Pharmacodynamics of Isavuconazole in an Aspergillus fumigatus Mouse Infection Model

Author:

Seyedmousavi SeyedmojtabaORCID,Brüggemann Roger J. M.,Meis Jacques F.,Melchers Willem J. G.,Verweij Paul E.,Mouton Johan W.ORCID

Abstract

ABSTRACTAzole resistance is an emerging problem inAspergillus fumigatuswhich translates into treatment failure. Alternative treatments with new azoles may improve therapeutic outcome in invasive aspergillosis (IA) even for strains with decreased susceptibility to current azoles. Thein vivoefficacy of 0.25, 1, 4, 16, 64, 128, 256, and 512 mg/kg of body weight/day prodrug isavuconazonium sulfate (BAL8557) (isavuconazole [ISA]-equivalent doses of 0.12, 0.48, 1.92, 7.68, 30.7, 61.4, 122.9, and 245.8 mg/kg/day, respectively) administered by oral gavage was assessed in an immunocompetent murine model of IA against four clinicalA. fumigatusisolates: a wild-type isolate (ISA MICEUCAST, 0.5 mg/liter) and three azole-resistant isolates harboring substitutions in thecyp51Agene: G54W (ISA MICEUCAST, 0.5 mg/liter), M220I (ISA MICEUCAST, 4 mg/liter), and TR34/L98H (ISA MICEUCAST, 8 mg/liter). The maximum effect (100% survival) was reached at a prodrug isavuconazonium sulfate dose of 64 mg/kg for the wild-type isolate, 128 mg/kg for the G54W mutant, and 256 mg/kg two times per day (q12) for the M220I mutant. A maximum response was not achieved with the TR34/L98H isolates with the highest dose of prodrug isavuconazonium sulfate (256 mg/kg q12). For a survival rate of 50%, the effective AUC0–24/MICEUCASTratio for ISA total drug was 24.73 (95% confidence interval, 22.50 to 27.18). The efficacy of isavuconazole depended on both the drug exposure and the isavuconazole MIC of the isolates. The quantitative relationship between exposure and effect (AUC0–24/MIC) can be used to optimize the treatment of human infections byA. fumigatus, including strains with decreased susceptibility.

Publisher

American Society for Microbiology

Subject

Infectious Diseases,Pharmacology (medical),Pharmacology

Reference72 articles.

1. Invasive aspergillosis in critically ill patients without malignancy;Am J Respir Crit Care Med,2004

2. Therapeutic outcome in invasive aspergillosis;Clin Infect Dis,1996

3. Aspergillosis. Pathogenesis, clinical manifestations, and therapy;Infect Dis Clin North Am,2002

4. Clinical implications of azole resistance in Aspergillus fumigatus, The Netherlands, 2007–2009;Emerg Infect Dis,2011

5. Voriconazole versus amphotericin B for primary therapy of invasive aspergillosis;Invasive Fungal Infections Group of the European Organisation for Research and Treatment of Cancer and the Global Aspergillus Study Group;N Engl J Med,2002

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