In vitro activity of Manogepix (APX001A) and comparators against contemporary moulds; MEC comparison and preliminary experience with colorimetric MIC determination.
Antimicrob Agents Chemother. 2020 Jun 08;:
Authors: Jørgensen KM, Astvad KMT, Arendrup MC
Manogepix (APX001A) is the active moiety of the drug candidate fosmanogepix (APX001), currently in clinical development for the treatment of invasive fungal infections. We compared manogepix EUCAST MECs to MICs of five comparators, to CLSI MECs and to MICs by a colorimetric method against contemporary moulds.EUCAST susceptibility testing was performed for 161 isolates. Inter-laboratory and inter-method reproducibility were determined by comparison with published manogepix MECs. Colorimetric MICs (measuring metabolic activity) were evaluated using three A. fumigatus and one A. flavus isolates with four inocula, 24-48h incubation and 1-3h XTT/MEN exposures.Manogepix modal MECs (range) (mg/L) against Aspergillus species were 0.03-0.06 (0.008-0.125) and unaffected by itraconazole resistance. Manogepix was as active against two Fusarium but inactive against Trichophyton interdigitale, Lichtheimia ramosa and Rhizomucor pusillus isolates (MECs >0.5). Modal MEC/MICs were ≥3 two-fold dilutions apart without overlapping ranges comparing manogepix with amphotericin B, isavuconazole, and voriconazole against Aspergillus isolates. Manogepix and posaconazole MECs/MICs correlated for A. niger (Pearson r=0.711, P=0.0044). MEC50, modes and MEC90 values were within ±1 dilution in all cases when compared with published EUCAST and CLSI data. The colorimetric method showed excellent agreement with the MECs when plates were inoculated with the lowest inoculum (1-2.5 x 102 CFU/mL), 24 h incubated and 1-3h XTT/MEN.Broad spectrum in vitro activity of manogepix against clinically relevant moulds was confirmed with excellent agreement across EUCAST and CLSI methods reported from experienced mycology laboratories. Colorimetric MIC determination warrants further investigation as a potential alternative that is less dependent on mycology expertise.
PMID: 32513793 [PubMed - as supplied by publisher]