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Antimicrobial Agents and Chemotherapy, April 2008, p. 1585-1586, Vol. 52, No. 4
0066-4804/08/$08.00+0     doi:10.1128/AAC.01611-07
Copyright © 2008, American Society for Microbiology. All Rights Reserved.

LETTER TO THE EDITOR

Failure of Deferasirox, an Iron Chelator Agent, Combined with Antifungals in a Case of Severe Zygomycosis{triangledown}


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Zygomycosis, an increasingly prevalent systemic fungal disease, mostly occurs in immunocompromised patients (6, 8). First-line therapeutic strategy includes surgery and lipid amphotericin B (2, 8). New iron chelators have recently been reported to be successful experimentally (3) and in a patient with refractory zygomycosis (5, 7). We report a case of abdominal zygomycosis which was refractory to a combination of antifungals, major surgery, and deferasirox, a recently approved iron chelator.

An 18-year-old leukemic woman presented a febrile neutropenia and abdominal pain after a first course of chemotherapy. Ultrasound showed a small liver abscess. All bacterial and fungal samples remained negative. Despite broad-spectrum antibacterials, peritonitis signs led to an emergency laparotomy that revealed an inflammatory parietal infiltration of the right colon. A peritoneal lavage and a liver biopsy were performed. Cultures of peritoneal samples remained negative. The microscopic liver examination revealed zygomycosis. A synergistic combination of liposomal amphotericin B (10 mg/kg of body weight/day) and caspofungin was started (9). Two weeks later, in the context of fever, posaconazole was added. Blood cell count was restored slowly, and fever resolved. One week later, after a clinical improvement, she was admitted to the intensive care unit for severe sepsis. A computed tomography (CT) scan revealed a right alveolar syndrome, multiple liver abscesses (Fig. 1a), and a large infiltration of the colon wall. A bronchoalveolar lavage and biopsy ruled out pulmonary zygomycosis. A new surgical intervention consisted of a right colectomy and a liver necrosectomy. Histopathology confirmed an extensive zygomycosis. Deferasirox (25 mg/kg/day) was added. One week later, peritonitis signs reappeared. The third surgical examination was combined with a right thoracotomy because of diaphragm necrosis extending to the lung. Diaphragm samples showed necrosis. Three weeks later, abdominal lesions of zygomycosis increased (Fig. 1b) and motivated a surgical debridement because of a complete liver necrosis. Major bleeding occurred during the hepatic dissection, and a right hepatectomy was required. In the postoperative setting, the patient died of multiple organ failure.


Figure 1
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  		FIG. 1. (a) Abdominal CT scan: multiple hypodense lesions and a large liver abscess related to zygomycosis. (b) Three weeks after deferasirox therapy onset, abdominal CT scan showed an increase of the liver lesions with a subcutaneous involvement.

 
The mortality of disseminated zygomycosis may reach 100% (8). Hepatic lesions are often considered as bowel fungal metastases by dissemination to the liver via portal venous circulation (4, 8). Through their marked angiotropism, zygomycetes create thrombosis, infarction, and bleeding (4, 8, 10). Because of the severity of this case, a combination of caspofungin, high-dose liposomal amphotericin B, and posaconazole therapy was initiated (9). Zygomycetes require iron storage for growth and pathogenicity (1). An iron chelator like deferoxamine acts as a xenosiderophore for zygomycetes, supplying previously unavailable iron (1). In contrast, other drugs such as deferiprone and deferasirox, the first orally bioavailable iron chelator, induce iron starvation for zygomycetes (1, 3, 5). Deferasirox decreases tissue fungal burden synergistically with liposomal amphotericin B (4). Deferasirox is also known to enhance the host inflammatory response to zygomycetes (3). We added deferasirox therapy 3 weeks after the diagnosis and for 1 month. But several potential factors may explain the deferasirox failure here: its poor bioavailability in the context of abdominal surgery or its lack of efficacy against the isolate encountered. In disseminated zygomycosis, further studies clarifying the role of iron chelators are thereby mandatory (3, 5).


   FOOTNOTES
 
{triangledown} Published ahead of print on 22 January 2008. Back

{dagger} A.S. and A.M. contributed equally. Back


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 REFERENCES
 

  1. Boelaert, J. R., M. Locht, J. Van Cutsem, V. Kerrels, and A. Cantinieaux. 1993. Mucormycosis during deferoxamine therapy is a siderophore-mediated infection. In vitro and in vivo animal studies. J. Clin. Investig. 91:1979-1986.[Medline]
  2. Dannaoui, E., J. Meletiadis, J. W. Mouton, J. F. G. M. Meis, P. E. Verweij, and the Eurofund Network. 2003. In vitro susceptibilities of zygomycetes to conventional and new antifungals. J. Antimicrob. Chemother. 51:45-52.[Abstract/Free Full Text]
  3. Ibrahim, A., T. Gerbermariam, Y. Fu, L. Lin, M. Husseiny, and S. French. 2007. The iron chelator deferasirox protects mice from mucormycosis through iron starvation. J. Clin. Investig. 117:2649-2657.[CrossRef][Medline]
  4. Ibrahim, A. S., B. Spellberg, V. Avanessian, Y. Fu, and J. E. Edwards. 2005. Rhizopus oryzae adheres to, is phagocytosed by, and damages endothelial cells in vitro. Infect. Immun. 73:778-783.[Abstract/Free Full Text]
  5. Ibrahim, A. S., J. E. Edwards, Jr., Y. Fu, and B. Spellberg. 2006. Deferiprone iron chelation as a novel therapy for experimental mucormycosis. J. Antimicrob. Chemother. 58:1070-1073.[Abstract/Free Full Text]
  6. Marty, F. M., L. A. Cosimi, and L. R. Baden. 2004. Breakthrough zygomy-cosis after voriconazole treatment in recipients of hematopoietic stem-cell transplants. N. Engl. J. Med. 26:350-352.
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Alexis Soummer{dagger}
Armelle Mathonnet{dagger}
Medical Intensive Care Unit
Cochin Hospital
27 rue du Faubourg Saint-Jacques
75679 Paris Cedex 14, France

Olivier Scatton
Pierre Philippe Massault
Department of Digestive Surgery
Cochin Hospital
27 rue du Faubourg Saint-Jacques
75679 Paris Cedex 14, France

André Paugam
Mycology Laboratory
Cochin Hospital
27 rue du Faubourg Saint-Jacques
75679 Paris Cedex 14, France

Virginie Lemiale
Jean Paul Mira
Medical Intensive Care Unit
Cochin Hospital
27 rue du Faubourg Saint-Jacques
75679 Paris Cedex 14, France

Eric Dannaoui
Parasitology Mycology Unit
Georges Pompidou Hospital
Paris, France

Alain Cariou
Medical Intensive Care Unit
Cochin Hospital
27 rue du Faubourg Saint-Jacques
75679 Paris Cedex 14, France

Olivier Lortholary*
Infectious and Tropical Diseases Department
Necker Pasteur Center for Infectious Diseases
Necker-Enfants Malades Hospital
149, rue de Sèvres
75015 Paris, France

* Phone: 33 1 42 19 26 63 Fax: 33 1 42 19 26 22 E-mail: olivier.lortholary{at}nck.aphp.fr

Antimicrobial Agents and Chemotherapy, April 2008, p. 1585-1586, Vol. 52, No. 4
0066-4804/08/$08.00+0     doi:10.1128/AAC.01611-07
Copyright © 2008, American Society for Microbiology. All Rights Reserved.




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