Abstrakt
Olorofim is a novel antifungal drug in phase 2 trials. It has shown promising in vitro activity against various molds, except for Mucorales. Initially, we observed a broad range of EUCAST MICs for Aspergillus fumigatus. Here, we explored the MIC variability in more detail and prospectively investigated the susceptibility of contemporary clinical mold isolates, as population data are needed for future epidemiological cutoff (ECOFF) settings. Fifteen A. fumigatus isolates previously found with low/medium/high MICs (<0.002 to 0.25 mg/liter) were tested repeatedly and EUCAST MICs read in a blinded fashion by three observers. pyrE, encoding the olorofim target enzyme dihydroorotate dehydrogenase (DHODH), was sequenced. A total of 1,423 mold isolates (10 Aspergillus species complexes [including 1,032 A. fumigatus isolates] and 105 other mold/dermatophyte isolates) were examined. Olorofim susceptibility (modal MIC, MIC50, MIC90, and wild-type upper limits [WT-ULs] [species complexes with >15 isolates]) was determined and compared to that of four comparators. MICs (mg/liter) were within two 2-fold dilutions (0.016 to 0.03) for 473/476 determinations. The MIC range spanned four dilutions (0.008 to 0.06). No significant pyrE mutations were found. Modal MIC/WT-UL97.5 (mg/liter) values were 0.03/0.06 (A. terreus and A. flavus), 0.06/0.125 (A. fumigatus and Trichophyton rubrum), and 0.06/0.25 (A. Niger and A. nidulans). The MIC range for Scedosporium spp. was 0.008 to 0.25. Olorofim susceptibility was similar for azole-resistant and -susceptible isolates of A. fumigatus but reduced for A. montevidensis and A. chevalieri (MICs of >1). With experience, olorofim susceptibility testing is robust. The testing of isolates from our center showed uniform and broad-spectrum activity. Single-center WT-ULs are suggested.
| Originalsprog | Engelsk |
|---|---|
| Artikelnummer | e01527-20 |
| Tidsskrift | Antimicrobial Agents and Chemotherapy |
| Vol/bind | 65 |
| Udgave nummer | 1 |
| Antal sider | 11 |
| ISSN | 0066-4804 |
| DOI | |
| Status | Udgivet - 16. dec. 2020 |
| Udgivet eksternt | Ja |
Bibliografisk note
Funding Information:Outside the current study, the authors have the following conflicts of interest. K.M.T.A. has, over the past 5 years, received travel grants from Gilead, Pfizer, and the Nordic Society for Medical Mycology and a speaker honorarium (personal fee) from Pfizer. K.M.J. has, over the past 5 years, received travel grants from F2G and Amplyx and a meeting grant from MSD. R.K.J. has, over the past 5 years, received a travel grant and an unrestricted research grant from Gilead. M.C.A. has, over the past 5 years, received research grants/payment for contract work (paid to the SSI) from Amplyx, Basilea, Cidara, F2G, Gilead, Novabiotics, Scynexis, and T2Biosystems and speaker honoraria (personal fees) from Astellas, Gilead, Novartis, MSD, and SEGES. She is the current chairman of the EUCAST-AFST. R.D. has no conflicts of interest to declare.
Funding Information:
This study was supported by an unrestricted grant from F2G. The funder had no influence on the study design or on the analysis of results.
Funding Information:
This study was supported by an unrestricted grant from F2G. The funder had no influence on the study design or on the analysis of results. Outside the current study, the authors have the following conflicts of interest. K.M.T.A. has, over the past 5 years, received travel grants from Gilead, Pfizer, and the Nordic Society for Medical Mycology and a speaker honorarium (personal fee) from Pfizer. K.M.J. has, over the past 5 years, received travel grants from F2G and Amplyx and a meeting grant from MSD. R.K.J. has, over the past 5 years, received a travel grant and an unrestricted research grant from Gilead. M.C.A. has, over the past 5 years, received research grants/payment for contract work (paid to the SSI) from Amplyx, Basilea, Cidara, F2G, Gilead, Novabiotics, Scynexis, and T2Biosystems and speaker honoraria (personal fees) from Astellas, Gilead, Novartis, MSD, and SEGES. She is the current chairman of the EUCAST-AFST.
Publisher Copyright:
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