Efficacy of aminocandin (IP960/HMR3270) in temporarily and persistently neutropenic murine models of disseminated aspergillosis

P. Warn, A. Sharp, D.W. Denning

Author address: 

Manchester, UK

Abstract: 

Background: Aminocandin (AC) (IP960) is an echinocandin antifungal agents with broad spectrum antifungal activity. Patients with invasive aspergillosis often have compromised immune systems. Concerns have been raised that due to the mode of action of the candins an effective immune system is required to clear damaged hyphae. We compared the activity of aminocandin® (AC), micafungin® (MFG) and caspofungin® (CAS) in persistently neutropenic (PN) mice; AC, itraconazole (ITZ) and amphotericin B (AMB) in temporarily neutropenic (TN) mouse models of disseminated aspergillosis. Method: Male CD1 mice were infected with either A. fumigatus AF293 (TN), AF91 (ITZ resistant) (TN) or CBS144 (PN). Mice were compromised using either one or multiple doses of 200 mg/kg cyclophosphamide every 3 days starting day -3. Mice were treated IV 4-24 hours later with either 10, 4 or 2 mg/kg/day or 4 mg/kg every 2 days AC, MFG or CAS (PN) or 0.25-5 mg/kg AC, 25 mg/kg ITZ, 5 mg/kg AMB (TN). Pk samples (0.25-2 mg/kg) were taken from a 2nd set of infected mice 4 days post infection. One set of mice were killed 96 hours post infection, a 2nd set were treated for 10 days then 4-6 days observation before assessment of tissue burden. Results: Mortality in untreated mice was 80-100%. Tissue burdens 4 days post infection in control mice were high with the liver (log 3.8 cfu/gm), spleen (log 3.7 cfu/gm) and kidneys (log 4.2 cfu/gm), the main target organs. Treatment reduced burdens in all organs in PN mice particularly the kidneys which had a log 1.5 cfu/gm reduction. Survival was excellent in both PN and TN models after treatment. In the PN model survival was AC 96%, MFG 93% and CAS 96%. In the TN models survival was 5 mg/kg AC 100%, 1 mg/kg AC 90%, 0.25 mg/kg AC 20%, ITC (AF293 only) 70%, AMB 90%. Mean burdens in the PN model at the end of the observation period were low at log0.5, log0.3 and log1.95 cfu/gm in the liver, spleen and kidneys respectively. Total clearance of Aspergillus in the PN model was found in 7/28, 4/27 and 8/28 survivors treated with AC, MFG and CAS respectively. PK of AC demonstrated peak and AUC increased in a linear fashion by dose, with AUC and half-life of 16-176 mg-hr*hr/L and 27-45 hrs for 0.25-2 mg/kg/day. Conclusions: AC at doses in excess of 1 mg/kg/day were highly effective both at improving survival and reducing tissue burdens even in persistently neutropenic mice with disseminated aspergillosis. Alternate day dosing of AC at twice the daily dose was also very effective.
2006

abstract No: 

P1147

Full conference title: 

16th European Congress of Clinical Microbiology and Infectious Diseases
    • ECCMID 16th (2006)