EFFICACY OF MICAFUNGIN (FK) ALONE OR IN COMBINATION AGAINST EXPERIMENTAL PULMONARY ASPERGILLOSIS

Clemons KV, and Stevens DA*.

Author address: 

Santa Clara Valley. Med. Ctr., Calif. Inst. for Med. Res., San Jose, CA and Stanford Univ., Stanford, CA,United States

Abstract: 

Mortality from invasive pulmonary aspergillosis approaches 80% with few useful therapeutic options available. We previously reported FK to have comparable efficacy to amphotericin B (AmB) and itraconazole (ITZ) versus systemic aspergillosis in immunocompetent animals, and FK + nikkomycin Z (Nik Z) were additive. We now examined the efficacy of FK, an echinocandin, alone or in combination in a murine model of pulmonary aspergillosis. Eight-week-old DBA/2 mice were immunosuppressed with 1 mg of triamcinolone s.c. one day prior to infection. In the initial study, animals were infected intranasally with 2.95 x 104 conidia of Aspergillus fumigatus 10AF. Beginning day 1, groups of 10 mice were given 10 days of saline, or 1, 3 or 10 mg/kg of FK b.i.d., s.c. The model was extremely lethal, with all saline controls and 90% of untreated mice succumbing to infection by day 8. The efficacy of FK was difficult to assess because of an apparent toxicity, with mice given FK at 10 mg/kg/dose dying sooner than those given a lower dose of FK. Antagonistic toxicity with steroids was confirmed in studies with uninfected animals. FK given at 1 mg/kg significantly prolonged survival over the saline controls (P = 0.008). FK at 3 mg/kg versus the saline controls approached significance (P = 0.072) as did FK at 10 mg/kg/dose (P = 0.09). No treatment regimen was different in efficacy. The efficacy of combination therapy was assessed. Immunosuppressed mice were infected intranasally with 3.9 x 104 conidia. Mice received either no treatment, FK at 1 mg/kg/dose, 0.8 mg/kg of AmB in D5W given QD i.v., 100 mg/kg of ITZ in hydroxypropyl-b-cyclodextrin given QD PO, or 100 mg/kg/dose of Nik Z given in 5% DMSO-PEG200. FK and Nik Z were given b.i.d., s.c. Through the 12 days of the experiment AmB alone and FK + AmB or FK + Nik Z significantly prolonged survival (P
2002

abstract No: 

none

Full conference title: 

12th Annual Focus on Fungal Infections
    • FFI 12th (2002)