Background: NKTR-024 is a novel dry-powder formulation of amphotericin B (AmB), and is directly delivered to the lung to produce lung AmB concentrations with potential to prevent fungal disease and eliminate systemic AmB toxicity. Prophylactic efficacy of NKTR-024 was evaluated in a guinea pig model of IPA and compared to untreated controls and animals treated with voriconazole (VRC). Methods: Guinea pigs were immunosuppressed with cortisone acetate and made temporarily neutropenic with cyclophosphamide d -2 pre, and d +3 post aerosolized challenge with 12 mL 109 CFU/mL Aspergillus fumigatus AF293 in an acrylic chamber. Groups of guinea pigs received prophylaxis with one dose of inhaled NKTR-024 (NKTR) at 0.05, 0.5, 4, or 10 mg/kg, given 24 h prior to infection, or treatment with oral VRC at 5 or 10 mg/kg/bid begun 24 h post challenge and continued for 8 d. Results: NKTR 4 (p=.02) and VRC 5 (p=.03) showed significantly improved survival vs controls. Decreased mortality (mean day of death), was also shown in a dose-dependent manner with NKTR 0.05, 0.5 and 4. Semi-quantitative assessment of lung tissue burden by colony forming units (CFU) revealed that NKTR 4 prophylaxis and therapy with either VRC dose yielded significantly reduced over controls. Similarly, assessment of lung burden by q-PCR (Conidial Equivalents; CE) showed NKTR 4 prophylaxis or VRC 5 or 10 therapy, vs controls, yielded significant reductions in counts. Galactomannan (GM) levels in lung homogenates showed that NKTR 4 prophylaxis or VRC 5 or10 therapy yielded significant reductions over controls or NKTR 0.05. Conclusions: NKTR-024 prophylaxis shows significant activity against A. fumigatus in this lethal model of IPA. Optimization of the dosing frequency and NKTR-024 dose should define the anti-Aspergillus efficacy in this stringent model of IPA.
Full conference title:
47th Interscience Conference on Antimicrobial agents and Chemotherapy
- ICAAC 47th