Efficacy of SPK-843, a Novel Polyene Antifungal, in a Murine Model of Systemic Cryptococcosis

Abstract

SPK-843, a new polyene antifungal, possessed efficacy in a murine model of systemic infection caused byCryptococcus neoformans. The administration of 4.0 mg/kg SPK-843 led to better survival prolongation and fungal reduction than those observed with the administration of 0.7 mg/kg amphotericin B and 80 mg/kg fluconazole (P < 0.001), without histopathological renal changes.Cryptococcus neoformans is fungus that is an important cause of morbidity and mortality in immunocompromised patients. Central nervous system infection by C. neoformans is a major clinical concern for those patients. Amphotericin B (AMB), lipid-associated formulations of AMB, and fluconazole (FLC) are current standard antifungals used against cryptococcal central nervous system infection; however, the toxicity of AMB and the fungistatic characteristics of FLC sometimes limit their usage and clinical efficacy. Consequently, effective antifungal agents with fungicidal activity and low toxicity are required.SPK-843 is a new polyene antifungal which is a water-soluble diascorbate salt from SPA-S-752, an amide derivative of partricin A produced by a mutant strain of Streptomyces aureofaciens. SPK-843 is reported to have in vitro inhibitory activity equal to or better than that of AMB against Candida spp., C. neoformans, and Aspergillus spp. (4,7,8), and the pharmacokinetics of SPK-843 was well determined to possess a profile suitable for its therapeutic effect (1, 2). In this work, we evaluated in a murine model of systemic cryptococcosis the treatment efficacy of SPK-843 compared to AMB and FLC.AMB (Fungizone; Bristol-Myers Squibb K.K., Tokyo, Japan) and FLC (Pfizer Inc., New York) were dissolved in a 5% glucose solution, and SPK-843 (Kaken Pharmaceutical Co., Tokyo, Japan) was dissolved in a 10% lipid emulsion (Terumo, Tokyo, Japan). The MICs of antifungals were determined by the microdilution method, according to standard M27-A of the Clinical Laboratory Standards Institute. In the cryptococcosis model, 8-week-old female BALB/c mice (Charles River Inc., Yokohama, Japan) were inoculated via the tail vein with a lethal dose of 6 ϫ 10 5 to 8 ϫ 10 5 cells of C. neoformans (YC-11) (3). The mice were treated once daily intravenously with the drugs or the vehicles (n ϭ 10) daily for 5 days after the fungal inoculation. Each experiment was repeated two times to confirm the reproducibility of results. The maximum tolerated dose of each drug was included as the highest dose for the mouse strain. For the analysis of fungal burden in the brain and histopathological changes in brain, kidneys, and liver, the animals were sacrificed 7 days after inoculation. The guidelines of the Nagasaki University Laboratory Animal Center for Biomedical Research for animal experimentation were followed. Tests for differences in survival distributions were based on a generalized log rank test from survival rates calculated by the Kaplan-Meier method. The mean numbers of CFU per brain from the mycological study were compared by Scheffe's multiple-comparison test. A P value of l...

Radioimmunotherapy Is More Effective than Antifungal Treatment in Experimental Cryptococcal Infection

“…The inability of amphotericin to reduce the fungal burden in the organs of partially complement deficient AJCr mice after 3 days of treatment was explained by the follow-up study with a trend towards reduction of CFUs in brains and lungs manifesting itself only on the 14 th day of treatment. These observations are in concert with literature showing that even in intact robust mice as CD-1 or Balb/c amphotericin as deoxycholate was also only able to produce 1–1.5 log reduction in CFUs and all mice died around day 24 (13, 14). It is also in concert with the data from clinical studies showing that a short course of amphotericin does not sterilize cerebrospinal fluid or blood and that the rate of sterilization correlates with survival (15).…”

Radiolabeled Antibodies for Therapy of Infectious Diseases

“…The explanation of the inability of amphotericin to decrease the fungal burden in the organs of partially complement deficient AJ/Cr mice 3 days post treatment was provided by the subsequent amphotericin study showing a trend towards decrease in CFUs in brains and lungs which manifested itself only on day 14 th of treatment with amphotericin B. Our results are in concordance with the published data showing that amphotericin was able to produce only a 1–1.5 log reduction in CFUs in immunocompetent mice such as CD-1 and Balb/c and all mice succumbed to CN infection around day 24 [8, 9]. Our results also agree with the clinical reports which showed that a short course of amphotericin was not able to sterilize cerebrospinal fluid or blood of patients and which also correlated the rate of sterilization with the patients survival [10].…”

Cryptococcus neoformansas a Model for Radioimmunotherapy of Infections

“…The inability of amphotericin to reduce the fungal burden in the organs of partially complement deficient AJCr mice after 3 days of treatment was explained by the follow-up study with a trend towards reduction of CFUs in brains and lungs manifesting itself only on the 14th day of treatment ( Figure 5(f) ). These observations are in concert with literature showing that even in intact robust mice as CD-1 or Balb/c amphotericin as deoxycholate was also only able to produce 1–1.5 log reduction in CFUs and all mice died around day 24 [ 27 , 28 ]. It is also in concert with the data from clinical studies showing that a short course of amphotericin does not sterilize cerebrospinal fluid or blood, and that the rate of sterilization correlates with survival [ 29 ].…”