667. Lack of Concordance Among Different Methods to Study in Vitro Interactions Among Echinocandins (ECN) against Aspergillus Fumigatus
Session: Abstracts: Mycology
Friday, October 22, 2010
Background: Drug combinations are increasingly explored as a means of improving outcomes in invasive aspergillosis. ECNs impair mycelial growth by inhibiting glucan synthase. However, it is unknown whether different ECNs have distinct binding sites, or if additional drug targets exist. Diverse ECN interactions with fungal targets could lead to therapeutically meaningful interactions among the ECNs.

Methods: We tested the in vitro interactions among the 3 ECNs [caspofungin (CSP), anidulafingin (ANF), and micafungin (MCF)] by three methods: (i) checkerboard (CLSI M38-A protocol with a modified plate reading method using XTT); (ii) disk diffusion assay; and (iii) E-test/agar dilution. The reference clinical A. fumigatus strain Af293 was used in checkerboard and disk diffusion experiments. Two additional strains, the ECN-resistant fks1 mutant strain Af1034 and the clonal FKS1 wild-type strain Af1035 were used in the E-test/agar dilution experiments. All experiments were performed at least in triplicate.

Results: Checkerboard experiments revealed different interactions between ECN pairs against Af293 depending on the specific drug combination tested. Specifically, the combination of CSF and either ANF or MCF yielded a fractional inhibitory concentration (FIC) index ranging from 0.15 to 2.0, while the combination of MCF and ANF yielded an FIC index range 0.19-0.31, consistent with synergistic interaction. In contrast, all ECN pairs appeared indifferent by the disk diffusion method. Moreover, the combination of MCF and ANF appeared antagonistic when the two drugs were tested using the E-test/agar dilution method for both the FKS1 wild-type and ECN-resistant fks1 mutant strains.

Conclusion: Discordant results were obtained with different methods to test ECN combinations against A. fumigatus. These results highlight methodological problems in in vitro antifungal combination testing. We did not find compelling evidence of inter-ECN synergy that could serve as a basis for in vivo experiments.  

Subject Category: M. Mycology including clinical and basic studies of fungal infections

Ronen Ben-Ami, MD , The University of Texas MD Anderson Cancer Center, Houston, TX
Russell Lewis, PharmD , University of Houston College of Pharmacy, Houston, TX
Dimitrios Kontoyiannis, MD, FIDSA , MD Anderson Cancer Ctr, Houston, TX


R. Ben-Ami, None

R. Lewis, Yes
Merck & Co: --, Grant Investigator and Speaker's Bureau, Grant recipient
Astellas: --, Consultant and Grant Investigator, Grant recipient

D. Kontoyiannis, Yes
Enzon: Grant Investigator, Speaker's Bureau and research grants,
Astellas: Grant Investigator, Speaker's Bureau and research grant,
Merck: Consultant, Consultant and Speaker's Bureau,
Pfizer: Speaker's Bureau,
Schering-Plough: Consultant and Consultant,

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