In vitro Evaluation of Combination of Ibrexafungerp and Azoles against Aspergillus spp. Isolated from Lung Transplant Recipients

Author:

V Jagadeesan1, E Driscoll1, B Hao1, S Barat2, K Borroto-Esoda2, D Angulo2, C Clancy1, M Nguyen1

Author address:

1Medicine, University of Pittsburgh, Pittsburgh, USA
2Scynexis, Inc, New Jersey, USA

Full conference title:

9th Advances Against Aspergillosis

Date: 27 February 2020

Abstract:

Purpose: Aspergillosis is the most common opportunistic mould infection. Over the past 2 decades, there has been a surge in non-Aspergillus fumigatus (non-Af) spp causing infections. This change in epidemiology might be partially attributable to increased use of broad-spectrum antifungal agents. Indeed, breakthrough infections while on azole prophylaxis or treatment have been attributed to azole-resistant non-Af species, and mortality associated with these infections is high. Ibrexafungerp (IBX) is a novel class of glucan synthase inhibitor that has broad activity against Candida, Aspergillus and Pneumocysitis. We evaluated the in vitro activity of IBX, either singly or in combination with isavuconazole (ISA), posaconazole (POSA) or voriconazole (VOR) against 51 Aspergillus isolates recovered from lung transplant recipients.

Methods: MICs of antifungals were determined according to CLSI M38-A2 susceptibility standard. Concentrations tested were from 0.015 to 16 µg/mL. For combination testing, we used the checkerboard method. Fractional inhibitory concentration index (FICi = MICIBX(single)/MICIBX(combo) + MICAZOLE(single)/MICAZOLE(combo)) was used to classify the interaction between 2 drugs as synergy (FICi<0.5), antagonism (FICi>4) or indifference (FICi 0.5-4).

Results: Fifty-one isolates were tested (A. calidoustus, 5; A. flavus, 11; Af, 20; A. glaucus, 1; A. niger, 7; and A. terreus, 7). IBX, ISA, POSA and VOR MIC50 were 0.06 (range ≤0.015->16), 0.5 (0.03->16), 0.125 (≤0.015->16), and 0.125 (0.06->16) µg/mL, respectively. Azole MIC≥2 µg/mL was observed in 80% and 14% of A. calidoustus and A. terreus isolates, respectively. Median MIC of IBX was higher for A. flavus (0.125 µg/mL) than other species (0.06 µg/mL; p=0.002). A. calidoustus exhibited significantly higher MICs to all 3 azoles (median MIC 4 µg/mL, range: 0.25 to 16) versus other species (<0.0001). 14, 1 and 5 isolates exhibited IBX, ISA and POSA MIC ≤0.015 µg/mL, respectively, thus FICi cannot be determined. Synergy was observed in 63% between IBX and ISA, 56% between IBX and POSA, and 54% between IBX and VORI. Antagonism was not observed with any combination tested. Among isolates exhibiting either IBX or azole MICs ≤0.015µg/mL, the beneficial effect of the combination was still seen: the MIC of the 2nd drug was reduced by at-least 4-fold in 100% of ISA+IBX, 75% of POSA+IBX and 94% of VORI+IBX. For the remaining cases, in which synergy was not achieved, there was still a decrease, although not as dramatic, in MICs of one or both drugs when used in combination. Remarkably, for azole-resistant A. calidoustus and A. terreus, ISA, POSA and ISA MICs in combination with IBX decreased from the range of 2 to 16 µg/mL to 0.06-0.2 5µg/mL (ISA) and 0.03-0.125 µg/mL (POSA and VORI).

Conclusion: The in vitro results with combinations of IBX and azoles against Aspergillus spp. are encouraging. Antagonism was not observed for this combination, and synergy was achieved against 54 to 63% of isolates. The effect of IBX on reducing azole MICs to low range for azole-resistant A. calidoustus and A. terreus is particularly noteworthy. Animal model and clinical studies are warranted to further elucidate the potential utility of IBX-azole combination therapy.

Abstract Number: 122

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AAAM 2020

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