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Molecular characterization of carbapenem-resistant and virulent plasmids in Klebsiella pneumoniae from patients with bloodstream infections in China.

ABSTRACT: Bloodstream infections (BSIs) caused by carbapenem-resistant Klebsiella pneumoniae (CRKP) are potentially life-threatening and an urgent threat to public health. The present study aims to clarify the characteristics of carbapenemase-encoding and virulent plasmids, and their interactions with the host bacterium. A total of 425 Kp isolates were collected from the blood of BSI patients from nine Chinese hospitals, between 2005 and 2019. Integrated epidemiological and genomic data showed that ST11 and ST307 Kp isolates were associated with nosocomial outbreak and transmission. Comparative analysis of 147 Kp genomes and 39 completely assembled chromosomes revealed extensive interruption of acrR by ISKpn26 in all Kp carbapenemase-2 (KPC-2)-producing ST11 Kp isolates, leading to activation of the AcrAB-Tolc multidrug efflux pump and a subsequent reduction in susceptibility to the last-resort antibiotic tigecycline and six other antibiotics. We described 29 KPC-2 plasmids showing diverse structures, two virulence plasmids in two KPC-2-producing Kp, and two novel multidrug-resistant (MDR)-virulent plasmids. This study revealed a multifactorial impact of KPC-2 plasmid on Kp, which may be associated with nosocomial dissemination of MDR isolates.

SUBMITTER: Yang Y

PROVIDER: S-EPMC8023600 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:Cefiderocol is a novel siderophore cephalosporin exhibiting potent antimicrobial activities. Although cefiderocol has not been approved in China, resistance is emerging. A multicenter study was performed to evaluate the cefiderocol resistance in carbapenem-resistant Klebsiella pneumoniae (CRKP) strains from bloodstream infections in patients with hematologic malignancies in China. Clinical data analysis and whole-genome sequencing were conducted for collected cefiderocol-resistant CRKP strains. CRISPR-Cas9 system was employed to construct site-specific mutagenesis for gene cirA. Plasmid curing and cloning were performed to assess the effect of β-lactamases on cefiderocol resistance. Total 86 CRKP strains were collected. The MICs of cefiderocol ranged from 0.06 to >256 mg/L. Among four cefiderocol-nonsusceptible strains (4/86, 4.7%), two cefiderocol-resistant strains AR8538 (MIC = 32 mg/L) and AR8416 (MIC > 256 mg/L) were isolated from two patients with acute lymphocytic leukemia (frequency of resistance, 2/86, 2.3%). Metallo- and serine-β-lactamase inhibitors addition would decrease the MIC of cefiderocol from 32 to 1 mg/L in AR8538, which harbors blaSHV-12, blaDHA-1, and two copies of blaNDM-1 in different plasmids. Avibactam did not impact cefiderocol susceptibility of AR8416, which produces NDM-5. However, we found a deficient CirA in AR8416. Using the same K serotype strain D3, we proved CirA deficiency or carrying NDM individually reduced cefiderocol susceptibility, but their simultaneously existence rendered a high-level cefiderocol resistance. In summary, the resistance of CRKP against cefiderocol is mediated by multiple factors, including the deficiency of CirA, metallo- or serine-β-lactamases, while a high-level cefiderocol resistance could be rendered by the combined effect of NDM expression and CirA deficiency. IMPORTANCE Cefiderocol-resistant CRKP strains are emerging in bloodstream infections in Chinese patients with hematologic malignancies, although cefiderocol has not been approved for clinical use in China. Our study proved that the resistance of CRKP against cefiderocol is mediated by multiple factors, including the deficiency of CirA, metallo- or serine-β-lactamases, while a high-level cefiderocol resistance could be rendered by the combined effect of NDM expression and CirA deficiency. As NDM production is one of the most critical mechanisms resulting in carbapenem resistance, it would pose great challenges on the clinical efficacy of cefiderocol in future.

Project description:Background: The increasing prevalence of carbapenem-resistant Klebsiella pneumoniae (CRKP) poses an immediate threat to treatment worldwide. This retrospective study assessed the molecular epidemiology and determined the risk factors for and outcomes of CRKP infections in a general teaching hospital in Shanghai, China. Methods: From January 2013 to July 2015, 100 consecutive unique CRKP isolates isolated from hospitalized patients were collected. Isolates were screened for antibiotic resistance genes by polymerase chain reaction and molecular typing was performed by pulsed-field gel electrophoresis (PFGE). Patients infected with CRKP comprised the case group and were compared to the control group of patients infected with carbapenem-susceptible Klebsiella pneumoniae. Therapeutic effects were compared in the CRKP infection group. Results: Among the 100 CRKP isolates, the percentages of multidrug-resistant, extensively drug-resistant (XDR), and pandrug-resistant were 50.0, 50.0, and 0%, respectively. All the CRKP isolates produced KPC-2 and could be divided into 18 PFGE clusters (A-O) and 70 subtypes. No dominant intra-hospital PFGE type was detected using a cutoff of 80% similarity. The ratio of CRKP infection to colonization was 51 to 49. Risk factors correlated with CRKP infection included pulmonary disease (p = 0.038), ICU stay (p = 0.002), invasive ventilation (p = 0.009), blood transfusion (p = 0.028), parenteral nutrition (p = 0.004), sputum suction (p = 0.006), medical history of previous hospitalization (p = 0.022), exposure to antibiotics 90 days before infection (p = 0.030), and antibiotic exposure during hospital stay including carbapenems (p = 0.013), enzyme inhibitors (p = 0.021), nitroimidazoles (p = 0.029), and glycopeptides (p = 0.000). Multivariable analysis showed that sputum suction (odds ratio 3.090, 95% confidence intervals 1.004-9.518, p = 0.049) was an independent risk factor for CRKP infections. Patients infected with CRKP with longer carbapenems treatment course (p = 0.002) showed better outcome. Conclusion: This study showed the severity of CRKP infection in eastern China. Sputum suction was an independent risk factor for CRKP infection. Prolonged duration of treatment with carbapenems benefited the patients infected with CRKP.

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Molecular characterization of carbapenem-resistant and virulent plasmids in Klebsiella pneumoniae from patients with bloodstream infections in China.

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