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

Howard, Susan J.; Lass‐Flörl, Cornelia; Cuenca‐Estrella, Manuel; Gómez-López, Alicia; Arendrup, Maiken Cavling

doi:10.1128/aac.01111-13

Cited by 64 publications

(68 citation statements)

References 21 publications

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“…However, the MICs were 1 dilution step higher for the EUCAST method than for the CLSI method. EUCAST has adopted a higher glucose and inoculum concentration, which facilitate increased growth, and higher endpoints have also been seen for other substances, including the new compound isavuconazole, when A. fumigatus isolates have been susceptibility tested using both methods (19,20). Similarly, MICs obtained using a 50% growth inhibition endpoint read by a spectrophotometer yielded lower MIC values, as expected when a less stringent endpoint criterion is adopted.…”

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confidence: 59%

In Vitro Activity of ASP2397 against Aspergillus Isolates with or without Acquired Azole Resistance Mechanisms

Arendrup

Hare

Cuenca‐Estrella

2016

Antimicrob Agents Chemother

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bASP2397 is a new compound with a novel and as-yet-unknown target different from that of licensed antifungal agents. It has activity against Aspergillus and Candida glabrata. We compared its in vitro activity against wild-type and azole-resistant A. fumigatus and A. terreus isolates with that of amphotericin B, itraconazole, posaconazole, and voriconazole. Thirty-four isolates, including 4 wild-type A. fumigatus isolates, 24 A. fumigatus isolates with alterations in CYP51A TR/L98H (5 isolates), M220 (9 isolates), G54 (9 isolates), and HapE (1 isolate), and A. terreus isolates (2 wild-type isolates and 1 isolate with an M217I CYP51A alteration), were analyzed. EUCAST E.Def 9.2 and CLSI M38-A2 MIC susceptibility testing was performed. ASP2397 MIC 50 values (in milligrams per liter, with MIC ranges in parentheses) determined by EUCAST and CLSI were 0.5 (0.25 to 1) and 0.25 (0.06 to 0.25) against A. fumigatus CYP51A wild-type isolates and were similarly 0.5 (0.125 to >4) and 0.125 (0.06 to >4) against azole-resistant A. fumigatus isolates, respectively. These values were comparable to those for amphotericin B, which were 0.25 (0.125 to 0.5) and 0.25 (0.125 to 0.25) against wild-type isolates and 0.25 (0.125 to 1) and 0.25 (0.125 to 1) against isolates with azole resistance mechanisms, respectively. In contrast, MICs for the azole compounds were elevated and highest for itraconazole: >4 (1 to >4) and 4 (0.5 to >4) against isolates with azole resistance mechanisms compared to 0.125 (0.125 to 0.25) and 0.125 (0.06 to 0.25) against wild-type isolates, respectively. ASP2397 was active against A. terreus CYP51A wildtype isolates (MIC 0.5 to 1), whereas MICs of both azole and ASP2397 were elevated for the mutant isolate. ASP2397 displayed in vitro activity against A. fumigatus and A. terreus isolates which was independent of the presence or absence of azole target gene resistance mutations in A. fumigatus. The findings are promising at a time when azole-resistant A. fumigatus is emerging globally.A spergillus causes invasive aspergillosis, which is a life-threatening infection, as well as a variety of less acute though still devastating chronic infections. The cornerstone in management of the disease is azole treatment due to the superiority of voriconazole in a randomized clinical trial and in postmarketing studies for treatment of invasive aspergillosis and the oral availability of azole drugs for outpatient treatment of chronic aspergillosis (1-8). However, increasing numbers of reports document emerging azole resistance in Europe, Africa, and the Asia-Pacific region, which highlights the importance of safe and efficacious alternatives (9-15). Amphotericin B is active but is associated with significant toxicity even in its lipid formulations, and echinocandins have only static activity against Aspergillus.ASP2397 is a new compound with activity against Aspergillus species, including A. fumigatus, A. terreus, A. flavus, and A. nidulans, with an MIC range of 1 to 4 mg/liter in human serum (16). It is actively incorporate...

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confidence: 59%

In Vitro Activity of ASP2397 against Aspergillus Isolates with or without Acquired Azole Resistance Mechanisms

Arendrup

Hare

Cuenca‐Estrella

2016

Antimicrob Agents Chemother

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“…The mutant collection included 10 mutant isolates with alterations involving each of the codons G54, M220, and TR 34 (TR)/L98H. Dotted line, the recently proposed EUCAST epidemiological cutoff value for isavuconazole and A. fumigatus (9). ratory and those from laboratories 1 to 3 using conidium counting was 0.3 Ϯ 1.1 and was equal to a mean Ϯ SD log 2 difference of Ϫ0.3 Ϯ 1.2 when the data from laboratories 1 to 3 (all of which used conidium counting) were compared.…”

Section: Figmentioning

confidence: 99%

EUCAST Testing of Isavuconazole Susceptibility in Aspergillus: Comparison of Results for Inoculum Standardization Using Conidium Counting versus Optical Density

Arendrup¹,

Howard²,

Lass‐Flörl³

et al. 2014

Antimicrob Agents Chemother

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fThe EUCAST E.DEF9.1 standard recommends standardization of the inoculum concentration by conidium counting using a hemocytometer rather than a spectrophotometer. In this study, we investigated whether the choice of these methods influenced isavuconazole MICs. A blinded collection of 30 molecularly characterized azole-resistant isolates and 10 wild-type Aspergillus fumigatus isolates was shared with four different laboratories. Additionally, each laboratory selected approximately 100 A. fumigatus isolates and 50 isolates each of A. flavus, A. nidulans, A. niger, and A. terreus (1,237 isolates in total). Three laboratories (laboratories 1 to 3) used conidium counting. One laboratory standardized the inoculum using a spectrophotometer (that is, by use of the optical density [OD]) and is referred to as the OD laboratory. Correlation coefficients, intraclass correlation coefficients, and essential agreement were calculated, and 2-log-unit differences were assessed (paired t test). The MIC range for the blinded collection was 0.25 to 16 mg/liter, and a 1-dilution-step difference between the MIC 50 and MIC 90 across the four laboratories was detected and a 2-dilution-step difference between the modal MICs was detected. Compared to the results for laboratories 1 and 2, a significant correlation was found for the OD laboratory MIC data (correlation coefficients, 0.85 and 0.93, respectively; intraclass correlation coefficients, 0.88 and 0.96, respectively). The number of mutant isolates whose MICs overlapped those of the wild-type isolates was the lowest for the OD laboratory (14/30 [46.7%] mutant isolates), whereas the numbers were 18/30 (60%) isolates for laboratory 1, 17/30 (56.7%) isolates for laboratory 2, and 21/30 (70%) isolates for laboratory 3. For the A. flavus, A. fumigatus, A. nidulans, A. niger, and A. terreus isolates, comparative analysis again defined the MIC distributions from the OD laboratory to be in excellent agreement with those from laboratories 1 and 2 across all five Aspergillus spp. The findings suggest that EUCAST testing using OD determination is an appropriate alternative for standardization of Aspergillus inoculum concentrations.T he first EUCAST reference method for the susceptibility testing of conidium-forming molds was published in 2008 (1). According to this standard, standardization of the inoculum concentration should be performed by conidium counting using a hemocytometer rather than measuring turbidity using a spectrophotometer. The reason for this recommendation was the concern that the conidia of various molds vary in size and color and, therefore, that the optical density (OD) might not predict the cell concentration with adequate precision. Although in their study Espinel-Ingroff and Kerkering (2) showed an acceptable prediction of the inoculum concentration using a spectrophotometer and 4 to 5 isolates of each of six different mold species, later studies using a greater number of isolates and species suggested the opposite (3-5). Indeed, one study showed that the spectrophotome...

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“…46 The greatest isavuconazole MIC elevations are observed in the TR34/L98H mutants. 43,46 In contrast, the isavuconazole MICs of the majority of G54 mutants were within the wild-type range. 43,46 Isolates with G54 alterations tend to demonstrate itraconazole and posaconazole resistance while maintaining voriconazole susceptibility.…”

Section: In Vitro Activity Against Aspergillus Speciesmentioning

confidence: 87%

“…43,46 In contrast, the isavuconazole MICs of the majority of G54 mutants were within the wild-type range. 43,46 Isolates with G54 alterations tend to demonstrate itraconazole and posaconazole resistance while maintaining voriconazole susceptibility. Therefore, in clinical practice, isavuconazole should be avoided for the treatment of infections with Aspergillus species with elevated voriconazole MICs.…”

Section: In Vitro Activity Against Aspergillus Speciesmentioning

confidence: 87%

“…37,38,40,41 When obtained by using the methodology set by the European Committee on Antimicrobial Susceptibility Testing (EUCAST), the MIC50 and MIC90 of isavuconazole against Aspergillus species appear similar. 39,42,43 The clinical significance of MIC variability according to Aspergillus species is not yet clear. However, it is important to identify organisms to the species level in the clinical microbiology laboratory because species-specific epidemiologic cutoff values (ECVs) will aid identification of resistant isolates.…”

Section: In Vitro Activity Against Aspergillus Speciesmentioning

confidence: 99%

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Orphan drugs for the treatment of aspergillosis: focus on isavuconazole

Jacobs¹,

Petraitis²,

Small³

et al. 2017

ODRR

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Invasive aspergillosis (IA) is a particularly devastating manifestation of Aspergillus infection affecting profoundly immunocompromised patients. Voriconazole has been approved as first-line therapy for IA since 2003; however, nonlinear pharmacokinetics, adverse effects, and drug-drug interactions at time hinder its use. Isavuconazole is a new broad-spectrum triazole with potent activity against Aspergillus species. In animal models and clinical trials in humans, isavuconazole has shown comparable efficacy to that of voriconazole in the treatment of IA. Advantages of isavuconazole include a more favorable pharmacokinetic profile and fewer adverse events. This review summarizes the pharmacologic characteristics, in vitro activity, and clinical data supporting the use of isavuconazole as an emerging alternative therapy for IA.

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

Cited by 64 publications

References 21 publications

In Vitro Activity of ASP2397 against Aspergillus Isolates with or without Acquired Azole Resistance Mechanisms

In Vitro Activity of ASP2397 against Aspergillus Isolates with or without Acquired Azole Resistance Mechanisms

EUCAST Testing of Isavuconazole Susceptibility in Aspergillus: Comparison of Results for Inoculum Standardization Using Conidium Counting versus Optical Density

Orphan drugs for the treatment of aspergillosis: focus on isavuconazole

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