<i>In Vitro</i>
            Activities of Isavuconazole and Comparator Antifungal Agents Tested against a Global Collection of Opportunistic Yeasts and Molds

Pfaller, Michael A.; Messer, S. A.; Rhomberg, Paul R.; Jones, Ronald N.; Castanheira, Mariana

doi:10.1128/jcm.00863-13

Cited by 80 publications

(67 citation statements)

References 37 publications

(54 reference statements)

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“…Thus, some of the isolates we receive for susceptibility testing may be more likely to be non-wild-type strains. However, the overall MIC distributions from our study shown in Table 3 are similar to those reported by others, including those from large surveillance studies (6,7,17). The results from our laboratory demonstrate that the rates of resistance for the echinocandins and the azoles may be increased with the use of the new CLSI antifungal breakpoints.…”

supporting

confidence: 77%

Impact of New Antifungal Breakpoints on Antifungal Resistance in Candida Species

et al. 2014

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We reviewed our antifungal susceptibility data for micafungin, anidulafungin, fluconazole, and voriconazole against Candida species and compared resistance rates determined by the previous and recently revised CLSI antifungal breakpoints. With the new breakpoints, resistance was significantly increased for micafungin (from 0.8% to 7.6%), anidulafungin (from 0.9% to 7.3%), and voriconazole (from 6.1% to 18.4%) against Candida glabrata. Resistance was also increased for fluconazole against Candida albicans (from 2.1% to 5.7%). The Clinical and Laboratory Standards Institute (CLSI) recently revised the azole and echinocandin clinical breakpoints against Candida species (1). These new breakpoints are now both drug and species specific, whereas the previous breakpoints were not. For most species, with the exception of Candida parapsilosis and Candida guilliermondii against the echinocandins, the breakpoints have been lowered, such that previously susceptible MICs are now classified as resistant. In addition, Candida glabrata isolates are no longer considered susceptible to fluconazole but are rather classified only as either dose-dependent susceptible or resistant. The breakpoint revisions were made based on information from clinical studies, case reports describing clinical failure at MIC values below the previous breakpoints, results from pharmacokinetic/pharmacodynamic studies, and epidemiologic cutoff values (2, 3). Additionally, a goal of harmonizing the antifungal breakpoints with those set by EUCAST was sought. Epidemiologic cutoff values for individual species are used to optimize the detection of non-wild-type strains and, thus, the acquisition of resistance mechanisms and to prevent the breakpoints from dividing wild-type populations (2-4). The impact of the revised clinical breakpoints regarding categorical placement of Candida strains as resistant is unknown. Our objective was to evaluate what effect the new antifungal clinical breakpoints may have on azole and echinocandin resistance patterns in Candida species.(This work was presented in part at the 53rd Interscience Conference on Antimicrobial Agents and Chemotherapy, Denver, CO, 2013.) The antifungal susceptibility database in the Fungus Testing Laboratory at the University of Texas Health Science Center at San Antonio was reviewed. Susceptibility data for fluconazole, voriconazole, anidulafungin, and micafungin against Candida albicans, C. glabrata, Candida tropicalis, Candida krusei, and C. parapsilosis isolates sent to our laboratory for testing between 1 January 2008 and 31 December 2012 were reviewed. During this period, antifungal powders were obtained from the appropriate manufacturers (Pfizer and Astellas) and stock solutions were prepared in water for agents with aqueous solubility or in dimethyl sulfoxide (DMSO) as recommended (1, 5). Susceptibility testing was performed by broth microdilution methodology in RPMI according to the CLSI M27-A3 guidelines (5), and a 50% inhibition of growth compared to the growth control well was used as the ...

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supporting

confidence: 77%

Impact of New Antifungal Breakpoints on Antifungal Resistance in Candida Species

et al. 2014

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“…Isavuconazole in vitro demonstrates superior hyphal growth inhibition and MICs against Aspergillus fumigatus in comparison to those of voriconazole (10)(11)(12)(13)(14). However, there is a paucity of laboratory animal data for isavuconazole against Aspergillus spp.…”

mentioning

confidence: 98%

Pharmacokinetics and Concentration-Dependent Efficacy of Isavuconazole for Treatment of Experimental Invasive Pulmonary Aspergillosis

Petraitis

Petraitienė

Moradi

et al. 2016

Antimicrob Agents Chemother

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We studied the pharmacokinetics and efficacy of the broad-spectrum triazole isavuconazole for the treatment of experimental invasive pulmonary aspergillosis (IPA) in persistently neutropenic rabbits. Treatment started 24 h after endotracheal administration of Aspergillus fumigatus inoculum; study subjects included rabbits receiving orally administered prodrug isavuconazonium sulfate (BAL8557) equivalent to active moiety isavuconazole (ISA; BAL4815) at 20 (ISA20), 40 (ISA40), and 60 (ISA60) mg/kg (of body weight)/day, with an initial loading dose of 90 mg/kg (ISA90), and untreated rabbits (UC). There were significant concentration-dependent reductions of residual fungal burden (log CFU/gram) and of organism-mediated pulmonary injury, lung weights, and pulmonary infarct scores in ISA40-and ISA60-treated rabbits in comparison to those of UC (P < 0.001). ISA20-treated (P < 0.05), ISA40-treated, and ISA60-treated (P < 0.001) rabbits demonstrated significantly prolonged survival in comparison to that of UC. ISA40-and ISA60-treated animals demonstrated a significant decline of serum (1¡3)-␤-D-glucan levels (P < 0.05) and galactomannan indices (GMIs) during therapy following day 4 in comparison to progressive GMIs of UC (P < 0.01). There also were significantly lower concentration-dependent GMIs in bronchoalveolar lavage (BAL) fluid from ISA40-and ISA60-treated rabbits (P < 0.001). There was a direct correlation between isavuconazole plasma area under the concentration-time curve from 0 to 24 h (AUC 0 -24 ) and residual fungal burdens in lung tissues, pulmonary infarct scores, and total lung weights. In summary, rabbits treated with isavuconazole at 40 and 60 mg/kg/day demonstrated significant dose-dependent reduction of residual fungal burden, decreased pulmonary injury, prolonged survival, lower GMIs in serum and BAL fluid, and lower serum (1¡3)-␤-D-glucan levels.

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“…Isavuconazole action includes in vitro activity against Aspergillus and Candida species, although the susceptibility of few clinical isolates has been studied (7)(8)(9)(10)(11)(12)(13). Epidemiological cutoff (ECOFF) values can assist in identifying isolates with raised MICs and/or a greater risk of the presence of a mechanism of resistance.…”

mentioning

confidence: 99%

Determination of Isavuconazole Susceptibility of Aspergillus and Candida Species by the EUCAST Method

Howard

Lass‐Flörl

Cuenca‐Estrella

et al. 2013

Antimicrob Agents Chemother

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Isavuconazole is a novel expanded-spectrum triazole, which has recently been approved by the FDA as an orphan drug to treat invasive aspergillosis and is currently being studied in phase III clinical trials for invasive candidiasis. The susceptibility of relatively few clinical isolates has been reported. In this study, the isavuconazole susceptibilities of 1,237 Aspergillus and 2,010 Candida geographically diverse clinical isolates were determined by EUCAST methodology at four European mycology laboratories, producing the largest multicenter data set thus far for this compound. In addition, a blinded collection of 30 cyp51A mutant Aspergillus fumigatus clinical isolates and 10 wild-type isolates was tested. From these two data sets, the following preliminary epidemiological cutoff (ECOFF) values were suggested: 2 mg/liter for Aspergillus fumigatus, Aspergillus terreus, and Aspergillus flavus; 4 mg/liter for Aspergillus niger; 0.25 mg/liter for Aspergillus nidulans; and 0.03 mg/liter for Candida albicans, Candida parapsilosis, and Candida tropicalis. Unfortunately, ECOFFs could not be determined for Candida glabrata or Candida krusei due to an unexplained interlaboratory MIC variation. For the blinded collection of A. fumigatus isolates, all MICs were <2 mg/ liter for wild-type isolates. Differential isavuconazole MICs were observed for triazole-resistant A. fumigatus isolates with different cyp51A alterations: TR 34 /L98H mutants had elevated isavuconazole MICs, whereas isolates with G54 and M220 alterations had MICs in the wild-type range, suggesting that the efficacy of isavuconazole may not be affected by these alterations. This study will be an aid in interpreting isavuconazole MICs for clinical care and an important step in the future process of setting official clinical breakpoints.

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In Vitro Activities of Isavuconazole and Comparator Antifungal Agents Tested against a Global Collection of Opportunistic Yeasts and Molds

Cited by 80 publications

References 37 publications

Impact of New Antifungal Breakpoints on Antifungal Resistance in Candida Species

Impact of New Antifungal Breakpoints on Antifungal Resistance in Candida Species

Pharmacokinetics and Concentration-Dependent Efficacy of Isavuconazole for Treatment of Experimental Invasive Pulmonary Aspergillosis

Determination of Isavuconazole Susceptibility of Aspergillus and Candida Species by the EUCAST Method

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