New Echinocandin Antifungal Effective Against Aspergillosis

TORONTO—Preliminary clinical trial results show that treatment with caspofungin acetate (Cancidas, investigational) produced a favorable response in 41% of patients with life-threatening invasive aspergillosis who were not responding to or were intolerant of other antifungal therapy.

Thomas Walsh, MD, chief, Immuno-compromised Host Section, National Cancer Institute, Bethesda, presented the study results at the 40th meeting of the Interscience Conference on Antimicrobial Agents and Chemotherapy (ICAAC).

Caspofungin is an echinocandin known as a glucan synthesis inhibitor that is being developed by Merck & Co., Inc. to treat serious fungal infections in adults.

“We are encouraged by the results of this clinical study in this extremely difficult-to-treat systemic infection,” Dr. Walsh said. “Prognosis is usually poor in seriously ill patients with pulmonary or extrapulmonary invasive aspergillosis who are not responding to initial therapy and with underlying conditions such as hematopoietic stem cell or organ transplantations.”

Patients in the multicenter, noncom-parative study were immunocompro-mised, had documented invasive aspergillosis, and were not responding to or intolerant of prior antifungal therapy.

Of the 56 patients, 46 (82%) were refractory (unresponsive) to previous therapy as evidenced by either progression of disease or failure to respond to at least 7 days of prior antifungal therapy. Ten patients (18%) were intolerant, defined as having creatinine levels of 2.5 mg/dL or higher, or other acute reactions or infusion-related toxicity.

Underlying diseases included hematologic malignancies (25 patients), allogeneic bone marrow trasnplant (14 patients), and other (17 patients).

A favorable response (complete or partial response) was defined as the resolution or clinically meaningful improvement of all attributable signs and symptoms as documented by radiographs and judged by an independent expert panel of physicians.

Patients received 70 mg of caspofungin on day 1, followed by 50 mg once daily thereafter, for a minimum of 28 days and for at least 7 days after resolution of symptoms. Duration of treatment was based on the severity of the patient’s underlying disease, recovery from immunosuppression, and onset of clinical response.

A favorable response was seen in 41% of patients receiving caspofungin (22 of 54 patients who met entry criteria and had outcomes data). For patients receiving more than 7 days of therapy, the response rate was 49% (22 of 45).

The response rate was 34% (15 of 44) in refractory patients and 70% (7 of 10) in intolerant patients.

Among patients with pulmonary disease, 18 of 40 (45%) had a favorable response. Two (20%) of the 10 patients with disseminated disease responded, as did two (50%) of the four patients with single-organ diseases.

Caspofungin, dosed for 1 to 160 days, was generally well tolerated, Dr. Walsh said. Two serious adverse events were reported as possibly drug-related (bilateral pulmonary infiltrates and hypercalcemia). Infusion-related reactions and nephrotoxicities were uncommon. Three patients (5.2%) discontinued use due to drug-related adverse events.

Several in vitro studies of caspofungin were also presented at the ICAAC meeting. One study showed that the combination of caspofungin and amphotericin B produced a synergistic result in more than half of Aspergillus and Fusarium isolates tested.

Another study showed that the agent had in vitro activity across nine different types of Candida species found in 1,808 isolates taken from 51 patients. The isolates included C albicans (1,388), C guilliermondii (59), C krusei (25), C parapsilosis (54), C kefyr (1), C tropicalis (78), C lipolytica (8), C lusitaniae (2), and C glabrata (193).

In a test of 86 Aspergillus isolates obtained from 34 patients, caspofungin showed potent activity, based on 24-hour MIC₈₀, against A fumigatus, A flavus, A niger, and A terreus.