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 (P0-24) 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 1 2016
Externally publishedYes

Fingerprint

Invasive Pulmonary Aspergillosis
Pharmacokinetics
Rabbits
Lung
Lung Injury
Weights and Measures
Dimercaprol
Triazoles
Aspergillus fumigatus
Prodrugs
Serum
Body Weight
isavuconazole

ASJC Scopus subject areas

  • Pharmacology (medical)
  • Pharmacology
  • Infectious Diseases

Cite this

Petraitis, V., Petraitiene, R., Moradi, P. W., Strauss, G. E., Katragkou, A., Kovanda, L. L., ... 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

Pharmacokinetics and concentration-dependent efficacy of isavuconazole for treatment of experimental invasive pulmonary aspergillosis. / Petraitis, Vidmantas; Petraitiene, Ruta; Moradi, Patriss W.; Strauss, Gittel E.; Katragkou, Aspasia; Kovanda, Laura L.; Hope, William W.; Walsh, Thomas J.

In: Antimicrobial Agents and Chemotherapy, Vol. 60, No. 5, 01.05.2016, p. 2718-2726.

Research output: Contribution to journalArticle

Petraitis, V, Petraitiene, R, Moradi, PW, Strauss, GE, Katragkou, A, Kovanda, LL, Hope, WW & Walsh, TJ 2016, 'Pharmacokinetics and concentration-dependent efficacy of isavuconazole for treatment of experimental invasive pulmonary aspergillosis', Antimicrobial Agents and Chemotherapy, vol. 60, no. 5, pp. 2718-2726. https://doi.org/10.1128/AAC.02665-15
Petraitis, Vidmantas ; Petraitiene, Ruta ; Moradi, Patriss W. ; Strauss, Gittel E. ; Katragkou, Aspasia ; Kovanda, Laura L. ; Hope, William W. ; Walsh, Thomas J. / Pharmacokinetics and concentration-dependent efficacy of isavuconazole for treatment of experimental invasive pulmonary aspergillosis. In: Antimicrobial Agents and Chemotherapy. 2016 ; Vol. 60, No. 5. pp. 2718-2726.
@article{7c20097350dd43e08ce1f465fdef70f4,
title = "Pharmacokinetics and concentration-dependent efficacy of isavuconazole for treatment of experimental invasive pulmonary aspergillosis",
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 (P0-24) 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.",
author = "Vidmantas Petraitis and Ruta Petraitiene and Moradi, {Patriss W.} and Strauss, {Gittel E.} and Aspasia Katragkou and Kovanda, {Laura L.} and Hope, {William W.} and Walsh, {Thomas J.}",
year = "2016",
month = "5",
day = "1",
doi = "10.1128/AAC.02665-15",
language = "English (US)",
volume = "60",
pages = "2718--2726",
journal = "Antimicrobial Agents and Chemotherapy",
issn = "0066-4804",
publisher = "American Society for Microbiology",
number = "5",

}

TY - JOUR

T1 - Pharmacokinetics and concentration-dependent efficacy of isavuconazole for treatment of experimental invasive pulmonary aspergillosis

AU - Petraitis, Vidmantas

AU - Petraitiene, Ruta

AU - Moradi, Patriss W.

AU - Strauss, Gittel E.

AU - Katragkou, Aspasia

AU - Kovanda, Laura L.

AU - Hope, William W.

AU - Walsh, Thomas J.

PY - 2016/5/1

Y1 - 2016/5/1

N2 - 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 (P0-24) 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.

AB - 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 (P0-24) 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.

UR - http://www.scopus.com/inward/record.url?scp=84964848899&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84964848899&partnerID=8YFLogxK

U2 - 10.1128/AAC.02665-15

DO - 10.1128/AAC.02665-15

M3 - Article

C2 - 26883703

AN - SCOPUS:84964848899

VL - 60

SP - 2718

EP - 2726

JO - Antimicrobial Agents and Chemotherapy

JF - Antimicrobial Agents and Chemotherapy

SN - 0066-4804

IS - 5

ER -