Comparative study of the efficacy of liposomal amphotericin B and amphotericin B deoxycholate against six species of Zygomycetes in a murine lethal infection model.
The objective of this study was to investigate the efficacy of liposomal amphotericin B (L-AMB) at a clinical dose (3 mg/kg) against six species (5 genera) of Zygomycetes in a murine lethal infection model, and to compare findings with those for deoxycholate amphotericin B (D-AMB). The correlation between in-vitro activity and in-vivo efficacy of L-AMB was also investigated. Cyclophosphamide-treated mice were inoculated intravenously with conidial suspensions. Four hours or 1 day after inoculation, a single dose of L-AMB or D-AMB was administered intravenously. The number of mice that survived for 14 days was recorded. L-AMB at a dose of at least ≥1 mg/kg significantly prolonged the survival time of infected mice compared with the control group. The ED₅₀ of L-AMB was nearly equivalent to that of D-AMB, except for the treatment initiated on day 1 in the Rhizopus oryzae model. At the maximum tolerated dose (MTD) of each agent, survival percentages with L-AMB (10 mg/kg) were equal to or higher than those with D-AMB (1 mg/kg). The ED₅₀ of L-AMB decreased as the MIC against the infecting strain decreased. In conclusion, L-AMB was effective at a clinical dosage, and at the MTD the efficacy of L-AMB was equal or superior to that of D-AMB in a murine model of disseminated zygomycosis. The in-vivo activity of L-AMB was correlated with its in-vitro activity.
Takemoto
Koji
K
Pharmacology Research Laboratories, Dainippon Sumitomo Pharma Co., Ltd., 3-1-98 Kasugadenaka, Konohana-ku, Osaka 554-0022, Japan. koji-takemoto@ds-pharma.co.jp
Yamamoto
Yutaka
Y
Kanazawa
Katsunori
K
D000666:Amphotericin B / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use*; D000818:Animals; D000935:Antifungal Agents / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use; D003840:Deoxycholic Acid / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use*; D004195:Disease Models, Animal; D004338:Drug Combinations; D006801:Humans; D008297:Male; D051379:Mice; D008826:Microbial Sensitivity Tests; D009090:Mucorales / Q000145:classification / Q000187:drug effects*; D009091:Mucormycosis / Q000188:drug therapy* / Q000382:microbiology / Q000401:mortality*; D013045:Species Specificity; D015996:Survival Rate; D016896:Treatment Outcome
D000935:Antifungal Agents; D004338:Drug Combinations; C068538:liposomal amphotericin B; D003840:Deoxycholic Acid; D000666:Amphotericin B; C059765:amphotericin B, deoxycholate drug combination