In vivo Efficacy of Posaconazole (POS) against Voriconazole Resistant (VCZ-R) Aspergillus flavus in an Inhalational Neutropenic Murine Model of Invasive Pulmonary Aspergillosis
Suganthini Krishnan Natesan *
John D Dingell VA Medical Center, MI, USA and Wayne State University, Detroit, MI, USA.
Jessica L. Cutright
Wayne State University, Detroit, MI, USA.
*Author to whom correspondence should be addressed.
Abstract
Invasive aspergillosis (IA) is a life-threatening infection in patients with cancer. Recent studies have reported that non-fumigatus Aspergillus spp., including Aspergillus flavus, are emerging as predominant pathogens in various transplant and cancer centers in the USA and around the world. Clinical and environmental isolates of Aspergillus species showing reduced susceptibility to VCZ have been reported. Mortality, despite therapy, remains high, and drug resistance might partly account for treatment failures. In this in vivo study, the virulence of a VCZ-R cyp51A mutant of A. flavus and the efficacy of POS against this mutant were evaluated using a neutropenic inhalational murine model of invasive pulmonary aspergillosis. VCZ-R A. flavus mutant was virulent in vivo, and had similar infectivity as the VCZ-S parent. Posaconazole had superior activity to that of VCZ in reducing fungal burden (p <0.05) and mortality (p <0.05) in this experimental model of VCZ-R A. flavus murine infection. This study demonstrated that POS may be a viable option for certain strains of VCZ-R A. flavus.
Keywords: Aspergillus flavus, azole-resistance, posaconazole, voriconazole resistance, pulmonary aspergillosis, Aspergillus fumigates, murine model, neutropenia.