Sequence type 11 (ST11) carbapenem-resistant Klebsiella pneumoniae (CRKP) has become the dominant clone in China. In this review, we trace the prevalence of ST11 CRKP in the China Antimicrobial Surveillance Network (CHINET), the key antimicrobial resistance mechanisms and virulence evolution. The recent emergence of ST11 carbapenem-resistant hypervirulent K. pneumoniae (CR-hvKP) strains in China due to the acquisition of a pLVPK-like virulence plasmid, which may cause severe infections in relatively healthy individuals that are difficult to treat with current antibiotics, has attracted worldwide attention. There is a very close linkage among IncF plasmids, NTEKPC and ST11 K. pneumoniae in China. Hybrid conjugative virulence plasmids are demonstrated to readily convert a ST11 CRKP strain to a CR-hvKP strain via conjugation. Understanding the molecular evolutionary mechanisms of resistance and virulence-bearing plasmids as well as the prevalence of ST11 CRKP in China allows improved tracking and control of such organisms.

Virulence evolution, molecular mechanisms of resistance and prevalence of ST11 carbapenem-resistant Klebsiella pneumoniae in China: A review over the last 10 years.

This is the first report of ceftazidime-avibactam resistance caused by the blaKPC-33 mutation through the D179Y variant during the treatment of blaKPC-2-positive Klebsiella pneumoniae-related infections in China. The blaKPC-33-containing K. pneumoniae was susceptible to meropenem-vaborbactam, cefepime-zidebactam, tigecycline, and polymyxin B. The blaKPC-33 gene was located on a 77 551-bp transformable plasmid harboring qnrS1 and blaLAP-2. Detecting blaKPC-33-positive K. pneumoniae clinical strains is important for infection control.

Emergence and Recovery of Ceftazidime-avibactam Resistance in blaKPC-33-Harboring Klebsiella pneumoniae Sequence Type 11 Isolates in China.

Antibiotic resistance occurs when microorganisms resist the drugs used against the infection caused by them and neutralize their effects over time using various mechanisms. These mechanisms include preventing drug absorption, changing drug targets, drug inactivating, and using efflux pumps, which ultimately cause drug resistance, which is named pan-drug-resistant (PDR) infection if it is resistant to all antimicrobial agents. This type of drug resistance causes many problems in society and faces the health system with difficulties; therefore their treatment is crucial and encourages doctors to develop new drugs to treat them. PDR Gram-negative bacteria, including Pseudomonas aeruginosa, Acinetobacter baumannii, Klebsiella pneumoniae, and Escherichia coli are among the most significant resistant bacteria to many antimicrobial agents, and only a limited range of antibiotics, especially synergistically are effective on them. For the therapy of PDR A. baumannii, tigecycline in combination with colestimethate, imipenem, amikacin, and ampicillin-sulbactam are the most effective treatments. The utilization of β-lactamase inhibitors such as ceftolozane-tazobactam, ceftazidime-avibactam, or imipenem-cilastatin-relebactam has the most efficacy against PDR P. aeruginosa. The PDR K. pneumoniae has been treated in the last decades with tigecycline and colistin, but currently, nitrofurantoin, fosfomycin, and pivmecillinam seem to be the most effective agent for the therapy of PDR E. coli. While these drugs impressively struggle with PDR pathogens, due to the daily increase in antibiotic resistance in microorganisms worldwide, there is still an urgent need for the expansion of novel medicines and methods of combating resistance. 

Antibiotic therapy for pan-drug-resistant infections

The emergence of carbapenem-resistant Klebsiella pneumoniae (CRKP) co-carrying multiple carbapenemases is complicating clinical treatment. This study aimed to investigate the global dissemination trends of CRKP strains that co-carry multiple carbapenemases. The CRKP isolate KP424 co-carrying blaNDM-1 and blaKPC-2, recovered from a stool specimen, was identified by the NG-Test Carba 5 test, and the genome sequence was further determined by using Nanopore MinION and Illumina NovaSeq 6000 technologies. The genome sequences of the CRKP strains carrying multiple carbapenemase genes were further retrieved from the NCBI GenBank database. Thirteen antimicrobial resistance genes, including blaNDM-1 and blaKPC-2, have been identified in KP424, with blaNDM-1 and blaKPC-2 located on different plasmids. In total, 832 genome sequences of CRKP strains co-carrying two carbapenemase genes were retrieved from the NCBI database. Strains carrying both blaNDM and blaOXA-48-like accounted for 665 (79.9 %) of the total strains, ranking first, and those carrying both blaKPC and blaNDM accounted for 103 (12.4 %), ranking second. The prevalence of CRKP strains co-carrying two carbapenemase genes increased significantly over time, from 0.40 % in 2010 to 9.67 % in 2021. The proportion of strains carrying both blaKPC and blaNDM has also increased, from 0.00 % in 2010 to 4.40 % in 2021. The strains carrying both blaKPC and blaNDM had the highest prevalence (66.7 %, 52/78) in China, while those carrying both blaNDM and blaOXA-48-like had the highest prevalence worldwide. Multiple-carbapenemase producers pose a great threat to public health; further research on the mechanisms underlying multiple carbapenemase gene occurrence is required to prevent their global dissemination.

Global emergence of carbapenem-resistant Klebsiella pneumoniae co-carrying multiple carbapenemases

One of the biggest threats we face globally is the emergence of antimicrobial-resistant (AMR) bacteria, which runs in parallel with the lack in the development of new antimicrobials. Among these AMR bacteria pathogens belonging to the ESKAPE group can be highlighted (Enterococcus spp., Staphylococcus aureus, Klebsiella pneumoniae, Acinetobacter baumannii, Pseudomonas aeruginosa and Enterobacter spp.) due to their profile of drug resistance and virulence. Therefore, innovative lines of treatment must be developed for these bacteria. In this review, we summarize the different strategies for the treatment and study of molecular mechanisms of AMR in the ESKAPE pathogens based on the clustered regularly interspaced short palindromic repeats (CRISPR) and CRISPR-associated (Cas) proteins' technologies: loss of plasmid or cellular viability, random mutation or gene deletion as well directed mutations that lead to a gene's loss of function.

/pdf/crispr-cas-a-revolution-in-the-treatment-and-study-of-eskape-3io0ewgz1x.pdf

CRISPR-Cas, a Revolution in the Treatment and Study of ESKAPE Infections: Pre-Clinical Studies.

Purpose Pandrug-resistant K. pneumoniae is still rare in China, and the lack of studies limits our understanding of the emergence mechanism of pandrug-resistant K. pneumoniae. Here, we report the rapid emergence of a pandrug-resistant K. pneumoniae ST11 strain in an inpatient after treatment with multiple broad-spectrum antibiotics in China. Patients and methods K. pneumoniae strain KP65 was isolated from a 55-year-old male patient hospitalized in the Department of Intensive Care Unit (ICU) of a teaching hospital in China. Antimicrobial susceptibility testing was conducted according to the guidelines of the Clinical and Laboratory Standards Institute (CLSI). The complete genome sequence of the strain was determined using the Illumina NovaSeq 6000 platform and long-read MinION sequencer. Genomic features and resistance mechanisms of the strain were comprehensively analysed using various bioinformatics approaches. Results K. pneumoniae strain KP65 was found to be resistant to all antibiotics tested, including beta-lactams, aminoglycosides, quinolones, tigecycline and colistin. Seven resistance genes were identified in the genome. The carbapenem-resistant gene bla KPC-2 and extended-spectrum β-lactamase (ESBL)-producing gene bla CTX-M-65 are located on the IncFII-type plasmid pKPC-2-KP65. No mcr genes were detected in the genome, but an IS5 insertion element was found at position 117 of the mgrB gene. Regarding the rpsJ gene, single-base substitution, G169C, leading to the amino acid substitution V57L was also identified. According to in silico MLST analysis, K. pneumoniae KP65 belongs to sequence type ST11. The closest relative of K. pneumoniae KP65 is another ST11 K. pneumoniae strain, which was isolated from a bloodstream infection in Hangzhou, differing by only 53 cgMLST loci. Conclusion Under the selective pressure of antibiotics, the KPC-2-producing K. pneumoniae ST11 strain can easily evolve pandrug resistance through chromosomal mutations. More attention is required to monitor the prevalence of the KPC-2-producing K. pneumoniae ST11 strain in China.

/pdf/rapid-emergence-of-a-pandrug-resistant-klebsiella-pneumoniae-3vhjua29gt.pdf

Rapid Emergence of a Pandrug-Resistant Klebsiella pneumoniae ST11 Isolate in an Inpatient in a Teaching Hospital in China After Treatment with Multiple Broad-Spectrum Antibiotics.

Objectives The resistance rate of Klebsiella pneumoniae to commonly used antibiotics has been increasing rapidly, causing serious concern among clinicians and microbiologists. Resistance to carbapenems in K. pneumoniae is increasing dramatically in Chinese hospitals. Here we report the genome sequence of an NDM-1 and KPC-2 co-producing K. pneumoniae (CRKP380) isolated from a bloodstream infection in Hangzhou, China. Methods The whole genome sequence of strain CRKP380 was determined using an Illumina NovaSeq 6000 platform. Antimicrobial resistance genes (ARGs) were identified using the BacWGSTdb server. The phylogenetic relationship between strain CRKP380 and other K. pneumoniae strains isolated from Hangzhou currently deposited in the NCBI GenBank database was analysed using a core genome-based single nucleotide polymorphism strategy. Results Klebsiella pneumoniae CRKP380 was resistant to all antibiotics tested except tigecycline and colistin. The genome sequence of K. pneumoniae CRKP380 consisted of 75 contigs comprising 5 590 460 bp. According to the Pasteur multilocus sequence typing (MLST) scheme, CRKP380 belongs to ST11. Eight ARGs were identified in CRKP380, including two carbapenemase genes (blaKPC-2 and blaNDM-1). Ten phylogenetically-related K. pneumoniae strains from Hangzhou were identified with identical ARGs and the same capsular serotype KL105, but none of these strains carried the blaNDM gene. Conclusion Here we report the genome sequence of a K. pneumoniae ST11 clinical strain co-carrying blaNDM-1 and blaKPC-2 from Hangzhou, China. The genome sequence of CRKP380 can be used as a reference sequence for future comparative genomic analysis, including the acquisition and mobilisation of carbapenem resistance genes.

Unravelling the genome sequence of NDM-1 and KPC-2 co-producing Klebsiella pneumoniae ST11 isolated from a bloodstream infection.

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Rapid Emergence of a Pandrug-Resistant Klebsiella pneumoniae ST11 Isolate in an Inpatient in a Teaching Hospital in China After Treatment with Multiple Broad-Spectrum Antibiotics.

Unravelling the genome sequence of NDM-1 and KPC-2 co-producing Klebsiella pneumoniae ST11 isolated from a bloodstream infection.