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.
Highlights
Carbapenem-resistant Klebsiella pneumoniae (CRKP) is a critical threat to public health (Van Duin and Doi, 2017)
Pus cultures from the lesion were shown to be tigecycline-susceptible carbapenem-resistant K. pneumoniae (CRKP), and the patient was treated with a combination of tigecycline and meropenem
The patient subsequently presented with fever, and a series of tigecyclinesusceptible CRKP strains were successively isolated from her blood and sputum samples, one of which, C2582, was recovered from a blood sample
Summary
Carbapenem-resistant Klebsiella pneumoniae (CRKP) is a critical threat to public health (Van Duin and Doi, 2017). In China, the meropenem resistance rate in K. pneumoniae has increased from 2.9% in 2005 to 24.2% in 2020 (CHINET, 2021). K. pneumoniae carbapenemase (KPC)–2–producing ST11 clones of CRKP are of Colistin Resistance in CR-hvKP particular concern because they can spread rapidly and cause severe infections in clinical settings (Fraenkel-Wandel et al, 2016; Wang et al, 2018). We have witnessed the emergence of carbapenem-resistant hypervirulent K. pneumoniae (CR-hvKP). The virulence increased in the KPC–2– producing ST11 clones in mainland China, from 2.1 to 7.0% between 2015 and 2017 (Zhang et al, 2020). More than 80% of patients with respiratory tract and bloodstream infections caused by CR-hvKP experience poor outcomes (Gu et al, 2018; Mohammad Ali Tabrizi et al, 2018)
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