Activity of aminocandin (IP960; HMR3270) compared with amphotericin B,itraconazole, caspofungin and micafungin in neutropenic murine models of disseminated infection caused by itraconazole-susceptible and -resistant strains of Aspergillus fumigatus |
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| Authors: | Peter A Warn Andrew Sharp Graham Morrissey David W Denning |
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| Institution: | 1. Department of Ecology, Institute for Biological Research ‘Sinisa Stankovic’, University of Belgrade, Belgrade 11000, Serbia;2. Department of Plant Physiology (Mycology Lab), Institute for Biological Research ‘Sinisa Stankovic’, University of Belgrade, Belgrade 11000, Serbia;3. Institute of Physiology and Biochemistry, Faculty of Biology, University of Belgrade, Belgrade 11000, Serbia;1. School of Environmental Science and Engineering, Suzhou University of Science and Technology, Suzhou, Jiangsu 215009, PR China;2. Key Laboratory of Energy Thermal Conversion and Control of Ministry of Education, School of Energy and Environment, Southeast University, Nanjing, Jiangsu 210096, PR China;3. School of Hydraulic, Energy and Power Engineering, Yangzhou University, Yangzhou, Jiangsu 225127, PR China;1. Clinical Pharmacokinetics Unit, Division of Intensive Care and Emergency Medicine, Department of Internal Medicine I, Innsbruck Medical University, Anichstrasse 35, A-6020 Innsbruck, Austria;2. Transplant Intensive Care Unit, Department of Anaesthesia and Critical Care, Centre of Operative Medicine, Innsbruck Medical University, Innsbruck, Austria;3. Department of Hygiene and Medical Microbiology, Innsbruck Medical University, Innsbruck, Austria;4. Department of Internal Medicine VI, Clinical Immunology and Infectious Diseases, Innsbruck Medical University, Innsbruck, Austria;5. Division of Intensive Care and Emergency Medicine, Department Internal Medicine I, Innsbruck Medical University, Innsbruck, Austria;1. Second Department of Internal Medicine, Nagasaki University School of Medicine, Nagasaki, Japan;2. Division of Respirology, Toho University Ohashi Medical Center, Tokyo, Japan;1. Unitat de Microbiologia, Facultat de Medicina i Ciències de la Salut, IISPV, Universitat Rovira i Virgili, Reus, Spain;2. Fungus Testing Laboratory, University of Texas Health Science Center, San Antonio, TX, USA;1. Department of Nanobiotechnology, Biology Centre, ISB, CAS, Na Sadkach 7, 370 05 Ceske Budejovice, Czech Republic;2. Department of General and Industrial Microbiology, Faculty of Biology, Sofia University “St. Kliment Ohridski”, 8 Dragan Tsankov Blvd, 1164 Sofia, Bulgaria;3. Laboratory Microwave Magnetics, Institute of Electronics, Bulgarian Academy of Sciences, 72 Tzarigradsko Chaussee Blvd, 1784 Sofia, Bulgaria;4. Global Change Research Institute, CAS, Na Sadkach 7, 370 05 Ceske Budejovice, Czech Republic;5. Department of Applied Chemistry, Faculty of Agriculture, University of South Bohemia, Branisovska 1457, 370 05 Ceske Budejovice, Czech Republic;6. Regional Centre of Advanced Technologies and Materials, Palacky University, Slechtitelu 27, 783 71 Olomouc, Czech Republic |
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| Abstract: | Aminocandin (IP960; HMR3270; NXL201) is a new echinocandin with broad-spectrum in vitro activity against Aspergillus and Candida spp. We compared the activity of aminocandin with that of amphotericin B (AmB), itraconazole (ITC) and caspofungin (CAS) in murine models of disseminated aspergillosis against three strains of A. fumigatus, two of which were fully susceptible (AF293 and A1163) and one was resistant to ITC (AF91). Mice were rendered temporarily neutropenic or persistently neutropenic with cyclophosphamide and were infected intravenously 3 days later. Temporarily neutropenic mice were treated with either intraperitoneal (i.p.) AmB (5 mg/kg/dose), oral (p.o.) ITC (25 mg/kg/dose), intravenous (i.v.) aminocandin (0.25–10 mg/kg/dose), i.p. aminocandin (1 mg/kg/dose) or solvent control for 9 days. Mice were euthanised 11 days post infection and the kidneys and liver were removed for quantitative culture. Following infection with AF293, only aminocandin 5 mg/kg i.v. yielded 100% survival. Aminocandin 1 mg/kg i.v., AmB 5 mg/kg i.p. or ITC 25 mg/kg p.o. were equivalent (P > 0.05). Aminocandin 5 mg/kg was superior to aminocandin 0.25 mg/kg (P < 0.0001) as well as all controls (P < 0.0001) in reducing mortality. Following infection with AF91, only aminocandin at 5 mg/kg and 1 mg/kg i.v. yielded 100% survival, which was superior to ITC, aminocandin 0.25 mg/kg and controls (all P < 0.0001). In the persistently neutropenic model with A1163, aminocandin, CAS and micafungin (2–10 mg/kg) were all effective at prolonging survival, with some impact on reducing culture burdens, even with alternate-day dosing (4 mg/kg). The only fungicidal regimen was aminocandin 5 mg/kg, which sterilised 40% and 50% of mice following infection with AF293 and AF91, respectively. Aminocandin at doses of ≥1 mg/kg is highly effective in reducing mortality and organ burden in disseminated infection caused by ITC-susceptible and -resistant A. fumigatus. |
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