Genetic basis for in vivo piperacillin-tazobactam resistance

Abstract

Abstract Piperacillin-tazobactam resistance (P/T-R) is increasingly reported among Escherichia coli isolates. Although in vitro experiments have suggested that blaTEM gene plays a key role in the P/T-R acquisition, no clinical in vivo study has yet confirmed the role of blaTEM or other genes. Therefore, we aimed to identify the mechanisms underlying P/T-R by following up patients with E. coli intraabdominal infections (IAI) who experienced P/T treatment failure. We found a higher copy number of blaTEM gene in P/T-R isolates, generated by three different genetic events: (1)IS26-mediated duplication of the blaTEM gene, (2) generation of a small multicopy plasmid (ColE-like) carrying blaTEM, and (3) adaptive evolution via reduction of plasmid size, leading to a higher plasmid copy number. Moreover, two P/T-R strains showed reduced expression of OmpC. Thus, P/T treatment may lead to the development of resistance in patients with IAI by E. coli, through three blaTEM-dependent mechanisms and downregulation of OmpC.