Itraconazole preexposure attenuates the efficacy of subsequent amphotericin B therapy in a murine model of acute invasive pulmonary aspergillosis.
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.
Lewis
Russell E
RE
Department of Infectious Diseases, Infection Control, and Employee Health, The University of Texas M. D. Anderson Cancer Center, Houston 77030, USA.
Prince
Randall A
RA
Chi
Jingduan
J
Kontoyiannis
Dimitrios P
DP
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
D000935:Antifungal Agents; D003470:Culture Media; D007166:Immunosuppressive Agents; D017964:Itraconazole; D000666:Amphotericin B; D003520:Cyclophosphamide; D003348:Cortisone