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Nathan P Wiederhold - One of the best experts on this subject based on the ideXlab platform.
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in vitro activity of Isavuconazole against opportunistic fungal pathogens from two mycology reference laboratories
Antimicrobial Agents and Chemotherapy, 2018Co-Authors: Michael A Pfaller, Paul R Rhomberg, Nathan P Wiederhold, Connie Fe C Gibas, Carmita Sanders, James Mele, Laura L Kovanda, Mariana CastanheiraAbstract:: Monitoring antifungal susceptibility patterns for new and established antifungal agents seems prudent given the increasing prevalence of uncommon species associated with higher antifungal resistance. We evaluated the activity of Isavuconazole against 4,856 invasive yeasts and molds collected worldwide. The 4,856 clinical fungal isolates, including 2,351 Candida species isolates, 97 non-Candida yeasts, 1,972 Aspergillus species isolates, and 361 non-Aspergillus molds, including 292 Mucorales isolates collected in 2015 to 2016, were tested using CLSI methods. The MIC values for Isavuconazole versus Aspergillus ranged from 0.06 to ≥16 μg/ml. The modal MIC for Isavuconazole was 0.5 μg/ml (range, 0.25 [A. nidulans and A. terreus species complex] to 4 μg/ml [A. calidoustus and A. tubingensis]). Eight A. fumigatus isolates had elevated Isavuconazole MIC values at ≥8 μg/ml (non-wild type). Isavuconazole showed comparable activity to itraconazole against the Mucorales The lowest modal Isavuconazole MIC values were seen for Rhizopus spp., R. arrhizus var. arrhizus, and R. microsporus (all 1 μg/ml). Candida species isolates were inhibited by ≤0.25 μg/ml of Isavuconazole (range, 96.1% [C. lusitaniae] to 100.0% [C. albicans, C. dubliniensis, C. kefyr, and C. orthopsilosis]). MIC values were ≤1 μg/ml for 95.5% of C. glabrata isolates and 100.0% of C. krusei isolates. Isavuconazole was active against the non-Candida yeasts, including Cryptococcus neoformans (100.0% at ≤0.5 μg/ml). Isavuconazole exhibited excellent activity against most species of Candida and Aspergillus Isavuconazole was comparable to posaconazole and voriconazole against the less common yeasts and molds. Isavuconazole was generally less active than posaconazole and more active than voriconazole against the 292 Mucorales isolates. We confirm the potentially useful activity of Isavuconazole against species of Rhizopus as determined by CLSI methods.
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Prophylaxis with Isavuconazole or Posaconazole Protects Immunosuppressed Mice from Pulmonary Mucormycosis.
Antimicrobial agents and chemotherapy, 2017Co-Authors: Teclegiorgis Gebremariam, Nathan P Wiederhold, Laura L Kovanda, Sondus Alkhazraji, Clara Baldin, Ashraf S. IbrahimAbstract:We assessed prophylactic or continuous therapy of Isavuconazole, posaconazole, or voriconazole in treating pulmonary murine mucormycosis. In the prophylaxis studies, only Isavuconazole treatment resulted in significantly improved survival and lowered tissue fungal burden of immunosuppressed mice infected with Rhizopus delemar. In the continuous treatment studies, Isavuconazole and posaconazole, but not voriconazole, equally prolonged survival time and lowered tissue fungal burden compared to placebo-treated mice. These results support the use of Isavuconazole and posaconazole in prophylaxis treatment.
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Monotherapy or combination therapy of Isavuconazole and micafungin for treating murine mucormycosis.
The Journal of antimicrobial chemotherapy, 2016Co-Authors: Teclegiorgis Gebremariam, Nathan P Wiederhold, Abdullah Alqarihi, Priya Uppuluri, Nkechi Azie, John E. Edwards, Ashraf S. IbrahimAbstract:OBJECTIVES Previously we demonstrated the benefit of Isavuconazole in treating murine mucormycosis due to Rhizopus. We wanted to determine the efficacy of Isavuconazole in treating murine mucormycosis caused by Mucor, the second most common cause of the disease. Furthermore, because we previously determined that Rhizopus possesses the target enzyme for echinocandins and micafungin has activity against murine mucormycosis, we compared the activity of combination therapy (Isavuconazole + micafungin) with placebo, either drug alone or standard therapy of liposomal amphotericin B (LAmB) in treating pulmonary murine mucormycosis caused by Rhizopus delemar. METHODS In vitro susceptibility to Isavuconazole of Mucorales was evaluated using the CLSI M38-A2 method. Immunosuppressed mice were intratracheally infected with either Mucor circinelloides or R. delemar. Treatment with Isavuconazole (orally), micafungin (intraperitoneally), a combination of both or LAmB (intravenously) was compared, with survival and tissue fungal burden serving as primary and secondary endpoints, respectively. RESULTS Isavuconazole was as effective as LAmB in prolonging survival of mice infected with M. circinelloides. Against R. delemar-induced mucormycosis, all monotherapy treatments significantly improved survival of mice versus placebo without showing superiority over one another. However, LAmB was superior in lowering fungal burden in target organs. Although combination therapy of Isavuconazole + micafungin did not enhance survival of mice over monotherapy, antagonism was not detected between the two drugs. CONCLUSION Isavuconazole is effective in treating pulmonary murine mucormycosis due to Mucor. In addition, combination therapy of Isavuconazole + micafungin does not demonstrate synergy and it is not antagonistic against Rhizopus-induced mucormycosis.
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In vitro activity of Isavuconazole against Trichosporon, Rhodotorula,
2016Co-Authors: Pichia Species, Nathan P Wiederhold, Deanna A. Sutton, George R. Thompson, Annette Fothergill, Thomas F. PattersonAbstract:Objectives: The emergence of less common, but clinically important, fungal pathogens including the rare yeasts has contributed to the substantial morbidity and mortality observed in immunocompro-mised patients. These organisms can be resistant or refractory to existing antifungal agents. We sought to evaluate the activity of the new triazole Isavuconazole against these difficult pathogens. Methods: MICs of Isavuconazole, voriconazole, posaconazole, fluconazole, amphotericin B and flucy-tosine were determined for 54 Trichosporon, 7 Geotrichum capitatum, 18 Saccharomyces cerevisiae, 11 Pichia and 14 Rhodotorula species in accordance with the M27-A2 reference method. Minimum fungicidal concentrations were also measured for each agent. Results: Isavuconazole demonstrated excellent in vitro activity against each species tested. MIC90 values ranged between 0.125 and 0.25 mg/L against Trichosporon isolates, and between 0.03 and 0.5 mg/L against the other yeast tested. The geometric mean MICs of Isavuconazole were similar to those of voriconazole and similar or less than those of posaconazole, fluconazole, amphotericin B and flucytosine for all species tested. This activity was also maintained against one Trichosporon asahii and nine Rhodotorula isolates that were resistant to fluconazole. Conclusions: Isavuconazole is a welcome addition to the growing antifungal armamentarium with potent in vitro activity against emerging yeast pathogens. Although this agent may be useful in the treatment of the rare yeasts, clinical data are needed to verify these results
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Isavuconazole Is Effective for the Treatment of Experimental Cryptococcal Meningitis
Antimicrobial agents and chemotherapy, 2016Co-Authors: Nathan P Wiederhold, Laura L Kovanda, Laura K. Najvar, Rosie Bocanegra, Marcos Olivo, William R. Kirkpatrick, Thomas F. PattersonAbstract:We evaluated the efficacy of Isavuconazole against cryptococcal meningitis. Treatment with either oral Isavuconazole (120 mg/kg and 240 mg/kg twice a day [BID]) or fluconazole as the positive control significantly improved survival in mice infected intracranially with either Cryptococcus neoformans USC1597 or H99 and significantly reduced brain fungal burdens for both isolates. Concentrations of Isavuconazole in plasma and brain tissue also demonstrated that the greatest improvements in survival and fungal burden were associated with elevated exposures.
Laura L Kovanda - One of the best experts on this subject based on the ideXlab platform.
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antifungal efficacy of Isavuconazole and liposomal amphotericin b in a rabbit model of exserohilum rostratum meningoencephalitis a preclinical paradigm for management of cns phaeohyphomycosis
Medical Mycology, 2021Co-Authors: Vidmantas Petraitis, Ruta Petraitiene, Laura L Kovanda, Aspasia Katragkou, Patriss W Moradi, Bo Bo Win Maung, Gittel E Sussmanstraus, Ethan Naing, Malcolm FinkelmanAbstract:Treatment options for Exserohilum rostratum meningoencephalitis and other causes of phaeohyphomycosis of the central nervous system (CNS) are limited, while mortality and morbidity remain high. We therefore evaluated Isavuconazole, a new antifungal triazole in comparison to liposomal amphotericin B (LAMB), in vitro and in the rabbit model of Exserohilum rostratum meningoencephalitis. We hypothesized that Isavuconazole alone or in combination with LAMB or micafungin may be alternative options for treatment of CNS phaeohyphomycosis. We therefore investigated the in vitro antifungal activity of Isavuconazole alone or in combination with amphotericin B deoxycholate (DAMB) or micafungin and efficacy of treatment with Isavuconazole and LAMB in a rabbit model of experimental E. rostratum meningoencephalitis. Combination checkerboard plates were used to determine the minimum inhibitory concentrations, minimal lethal concentrations, fractional inhibitory concentration indices, and Bliss surface analysis of Isavuconazole and amphotericin B deoxycholate (DAMB), either alone or in combination. As there were no in vitro synergistic or antagonistic interactions for either combination of antifungal agents against the E. rostratum isolates, in vivo studies were conducted with Isavuconazole and LAMB as monotherapies. Rabbits were divided in following groups: treated with Isavuconazole at 60 mg/kg/d (ISAV60), LAMB at 5.0 (LAMB5), 7.5 (LAMB7.5), and 10 mg/kg/d (LAMB10), and untreated controls (UC). In ISAV60-, LAMB5-, LAMB7.5-, and LAMB10-treated rabbits, significant reductions of fungal burden of E. rostratum in cerebral, cerebellar, and spinal cord tissues (P < 0.01) were demonstrated in comparison to those of UC. These antifungal effects correlated with significant reduction of CSF (1→3)-β-D-glucan levels vs UC (P < 0.05). These data establish new translational insights into treatment of CNS phaeohyphomycosis.
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in vitro activity of Isavuconazole against opportunistic fungal pathogens from two mycology reference laboratories
Antimicrobial Agents and Chemotherapy, 2018Co-Authors: Michael A Pfaller, Paul R Rhomberg, Nathan P Wiederhold, Connie Fe C Gibas, Carmita Sanders, James Mele, Laura L Kovanda, Mariana CastanheiraAbstract:: Monitoring antifungal susceptibility patterns for new and established antifungal agents seems prudent given the increasing prevalence of uncommon species associated with higher antifungal resistance. We evaluated the activity of Isavuconazole against 4,856 invasive yeasts and molds collected worldwide. The 4,856 clinical fungal isolates, including 2,351 Candida species isolates, 97 non-Candida yeasts, 1,972 Aspergillus species isolates, and 361 non-Aspergillus molds, including 292 Mucorales isolates collected in 2015 to 2016, were tested using CLSI methods. The MIC values for Isavuconazole versus Aspergillus ranged from 0.06 to ≥16 μg/ml. The modal MIC for Isavuconazole was 0.5 μg/ml (range, 0.25 [A. nidulans and A. terreus species complex] to 4 μg/ml [A. calidoustus and A. tubingensis]). Eight A. fumigatus isolates had elevated Isavuconazole MIC values at ≥8 μg/ml (non-wild type). Isavuconazole showed comparable activity to itraconazole against the Mucorales The lowest modal Isavuconazole MIC values were seen for Rhizopus spp., R. arrhizus var. arrhizus, and R. microsporus (all 1 μg/ml). Candida species isolates were inhibited by ≤0.25 μg/ml of Isavuconazole (range, 96.1% [C. lusitaniae] to 100.0% [C. albicans, C. dubliniensis, C. kefyr, and C. orthopsilosis]). MIC values were ≤1 μg/ml for 95.5% of C. glabrata isolates and 100.0% of C. krusei isolates. Isavuconazole was active against the non-Candida yeasts, including Cryptococcus neoformans (100.0% at ≤0.5 μg/ml). Isavuconazole exhibited excellent activity against most species of Candida and Aspergillus Isavuconazole was comparable to posaconazole and voriconazole against the less common yeasts and molds. Isavuconazole was generally less active than posaconazole and more active than voriconazole against the 292 Mucorales isolates. We confirm the potentially useful activity of Isavuconazole against species of Rhizopus as determined by CLSI methods.
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Isavuconazole Concentration in Real-World Practice: Consistency with Results from Clinical Trials.
Antimicrobial agents and chemotherapy, 2018Co-Authors: David R. Andes, Laura L Kovanda, Amit Desai, Therese M Kitt, Miao Zhao, Thomas J. WalshAbstract:Clinical use of voriconazole, posaconazole, and itraconazole revealed the need for therapeutic drug monitoring (TDM) of plasma concentrations of these antifungal agents. This need for TDM was not evident from clinical trials. In order to establish whether this requirement also applies to Isavuconazole, we examined the plasma concentrations of 283 samples from patients receiving Isavuconazole in clinical practice and compared the values with those from clinical trials. The concentration distributions from real-world use and clinical trials were nearly identical (>1 μg/ml in 90% of patients). These findings suggest that routine TDM may not be necessary for Isavuconazole in most instances.
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in vitro combination therapy with Isavuconazole against candida spp
Medical Mycology, 2017Co-Authors: Aspasia Katragkou, Matthew W. Mccarthy, Ruta Petraitiene, Laura L Kovanda, Joseph Meletiadis, Kaiser Hussain, Patriss W Moradi, Gittel E Strauss, Kyaw L Myint, Emmanuel RoilidesAbstract:: Combination therapy may be an alternative therapeutic approach for difficult-to-treat Candida infections with the aim of increasing efficacy of antifungal therapy. Whether Isavuconazole, an extended-spectrum triazole, possesses synergistic activity in combination therapy with echinocandins or polyenes for the treatment of invasive candidiasis has not been studied. We used Bliss independence drug interaction analysis and time-kill assays to examine the in vitro interactions of Isavuconazole with amphotericin B or micafungin, an echinocandin, against strains of Candida albicans, Candida parapsilosis, Candida glabrata, Candida tropicalis, and Candida krusei. The Bliss independence-based drug interactions modeling showed that the combination of Isavuconazole and micafungin resulted in synergistic interactions against C. albicans, C. parapsilosis, and C. krusei. The degree of synergy ranged from 1.8% to 16.7% (mean %ΔE value) with the highest synergy occurring against C. albicans (⊙SYN% = 8.8%-110%). Time-kill assays showed that the Isavuconazole-micafungin combination demonstrated concentration-depended synergy against C. albicans and C. parapsilosis. The combined interaction by Bliss analysis between Isavuconazole and amphotericin B was indifferent for C. albicans, C. parapsilosis, and C. tropicalis while for C. glabrata was antagonistic (-2% to -6%) and C. krusei synergistic (3.4% to 7%). The combination of Isavuconazole-amphotericin B by time-kill assay was antagonistic against C. krusei and C. glabrata. Collectively, our findings demonstrate that combinations of Isavuconazole and micafungin are synergistic against Candida spp., while those of Isavuconazole and amphotericin B are indifferent in vitro.
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Prophylaxis with Isavuconazole or Posaconazole Protects Immunosuppressed Mice from Pulmonary Mucormycosis.
Antimicrobial agents and chemotherapy, 2017Co-Authors: Teclegiorgis Gebremariam, Nathan P Wiederhold, Laura L Kovanda, Sondus Alkhazraji, Clara Baldin, Ashraf S. IbrahimAbstract:We assessed prophylactic or continuous therapy of Isavuconazole, posaconazole, or voriconazole in treating pulmonary murine mucormycosis. In the prophylaxis studies, only Isavuconazole treatment resulted in significantly improved survival and lowered tissue fungal burden of immunosuppressed mice infected with Rhizopus delemar. In the continuous treatment studies, Isavuconazole and posaconazole, but not voriconazole, equally prolonged survival time and lowered tissue fungal burden compared to placebo-treated mice. These results support the use of Isavuconazole and posaconazole in prophylaxis treatment.
Mariana Castanheira - One of the best experts on this subject based on the ideXlab platform.
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In vitro activity of Isavuconazole versus opportunistic filamentous fungal pathogens from the SENTRY Antifungal Surveillance Program, 2017-2018.
Diagnostic microbiology and infectious disease, 2020Co-Authors: Shawn A. Messer, Mariana Castanheira, Cecilia G. Carvalhaes, Michael A PfallerAbstract:Abstract The increasing prevalence of uncommon fungal species and higher antifungal resistance has turned antifungal susceptibility testing into an important monitoring tool. In response, we evaluated the activity of Isavuconazole against 522 clinical mold isolates collected worldwide in 2017–2018, including 436 Aspergillus spp. isolates and 86 non-Aspergillus molds. The MIC values using Clinical and Laboratory Standards Institute methods for Isavuconazole versus Aspergillus ranged from 0.015 mg/L to >8 mg/L. Isavuconazole showed comparable activity to itraconazole, posaconazole, and voriconazole against A. fumigatus species complex. Most of the Aspergillus spp. isolates tested (>90%) were wild type to all azoles and echinocandins. Eleven isolates were non–wild type to Isavuconazole and the other 3 azoles, and 10 of those isolates were from Europe. The azoles and echinocandins showed poor activity against Fusarium and Scedosporium spp. Isavuconazole exhibited excellent activity against most species of Aspergillus and was comparable to itraconazole, posaconazole, and voriconazole against the less common molds.
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in vitro activity of Isavuconazole against opportunistic fungal pathogens from two mycology reference laboratories
Antimicrobial Agents and Chemotherapy, 2018Co-Authors: Michael A Pfaller, Paul R Rhomberg, Nathan P Wiederhold, Connie Fe C Gibas, Carmita Sanders, James Mele, Laura L Kovanda, Mariana CastanheiraAbstract:: Monitoring antifungal susceptibility patterns for new and established antifungal agents seems prudent given the increasing prevalence of uncommon species associated with higher antifungal resistance. We evaluated the activity of Isavuconazole against 4,856 invasive yeasts and molds collected worldwide. The 4,856 clinical fungal isolates, including 2,351 Candida species isolates, 97 non-Candida yeasts, 1,972 Aspergillus species isolates, and 361 non-Aspergillus molds, including 292 Mucorales isolates collected in 2015 to 2016, were tested using CLSI methods. The MIC values for Isavuconazole versus Aspergillus ranged from 0.06 to ≥16 μg/ml. The modal MIC for Isavuconazole was 0.5 μg/ml (range, 0.25 [A. nidulans and A. terreus species complex] to 4 μg/ml [A. calidoustus and A. tubingensis]). Eight A. fumigatus isolates had elevated Isavuconazole MIC values at ≥8 μg/ml (non-wild type). Isavuconazole showed comparable activity to itraconazole against the Mucorales The lowest modal Isavuconazole MIC values were seen for Rhizopus spp., R. arrhizus var. arrhizus, and R. microsporus (all 1 μg/ml). Candida species isolates were inhibited by ≤0.25 μg/ml of Isavuconazole (range, 96.1% [C. lusitaniae] to 100.0% [C. albicans, C. dubliniensis, C. kefyr, and C. orthopsilosis]). MIC values were ≤1 μg/ml for 95.5% of C. glabrata isolates and 100.0% of C. krusei isolates. Isavuconazole was active against the non-Candida yeasts, including Cryptococcus neoformans (100.0% at ≤0.5 μg/ml). Isavuconazole exhibited excellent activity against most species of Candida and Aspergillus Isavuconazole was comparable to posaconazole and voriconazole against the less common yeasts and molds. Isavuconazole was generally less active than posaconazole and more active than voriconazole against the 292 Mucorales isolates. We confirm the potentially useful activity of Isavuconazole against species of Rhizopus as determined by CLSI methods.
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Direct in vitro comparison of the prodrug isavuconazonium sulfate with the Isavuconazole active compound against Aspergillus spp. and 2 rare moulds.
Diagnostic microbiology and infectious disease, 2018Co-Authors: Michael A Pfaller, Paul R Rhomberg, Mariana CastanheiraAbstract:Abstract Isavuconazonium sulfate is a prodrug of Isavuconazole, a broad-spectrum mould-active triazole antifungal drug. We provide a direct comparison of the in vitro activity of the prodrug versus the active metabolite against clinical isolates of Aspergillus spp., Sarocladium kiliense, and Scedosporium apiospermum using CLSI broth microdilution methods. The MIC values obtained for the prodrug were one 2-fold dilution higher than those of Isavuconazole for all isolates tested. Using previously defined epidemiological cutoff values for Isavuconazole and Aspergillus spp., 96.4% of isolates were wild type (WT) to Isavuconazole and only 75% were WT to the prodrug. The essential agreement (±2 log2 dilutions) between prodrug and Isavuconazole MIC values was 96.4% across all tested isolates. The active metabolite, Isavuconazole, is recommended to use during in vitro susceptibility testing of fungal isolates.
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Isavuconazole and Nine Comparator Antifungal Susceptibility Profiles for Common and Uncommon Candida Species Collected in 2012: Application of New CLSI Clinical Breakpoints and Epidemiological Cutoff Values
Mycopathologia, 2014Co-Authors: Mariana Castanheira, Paul R Rhomberg, Shawn A. Messer, Ronald N. Jones, Rachel R. Dietrich, Michael A PfallerAbstract:The in vitro activity of Isavuconazole and nine antifungal comparator agents was assessed using reference broth microdilution methods against 1,421 common and uncommon species of Candida from a 2012 global survey. Isolates were identified using CHROMagar, biochemical methods and sequencing of ITS and/or 28S regions. Candida spp. were classified as either susceptible or resistant and as wild type (WT) or non-WT using CLSI clinical breakpoints or epidemiological cutoff values, respectively, for the antifungal agents. Isolates included 1,421 organisms from 21 different species of Candida . Among Candida spp., resistance to all 10 tested antifungal agents was low (0.0–7.9 %). The vast majority of each species of Candida , with the exception of Candida glabrata , Candida krusei , and Candida guilliermondii (modal MICs of 0.5 µg/ml), were inhibited by ≤0.12 µg/ml of Isavuconazole (99.0 %; range 94.3 % [ Candida tropicalis ] to 100.0 % [ Candida lusitaniae and Candida dubliniensis ]). C. glabrata, C. krusei, and C. guilliermondii were largely inhibited by ≤1 µg/ml of Isavuconazole (89.7, 96.9 and 92.8 %, respectively). Decreased susceptibility to Isavuconazole was most prominent with C. glabrata where the modal MIC for Isavuconazole was 0.5 µg/ml for those strains that were SDD to fluconazole or WT to voriconazole, and was 4 µg/ml for those that were either resistant or non-WT to fluconazole or voriconazole, respectively. In conclusion, these data document the activity of Isavuconazole and generally the low resistance levels to the available antifungal agents in a large, contemporary (2012), global collection of molecularly characterized species of Candida .
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In Vitro Activities of Isavuconazole and Comparator Antifungal Agents Tested against a Global Collection of Opportunistic Yeasts and Molds
Journal of clinical microbiology, 2013Co-Authors: Michael A Pfaller, Paul R Rhomberg, Shawn A. Messer, Ronald N. Jones, Mariana CastanheiraAbstract:ABSTRACT Isavuconazole is a new broad-spectrum triazole with a favorable pharmacokinetic and safety profile. We report the MIC distributions for Isavuconazole and 111 isolates of Candida (42 Candida albicans, 25 Candida glabrata, 22 Candida parapsilosis, 14 Candida tropicalis, and 8 Candida krusei isolates), as determined by Clinical and Laboratory Standards Institute (CLSI) and European Committee on Antimicrobial Susceptibility Testing (EUCAST) broth microdilution (BMD) methods. Also, the relative activities of Isavuconazole, itraconazole, fluconazole, posaconazole, voriconazole, and the three echinocandins were assessed against a recent (2011) global collection of 1,358 isolates of Candida spp., 101 of Aspergillus spp., 54 of non-Candida yeasts, and 21 of non-Aspergillus molds using CLSI BMD methods. The overall essential agreement (EA) (±2 log2 dilutions) between the CLSI and EUCAST methods was 99.1% (EA at ±1 log2 dilution, 90.1% [range, 80.0 to 100.0%]). The activities of Isavuconazole against the larger collection of Candida spp. and Aspergillus spp. were comparable to those of posaconazole and voriconazole; the MIC90 values for Isavuconazole, posaconazole, and voriconazole against Candida spp. were 0.5, 1, and 0.25 μg/ml and against Aspergillus spp. were 2, 1, and 1 μg/ml, respectively. Isavuconazole showed good activities against Cryptococcus neoformans (MIC90, 0.12 μg/ml) and other non-Candida yeasts (MIC90, 1 μg/ml) but was less potent against non-Aspergillus molds (MIC90, >8 μg/ml). Isavuconazole MIC values for three mucormycete isolates were 4, 1, and 2 μg/ml, whereas all three were inhibited by 1 μg/ml posaconazole. Isavuconazole demonstrates broad-spectrum activity against this global collection of opportunistic fungi, and the CLSI and EUCAST methods can be used to test this agent against Candida, with highly comparable results.
Peter Warn - One of the best experts on this subject based on the ideXlab platform.
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in vitro antifungal activity of Isavuconazole against 345 mucorales isolates collected at study centers in eight countries
Journal of Chemotherapy, 2009Co-Authors: Paul E. Verweij, Nathan P Wiederhold, Peter Warn, Markus Heep, Gloria M Gonzalez, Cornelia Lassflorl, Mahmoud A Ghannoum, Jesús GuineaAbstract:Although mucormycoses (formerly zygomycoses) are relatively uncommon, they are associated with high mortality and treatment options are limited. Isavuconazole is a novel, water soluble, broad-spectrum azole in clinical development for the treatment of invasive aspergillosis and candidiasis. The objective of this report was to collate data on the in vitro activity of Isavuconazole against a collection of 345 diverse mucorales isolates, collected and tested at eight study centers in europe, mexico and North America. Each study center undertook minimum inhibitory concentration (MIC) susceptibility testing of their isolates, according to EUCAST or CLSI guidelines. Across all study centers, Isavuconazole exhibited MIC(50 )values of 1-4 mg/l and MIC(90 )values of 4-16 mg/l against the five genera. There were also marked differences in MIC distributions, which could be ascribed to differences in inoculum and/or endpoint. EUCAST guidelines appeared to generate modal MICs 2-fold higher than CLSI. These results confirm that Isavuconazole possesses at least partial antifungal activity against mucorales.
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efficacy of Isavuconazole voriconazole and fluconazole in temporarily neutropenic murine models of disseminated candida tropicalis and candida krusei
Journal of Antimicrobial Chemotherapy, 2008Co-Authors: Jayesh Majithiya, Andrew Sharp, A Parmar, David W Denning, Peter WarnAbstract:OBJECTIVES: The aim of this study was to assess the dose-response of Isavuconazole, voriconazole and fluconazole in disseminated Candida tropicalis and Candida krusei infections. METHODS: Mice were immunosuppressed using either one dose [temporarily neutropenic (TN)] or two doses [persistently neutropenic (PN)] of cyclophosphamide. Treatment was started 5 h after infection with oral Isavuconazole (6, 15, 30, 60, 90, 120 or 150 mg/kg equivalent active compound), intravenous voriconazole (5, 20 or 40 mg/kg plus grapefruit gavage twice daily) or oral fluconazole (15, 50 or 150 mg/kg) all administered twice daily. Kidney burden was assessed for C. tropicalis, and kidney and brain burden for C. krusei. RESULTS: Vehicle controls developed a non-lethal infection with high burdens in both models. In the TN models, Isavuconazole, voriconazole and fluconazole (>50 mg/kg) reduced kidney burden compared with controls; >60 mg/kg Isavuconazole and 50 mg/kg fluconazole were superior to alternative treatments (other than voriconazole 40 mg/kg). Isavuconazole (all doses) reduced brain burden (P 5 mg/kg) and fluconazole (all doses) reduced kidney burden (P<0.05). Only Isavuconazole (all doses) and 40 mg/kg voriconazole were effective against C. krusei in the brain, Isavuconazole and voriconazole reduced tissue burden (P<0.05). Fluconazole had no significant effect on brain burden even at 150 mg/kg. CONCLUSIONS: Isavuconazole significantly reduced kidney burden in mice infected with C. tropicalis and both kidney and brain burdens in mice infected with C. krusei. Isavuconazole was as effective as voriconazole and much more effective than fluconazole at reducing brain burden.
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Efficacy of Isavuconazole, voriconazole and fluconazole in temporarily neutropenic murine models of disseminated Candida tropicalis and Candida krusei
The Journal of antimicrobial chemotherapy, 2008Co-Authors: Jayesh Majithiya, Andrew Sharp, A Parmar, David W Denning, Peter WarnAbstract:OBJECTIVES: The aim of this study was to assess the dose-response of Isavuconazole, voriconazole and fluconazole in disseminated Candida tropicalis and Candida krusei infections. METHODS: Mice were immunosuppressed using either one dose [temporarily neutropenic (TN)] or two doses [persistently neutropenic (PN)] of cyclophosphamide. Treatment was started 5 h after infection with oral Isavuconazole (6, 15, 30, 60, 90, 120 or 150 mg/kg equivalent active compound), intravenous voriconazole (5, 20 or 40 mg/kg plus grapefruit gavage twice daily) or oral fluconazole (15, 50 or 150 mg/kg) all administered twice daily. Kidney burden was assessed for C. tropicalis, and kidney and brain burden for C. krusei. RESULTS: Vehicle controls developed a non-lethal infection with high burdens in both models. In the TN models, Isavuconazole, voriconazole and fluconazole (>50 mg/kg) reduced kidney burden compared with controls; >60 mg/kg Isavuconazole and 50 mg/kg fluconazole were superior to alternative treatments (other than voriconazole 40 mg/kg). Isavuconazole (all doses) reduced brain burden (P 5 mg/kg) and fluconazole (all doses) reduced kidney burden (P
Michael A Pfaller - One of the best experts on this subject based on the ideXlab platform.
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In vitro activity of Isavuconazole versus opportunistic filamentous fungal pathogens from the SENTRY Antifungal Surveillance Program, 2017-2018.
Diagnostic microbiology and infectious disease, 2020Co-Authors: Shawn A. Messer, Mariana Castanheira, Cecilia G. Carvalhaes, Michael A PfallerAbstract:Abstract The increasing prevalence of uncommon fungal species and higher antifungal resistance has turned antifungal susceptibility testing into an important monitoring tool. In response, we evaluated the activity of Isavuconazole against 522 clinical mold isolates collected worldwide in 2017–2018, including 436 Aspergillus spp. isolates and 86 non-Aspergillus molds. The MIC values using Clinical and Laboratory Standards Institute methods for Isavuconazole versus Aspergillus ranged from 0.015 mg/L to >8 mg/L. Isavuconazole showed comparable activity to itraconazole, posaconazole, and voriconazole against A. fumigatus species complex. Most of the Aspergillus spp. isolates tested (>90%) were wild type to all azoles and echinocandins. Eleven isolates were non–wild type to Isavuconazole and the other 3 azoles, and 10 of those isolates were from Europe. The azoles and echinocandins showed poor activity against Fusarium and Scedosporium spp. Isavuconazole exhibited excellent activity against most species of Aspergillus and was comparable to itraconazole, posaconazole, and voriconazole against the less common molds.
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in vitro activity of Isavuconazole against opportunistic fungal pathogens from two mycology reference laboratories
Antimicrobial Agents and Chemotherapy, 2018Co-Authors: Michael A Pfaller, Paul R Rhomberg, Nathan P Wiederhold, Connie Fe C Gibas, Carmita Sanders, James Mele, Laura L Kovanda, Mariana CastanheiraAbstract:: Monitoring antifungal susceptibility patterns for new and established antifungal agents seems prudent given the increasing prevalence of uncommon species associated with higher antifungal resistance. We evaluated the activity of Isavuconazole against 4,856 invasive yeasts and molds collected worldwide. The 4,856 clinical fungal isolates, including 2,351 Candida species isolates, 97 non-Candida yeasts, 1,972 Aspergillus species isolates, and 361 non-Aspergillus molds, including 292 Mucorales isolates collected in 2015 to 2016, were tested using CLSI methods. The MIC values for Isavuconazole versus Aspergillus ranged from 0.06 to ≥16 μg/ml. The modal MIC for Isavuconazole was 0.5 μg/ml (range, 0.25 [A. nidulans and A. terreus species complex] to 4 μg/ml [A. calidoustus and A. tubingensis]). Eight A. fumigatus isolates had elevated Isavuconazole MIC values at ≥8 μg/ml (non-wild type). Isavuconazole showed comparable activity to itraconazole against the Mucorales The lowest modal Isavuconazole MIC values were seen for Rhizopus spp., R. arrhizus var. arrhizus, and R. microsporus (all 1 μg/ml). Candida species isolates were inhibited by ≤0.25 μg/ml of Isavuconazole (range, 96.1% [C. lusitaniae] to 100.0% [C. albicans, C. dubliniensis, C. kefyr, and C. orthopsilosis]). MIC values were ≤1 μg/ml for 95.5% of C. glabrata isolates and 100.0% of C. krusei isolates. Isavuconazole was active against the non-Candida yeasts, including Cryptococcus neoformans (100.0% at ≤0.5 μg/ml). Isavuconazole exhibited excellent activity against most species of Candida and Aspergillus Isavuconazole was comparable to posaconazole and voriconazole against the less common yeasts and molds. Isavuconazole was generally less active than posaconazole and more active than voriconazole against the 292 Mucorales isolates. We confirm the potentially useful activity of Isavuconazole against species of Rhizopus as determined by CLSI methods.
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Direct in vitro comparison of the prodrug isavuconazonium sulfate with the Isavuconazole active compound against Aspergillus spp. and 2 rare moulds.
Diagnostic microbiology and infectious disease, 2018Co-Authors: Michael A Pfaller, Paul R Rhomberg, Mariana CastanheiraAbstract:Abstract Isavuconazonium sulfate is a prodrug of Isavuconazole, a broad-spectrum mould-active triazole antifungal drug. We provide a direct comparison of the in vitro activity of the prodrug versus the active metabolite against clinical isolates of Aspergillus spp., Sarocladium kiliense, and Scedosporium apiospermum using CLSI broth microdilution methods. The MIC values obtained for the prodrug were one 2-fold dilution higher than those of Isavuconazole for all isolates tested. Using previously defined epidemiological cutoff values for Isavuconazole and Aspergillus spp., 96.4% of isolates were wild type (WT) to Isavuconazole and only 75% were WT to the prodrug. The essential agreement (±2 log2 dilutions) between prodrug and Isavuconazole MIC values was 96.4% across all tested isolates. The active metabolite, Isavuconazole, is recommended to use during in vitro susceptibility testing of fungal isolates.
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Isavuconazole and Nine Comparator Antifungal Susceptibility Profiles for Common and Uncommon Candida Species Collected in 2012: Application of New CLSI Clinical Breakpoints and Epidemiological Cutoff Values
Mycopathologia, 2014Co-Authors: Mariana Castanheira, Paul R Rhomberg, Shawn A. Messer, Ronald N. Jones, Rachel R. Dietrich, Michael A PfallerAbstract:The in vitro activity of Isavuconazole and nine antifungal comparator agents was assessed using reference broth microdilution methods against 1,421 common and uncommon species of Candida from a 2012 global survey. Isolates were identified using CHROMagar, biochemical methods and sequencing of ITS and/or 28S regions. Candida spp. were classified as either susceptible or resistant and as wild type (WT) or non-WT using CLSI clinical breakpoints or epidemiological cutoff values, respectively, for the antifungal agents. Isolates included 1,421 organisms from 21 different species of Candida . Among Candida spp., resistance to all 10 tested antifungal agents was low (0.0–7.9 %). The vast majority of each species of Candida , with the exception of Candida glabrata , Candida krusei , and Candida guilliermondii (modal MICs of 0.5 µg/ml), were inhibited by ≤0.12 µg/ml of Isavuconazole (99.0 %; range 94.3 % [ Candida tropicalis ] to 100.0 % [ Candida lusitaniae and Candida dubliniensis ]). C. glabrata, C. krusei, and C. guilliermondii were largely inhibited by ≤1 µg/ml of Isavuconazole (89.7, 96.9 and 92.8 %, respectively). Decreased susceptibility to Isavuconazole was most prominent with C. glabrata where the modal MIC for Isavuconazole was 0.5 µg/ml for those strains that were SDD to fluconazole or WT to voriconazole, and was 4 µg/ml for those that were either resistant or non-WT to fluconazole or voriconazole, respectively. In conclusion, these data document the activity of Isavuconazole and generally the low resistance levels to the available antifungal agents in a large, contemporary (2012), global collection of molecularly characterized species of Candida .
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In Vitro Activities of Isavuconazole and Comparator Antifungal Agents Tested against a Global Collection of Opportunistic Yeasts and Molds
Journal of clinical microbiology, 2013Co-Authors: Michael A Pfaller, Paul R Rhomberg, Shawn A. Messer, Ronald N. Jones, Mariana CastanheiraAbstract:ABSTRACT Isavuconazole is a new broad-spectrum triazole with a favorable pharmacokinetic and safety profile. We report the MIC distributions for Isavuconazole and 111 isolates of Candida (42 Candida albicans, 25 Candida glabrata, 22 Candida parapsilosis, 14 Candida tropicalis, and 8 Candida krusei isolates), as determined by Clinical and Laboratory Standards Institute (CLSI) and European Committee on Antimicrobial Susceptibility Testing (EUCAST) broth microdilution (BMD) methods. Also, the relative activities of Isavuconazole, itraconazole, fluconazole, posaconazole, voriconazole, and the three echinocandins were assessed against a recent (2011) global collection of 1,358 isolates of Candida spp., 101 of Aspergillus spp., 54 of non-Candida yeasts, and 21 of non-Aspergillus molds using CLSI BMD methods. The overall essential agreement (EA) (±2 log2 dilutions) between the CLSI and EUCAST methods was 99.1% (EA at ±1 log2 dilution, 90.1% [range, 80.0 to 100.0%]). The activities of Isavuconazole against the larger collection of Candida spp. and Aspergillus spp. were comparable to those of posaconazole and voriconazole; the MIC90 values for Isavuconazole, posaconazole, and voriconazole against Candida spp. were 0.5, 1, and 0.25 μg/ml and against Aspergillus spp. were 2, 1, and 1 μg/ml, respectively. Isavuconazole showed good activities against Cryptococcus neoformans (MIC90, 0.12 μg/ml) and other non-Candida yeasts (MIC90, 1 μg/ml) but was less potent against non-Aspergillus molds (MIC90, >8 μg/ml). Isavuconazole MIC values for three mucormycete isolates were 4, 1, and 2 μg/ml, whereas all three were inhibited by 1 μg/ml posaconazole. Isavuconazole demonstrates broad-spectrum activity against this global collection of opportunistic fungi, and the CLSI and EUCAST methods can be used to test this agent against Candida, with highly comparable results.
