Molecular epidemiology of carbapenem-resistant hypervirulentKlebsiella pneumoniae: Risk factors and resistance mechanism of ceftazidime/avibactam in China

Molecular epidemiology of carbapenem-resistant hypervirulent Klebsiella pneumoniae: Risk factors and resistance mechanism of ceftazidime/avibactam in China | bioRxiv /* */ /* */ <!-- <!-- /*! * yepnope1.5.4 * (c) WTFPL, GPLv2 */ (function(a,b,c){function d(a){return"[object Function]"==o.call(a)}function e(a){return"string"==typeof a}function f(){}function g(a){return!a||"loaded"==a||"complete"==a||"uninitialized"==a}function h(){var a=p.shift();q=1,a?a.t?m(function(){("c"==a.t?B.injectCss:B.injectJs)(a.s,0,a.a,a.x,a.e,1)},0):(a(),h()):q=0}function i(a,c,d,e,f,i,j){function k(b){if(!o&&g(l.readyState)&&(u.r=o=1,!q&&h(),l.onload=l.onreadystatechange=null,b)){"img"!=a&&m(function(){t.removeChild(l)},50);for(var d in y[c])y[c].hasOwnProperty(d)&&y[c][d].onload()}}var 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Jiatong Hao , Na Jia , Baoliang Li , Chunmei Lei , Teng Wang , Shuting Liu , Caiqing Li , Bu Wang , Wei Zhang doi: https://doi.org/10.1101/2024.11.27.625653 Na Wang 1 Microbiology Department, The First Affiliated Hospital of Hebei North University , No. 12, Changqing Road, Zhangjiakou, 075000, Hebei Province, People’s Republic of China 2 Infection Management Department, The First Affiliated Hospital of Hebei North University , No. 12, Changqing Road, Zhangjiakou, 075000, Hebei Province, People’s Republic of China Find this author on Google Scholar Find this author on PubMed Search for this author on this site ORCID record for Na Wang Minghua Zhan 3 Clinical Laboratory, The First Affiliated Hospital of Hebei North University , No. 12, Changqing Road, Zhangjiakou, 075000, Hebei Province, People’s Republic of China Find this author on Google Scholar Find this author on PubMed Search for this author on this site Lexiu Deng 4 Respiratory Department, The First Affiliated Hospital of Hebei North University , No. 12, Changqing Road, Zhangjiakou, 075000, Hebei Province, People’s Republic of China Find this author on Google Scholar Find this author on PubMed Search for this author on this site Huiying Li 5 Obstetrics and Gynecology Department, The First Affiliated Hospital of Hebei North University , No. 12, Changqing Road, Zhangjiakou, 075000, Hebei Province, People’s Republic of China Find this author on Google Scholar Find this author on PubMed Search for this author on this site Xiaocui Peng 4 Respiratory Department, The First Affiliated Hospital of Hebei North University , No. 12, Changqing Road, Zhangjiakou, 075000, Hebei Province, People’s Republic of China Find this author on Google Scholar Find this author on PubMed Search for this author on this site Jianliang Chang 4 Respiratory Department, The First Affiliated Hospital of Hebei North University , No. 12, Changqing Road, Zhangjiakou, 075000, Hebei Province, People’s Republic of China Find this author on Google Scholar Find this author on PubMed Search for this author on this site Jiatong Hao 4 Respiratory Department, The First Affiliated Hospital of Hebei North University , No. 12, Changqing Road, Zhangjiakou, 075000, Hebei Province, People’s Republic of China Find this author on Google Scholar Find this author on PubMed Search for this author on this site Na Jia 6 Clinical Laboratory, Tianjin Nankai Tianyun Hospital , NO. 38, Weijin South Road, Nankai District, Tianjin, 300100, People’s Republic of China Find this author on Google Scholar Find this author on PubMed Search for this author on this site Baoliang Li 1 Microbiology Department, The First Affiliated Hospital of Hebei North University , No. 12, Changqing Road, Zhangjiakou, 075000, Hebei Province, People’s Republic of China 2 Infection Management Department, The First Affiliated Hospital of Hebei North University , No. 12, Changqing Road, Zhangjiakou, 075000, Hebei Province, People’s Republic of China Find this author on Google Scholar Find this author on PubMed Search for this author on this site Chunmei Lei 1 Microbiology Department, The First Affiliated Hospital of Hebei North University , No. 12, Changqing Road, Zhangjiakou, 075000, Hebei Province, People’s Republic of China Find this author on Google Scholar Find this author on PubMed Search for this author on this site Teng Wang 7 Otolaryngology Head and Neck Surgery, Zhangjiakou First Hospital , No. 52, Xibagang Road, Zhangjiakou City, 075000, Hebei Province, People’s Republic of China Find this author on Google Scholar Find this author on PubMed Search for this author on this site Shuting Liu 8 Hemodialysis Department, The First Affiliated Hospital of Hebei North University , No. 12, Changqing Road, Zhangjiakou, 075000, Hebei Province, People’s Republic of China Find this author on Google Scholar Find this author on PubMed Search for this author on this site Caiqing Li 1 Microbiology Department, The First Affiliated Hospital of Hebei North University , No. 12, Changqing Road, Zhangjiakou, 075000, Hebei Province, People’s Republic of China Find this author on Google Scholar Find this author on PubMed Search for this author on this site Bu Wang 4 Respiratory Department, The First Affiliated Hospital of Hebei North University , No. 12, Changqing Road, Zhangjiakou, 075000, Hebei Province, People’s Republic of China Find this author on Google Scholar Find this author on PubMed Search for this author on this site For correspondence: 15369318318{at}163.com 289974726{at}qq.com Wei Zhang 9 Central Laboratory, The First Affiliated Hospital of Hebei North University , No. 12, Changqing Road, Zhangjiakou, 075000, Hebei Province, People’s Republic of China Find this author on Google Scholar Find this author on PubMed Search for this author on this site For correspondence: 15369318318{at}163.com 289974726{at}qq.com Abstract Full Text Info/History Metrics Preview PDF Abstract The high morbidity and mortality rates associated with carbapenem-resistant hypervirulent Klebsiella pneumoniae have become a global public health problem. We analyzed the whole genome sequence and epidemiological data of 81 carbapenem-resistant Klebsiella pneumoniae strains and conducted sensitivity experiments to explore the optimal concentration of carbapenem-resistant Klebsiella pneumoniae . We verified the resistance and virulence genes of carbapenem-resistant Klebsiella pneumoniae using polymerase chain reaction and compared virulence between carbapenem-resistant hypervirulent Klebsiella pneumoniae a ndcarbapenem-resistant-non-hypervirulent Klebsiella pneumoniae through Galleria mellonella assays.The prevalent types of multilocus sequence typing in our carbapenem-resistant Klebsiella pneumoniae strains were ST11 (69.14%, 56/81). ST11-K64-O1/O2v1 has become an epidemic type in our hospital, with drug-resistance genes dominated by bla KPC-2 (90.12%, 73/81). Ceftazidime/avibactam has better antibacterial effects on carbapenem-resistant Klebsiella pneumoniae , and its resistance is mainly mediated by a resistance plasmid containing the bla KPC-2 gene. 52 carbapenem-resistant hypervirulent Klebsiella pneumoniae strains carry the bla KPC-2 , with a high detection rate of siderophore. Further research has shown that the genetic environment of the bla KPC-2 contains TnpR_Tn3 and ISKpn27 upstream and ISKpn6 insertion sequences downstream. Galleria mellonella revealed that the survival rate of carbapenem-resistant hypervirulent Klebsiella pneumoniae was lower than that of carbapenem-resistant-non-hypervirulent Klebsiella pneumoniae , and the survival rate of carbapenem-resistant hypervirulent Klebsiella pneumoniae -K64 was lower than that of carbapenem-resistant hypervirulent Klebsiella pneumoniae -K47.The spread of carbapenem-resistant hypervirulent Klebsiella pneumoniae strains is alarming, necessitating molecular monitoring of hypervirulent strains and strengthening the nosocomial infection prevention and control measures. Antibiotics should be used reasonably based on patients’ infection status and local epidemiological data. Importance Carbapenem-resistant Klebsiella pneumonia is a global public health concern. We conducted a molecular epidemiological analysis of 81 carbapenem-resistant hypervirulent Klebsiella pneumoniae strains from our hospital and explored the resistance mechanism of ceftazidime/avibactam. We identified the bla KPC-2 gene to be primarily responsible for carbapenem resistance in our hospital, and ST11-K64 was the dominant clone. A high-risk clone, ST307-K102, was detected, necessitating strengthened surveillance to prevent its spread. This study’s findings contribute to the optimization of antimicrobial management and indicate that genomic research can assist with the tracking of hospital infection outbreaks and the improvement of infection-control measures. Introduction Carbapenem-resistant Klebsiella pneumoniae (CRKP) has become a major global public health threat, and the prevalence of carbapenem-resistant hypervirulent Klebsiella pneumoniae (CR-hvKP) has sharply increased in China, leading to high morbidity and mortality rates due to the lack of effective treatment options ( 1 , 2 ). Klebsiella pneumoniae Carbapenemase (KPC) belongs to class A serine carbapenemases and is the main mechanism of resistance in Enterobacteriaceae. The proportion of bla KPC-2 producing CRKP in China exceeds 70%( 2 ). In China, ST11 CRKP has become the major clonal type ( 3 ), whereas in the United States and Europe, ST258/512 is predominant( 4 ). Owing to ceftazidime/avibactam having good in vitro sensitivity and safety against serine carbapenemases, it has become the last line of defense against CRKP infections. However, CRKP can generate bla KPC mutations via various mechanisms, causing resistance to ceftazidime/avibactam( 5 , 6 ). Research has found that the diversity of the CRKP genome is mainly due to horizontal transfer, including plasmids, phages, integration, and binding elements. The spread of bla KPC-2 is typically mediated by two mobile elements, Tn4401 and NTEKPC ( 7 ). Globally, CR-hvKP is increasingly reported, and its emergence is devastating as CR-hvKP possesses high resistance, virulence, and transmissibility. Most clinical cases occur in Asia, particularly in China, where studies have shown that the prevalence of CR-hvKP has increased from 28.2% in 2016 to 45.7% in 2020 ( 3 ), causing serious nosocomial infection in the intensive care unit ward ( 8 ). CR-hvKP virulence factors include capsules, siderophores, virulence plasmids, and other virulence genes, which help differentiate hypervirulent strains ( 9 ). Various complex mechanisms have led to the rapid spread of strains in the clinic ( 9 ). Previous studies have mainly focused on resistant or virulent strains of hvKP, with little attention paid to the correlations among virulence genes, resistance genes, and antimicrobial susceptibility of CR-hvKP. Therefore, this study aimed to summarize the molecular epidemiological characteristics of CR-hvKP isolated from this region and discuss the evolution of virulence and resistance genes in CR-hvKP and their relationship with clinical phenotypes. Materials and methods 1. Isolate and antimicrobial susceptibility testing In this study, 81 non-duplicate CRKP strains were collected from the First Affiliated Hospital of Hebei North University between 2020 and 2021 for analysis. The PubMLST database was downloaded for comparative analysis of Klebsiella pneumoniae containing bla KPC-2 and/or bla NDM-1 in November 2024 ( https://bigsdb.pasteur.fr/klebsiella/ ). This study employed the microbroth dilution method recommended by the Clinical and Laboratory Standards Institute to perform in vitro antimicrobial susceptibility testing of 81 CRKP strains. Sensitivity, intermediate resistance, and resistance were determined according to the Clinical and Laboratory Standards Institute-M100 ED33 guidelines. A minimum inhibitory concentration (MIC) of ≥4 mg/L for imipenem or meropenem against KP was defined as CRKP. 2. Polymerase chain reaction Polymerase chain reaction experiments were conducted on the 81 collected CRKP strains using the following reaction system: The total reaction volume was 25 μL, which included 12.5, 8.5, 1, 1, and 2 μL of 2x Taq Plus Master Mix II (Dye Plus), deionized water, forward primer, reverse primer, and template DNA, respectively. The reaction program was set as follows: initial denaturation at 95°C for 3 min, denaturation at 95°C for 15 s, annealing at 60°C for 20 s, and extension at 72 ° C for 60 s, with a total of 30 cycles. After the reaction, agarose gel electrophoresis was performed to record the experimental results. 3. Whole genome sequencing and annotation Genomic DNA was extracted using the sodium dodecyl sulfate method, and the harvested DNA was analyzed through agarose gel electrophoresis. Quantitative analysis of the DNA was performed using a Qubit® 2.0 fluorometer (Thermo Scientific). Sequencing libraries were prepared using the NEBNext Ultra DNA Library Prep Kit (Illumina, USA), and index codes were added to classify the sequences for each sample. Whole-genome sequencing was performed on an Illumina NovaSeq PE150 platform using a 2 × 150 bp paired-end strategy. The genome was annotated using Prokka V1.14.6, and resistance, virulence genes, and plasmid replicons were predicted using Abricate V1.0.1. Capsular serotypes were predicted using PathogenWatch ( https://pathogen.watch ). Multilocus sequence typing (MLST) of all strains was conducted using the Pasteur database ( https://bigsdb.pasteur.fr/klebsiella/ ), and newly identified sequence typing (ST) was submitted to the MLST database administrator for approval and were assigned ST numbers. A minimum spanning tree based on the allelic difference between isolates of the seven housekeeping genes was constructed using PHYLOViZ ( 10 ). 4. Phylogenetic analysis Single nucleotide polymorphisms were extracted using Snippy v4.6.0 ( https://github.com/tseemann/snippy ) to generate a core genome alignment. This core genome alignment was employed to construct a maximum likelihood phylogenetic tree using FastTree V2.1.11-2, with KP subsp. pneumoniae HS11286 (GCA_000240185.2) as the reference genome. The resulting phylogenetic tree was visualized using iTOL ( https://itol.embl.de/ ) ( 11 ). 5. Galleria mellonella killing assay Bacterial suspensions were prepared at concentrations of 10⁴ cfu/mL, 10⁵ cfu/mL, and 10⁶ cfu/mL, and 10 microliters of each were injected into the larvae of the greater wax moth. The control group was injected with an equal volume of phosphate-buffered saline. This procedure was used to establish an infection model for the larvae. To ensure consistency in the infection model, the injection was made approximately 5 mm deep into the second-to-last right legs of the larvae, and the entire volume of the bacterial suspension was injected simultaneously. The infection models were incubated at 37°C, and the number of dead larvae was recorded every 2 h over an observation period of 48 h. Subsequently, the mortality rate of the larvae was calculated. 6. Antibiotic-resistant plasmids and mobile genetic elements containing bla KPC-2 gene The assembled contigs of six CR-hvKP strains resistant to cefotaxime/avibactam were input into the VRprofile2 pipeline ( https://tool2-mml.sjtu.edu.cn/VRprofile/home.php ) [12] to divide the contigs into chromosome or plasmid fragments and identify whether they carry resistance genes. To further identify plasmids carrying resistance genes, we compared these contigs with the NCBI database ( https://www.ncbi.nlm.nih.gov/ ) using blstn to search for reference sequences. For the plasmid resistant to cefotaxime/avibactam, we used pC76 KPC (NZ_CP080299.1) with a coverage of 93.82% and an identity of 99.37% as a reference sequence to study the structure of the plasmid. MAUVE ( 12 ) was used to identify all contigs located in drug-resistant plasmids by comparing the contigs of the strain with the reference plasmid pC76 KPC (NZ_CP080299.1). Plasmid maps were presented using BRIG ( 13 ).To determine whether contigs carrying the bla KPC-2 gene all contain insertion and repeat sequences, we submitted them to Isfinder ( 14 )( https://www-is.biotoul.fr/index.php ). Easyfig ( 15 ) is used to visualize the structure of the bla KPC-2 gene. Statistical methods In this study, the chi-square test was used to compare differences between the CR-hvKP and CR-non-hvKP groups. The Log-rank (Mantel-Cox) test was used to analyze survival differences between the two groups. The Wilcoxon rank-sum and Kruskal–Wallis tests were used to analyze drug susceptibility differences among the three groups. Statistical significance was set at p-value <0.05. Visualization was performed using Xiantao Academic ( https://www.xiantaozi.com/ ). Spearman’s correlation analysis was conducted to explore the relationships between plasmids and virulence genes, plasmids and resistance genes, resistance genes and clinical data, and virulence genes and clinical data. Heatmap visualization was performed using the Microbiome Cloud Platform ( https://www.bioincloud.tech/task-meta ). Statistical analyses were performed using IBM SPSS Statistics for Windows, version 27.0 (IBM Corp., Armonk, N.Y., USA), and graphing was performed using Origin 2021 (OriginLab Co. MA, USA) and GraphPad Prism 8 (GraphPad Software, LaJolla, CA, USA). Results 1. Molecular epidemiology CRKP has become popular worldwide, with China, the United States, and Brazil being the majority ( Figure 2A ). In China, CRKP is most common in Beijing, followed by Shanghai and Hunan ( Figure 2B ). The MLST of CRKP in our hospital is mainly ST11, followed by ST15, which is consistent with the popular trend in China ( Figure 3 ). Our hospital has detected 12 types of ST, among which ST11 (69.14%) and ST15 (11.11%) are the main prevalent types. Capsular (K) antigen serotyping revealed 16 different types, with K64 being the most common (60.49%, 49/81). Lipopolysaccharide (O) antigen serotyping showed that the most common serotypes were O1/O2v1 (66.67%, 54/81). Overall, 81 CRKP strains were primarily isolated from sputum samples (65.43%, 53/81), followed by urine (16.05%, 13/81) and secretion (4.94%, 4/81) samples. Phylogenetic analysis revealed that evolutionary relationships were associated with ST classification and independent of specimen type. Strains of the same ST clustered mostly on the same evolutionary branch, whereas ST11 and ST15 clustered on different branches. The main clusters were ST11-K64-O1/O2v1, ST11-K47-OL101, and ST15-K19-O1/O2v2. The ST11 strains were distinctly categorized into the following three branches: ST11-K64-O1/O2v1, ST11-K47-OL101, and ST11-K25-other O serotypes, suggesting that ST11 strains with various serotypes evolved in different directions ( Figures 4 and 5 ). Download figure Open in new tab Figure 1. Design and experimental flowchart of this study. Download figure Open in new tab Figure 2. Global and Chinese distribution of CRKP infection by country. A. Global distribution of CRKP infection. B. Chinese distribution of CRKP infection. CRKP, carbapenem-resistant Klebsiella pneumonia Download figure Open in new tab Figure 3. ST-type minimum-spanning tree. A.Genetic relationship of carbapenem-resistant klebsiella pneumoniae isolates of China. B. Genetic relationship of carbapenem-resistant Klebsiella pneumonia isolates of this study;C. Genetic relationship between MLST and K-type of carbapenem-resistant Klebsiella pneumonia isolates of this study. The size of the dots is proportional to the number of strains. Numbers on the connecting line represent genetic distance. ST, sequence typing Download figure Open in new tab Figure 4. Evolutionary relationship diagram of 81 CRKP strains CRKP: carbapenem-resistant Klebsiella pneumonia Download figure Open in new tab Figure 5. Overall distribution of 81 CRKP strains A. ST distribution; B. K-type distribution; C. O-type distribution; D. Sample distribution CRKP: carbapenem-resistant Klebsiella pneumonia; ST, sequence typing 2. Multivariate logistic regression analysis of independent risk factors for CR-hvKP infection For the convenience of analysis, we categorized 81 CRKP strains into the following two groups: the high virulence (rmpA, rmpA2, iucA, iroB, and peg-344) ( 16 ) and low virulence groups. We collected clinical data from 81 patients with CRKP, including patient Basic Data, Department, Underlying diseases, Infection type, Invasive procedures and devices, Antimicrobial exposure, and Outcomes. After analysis, significant differences (p<0.05) were found between the two groups of patients regarding Antimicrobial usage time, Pulmonary disease, Malignant tumors, and Carbapenem antimicrobial exposure and Outcomes. Logistic multiple regression analysis was conducted on the items with significant differences mentioned above, and it was found that Antibiotic usage time, Carbapenem antibiotic exposure, and Malignant tumors were independent risk factors for CR-hvKP infection ( Tables 1 and 2 ). View this table: View inline View popup Table 1 Clinical characteristics of CR-hvKP and CR-non-hvKP View this table: View inline View popup Download powerpoint Table 2 Multivariate logistic regression analysis of independent risk factors for CR-hvKP infection 3. Antimicrobial susceptibility tests We conducted a new antibiotics combination β-lactam/β-lactase inhibitor, tigecycline and polymyxin susceptibility test on 81 CRKP strains, including Aztreonam/Avibactam, Ceftaroline/Avibactam, Ceftazidim/Avibactam, Imipenem/Avibactam, Meropenem/Avibactam, and Etapenem/Avibatanm, and classified them into high (4 μg/mL) and low (8 μg/mL) concentration inhibitor groups. Except for Ceftaroline, significant differences (p<0.05) were found in the drug sensitivity results of the other five antibiotics after adding low-concentration avibactam inhibitors. The MIC values of Ceftazidim/Avibactam, Meropenem/Avibactam, and Etapenem/Avibatan increased as the inhibitor concentration rose (p<0.05). However, no significant change was observed in MIC values after adding high-concentration inhibitors, including Aztreonam/Avibactam and Imipenem/Avibactam ( Figure 6 ). The resistance rate of polymyxin (79.01%) was lower than that of tigecycline (96.30%), and the resistance rate and MIC range values of the CR-hvKP group were generally higher than those of the CR-non-hvKP group ( Tables 3 and 4 ). Download figure Open in new tab Figure 6. Comparison of MIC values of CRKP strains against novel antibiotics β-lactam/β-lactase inhibitors A.MIC values of Aztreonam, Aztreonam/Avibactam-4, and Aztreonam/Avibactam-8; B. MIC values of Ceftazidim, Ceftazidim/Avibactam-4, and Ceftazidim/Avibactam-8; C. MIC values of Ceftaroline, Ceftaroline/Avibactam-4, and Ceftaroline/Avibactam-8; D. MIC values of Imipenem, Imipenem/Avibactam-4, and Imipenem/Avibactam-8; E. MIC values of Mero penem, Meropenem/Avibactam-4, and Meropenem/Avibactam-8; F. MIC values of Etapene m, Etapenem/Avibatan-4, and Etapenem/Avibatan-8. “*” represents the size of P value, ns represents p≥0.05, *represents p<0.05, **represents p<0.01, and ***represents P<0.001. CRKP: carbapenem-resistant Klebsiella pneumonia ; MIC: minimum inhibitory concentration; ST, sequence typing;Azt, Aztreonam;Ceftazi, Ceftazidime;Ceftaro, Ceftaroline;Imi, Imipenem;Mero, Meropenem;Eta, Ertapenem;Avi, Avibactam View this table: View inline View popup Table 3. Drug susceptibility characteristics of novel enzyme inhibitor antibiotics View this table: View inline View popup Table 4. Resistance rates of CR-hvKP and CR-non-hvKP 4. Antimicrobial resistance genes, virulence genes, and plasmids of CR-hvKP All 52 CR-hvKP strains carried the carbapenemase gene bla KPC-2 . Carbapenem resistance genes included bla KPC-2 and bla OXA-1 . Chloramphenicol resistance genes were found only in the ST11-K47-OL101 strain. The bla CTX-M-15 gene was detected only in ST307-K102-O1/O2v2, while SHV-182 was found in both ST307-K102-O1/O2v2 and ST1-K64-O1/O2v1. All strains carry bla KPC-2 , ompk35, and ompk36 genes ( Figure 7 and Figure 8A ). Carbapenem resistance genes bla OXA-1 and bla CTX-M-15 were strongly correlated with IncFII_1_pKP91, while tetracycline resistance genes were strongly associated with IncFII(pCRY) ( Figure 9B ). The resistance genes of macrolides antibiotics were positively correlated with CRP ( Figure 9D ). Download figure Open in new tab Figure 7. Evolutionary relationship diagram of 52 CR-hvKP strains. CR-hvKP: carbapenem-resistant hypervirulent Klebsiella pneumoniae Download figure Open in new tab Figure 8. The characteristic distribution of resistance and virulence genes. A. Distribution of resistance genes; B. Distribution of virulence genes. Download figure Open in new tab Figure 9. Correlations among virulence genes, resistance genes, plasmid replicons, and clinical data of CR-hvKP strain. A. Spearman correlation between virulence genes and plasmid replicon. B. Spearman correlation between resistance genes and plasmid replicon. C. Spearman correlation between virulence genes and clinical data. D. Spearman correlation between resistance genes and clinical data. “*” represents the size of the P value, ns represents p≥0.05, *represents p<0.05, **represents p<0.01, and ***represents p<0.001. CR-hvKP: carbapenem-resistant hypervirulent Klebsiella pneumoniae Virulence gene analysis revealed that 28 CR-hvKP strains carried all tested virulence genes. The lowest detection rates were observed for iroB (61.54%) ( Figure 8B ). Siderophore virulence genes showed high carrying rates in all strains. Salmonella was detected in 61.54% of the strains, which was lower than that for aerobactin (92.31%), yersiniabactin (98.08%), and enterobactericin (100%). The yersiniabactin gene was not detected in ST307-K102-O1/O2v2. No strains tested positive for peg-344 (metabolite transporter) virulence genes. Among the 52 CR-hvKP strains, 10 plasmid replicon types were identified ( Figure 7 ). Aerobactin and yersiniabactin virulence genes were strongly correlated with the IncR_1 ( Figure 9A ). The virulence genes of Salmochelin were positively correlated with CRP ( Figure 9C ). The experiment on the Galleria mellonella showed that the survival rate of CR-non-hvKP was higher than that of CR-hvKP. The survival rate of CR-hvKP-47 was higher than that of CR-hvKP-64, indicating that the virulence of CR-hvKP-64 was higher than that of CR-hvKP-47 ( Figure 10 ). Download figure Open in new tab Figure 10. The Galleria mellonella infection model. A. Survival rates of Galleria mellonella infected (1:10) with CR-hvKP and CR-non-hvKP; B. Survival rates of Galleria mellonella infected (1:100) with CR-hvKP and CR-non-hvK P; C. Survival rates of Galleria mellonella infected (1:10) with CR-hvKP-K47 and CR-h vKP-K64; D. Survival rates of Galleria mellonella infected (1:100) with CR-hvKP-K47 and CR-hvKP-K64 5. Antibiotic resistance plasmids and mobile genetic elements Blast analysis showed that these drug-resistant plasmids were highly similar to the reference plasmid pC76 KPC (NZ_CP080299.1) with 99.37% identity and 93.25% coverage. The plasmid does not contain the fusion plasmid of virulence, non-drug resistance and virulence genes. pKpn30, pKpn45, and pKpn46 were similar in structure and belonged to the plasmid replicons of IncFIB(AP001918)_1, IncFIC(FII)_1, and IncFII(pHN7A8)_1. The structures of pKpn32, pKpn38, and pKpn70 were similar, belonging to repB_KLEB_VIR, IncHI1B(pNDM-MAR)_1, and IncFII(pHN7A8)_1 plasmid replicons. After analysis, the bla KPC-2 genes of the six CR-hvKP strains were all located on plasmids and carried bla TEM-1B , bla SHV-12, and rmtB_1 resistance genes. Various transposons and insertion sequences around the resistance genes predicted the possibility of horizontal transfer of the resistance genes. Further study of the genetic environment of bal KPC-2 genes revealed that the upstream and downstream of the bal KPC-2 gene integrated TnpR_Tn3, ISKpn27, and ISKpn6. ISKpn27 contained IRL and IRR, while ISKpn6 only had IRR ( Figures 11 and 12 ). Download figure Open in new tab Figure 11. Comparative genomic analysis of antibiotic-resistant plasmids in CR-hvKP strains. From the inner circle to the outer circle, use this as follows: circle 1, GC Content; circle 2, GC Skew; circle 3, reference plasmid pC76 KPC(NZ_CP080299.1); circle 4, pKpn30; circle 5, pKpn45; circle 6, pKpn46; circle 7, pKpn32; circle 8, pKpn38; circle 9, pKpn 70; and circle 10, Annotated mobile genetic elements and carbapenem resistance genes. CR-hvKP: carbapenem-resistant hypervirulent Klebsiella pneumoniae Download figure Open in new tab Figure 12. Linear alignment of gene environment in bla KPC-2 . Discussion Recently, the prevalence of CR-hvKP has been on the rise globally ( 17 ). According to the China Antimicrobial Surveillance Network, the resistance rate of KP to carbapenems has increased approximately ninefold, from 2.95% in 2005 to 25.4% in 2023, making it the second most commonly detected bacterium after Escherichia coli ( https://www.chinet.gov/Data/GermYear ). Similarly, data from the European Center for Disease Prevention and Control show an increase in carbapenem resistance in KP from 7.1% in 2017 to 11.7% in 2021 ( https://www.ecdc.europa.eu/en ). The high pathogenicity and resistance of CR-hvKP frequently lead to poor clinical outcomes, posing significant challenges for infection control in healthcare settings owing to its rapid spread and outbreaks. Studies have demonstrated that underlying chronic comorbidities, diabetes, age <65 years, and mechanical ventilation are risk factors for CR-hvKP infections ( 18 , 19 ). In our hospital, the predominant MLST is ST11, consistent with the findings of previous studies by Cao et al. ( 5 ). In contrast, ST258 is the major circulating type in Europe and the United States ( 20 , 21 ). Recent research from Turkey has identified ST101 as the most common type among CRKP infection strains ( 22 ), while a study on mother-child cohorts in Madagascar found that ST23 and ST25 are associated with high virulence ( 23 ). In Argentina, high-mucoviscosity CRKP strains were primarily isolated from respiratory and urinary samples (34.2%), with 40% of strains belonging to ST25 and all strains carrying the bla KPC-2 resistance gene ( 24 ). In Greece, bloodstream infections are the primary type of CRKP infections, and ST39 carrying bla KPC-2 is considered a high-risk clone ( 4 ). Regions such as Egypt, India, Pakistan, and Serbia are major hotspots for the spread of the Class B carbapenemase NDM ( 25 ). The Class D carbapenemase OXA-48 has lower hydrolytic activity but frequently combines with other resistance mechanisms to increase its effectiveness. The spread of bla OXA-232 ST15 KP clones has occurred globally, particularly in China, although they likely originated in the United States ( 26 ). However, the emergence of CRKP strains that produce more than one type of carbapenemase is a concern ( 27 ). In our study, one high-risk clone, ST307, contained no yersiniabactin , aerobactin , or salmochelin . Some studies have demonstrated that ST307 KP can increase the MIC value of ceftazidime/avibactam, leading to resistance ( 28 ). In some regions, ST307 has replaced the high-risk clones ST512 and ST258 ( 29 ). We should be vigilant about the emergence of ST307 KP and strengthen monitoring of this clone type promptly. It has been discovered that KP contains at least 79 K-capsule types. In China, the most common K types of CRKP are K64 (50.4%) and K47 (25.9%). The detection rate of K64 has been increasing, mainly in eastern and central China, whereas that of K47 has significantly declined and is primarily found in northern and northeastern China ( 3 ). Hu et al. indicated that capsule-deficient strains have defects in transmission and resistance to phagocytosis; however, their antibiotic resistance increases correspondingly ( 3 ). This was confirmed in previous studies, which reported that capsule-deficient strains cause untreatable persistent urinary tract infections, whereas hypercapsular strains showed enhanced resistance to phagocytosis, increased dissemination, and higher mortality rates ( 21 ). The rising prevalence of CRKP and changes in its serotypes suggest an urgent need to develop vaccines against CRKP infections. Our study found that the virulence of CR-hvKP-K64 was higher than that of K47-CR-hvKP, which is consistent with the findings of Jia et al. ( 30 ). Avibactam is a β-lactamase inhibitor that can inhibit serine protease activity but is ineffective against metalloenzyme activity. Owing to its excellent in vitro efficacy and safety against serine carbapenemases, ceftazidime/avibactam has become the first-line treatment for CRKP ( 31 ). However, the emergence of bla KPC mutations, including bla KPC-135 and bla KPC-112 , which are resistant to ceftazidime/avibactam, has been reported due to the improper use of antibiotics ( 6 , 32 ). The spread of bla KPC can be mediated through various molecular mechanisms, including small genetic elements, horizontal transfer of plasmids, and clonal transmission. In our study, Ceftaroline/Avibactam resistance is mainly mediated by the plasmid pC76 KPC (NZ_CP080299.1) carrying bla KPC-2 . This plasmid is nonclassical, and it was first included in the RefSeq microbial genomes database in the United States ( 33 ). The pKpQIL plasmid was the first identified from the ST258 strain carrying bla KPC , while the pQP048 plasmid, widely prevalent in China, carries bla KPC and is most commonly associated with the ST11 strain ( 7 ). Mobile elements play a crucial role in the transfer of bla KPC genes to different plasmids. The most common mobile element containing bla KPC is the Tn4401 transposon based on Tn3, predominantly found in the United States, while NTEXPC-I and NTEXPC-II are primarily distributed in China and Brazil ( 34 ). Further research on the genetic environment of the bla KPC-2 gene revealed that the upstream and downstream regions of bla KPC-2 genes contain insertion sequences of ISKpn27 and ISKpn6, respectively. There are incomplete reverse repeat sequences on both sides of ISKpn27, which makes the bla KPC-2 gene easy to spread. Current research has found that various bla KPC-2 subtypes are associated with distinct mobile genetic elements and located in different plasmids. Notably, a study found that a non-ribosomal tobramycin-cyclohexane conjugate could enhance the efficacy of β-lactam/β-lactamase inhibitors against carbapenem-resistant clinical isolates ( 35 ), providing a new approach to maintaining the therapeutic utility of β-lactamase antibiotics. Our study showed that the rate of resistance to polymyxins was lower than that to tigecycline. Yu et al. demonstrated that hypervirulent ST11-K64 could develop resistance through rapid and diverse mechanisms during tigecycline and polymyxin treatment ( 36 ). Additionally, the emergence of tmexCD-toprJ has significantly reduced the effectiveness of tigecycline against CRKP ( 37 ). Recently, increasing reports of polymyxin-resistant KP have highlighted a major challenge to public health owing to the emergence of colistin-resistant and hvKP ( 38 ). The limitations of this study include its single-center data, which only represents the epidemiological characteristics of CRKP in this specific region. In future research, we plan to use third-generation genome sequencing for a comprehensive analysis of whole-genome sequences and continue expanding the data collection to complete a multi-center data analysis. Conclusion In this study, we conducted a systematic molecular epidemiological analysis of CRK P. The bla KPC-2 gene was identified as the primary mechanism of carbapenem resistance in our hospital, with ST11-K64 emerging as the dominant clone. The drug-resistant plasmid pC76-KPC(NZ_CP080299.1) containing the bla KPC-2 gene mediates Ceftazidim/Avibactam resistance. This study contributes to the optimization of antimicrobial management; moreover, genomic research can aid in tracking hospital infection outbreaks and improving infection control measures. Data availability statement Data from this study can be available upon request from the author. Ethics declarations Ethics approval and consent to participate The study was approved by the Ethics Committee of the First Affiliated Hospital of Hebei North University (ethical approval No. K2019147), which waived the requirement of written informed consent from patients. All strains are part of the routine laboratory procedures of the hospital and do not involve any human genetic resources. This study was conducted in accordance with the principles outlined in the Declaration of Helsinki. Consent for publication Not applicable. Competing interests The authors report no conflicts of interest in this work. Funding This research was supported by the Hebei Provincial Department of Finance’s “Government Funded Clinical Medicine Excellent Talent Training Project” (ZF2024224), the Scientific Research Fund of Hebei Health Commission (No.20231461), and the Key R&D project of Zhangjiakou City (No.2221114D). Authors’ contributions WZ was responsible for conceptualization. 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Share Molecular epidemiology of carbapenem-resistant hypervirulent Klebsiella pneumoniae : Risk factors and resistance mechanism of ceftazidime/avibactam in China Na Wang , Minghua Zhan , Lexiu Deng , Huiying Li , Xiaocui Peng , Jianliang Chang , Jiatong Hao , Na Jia , Baoliang Li , Chunmei Lei , Teng Wang , Shuting Liu , Caiqing Li , Bu Wang , Wei Zhang bioRxiv 2024.11.27.625653; doi: https://doi.org/10.1101/2024.11.27.625653 Share This Article: Copy Citation Tools Molecular epidemiology of carbapenem-resistant hypervirulent Klebsiella pneumoniae : Risk factors and resistance mechanism of ceftazidime/avibactam in China Na Wang , Minghua Zhan , Lexiu Deng , Huiying Li , Xiaocui Peng , Jianliang Chang , Jiatong Hao , Na Jia , Baoliang Li , Chunmei Lei , Teng Wang , Shuting Liu , Caiqing Li , Bu Wang , Wei Zhang bioRxiv 2024.11.27.625653; doi: https://doi.org/10.1101/2024.11.27.625653 Citation Manager Formats BibTeX Bookends EasyBib EndNote (tagged) EndNote 8 (xml) Medlars Mendeley Papers RefWorks Tagged Ref Manager RIS Zotero Tweet Widget Facebook Like Google Plus One Subject Area Microbiology Subject Areas All Articles Animal Behavior and Cognition (7644) Biochemistry (17726) Bioengineering (13916) Bioinformatics (42033) Biophysics (21486) Cancer Biology (18635) Cell Biology (25549) Clinical Trials (138) Developmental Biology (13397) Ecology (19940) Epidemiology (2067) Evolutionary Biology (24361) Genetics (15620) Genomics (22541) Immunology (17763) Microbiology (40468) Molecular Biology (17207) Neuroscience (88739) Paleontology (667) Pathology (2842) Pharmacology and Toxicology (4834) Physiology (7659) Plant Biology (15175) Scientific Communication and Education (2047) Synthetic Biology (4304) Systems Biology (9834) Zoology (2272)