Opportunistic fungal infections cannot always be treated with azole and triazole drugs as an alternative to polyene derivatives, because the latter may be indispensable in serious pathologic conditions, like deep-seated infections. This justifies the number of studies performed to find new low-toxicity polyene derivatives. SPK-843(N-dimethylaminoacetyl-partricin A2-dimethylamino ethylamide diascorbate) is a water soluble polyene derivative of partricin A.It possesses unusual stability and high activity against sensitive fungal isolates in comparison with amphotericin B (AMB).We investigated the activity of SPK-843 compared with AMB against yeasts (Candida albicans, C.tropicalis, C. glabrata, C. guilliermondii, C. krusei, C. humicola, C. intermedia, Cryptococcus neoformans, Trichosporon cutaneum), filamentous fungi (Aspergillus fumigatus, A. niger, A. terreus, Syncephalastrum racemosum) and protozoa (Trichomonas vaginalis, Leishmania infantum). Cytocidal activity was evaluated by contact tests and by potassium ons (K) release tests. The contact tests were performed by the direct contact of cell suspensions with the drug (between 10 and 100 mg/L) and colony forming units after 48 h of incubation at 37 Â°C and the killing times were reported. K release was evaluated with a Microion electrode (2008 Cryson) after a time contact (1-20min.) between cell suspensions and drug concentrations (10-100 mg/L). T. vaginalis tests were performed in cysteine-pepton-liver-maltose medium plus drug; MICs were read by microscope observation (Carl Zeiss X320)after 48 h at 37 Â°C. Our results demonstrated a remarkable cytocidal activity with a killing time (100% inhibition) ranging between 3 min to 10 min for Candida spp. and 15-30min for filamentous fungi. The SPK-843 cytocidal activity was very marked against Candida spp. with a complete K release within 3 min (10 mg/L drug concentration). MICs for T. vaginalis and L. infantum were of 3.2 mg/L (AMB 7.4 mg/L) and 0.015 mg/L, respectively. The killing time (100% inhibition) was measured within 10 min for all the protozoa tested at SPK-843 concentration of 0.03 mg/L. In conclusion SPK-843 presents a higher cytocidal activity in vitro with respect to AMB. This activity seems to be related to the induction of the greater cellular damage with accelerated leakage of K ions. Data show a SPK-843 wide spectrum extended to yeasts, filamentous fungi and also to protozoa. These results and drug low toxicity make it a suitable potential alternative to amphotericin B.
Full conference title:
11th European Congress of Clinical Microbiology and Infectious Diseases
- ECCMID 11th (2001)