Pharmacokinetics and concentration-dependent efficacy of isavuconazole for treatment of experimental invasive pulmonary aspergillosis

Vidmantas Petraitis, Ruta Petraitiene, Patriss W. Moradi, Gittel E. Strauss, Aspasia Katragkou, Laura L. Kovanda, William W. Hope, Thomas J. Walsh

Research output: Contribution to journalArticle

Abstract

We studied the pharmacokinetics and efficacy of the broad-spectrum triazole isavuconazole for the treatment of experimental invasive pulmonary aspergillosis (IPA) in persistently neutropenic rabbits. Treatment started 24 h after endotracheal administration of Aspergillus fumigatus inoculum; study subjects included rabbits receiving orally administered prodrug isavuconazonium sulfate (BAL8557) equivalent to active moiety isavuconazole (ISA; BAL4815) at 20 (ISA20), 40 (ISA40), and 60 (ISA60) mg/kg (of body weight)/day, with an initial loading dose of 90 mg/kg (ISA90), and untreated rabbits (UC). There were significant concentration-dependent reductions of residual fungal burden (log CFU/gram) and of organism-mediated pulmonary injury, lung weights, and pulmonary infarct scores in ISA40- and ISA60-treated rabbits in comparison to those of UC (P<0.001). ISA20-treated (P<0.05), ISA40-treated, and ISA60-treated (P<0.001) rabbits demonstrated significantly prolonged survival in comparison to that of UC. ISA40- and ISA60-treated animals demonstrated a significant decline of serum (1→3)-β-D-glucan levels (P<0.05) and galactomannan indices (GMIs) during therapy following day 4 in comparison to progressive GMIs of UC (P<0.01). There also were significantly lower concentration-dependent GMIs in bronchoalveolar lavage (BAL) fluid from ISA40- and ISA60-treated rabbits (P<0.001). There was a direct correlation between isavuconazole plasma area under the concentration-time curve from 0 to 24 h (AUC0-24) and residual fungal burdens in lung tissues, pulmonary infarct scores, and total lung weights. In summary, rabbits treated with isavuconazole at 40 and 60 mg/kg/day demonstrated significant dose-dependent reduction of residual fungal burden, decreased pulmonary injury, prolonged survival, lower GMIs in serum and BAL fluid, and lower serum (1→3)-β-D-glucan levels.

Original languageEnglish (US)
Pages (from-to)2718-2726
Number of pages9
JournalAntimicrobial agents and chemotherapy
Volume60
Issue number5
DOIs
StatePublished - May 2016

ASJC Scopus subject areas

  • Pharmacology
  • Pharmacology (medical)
  • Infectious Diseases

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  • Cite this

    Petraitis, V., Petraitiene, R., Moradi, P. W., Strauss, G. E., Katragkou, A., Kovanda, L. L., Hope, W. W., & Walsh, T. J. (2016). Pharmacokinetics and concentration-dependent efficacy of isavuconazole for treatment of experimental invasive pulmonary aspergillosis. Antimicrobial agents and chemotherapy, 60(5), 2718-2726. https://doi.org/10.1128/AAC.02665-15