Ibrahim Ashraf S, Edwards John E, Fu Yue, Spellberg Brad
David Geffen School of Medicine at UCLA, Los Angeles, CA, USA.
J Antimicrob Chemother. 2006 Nov;58(5):1070-3. doi: 10.1093/jac/dkl350. Epub 2006 Aug 23.
Patients treated with the iron chelator deferoxamine are known to be more susceptible to mucormycosis. However, while deferoxamine is an iron chelator from the perspective of the human host, deferoxamine actually serves as a siderophore, delivering free iron to Rhizopus oryzae, the major cause of mucormycosis. Other iron chelators, including deferiprone, which do not deliver iron to R. oryzae have been described. We therefore sought to determine whether iron-chelation therapy with deferiprone would effectively treat mucormycosis.
In vitro MIC and minimum fungicidal concentration (MFC) of the iron chelator, deferiprone, for R. oryzae were determined by microdilution assay. In addition, we compared the efficacy of deferiprone with that of liposomal amphotericin B (LAmB) in treating mucormycosis in diabetic ketoacidotic mice.
Deferiprone demonstrated static activity against R. oryzae at 24 h, but showed cidality at 48 h of incubation. Deferiprone was as effective as LAmB at improving survival and decreasing brain fungal burden, and both drugs were more effective than placebo in non-iron-overloaded animals. Administration of free iron with deferiprone reversed protection, confirming that the mechanism of protection was iron chelation.
Iron chelation is a promising, novel therapeutic strategy for refractory mucormycosis infections. Further studies are warranted to evaluate combination antifungal/iron chelation therapy and to evaluate the efficacy of other iron-chelating agents.
已知接受铁螯合剂去铁胺治疗的患者更容易感染毛霉菌病。然而，尽管从人类宿主的角度来看去铁胺是一种铁螯合剂，但它实际上作为一种铁载体，将游离铁输送给毛霉菌病的主要致病菌米根霉。已经描述了其他不会将铁输送给米根霉的铁螯合剂，包括去铁酮。因此，我们试图确定去铁酮进行铁螯合治疗是否能有效治疗毛霉菌病。
通过微量稀释法测定铁螯合剂去铁酮对米根霉的体外最低抑菌浓度（MIC）和最低杀菌浓度（MFC）。此外，我们比较了去铁酮与两性霉素B脂质体（LAmB）治疗糖尿病酮症酸中毒小鼠毛霉菌病的疗效。
去铁酮在24小时时对米根霉表现出抑菌活性，但在培养48小时时显示出杀菌作用。在提高生存率和降低脑真菌负荷方面，去铁酮与LAmB一样有效，并且在非铁过载动物中，这两种药物都比安慰剂更有效。与去铁酮一起给予游离铁会逆转保护作用，证实保护机制是铁螯合作用。
铁螯合是一种有前景的、用于难治性毛霉菌病感染的新型治疗策略。有必要进一步开展研究，以评估抗真菌/铁螯合联合治疗，并评估其他铁螯合剂的疗效。
