amphotericin-b and Iron-Overload

Zygomycosis is an invasive fungal infection with extremely high mortality caused by filamentous fungi which belong to Class Zygomycetes (Rhizopus spp., Mucor spp., Cunninghamella spp., etc). Despite of the similarities of the ecological characteristics and of the patients' backgrounds, zygomycosis is much rarer than invasive aspergillosis. In addition to well known immunosuppressive risk factors (hematological malignancy, hematopoietic stem cell or solid organ transplant, prolonged neutropenia, corticosteroid, etc), diabetic ketoacidosis, iron overload, and administration of deferoxamine are specific factors predisposing zygomycosis. Rhinocerebral, pulmonary and disseminated disease is characteristic forms. The mainstay of the treatment is surgical resection, reversal of immunosuppressive factors, and administration of high-dose amphotericin B or its liposomal formulation. Because of the difficulty of culture detection and the absence of reliable serological diagnostic methods, premortem diagnosis and no delaying of effective treatment remain a challenge to physicians.

Topics: Amphotericin B; Antifungal Agents; Brain Diseases; Central Nervous System Fungal Infections; Diabetes Complications; Drug Delivery Systems; Humans; Immunocompromised Host; Iron Overload; Liposomes; Lung Diseases, Fungal; Neutropenia; Prognosis; Risk Factors; Surgical Procedures, Operative; Zygomycosis

Iron chelator has previously demonstrated fungicidal effects. This study aimed to investigate the antifungal activity of the iron chelators deferoxamine (DFO) and deferasirox (DSX) against Cryptococcus.. Cryptococcus neoformans and Cryptococcus gattii were used to determine the minimal inhibitory concentrations (MICs) of DFO and DSX, and the fractional inhibitory concentration index (FICI) of DFO and DSX when combined with amphotericin B (AMB). Expression of cryptococcal CFT1, CFT2, and CIR1 genes was determined using real-time polymerase chain reaction (PCR).. Neither DFO nor DSX alone showed antifungal activity against Cryptococcus strains. When combined with AMB, the MICs of DFO and DSX decreased from>200μg/mL to 6.25 or 12.5μg/mL. The MIC of AMB decreased one-fold dilution in most strains when combined with iron chelators. The FICI of DFO+AMB and DSX+AMB was 0.5 and 1, respectively. C. neoformans showed significant growth retardation when incubated with a combination of sub-MIC concentrations of AMB and DFO; whereas, C. gattii demonstrated lesser growth retardation in DFO+AMB. No cryptococcal growth retardation was observed when DSX was combined with AMB. When C. neoformans was grown in DFO, the CFT1, CFT2, and CIR1 proteins were expressed 1.7, 2.0, and 0.9 times, respectively. When C. neoformans was grown in DSX, the CFT1, CFT2, and CIR1 genes were expressed 0.5, 0.6, and 0.3 times, respectively.. Synergistic antifungal activity of combination DFO and AMB was observed in Cryptococcus. Relatively increased CFT1 and CFT2 expression may be associated with the effect of DFO that inhibits the growth of fungi.

Topics: Amphotericin B; Antifungal Agents; Cryptococcosis; Cryptococcus; Cryptococcus neoformans; Deferasirox; Deferoxamine; Drug Synergism; Fungal Capsules; Gene Expression Regulation, Fungal; Humans; Invasive Fungal Infections; Iron; Iron Chelating Agents; Iron Overload; Metabolic Networks and Pathways; Microbial Sensitivity Tests; Virulence Factors

Well-recognized risk factors for zygomycosis include diabetic ketoacidosis, immunocompromise, and deferoxamine therapy for iron or aluminum overload, usually in patients undergoing kidney dialysis. We report a case of fatal nasal-orbital-cerebral zygomycosis in an 82-year-old man with known myelodysplasia and well-controlled diabetes. He was not receiving deferoxamine. Despite radical surgery and amphotericin B therapy, he died; primary hemochromatosis with gross iron overload was found post mortem. Experimental evidence suggests iron overload without deferoxamine therapy may be a risk factor for zygomycosis; the findings in this case would support this hypothesis.

Topics: Aged; Amphotericin B; Antifungal Agents; Biopsy; Brain Diseases; Eye Infections, Fungal; Fatal Outcome; Follow-Up Studies; Humans; Iron; Iron Overload; Male; Mucor; Mucormycosis; Orbit Evisceration; Orbital Diseases; Paranasal Sinus Diseases; Risk Factors; Tomography, X-Ray Computed