Combination Micafungin (Mica) and Amphotericin B Desoxycholate (Amb-d) has In Vitro Antagonism but Prolongs Survival in the p47phox-/- Mouse Model of Chronic Granulomatous Disease (CGD) with Experimental Pulmonary Aspergillosis

C. G. DENNIS 1, W. R. GRECO 1, H. K. SLOCUM 1, R. BERNACKI 1, P. PERA 1, C. FAILING 1, R. LEWIS 2, N. WIEDERHOLD 2, S. M. HOLLAND 3, T. J. WALSH 4, B. H. SEGAL 1

Author address: 

1 Roswell Park Cancer Institute, Buffalo, NY, 2 MD Anderson Cancer Center, Houston, TX, 3 NIAID, NIH, Bethesda, MD, 4 NCI, NIH, Bethesda, MD

Abstract: 

Background: CGD is an inherited disorder of the NADPH oxidase characterized by severe bacterial and fungal infections. We evaluated combination Amb-d and Mica in vitro and in CGD mice with aspergillosis. Methods: Amb-d and Mica were paired in fixed ratios (Amb-d alone; 1:0.25; 1:0.5; 1:1) corresponding to their IC50s, serially diluted, and randomly added to 96-well plates. A. fumigatus conidia were added, and viability assessed by the XTT assay at 24h. Hyphal growth in response to antifungal agents was evaluated by time-lapse video. CGD mice were challenged with intratracheal A. fumigatus conidia (1.25 x 10E4 CFU/mouse). Mice (n=19-20 per treatment) received 1 of the following regimens daily from day 0 to 4 after challenge: 1) IV+IP vehicle; 2) IV Mica (10 mg/kg) + IP vehicle; 3) IV vehicle + IP Amb-d (1 mg/kg); or 4) IV Mica (10 mg/kg) + IP Amb-d B (1 mg/kg). Results: In XTT assays, curves and IC50s were normalized to Amb-d alone. Addition of Mica led to dose-dependent antagonism. In time-lapse video experiments, Mica alone was more effective in suppressing hyphal growth than the combination of Mica + sub-therapeutic Amb-D. In survival experiments in CGD mice, all 4 treatment groups significantly different from each other (log-rank: p Amb-D>Mica>vehicle. Conclusions: Combination Mica and Amb-d was more effective than either agent alone in prolonging survival in CGD mice after Aspergillus challenge. In contrast, the combination regimen showed antagonism in vitro. The discrepancy between the in vitro and in vivo data reflects the more complex pharmacodynamic and host factors occurring in vivo.
2004

abstract No: 

M-232-2004

Full conference title: 

44th Interscience Conference on Antimicrobial Agents and Chemotherapy
    • ICAAC 44th