Efficacy of LY303366 against invasive pulmonary aspergillosis

V. Petraitis, R. Petraitiene, A. Bell, T. Sein, B. Schaufele, D. P. Callender, A. Groll, M. Candelario, C. A. Lyman, A. Francesconi, J. Bacher, T. J. Walsh

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Abstract

LY303366 (LY) is a novel semisynthetic derivative of echinocandin B and a potent inhibitor of fungal (1,3)-β-D-glucan synthase. We studied the activity of LY in escalating dosages against experimental invasive pulmonary aspergillosis in persistently neutropenic rabbits. Antifungal therapy was administered for 12 days starting one day after endotracheal inoculation of 1×108 Asptrgillus fumigatus conidia. Study groups consisted of untreated controls (UC), amphotericin B (1mg/kg/d [AmB]), or LY at 1(LY 1), 5(LY 5), 10(LY 10), or 20(LY20) mg/kg/d. Treatment Controls AmB LY1 LY5 LY10 LY20 Group (n=16) (n=8) (n=8) (n=8) (n=16) (n=16) log[CFU/g] 1.77 0.48 2.03 2.44 1.94 2.25 ±0.23 ±0.12a ±0.33e ±0.28e ±0.18e ±0.14e Pulmonary 5.56 2.62 3.25 4.38 2.31 2.75 infarct score ±0.32 ±0.60a ±0.90c ±0.60e ±0.66c ±0.56c Mean 40.54 20.90 25.20 22.45 29.96 32.85 lung weight ±3.64 ±3.18c ±3.06c ±2.44c ±4.33d ±3.24e Mann-Whitney U Test (controls vs. treated rabbits): a p≤0.0001; b p≤0.001; c p≤0.01; d p≤0.05; e not significant LY and AmB-treated animals showed a significant reduction in organism-mediated pulmonary injury as measured by infarct score and lung wt. Survival through the entire study was achieved in 6 (19%) of 32 LY(1,5&10)-treated rabbits vs 1 (8%) of 8 AmB-treated rabbits, none of 16 in LY(20), and none of 16 UC (p=0.04). Serum creatinine was greater in AmB rabbits than in UC and LY rabbits (2.66±0.4 vs 1.04±0.03 and 1.04±0.02 mg/dL, respectively, p≤0.001). In summary, LY was safe and effective in treating invasive pulmonary aspergillosis in neutropenic rabbits and warrants clinical evaluation as a new therapeutic intervention.

Original languageEnglish (US)
Number of pages1
JournalClinical Infectious Diseases
Volume25
Issue number2
StatePublished - 1997

ASJC Scopus subject areas

  • Microbiology (medical)
  • Infectious Diseases

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    Petraitis, V., Petraitiene, R., Bell, A., Sein, T., Schaufele, B., Callender, D. P., Groll, A., Candelario, M., Lyman, C. A., Francesconi, A., Bacher, J., & Walsh, T. J. (1997). Efficacy of LY303366 against invasive pulmonary aspergillosis. Clinical Infectious Diseases, 25(2).