Efficacy of Antifungal Therapy with Inhaled Itraconazole against Murine Invasive Pulmonary Aspergillosis with azole – Low Susceptible Aspergillus fumigatus

Ref ID: 19481

Author:

K Hirano1, K Izumikawa1, M Yoshida1*, K Takeda1, N Kaku2, N Iwanaga1, S Ide1, A Minematsu1,
Y Harada2, T Takazono1, K Kosai1, Y Morinaga2, S Kurihara1, S Nakamura1, Y Imamura1,
T Miyazaki1, M Tsukamoto1, K Yanagihara2, T Tashiro1, S Kohno1

Author address:

1Department of Molecular Microbiology and Immunology, Nagasaki University Graduate School of
Biomedical Sciences, Nagasaki, Japan
2Department of Laboratory Medicine, Nagasaki University Hospital, Nagasaki, Japan

Full conference title:

6th Advances Against Aspergillosis 2014

Abstract:

Background:
Fungal infection is one of the most serious problems in immunocompromised patients during the
medication of anticancer and immunosuppressant drugs, and among HIV/AIDS patients. Invasive
pulmonary aspergillosis (IPA) results in significant mortality in severely immunocompromised
patients. We found the case of itraconazole (ITCZ) resistant Aspergillus fumigatus (Af) strains
isolated. The tolerance to azole antifungal drug has become a serious concern recently. Targeted
intrapulmonary delivery of antifungals has the potential to reduce systemic toxicity and improve
treatment efficacy as well as prophylaxis. Therefore, we investigated inhalation of ITCZ treatment
against IPA model with ITCZ-low susceptible A. fumigatus.
Objective and Method:
A. fumigatus MF367 and MF469 were clinically obtained from a patient admitted to the Nagasaki
University Hospital. The MIC of MF367 was 0.5mg/L and that of MF469 was 8.0mg/L which were
determined by Clinical and Laboratory Standards Institute (CLSI) M38-A2 broth microdilution
method. Six-week-old female ICR mice (Charles River Breeding Laboratories, Shiga, Japan) were
immunosuppressed and then challenged on day 0 with 5x 104 conidia of A. fumigatus MF367 or
MF469 intratracheally for monitoring of survival for 14 days. Mice were immunosuppressed by
intraperitoneal injection of cortisone acetate (Sigma, Tokyo, Japan) at 250 mg/kg of body weight
and cyclophosphamide (Sigma, Tokyo, Japan) at 200 mg/kg on days -2 and 0 for the survival study.
Mice were assigned into the following groups: control mice challenged with MF367 or MF469
without treatment, the mice challenged with MF367 or MF469 receiving ITCZ oral administration
(20mg/kg,40mg/kg,80mg/kg), and the mice challenged with MF367 or MF469 receiving ITCZ
inhalation (5ml mixture solution of ITCZ and saline of 20%, 40%, 80% and 100%).
Result:
The survival rate of MF-367-infected mice treated with nebulized ITCZ (40%, 80%, and 100%)
were 63%, 71%, and 80%, respectively, and that of ITCZ (80mg/kg) oral administration was 62%.
The survival rate of MF-469-infected mice treated with nebulized ITCZ (80% and 100%) were 60%,
and 71%, respectively, and that of ITCZ (80mg/kg) oral administration was 50%. The survival rates
of the group of mice receiving nebulized ITCZ were significantly higher than those of the group of
mice receiving oral ITCZ administration. Additionally, MF-367 (ITCZ-susceptible strain)-infected
mice were more sensitive to nebulized ITCZ compared to MF-469 (ITCZ-low susceptible strain)-
infected mice.
Conclusion:
Our result indicated the possibility of inhalation of ITCZ administration is effective to IPA with
ITCZ-low susceptible A. fumigatus strain.

Abstract Number: 9

Conference Year: 2014

Link to conference website: http://www.AAA2014.org

New link: NULL

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