Role of TEM-1 β-Lactamase in the Predominance of Ampicillin-Sulbactam-Nonsusceptible Escherichia coli in Japan

Abstract

We investigated the epidemiology and resistance mechanisms of ampicillin-sulbactam-nonsusceptible Escherichia coli, focusing on the role of the TEM-1 β-lactamase. We collected all nonduplicate E. coli clinical isolates at 10 Japanese hospitals during December 2014 and examined their antimicrobial susceptibility, β-lactamases, TEM-1 transferability, TEM-1 β-lactamase activity, outer membrane protein profile, membrane permeability, and clonal genotypes. Among the 329 isolates collected, 95 were ampicillin-sulbactam nonsusceptible. Of these ampicillin-sulbactam-nonsusceptible isolates, β-lactamases conferring resistance to sulbactam, such as AmpC, were present in 33%. Hyperproduction of sulbactam-susceptible β-lactamases, TEMs with a strong promoter, were rare (5%). The remaining 59 isolates (62%) had only sulbactam-susceptible β-lactamases, including TEM-1 with a wild-type promoter (n = 28), CTX-Ms (n = 13), or both (n = 17). All 45 transconjugants from 96 donors with TEM-1 had higher ampicillin-sulbactam MICs (4 to 96 mg/liter) than the recipient (2 mg/liter). In donors with only TEM-1, TEM-1 activity correlated with the 50% inhibitory concentration of sulbactam and ampicillin-sulbactam MICs. The decreased membrane permeation of sulbactam was associated with an increased ampicillin-sulbactam MIC. The reduced permeation was partly attributable to deficient outer membrane proteins, which were observed in 57% of the ampicillin-sulbactam-nonsusceptible isolates with only TEM-1 and a wild-type promoter. Sequence type 131 (ST131) was the most common clonal type (52%). TEM-1 with a wild-type promoter primarily contributed to ampicillin-sulbactam nonsusceptibility in E. coli, with the partial support of other mechanisms, such as reduced permeation. Conjugative TEM-1 and the clonal spread of ST131 may contribute to the prevalence of Japanese ampicillin-sulbactam-nonsusceptible isolates.

Diminished Susceptibility to Cefoperazone/Sulbactam and Piperacillin/Tazobactam in Enterobacteriaceae Due to Narrow-Spectrum β-Lactamases as Well as Omp Mutation

“…It is reported that the gene mutation-induced single amino acid substitutions at Ambler positions Met 69 , Ser 130 , Arg 244 , Arg 275 , and Asp 276 in TEM and SHV β-lactamases may result in enzymes with reduced affinity for β-lactamase inhibitors ( Ramdani-Bouguessa et al 2011 ; Winkler et al 2015 ). Another possible mechanism is that resistance to BL/BLIs may result from gene amplification, and subsequent hyperproduction of β-lactamase ( Sun et al 2013 ; Noguchi et al 2019 ; Zhou et al 2019 ; Hubbard et al 2020 ). Mutations in the promoters have been shown to be responsible for bla OXY-1 and bla SHV-1 amplification ( Fournier et al 1999 ; Han et al 2020 ).…”

Comprehensive Genomic Survey of Antimicrobial-Resistance Bacteria in the Sewage Tank Replacement with Hospital Relocation

“…34 Particularly, ST131 is an E. coli strain responsible for a worldwide pandemic and it carries a broad range of pathogenicity and ARGs, including a variety of β-lactamase genes on a transferable plasmid. [35][36][37] In Japan, it has been reported that 92.9% of EPOs are bla CTX-M gene positive. 38 The CTX-M genes (bla CTX-M-14 , bla CTX-M-15 , bla CTX-M-27 and bla CTX-M-2 , listed in descending order of size) 39 have been identified in Japan as well, and gene sequences obtained in this study are similar to that (Table 2).…”

Metagenomic survey and whole genome sequencing of antimicrobial resistant bacteria in the sewage of a Japanese hospital

“…6). ST131 is an E. coli isolate responsible for a worldwide pandemic and carries a broad range of pathogenicity and antimicrobial resistance-associated genes, including a variety of βlactamase genes (CTX-M family, TEM, SHV, and CMY β-lactamases) on a transferable plasmid [74][75][76][77].…”