Assessment of the paradoxical effect of caspofungin in therapy of candidiasis

Abstract

Paradoxical growth of some Candida albicans isolates in the presence of caspofungin (CAS) in vitro has been demonstrated previously. We sought to determine whether a similar phenomenon occurred in vivo. A systemic model of candidiasis was studied in CD-1 mice by intravenous inoculation of different isolates of C. albicans. Infected animals were treated with CAS at various dosages (0.01 to 20 mg/kg) and CFU remaining in the kidneys determined. Four clinical isolates that showed paradoxical growth in vitro and one that did not were tested. Recovery of CFU from the kidneys showed that dosages of CAS at 0.1 mg/kg and above were efficacious in the reduction of C. albicans, but were not curative. Against isolates that show paradoxical growth in vitro, CAS was efficacious, but lacked dose responsiveness above 0.5 mg/kg against three of the four. One isolate, 95-68, showed paradoxical growth in vivo with significantly higher CFU recovered from mice given CAS at 20 mg/kg than those given CAS at 5 mg/kg, but the effect was not reproducible in a subsequent experiment. When CAS was given prophylactically and therapeutically, improved efficacy and cure rate were observed. Overall, these data indicate that CAS is highly efficacious against systemic murine candidiasis and a paradoxical effect was not reproducibly demonstrated in vivo.

FIG. 1.

Recovery of C. albicans isolates 98-144 and 03-321 from the kidneys of mice given (A) no treatment (controls) or treated with CAS at 0.01, 5, or 15 mg/kg or (B) no treatment or treated with CAS at 0.1, 5, or 20 mg/kg. Bars represent the median group value. Isolates 98-144 and 03-321 do not and do, respectively, demonstrate paradoxical growth in the presence of caspofungin in vitro.

FIG. 2.

Cumulative mortality of mice infected systemically with C. albicans 95-68, 03-178, or 03-202 and given no treatment (controls) or treated with CAS at 0.1, 5, or 20 mg/kg. All three isolates demonstrate paradoxical growth in the presence of high concentrations of CAS in vitro.

FIG. 3.

Recovery of C. albicans isolates 95-68, 03-178, or 03-202 from the kidneys of mice given no treatment (controls) or treated with CAS at 0.1, 5, or 20 mg/kg. Bars represent the median group value.

FIG. 4.

Recovery of C. albicans isolate 95-68 from the kidneys of mice given no treatment (controls) or treated with CAS at 0.5, 2.5, 5, 10, or 20 mg/kg therapeutically or CAS at 5 or 20 mg/kg prophylactically (proph.) and therapeutically. Bars represent the median group value (n = 10).