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 10(4) 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.