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Antimicrobial Agents and Chemotherapy, February 2006, p. 422-427, Vol. 50, No. 2
0066-4804/06/$08.00+0     doi:10.1128/AAC.50.2.422-427.2006
Copyright © 2006, American Society for Microbiology. All Rights Reserved.

Effect of Amphotericin B and Micafungin Combination on Survival, Histopathology, and Fungal Burden in Experimental Aspergillosis in the p47phox–/– Mouse Model of Chronic Granulomatous Disease

Carly G. Dennis,1 William R. Greco,2 Yseult Brun,2 Richard Youn,1 Harry K. Slocum,3 Ralph J. Bernacki,3 Russell Lewis,4 Nathan Wiederhold,4 Steven M. Holland,5 Ruta Petraitiene,6 Thomas J. Walsh,6 and Brahm H. Segal1,7*

Departments of Medicine,1 Biostatistics,2 Pharmacology and Therapeutics,3 Immunology, Roswell Park Cancer Institute, Buffalo, New York,7 University of Houston College of Pharmacy, M. D. Anderson Cancer Center, Houston, Texas,4 Laboratory of Clinical Infectious Diseases, National Institute of Allergy and Infectious Diseases,5 Immunocompromised Host Section, Pediatric Oncology Branch, National Cancer Institute, National Institutes of Health, Bethesda, Maryland6

Received 20 August 2005/ Returned for modification 28 September 2005/ Accepted 14 October 2005

Chronic granulomatous disease (CGD) is an inherited disorder of the NADPH oxidase characterized by recurrent life-threatening bacterial and fungal infections. We characterized the effects of single and combination antifungal therapy on survival, histopathology, and laboratory markers of fungal burden in experimental aspergillosis in the p47phox–/– knockout mouse model of CGD. CGD mice were highly susceptible to intratracheal Aspergillus fumigatus challenge, whereas wild-type mice were resistant. CGD mice were challenged intratracheally with a lethal inoculum (1.25 x 104 CFU/mouse) of A. fumigatus and received one of the following regimens daily from day 0 to 4 after challenge (n = 19 to 20 per treatment group): (i) vehicle, (ii) amphotericin B (intraperitoneal; 1 mg/kg of body weight), (iii) micafungin (intravenous; 10 mg/kg), or (iv) amphotericin B plus micafungin. The rank order of therapeutic efficacy based on prolonged survival, from highest to lowest, was as follows: amphotericin B plus micafungin, amphotericin B alone, micafungin alone, and the vehicle. Lung histology showed pyogranulomatous lesions and invasive hyphae, but without hyphal angioinvasion or coagulative necrosis. Treatment with micafungin alone or combined with amphotericin B produced swelling of invasive hyphae that was not present in mice treated with the vehicle or amphotericin B alone. Assessment of lung fungal burden by quantitative PCR showed no significant difference between treatment groups. Serum galactomannan levels were at background despite documentation of invasive aspergillosis by histology. Our findings showed the superior efficacy of the amphotericin B and micafungin combination compared to either agent alone after A. fumigatus challenge and also demonstrated unique features of CGD mice as a model for experimental aspergillosis.

* Corresponding author. Mailing address: Division of Infectious Diseases, Roswell Park Cancer Institute, Elm and Carlton Streets, Buffalo, NY 14263. Phone: (716) 845-5721. Fax: (716) 845-3423. E-mail: brahm.segal{at}roswellpark.org.

Antimicrobial Agents and Chemotherapy, February 2006, p. 422-427, Vol. 50, No. 2
0066-4804/06/$08.00+0     doi:10.1128/AAC.50.2.422-427.2006
Copyright © 2006, American Society for Microbiology. All Rights Reserved.



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