Breakthrough Zygomycosis during Empirical Voriconazole Therapy in Febrile Patients with Neutropenia

Sir—Voriconazole, a novel, wide-spectrum triazole, is considered to be superior to amphotericin B in the treatment of infections caused by Aspergillus species [1] and to be equally as effective as amphotericin B in empirical antifungal therapy in cases of febrile neutropenia [2]. Nevertheless, because of its high cost, it is not widely used in Israel. During the late fall of 2003, there was a temporary shortage in the supply of amphotericin B deoxycholate in Israel that lasted for several weeks. During this period, voriconazole was used for empirical antifungal treatment in high-risk cases involving neutropenic patients in our medical center (Rambam Medical Center; Haifa, Israel). We report 2 patients with cases of invasive zygomycosis diagnosed in our hematology ward during this period who received this treatment.

The first patient was a 65-year-old man who was admitted for chemotherapy treatment for high-grade lymphoma (stage IV) on 16 November 2003. He was febrile and neutropenic at admission, and therapy with broad-spectrum antibiotics was started. On 24 November, voriconazole was added to his regimen as empirical antifungal treatment for persistent fever unresponsive to broad-spectrum antibiotics. On 2 December, right maxillary sinusitis was diagnosed, and a culture from the sinus grew Mucor species. Therapy with liposomal amphotericin B was started, but the patient died on 6 December.

The second patient was a 72-year-old man who was admitted to the hospital on 28 November 2003 for remission induction treatment of newly diagnosed acute myeloid leukemia. The patient was neutropenic and febrile at admission, and broad-spectrum antibacterial therapy was started. After several days of fever, pulmonary infiltrates appeared, and voriconazole treatment was added to the patient's regimen on 10 December, although the fungal etiology was not identified by bronchoscopy. On 18 December, severe abdominal pain developed, and a diagnosis of typhlitis was given. On 21 December, exploratory laparotomy was performed, and left hemicolectomy for gangrenous colon was performed. Pathological examination revealed invasive zygomycosis, and a culture grew Mucur species. Liposomal amphotericin B therapy was started, but the patient died on 30 December.

We report here 2 cases of invasive zygomycosis, diagnosed 11 days and 9 days after voriconazole administration was started as empirical antifungal treatment, which were diagnosed in our hematology ward within a 19-day period. These 2 cases represent an increased incidence of this infection, because only 1 case was diagnosed in our medical center during the previous 2 years. There is 1 previous report in the literature of breakthrough zygomycosis in 4 recipients of allogeneic hematopoietic stem cell transplants who received voriconazole as prophylaxis or empirical therapy [3]. Given the limited activity of voriconazole against Zygomycota species, we suggest that breakthrough zygomycosis infections during voriconazole treatment may be an emerging syndrome.

• © 2005 by the Infectious Diseases Society of America