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

K. Hirano, K. Izumikawa, T. Takazono, K. Kosai, Y. Morinaga, S. Kurihara, S. Nakamura, Y. Imamura, T. Miyazaki, M. Tsukamoto, H. Kakeya, K. Yanagihara, T. Tashiro, S. Kohno

Author address: 

Nagasaki Univ., Nagasaki, JAPAN.

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 strains isolated.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. Methods: 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. Six-week-old female ICR mice were immunosuppressed and then challenged on day 0 with 5x 104 conidia of A.fumigatus intratracheally for monitoring of survival for 14 days. 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,40mg,80mg/kg), and the mice challenged with MF367 or MF469 receiving ITCZ inhalation (5ml mixture solution of ITCZ and saline of 20%, 40%, 80%,100%). Results: The survival rate of MF- 367-infected mice treated with nebulized ITCZ (40%, 80%,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%,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)- infected mice were more sensitive to nebulized ITCZ compared to MF-469 (ITCZ-low susceptible)-infected mice. Conclusions: Our result indicated the possibility of inhalation of ITCZ administration is effective to IPA with ITCZ-low susceptible A.fumigatus strain.
2013

abstract No: 

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Full conference title: 

53rd Interscience Conference on Antimicrobial Agents and Chemotherapy
    • ICAAC, 53rd (2013)