Investigational Antifungal Agents

Ernst, Erika J.

doi:10.1592/phco.21.12.165s.34509

Cited by 50 publications

(45 citation statements)

References 42 publications

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“…Thirteen of these isolates were separated from the rest of the population by a zone diameter threshold of Յ13 mm. Although a single preliminary interpretive category of susceptible by use of an MIC threshold of Յ1 g/ml and a zone diameter of Ͼ13 mm may be supported by pharmacokinetic and pharmacodynamic profiles (6,12,34), the establishment of clinical correlates is imperative before breakpoints can be used clinically (30). Despite these concerns, the overall categorical agreement of the results obtained by using these threshold values was 99.4% for the voriconazole disk method and the BMD MIC test.…”

Section: Resultsmentioning

confidence: 99%

Activities of Fluconazole and Voriconazole against 1,586 Recent Clinical Isolates of Candida Species Determined by Broth Microdilution, Disk Diffusion, and Etest Methods: Report from The ARTEMIS Global Antifungal Susceptibility Program, 2001

Pfaller

Diekema²,

Messer³

et al. 2003

J Clin Microbiol

173

136

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The ARTEMIS Global Antifungal Susceptibility Program (ARTEMIS Program) was initiated in 2001 to provide focused surveillance of the activities of fluconazole and voriconazole against Candida spp. isolated from blood and other normally sterile sites. A total of 1,586 episodes of infection were detected at 61 international study sites. Overall, 57.7% of the infections were due to Candida albicans, followed by C. glabrata (14.8%), C. parapsilosis (12.5%), C. tropicalis (9.4%), C. krusei (2.7%), and C. lusitaniae (1.5%). Isolates of C. albicans, C. parapsilosis, and C. tropicalis were all highly susceptible to fluconazole (for 99% of the isolates the MICs were <8 g/ml). Likewise, 99 to 100% of these species were inhibited by <1 g of voriconazole per ml. Voriconazole was also active against C. glabrata (93% of the isolates were susceptible [MICs < 1 g/ml]) and C. krusei (100% of the isolates were susceptible). The agar-based Etest and disk diffusion methods performed well for the testing of both fluconazole and voriconazole compared to the broth microdilution MIC reference method. These observations establish the continued importance of C. albicans as a pathogen and the sustained activity of fluconazole and the broad spectrum of activity of voriconazole and will serve as the first-year benchmark for the ARTEMIS Program. Continued surveillance and refinement of broth-and agar-based test methods will help to identify susceptibility trends and improve the laboratory capability for antifungal susceptibility testing.

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Section: Resultsmentioning

confidence: 99%

Activities of Fluconazole and Voriconazole against 1,586 Recent Clinical Isolates of Candida Species Determined by Broth Microdilution, Disk Diffusion, and Etest Methods: Report from The ARTEMIS Global Antifungal Susceptibility Program, 2001

Pfaller

Diekema²,

Messer³

et al. 2003

J Clin Microbiol

173

136

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“…6) (23, 24). Increased susceptibility is also noted for drugs that act to disrupt the cell wall, such as calcofluor white, a chitin deposition inhibitor (1), and nikkomycin Z, an antifungal drug that competitively inhibits chitin synthetase in the fungal cell (7). This increased susceptibility is unlikely to be related to the weakened cell wall these drugs produce; it is more likely to be related to a weakened plasma membrane, which may lyse in the presence of an unstable cell wall.…”

Section: Fig 6 (A)mentioning

confidence: 99%

Role of Candida albicans Transcription Factor Upc2p in Drug Resistance and Sterol Metabolism

2004

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In Candida albicans, drug resistance to clinically important antifungal drugs may be regulated through the action of transcription factors in a manner that may or may not be similar to regulation in Saccharomyces cerevisiae. A search of the C. albicans genome identified a single homolog of the S. cerevisiae transcription factor genes UPC2 (ScUPC2) and ECM22 (ScECM22) that have been associated with regulation of ergosterol biosynthesis. Sequence analysis of this C. albicans UPC2 (CaUPC2) gene identifies two domains, an anchoring transmembrane domain and a transcription factor region containing multiple nuclear localization signals and a fungal Zn(2)-Cys(6) binuclear cluster domain. Heterozygous deletion, homozygous deletion, and reconstructed strains of CaUPC2 as well as the parental strain were tested against several antifungal drugs, including ergosterol biosynthesis inhibitors. The CaUPC2 homozygous deletion strain showed marked hypersusceptibility to most drugs, compared to the parental and reconstructed strains. The deletion strains accumulate significantly less radiolabeled cholesterol, suggesting reduced ergosterol scavenging in those strains. When grown under azole drug pressure, the parental, heterozygous deletion and reconstructed strains of CaUPC2 upregulate the ERG2 and ERG11 ergosterol biosynthesis genes, while the homozygous deletion strain shows no such upregulation. Consistent with these results, CaUPC2 deletion strains show reduced ergosterol levels, which may explain the increased susceptibilities of the CaUPC2 deletion strains. Thus, it appears that CaUPC2 acts as a transcription factor involved in the regulation of ergosterol biosynthetic genes and as a regulator of sterol uptake across the plasma membrane.

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“…but not against Aspergillus spp. (6)(7)(8)(9)(10)(11)19).Caspofungin is an echinocandin antifungal agent which has recently been approved for treatment of aspergillosis in patients refractory to or intolerant of other therapies (6,11). Caspofungin also has demonstrated potent in vitro and in vivo activity against Candida spp.…”

mentioning

confidence: 99%

“…Both the new triazoles and the echinocandins exhibit a spectrum of activity that includes Candida and Aspergillus (6,10,15,20,21,23). Whereas the new triazoles have the same mechanism of action (inhibition of ergosterol synthesis) as the licensed antifungal agents, fluconazole and itraconazole, the echinocandins exhibit a novel mechanism of action based on the inhibition of cell wall glucan synthesis (6,23). In contrast to the triazoles, which are fungistatic for Candida spp., the echinocandins exhibit concentration-dependent fungicidal activity against Candida spp.…”

mentioning

confidence: 99%

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

Pfaller¹,

Diekema

Messer³

et al. 2003

Antimicrob Agents Chemother

150

119

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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 g/ml; 96% of MICs were <2 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 g/ml), and C. guilliermondii was the least susceptible (MIC 90 , >8 g/ml). Caspofungin was very active against Candida spp., exhibiting high-level resistance to fluconazole and itraconazole (99% of MICs were <1 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.Presently we are witnessing the development and introduction into clinical practice of several new systemic antifungal agents, including both extended-spectrum triazoles and echinocandin antifungal agents (2, 3, 6, 15, 19-21, 23, 26). Both the new triazoles and the echinocandins exhibit a spectrum of activity that includes Candida and Aspergillus (6,10,15,20,21,23). Whereas the new triazoles have the same mechanism of action (inhibition of ergosterol synthesis) as the licensed antifungal agents, fluconazole and itraconazole, the echinocandins exhibit a novel mechanism of action based on the inhibition of cell wall glucan synthesis (6,23). In contrast to the triazoles, which are fungistatic for Candida spp., the echinocandins exhibit concentration-dependent fungicidal activity against Candida spp. but not against Aspergillus spp. (6)(7)(8)(9)(10)(11)19).Caspofungin is an echinocandin antifungal agent which has recently been approved for treatment of aspergillosis in patients refractory to or intolerant of other therapies (6,11). Caspofungin also has demonstrated potent in vitro and in vivo activity against Candida spp. and has approved indications for treatment of candidemia, intra-abdominal abscesses, peritonitis, pleural space infections, and esophageal candidiasis (1, 15, 16a, 26). Although numerous studies documenting the in vitro activity of caspofungin against Candida spp. have been published, these studies are limited in the number of isolates of the various species of Candida tested and also are restricted in the geographic distribution of the tested strains (5,10,13,15,20,21,25). In the present study we determined the in vitro activity of caspofungin against an international collection of 3,959 clinical isolates of Candida spp. representing predominantly bloodstream infection and other invasive forms of candidiasis. We compare the activity of caspofungin against those of the...

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Investigational Antifungal Agents

Cited by 50 publications

References 42 publications

Activities of Fluconazole and Voriconazole against 1,586 Recent Clinical Isolates of Candida Species Determined by Broth Microdilution, Disk Diffusion, and Etest Methods: Report from The ARTEMIS Global Antifungal Susceptibility Program, 2001

Activities of Fluconazole and Voriconazole against 1,586 Recent Clinical Isolates of Candida Species Determined by Broth Microdilution, Disk Diffusion, and Etest Methods: Report from The ARTEMIS Global Antifungal Susceptibility Program, 2001

Role of Candida albicans Transcription Factor Upc2p in Drug Resistance and Sterol Metabolism

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

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