activity against Candida albicans strains with low levels of susceptibility to fluconazole (fluconazole MIC, 4 to 32 microg/ml). Against Aspergillus spp. and Cryptococcus neoformans, the activity of CS-758 was at least fourfold superior to those of the other drugs tested. CS-758 also exhibited potent in vivo activity against murine systemic infections caused by C. albicans, C. neoformans, Aspergillus fumigatus, and Aspergillus flavus. The 50% effective doses against these infections were 0.41 to 5.0 mg/kg of body weight. These results suggest that CS-758 may be useful in the treatment of candidiasis, cryptococcosis, and aspergillosis.     

Azole Cross-Resistance in Aspergillus fumigatus

We susceptibility tested 17 clinical isolates of Aspergillus fumigatus, for most of which MICs of itraconazole were elevated (MIC at which 50% of the isolates tested are inhibited, 16 microg/ml), against itraconazole, posaconazole, ravuconazole, and voriconazole. Posaconazole was the most active against itraconazole-susceptible isolates. A complex pattern of cross-resistance and hypersusceptibility was seen with voriconazole and ravuconazole, suggesting marked differences in activity and mechanisms of resistance.