Abstract
Isavuconazole, the active moiety of the prodrug isavuconazonium sulfate, has potent activity against a wide spectrum of fungal pathogens and is approved for the treatment of invasive aspergillosis, yet little is known about the tissue penetration of isavuconazole at the target sites of infection. Here, we explored the spatial and quantitative distribution of isavuconazole in tissue lesions in experimental pulmonary aspergillosis established in mice with chronic granulomatous disease (CGD) (gp91phox-). Matrix-assisted laser desorption ionization mass spectrometry imaging (MALDI-MSI) and laser capture microdissection (LCM)-directed high-pressure liquid chromatography coupled to tandem mass spectrometry (LC-MS/MS) were used to analyze infected lungs and brain tissues collected 1, 3, 6, and 24 h after a single oral administration of the prodrug at a dose of 256 mg/kg of body weight (corresponding to 122.9 mg/kg of isavuconazole). Drug enrichment within granulomatous lesions was observed in lung tissue at 1 h postdose, although drug levels quickly equilibrated afterwards between lesion and nonlesion areas. A prominent antifungal effect in the infected lung tissue was revealed by histopathological analysis. Isavuconazole also penetrated into the brain with high efficiency. These data further support the value of isavuconazole to treat patients with invasive aspergillosis.
Highlights
Invasive aspergillosis (IA) is a devastating infection and a common cause of death for the immunocompromised patient population [1,2,3]
As the new member of the triazole antifungal class, isavuconazole has demonstrated potent activity against a wide spectrum of fungal pathogens in a number of studies both in vitro and in vivo [8, 9, 23,24,25,26,27]. It has been approved by the U.S Food and Drug Administration (FDA) for the treatment of invasive aspergillosis and mucormycosis
Isavuconazonium sulfate has demonstrated clinical efficacy, and there are a few case reports of successful treatment of cerebral infections [28, 29], we generally lack a full appreciation of how isavuconazole distributes and penetrates at infected tissue sites, except for the limited data acquired in healthy animals by quantitative whole-body autoradiography (QWBA) [30] and drug concentrations determined in Candida-infected mouse kidney homogenates [31]
Summary
Invasive aspergillosis (IA) is a devastating infection and a common cause of death for the immunocompromised patient population [1,2,3]. Isavuconazole, the active moiety of the novel prodrug triazole compound isavuconazonium sulfate, has potent activity against a wide spectrum of fungal pathogens, including Aspergillus species [8, 9]. There is a paucity of data assessing tissue penetration of isavuconazole or other antifungal drugs at infected tissue sites. We investigated drug penetration of isavuconazole at the site of infection in experimental IA established in mice with CGD (gp91phoxϪ). This model recapitulates human disease, and the animals are highly susceptible to Aspergillus infection [18, 19]. Using matrix-assisted laser desorption ionization mass spectrometry imaging (MALDI-MSI) [20] and laser capture microdissection (LCM)-directed high-pressure liquid chromatography coupled to tandem mass spectrometry (LC-MS/MS) [21, 22], we visualized the spatial distribution of isavuconazole in infected lungs and brains, quantified absolute drug levels in distinct subcompartments of infected tissue, and correlated these levels with histopathological results
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
