title: 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.
authors.affiliation: Department of Infectious Diseases, Infection Control, and Employee Health, The University of Texas M. D. Anderson Cancer Center, Houston 77030, USA.
authors.forename: Russell E
authors.initials: RE
authors.lastname: Lewis
authors.forename: Randall A
authors.initials: RA
authors.lastname: Prince
authors.forename: Jingduan
authors.initials: J
authors.lastname: Chi
authors.forename: Dimitrios P
authors.initials: DP
authors.lastname: Kontoyiannis
mesh_terms: D000666:Amphotericin B / Q000037:antagonists & inhibitors* / Q000493:pharmacokinetics / Q000627:therapeutic use*; D000818:Animals; D000935:Antifungal Agents / Q000037:antagonists & inhibitors* / Q000493:pharmacokinetics / Q000627:therapeutic use*; D001228:Aspergillosis / Q000188:drug therapy* / Q000382:microbiology / Q000473:pathology / Q000517:prevention & control; D001232:Aspergillus fumigatus / Q000187:drug effects / Q000302:isolation & purification; D018890:Chemoprevention; D003348:Cortisone / Q000008:administration & dosage; D003470:Culture Media; D003520:Cyclophosphamide / Q000008:administration & dosage; D004336:Drug Antagonism; D005260:Female; D006801:Humans; D007165:Immunosuppression Therapy; D007166:Immunosuppressive Agents / Q000008:administration & dosage; D017964:Itraconazole / Q000037:antagonists & inhibitors* / Q000493:pharmacokinetics / Q000627:therapeutic use*; D008168:Lung / Q000382:microbiology / Q000473:pathology; D008172:Lung Diseases, Fungal / Q000188:drug therapy* / Q000382:microbiology / Q000473:pathology / Q000517:prevention & control; D051379:Mice; D008826:Microbial Sensitivity Tests
chemical_list: D000935:Antifungal Agents; D003470:Culture Media; D007166:Immunosuppressive Agents; D017964:Itraconazole; D000666:Amphotericin B; D003520:Cyclophosphamide; D003348:Cortisone