New mutations in genes associated with cefiderocol resistance in a clinical isolate of Pseudomonas aeruginosa

Objective.

To assess the effects of chromosomal mutations on emergence of cefiderocol resistance among Pseudomonas aeruginosa clinical isolates.

Materials and Methods.

Study design purported to compare the characteristics of phenotypic antibiotic resistance and chromosomal mutations of P. aeruginosa strains of a common origin possessing different resistance levels to cefiderocol. Two P. aeruginosa isolates from the sputum of a patient with cystic fibrosis who had not previously received cefiderocol were analyzed. Species identification was performed using an MALDI-TOF MS instrument and whole genome sequencing (WGS) data obtained from the MGISEQ-2000 platform. Antibiotic resistance was estimated based on minimum inhibitory concentration (MIC) testing. Plasmid-borne resistance genes and mutations in chromosomal genes associated with cefiderocol resistance were revealed based on WGS data.

Results.

Both P. aeruginosa isolates had the same antibiotic MIC values excluding meropenem and cefiderocol MIC values. Cefiderocol MICs were significantly different between the two strains corresponding to the resistant clinical category for one isolate and to the susceptible category for another one. Both strains belonged to 2554 sequence type. Eight potentially significant mutations in iron-uptake genes and genes associated with beta-lactam resistance were detected in the genome of the cefiderocol-resistant isolate, which were absent in the cefiderocol-susceptible strain. Cefiderocol resistant isolate harbored frameshift mutations in pirA, pirR and piv and nonsynonymous mutations in pfeA, cirA, iutA, pbpА and pchD.

Conclusions.

Cefiderocol resistance can emerge among P. aeruginosa isolates which were not exposed to cefiderocol as the phenomenon of cross-resistance. Resistance to cefiderocol can be conferred not by a single mutation, but by a combination of chromosomal gene alterations.