Impact of PBP3 insertions and β-lactamase-encoding genes on the susceptibility of Escherichia coli isolates belonging to high-risk clones against aztreonam-avibactam and comparator agents

ABSTRACT We evaluated the presence and phenotypic impact of PBP3 insertions YRIN ( n = 44) and YRIK ( n = 18) among 124 Escherichia coli isolates belonging to high-risk lineages selected from 1,471 isolates displaying resistance to β-lactams. PBP3 insertions were detected among 62 isolates. YRIN insertions were detected among isolates belonging to ST167 ( n = 23), ST361 ( n = 7), ST410 ( n = 10), ST617 ( n = 1), and ST648 ( n = 3), while YRIK insertions were observed in ST405 ( n = 9), ST410 ( n = 5), and ST617 ( n = 4). Aztreonam-avibactam inhibited 90.3% of all isolates from high-risk clones and 80.6% of the isolates harboring PBP3 insertions when applying the EUCAST breakpoints. Aztreonam-avibactam inhibited 66.7% of the YRIK-harboring isolates (MIC 50/90 , 2/16 mg/L) and 86.4% of the ones harboring YRIN insertions (MIC 50/90 , 1/8 mg/L); however, the susceptibilities to other β-lactams were lower among YRIN isolates (25.6%–60.5%) compared to YRIK (55.6%–88.9%). Overall, ST617 was more resistant to all agents when compared to other STs, regardless of PBP3 insertions or the presence of other examined resistance mechanisms. Acquired β-lactamase genes and OmpC deleterious alterations were present in all isolates. CMY-42, CMY-141, and CMY-145 that have been associated with elevated aztreonam-avibactam MICs were detected among 13 isolates, and 4 (30.8%) were susceptible to this combination. All isolates harboring bla NDM-5 ( n = 37) possessed PBP3 insertions. Aztreonam-avibactam inhibited 83.8% of these isolates. Resistance to aztreonam-avibactam is multifactorial, and singular resistance mechanisms are unable to elevate MIC values to resistant categories. Additionally, lineage-specific contributions to resistance play an important role in the overall development of β-lactam resistance, although these mechanisms appear to function outside the known repertoire of resistance-conferring mutations and warrant further study.