Acquisition of a Stable and Transferable blaNDM-5-Positive Plasmid With Low Fitness Cost Leading to Ceftazidime/Avibactam Resistance in KPC-2-Producing Klebsiella pneumoniae During Treatment.

Jiangqing Huang,Min Chen,Zhichang Zhao,Bin Li,Shengcen Zhang,Yingping Cao

doi:10.3389/fcimb.2021.658070

Abstract

The emergence and prevalence of carbapenem-resistant Enterobacteriaceae (CRE) have drawn worldwide attention. Ceftazidime/avibactam (CAZ/AVI) gives us a valuable alternative strategy to treat CRE infections. Unfortunately, CAZ/AVI resistance could occur during CAZ/AVI treatment. The CAZ/AVI-resistant Carbapenem-resistant Klebsiella pneumoniae (CR-KP) (KP137060) and earlier CAZ/AVI-susceptible isolate (KP135194) from the same hospitalized patient were collected at Fujian Medical University Union Hospital between October and November 2019. In this study, CAZ/AVI MICs of CAZ/AVI-susceptible and -resistant isolates (KP135194 and KP137060) were 4 mg/L and 128 mg/L, respectively; and the two isolates had the same antibiotic resistance pattern to other carbapenems. Two strains were then submitted for whole-genome sequencing and bioinformatic analysis. ompK36 was not detected in two isolates. No mutation was observed in bla KPC-2, ompK35 and ompK37 in this study and there was no significant difference of the expression in bla KPC-2, ompK35 and ompK37 between the two isolates (p>0.05). Two isolates were sequence type 11 and harbored bla KPC-2, bla SHV-182 and bla TEM-1B. Compared with KP135194, KP137060 harbored an additional bla NDM-5 positive plasmid. bla NDM-5 gene could be successfully transferred into E. coli J53 at a conjugation frequency of 1.14×10-4. Plasmid stability testing showed that bla KPC-2- and bla NDM-5-harboring plasmids were still stably maintained in the hosts. Growth assay and growth competition experiments showed there was no significant difference in fitness cost between two CR-KP isolates. Our study described the acquisition of a bla NDM-5-harboring plasmid leading to resistance to ceftazidime/avibactam in KPC-2-producing Klebsiella pneumoniae during treatment. This phenomenon deserves further exploration.

Highlights

The emergence and prevalence of carbapenem-resistant Enterobacteriaceae (CRE) have attracted extensive attention (Potter et al, 2016)
We reported the emergence of CAZ/AVI-resistance due to acquisition of a metallo-b-lactamase gene during treatment of Klebsiella pneumoniae carbapenemase (KPC)-2-producing Klebsiella pneumoniae infections and identify and validate the reason for CAZ/AVI-resistance emergence using genomic and molecular genetic approaches
Antimicrobial susceptibility profiles of the two Carbapenem-resistant Klebsiella pneumoniae (CR-KP) were shown in Table 1. blaKPC-2 was found in both isolates, and blaNDM-5 was detected in KP137060

Summary

Introduction

The emergence and prevalence of carbapenem-resistant Enterobacteriaceae (CRE) have attracted extensive attention (Potter et al, 2016). Carbapenem-resistant Klebsiella pneumoniae (CR-KP) is the most common CRE worldwide (Grundmann et al, 2017; Han et al, 2020). CR-KP can lead to many kinds of infections, such as pneumonia, bloodstream infections and urinary tract infections, resulting in high morbidity and mortality (Huang et al, 2018). Patients with CR-KP infections had few effective treatment options, including polymyxins, tigecycline, aminoglycosides and fosfomycin (Zhang et al, 2019). These antibiotics are limited by efficacy and safety (Satlin et al, 2011)

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