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Breakthrough Rhizopus infection on posaconazole prophylaxis following allogeneic stem cell transplantation

Bone Marrow Transplantation volume 42, pages 551–552 (2008)Cite this article

Invasive fungal infections, particularly Aspergillus, are one of the leading causes of death in patients undergoing allogeneic stem cell transplantation (alloSCT). Posaconazole is a new azole compound that has been shown to be effective for prophylaxis against invasive fungal infections in patients with severe GVHD and in patients with prolonged neutropenia, significantly reducing the incidence of invasive aspergillosis.1, 2 Posaconazole is also the only orally available antifungal agent with in vitro and in vivo activity against zygomycosis, another life-threatening invasive fungal infection, and indeed no case of zygomycete infection has been reported among patients receiving posaconazole prophylaxis in two pivotal studies.1, 2, 3, 4, 5, 6 Therefore, posaconazole prophylaxis is likely to be widely used in alloSCT recipients with severe GVHD.

We present here a 55-year-old man who was diagnosed with follicular lymphoma 6 years before admission and relapsed despite treatment intensification with two autoSCT. He therefore underwent myeloablative alloSCT from his HLA-identical sister 8 months before admission. Post transplant complications included acute digestive GVHD occurring at day 50 and relapsing at month 3 for which he received high-dose steroids (1 mg/kg/day) and CYA, steroid-induced diabetes mellitus, CMV reactivation and invasive pulmonary aspergillosis at month 6. Aspergillosis was treated with oral voriconazole for 2 weeks, which was then replaced by posaconazole (400 mg b.i.d.) because of increased hepatic enzymes. The patient was admitted 8.5 months after haematopoietic SCT with a 1-week history of fever, asthenia and left orbital pain. He had been receiving posaconazole 400 mg b.i.d. for the last 8 weeks and was still on steroids (0.7 mg/kg/day). A trough plasma level of posaconazole measured 1 week before admission was in the normal range (0.92 mg/l). On admission, the patient presented with fever (38.2 °C), facial pain, peri-orbital oedema, nasal obstruction and a central palatine necrotic lesion. A head computed tomography scan showed rhino-orbital and sinusal involvement consistent with rhino-sinusal zygomycosis. Biopsy samples confirmed invasive zygomycosis and cultures grew Rhizopus oryzae 3 days later. Using the EUCAST method, minimal inhibitory concentrations were 0.125 mg/l for amphotericin B, 4 mg/l for itraconazole, ⩾8 mg/l for voriconazole, ⩾8 mg/l for caspofungin and 0.5 mg/l for posaconazole. Parenteral treatment with liposomal amphotericin B (5 mg/kg/day) and broad-spectrum antibiotics (imipenem, vancomycin and amikacine) was started on admission. Three days later, the disease rapidly worsened with extension of the necrotic area. Antibiotics were stopped and the dose of liposomal amphotericin B was increased to 10 mg/kg/day. Adjuvant therapy consisted in lowering immunosuppressive therapy (discontinuation of CYA and tapering of steroids), strict equilibration of diabetes and use of granulocyte-growth-stimulating factor because of moderate neutropenia (1000/mm3). Surgical debridement was not performed due to the rapidly progressing infection, with extension of palatine necrosis and left peri-orbital subcutaneous tissues involvement, the occurrence of digestive bleeding and of two generalized seizures. Neurological status progressively worsened without clinical and radiological evidence on MRI for cerebral involvement. The patient died 20 days after admission. No autopsy was performed.

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Acknowledgements

We thank the Centre National de Référence des Mycoses of Institut Pasteur, Paris, France for the help in identifying Rhyzopus and in determining the minimal inhibitory concentration.

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  1. University of Paris Diderot, Paris 7, Paris, France

Authors and Affiliations

  1. Department of Infectious Diseases, Saint-Louis Hospital, Assistance-Publique Hôpitaux de Paris, Paris, France

    F Schlemmer, M Lagrange-Xélot & J-M Molina

  2. Laboratory of Mycology, Saint-Louis Hospital, Assistance-Publique Hôpitaux de Paris, Paris, France

    C Lacroix

  3. Department of Bone-Marrow Transplantation, Saint-Louis Hospital, Assistance-Publique Hôpitaux de Paris, Paris, France

    R de La Tour & G Socié

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  1. F Schlemmer
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Correspondence to M Lagrange-Xélot.

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Schlemmer, F., Lagrange-Xélot, M., Lacroix, C. et al. Breakthrough Rhizopus infection on posaconazole prophylaxis following allogeneic stem cell transplantation. Bone Marrow Transplant 42, 551–552 (2008). https://doi.org/10.1038/bmt.2008.199

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