Successful treatment of disseminated fusariosis

Bone Marrow Transplantation (2003) 31, 411–412 & 2003 Nature Publishing Group All rights reserved 0268-3369/03 $25.00

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Correspondence Successful treatment of disseminated fusariosis Bone Marrow Transplantation (2003) 31, 411–412. doi:10.1038/sj.bmt.1703857 Disseminated Fusarium spp infections are associated with high mortality in immunocompromised patients. The persistent and profound neutropenia in severe forms of aplastic anemia (SAA) limits survival of these patients in the setting of invasive fungal infections. Therapeutic options are scarce and mortality reached 80% in the largest review of patients with SAA and disseminated fusariosis.1 We report the first case of a pediatric patient with SAA and disseminated fusariosis successfully treated with combination therapy including voriconazole and only the second patient with SAA to survive disseminated Fusarium infection. Furthermore, the patient underwent two CD34+ haplo-identical hematopoietic stem cell transplants (HSCT) without evidence of disease progression. A 3-year-old female with SAA presented with cellulitis of the right knee after a fall. Wound cultures yielded Bacillus cereus and she received a 35-day course of meropenem. The ulcerated mass persisted after 1 month of therapy and a nonerythematous, soft tissue mass developed on the anterior medial left chest wall below a central venous catheter exit site. MRI of the knee demonstrated involvement of medial and lateral compartments with a small suprapatellar effusion and diffuse enhancement of the soft tissues. A chest and abdominal CT revealed a 4-cm anterior left chest wall mass and a 4-mm subcapsular hypodense splenic lesion. A punch biopsy of the knee demonstrated infiltration of the dermis by branching septate hyphae; cultures yielded Fusarium oxysporum. Susceptibility testing of the isolate performed at the University of Texas Health Science Center at San Antonio revealed an MIC for amphotericin B of 2 mg/ml and 4 mg/ml for voriconazole. Treatment with 12 mg/kg/day of a liposomal formulation of amphotericin B (Ambisome, Fujisawa USA, Deerfield, IL, USA) was begun. Owing to the historically poor outcomes of similar cases, compassionate use of voriconazole (Vfend, Pfizer, Groton, CO), 6 mg/kg loading dose followed by 4 mg/kg twice daily i.v. was added 4 days later, after approval by the Institutional Review Board and informed consent was obtained. We elected to use both agents since there is little experience with the use of voriconazole as single-agent therapy in this setting. In addition, granulocyte infusions and surgical debridement of the knee lesion and chest wall mass were performed. Branching septate hyphae morphologically consistent with Fusarium spp were present on microscopic examination and Fusarium was isolated from both sites. Persistent drainage from the knee and enlargement of the splenic lesion prompted repeat debridement of the knee, a CT-

guided splenic biopsy and removal of the central venous catheter 2 weeks after the initial surgery, but thereafter the patient did well. Therapy with liposomal amphotericin B and voriconazole was continued for 7 months with progressive clinical and radiological resolution of the skin, chest wall, and splenic lesions. A total of 19 granulocyte transfusions, in a three times per week schedule, were administered during the initial 2 months of therapy. At 77 days after diagnosis of Fusarium infection, the patient underwent a CD34+ haploidentical HSCT. The transplant was complicated by graft rejection, and a second CD34+ haplo-HSCT was performed 35 days later. No clinical or radiological evidence of relapse of fungal infection occurred. The patient died 213 days after the diagnosis of fusariosis from suspected cytomegalovirus pneumonitis and GVHD. No autopsy was performed. Fusarium spp have emerged as a serious pathogen in patients undergoing intense myeloablative therapy. These monomorphic molds can easily be confused in tissue sections with Aspergillus spp as both have similar histopathologic appearance with septate, dichotomously branching hyphae. Definitive identification is necessary since this has significant implications for antifungal therapy. Current treatment options for Fusarium spp are limited and most patients with disseminated infection die. Amphotericin B remains the treatment of choice for fusariosis; however, in vitro data suggest that new agents such as voriconazole may be effective.2–4 Voriconazole is a triazole that acts through inhibition of the fungal cytochrome P450-dependent ergosterol synthesis.2 In vitro and in vivo studies indicate that voriconazole has significant activity against many fungal pathogens including Aspergillus spp, Candida spp, Fusarium spp, Cryptococcus neoformans, Bipolaris spp, Pseudallescheria boydii, and Histoplasma capsulatum.3,4 Some pathogens including Candida glabrata, Sporothrix schenckii, Sporobolomyces salmonicolor, Rhizopus arrhizus, and Paecilomyces variotti, however, are intrinsically moderately or highly resistant.2,4 Voriconazole has been shown to be both safe and effective in the treatment of invasive aspergillosis and as empirical antifungal therapy for adults with neutropenia and persistent fever.5,6 It has been successfully used in some pediatric patients with invasive fungal infections who were intolerant of or refractory to conventional antifungal therapy. However, voriconazole therapy failed in the two cases of fusariosis included in this study.7 We hypothesize that the combination of antifungal therapy (liposomal amphotericin B and voriconazole), surgery, and augmentation of host response with granulocyte transfusions likely resulted in clinical benefit and successful treatment of this severe infection.

Correspondence

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CA Rodriguez1 J Luja´n-Zilbermann1 P Woodard M Andreansky1,2 EE Adderson1

1

Department of Infectious Diseases, St. Jude Children’s Research Hospital and University of Tennessee, Health Science Center, 332 N. Lauderdale, St Memphis, TN 38105, USA; and 2 Department of HematologyOncology, St. Jude Children’s Research Hospital and University of Tennessee, Health Science Center, 332 N. Lauderdale, St Memphis, TN 38105, USA

References 1 Girmenia C, Iori AP, Boecklin F et al. Fusarium infections in patients with severe aplastic anemia: review and implications for management. Haematologica 1999; 84: 114–118.

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2 Espinel-Ingroff A. In vitro activity of the new triazole voriconazole (UK-109,496) against opportunistic filamentous and dimorphic fungi and common and emerging yeast pathogens. J Clin Microbiol 1998; 36: 198–202. 3 Clancy CJ, Nguyen MH. In vitro efficacy and fungicidal activity of voriconazole against Aspergillus and Fusarium species. Eur J Clin Microbiol Infect Dis 1998; 17: 573–575. 4 Radford SA, Johnson EM, Warnock DW. In vitro studies of activity of voriconazole (UK-109,496), a new triazole antifungal agent, against emerging and less-common mold pathogens. Antimicrob Agents Chemother 1997; 41: 841–843. 5 Denning DW, Ribaud P, Milpied N et al. Efficacy and safety of voriconazole in the treatment of acute invasive aspergillosis. Clin Infect Dis 2002; 34: 563–571. 6 Walsh TJ, Pappas P, Winston DJ et al. Voriconazole compared with liposomal amphotericin B for empirical antifungal therapy in patients with neutropenia and persistent fever. N Engl J Med 2002; 346: 225–234. 7 Walsh TJ, Lutsar I, Driscoll T et al. Voriconazole in the treatment of aspergillosis, scedosporiosis and other invasive fungal infections in children. Pediatr Infect Dis J 2002; 21: 240–248.