Background: Combination antifungal therapy provides a potential strategy to improve antifungal activity and clinical outcome of invasive mould infections caused by Aspergillus spp., Fusarium spp.,Scedosporium spp., and Mucorales. Discovery and development of isavuconazole (ISA) with its unique structure-activity relationship has the potential to enhance antifungal therapy and achieve synergy in combination with other antifungal agents. We therefore studied the combination of ISA with micafungin (MFG) or amphotericin B (AMB) against these fungal pathogens. Methods: Combinations were studied in 96-well plates by checkerboard method in triplicates with folowing dilutions: ISA (0.0625 - 32 μg/mL), MFG (0.5 - 32 μg/mL), and AMB (0.125 - 8 μg/mL). Plates were inoculated with 0.25-5 104 CFU/mL. After 48 h of incubation at 37Â°C, OD measurements were recorded at 530 nm for Bliss independence drug interaction (BIDI) analysis and drug interactions were calculated. Four isolates each of A. fumigatus(AF), A. terreus (AT), A. flavus (AFL), F. solani (FS), S. apiospermum (SA), R. oryzae (RO), R. microsporous (RM), M. circinelloides (MC), C. bertholettiae (CB) and L. corymbifera (LC) were used in triplicate experiments. Results: Synergistic interaction (SI) between ISA and MFG by BIDI analysis occurred against AF (28%Â±9%), AT (32%Â±14%), AFL (29%Â±11%), and SA (12%Â±4%). Antagonistic interaction (AI) occurred against MC (-10%Â±4%). Concentration dependent interaction (CDI) was against LC (10%Â±5% SI, -12%Â±5% AI), FS (12%Â±4% SI, -11%Â±3% AI), CB (8%Â±1% SI, -7%Â±2% AI), RO (16%Â±1% SI, -10%Â±2% AI), and RM (23%Â±1% SI, -12%Â±6% AI). The combination of ISA and AMB showed SI against SA (12%Â±4%) and RM (46%Â±28%). AI was observed against AF (-28%Â±16%), AFL (-42%Â±17%), and AT (-28%Â±16%). CDI was observed against LC (19%Â±14% SI, -20%Â±8% AI), FS (15%Â±6% SI, - 12%Â±5% AI), CB (14%Â±7% SI, -11%Â±6% AI), RO (19%Â±16% SI, -22%Â±8% AI), and MC (18%Â±13% SI, - 12%Â±9% AI). Conclusions: Synergistic interactions defined by BIDI analysis occured in vitro between ISA and MFG against Aspergillus spp. and Scedosporium apiospermum. Synergistic interactions also occured between ISA and AMB against S. apiospermum and R. microsporus.
Full conference title:
53rd Interscience Conference on Antimicrobial Agents and Chemotherapy
- ICAAC, 53rd (2013)