Methods: Female 6-8 week old CD1 mice weighing 18-22 g were infected intraperitoneally (IP) with 1x107 CFU of C. albicans SC5314 mixed with sterile stool matrix. Single IP doses of CD101 at 5 or 20 mg/kg (equivalent to humanized therapeutic dose) or micafungin at 5 mg/kg (therapeutic dose) were administered to mice at day 3 post-inoculation. Mice were sacrificed at just before antifungal treatment (n=1), and at 1, 3, 6, 24, and 48 h post-dose (n=3 per group per time point). Liver and kidney lesions were collected for MALDI imaging. Laser capture microdissection (LCM) followed by liquid chromatography coupled tandem mass spectrometry (LC/MS-MS) was applied to 6 and 24h samples for drug exposure measurement. In a separate experiment, mice were treated with 2 or 3 doses of micafungin (5 mg/kg), or a single dose of CD101 (20 mg/kg). Drug accumulation was analyzed at 48 and 72h post the first dose.
Results: Drug accumulation within lesions was observed with both drugs at their humanized therapeutic dose. However, micafungin, even at steady-state, failed to approach the mutant prevention concentration (MPC) (16 µg/ml) of the infecting strain. CD101 demonstrated extensive penetration into the lesions after a single dose administration and persisted in lesions at above MPC level of 29.7 µg/ml at 72h postdose.
Conclusion: These findings indicate that current echinocandin drugs may be limited by penetration at the site of infection, which have implications for clinical outcomes and emergence of resistance in patients with IAC.
Y. Nagasaki, None
M. H. Lee, None
P. Y. Chen, None
L. Blanc, None
H. Ho, None
C. J. Clancy, Merck: Received research funding , Research support
Astellas: Received research funding , Research support
Cidara: Received research funding , Research support
Astellas: Scientific Advisor , Advisory board
Merck: Scientific Advisor , Advisory board
Cidara: Scientific Advisor , Advisory board
Medicines Company: Scientific Advisor , Advisory board
M. H. Nguyen, None
V. Dartois, None
D. Perlin, Cidara: Research Contractor and Scientific Advisor , Research grant
Amplyx: Research Contractor and Scientific Advisor , Research grant
Matinas: Scientific Advisor , Research support
Scynexis: Research Contractor and Scientific Advisor , Research grant
Merck: Research Contractor , Research grant
Astellas: Research Contractor , Research grant
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