Posttreatment Antifungal Resistance among Colonizing Candida Isolates in Candidemia Patients: Results from a Systematic Multicenter Study

Abstract

The prevalence of intrinsic and acquired resistance among colonizing Candida isolates from patients after candidemia was investigated systematically in a 1-year nationwide study. Patients were treated at the discretion of the treating physician. Oral swabs were obtained after treatment. Species distributions and MIC data were investigated for blood and posttreatment oral isolates from patients exposed to either azoles or echinocandins for <7 or ≥ 7 days. Species identification was confirmed using matrix-assisted laser desorption ionization-time of flight mass spectrometry (MALDI-TOF MS) and internal transcribed spacer (ITS) sequencing, susceptibility was examined by EUCAST EDef 7.2 methodology, echinocandin resistance was examined by FKS sequencing, and genetic relatedness was examined by multilocus sequence typing (MLST). One hundred ninety-three episodes provided 205 blood and 220 oral isolates. MLST analysis demonstrated a genetic relationship for 90% of all paired blood and oral isolates. Patients exposed to azoles for ≥ 7 days (n = 93) had a significantly larger proportion of species intrinsically less susceptible to azoles (particularly Candida glabrata) among oral isolates than among initial blood isolates (36.6% versus 12.9%; P < 0.001). A similar shift toward species less susceptible to echinocandins among 85 patients exposed to echinocandins for ≥ 7 days was not observed (4.8% of oral isolates versus 3.2% of blood isolates; P > 0.5). Acquired resistance in Candida albicans was rare (<5%). However, acquired resistance to fluconazole (29.4%; P < 0.05) and anidulafungin (21.6%; P < 0.05) was common in C. glabrata isolates from patients exposed to either azoles or echinocandins. Our findings suggest that the colonizing mucosal microbiota may be an unrecognized reservoir of resistant Candida species, especially C. glabrata, following treatment for candidemia. The resistance rates were high, raising concern in general for patients exposed to antifungal drugs.

FIG 1

Flowchart illustrating the numbers of eligible patients, included patients, and episodes, divided into those for patients receiving ≥7 days of exposure to azoles (93), echinocandins (62), polyenes (7), or a combination thereof (26). The total numbers of episodes for patients exposed to azoles, echinocandins, and polyenes for ≥7 days (irrespective of sequential or concomitant additional treatment) were 114, 85, and 16, respectively.

FIG 2

Pie charts displaying species distributions in the indicated groups. N, number of isolates. Blood isolates represented baseline colonization in patients subsequently exposed to either azoles or echinocandins. Oral isolates (≥7 days of exposure) represented end-of-treatment colonization. NS, not significant. On the patient level (pie charts on the same horizontal level), only the species with the highest ECOFF value was counted in case of polyfungal samples; however, the distribution of all oral isolates is also shown (above for azoles and below for echinocandins). Proportion analysis was performed by chi-square and Fisher's exact tests.

FIG 3

MIC distributions for C. glabrata (left) and C. albicans (right). MICs are given in milligrams per liter. White bars show data for blood isolates, gray bars are for swab isolates obtained after <7 days of exposure to either azoles or echinocandins, and black bars are for swab isolates obtained after ≥7 days of exposure to either drug class. The rows display MIC distributions for (top to bottom) fluconazole, voriconazole, anidulafungin, and micafungin. The y axis indicates the number of isolates either from blood (positive) or from swabs (negative).