Effects of deferoxamine, feroxamine and iron on experimental mucormycosis (zygomycosis).
Mucormycosis was induced in healthy guinea pigs by the i.v. injection of spores from Rhizopus microsporus var. rhizopodiformis or from Rhizopus oryzae, leading to a reproducible mortality. Pretreatment with one dose of 50 mg of deferoxamine (DFO) shortened animal survival from 4.2 +/- 0.4 to 3.3 +/- 0.5 days for Rh. rhizopodiformis and from 8.8 +/- 0.4 to 7.3 +/- 1.9 days for Rh. oryzae (P less than 0.05). Survival was shortened even more after 4 doses of DFO (P = 0.0013 for Rh. rhizopodiformis and P = 0.002 for Rh. oryzae). After Rh. oryzae infection, animal survival decreased similarly after DFO, feroxamine or DFO combined with Fe3+ citrate (P less than 0.001). Fe3+ citrate also decreased survival (P = 0.0011), although significantly less than DFO either alone or combined with Fe3+. In vitro growth of both fungal strains was enhanced by addition of either DFO or Fe3+ at 0.001 to 1 mmol in the medium. DFO abolished the prolonged survival induced by amphotericin B in vivo and in vitro. Indeed, four doses of DFO abolished the improved survival due to amphotericin B (P = 0.0019 for Rh. rhizopodiformis and P = 0.002 for Rh. oryzae); DFO combined with Fe3+ at greater than or equal to 0.1 mmol decreased the antifungal activity of amphotericin B in vitro. These results point to a major role of DFO in the pathogenesis of mucormycosis in dialysis patients and suggest that DFO behaves as a siderophore for Rhizopus strains, stimulating their growth.
Van Cutsem
J
J
Department of Bacteriology and Mycology, Janssen Research Foundation, Beerse, Belgium.
Boelaert
J R
JR
D000666:Amphotericin B / Q000627:therapeutic use; D000818:Animals; D003676:Deferoxamine / Q000494:pharmacology*; D005290:Ferric Compounds / Q000494:pharmacology*; D006168:Guinea Pigs; D007501:Iron / Q000494:pharmacology*; D007502:Iron Chelating Agents / Q000494:pharmacology*; D008297:Male; D009091:Mucormycosis / Q000188:drug therapy / Q000209:etiology*; D012233:Rhizopus / Q000187:drug effects / Q000254:growth & development; D013268:Stimulation, Chemical
D005290:Ferric Compounds; D007502:Iron Chelating Agents; C002577:ferrioxamine B; C025314:ferric citrate; D000666:Amphotericin B; D007501:Iron; D003676:Deferoxamine