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Antimicrobial Agents and Chemotherapy, February 1999, p. 322-328, Vol. 43, No. 2
0066-4804/99/$04.00+0
Copyright © 1999, American Society for Microbiology. All rights reserved.
Comparison of a New Triazole Antifungal Agent, Schering
56592, with Itraconazole and Amphotericin B for Treatment of
Histoplasmosis in Immunocompetent Mice
Patricia
Connolly,1,2
Joe
Wheat,1,2,3,4,*
Carol
Schnizlein-Bick,1
Michelle
Durkin,1,2
Steve
Kohler,2,4
Melinda
Smedema,1,2
Janet
Goldberg,1,2
Edward
Brizendine,1 and
David
Loebenberg5
Department of
Medicine1 and
Department of Pathology
and Laboratory Medicine,3 Indiana University
School of Medicine,
Department of Veterans' Affairs
Hospital,4 and
Histoplasmosis Reference
Laboratory,2 Indianapolis, Indiana, and
Schering-Plough Research Institute, Kenilworth, New
Jersey5
Received 10 July 1998/Returned for modification 18 August
1998/Accepted 11 November 1998
A murine model of intratracheally induced histoplasmosis was used
to evaluate a new triazole antifungal agent, Schering (SCH) 56592, for
treatment of histoplasmosis. MICs were determined for SCH 56592, amphotericin B, and itraconazole by testing yeast-phase isolates from
20 patients by a macrobroth dilution method. The MICs at which 90% of
the isolates are inhibited were for 0.019 µg/ml for SCH 56592, 0.5 µg/ml for amphotericin B, and
0.019 µg/ml for itraconazole.
Survival studies were done on groups of 10 B6C3F1 mice with
a lethal inoculum of 105. All mice receiving 5, 1, or 0.25 mg of SCH 56592 per kg of body weight per day, 2.5 mg of amphotericin B
per kg every other day (qod), or 75 mg of itraconazole per kg per day
survived to day 29. Only 44% of mice receiving 5 mg of
itraconazole/kg/day survived to day 29. Fungal burden studies done in
similar groups of mice with a sublethal inoculum of 104
showed a reduction in CFUs and Histoplasma antigen levels
in lung and spleen tissue in animals treated with 2 mg of amphotericin B/kg qod, 1 mg of SCH 56592/kg/day, and 75 mg of itraconazole/kg/day, but not in those treated with lower doses of the study drugs (0.2 mg of
amphotericin B/kg qod, 0.1 mg of SCH 56592/kg/day, or 10 mg of
itraconazole/kg/day). Serum drug concentrations were measured 3 and
24 h after the last dose in mice (groups of five to seven mice),
each treated for 7 days with SCH 56592 (10 and 1 mg/kg/day) and
itraconazole (75 and 10 mg/kg/day). Mean levels measured by bioassay
were as follows: SCH 56592, 10 mg/kg/day (2.15 µg/ml at 3 h and
0.35 µg/ml at 24 h); SCH 56592, 1 mg/kg/day (0.54 µg/ml at
3 h and none detected at 24 h); itraconazole, 75 mg/kg/day (22.53 µg/ml at 3 h and none detected at 24 h);
itraconazole, 10 mg/kg/day (1.33 µg/ml at 3 h and none detected
at 24 h). Confirmatory results were obtained by high-pressure
liquid chromatography assay. These studies show SCH 56592 to be a
promising candidate for studies of treatment of histoplasmosis in humans.
*
Corresponding author. Mailing address: Histoplasmosis
Reference Laboratory, 1001 W. Tenth St., OPW 430, Indianapolis, IN
46202. Phone: (317) 630-6262. Fax: (317) 630-7522. E-mail:
lwheat{at}iupui.edu.
Antimicrobial Agents and Chemotherapy, February 1999, p. 322-328, Vol. 43, No. 2
0066-4804/99/$04.00+0
Copyright © 1999, American Society for Microbiology. All rights reserved.
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