Decreased echinocandin susceptibility in Candida parapsilosis causing candidemia and emergence of a pan-echinocandin resistant case in China

Figures & data

Figure 1. Profile of C. parapsilosis susceptibility to echinocandins. (A) Distribution of susceptibility to three echinocandins of 2523 clinical isolates from China collected by CHIF-NET 2015–2019 programme. (B and C) Susceptibility differences of isolates regarding different samples (B), and hospital departments (C). Geometric mean of the MIC (GM) values are shown in the boxes; differences between each two groups were analyzed, while only significant differences compared to the “others” group are shown in the figure. AND, anidulafungin; CAS, caspofungin; MF, micafungin. *, P < 0.05; ****, P < 0.0001.

Table 1. Clinical characteristics of a patient with breakthrough candidemia caused by pan-echinocandin resistant C. parapsilosis.

Characteristics	Patient infected with TJ1197
Age at admission	7 weeks
Gender	Male
Department of admission	Pediatric ICU
Reason for admission	Intermittent fever
Admitting diagnosis	Pulmonary infection and severe diarrhea
Site of isolation	Blood
Clinical status at time of positive culture
Prematurity	NO
Immunosuppressive state	YES
Neutropenia (<10^9/L)	NO
Catheter insertion	YES
Indwelling urinary catheter	YES
Total parenteral nutrition	YES
Abdominal surgery within 30 days	YES; ileostomy
Broad-spectrum antibiotics	YES
Prior antifungal treatment	YES; micafungin, 45 days
Prolonged ICU stay	YES; 45 days
Therapy & Outcome
CVC removal	NO
Antifungal therapy after culture	Voriconazole and 5-flucytosine
Outcome	Poor condition and discharged voluntarily
Characteristics of the clinical isolate TJ1197*
Antifungal resistance	Echinocandins, fluconazole, voriconazole
Colony morphology	Crepe
Cell shape	Pseudohyphal and yeast-form cells
Aggregation in liquid culture	High^#
Biofilm formation	Strong^#
Agar invasiveness	High^#

*See Figure S1 for detail; ^#Compared to ATCC 22019.

Figure 2. Strain characteristics of the pan-echinocandin resistant C. parapsilosis clinical isolate. (A) In vitro susceptibility to nine common antifungal drugs. The dashed red line indicates the breakpoints for defining drug resistance or cut-off values for non-wild type. (B) Transmembrane helix predictions for Fks1 of C. parapsilosis. The location of the amino acid 656 is labelled.

Figure 3. Structural and functional effect of the S656P substitution in Fks1. (A) The predicted structural model for the variants of the Fks1 protein (amino acids 400∼900), the S656P substitution would result in the helix-to-coil transition, disrupting conformation of this ɑ-helix. (B) Echinocandin MICs for susceptible C. parapsilosis strain ATCC 22019 and its mutant harbouring Fks1 S656P, and the pan-echinocandin resistant clinical isolate TJ1197 and its mutant with WT of Fks1. (C) Changes in expression of the FKS1 and CHS3 genes in response to micafungin at the sub-MICs. (D) Echinocandin MICs for susceptible C. orthopsilosis ATCC 96139, C. metapsilosis ATCC 96143, and their mutants carrying homologous modifications, S649P and S656P, respectively. Dashed red lines indicate the breakpoints for defining drug resistance or cut-off values for non-wild type. AND, anidulafungin; CAS, caspofungin; MF, micafungin. **, P < 0.01; ***, P < 0.001.