Editorial commentary: Is the debate about treatment of Candida parapsilosis complex infections with echinocandins much ado about nothing?

The development of the echinocandin class of antifungals represents an important advance in the treatment of candidemia and other forms of invasive candidiasis. The echinocandins demonstrate very good efficacy, a favorable safety profile, and very few drug interactions. They have significant fungicidal activity against all Candida species. They are emerging as the treatment of choice for candidemia—but are they a panacea? They are only available for parenteral administration, have poor penetration into cerebrospinal fluid, and some species, such as Candida parapsilosis complex, demonstrate less in vitro susceptibility to the echinocandins than do most other Candida species, which raises the concern that infections caused by C. parapsilosis complex may be less responsive clinically to echinocandin therapy. A recent study in a murine model of disseminated Candida infection evaluated the efficacy of caspofungin against strains of C. parapsilosis with a range of susceptibilities and revealed differences among isolates. Caspofungin reduced the tissue burden of mice infected with isolates with minimum inhibitory concentrations (MICs) ≤0.5 μg/mL but was less effective against those with MICs of 1 μg/mL [1]. This concern has not been definitively addressed by the published, randomized clinical trials of the 3 echinocandins. Clinical and microbiological response rates for the echinocandins vs comparators in C. parapsilosis complex infection were not statistically significantly different in clinical trials. However, there were numerically higher numbers of persistent candidemia due to C. parapsilosis complex in the caspofungin arm compared with the amphotericin B deoxycholate arm and during standard-dose caspofungin compared with high-dose caspofungin, and the eradication rate of C. parapsilosis complex infection was lower with anidulafungin than with fluconazole [2–4]. None of these trials had sufficient power to assess noninferiority of echinocandins for C. parapsilosis complex, however. In a recent patient-level quantitative review of the same clinical trials, the species for which an echinocandin appeared least effective in univariate analysis was C. parapsilosis complex, and for this species only disease severity predicted survival [5]. This finding is consistent with the higher MICs of echinocandins with C. parapsilosis complex. Higher mortality, however, has not been definitively demonstrated for C. parapsilosis complex when treated with an echinocandin in clinical trials. This may be explained by the species’ relatively lower virulence, and lower virulence may partially explain the response of most C. parapsilosis complex infections to echinocandin therapy, regardless of reduced susceptibility. There is an ongoing debate on whether echinocandins are appropriate for treating C. parapsilosis complex infection. Candida parapsilosis complex has emerged as one of the most commonly isolated Candida species causing bloodstream infections in Asia, Latin America, and parts of Europe. The observational study by Fernández-Ruiz et al, a subanalysis of the CANDIPOP study (a prospective surveillance program of hospitals in Spain), focuses on a large cohort of patients with C. parapsilosis complex bloodstream infection [6]. This study examines the impact of initial treatment on outcome—specifically, whether the use of an echinocandin entails a worse outcome compared with an azole. The populationbased approach of the study enhances the validity of the results. Studies such as this also give an indication of what is Received 28 February 2014; accepted 1 March 2014; electronically published 18 March 2014. Correspondence: Annette C. Reboli, MD, Cooper Hospital University Medical Center, 270 Education and Research Bldg, 401 Haddon Ave, Camden, NJ 08103 (reboli@rowan. edu). Clinical Infectious Diseases 2014;58(10):1422–3 © The Author 2014. Published by Oxford University Press on behalf of the Infectious Diseases Society of America. All rights reserved. For Permissions, please e-mail: journals. [email protected]. DOI: 10.1093/cid/ciu160