Caspofungin and Liposomal Amphotericin B Therapy of Experimental Murine Scedosporiosis

Abstract

Immunosuppressed mice were infected intravenously with conidia of Scedosporium prolificans. Treatment was begun 1 day later with liposomal amphotericin B, caspofungin, or both drugs initiated concurrently. Amphotericin B and caspofungin were each effective, but combined therapy did not appear to offer advantages over liposomal amphotericin B alone.Scedosporium apiospermum and S. prolificans cause up to 10% of invasive mycelial fungal infections in predisposed patients (4, 7). S. prolificans is resistant in vitro to virtually all antifungal agents and has responded poorly to voriconazole, with only 3 of 10 patients improving (1)(2)(3)(8)(9)(10). A recent review of scedosporiosis in solid organ transplant patients reported only four survivors among 18 patients with S. prolificans infection (5).In this setting, we evaluated a new echinocandin, caspofungin, in the treatment of S. prolificans infection. We compared the changes in survival and CFU (as measurements of tissue burden) in neutropenic mice undergoing an acute infection with S. prolificans. In addition to caspofungin, we evaluated liposomal amphotericin B alone and in combination with caspofungin.S. prolificans strain 95-2409 was cultured on potato flake agar. Conidia were washed, filtered, counted in a hemacytometer, and suspended in sterile saline. The MIC was determined using the CLSI (formerly NCCLS) method adapted for mycelial fungi, along with the minimal effective concentration according to the method of Kurtz et al. (6). The MIC of caspofungin and liposomal amphotericin B was 8 g/ml at 24 and 48 h of incubation. The minimal effective concentration of caspofungin was 8 g/ml at 24 and 48 h.Male outbred ICR mice were made neutropenic by a single intraperitoneal (i.p.) dose of cyclophosphamide at 200 mg/kg of body weight 1 day prior to infection. Mice were infected intravenously (i.v.) with conidia in a 0.2-ml volume. Beginning 1 day after infection, control mice were treated with sterile water i.p., liposomal amphotericin B (Astellas Pharma Inc., formally Fujisawa) i.v. at 10, 20, or 30 mg/kg once daily, or caspofungin (Merck & Co., Inc) i.p. at 5, 10, or 20 mg/kg once daily. For survival studies, groups of 10 to 12 mice were treated from day 1 through day 10, with observation through day 21 or day 25. Mice which appeared moribund were sacrificed and considered to have died the next day. For studies of tissue burden, mice were treated from day 1 through day 7 after infection and sacrificed on day 8 for quantitative tissue cultures of kidneys. The log rank test was used for comparison of survival studies. The Mann-Whitney U test was used for comparison of CFU counts. Because of multiple comparisons, a P value of Յ0.02 was required for significance.Survival following infection with a low inoculum dose of S. prolificans is shown in Fig. 1A. Liposomal amphotericin B at a dose of 10 or 20 mg/kg significantly prolonged survival over that of controls (P Ͻ 0.0003), but 30 mg/kg appeared toxic. As shown in Fig. 1B, caspofungin at 5 mg/kg was ineffective, but 10...

Infections Caused byScedosporiumspp

“…In the same mouse model, caspofungin prolonged mouse survival by 30% at a dosage of 10 mg/kg/day. However, fungal burden reduction was observed only with liposomal amphotericin B (45). The MIC of amphotericin B and the minimal effective concentration of caspofungin were 8 g/ml for the isolates of S. prolificans used in these studies.…”

Macrophage Reporter Cell Assay for Screening Immunopharmacological Activity of Cell Wall-Active Antifungals

“…Indirect immunological effects may be especially important for cell wall-active antifungals, such as the echinocandins. For example, despite their lack of appreciable in vitro activity against a number of clinically important molds (Mucorales, Fusarium, and Scedosporium), echinocandins have been found to be modestly effective in vivo, and sometimes highly effective in combination with other agents, in experimental models of mucormycosis (17)(18)(19), fusariosis (20), and scedosporiosis (21). Counterintuitively, lower doses of echinocandins were generally more effective than higher doses in these animal infection models.…”

Immunomodulating effects of antifungal therapy

“…Moreover, in a study of the treatment of rhino-orbital-cerebral mucormycosis with combination polyene/caspofungin therapy, the combination represented a promising potential alternative to polyene monotherapy for these patients [50]. Data from murine models of infections caused by emerging molds, such as Fusarium species [51] and Scedosporium species [52], show that caspofungin has activity in these cases.…”