Deferasirox, an Iron-Chelating Agent, as Salvage Therapy for Rhinocerebral Mucormycosis

Reed, Caitlin; Ibrahim, Ashraf S.; Edwards, John E.; Walot, Irwin; Spellberg, Brad

doi:10.1128/aac.01065-06

Cited by 127 publications

(85 citation statements)

References 7 publications

(2 reference statements)

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“…In particular, combination deferasirox plus LAmB dramatically reduced brain fungal burden compared with either drug alone. These data are concordant with our recent, successful treatment of a patient with advanced, refractory cerebral mucormycosis by adding salvage deferasirox therapy to LAmB (26).…”

Section: Figuresupporting

confidence: 80%

The iron chelator deferasirox protects mice from mucormycosis through iron starvation

Ibrahim¹,

Gebermariam²,

Fu³

et al. 2007

J. Clin. Invest.

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288

274

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Mucormycosis causes mortality in at least 50% of cases despite current first-line therapies. Clinical and animal data indicate that the presence of elevated available serum iron predisposes the host to mucormycosis. Here we demonstrate that deferasirox, an iron chelator recently approved for use in humans by the US FDA, is a highly effective treatment for mucormycosis. Deferasirox effectively chelated iron from Rhizopus oryzae and demonstrated cidal activity in vitro against 28 of 29 clinical isolates of Mucorales at concentrations well below clinically achievable serum levels. When administered to diabetic ketoacidotic or neutropenic mice with mucormycosis, deferasirox significantly improved survival and decreased tissue fungal burden, with an efficacy similar to that of liposomal amphotericin B. Deferasirox treatment also enhanced the host inflammatory response to mucormycosis. Most importantly, deferasirox synergistically improved survival and reduced tissue fungal burden when combined with liposomal amphotericin B. These data support clinical investigation of adjunctive deferasirox therapy to improve the poor outcomes of mucormycosis with current therapy. As iron availability is integral to the pathogenesis of other infections (e.g., tuberculosis, malaria), broader investigation of deferasirox as an antiinfective treatment is warranted.

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Section: Figuresupporting

confidence: 80%

The iron chelator deferasirox protects mice from mucormycosis through iron starvation

Ibrahim¹,

Gebermariam²,

Fu³

et al. 2007

J. Clin. Invest.

Self Cite

288

274

View full text Add to dashboard Cite

show abstract

“…107 Further anecdotal evidence of the beneficial effect of adjunctive deferasirox was published in a case report. 108 Failure, however, of deferasirox as adjunctive treatment in a severe case of mucormycosis has also been reported, therefore underlining the multifactorial nature of the disease. 109 A double-blinded, randomized, placebo-controlled phase II clinical trial of the safety and exploratory efficacy of adjunctive deferasirox therapy for patients with mucormycosis treated with L-AmB (the deferasirox-AmBisome therapy for mucormycosis (DEFEAT Mucor) study; NCT00419770) failed to demonstrate any benefit from combination therapy.…”

Section: Adjunctive Treatment With Deferasirox or Deferipronementioning

confidence: 99%

Diagnosis and treatment of mucormycosis in patients with hematological malignancies: guidelines from the 3rd European Conference on Infections in Leukemia (ECIL 3)

et al. 2012

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“…Deferiprone and deferasirox have been successfully used to treat mucormycosis and aspergillosis in mice (61)(62)(63)(64) and human patients (65)(66)(67). Collectively, these findings and our data indicate that zinc and iron chelators do not interfere with other key metabolic processes of the host and can be a promising treatment option.…”

Section: Figmentioning

confidence: 48%

“…Combination treatments are widely used for treating aspergillosis as well as other infections (69). For instance, iron chelators have been used in combination therapy against fungal infections both in laboratory animals (62)(63)(64)70) and in humans (65)(66)(67). Combination treatment is thought to improve survival in both patients and animal models (39,71).…”

Section: Figmentioning

confidence: 99%

Administration of Zinc Chelators Improves Survival of Mice Infected with Aspergillus fumigatus both in Monotherapy and in Combination with Caspofungin

Laskaris

Atrouni

Calera

et al. 2016

Antimicrob Agents Chemother

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f Aspergillus fumigatus can infect immunocompromised patients, leading to high mortality rates due to the lack of reliable treatment options. This pathogen requires uptake of zinc from host tissues in order to successfully grow and cause virulence. Reducing the availability of that micronutrient could help treat A. fumigatus infections. In this study, we examined the in vitro effects of seven chelators using a bioluminescent strain of A. fumigatus. 1,10-Phenanthroline and N,N,N=,N=-tetrakis(2-pyridylmethyl) ethane-1,2-diamine (TPEN) proved to be the chelators most effective at inhibiting fungal growth. Intraperitoneal administration of either phenanthroline or TPEN resulted in a significant improvement in survival and decrease of weight loss and fungal burden for immunosuppressed mice intranasally infected with A. fumigatus. In vitro both chelators had an indifferent effect when employed in combination with caspofungin. The use of TPEN in combination with caspofungin also significantly increased survival compared to that when using these drugs individually. Our results suggest that zinc chelation may be a valid strategy for dealing with A. fumigatus infections and that both phenanthroline and TPEN could potentially be used either independently or in combination with caspofungin, indicating that their use in combination with other antifungal treatments might also be applicable.A spergillus fumigatus is a widespread soil-dwelling fungal saprotroph (1). It is one of the most ubiquitous fungal species with airborne conidia, and it is estimated that all humans inhale several hundred conidia each day (2). These are completely innocuous to immunocompetent hosts. However, the conidia are able to develop and cause invasive pulmonary aspergillosis (IPA) in immunocompromised individuals (3). This disease is difficult to treat, with a mortality rate of 45.6% (4). Commonly used drug treatment options include triazoles such as voriconazole, which inhibit ergosterol synthesis, amphotericin B, which binds to ergosterol and thus results in increased permeability of the cell membrane, and echinocandins such as caspofungin, which inhibit glucan synthesis (5).Both fungal and bacterial pathogens require cations to grow within their hosts and utilize specialized mechanisms in order to obtain them (6). Zinc is considered essential for all organisms, including pathogens (7). The average concentration of free Zn 2ϩ in human serum is 0.08 M, which is about 150 times lower than the minimal concentration required for A. fumigatus to grow optimally in a defined liquid medium (8). A. fumigatus possesses three genes, zrfA, zrfB, and zrfC, encoding plasma membrane zinc transporters (8). The zrfA and zrfB genes are required for zinc uptake in acidic Zn-limited environments (7), while zrfC is required for zinc uptake in alkaline environments (9) The zrfC gene is primarily responsible for zinc acquisition within a host's lungs and is required for virulence; zrfA and zrfB contribute to fungal pathogenesis to a lesser extent than zrfC and are not r...

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Deferasirox, an Iron-Chelating Agent, as Salvage Therapy for Rhinocerebral Mucormycosis

Cited by 127 publications

References 7 publications

The iron chelator deferasirox protects mice from mucormycosis through iron starvation

The iron chelator deferasirox protects mice from mucormycosis through iron starvation

Diagnosis and treatment of mucormycosis in patients with hematological malignancies: guidelines from the 3rd European Conference on Infections in Leukemia (ECIL 3)

Administration of Zinc Chelators Improves Survival of Mice Infected with Aspergillus fumigatus both in Monotherapy and in Combination with Caspofungin

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