<i>In vitro</i> susceptibility of 188 clinical and environmental isolates of <i>Aspergillus flavus</i> for the new triazole isavuconazole and seven other antifungal drugs

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Invasive aspergillosis (IA) due to Aspergillus flavus is associated with high mortality. Although voriconazole (VRC) is widely recommended as the first-line treatment for IA, emergence of azole resistance in Aspergillus spp. is translating to treatment failure. We evaluated the efficacy of voriconazole in a nonneutropenic murine model of disseminated A. flavus infection using two voriconazole-resistant isolates (one harboring the Y319H substitution in the cyp51C gene) and two wild-type isolates without mutations. All isolates exhibited a dose-response relationship, and voriconazole treatment improved mouse survival in a dose-dependent manner. At 40 mg/kg of body weight, 100% efficacy was observed for 1 susceptible isolate and 1 resistant isolate (with mutation), whereas for another susceptible isolate and resistant isolate (without mutation), survival rates were 81% and 72%, respectively. The Hill equation with a variable slope fitted the relationship between the area under the concentration-time curve (AUC)/MIC ratio and 14-day survival well for each strain. An F test showed the 50% effective doses to be significantly different from each other (P ϭ 0.0023). However, contrary to expectation, there was a significant difference in exposure-response relationships between strains, and it appeared that the susceptible strains required a relatively higher exposure than the resistant ones to result in the same treatment effect, the 50% effective pharmacokinetic/pharmacodynamic (PK/PD) index (EI 50 ) required being negatively and log-linearly related to the MIC (P ϭ 0.04). We conclude that the efficacy of voriconazole depended on drug exposure and the voriconazole MIC of the isolates, but lower exposures are required for strains with higher MICs. These findings may have profound significance in clinical practice with respect to dosing and drug choice.

Section: Discussionmentioning

confidence: 72%

Section: Fungal Isolates Four Clinicalmentioning

confidence: 99%

Pharmacodynamics of Voriconazole against Wild-Type and Azole-Resistant Aspergillus flavus Isolates in a Nonneutropenic Murine Model of Disseminated Aspergillosis

Rudramurthy

Seyedmousavi

Dhaliwal

et al. 2017

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“…This may be less surprising, as itraconazole and voriconazole MICs are also higher for this species than for A. fumigatus (EUCAST ECOFFs of 4 mg/liter and 2 mg/liter for these compounds, respectively, compared to 1 mg/liter for both agents and A. fumigatus) (17,18). Additional isavuconazole susceptibility studies which used the CLSI method were also analogous (10,12,13,19,20). The clinical implications of these differences in susceptibility within species remain to be elucidated.…”

Section: Discussionmentioning

confidence: 94%

“…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

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.

“…Similarly, Shivaparkash et al studied the antifungal susceptibility profiles of triazoles against a large collection of clinical (n ϭ 178) and environmental (n ϭ 10) strains of A. flavus originating from India, using the Clinical and Laboratory Standards Institute (CLSI) method (21). Posaconazole had the highest activity (GM MIC, 0.123 mg/liter; MIC range, 0.062 to 0.25 mg/liter), followed by itraconazole (GM MIC, 0.177 mg/liter; MIC range, 0.062 to 0.5 mg/liter), isavuconazole (GM MIC, 0.697 mg/liter; MIC range, 0.125 to 2 mg/liter), and voriconazole (GM MIC, 1.167 mg/liter; MIC range, 0.05 to 4 mg/liter).…”

Section: Discussionmentioning

confidence: 99%

Genetic Diversity and In Vitro Antifungal Susceptibility of 200 Clinical and Environmental Aspergillus flavus Isolates

Armaki

Hedayati

Ansari

et al. 2017

Aspergillus flavus has been frequently reported as the leading cause of invasive aspergillosis in certain tropical and subtropical countries. Two hundred A. flavus strains originating from clinical and environmental sources and collected between 2008 and 2015 were phylogenetically identified at the species level by analyzing partial ␤-tubulin and calmodulin genes. In vitro antifungal susceptibility testing was performed against antifungals using the European Committee on Antimicrobial Susceptibility Testing (EUCAST) broth microdilution method. In addition, genotyping was performed using a short-tandem-repeat (STR) assay of a panel of six microsatellite markers (A. flavus 2A, 2B, 2C, 3A, 3B, and 3C), in order to determine the genetic variation and the potential relationship between clinical and environmental isolates. The geometric means of the minimum inhibitory concentrations/minimum effective concentrations (MICs/MECs) of the antifungals across all isolates were (in increasing order): posaconazole, 0.13 mg/liter; anidulafungin, 0.16 mg/liter; itraconazole, 0.29 mg/liter; caspofungin, 0.42 mg/liter; voriconazole, 0.64 mg/liter; isavuconazole, 1.10 mg/liter; amphotericin B, 3.35 mg/liter; and flucytosine, 62.97 mg/liter. All of the clinical isolates were genetically different. However, an identical microsatellite genotype was found between a clinical isolate and two environmental strains. In conclusion, posaconazole and anidulafungin showed the greatest in vitro activity among systemic azoles and echinocandins, respectively. However, the majority of the A. flavus isolates showed reduced susceptibility to amphotericin B. Antifungal susceptibility of A. flavus was not linked with the clinical or environmental source of isolation. Microsatellite genotyping may suggest an association between clinical and environmental strains, although this requires further investigation.