Breakthrough Bloodstream Infections Caused by Echinocandin-Resistant : An Emerging Threat to Immunocompromised Patients with Hematological Malignancies.

BACKGROUND

is a virulent fungal pathogen for which echinocandins are the primary therapy. Emergence of resistance to echinocandins of carries potentially ominous therapeutic implications.

METHODS

We describe herein two patients with breakthrough fungemia during echinocandin therapy, characterize their molecular mechanism of resistance, and systematically review 13 previously reported cases of echinocandin-resistant bloodstream infections (BSIs) and other diseases.

RESULTS

Among these 15 patients with echinocandin-resistant infections, the median age was 61 years (ages 28-84 years) and 13 (86%) were immunocompromised. Thirteen (86%) of all patients had a history of pervious or concurrent exposure to echinocandins. Isolates of from 11 cases, including the two index cases, underwent DNA sequencing of the gene for mutations known to confer echinocandin resistance. The amino acid substitution Ser654Pro was shown in four cases, while other mutations encoded Ser80S/Pro, Phe641Leu, Phe641Ser, Ser80S/Pro substitutions. These mutational events were not associated with collateral increases in minimum inhibitory concentrations to antifungal triazoles and amphotericin B. Overall mortality in patients with echinocandin-resistant infections was 40%. Among those six patients who died, two received monotherapy with voriconazole, one was treated with fluconazole, one remained on caspofungin, and two were switched to liposomal amphotericin B. Nine patients (60%) survived after being treated with an antifungal agent other than an echinocandin.

CONCLUSIONS

Emergence of resistance to echinocandins by occurs during antifungal therapy, is associated with high mortality, is mediated by a diverse range of mutations, retains in vitro susceptibility to triazoles and amphotericin B, and constitutes an emerging threat to patients with hematological malignancies.