Mucormycosis is a severe fungal infection caused by Mucorales fungi and is associated with high morbidity and mortality. Lipid amphotericin B is used as primary treatment, and the combined use with posaconazole could improve tolerance and adherence to treatment.
Isavuconazole (ISA) is a new extended-spectrum triazole that has been approved for the treatment of invasive mucormycosis.
The antifungal susceptibility profile varies upon Mucorales fungi, and little is known regarding whether synergistic activity occurs when polyenes and azole drugs are combined.
Objectives
To evaluate the combination of AB + ISA or AB + PZ against medically important Mucorales isolates.
Methods
The species studied were: Rhizopus microsporus (11), R. arrhizus (3), Mucor racemosus (4), M. circinelloides (1), Lichtheimia ramosa (3) and L. corymbifera (1). Molecular identification was performed by sequencing ribosomal DNA (primers ITS1-ITS4) and homology search using BLASTn.
The antifungal susceptibility testing (MICs) was performed according to M38 3rd ed. from the CLSI. The range of MIC values, MIC90, mode, and geometric mean was calculated.
Drug interactions were evaluated using a two-dimensional (8-by-12) checkerboard titration method for the following combinations: AB + ISA or AB + PZ.
Interactions between the antifungal agents were analyzed using the fractional inhibitory concentration index (FICI). Drug interactions were considered as synergistic (SYN) for FICI ≤ 0.5, not interactive (NI) when the FICI was between 0.5 and 4, and antagonistic (ANT) for FICI > 4.
Results
The overall MIC90 values (mg/L) for posaconazole was of 1 for all species tested; for amphotericin B from 1 (Lichtheimia spp. and Mucor spp.) to 2 (Rhizopus spp.), while for isavuconazole was from 1 (Lichtheimia spp) to 8 (Mucor spp. and Rhizopus spp.).
The interaction between antifungal combination assays is summarized in the table.
Overall, for the interaction AB + PZ, 20 (87%) was synergistic; 2 (8.7%) no-interactive and 1 (4.3%) antagonistic. For the interaction AB + ISA, 13 (57%) was synergistic; 6 (26%) no interactive and 4 (17 %) antagonistic.
Conclusions
When tested alone, amphotericin B and posaconazole, seem to be slightly more active than isavuconazole.
For mucormycosis treatment, antifungal options are limited, thus, despite combination AB + PZ was more effective than AB + ISA, the last one could be considered for potential treatment.
