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

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 blaKPC-2, ompK35 and ompK37 in this study and there was no significant difference of the expression in blaKPC-2, ompK35 and ompK37 between the two isolates (p>0.05). Two isolates were sequence type 11 and harbored blaKPC-2, blaSHV-182 and blaTEM-1B. Compared with KP135194, KP137060 harbored an additional blaNDM-5 positive plasmid. blaNDM-5 gene could be successfully transferred into E. coli J53 at a conjugation frequency of 1.14×10-4. Plasmid stability testing showed that blaKPC-2- and blaNDM-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 blaNDM-5-harboring plasmid leading to resistance to ceftazidime/avibactam in KPC-2-producing Klebsiella pneumoniae during treatment. This phenomenon deserves further exploration.

Carbapenemase Production and Epidemiological Characteristics of Carbapenem-Resistant Klebsiella pneumoniae in Western Chongqing, China

“…In addition, the detection rate of bla NDM in children was significantly higher than that in adults. Our results are similar to those of a previous study indicating that acquiring a bla NDM-5 -harboring plasmid led to resistance to CAZ-AVI in KPC-2-producing K. pneumoniae during treatment ( Huang et al., 2021 ). With the CAZ-AVI combination, AVI protects CAZ from degradation by various serine beta-lactamases, thus promoting CAZ-AVI activity.…”

Genomic Analysis Revealed the International and Domestic Transmission of Carbapenem-Resistant Klebsiella pneumoniae in Chinese Pediatric Patients

“…We also found eight isolates that encoded two carbapenemases, either IMP-4 and NDM-1 or KPC-2 and NDM-5. Several studies have revealed that the convergence of bla KPC-2 and bla NDM-5 or the coexistence of bla IMP-4 and bla NDM-1 in a single strain has the ability to extend the resistance profile of the bacteria, allowing the bacteria to potentially be transmitted between patients ( 31 – 33 ), posing a significant threat to public health. Therefore, it is necessary to strengthen the surveillance of these isolates among children to improve clinical treatment and management.…”

Large-Scale Analysis of Fitness Cost of tet(X4)-Positive Plasmids in Escherichia coli

“…However, many studies have shown that some plasmids can persist in bacterial populations for a long time, even without positive selection, which is referred to as the "plasmid paradox" (Harrison and Brockhurst, 2012). For example, it is reported that the acquisition of mobile bla NDM-5positive plasmids in Enterobacteriaceae or K. pneumoniae showed little fitness cost on host bacteria (Ma et al, 2020;Huang et al, 2021). It is plausible that antibiotic resistance is determined by interactions between the resistance gene and bacterial host, not only by the existence of the resistance gene (Praski Alzrigat et al, 2021).…”

“…These two drugs have been identified by the World Health Organization as the last lines of defense against infections caused by MDR Gramnegative bacteria (He et al, 2019). With the dissemination of carbapenem resistance gene bla NDM and polymyxin resistance gene mcr, tigecycline has been the final choice in the treatment of MDR infections (Choi et al, 2020;Huang et al, 2021). However, novel plasmid-mediated tigecycline resistance genes tet(X3/X4) in bacteria of human and animal origin were identified in 2019 in China.…”