title: 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.
abstract: 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.
authors.affiliation: Department of Medicine, Roswell Park Cancer Institute, Buffalo, NY 14263, USA.
authors.forename: Carly G
authors.initials: CG
authors.lastname: Dennis
authors.forename: William R
authors.initials: WR
authors.lastname: Greco
authors.forename: Yseult
authors.initials: Y
authors.lastname: Brun
authors.forename: Richard
authors.initials: R
authors.lastname: Youn
authors.forename: Harry K
authors.initials: HK
authors.lastname: Slocum
authors.forename: Ralph J
authors.initials: RJ
authors.lastname: Bernacki
authors.forename: Russell
authors.initials: R
authors.lastname: Lewis
authors.forename: Nathan
authors.initials: N
authors.lastname: Wiederhold
authors.forename: Steven M
authors.initials: SM
authors.lastname: Holland
authors.forename: Ruta
authors.initials: R
authors.lastname: Petraitiene
authors.forename: Thomas J
authors.initials: TJ
authors.lastname: Walsh
authors.forename: Brahm H
authors.initials: BH
authors.lastname: Segal
mesh_terms: D000666:Amphotericin B / Q000008:administration & dosage*; D000818:Animals; D000935:Antifungal Agents; D001228:Aspergillosis / Q000188:drug therapy* / Q000382:microbiology / Q000473:pathology; D001232:Aspergillus fumigatus / Q000302:isolation & purification*; D004359:Drug Therapy, Combination; D054714:Echinocandins; D006105:Granulomatous Disease, Chronic / Q000150:complications*; D055666:Lipopeptides; D008074:Lipoproteins / Q000008:administration & dosage*; D008168:Lung / Q000382:microbiology / Q000473:pathology; D000077551:Micafungin; D051379:Mice; D019255:NADPH Oxidases; D010456:Peptides, Cyclic / Q000008:administration & dosage*; D010750:Phosphoproteins / Q000172:deficiency*
chemical_list: D000935:Antifungal Agents; D054714:Echinocandins; D055666:Lipopeptides; D008074:Lipoproteins; D010456:Peptides, Cyclic; D010750:Phosphoproteins; D000666:Amphotericin B; D019255:NADPH Oxidases; C060505:neutrophil cytosolic factor 1; D000077551:Micafungin