Micafungin for Invasive Candidiasis

Abstract & Commentary

By Stan Deresinski, MD, FACP, Clinical Professor of Medicine, Stanford University; Associate Chief of Infectious Diseases, Santa Clara Valley Medical Center; Dr. Deresinski serves on the speaker's bureau for Merck, Pharmacia, GlaxoSmithKline, Pfizer, Bayer, and Wyeth, and does research for Merck. This article originally appeared in the November 2007 issue of Infectious Disease Alert. It was peer reviewed by Connie Price, MD. Dr. Price is Assistant Professor, University of Colorado School of Medicine. She reports no financial relationship relevant to this field of study

Synopsis: Micafungin at doses of both 100 mg and 150 mg daily was non-inferior to caspofungin in the treatment of invasive candidiasis and there was no significant difference in outcomes when the two doses of micafungin were compared.

Source: Pappas PG, et al. Micafungin versus caspofungin for treatment of candidemia and other forms of invasive candidiasis. Clin Infect Dis. 2007;45:883-893.

Patients with invasive candidiasis were randomized to blinded treatment with either caspofungin (70 mg on day one, followed by 50 mg daily), or one of 2 doses of micafungin (100 mg or 150 mg daily). Approximately 85% of the 595 randomized patients had candidemia. Patients in each treatment arm received a median of 14 days of therapy, including 4-7.5 days of oral fluconazole in 15.1%-21.9% in each arm, as allowed by protocol. Almost three-fourths of infections were due to Candida albicans, followed in frequency by C. tropicalis (16.6%), C. glabrata (16.4%), and C. parapsilosis (15.9%). Neutropenia was present at baseline in 8.4% of patients.

The size of the population randomized was chosen in order to have a > 90% power to determine non-inferiority of micafungin at a lower bound of the difference between treatment arms of -15%. Treatment success, defined as investigator-determined clinical and mycological success at the end of blinded intravenous therapy in the modified intent-to-treat population, was the primary efficacy end point, and was achieved in 76.4%, 71.4%, and 72.3% of patients assigned micafungin 100 mg, micafungin 150 mg, and caspofungin, respectively. Both micafungin regimens were noninferior to treatment with caspofungin. This remained true at subsequent evaluations, with the last occurring 6 weeks after the end of all antifungal therapy. There was no significant difference between treatment arms in the treatment of infections due to C. albicans or the non-albicans species. The median time to blood culture negativity was 2 days in the micafungin 100 mg group, as well as in the caspofungin group; it was 3 days in the group given micafungin 150 mg.

Approximately one-fourth of patients in each group did not have their intravenous catheters removed, a feature associated with poorer overall response, regardless of assigned treatment. Thus, treatment success was achieved in 77.9% of 384 patients whose IV catheter was removed or replaced, while only 63.2% of 144 patients whose catheter remained in place were successfully treated (P = .001). The overall mortality was 29.6%, and did not differ significantly among the treatment groups.

Commentary

This is the latest in the past several years in a series of randomized, therapeutic trials evaluating newer antifungal agents in the treatment of invasive candidiasis, and the first to compare 2 echinocandins. Previously, caspofungin therapy was comparable to the use of amphotericin B deoxycholate in a primary analysis and superior in a clinically evaluable population.1 Anidulafungin was found to be superior to fluconazole,2 while voriconazole was non-inferior to amphotericin B deoxycholate,3 and micafungin was non-inferior to liposomal amphotericin B.4 Thus, we have a variety of trials that provide us with data to assist us in deciding on optimal anti-candidal therapy, but strangely, the answer remains somewhat muddy. It seems to me that it would be generally preferred to use an agent other than an amphotericin B preparation, given the complexities of administration and toxicity of these products. Fluconazole is active against most, but not all Candida isolates, so that it probably should not be used as empiric therapy in patients with severe, potentially life-threatening infections. Voriconazole is active against some fluconazole-resistant Candida. The echinocandins seem to be emerging as the preferred initial empiric therapy of many clinicians, but the choice among the 3 available echinocandins is more difficult and is not made easier by the study reviewed here.

Some comparisons indicated a non-significant trend toward superior outcomes in patients receiving 100 mg of micafungin daily compared to those receiving a higher dose. If correct, this finding would be consistent with a paradoxical effect, in which higher concentrations are less effective at inhibiting growth of the microorganism than are some lower doses.

Another interesting observation was that only 11 of 595 (1.8%) had chorioretinits at baseline, a figure much lower than has been reported in the past with candidemia, but consistent with the results in some other clinical trials. This suggests that earlier observational studies, which reported an incidence as high as 30%, were either grossly inaccurate or the patients had suffered from prolonged candidemia before it was recognized and treated.

References

1. Mora-Duarte J, et al. Comparison of caspofungin and amphotericin B for invasive candidiasis. N Engl J Med. 2002;347:2020-2029.

2. Reboli AC, et al. Anidulafungin versus fluconazole for the treatment of invasive candidiasis. N Engl J Med. 2007;356:2472-2482.

3. Kullberg BJ, et al. Voriconazole versus a regimen of amphotericin B followed by fluconazole for candidaemia in non-neutropenic patients: A randomised non-inferiority trial. Lancet. 2005;366:1435-1442.

4. Kuse ER, et al. Micafungin versus liposomal amphotericin B for candidaemia and invasive candidiasis: A phase III randomised double-blind trial. Lancet. 2007;369:1519-1527.