1 Infectious Diseases Dept., University of Genoa School of Medicine, San Martino Hospital, Genova; 2 Division of Haematology, University of Genoa School of Medicine, Genova, Italy
Keywords: antifungal agents , echinocandins , neutropenia
Sir,
Disseminated Trichosporon infection is increasingly common in immunocompromised patients, and it is usually unresponsive to antifungal treatment.1 The mortality rate in neutropenic patients receiving amphotericin B or azole therapy is approaching 80% but may reach 100% in patients with persistent neutropenia.
Here we report a case of Trichosporon asahii fungaemia in a neutropenic patient with acute leukaemia that did not respond to fluconazole, liposomal amphotericin B and voriconazole treatment. Microbiological eradication of fungaemia was achieved after treatment with caspofungin combined with amphotericin B.
A 54-year-old man was referred to our institution in October 2002 because of occurrence of high fever resistant to broad-spectrum antibiotic therapy. He had a 6 month history of acute myeloid leukaemia treated with induction chemotherapy followed by three cycles of aracytine, daunorubicin and etoposide. On admission, physical examination was normal, except for oral candidiasis and fever (39.5°C). Laboratory tests disclosed a leucocyte count of 50/mm3, a haemoglobin level of 8.7 g/dL and a platelet count of 7000/mm3. Galactomannan antigen for Aspergillus and quantitative real-time polymerase chain reaction for cytomegalovirus, as well as routine blood cultures and Mycobacterium tuberculosis cultures, were negative. Treatment with granulocyte-colony stimulating factor 300 µg/day, meropenem 3 g/day, teicoplanin 600 mg/day and fluconazole 400 mg/day was started. On 18 October 2002, three blood cultures yielded Trichosporon spp., which were then identified as Trichosporon asahii (carbohydrate utilization panel, API ID 32 C; bioMérieux, Marcy l'Étoile, France). Treatment with liposomal amphotericin B (5 mg/kg/day) was started, fluconazole and teicoplanin were stopped and meropenem was continued. Six days later, due to the persistence of fever (40°C) together with T. asahii in blood cultures, amphotericin B was discontinued, and intravenous voriconazole (800 mg/day the first day, then 600 mg/day) started.
The patient remained febrile and blood cultures still yielded T. asahii (Figure 1). Meanwhile, an increase in the values of bilirubinaemia, transaminases and alkaline phosphatase was observed. Histological examination and microbiological culture of liver biopsy were not diagnostic. Cardiac echography, chest X-rays, cerebral CT scan and funduscopic examination were normal. After 7 days of voriconazole therapy, the patient remained febrile and the hepatic values continued to increase, even though drug dosage was reduced to 400 mg daily. Voriconazole was interrupted, and caspofungin (70 mg the first day then 50 mg/day) in combination with liposomal amphotericin B (5 mg/kg/day) was started. We observed general improvement, as the patient felt better and the fever showed a resolution within 5 days; meanwhile, blood cultures became negative and remained so thereafter. Despite initial improvement, the clinical condition of the patient started to deteriorate, and he died 3 weeks later due to the recurrence of leukaemia. No clinical findings compatible with systemic infection were present. An autopsy was not performed because of the family's refusal.
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Limited in vitro data show that caspofungin lacks activity against Trichosporon species.1 In the treatment of Trichosporon infection, the clinical experience with caspofungin is scanty. Caspofungin has been successfully used in one case of Trichosporon inkin peritonitis associated with peritoneal dialysis.3 By contrast, a breakthrough invasive trichosporonosis in a bone marrow transplant recipient receiving caspofungin as prophylaxis against Aspergillus infection has been reported.4
To our knowledge, this is the first case of disseminated Trichosporon infection treated with caspofungin combined with liposomal amphotericin B. In vitro data with caspofungin combined with azoles or amphotericin B have demonstrated synergy or indifference against clinical isolates of Candida spp., Cryptococcus neoformans and Aspergillus spp.5,6 Clinical experience with caspofungin in combination with either conventional or liposomal amphotericin B for the treatment of aspergillosis is now accumulating.5 Combination therapy was well tolerated and a favourable response was observed in a significant proportion of patients (21%77%) with possible or proven invasive aspergillosis for whom amphotericin B monotherapy had failed.
Our report underlines the difficulties of treatment of Trichosporon infection in neutropenic patients. Unfortunately, the lack of a post-mortem examination does not allow us to draw firm conclusions. However, in our patient, liposomal amphotericin B and voriconazole were not clinically and microbiologically effective when used as sole antifungal agents. By contrast, the combination therapy with caspofungin and liposomal amphotericin B was found to be effective in eradicating T. asahii from blood, and was also well tolerated and associated with resolution of fever.
Disseminated trichosporonosis is a life-threatening infection with poor prognosis unless the neutrophil count recovers. In our patient, the neutrophil count fell below 100/mm3 and remained at this level throughout the hospitalization course. In neutropenic patients, therapeutic outcome seems to be dependent on fungicidal drug activity. For trichosporonosis, as for aspergillosis, it is possible that combination therapy with drugs acting synergistically on different cell targets, such as caspofungin and amphotericin B, may overcome the problem of lack of fungicidal activity of antifungal agents when used alone.
Footnotes
* Correspondence address. Clinica Malattie Infettive, A.O. Ospedale Università San Martino di Genova, Largo R.Benzi 10, 16132 Genova, Italy. Tel: +39-010-555-5132; Fax: +39-010-353-7680; Email: mattba{at}tin.it
References
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2 . Anaissie, E., Gokaslan, A., Hachem, R. et al. (1992). Azole therapy for trichosporonosis: clinical evaluation of eight patients, experimental therapy for murine infection, and review. Clinical Infectious Diseases 15, 7817.[ISI][Medline]
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Madariaga, M. G., Tenorio, A. & Proia, L. (2003). Trichosporon inkin peritonitis treated with caspofungin. Journal of Clinical Microbiology 41, 58279.
4 . Goodman, D., Pamer, E., Jakubowski, A. et al. (2002). Breakthrough trichosporonosis in a bone marrow transplant recipient receiving caspofungin acetate. Clinical Infectious Diseases 35, E356.[CrossRef][ISI][Medline]
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Johnson, M. D., MacDougall, C., Ostrosky-Zeichner, L. et al. (2004). Combination antifungal therapy. Antimicrobial Agents and Chemotherapy 48, 693715.
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