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JAC Advance Access published online on May 22, 2009
Journal of Antimicrobial Chemotherapy, doi:10.1093/jac/dkp175
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© The Author 2009. Published by Oxford University Press on behalf of the British Society for Antimicrobial Chemotherapy. All rights reserved. For Permissions, please e-mail: journals.permissions@oxfordjournals.org

Original research

Combination therapy with micafungin and amphotericin B for invasive pulmonary aspergillosis in an immunocompromised mouse model

Yoji Nagasaki1, Yoshihiro Eriguchi1, Yujiro Uchida2, Noriko Miyake1, Yoriko Maehara1, Masako Kadowaki1, Mine Harada1,3, Koichi Akashi1 and Nobuyuki Shimono1,*

1 Faculty of Medicine and Biosystemic Science, Graduate School of Medical Science, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka City, Fukuoka 812-8582, Japan 2 Faculty of Clinical Chemistry and Laboratory Medicine, Kyushu University Hospital, 3-1-1 Maidashi, Higashi-ku, Fukuoka City, Fukuoka 812-8582, Japan 3 National Hospital Organization Omuta Hospital, 1044-1 Oaza, Tachibana, Omuta City, Fukuoka 837-0911, Japan

Received 26 January 2009; returned 21 February 2009; revised 20 April 2009; accepted 21 April 2009

* Corresponding author. Tel: +81-92-642-5228; Fax: +81-92-642-5247; E-mail: shimono{at}intmed1.med.kyushu-u.ac.jp

Objectives: Antifungal monotherapy with polyenes, azoles or echinocandins is not always effective for invasive pulmonary aspergillosis (IPA). The main purpose of this study was to evaluate the efficacy of a combination of micafungin and amphotericin B for the primary treatment of IPA in an immunocompromised mouse model.

Methods: Female ICR mice were used in all experiments. An immunosuppressive state was induced in mice by an intraperitoneal injection of cyclophosphamide. Mice were intratracheally inoculated with Aspergillus fumigatus conidia, treated with micafungin, amphotericin B or both for 7 days, and were tested for their survival 20 days after the Aspergillus inoculation. Fungal burden in lungs, serum galactomannan index (GMI) and histopathology of lungs, spleen and kidneys were also evaluated.

Results: Combination therapy with micafungin and amphotericin B gave excellent survival of infected mice compared with monotherapy with micafungin or amphotericin B alone. Combined therapy reduced the fungal burden in the lungs and the serum GM levels compared with monotherapy or untreated controls, resulting in a significant histological improvement with disappearance of fungi in the lungs.

Conclusions: These findings suggest that combination therapy with micafungin and amphotericin B is more effective compared with monotherapy with either of them alone for IPA treatment.

Key Words: primary therapy , histopathology , fungal burden , galactmannan index


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