Amphotericin B-resistant Aspergillus flavus infection successfully treated with caspofungin, a novel antifungal agent

Amphotericin B-resistant Aspergillus flavus infection successfully treated with caspofungin, a novel antifungal agent

Amphotericin B–resistant Aspergillus flavus infection successfully treated with caspofungin, a novel antifungal agent Tamara Koss, MD,a Bita Bagheri, ...

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Amphotericin B–resistant Aspergillus flavus infection successfully treated with caspofungin, a novel antifungal agent Tamara Koss, MD,a Bita Bagheri, MD,a Cosmina Zeana, MD,b Mario F. Romagnoli, MD,b Marc E. Grossman, MDa New York, New York Invasive aspergillosis is uncommon in immunocompetent hosts but is the second most common opportunistic fungal infection in immunocompromised patients. There has been a dramatic increase in the incidence of life-threatening aspergillosis during the past 2 decades, and the morbidity and mortality of these infections despite antifungal therapy remain unacceptably high. We describe a patient with amphotericin B–resistant Aspergillus flavus successfully treated with caspofungin, an agent belonging to a new class of antifungal drugs. Caspofungin shows great promise in the treatment of invasive aspergillosis. (J Am Acad Dermatol 2002;46:945-7.)

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spergillosis refers to a spectrum of diseases caused by ubiquitous saprophytic fungi found worldwide in soil, water, and decaying vegetation. Invasive aspergillosis is rarely seen in immunocompetent hosts but can be life threatening in immunocompromised patients.1 Aspergillosis is second only to candidiasis as a cause of opportunistic fungal infections in immunosuppressed patients.2-5 The incidence of serious Aspergillus infections has increased dramatically over the past 2 decades. Several factors are responsible, including the advent of HIV/AIDS, the increasing use of potent immunosuppressive medications for transplantation, and more aggressive chemotherapeutic regimens.6 Nevertheless, the morbidity and mortality of these infections remain unacceptably high; until recently, only amphotericin B and itraconazole were approved for the treatment of aspergillosis.7 We describe a patient with acute myelogenous leukemia and primary cutaneous aspergillosis resistant to amphotericin B therapy who responded to caspofungin, a new antifungal agent.

From the Department of Dermatology,a and the Division of Infectious Diseases, Department of Medicine,b Columbia-Presbyterian Medical Center. Dr Marlo F. Romagnoli is on the Speakers Bureau of Merck Laboratories, Inc. Reprint requests: Marc E. Grossman, MD, 12 Greenridge Ave #403, White Plains, NY 10605. Published online December 5, 2001. Copyright © 2001 by the American Academy of Dermatology, Inc. 0190-9622/2001/$35.00 ⫹ 0 16/91/120627 doi:10.1067/mjd.2001.120627

CASE REPORT A 73-year-old woman had a 17-year history of essential thrombocythemia that had transformed into acute myelogenous leukemia 2 years before presentation. The patient was treated with a standard course of chemotherapy (idarubicin, mitoxantrone, and high-dose cytarabine) but relapsed shortly thereafter. She was admitted to the hospital in January 2001 for therapy with an anti-CD33 monoclonal antibody (Myelotarg, Wyeth-Ayerst Laboratories, Philadelphia, Pa) and traditional chemotherapy. The patient was treated with multiple antibiotics as well as amphotericin B lipid complex 5 mg/kg daily for persistent neutropenic fevers. Five weeks after receiving chemotherapy and starting amphotericin B lipid complex, she developed a solitary 3-cm erythematous plaque with a large central necrotic eschar on the lateral aspect of her upper right arm (Fig 1). The plaque was 4 cm proximal to her peripheral intravenous central catheter under the taped dressing. A skin biopsy specimen showed the characteristic dichotomously branching septate hyphae of Aspergillus (Fig 2), and culture of the skin biopsy specimen grew A flavus (Fig 3). The plaque did not improve after 5 days of continued treatment with amphotericin B lipid complex, and therapy was changed to caspofungin acetate (Cancidas, Merck Laboratories, Rahway, NJ). The patient was given a loading dose of 70 mg of caspofungin on day 1 and 50 mg of caspofungin daily thereafter, administered intravenously. The skin lesion showed dramatic improvement after 1 week of caspofungin. The necrotic eschar detached and fell off after approximately 3 weeks, and the patient was discharged home soon after. Subsequently, susceptibility anal945

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Fig 3. Aspergillus flavus culture of patient’s skin biopsy specimen.

Fig 1. Erythematous plaque with large central necrotic eschar located proximal to intravenous catheter.

Fig 2. Characteristic dichotomously branching hyphae of Aspergillosis. (Hematoxylin-eosin stain; original magnification ⫻100.)

ysis of the patient’s A flavus isolate demonstrated that it was resistant to amphotericin B lipid complex with a minimal inhibitory concentration (MIC) of 2 mg/L.

DISCUSSION Caspofungin was approved by the Food and Drug Administration in January 2001 for the treatment of invasive aspergillosis in patients who are refractory to or intolerant of other treatments. The approval was based on a multicenter, open-label, noncomparative trial of 69 immunocompromised patients with invasive aspergillosis in which 41% of patients treated for 7 days or longer had a favorable

response. This efficacy is significantly better than the 10% to 25% response rate seen with amphotericin B. Caspofungin is given intravenously with a loading dose of 70 mg on day 1 and 50 mg daily thereafter. Caspofungin, a semisynthetic lipopeptide synthesized from a fermentation product of Glarea lozoyensis, belongs to a new class of antifungal agents called echinocandins. These drugs inhibit synthesis of (1,3)-␤-D-glucan, an integral component of the fungal cell wall.8-10 Because this molecule is not found in human cells, caspofungin has few serious side effects.11 The most commonly reported adverse reactions are headache, fever, nausea, vomiting, rash, facial swelling, pruritus, and sensation of warmth.12 Phlebitis, thrombophlebitis, and mild liver function test elevations as well as one case of anaphylaxis have been reported.12 Importantly, nephrotoxicity, often a dose-limiting side effect of amphotericin, is uncommon with caspofungin. In conclusion, caspofungin appears to be an effective therapy for life-threatening Aspergillus infections in immunocompromised patients. Additional studies are necessary to further evaluate its efficacy and indications. We are grateful to Christine Kubin, PharmD, for performing susceptibility testing on the patient’s A flavus isolate. REFERENCES 1. Isaac M. Cutaneous aspergillosis. Dermatol Clin 1996;14:137-40. 2. Patel R, Paya CV. Infections in solid-organ transplant recipients. Clin Microbiol Rev 1997;10:86-124. 3. Grossman ME, Roth J. Cutaneous manifestations of infection in the immunocompromised host. Baltimore: Williams & Wilkins; 1995. 4. Emmanouilides C, Glaspy J. Opportunistic infections in oncologic patients. Hematol Oncol Clin North Am 1996;10:841-60. 5. Radentz WH. Opportunistic fungal infections in the immunocompromised host. J Am Acad Dermatol 1989;20:989-1003.

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6. Schwartz S, Thiel E. Clinical presentation of invasive aspergillosis. Mycoses 1997;40:21-4. 7. Stevens DA, Kan VL, Judson MA, Morrison VA, Dummer S, Denning DW, et al. Practice guidelines for diseases caused by Aspergillus. Clin Infect Dis 2000;30:696-709. 8. Bouffard FA, Zambias RA, Dropinski JF, Balkovec JM, Hammond LM, Abruzzo GK, et al. Synthesis and antifungal activity of novel cationic pneumocandin B0 derivatives. J Med Chem 1994;37: 222-5. 9. Kurtz MB, Douglas C, Marhnan J, Nollstadt K, Onishi J, Dreikorn S, et al. The increased antifungal activity of L-733560, a water sol-

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uble semisynthetic pneumocandin, is due to enhanced inhibition of cell wall synthesis. Antimicrob Agents Chemother 1994; 38:2750-7. 10. Kurtz MB, Heath LB, Marinan J, Dreikorn S, Douglas C. Morphological effects of pneumocandins against Aspergillus fumigatus correlate with activity against (1,3)-␤-D-glucan synthase. Antimicrob Agents Chemother 1994;38:1480-9. 11. Denning DW. Echinocandins and pneumocandins— a new antifungal class with a novel mode of action. J Antimicrob Chemother 1997;40:611-4. 12. Micromedex Healthcare Editorial Preview, Feb 2, 2001.