Emergence of Colistin Resistance in Carbapenem-Resistant Hypervirulent Klebsiella pneumoniae Under the Pressure of Tigecycline

Abstract

Colistin and tigecycline are the last options against carbapenem-resistant hypervirulent Klebsiella pneumoniae (CR-hvKP). Intersecting resistance determinants have been detected between these antibiotics; however, there is only limited evidence of such association. Here, we describe a colistin-resistant CR-hvKP isolated from a patient with severe neonatal bacteremia treated with tigecycline as opposed to colistin before isolation of this strain, providing a clinical clue to colistin resistance under tigecycline pressure. Furthermore, an ST11-K64 KPC-2–producing, colistin-susceptible CR-hvKP strain was subjected to experimental evolution toward colistin resistance under tigecycline and colistin pressure to verify this phenomenon in vitro. The biological impact of acquiring colistin resistance on fitness and virulence was also studied. As expected, the parental strain rapidly developed colistin resistance under both tigecycline and colistin selection. However, different from the colistin resistance mechanism in the clinical strain that was due to an ISKpn26 insertion in the mgrB gene, the mutants in this study developed colistin resistance through a ∼4.4 or ∼4.6 kb deletion including the mgrB locus as well as the kdgR, yobH, yebO, yobF, cspC, ftsI, and rlmA genes. Although the virulence of the colistin-resistant mutants, as determined in the Galleria mellonella model, decreased compared with that of the parent strain, it was still higher than that of NTUH-K2044. This suggests a slight virulence cost when CR-hvKP develops colistin resistance under tigecycline or colistin pressure. Together, our results provide clinical and experimental evidence for the association between colistin resistance and tigecycline pressure in CR-hvKP, highlighting a critical issue in the clinical setting.

Rapid Evolution of Colistin Resistance in a Bioreactor Model of Infection of Klebsiella pneumoniae

“…Consistent with the broader literature 1,5,37 , our challenge experiments also demonstrate the emergence of variants harbouring mutations in both crrB and pmrB genes. Notably, in our experiments mgrB mutations occurred at an extremely low frequency.…”

“…Klebsiella pneumoniae is an opportunistic highly antibiotic resistant Gram-negative pathogen, currently recognised by CDC and WHO as a severe threat to both human and animal health 1,2,3 . The emergence of pan-drug resistant variants of K. pneumoniae significantly limit treatment options, demanding an increased reliance on last-resort agents such as tigecycline, carbapenems and colistin 4,5 .…”

“…5, or whichever happened first. To dilute, an appropriate volume of fresh media (LB only, or LB + colistin) was first added.…”

Molecular and clinical characterization of hypervirulent Klebsiella pneumoniae isolates from individuals with urinary tract infections

“…The hypervirulence combined with drug-resistant strains is associated with increasing emergence of such strains and poses a major challenge to clinical anti-infective therapy ( Lee et al., 2017 ; Mataseje et al., 2019 ; Zhu et al., 2020 ; Zhang et al., 2021 ). In this study, the detection rate of CRE in hvKP was higher than it was in cKP; this could be attributed to bla KPC-2 , which was identified to be successfully transferred into EC600 by conjugation test, indicating that this hypervirulent strain could acquire resistance genes by horizontal gene transfer (HGT) ( Lan et al., 2021 ).…”

Epidemiological characteristics and molecular evolution mechanisms of carbapenem-resistant hypervirulent Klebsiella pneumoniae

“…OmpK36 can reduce the sensitivity of ESBL and AmpC β-lactamase of CRKP and is closely related to the resistance of CRKP to carbapenems (Wang et al, 2009). In a retrospective study with 28 cases of CRKP infections Yao et al, 2015;Zhang et al, 2015;Liu et al, 2016;Zhang et al, 2016;Liu et al, 2017;Zhan et al, 2017;Dong et al, 2018;Feng et al, 2018;Huang et al, 2018;Wei et al, 2018;Gu et al, 2018a,b;Dong et al, 2019;Liu and Su, 2019;Shen et al, 2019;Shu et al, 2019;Xu et al, 2019;Yuan et al, 2019;Zhou et al, 2019;Li et al, 2019b;Hao et al, 2020;Jin et al, 2020;Liu et al, 2020;Yang et al, 2020;Zhang et al, 2020;Zheng et al, 2020;Zhou et al, 2020;Li et al, 2020a,b;Huang et al, 2021;Jin et al, 2021;Liu et al, 2021;Shao et al, 2021;Su et al, 2021;Xie et al, 2021;Yan et al, 2021;Zhang et al, 2021;Zhao et al, 2021;Zhou et al, 2021;Li et al, 2021a,b;Yang et al, 2021b;Wei et al, 2022;Zhou et al, 2022; f...…”