Caspofungin in Combination with Itraconazole for the Treatment of Invasive Aspergillosis in Humans

SIR—Caspofungin (Cancidas; Merck) belongs to a new class of antifungal agents, the echinocandins. It has in vitro fungicidal activity against numerous fungal pathogens, including Aspergillus species. Although no published studies have evaluated the use of caspofungin for treatment of invasive aspergillosis (IA) in humans, limited data have been reported that clinical improvement or complete response occurred in 41% of caspofungin-treated patients with IA who were intolerant of or had infections refractory to standard antifungal therapies [1]. No clinical data exist on the use of caspofungin in combination with other antifungal agents, which is an intriguing possibility, given caspofungin's unique mechanism of action. We report our experience with the use of caspofungin in combination with itraconazole in 2 immunocompromised patients with IA. The first patient was a 50-year-old woman with acute lymphoblastic leukemia who underwent induction chemotherapy. By day 28 of chemotherapy, she was not in remission, so she underwent reinduction and soon developed neutropenic fever and a dry cough. Administration of broad-spectrum antibiotics was started, and a chest radiograph revealed right upper and right lower lobe opacities. A thoracic CT scan revealed a cavitary lesion in the right lower lobe. Shortly thereafter, the patient complained of pain and rapidly progressive vision loss in her right eye. Bronchoscopic evaluation with lavage and vitrectomy were performed. Cultures of samples obtained from both procedures grew Aspergillus terreus, an amphotericin B–resistant organism. The patient received caspofungin (50 mg/day given iv) and itraconazole (200 mg t.i.d. given by mouth [po]), which she tolerated well. She stabilized clinically and underwent right lower lobectomy 4 weeks later. She received a total of 8 weeks of combination antifungal therapy. Five weeks after completing therapy, she underwent bone marrow transplantation; although the transplantation was not successful, she remained free of Aspergillus infection for >7 months before dying of leukemia. The second patient was a 64-year-old man who underwent left single-lung transplantation for end-stage obstructive airway disease. In the 7 months after undergoing transplantation, he received high-dose corticosteroid therapy and antiviral therapy for recurrent acute and chronic rejection and cytomegalovirus pneumonia. Nine months after he underwent transplantation, a chest radiograph revealed a new nodule in his native lung. Despite administration of empiric antimicrobial therapy, the nodule progressed into a consolidative process involving the right lower lobe. A specimen obtained by CT-guided fine-needle aspiration of the lung grew Aspergillus fumigatus on culture. Therapy with itraconazole (400 mg/day given po) and amphotericin B lipid complex (5 mg/kg/day given iv) was initiated, but the patient's serum creatinine level increased from 1.1 mg/dL to 2.5 mg/dL while he was receiving the initial doses of amphotericin B lipid complex. Consequently, amphotericin B lipid complex was replaced with caspofungin (70 mg/day given iv) and itraconazole treatment was continued. The patient tolerated this combination without difficulty, and his serum creatinine level returned to the baseline value. The chest radiograph findings improved gradually, and administration of both medications was discontinued after 12 weeks. He has had no recurrence of Aspergillus infection in the subsequent 6 months. We were able to use caspofungin in combination with itraconazole in 2 immunocompromised patients to eradicate IA that likely would have otherwise resulted in significant morbidity or death. On the basis of this limited experience, we believe that caspofungin can be successfully used in combination with itraconazole to treat invasive fungal infections, such as IA, that have traditionally been difficult to treat. Its unique mechanism of action and fungicidal activity may provide an alternative when standard therapy, such as treatment with amphotericin B, is either ineffective or intolerable.