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Itraconazole preexposure attenuates the efficacy of subsequent amphotericin B therapy in a murine model of acute invasive pulmonary aspergillosis.

Abstract
Antagonism has been described in vitro and in vivo for azole-polyene combinations against Aspergillus species. Using an established murine model of invasive pulmonary aspergillosis, we evaluated the efficacy of several amphotericin B (AMB) dosages given alone or following preexposure to itraconazole (ITC). Mice were immunosuppressed with cortisone acetate and cyclophosphamide. During immunosuppression, animals were administered either ITC solution (50 mg/kg of body weight) or saline by oral gavage twice daily for 3 days prior to infection. Infection was induced by intranasally inoculating mice with a standardized conidial suspension (1 x 10(8) CFU/ml) of Aspergillus fumigatus strain AF 293. AMB was then administered by daily intraperitoneal injections (0.25, 0.5, 1.0, and 3.0 mg/kg) starting 24 h after inoculation and continuing for a total of 72 h. Drug pharmacokinetics of AMB and ITC in plasma were determined by high-performance liquid chromatography. Four different endpoints were used to examine the efficacy of antifungal therapy: (i) viable counts from harvested lung tissue (in CFU per milliliter), (ii) the whole-lung chitin assay, (iii) mortality at 96 h, and (iv) histopathology of representative lung sections. At AMB doses of >0.5 mg/kg/day, fewer ITC-preexposed mice versus non-ITC-preexposed mice were alive at 96 h (0 to 20 versus 60%, respectively). At all time points, the fungal lung burden was consistently and significantly higher in animals preexposed to ITC, as measured by the CFU counts (P = 0.001) and the chitin assay (P = 0.03). Higher doses of AMB did not overcome this antagonism. ITC preexposure was associated with poorer mycological efficacy and survival in mice treated subsequently with AMB for invasive pulmonary aspergillosis.
AuthorsRussell E Lewis, Randall A Prince, Jingduan Chi, Dimitrios P Kontoyiannis
JournalAntimicrobial agents and chemotherapy (Antimicrob Agents Chemother) Vol. 46 Issue 10 Pg. 3208-14 (Oct 2002) ISSN: 0066-4804 [Print] United States
PMID12234846 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
Chemical References
  • Antifungal Agents
  • Culture Media
  • Immunosuppressive Agents
  • Itraconazole
  • Amphotericin B
  • Cyclophosphamide
  • Cortisone
Topics
  • Amphotericin B (antagonists & inhibitors, pharmacokinetics, therapeutic use)
  • Animals
  • Antifungal Agents (antagonists & inhibitors, pharmacokinetics, therapeutic use)
  • Aspergillosis (drug therapy, microbiology, pathology, prevention & control)
  • Aspergillus fumigatus (drug effects, isolation & purification)
  • Chemoprevention
  • Cortisone (administration & dosage)
  • Culture Media
  • Cyclophosphamide (administration & dosage)
  • Drug Antagonism
  • Female
  • Humans
  • Immunosuppression Therapy
  • Immunosuppressive Agents (administration & dosage)
  • Itraconazole (antagonists & inhibitors, pharmacokinetics, therapeutic use)
  • Lung (microbiology, pathology)
  • Lung Diseases, Fungal (drug therapy, microbiology, pathology, prevention & control)
  • Mice
  • Microbial Sensitivity Tests

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