Acquired Flucytosine Resistance during Combination Therapy with Caspofungin and Flucytosine for Candida glabrata Cystitis

Abstract

Treatment of Candida glabrata cystitis remains a therapeutic challenge, and an antifungal combination using flucytosine is one option. We describe two patients with refractory C. glabrata cystitis who failed flucytosine combined with caspofungin with early-acquired high-level resistance to flucytosine due to nonsense mutations in the FUR1 gene. Rapidly acquired flucytosine resistance with microbiological failure should discourage combination of caspofungin and flucytosine during urinary candidiasis.

FIG 1

Schematic representation of the transition between the FUR1 allele of the flucytosine-susceptible strain and the mutated version (fur1) of the flucytosine-resistant strain in patient 1. (A) Schematic representation of the region of C. glabrata FUR1 gene of the sensitive strain, which includes two 4-bp homologous sequences, R1 and R2 (AAGG). The DNA sequence between the 3′ ends of the two repeats is 29 bp long. (B) When transient denaturation occurs during DNA replication, the replicating strand sometimes anneals to another site (R2 on R1), forming a transient bubble. When replication starts again, the 25-bp segment located between the two repeated priming sites (R1 and R2) will be duplicated, as well as the proximal repeat, resulting in a third homologous sequence (R3) and a 29-bp duplication. (C) Schematic representation of the region of C. glabrata fur1 gene of the resistant strain, which includes a duplicated region of 29 bp. This insertion creates a frameshift and a premature Stop codon (*).