The resistance mechanisms and risk factors of carbapenem-resistant Klebsiella pneumoniae to ceftazidime-avibactam

The resistance mechanisms and risk factors of carbapenem-resistant Klebsiella pneumoniae to ceftazidime-avibactam | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Short Report The resistance mechanisms and risk factors of carbapenem-resistant Klebsiella pneumoniae to ceftazidime-avibactam Xiaqin He, Meng Liu, Xiaoqian Wang, Sijia Li, Yi Zhang, Zhe Liu, and 1 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-7507415/v1 This work is licensed under a CC BY 4.0 License Status: Under Review Version 1 posted 13 You are reading this latest preprint version Abstract Objective To investigate the molecular epidemiological characteristics of carbapenem-resistant Klebsiella pneumoniae (CRKP),elucidate the resistance mechanisms to ceftazidime-avibactam (CZA) and identify the risk factors associated with CZA resistance. Clinical and microbiological data from 293 hospitalized patients with CRKP infections were retrospectively collected at the First Affiliated Hospital of Xi'an Jiaotong University from January 2024 to March 2025. Based on CZA susceptibility results, patients were divided into the CZA-sensitive CRKP group (n = 228) and the CZA-resistant CRKP group (n = 64). The colloidal gold detection method was used to identify five carbapenemase genes( bla KPC, bla NDM, bla VIM, bla IMP, and bla OXA)and their subtypes were determined through PCR amplification and sanger sequencing. The relative expression of the bla KPC gene was measured using real-time quantitative PCR (RT-qPCR). Multivariate logistic regression analysis was performed to identify risk factors for CZA-resistant CRKP infections. Results The primary resistance mechanisms for CZA-resistant CRKP in our hospital are the production of metal enzymes, especially KPC-2 and NDM-1 co-producing strains. Some strains exhibit resistance to CZA due to blaKPC-2 mutations and increased gene expression. Multivariate logistic regression analysis revealed that renal replacement therapy ( OR = 2.611, 95% CI 1.192–5.721) and prior CZA exposure ( OR = 2.749, 95% CI 1.269 ~ 5.953) were independent risk factors for CZA-resistant CRKP infections. ceftazidime-avibactam resistance carbapenem-resistant Klebsiella pneumoniae resistance mechanisms risk factors Figures Figure 1 Figure 2 Introduction Klebsiella pneumoniae is recognized as an opportunistic pathogen that evolves into the highly concerning superbug carbapenem-resistant Klebsiella pneumoniae (CRKP) upon acquiring plasmids that harbor carbapenemase resistance genes [ 1 ] . The primary mechanisms conferring resistance in CRKP include the synthesis of carbapenemases, which encompass class A enzymes (KPC), class B enzymes (NDM, IMP), and class D enzymes (OXA-48), alongside the loss of porins OmpK35 and/or OmpK36 [ 2 ] . According to the China Antimicrobial Drug Monitoring Network (CHINET)( http://www.chinets.com/ ), the resistance rate of Klebsiella pneumoniae to meropenem has surged from 2.9% in 2005 to 23.4% in 2024. The increasing prevalence of drug-resistant phenotypes and the dissemination of mobile genetic elements contribute to a continuous rise in CRKP cases globally, significantly limiting antibiotic treatment options and posing a major challenge for clinical management and infection control [ 3 ] . Ceftazidime-avibactam (CAZ/AVI) as a novel combination of ceftazidime and the β-lactamase inhibitor, has been approved by the Food and Drug Administration (FDA) for treatment of complicated intra-abdominal and urinary tract infections [ 4 ] . It can inhibit the activity of Ambler class A, class C and class D β-lactamases, however, it is ineffective against class B metallo-β-lactamases (MBL) [ 3 , 5 ] . In recent years, CZA has demonstrated considerable efficacy in treating KPC-producing Klebsiella pneumoniae (KPC-Kp), leading to improved clinical survival outcomes. Nonetheless, the increased utilization of CZA has been paralleled by a rising incidence of CZA-resistant CRKP in various regions [ 3 , 6 ] . In 2024, CHINET reported a resistance rate of 15.8% for CRKP against CZA( http://www.chinets.com/).Patient s infected with CZA-resistant CRKP had higher 28-day and in-hospital mortality rates [ 7 ] .This emerging resistance has created new challenges for selecting effective therapies [ 8 ] . In order to facilitate the proactive monitoring of resistance to ceftazidime-avibactam and curb its dissemination, we systematically investigated the predominant resistance mechanisms, thereby establishing a theoretical framework to enhance clinical drug utilization and resistance management within our institution. Moreover, there exists a notable gap in the systematic analysis of risk factors pertinent to CZA-resistant CRKP infections. Consequently, this study amalgamates molecular biology testing and clinical epidemiological data to conduct a thorough analysis of the risk factors associated with CZA-resistant CRKP, thereby providing a scientific foundation for the early identification of high-risk patients. Methods Study design and patients We retrospectively collected clinical data from 293 hospitalized CRKP-infected patients at the First Affiliated Hospital of Xi’an Jiaotong University between January 2024 and March 2025. Inclusion criteria: (a) micro- biologically confirmed CRKP bacteremia within 48 h of admission;(b) Inclusion of CZA susceptibility testing; (c) Complete clinical data. Exclusion criteria: (a) immunocompromised individuals; (b) age < 18 years;(c) patients exhibiting multiple positive cultures for the same pathogen during the same hospital stay, with each counted only once.The study protocol was approved by the Medical Ethics Review Committee of the First Affiliated Hospital of Xi’an Jiaotong University. Clinical data collection Date extracted from the hospital's electronic medical record system included their comorbidities,invasive procedures,laboratory results,microbiological profiles,prior antibiotic exposure and outcomes.The 293 CRKP infection patients were divided into CZA-resistant CRKP group and CZA-sensitive CRKP group based on CZA susceptibility results. Strain identification and susceptibility testing Isolates were identified by matrix-assisted laser desorption-ionization time-of-flight mass spectrometry (MALDI-TOF MS) and antimicrobial susceptibility testing (AST) was performed using the VITEK-2 system (bioMérieux SA, Marcy l’Etoile, France).The minimum inhibitory concentration (MIC) of CZA was evaluated using E-test strips, with results interpreted according to Clinical and Laboratory Standards Institute(CLSI) guidelines.Polymyxins interpretation followed standards of the American Committee on Antimicrobial Susceptibility Testing [ 9 ] . Tigecycline interpretation followed the standards of the U.S. Food and Drug Administration. Quality control strains ( Escherichia coli ATCC 25922,ATCC35218 and Pseudomonas aeruginosa ATCC 27853) were included in all AST procedures to ensure methodological consistency. Carbapenemase detection (1) The detection of carbapenemase production was executed utilizing the Dynamiker CGI test (Dynamiker Biotechnology, Tianjin, China), with colloidal gold immunoassay kits employed according to the manufacturer's instructions.(2)Carbapenemase Genes type ( bla KPC, bla IMP, bla NDM, bla VIM and bla OXA-48)were detected by polymerase chain reaction (PCR) followed by Sanger sequencing (Qingke Biotechnology) and were compared with available sequences in GenBank.The primer sequences for PCR referenced from the literature [ 10 ] . Quantitative real-time PCR Ten Klebsiella pneumoniae strains were analyzed through qualitative real-time PCR (qRT-PCR) to evaluate the relative expression of bla KPC, normalized against an internal housekeeping gene, rpoB. Total RNA was isolated from bacteria utilizing TRIzol reagent (Invitrogen China Limited, Beijing, China), with RNA subsequently reverse transcribed into complementary DNA (cDNA) using the ARScript 1st Strand cDNA synthesis kit (AccuRef Scientific, Xi'an, China). Quantitative Real-Time PCR was performed using HS Universal qPCR Master Mix (ACE Biotechnology) according to the manufacturer’s instructions.Mean Ct values were used to calculate relative transcript levels by the 2^(−∆∆CT) method.The qPCR primer sequences were qKPC-F (5’-CGGAACCTGCGGAGTGTATGG-3’)and qKPC-R (5’-CGCTGTGCTTGTCATCCTTGTTA-3’) for blaKPC gene, RPOB-F (5’-TGTAGAGCGTGCGGTGAAAGAG-3’) and RPOB-R (5’-GGAAATCGGCTTGGCGTTGATC-3’) for rpoB gene. Statistical analysis All analyses were performed in SPSS 26.0. continuous variables were presented as medians and interquartile ranges (IQR),the Student’s t test and Mann-Whitney U test for continuous data.While categorical variables were reported as numbers and percentage (%) and evaluated with Chi-square test or Fisher's exact test. RT-qPCR data were analyzed using Welch’s t-test.Potential risk factors were first screened by univariate analysis,variables with P < 0.05 were entered into a multivariate logistic regression to identify independent predictors. P < 0.05 was considered statistically significant. Results Specimen Sources and departmental distribution of CRKP Strains The 64 CZA-resistant CRKP strains were mainly sourced from Sputum and bronchoalveolar lavage fluid(45.32%), they were primarily isolated from the Intensive Care Unit (ICU) (29.69%) and surgical ICU (34.38%).see Table 1 . Table 1 Specimen Sources and departmental distribution of CRKP Strains Source CZA-Susceptible Group(n = 228) CZA-Resistant Group (n = 64) Number of Isolates Proportion(%) Number of Isolates Proportion(%) Specimen types Sputum and Lavage Fluid 103 45.17 29 45.32 Whole blood 34 14.91 5 7.81 Urine 34 14.91 11 17.19 Drainage fluid 15 6.58 6 9.38 Bile 14 6.14 2 3.13 Rectal swab 8 3.51 4 6.25 Catheter 7 3.07 3 4.69 Ascites 6 2.63 3 4.69 Others 7 3.07 1 1.56 Departmental Distribution Critical Care Medicine 80 35.09 19 29.69 Surgical ICU 42 18.42 22 34.38 Hepatobiliary Surgery 20 8.77 3 4.69 LiverTransplantation Department 19 8.33 2 3.13 Hematology 10 4.39 - - Rehabilitation 10 4.39 - - Respiratory RCU 7 3.07 4 6.25 Cardiovascular Surgery 4 1.75 - - Neurology 5 2.19 - - Urology 4 1.75 1 1.56 Emergency Center 4 1.75 6 9.38 Department of Infectious Diseases 4 1.75 2 3.13 Nephrology 3 1.32 1 1.56 Neurosurgery 4 1.75 2 3.13 Others 12 5.26 2 3.13 Table 2 Resistance of CZA-sensitive and CZA-resistant CRKP to common antibiotics Antimicrobial agent CZA-sensitive CRKP (n = 228) CZA-resistant CRKP(n = 64) χ² P Ceftazidime 227 (99.56) 63 (98.44) - 0.391 Cefepime 225 (98.68) 62 (96.88) 0.19 0.659 Cefotetan 220 (96.49) 60 (93.75) 0.38 0.535 Piperacillin/tazobactam 227 (99.56) 64 (100.00) - 1.000 Cefoperazone/sulbactam 227 (99.56) 64 (100.00) - 1.000 Ticarcillin/clavulanate 224 (98.25) 57 (89.063) 9.23 0.002 Aztreonam 227 (99.56) 60 (93.75) 6.87 0.009 Amikacin 191 (83.77) 44 (68.75) 7.18 0.007 Gentamicin 195 (85.53) 48 (75.00) 3.97 0.046 Tobramycin 195 (85.53) 56 (87.50) 0.16 0.688 Ciprofloxacin 227 (99.56) 61 (95.31) - 0.034 Levofloxacin 226 (99.12) 57 (89.06) 13.73 < .001 Imipenem 227 (99.56) 57 (89.06) 16.92 < .001 Meropenem 228 (100.00) 60 (93.75) - 0.002 Trimethoprim/sulfamethoxazole 182 (79.83) 42 (65.63) 5.64 0.018 Tigecycline 4 (1.75) 0 (0.00) - 0.58 Colistin 62 (27.19) 28 (43.75) 6.43 0.011 Ceftazidime/avibactam 0 (0.00) 64 (100.00) 292.00 < .001 Table 3 Distribution of carbapenemase gene types detected by two methods in CZA-resistant CRKP strains Carbapenemse genotype Colloidal Gold PCR Number of Isolates Proportion(%) Number of Isolates Proportion(%) bla NDM + bla KPC 27 42.18 27 42.18 blaKPC-2 + bla NDM-1 - - 26 40.62 bla KPC-2 + bla NDM-4 - - 1 1.56 bla KPC 9 14.06 10 15.63 bla KPC-33 - - 5 7.81 bla KPC-90 - - 2 3.13 bla KPC-2 - - 2 3.13 bla KPC-134 - - 1 1.56 bla NDM 23 35.94 23 35.94 bla NDM-1 - - 12 18.75 bla NDM-5 - - 10 15.63 bla NDM-4 - - 1 1.56 bla NDM + bla IMP 1 1.56 1 1.56 bla NDM-1 + bla IMP-4 - - 1 1.56 Negative 4 6.25 3 4.69 Table 4 Comparison of clinical characteristics between patients with CZA-sensitive and CZA-resistant CRKP Variable CZA-Susceptible Group (n = 228) CZA-Resistant Group (n = 64) P Age, M (Q₁, Q₃) 60.00 (51.00, 70.00) 64.00 (53.00, 71.50) 0.374 APACHE II, M (Q₁, Q₃) 6.50 (0.00, 17.25) 11.50 (0.00, 19.00) 0.059 SOFA, M (Q₁, Q₃) 1.50 (0.00, 7.00) 4.00 (0.00, 7.25) 0.066 Pre-CRKP infection hospital stay, M (Q₁, Q₃) 12.00 (4.00, 21.00) 21.00 (10.50, 34.75) < .001 Total hospital stay, M (Q₁, Q₃) 24.50 (15.00, 36.25) 35.50 (24.75, 61.00) < .001 Laboratory tests, M (Q₁, Q₃) White blood cell count 9.51 (5.63, 13.09) 8.99 (6.21, 12.52) 0.983 Platelets 115.00 (49.00, 226.50) 154.00(73.25,248.25) 0.057 Hemoglobin 89.50 (78.75, 101.00) 92.00 (83.00, 105.00) 0.164 Albumin 31.65 (28.68, 35.05) 31.85 (27.88, 34.83) 0.615 Procalcitonin 0.54 (0.18, 1.91) 0.74 (0.22, 4.10) 0.106 Gender, male 163 (71.49) 41 (64.06) 0.252 Comorbidities Hypertension 94 (41.23) 37 (57.81) 0.026 Diabetes mellitus 63 (27.63) 14 (21.88) 0.356 Malignant tumor 52 (22.81) 9 (14.06) 0.128 Respiratory disease 14 (6.14) 7 (10.94) 0.299 Renal disease 19 (8.33) 10 (15.63) 0.085 History of stroke 56 (24.56) 16 (25.00) 0.943 Chronic liver disease 34 (14.91) 14 (21.88) 0.184 Coronary heart disease 48 (21.05) 8 (12.50) 0.125 History of ICU admission 134 (58.77) 49 (76.56) 0.009 Septic shock 60 (26.32) 28 (43.75) 0.007 Previous invasive procedures Indwelling urinary catheter 150 (65.79) 56 (87.50) < .001 Central venous catheter 177 (77.63) 58 (90.63) 0.02 Mechanical ventilation 132 (57.90) 50 (78.13) 0.003 Tracheostomy/Intubation 117 (51.32) 43 (67.19) 0.024 Percutaneous drainage 116 (50.88) 32 (50.00) 0.901 Surgery 100 (43.86) 25 (39.06) 0.493 Renal replacement therapy 56 (24.56) 34 (53.13) < .001 Nasogastric tube 137 (60.09) 50 (78.13) 0.008 Bronchoscopy 98 (42.98) 39 (60.94) 0.011 Co-infections Bloodstream infection 34 (14.91) 5 (7.81) 0.140 Pulmonary infection 103 (45.18) 29 (45.31) 0.984 Abdominal infection 16 (7.02) 10 (15.63) 0.033 Urinary tract infection 34 (14.91) 11 (17.19) 0.656 Other infections 45 (19.74) 8 (12.50) 0.184 Previous antimicrobial exposure β-Lactam/β-Lactamase inhibitor combination 144 (63.16) 47 (73.44) 0.127 Carbapenems 150 (65.79) 43 (67.19) 0.835 Quinolones 42 (18.42) 12 (18.75) 0.952 Aminoglycosides 8 (3.51) 4 (6.25) 0.535 Tigecycline 33 (14.47) 17 (26.56) 0.023 Polymyxins 41 (17.98) 25 (39.06) < .001 Ceftazidime-avibactam 34 (14.91) 28 (43.75) < .001 Glycopeptides 88 (38.60) 36 (56.25) 0.012 Linezolid 50 (21.93) 17 (26.56) 0.436 Poor prognosis 73 (32.02) 31 (48.44) 0.015 Table 5 Multivariate analysis of risk factors for ceftazidime–avibactam resistant carbapenem-resistant Klebsiella pneumoniae infection Variables β S.E Z P OR (95% CI ) Renal replacement therapy 0.960 0.400 2.398 0.016 2.611 (1.192 ~ 5.721) Previous CZA exposure 1.011 0.394 2.565 0.010 2.749 (1.269 ~ 5.953) Resistance of CRKP strains to common antibiotics Compared with the CZA-susceptible group, the CZA-resistant CRKP group had lower resistance rates to piperacillin/tazobactam, aztreonam, amikacin, gentamicin, ciprofloxacin, levofloxacin, imipenem, and meropenem, but higher resistance to colistin (all P 0.05). Carbapenemase genotype of 64 CZA-resistant CRKP Strains Colloidal gold detection revealed that 60 of 64 CZA-resistant CRKP strains tested positive for carbapenemase genes. Among these, 27 strains exhibited co-production of KPC and NDM, 23 produced NDM exclusively, 1 strain co-produced NDM and IMP, 9 strains generated KPC alone, and 4 strains were negative for carbapenemases. PCR and sequencing confirmed carbapenemase genes in 61 isolates, yielding 98.4% concordance with the colloidal-gold assay. Notably, one isolate carrying blaKPC-134 was missed by the colloidal-gold assay. Relative expression of bla KPC in KPC-KP To assess whether blaKPC expression level drives CAZ-AVI resistance,10 CZA resistant and ATCC BAA-1705 strains were identified. The results showed that expression levels of bla KPC were significantly higher in 8 of the 10 KPC-KP strains compared with the control strain Klebsiella pneumoniae ATCC BAA-1705( p < 0.05),while isolates KP-63 and KP-70 exhibited no elevation. Risk factor for ceftazidime-avibactam resistant CRKP infections Univariate analysis showed that patients in the CZA-resistant CRKP group had a higher proportion of hypertension, ICU admission history, septic shock, prior invasive procedures (such as indwelling catheters, central venous catheters, mechanical ventilation, tracheostomy/intubation, renal replacement therapy, nasogastric tubes, bronchoscopy), prior antibiotic exposure to tigecycline, polymyxins, ceftazidime-avibactam, and glycopeptide antibiotics, and poor prognosis compared to the CZA-sensitive CRKP group. Additionally, the length of hospitalization prior to CRKP infection and total length of hospitalization were longer in the CZA-resistant CRKP group. Variables with P < 0.05 in univariate analysis were included in multivariate analysis, which further revealed that renal replacement therapy ( OR = 2.611,95% CI 1.192–5.721) and prior exposure to ceftazidime-avibactam ( OR = 2.749,95% CI 1.269 ~ 5.953) were independent risk factors for CZA-resistant CRKP infections. Discussion This study found that the 64 CZA-resistant CRKP strains mainly originated from respiratory specimens (45.32%), which is similar to the results of previous studies [ 11 ] . The strains were mainly distributed in the intensive care unit,where immunosuppressed patients and invasive procedures increase infection risk. Studies have shown that there is a significant correlation between ICU admission history and the incidence of CRKP infection [ 12 ] .The closed ICU environment allows for easy spread of resistant bacteria among patients, highlighting the need for improved infection control and shorter ICU stays to prevent CRKP infections. Compared with the CZA-susceptible CRKP patients, the CZA-resistant group showed increased polymyxin resistance, but the resistance rate to some β-lactams was actually decreased. This phenotype may be related to the production of KPC variant strains. Studies have shown that KPC variant strains are more likely to regain sensitivity to meropenem while exhibiting higher levels of CZA resistance [ 13 ] . we found that the imipenem MIC of most KPC variant strains was reduced (≤ 4µg/mL), while acquiring high-level CZA resistance (MIC ≥ 64µg/mL). Wild-type KPC-2 strains exhibited low CZA resistance (MIC < 64µg/mL), consistent with previous studies [ 13 ] . In this study,Genotyping of CZA-resistant CRKP by colloidal-gold assay and sequencing showed 98.44% concordance.One strain that produced only KPC enzyme was negative by colloidal gold, but identified as blaKPC-134 by sequencing. The colloidal-gold may produce false-negative results for KPC variants, which can lead to incorrect clinical decisions and treatment failure, Molecular detection technology can overcome this problem [ 14 ] . A study results showed that the positive percentages of three colloidal gold immunochromatographic methods for 16 KPC-2 variants were 87.5%, 87.5% and 68.8% compared with GeneXpert Carba-R [ 14 ] .Negative colloidal gold immunochromatographic results that don't match resistance phenotypes should be retested with another kit or GeneXpert Carba-R for better accuracy. In this study, among the 64 CZA-resistant CRKP strains, 50 strains produced NDM, of which 42.18% were co-producing KPC and NDM, 35.94% were blaNDM, and in addition, one strain co-producing NDM and IMP metalloenzyme was found, indicating that the production of metalloenzyme, especially the co-production of KPC and NDM, is the main mechanism of CZA resistance in CRKP in this hospital. In addition to the production of metalloenzyme, KPC mutation is the main mechanism of high-level CZA resistance in this region, which is similar to the results of a study in Taiwan [ 15 ] . Studies have shown that the genomes carrying KPC and NDM are mainly reported in China (45.1%) and the United States (23.0%) [ 13 ] . with a 3.5-fold increase in strains from 2018 to 2022.common combinations include KPC-2 plus NDM-1 (53.6%), KPC-2 plus NDM-5 (18.5%), and KPC-3 plus NDM-1 (14.1%). It is worth noting that the co-production of KPC and NDM in Klebsiella pneumoniae seems to originate from high-risk clones positive for KPC worldwide, which then acquired plasmids carrying NDM. The emergence of multi-replicon plasmids carrying KPC and NDM is an important mechanism for pan-β-lactam resistance [ 16 ] . The emergence of KPC-NDM-CRKP leads to higher levels of antimicrobial resistance and extremely limited treatment options, which may further lead to increased mortality [ 17 ] . Therefore, clinical laboratories should actively carry out enzyme typing and genotyping detection. For strains producing double enzymes, clinicians can give combination therapy (ceftazidime-avibactam combined with aztreonam) based on enzyme typing and genotyping results to prevent the spread and prevalence of this resistant bacteria in medical institutions. Since 2019, the incidence of new KPC gene subtypes has increased significantly. According to the NCBI database, more than 200 bla KPC gene variants have been found worldwide, half of which may have CZA resistance [ 18 ] . In addition, the spread of these bla KPC genes is mainly mediated by plasmids or small genetic elements on them, especially the Tn4401 transposon [ 8 ] . Klebsiella pneumoniae bearing with KPC variant often mislead clinical anti-infection treatment because of their unique antimicro­bial susceptibility profile and the tendency of conventional carbapenemase assays to give false negative results. Therefore, timely identification of KPC variants and effective anti-infective therapy are key to saving infected patients [ 19 ] .In this study, sequencing identified 10 KPC-only producers, eight of which carried variants: five blaKPC-33, two blaKPC-90, and one blaKPC-134. Although these three alleles have previously been reported in Beijing [ 20 ] , Shanghai [ 21 ] , Fujian [ 22 ] , and Sichuan [ 19 ] , but this is their first detection in Shaanxi.In addition, two isolates harboring wild-type blaKPC-2 were found. Studies have reported that wild-type KPC strains resistant to CZA is related to the high expression of blaKPC genes and the loss of outer membrane porins [ 23 ] . RT-qPCR revealed that bla KPC-2 expression in both isolates was significantly elevated compared with control strain Klebsiella pneumoniae ATCC BAA-1705, likely accounting for their CZA resistance. However, whether there is a combination of membrane porin loss and overexpression of efflux pumps needs further study. Although meropenem-vaborbactam is considered a salvage treatment for CZA-resistant KPC variant-producing Klebsiella pneumoniae [ 24 ] . However, this new agent remains unavailable in many regions, especially resource-limited settings,Consequently, evaluating alternative regimens such as ceftazidime–avibactam plus imipenem is urgently needed [ 3 , 21 ] . Most studies mainly focus on the resistance mechanisms of CZA-resistant CRKP, with few on risk factors. The study showed that renal replacement therapy and previous CZA exposure as independent risk factors for CZA-resistant CRKP infection. Renal-replacement therapy promotes CRKP colonization and linadequate drug exposure, thereby increasing the risk of CAZ-AVI-resistant infection. [ 7 ] . In addition, it was also found that the proportion of previous CZA exposure in the CZA-resistant CRKP group was significantly higher than that in the CZA-susceptible CRKP group. Previous studies have shown that CZA treatment may be an independent risk factor for inducing mutations of blaKPC [ 25 ] .New KPC mutations are usually associated with clinical use of CZA for 9–19 days [ 20 , 25 – 26 ] . In this study, we found that KPC mutations were closely related to CZA treatment. Among the eight patients with KPC-mutant CRKP, six had received CZA for a median of 11 days before resistance was detected, whereas the remaining two developed resistance without any CZA exposure, confirming previous studies [ 27 ] 。 Strengthen and limitation Our study has several limitations. Firstly, the single-center retrospective study design may introduce selection bias. Secondly, molecular mechanisms such as porin loss and overexpression of efflux pumps were not thoroughly explored. Moreover, the limited sample size restricted the detection of rare resistance subtypes. Conclusions This study demonstrates that CZA-resistant CRKP in our hospital is driven primarily by metalloenzyme production—especially KPC-2/NDM-1 co-producers—while KPC mutations and over-expression are additional key mechanisms. Renal replacement therapy and a history of previous CZA exposure are identified as independent risk factors for CZA-resistant CRKP. Declarations Ethics approval This retrospective study was conducted in accordance with the Declaration of Helsinki and was approved by the Medical Ethics Committee of the First Affiliated Hospital of Xi’an Jiaotong University, which waived pan-informed consent. Consent for publication Not applicable. Competing interests The authors declare no competing interests. Funding This work was supported by the Shaanxi Provincial natural science basic research Project (S2024JC-YBQN-0836, S2024JC-YBQN-0986). Author Contribution Xiaqin He and Meng Liu carried out the medical records database search, statistical analysis, and drafted the manuscript.Xiaoqian Wang, Sijia Li,Yi Zhang，Zhe Liu and Xiaoqin Wang participated in the design and coordination of the study and helped to draft the manuscript. All authors read and approved the final manuscript. Data Availability All data generated or analyzed in the study are included in the article and further inquiries can be directly contacted with the corresponding author Xiaoqin Wang via e-mail. References He J, Shi Q, Chen Z et al. Opposite evolution of pathogenicity driven by in vivo wzc and wcaJ mutations in ST11-KL64 carbapenem-resistant Klebsiella pneumoniae [J]. Drug Resist Updat,2023,66:100891. Liu E, Jia P, Li X, et al. In vitro and in vivo Effect of Antimicrobial Agent Combinations Against Carbapenem-Resistant Klebsiella pneumoniae with Different Resistance Mechanisms in China[J]. Infect Drug Resist. 2021;14:917–28. 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Cite Share Download PDF Status: Under Review Version 1 posted Editorial decision: Revision requested 23 Apr, 2026 Reviews received at journal 02 Apr, 2026 Reviewers agreed at journal 30 Mar, 2026 Reviewers agreed at journal 27 Mar, 2026 Reviews received at journal 23 Nov, 2025 Reviewers agreed at journal 22 Nov, 2025 Reviews received at journal 13 Oct, 2025 Reviewers agreed at journal 12 Oct, 2025 Reviewers invited by journal 12 Oct, 2025 Editor assigned by journal 11 Sep, 2025 Editor invited by journal 11 Sep, 2025 Submission checks completed at journal 11 Sep, 2025 First submitted to journal 11 Sep, 2025 You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. 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15:43:19","extension":"xml","order_by":13,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":169121,"visible":true,"origin":"","legend":"","description":"","filename":"e51d9857ca404289aea359f4063db2bf1structuring.xml","url":"https://assets-eu.researchsquare.com/files/rs-7507415/v1/3d40aa2c120b945e1c8e7979.xml"},{"id":94473444,"identity":"0d58f97f-eb63-483d-8bed-ea2a3a07f193","added_by":"auto","created_at":"2025-10-27 15:44:20","extension":"html","order_by":14,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":178067,"visible":true,"origin":"","legend":"","description":"","filename":"earlyproof.html","url":"https://assets-eu.researchsquare.com/files/rs-7507415/v1/956ed26d19b900ef6e6808cf.html"},{"id":94473569,"identity":"bf6edfcb-ebbb-4267-8ba6-8c17a6b46eda","added_by":"auto","created_at":"2025-10-27 15:44:51","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":135632,"visible":true,"origin":"","legend":"\u003cp\u003eDetection of Carbapenemase genes by agarose gel electrophoresis. Lane M shows a 2000 bp molecular strand DNA ladder, + is the positive control for\u003cem\u003e bla\u003c/em\u003eKPC,\u003cem\u003e bla\u003c/em\u003eKPC gene; 1 Lanes show positive specimens (811bp),\u003cem\u003e bla\u003c/em\u003eNDM gene; 2 and 3 Lanes show positive specimens (704bp),\u003cem\u003ebla\u003c/em\u003eVIM gene; 4 Lanes show positive specimens (383bp).\u003c/p\u003e","description":"","filename":"1.png","url":"https://assets-eu.researchsquare.com/files/rs-7507415/v1/67ef4388e9eebe3aaedcb482.png"},{"id":94473235,"identity":"df568b9e-3505-4841-a19e-539e5bdbad6b","added_by":"auto","created_at":"2025-10-27 15:43:30","extension":"png","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":100204,"visible":true,"origin":"","legend":"\u003cp\u003eRelative expression of \u003cem\u003ebla\u003c/em\u003eKPC in CZA-resistant CRKP.The relative expression levels of \u003cem\u003ebla\u003c/em\u003eKPC were significantly higher in isolates KP-19, KP-22, KP-64, KP-69,KP-74,KP78,KP79 and KP86 compared with the control strain \u003cem\u003eKlebsiella pneumoniae \u003c/em\u003eATCC BAA-1705, \u003cem\u003ebla\u003c/em\u003eKPC-33;isolates KP-19, KP-64, KP-69, KP-74 and KP-78 was positive,\u003cem\u003ebla\u003c/em\u003eKPC-90;isolates KP-70 and KP-79 was positive, \u003cem\u003ebla\u003c/em\u003eKPC-134; isolates KP-63 was postive;\u003cem\u003ebla\u003c/em\u003eKPC-2;isolates KP-22 and KP-86 was postive.\u003c/p\u003e","description":"","filename":"2.png","url":"https://assets-eu.researchsquare.com/files/rs-7507415/v1/d991f742b3dbf26c96d00d2b.png"},{"id":94490148,"identity":"65412349-5391-4e19-9b92-566b76abd2c2","added_by":"auto","created_at":"2025-10-27 17:07:52","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":1515141,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-7507415/v1/dc2347a1-6518-40bd-bd71-e42e2f18357c.pdf"}],"financialInterests":"No competing interests reported.","formattedTitle":"The resistance mechanisms and risk factors of carbapenem-resistant Klebsiella pneumoniae to ceftazidime-avibactam","fulltext":[{"header":"Introduction","content":"\u003cp\u003e\u003cem\u003eKlebsiella pneumoniae\u003c/em\u003e is recognized as an opportunistic pathogen that evolves into the highly concerning superbug carbapenem-resistant \u003cem\u003eKlebsiella pneumoniae\u003c/em\u003e (CRKP) upon acquiring plasmids that harbor carbapenemase resistance genes\u003csup\u003e[\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e]\u003c/sup\u003e. The primary mechanisms conferring resistance in CRKP include the synthesis of carbapenemases, which encompass class A enzymes (KPC), class B enzymes (NDM, IMP), and class D enzymes (OXA-48), alongside the loss of porins OmpK35 and/or OmpK36\u003csup\u003e[\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e]\u003c/sup\u003e. According to the China Antimicrobial Drug Monitoring Network (CHINET)(\u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttp://www.chinets.com/\u003c/span\u003e\u003cspan address=\"http://www.chinets.com/\" targettype=\"URL\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e), the resistance rate of \u003cem\u003eKlebsiella pneumoniae\u003c/em\u003e to meropenem has surged from 2.9% in 2005 to 23.4% in 2024. The increasing prevalence of drug-resistant phenotypes and the dissemination of mobile genetic elements contribute to a continuous rise in CRKP cases globally, significantly limiting antibiotic treatment options and posing a major challenge for clinical management and infection control\u003csup\u003e[\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e]\u003c/sup\u003e.\u003c/p\u003e\u003cp\u003eCeftazidime-avibactam (CAZ/AVI) as a novel combination of ceftazidime and the β-lactamase inhibitor, has been approved by the Food and Drug Administration (FDA) for treatment of complicated intra-abdominal and urinary tract infections\u003csup\u003e[\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e]\u003c/sup\u003e. It can inhibit the activity of Ambler class A, class C and class D β-lactamases, however, it is ineffective against class B metallo-β-lactamases (MBL)\u003csup\u003e[\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e, \u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e]\u003c/sup\u003e. In recent years, CZA has demonstrated considerable efficacy in treating KPC-producing \u003cem\u003eKlebsiella pneumoniae\u003c/em\u003e (KPC-Kp), leading to improved clinical survival outcomes. Nonetheless, the increased utilization of CZA has been paralleled by a rising incidence of CZA-resistant CRKP in various regions\u003csup\u003e[\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e, \u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e]\u003c/sup\u003e. In 2024, CHINET reported a resistance rate of 15.8% for CRKP against CZA(\u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttp://www.chinets.com/).Patient\u003c/span\u003e\u003cspan address=\"http://www.chinets.com/).Patient\" targettype=\"URL\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003es infected with CZA-resistant CRKP had higher 28-day and in-hospital mortality rates\u003csup\u003e[\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e]\u003c/sup\u003e.This emerging resistance has created new challenges for selecting effective therapies\u003csup\u003e[\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e]\u003c/sup\u003e.\u003c/p\u003e\u003cp\u003eIn order to facilitate the proactive monitoring of resistance to ceftazidime-avibactam and curb its dissemination, we systematically investigated the predominant resistance mechanisms, thereby establishing a theoretical framework to enhance clinical drug utilization and resistance management within our institution. Moreover, there exists a notable gap in the systematic analysis of risk factors pertinent to CZA-resistant CRKP infections. Consequently, this study amalgamates molecular biology testing and clinical epidemiological data to conduct a thorough analysis of the risk factors associated with CZA-resistant CRKP, thereby providing a scientific foundation for the early identification of high-risk patients.\u003c/p\u003e"},{"header":"Methods","content":"\u003cdiv id=\"Sec3\" class=\"Section2\"\u003e\u003ch2\u003eStudy design and patients\u003c/h2\u003e\u003cp\u003eWe retrospectively collected clinical data from 293 hospitalized CRKP-infected patients at the First Affiliated Hospital of Xi\u0026rsquo;an Jiaotong University between January 2024 and March 2025. Inclusion criteria: (a) micro-\u003c/p\u003e\u003cp\u003ebiologically confirmed CRKP bacteremia within 48 h of admission;(b) Inclusion of CZA susceptibility testing; (c) Complete clinical data. Exclusion criteria: (a) immunocompromised individuals; (b) age\u0026thinsp;\u0026lt;\u0026thinsp;18 years;(c) patients exhibiting multiple positive cultures for the same pathogen during the same hospital stay, with each counted only once.The study protocol was approved by the Medical Ethics Review Committee of the First Affiliated Hospital of Xi\u0026rsquo;an Jiaotong University.\u003c/p\u003e\u003c/div\u003e\n\u003ch3\u003eClinical data collection\u003c/h3\u003e\n\u003cp\u003eDate extracted from the hospital's electronic medical record system included their comorbidities,invasive procedures,laboratory results,microbiological profiles,prior antibiotic exposure and outcomes.The 293 CRKP infection patients were divided into CZA-resistant CRKP group and CZA-sensitive CRKP group based on CZA susceptibility results.\u003c/p\u003e\n\u003ch3\u003eStrain identification and susceptibility testing\u003c/h3\u003e\n\u003cp\u003eIsolates were identified by matrix-assisted laser desorption-ionization time-of-flight mass spectrometry (MALDI-TOF MS) and antimicrobial susceptibility testing (AST) was performed using the VITEK-2 system (bioM\u0026eacute;rieux SA, Marcy l\u0026rsquo;Etoile, France).The minimum inhibitory concentration (MIC) of CZA was evaluated using E-test strips, with results interpreted according to Clinical and Laboratory Standards Institute(CLSI) guidelines.Polymyxins interpretation followed standards of the American Committee on Antimicrobial Susceptibility Testing\u003csup\u003e[\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e]\u003c/sup\u003e. Tigecycline interpretation followed the standards of the U.S. Food and Drug Administration. Quality control strains (\u003cem\u003eEscherichia coli\u003c/em\u003e ATCC 25922,ATCC35218 and \u003cem\u003ePseudomonas aeruginosa\u003c/em\u003e ATCC 27853) were included in all AST procedures to ensure methodological consistency.\u003c/p\u003e\n\u003ch3\u003eCarbapenemase detection\u003c/h3\u003e\n\u003cp\u003e\u003cul\u003e\u003cli\u003e\u003cp\u003e(1) The detection of carbapenemase production was executed utilizing the Dynamiker CGI test (Dynamiker Biotechnology, Tianjin, China), with colloidal gold immunoassay kits employed according to the manufacturer's instructions.(2)Carbapenemase Genes type (\u003cem\u003ebla\u003c/em\u003eKPC, \u003cem\u003ebla\u003c/em\u003eIMP, \u003cem\u003ebla\u003c/em\u003eNDM, \u003cem\u003ebla\u003c/em\u003eVIM and \u003cem\u003ebla\u003c/em\u003eOXA-48)were detected by polymerase chain reaction (PCR) followed by Sanger sequencing (Qingke Biotechnology) and were compared with available sequences in GenBank.The primer sequences for PCR referenced from the literature\u003csup\u003e[\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e]\u003c/sup\u003e.\u003c/p\u003e\u003c/li\u003e\u003c/ul\u003e\u003c/p\u003e\n\u003ch3\u003eQuantitative real-time PCR\u003c/h3\u003e\n\u003cp\u003eTen \u003cem\u003eKlebsiella pneumoniae\u003c/em\u003e strains were analyzed through qualitative real-time PCR (qRT-PCR) to evaluate the relative expression of \u003cem\u003ebla\u003c/em\u003eKPC, normalized against an internal housekeeping gene, rpoB. Total RNA was isolated from bacteria utilizing TRIzol reagent (Invitrogen China Limited, Beijing, China), with RNA subsequently reverse transcribed into complementary DNA (cDNA) using the ARScript 1st Strand cDNA synthesis kit (AccuRef Scientific, Xi'an, China). Quantitative Real-Time PCR was performed using HS Universal qPCR Master Mix (ACE Biotechnology) according to the manufacturer\u0026rsquo;s instructions.Mean Ct values were used to calculate relative transcript levels by the 2^(\u0026minus;∆∆CT) method.The qPCR primer sequences were qKPC-F (5\u0026rsquo;-CGGAACCTGCGGAGTGTATGG-3\u0026rsquo;)and qKPC-R (5\u0026rsquo;-CGCTGTGCTTGTCATCCTTGTTA-3\u0026rsquo;) for blaKPC gene, RPOB-F (5\u0026rsquo;-TGTAGAGCGTGCGGTGAAAGAG-3\u0026rsquo;) and RPOB-R (5\u0026rsquo;-GGAAATCGGCTTGGCGTTGATC-3\u0026rsquo;) for rpoB gene.\u003c/p\u003e\u003cdiv id=\"Sec8\" class=\"Section2\"\u003e\u003ch2\u003eStatistical analysis\u003c/h2\u003e\u003cp\u003eAll analyses were performed in SPSS 26.0. continuous variables were presented as medians and interquartile ranges (IQR),the Student\u0026rsquo;s t test and Mann-Whitney U test for continuous data.While categorical variables were reported as numbers and percentage (%) and evaluated with Chi-square test or Fisher's exact test. RT-qPCR data were analyzed using Welch\u0026rsquo;s t-test.Potential risk factors were first screened by univariate analysis,variables with P\u0026thinsp;\u0026lt;\u0026thinsp;0.05 were entered into a multivariate logistic regression to identify independent predictors. P\u0026thinsp;\u0026lt;\u0026thinsp;0.05 was considered statistically significant.\u003c/p\u003e\u003c/div\u003e"},{"header":"Results","content":"\u003cdiv id=\"Sec10\" class=\"Section2\"\u003e\u003ch2\u003eSpecimen Sources and departmental distribution of CRKP Strains\u003c/h2\u003e\u003cp\u003eThe 64 CZA-resistant CRKP strains were mainly sourced from Sputum and bronchoalveolar lavage fluid(45.32%), they were primarily isolated from the Intensive Care Unit (ICU) (29.69%) and surgical ICU (34.38%).see Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e.\u003c/p\u003e\u003cp\u003e\u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab1\" border=\"1\"\u003e\u003ccaption language=\"En\"\u003e\u003cdiv class=\"CaptionNumber\"\u003eTable 1\u003c/div\u003e\u003cdiv class=\"CaptionContent\"\u003e\u003cp\u003eSpecimen Sources and departmental distribution of CRKP Strains\u003c/p\u003e\u003c/div\u003e\u003c/caption\u003e\u003ccolgroup cols=\"5\"\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e\u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e\u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e\u003cthead\u003e\u003ctr\u003e\u003cth align=\"left\" colname=\"c1\" morerows=\"1\" rowspan=\"2\"\u003e\u003cp\u003eSource\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colspan=\"2\" nameend=\"c3\" namest=\"c2\"\u003e\u003cp\u003eCZA-Susceptible Group(n\u0026thinsp;=\u0026thinsp;228)\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colspan=\"2\" nameend=\"c5\" namest=\"c4\"\u003e\u003cp\u003eCZA-Resistant Group (n\u0026thinsp;=\u0026thinsp;64)\u003c/p\u003e\u003c/th\u003e\u003c/tr\u003e\u003ctr\u003e\u003cth align=\"left\" colname=\"c2\"\u003e\u003cp\u003eNumber of Isolates\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c3\"\u003e\u003cp\u003eProportion(%)\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c4\"\u003e\u003cp\u003eNumber of Isolates\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c5\"\u003e\u003cp\u003eProportion(%)\u003c/p\u003e\u003c/th\u003e\u003c/tr\u003e\u003ctr\u003e\u003cth align=\"left\" colname=\"c1\"\u003e\u003cp\u003eSpecimen types\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/th\u003e\u003cth align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/th\u003e\u003cth align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/th\u003e\u003cth align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/th\u003e\u003c/tr\u003e\u003c/thead\u003e\u003ctbody\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eSputum and Lavage Fluid\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e103\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e45.17\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e29\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e45.32\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eWhole blood\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e34\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e14.91\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e5\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e7.81\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eUrine\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e34\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e14.91\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e11\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e17.19\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eDrainage fluid\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e15\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e6.58\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e6\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e9.38\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eBile\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e14\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e6.14\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e2\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e3.13\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eRectal swab\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e8\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e3.51\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e4\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e6.25\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eCatheter\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e7\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e3.07\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e3\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e4.69\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eAscites\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e6\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e2.63\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e3\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e4.69\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eOthers\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e7\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e3.07\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e1\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e1.56\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u003cb\u003eDepartmental Distribution\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eCritical Care Medicine\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e80\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e35.09\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e19\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e29.69\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eSurgical ICU\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e42\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e18.42\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e22\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e34.38\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eHepatobiliary Surgery\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e20\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e8.77\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e3\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e4.69\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eLiverTransplantation Department\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e19\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e8.33\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e2\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e3.13\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eHematology\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e10\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e4.39\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e-\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e-\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eRehabilitation\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e10\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e4.39\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e-\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e-\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eRespiratory RCU\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e7\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e3.07\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e4\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e6.25\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eCardiovascular Surgery\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e4\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e1.75\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e-\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e-\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eNeurology\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e5\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e2.19\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e-\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e-\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eUrology\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e4\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e1.75\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e1\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e1.56\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eEmergency Center\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e4\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e1.75\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e6\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e9.38\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eDepartment of Infectious Diseases\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e4\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e1.75\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e2\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e3.13\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eNephrology\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e3\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e1.32\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e1\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e1.56\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eNeurosurgery\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e4\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e1.75\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e2\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e3.13\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eOthers\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e12\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e5.26\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e2\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e3.13\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003c/tbody\u003e\u003c/colgroup\u003e\u003c/table\u003e\u003c/div\u003e\u003c/p\u003e\u003cp\u003e\u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab2\" border=\"1\"\u003e\u003ccaption language=\"En\"\u003e\u003cdiv class=\"CaptionNumber\"\u003eTable 2\u003c/div\u003e\u003cdiv class=\"CaptionContent\"\u003e\u003cp\u003eResistance of CZA-sensitive and CZA-resistant CRKP to common antibiotics\u003c/p\u003e\u003c/div\u003e\u003c/caption\u003e\u003ccolgroup cols=\"5\"\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e\u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e\u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e\u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e\u003cthead\u003e\u003ctr\u003e\u003cth align=\"left\" colname=\"c1\"\u003e\u003cp\u003eAntimicrobial agent\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c2\"\u003e\u003cp\u003eCZA-sensitive CRKP (n\u0026thinsp;=\u0026thinsp;228)\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c3\"\u003e\u003cp\u003eCZA-resistant CRKP(n\u0026thinsp;=\u0026thinsp;64)\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c4\"\u003e\u003cp\u003e\u003cem\u003eχ\u0026sup2;\u003c/em\u003e\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c5\"\u003e\u003cp\u003e\u003cem\u003eP\u003c/em\u003e\u003c/p\u003e\u003c/th\u003e\u003c/tr\u003e\u003c/thead\u003e\u003ctbody\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eCeftazidime\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e227 (99.56)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e63 (98.44)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e-\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e\u003cp\u003e0.391\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eCefepime\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e225 (98.68)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e62 (96.88)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e0.19\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e\u003cp\u003e0.659\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eCefotetan\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e220 (96.49)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e60 (93.75)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e0.38\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e\u003cp\u003e0.535\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003ePiperacillin/tazobactam\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e227 (99.56)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e64 (100.00)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e-\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e\u003cp\u003e1.000\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eCefoperazone/sulbactam\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e227 (99.56)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e64 (100.00)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e-\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e\u003cp\u003e1.000\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eTicarcillin/clavulanate\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e224 (98.25)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e57 (89.063)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e9.23\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e\u003cp\u003e0.002\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eAztreonam\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e227 (99.56)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e60 (93.75)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e6.87\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e\u003cp\u003e0.009\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eAmikacin\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e191 (83.77)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e44 (68.75)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e7.18\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e\u003cp\u003e0.007\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eGentamicin\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e195 (85.53)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e48 (75.00)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e3.97\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e\u003cp\u003e0.046\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eTobramycin\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e195 (85.53)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e56 (87.50)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e0.16\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e\u003cp\u003e0.688\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eCiprofloxacin\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e227 (99.56)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e61 (95.31)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e-\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e\u003cp\u003e0.034\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eLevofloxacin\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e226 (99.12)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e57 (89.06)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e13.73\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e\u003cp\u003e\u0026lt;\u0026thinsp;.001\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eImipenem\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e227 (99.56)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e57 (89.06)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e16.92\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e\u003cp\u003e\u0026lt;\u0026thinsp;.001\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eMeropenem\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e228 (100.00)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e60 (93.75)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e-\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e\u003cp\u003e0.002\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eTrimethoprim/sulfamethoxazole\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e182 (79.83)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e42 (65.63)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e5.64\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e\u003cp\u003e0.018\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eTigecycline\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e4 (1.75)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e0 (0.00)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e-\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e\u003cp\u003e0.58\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eColistin\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e62 (27.19)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e28 (43.75)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e6.43\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e\u003cp\u003e0.011\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eCeftazidime/avibactam\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e0 (0.00)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e64 (100.00)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e292.00\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e\u003cp\u003e\u0026lt;\u0026thinsp;.001\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003c/tbody\u003e\u003c/colgroup\u003e\u003c/table\u003e\u003c/div\u003e\u003c/p\u003e\u003cp\u003e\u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab3\" border=\"1\"\u003e\u003ccaption language=\"En\"\u003e\u003cdiv class=\"CaptionNumber\"\u003eTable 3\u003c/div\u003e\u003cdiv class=\"CaptionContent\"\u003e\u003cp\u003eDistribution of carbapenemase gene types detected by two methods in CZA-resistant CRKP strains\u003c/p\u003e\u003c/div\u003e\u003c/caption\u003e\u003ccolgroup cols=\"5\"\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e\u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e\u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e\u003cthead\u003e\u003ctr\u003e\u003cth align=\"left\" colname=\"c1\" morerows=\"1\" rowspan=\"2\"\u003e\u003cp\u003eCarbapenemse genotype\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colspan=\"2\" nameend=\"c3\" namest=\"c2\"\u003e\u003cp\u003eColloidal Gold\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colspan=\"2\" nameend=\"c5\" namest=\"c4\"\u003e\u003cp\u003ePCR\u003c/p\u003e\u003c/th\u003e\u003c/tr\u003e\u003ctr\u003e\u003cth align=\"left\" colname=\"c2\"\u003e\u003cp\u003eNumber of Isolates\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c3\"\u003e\u003cp\u003eProportion(%)\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c4\"\u003e\u003cp\u003eNumber of Isolates\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c5\"\u003e\u003cp\u003eProportion(%)\u003c/p\u003e\u003c/th\u003e\u003c/tr\u003e\u003c/thead\u003e\u003ctbody\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u003cem\u003ebla\u003c/em\u003eNDM\u0026thinsp;+\u0026thinsp;\u003cem\u003ebla\u003c/em\u003eKPC\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e27\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e42.18\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e27\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e\u003cp\u003e42.18\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eblaKPC-2\u0026thinsp;+\u0026thinsp;\u003cem\u003ebla\u003c/em\u003eNDM-1\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e-\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e-\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e26\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e\u003cp\u003e40.62\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u003cem\u003ebla\u003c/em\u003eKPC-2\u0026thinsp;+\u0026thinsp;\u003cem\u003ebla\u003c/em\u003eNDM-4\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e-\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e-\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e1\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e\u003cp\u003e1.56\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u003cem\u003ebla\u003c/em\u003eKPC\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e9\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e14.06\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e10\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e\u003cp\u003e15.63\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u003cem\u003ebla\u003c/em\u003eKPC-33\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e-\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e-\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e5\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e\u003cp\u003e7.81\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u003cem\u003ebla\u003c/em\u003eKPC-90\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e-\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e-\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e2\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e\u003cp\u003e3.13\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u003cem\u003ebla\u003c/em\u003eKPC-2\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e-\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e-\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e2\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e\u003cp\u003e3.13\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u003cem\u003ebla\u003c/em\u003eKPC-134\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e-\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e-\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e1\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e\u003cp\u003e1.56\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u003cem\u003ebla\u003c/em\u003eNDM\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e23\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e35.94\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e23\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e\u003cp\u003e35.94\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u003cem\u003ebla\u003c/em\u003eNDM-1\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e-\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e-\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e12\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e\u003cp\u003e18.75\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u003cem\u003ebla\u003c/em\u003eNDM-5\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e-\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e-\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e10\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e\u003cp\u003e15.63\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u003cem\u003ebla\u003c/em\u003eNDM-4\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e-\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e-\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e1\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e\u003cp\u003e1.56\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u003cem\u003ebla\u003c/em\u003eNDM\u0026thinsp;+\u0026thinsp;\u003cem\u003ebla\u003c/em\u003eIMP\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e1\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e1.56\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e1\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e\u003cp\u003e1.56\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u003cem\u003ebla\u003c/em\u003eNDM-1\u0026thinsp;+\u0026thinsp;\u003cem\u003ebla\u003c/em\u003eIMP-4\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e-\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e-\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e1\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e\u003cp\u003e1.56\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eNegative\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e4\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e6.25\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e3\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e\u003cp\u003e4.69\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003c/tbody\u003e\u003c/colgroup\u003e\u003c/table\u003e\u003c/div\u003e\u003c/p\u003e\u003cp\u003e\u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab4\" border=\"1\"\u003e\u003ccaption language=\"En\"\u003e\u003cdiv class=\"CaptionNumber\"\u003eTable 4\u003c/div\u003e\u003cdiv class=\"CaptionContent\"\u003e\u003cp\u003eComparison of clinical characteristics between patients with CZA-sensitive and CZA-resistant CRKP\u003c/p\u003e\u003c/div\u003e\u003c/caption\u003e\u003ccolgroup cols=\"4\"\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e\u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e\u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e\u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e\u003cthead\u003e\u003ctr\u003e\u003cth align=\"left\" colname=\"c1\"\u003e\u003cp\u003eVariable\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c2\"\u003e\u003cp\u003eCZA-Susceptible Group (n\u0026thinsp;=\u0026thinsp;228)\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c3\"\u003e\u003cp\u003eCZA-Resistant Group (n\u0026thinsp;=\u0026thinsp;64)\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c4\"\u003e\u003cp\u003e\u003cem\u003eP\u003c/em\u003e\u003c/p\u003e\u003c/th\u003e\u003c/tr\u003e\u003c/thead\u003e\u003ctbody\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eAge, M (Q₁, Q₃)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e60.00 (51.00, 70.00)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e64.00 (53.00, 71.50)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e0.374\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eAPACHE II, M (Q₁, Q₃)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e6.50 (0.00, 17.25)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e11.50 (0.00, 19.00)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e0.059\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eSOFA, M (Q₁, Q₃)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e1.50 (0.00, 7.00)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e4.00 (0.00, 7.25)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e0.066\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003ePre-CRKP infection hospital stay, M (Q₁, Q₃)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e12.00 (4.00, 21.00)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e21.00 (10.50, 34.75)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e\u0026lt;\u0026thinsp;.001\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eTotal hospital stay, M (Q₁, Q₃)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e24.50 (15.00, 36.25)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e35.50 (24.75, 61.00)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e\u0026lt;\u0026thinsp;.001\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u003cb\u003eLaboratory tests, M (Q₁, Q₃)\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eWhite blood cell count\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e9.51 (5.63, 13.09)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e8.99 (6.21, 12.52)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e0.983\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003ePlatelets\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e115.00 (49.00, 226.50)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e154.00(73.25,248.25)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e0.057\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eHemoglobin\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e89.50 (78.75, 101.00)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e92.00 (83.00, 105.00)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e0.164\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eAlbumin\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e31.65 (28.68, 35.05)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e31.85 (27.88, 34.83)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e0.615\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eProcalcitonin\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e0.54 (0.18, 1.91)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e0.74 (0.22, 4.10)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e0.106\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eGender, male\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e163 (71.49)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e41 (64.06)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e0.252\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u003cb\u003eComorbidities\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eHypertension\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e94 (41.23)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e37 (57.81)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e0.026\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eDiabetes mellitus\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e63 (27.63)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e14 (21.88)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e0.356\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eMalignant tumor\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e52 (22.81)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e9 (14.06)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e0.128\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eRespiratory disease\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e14 (6.14)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e7 (10.94)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e0.299\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eRenal disease\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e19 (8.33)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e10 (15.63)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e0.085\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eHistory of stroke\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e56 (24.56)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e16 (25.00)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e0.943\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eChronic liver disease\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e34 (14.91)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e14 (21.88)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e0.184\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eCoronary heart disease\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e48 (21.05)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e8 (12.50)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e0.125\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eHistory of ICU admission\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e134 (58.77)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e49 (76.56)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e0.009\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eSeptic shock\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e60 (26.32)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e28 (43.75)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e0.007\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u003cb\u003ePrevious invasive procedures\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eIndwelling urinary catheter\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e150 (65.79)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e56 (87.50)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e\u0026lt;\u0026thinsp;.001\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eCentral venous catheter\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e177 (77.63)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e58 (90.63)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e0.02\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eMechanical ventilation\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e132 (57.90)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e50 (78.13)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e0.003\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eTracheostomy/Intubation\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e117 (51.32)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e43 (67.19)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e0.024\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003ePercutaneous drainage\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e116 (50.88)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e32 (50.00)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e0.901\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eSurgery\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e100 (43.86)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e25 (39.06)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e0.493\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eRenal replacement therapy\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e56 (24.56)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e34 (53.13)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e\u0026lt;\u0026thinsp;.001\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eNasogastric tube\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e137 (60.09)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e50 (78.13)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e0.008\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eBronchoscopy\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e98 (42.98)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e39 (60.94)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e0.011\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u003cb\u003eCo-infections\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eBloodstream infection\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e34 (14.91)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e5 (7.81)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e0.140\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003ePulmonary infection\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e103 (45.18)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e29 (45.31)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e0.984\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eAbdominal infection\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e16 (7.02)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e10 (15.63)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e0.033\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eUrinary tract infection\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e34 (14.91)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e11 (17.19)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e0.656\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eOther infections\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e45 (19.74)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e8 (12.50)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e0.184\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u003cb\u003ePrevious antimicrobial exposure\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eβ-Lactam/β-Lactamase inhibitor combination\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e144 (63.16)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e47 (73.44)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e0.127\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eCarbapenems\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e150 (65.79)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e43 (67.19)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e0.835\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eQuinolones\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e42 (18.42)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e12 (18.75)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e0.952\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eAminoglycosides\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e8 (3.51)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e4 (6.25)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e0.535\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eTigecycline\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e33 (14.47)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e17 (26.56)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e0.023\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003ePolymyxins\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e41 (17.98)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e25 (39.06)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e\u0026lt;\u0026thinsp;.001\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eCeftazidime-avibactam\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e34 (14.91)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e28 (43.75)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e\u0026lt;\u0026thinsp;.001\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eGlycopeptides\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e88 (38.60)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e36 (56.25)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e0.012\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eLinezolid\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e50 (21.93)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e17 (26.56)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e0.436\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u003cb\u003ePoor prognosis\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e73 (32.02)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e31 (48.44)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e0.015\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003c/tbody\u003e\u003c/colgroup\u003e\u003c/table\u003e\u003c/div\u003e\u003c/p\u003e\u003cp\u003e\u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab5\" border=\"1\"\u003e\u003ccaption language=\"En\"\u003e\u003cdiv class=\"CaptionNumber\"\u003eTable 5\u003c/div\u003e\u003cdiv class=\"CaptionContent\"\u003e\u003cp\u003eMultivariate analysis of risk factors for ceftazidime\u0026ndash;avibactam resistant carbapenem-resistant \u003cem\u003eKlebsiella pneumoniae\u003c/em\u003e infection\u003c/p\u003e\u003c/div\u003e\u003c/caption\u003e\u003ccolgroup cols=\"6\"\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e\u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e\u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e\u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e\u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e\u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c6\" colnum=\"6\"\u003e\u003c/div\u003e\u003cthead\u003e\u003ctr\u003e\u003cth align=\"left\" colname=\"c1\"\u003e\u003cp\u003eVariables\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c2\"\u003e\u003cp\u003e\u003cem\u003eβ\u003c/em\u003e\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c3\"\u003e\u003cp\u003e\u003cem\u003eS.E\u003c/em\u003e\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c4\"\u003e\u003cp\u003e\u003cem\u003eZ\u003c/em\u003e\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c5\"\u003e\u003cp\u003e\u003cem\u003eP\u003c/em\u003e\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c6\"\u003e\u003cp\u003e\u003cem\u003eOR\u003c/em\u003e (95%\u003cem\u003eCI\u003c/em\u003e)\u003c/p\u003e\u003c/th\u003e\u003c/tr\u003e\u003c/thead\u003e\u003ctbody\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eRenal replacement therapy\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e0.960\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e0.400\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e2.398\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e\u003cp\u003e0.016\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e\u003cp\u003e2.611 (1.192\u0026thinsp;~\u0026thinsp;5.721)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003ePrevious CZA exposure\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e1.011\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e0.394\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e2.565\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e\u003cp\u003e0.010\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e\u003cp\u003e2.749 (1.269\u0026thinsp;~\u0026thinsp;5.953)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003c/tbody\u003e\u003c/colgroup\u003e\u003c/table\u003e\u003c/div\u003e\u003c/p\u003e\u003c/div\u003e\u003cdiv id=\"Sec11\" class=\"Section2\"\u003e\u003ch2\u003eResistance of CRKP strains to common antibiotics\u003c/h2\u003e\u003cp\u003eCompared with the CZA-susceptible group, the CZA-resistant CRKP group had lower resistance rates to piperacillin/tazobactam, aztreonam, amikacin, gentamicin, ciprofloxacin, levofloxacin, imipenem, and meropenem, but higher resistance to colistin (all \u003cem\u003eP\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.05). All other antibiotics showed no significant differences(\u003cem\u003eP\u003c/em\u003e\u0026thinsp;\u0026gt;\u0026thinsp;0.05).\u003c/p\u003e\u003c/div\u003e\u003cdiv id=\"Sec12\" class=\"Section2\"\u003e\u003ch2\u003eCarbapenemase genotype of 64 CZA-resistant CRKP Strains\u003c/h2\u003e\u003cp\u003eColloidal gold detection revealed that 60 of 64 CZA-resistant CRKP strains tested positive for carbapenemase genes. Among these, 27 strains exhibited co-production of KPC and NDM, 23 produced NDM exclusively, 1 strain co-produced NDM and IMP, 9 strains generated KPC alone, and 4 strains were negative for carbapenemases. PCR and sequencing confirmed carbapenemase genes in 61 isolates, yielding 98.4% concordance with the colloidal-gold assay. Notably, one isolate carrying blaKPC-134 was missed by the colloidal-gold assay.\u003c/p\u003e\u003cp\u003e\u003cb\u003eRelative expression of\u003c/b\u003e \u003cb\u003ebla\u003c/b\u003e\u003cb\u003eKPC in KPC-KP\u003c/b\u003e\u003c/p\u003e\u003cp\u003eTo assess whether blaKPC expression level drives CAZ-AVI resistance,10 CZA resistant and ATCC BAA-1705 strains were identified. The results showed that expression levels of \u003cem\u003ebla\u003c/em\u003eKPC were significantly higher in 8 of the 10 KPC-KP strains compared with the control strain \u003cem\u003eKlebsiella pneumoniae\u003c/em\u003e ATCC BAA-1705(\u003cem\u003ep\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.05),while isolates KP-63 and KP-70 exhibited no elevation.\u003c/p\u003e\u003c/div\u003e\u003cdiv id=\"Sec13\" class=\"Section2\"\u003e\u003ch2\u003eRisk factor for ceftazidime-avibactam resistant CRKP infections\u003c/h2\u003e\u003cp\u003eUnivariate analysis showed that patients in the CZA-resistant CRKP group had a higher proportion of hypertension, ICU admission history, septic shock, prior invasive procedures (such as indwelling catheters, central venous catheters, mechanical ventilation, tracheostomy/intubation, renal replacement therapy, nasogastric tubes, bronchoscopy), prior antibiotic exposure to tigecycline, polymyxins, ceftazidime-avibactam, and glycopeptide antibiotics, and poor prognosis compared to the CZA-sensitive CRKP group. Additionally, the length of hospitalization prior to CRKP infection and total length of hospitalization were longer in the CZA-resistant CRKP group. Variables with \u003cem\u003eP\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.05 in univariate analysis were included in multivariate analysis, which further revealed that renal replacement therapy (\u003cem\u003eOR\u003c/em\u003e\u0026thinsp;=\u0026thinsp;2.611,95% \u003cem\u003eCI\u003c/em\u003e 1.192\u0026ndash;5.721) and prior exposure to ceftazidime-avibactam (\u003cem\u003eOR\u003c/em\u003e\u0026thinsp;=\u0026thinsp;2.749,95% \u003cem\u003eCI\u003c/em\u003e 1.269\u0026thinsp;~\u0026thinsp;5.953) were independent risk factors for CZA-resistant CRKP infections.\u003c/p\u003e\u003c/div\u003e"},{"header":"Discussion","content":"\u003cp\u003eThis study found that the 64 CZA-resistant CRKP strains mainly originated from respiratory specimens (45.32%), which is similar to the results of previous studies\u003csup\u003e[\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e]\u003c/sup\u003e. The strains were mainly distributed in the intensive care unit,where immunosuppressed patients and invasive procedures increase infection risk. Studies have shown that there is a significant correlation between ICU admission history and the incidence of CRKP infection\u003csup\u003e[\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e]\u003c/sup\u003e.The closed ICU environment allows for easy spread of resistant bacteria among patients, highlighting the need for improved infection control and shorter ICU stays to prevent CRKP infections.\u003c/p\u003e\u003cp\u003eCompared with the CZA-susceptible CRKP patients, the CZA-resistant group showed increased polymyxin resistance, but the resistance rate to some β-lactams was actually decreased. This phenotype may be related to the production of KPC variant strains. Studies have shown that KPC variant strains are more likely to regain sensitivity to meropenem while exhibiting higher levels of CZA resistance \u003csup\u003e[\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e]\u003c/sup\u003e. we found that the imipenem MIC of most KPC variant strains was reduced (\u0026le;\u0026thinsp;4\u0026micro;g/mL), while acquiring high-level CZA resistance (MIC\u0026thinsp;\u0026ge;\u0026thinsp;64\u0026micro;g/mL). Wild-type KPC-2 strains exhibited low CZA resistance (MIC\u0026thinsp;\u0026lt;\u0026thinsp;64\u0026micro;g/mL), consistent with previous studies\u003csup\u003e[\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e]\u003c/sup\u003e.\u003c/p\u003e\u003cp\u003eIn this study,Genotyping of CZA-resistant CRKP by colloidal-gold assay and sequencing showed 98.44% concordance.One strain that produced only KPC enzyme was negative by colloidal gold, but identified as blaKPC-134 by sequencing. The colloidal-gold may produce false-negative results for KPC variants, which can lead to incorrect clinical decisions and treatment failure, Molecular detection technology can overcome this problem\u003csup\u003e[\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e]\u003c/sup\u003e. A study results showed that the positive percentages of three colloidal gold immunochromatographic methods for 16 KPC-2 variants were 87.5%, 87.5% and 68.8% compared with GeneXpert Carba-R\u003csup\u003e[\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e]\u003c/sup\u003e.Negative colloidal gold immunochromatographic results that don't match resistance phenotypes should be retested with another kit or GeneXpert Carba-R for better accuracy. In this study, among the 64 CZA-resistant CRKP strains, 50 strains produced NDM, of which 42.18% were co-producing KPC and NDM, 35.94% were blaNDM, and in addition, one strain co-producing NDM and IMP metalloenzyme was found, indicating that the production of metalloenzyme, especially the co-production of KPC and NDM, is the main mechanism of CZA resistance in CRKP in this hospital. In addition to the production of metalloenzyme, KPC mutation is the main mechanism of high-level CZA resistance in this region, which is similar to the results of a study in Taiwan\u003csup\u003e[\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e]\u003c/sup\u003e. Studies have shown that the genomes carrying KPC and NDM are mainly reported in China (45.1%) and the United States (23.0%)\u003csup\u003e[\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e]\u003c/sup\u003e. with a 3.5-fold increase in strains from 2018 to 2022.common combinations include KPC-2 plus NDM-1 (53.6%), KPC-2 plus NDM-5 (18.5%), and KPC-3 plus NDM-1 (14.1%). It is worth noting that the co-production of KPC and NDM in \u003cem\u003eKlebsiella pneumoniae\u003c/em\u003e seems to originate from high-risk clones positive for KPC worldwide, which then acquired plasmids carrying NDM. The emergence of multi-replicon plasmids carrying KPC and NDM is an important mechanism for pan-β-lactam resistance\u003csup\u003e[\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e]\u003c/sup\u003e. The emergence of KPC-NDM-CRKP leads to higher levels of antimicrobial resistance and extremely limited treatment options, which may further lead to increased mortality\u003csup\u003e[\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e]\u003c/sup\u003e. Therefore, clinical laboratories should actively carry out enzyme typing and genotyping detection. For strains producing double enzymes, clinicians can give combination therapy (ceftazidime-avibactam combined with aztreonam) based on enzyme typing and genotyping results to prevent the spread and prevalence of this resistant bacteria in medical institutions.\u003c/p\u003e\u003cp\u003eSince 2019, the incidence of new KPC gene subtypes has increased significantly. According to the NCBI database, more than 200 \u003cem\u003ebla\u003c/em\u003eKPC gene variants have been found worldwide, half of which may have CZA resistance\u003csup\u003e[\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e]\u003c/sup\u003e. In addition, the spread of these \u003cem\u003ebla\u003c/em\u003eKPC genes is mainly mediated by plasmids or small genetic elements on them, especially the Tn4401 transposon\u003csup\u003e[\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e]\u003c/sup\u003e. \u003cem\u003eKlebsiella pneumoniae\u003c/em\u003e bearing with KPC variant often mislead clinical anti-infection treatment because of their unique antimicro\u0026shy;bial susceptibility profile and the tendency of conventional carbapenemase assays to give false negative results. Therefore, timely identification of KPC variants and effective anti-infective therapy are key to saving infected patients\u003csup\u003e[\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e]\u003c/sup\u003e.In this study, sequencing identified 10 KPC-only producers, eight of which carried variants: five blaKPC-33, two blaKPC-90, and one blaKPC-134. Although these three alleles have previously been reported in Beijing\u003csup\u003e[\u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e]\u003c/sup\u003e, Shanghai\u003csup\u003e[\u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e]\u003c/sup\u003e, Fujian\u003csup\u003e[\u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e]\u003c/sup\u003e, and Sichuan\u003csup\u003e[\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e]\u003c/sup\u003e, but this is their first detection in Shaanxi.In addition, two isolates harboring wild-type blaKPC-2 were found. Studies have reported that wild-type KPC strains resistant to CZA is related to the high expression of blaKPC genes and the loss of outer membrane porins\u003csup\u003e[\u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e]\u003c/sup\u003e. RT-qPCR revealed that \u003cem\u003ebla\u003c/em\u003eKPC-2 expression in both isolates was significantly elevated compared with control strain \u003cem\u003eKlebsiella pneumoniae\u003c/em\u003e ATCC BAA-1705, likely accounting for their CZA resistance. However, whether there is a combination of membrane porin loss and overexpression of efflux pumps needs further study. Although meropenem-vaborbactam is considered a salvage treatment for CZA-resistant KPC variant-producing \u003cem\u003eKlebsiella pneumoniae\u003c/em\u003e\u003csup\u003e[\u003cspan citationid=\"CR24\" class=\"CitationRef\"\u003e24\u003c/span\u003e]\u003c/sup\u003e. However, this new agent remains unavailable in many regions, especially resource-limited settings,Consequently, evaluating alternative regimens such as ceftazidime\u0026ndash;avibactam plus imipenem is urgently needed\u003csup\u003e[\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e, \u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e]\u003c/sup\u003e.\u003c/p\u003e\u003cp\u003eMost studies mainly focus on the resistance mechanisms of CZA-resistant CRKP, with few on risk factors. The study showed that renal replacement therapy and previous CZA exposure as independent risk factors for CZA-resistant CRKP infection. Renal-replacement therapy promotes CRKP colonization and linadequate drug exposure, thereby increasing the risk of CAZ-AVI-resistant infection.\u003csup\u003e[\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e]\u003c/sup\u003e. In addition, it was also found that the proportion of previous CZA exposure in the CZA-resistant CRKP group was significantly higher than that in the CZA-susceptible CRKP group. Previous studies have shown that CZA treatment may be an independent risk factor for inducing mutations of blaKPC\u003csup\u003e[\u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e]\u003c/sup\u003e.New KPC mutations are usually associated with clinical use of CZA for 9\u0026ndash;19 days\u003csup\u003e[\u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e, \u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR26\" class=\"CitationRef\"\u003e26\u003c/span\u003e]\u003c/sup\u003e. In this study, we found that KPC mutations were closely related to CZA treatment. Among the eight patients with KPC-mutant CRKP, six had received CZA for a median of 11 days before resistance was detected, whereas the remaining two developed resistance without any CZA exposure, confirming previous studies\u003csup\u003e[\u003cspan citationid=\"CR27\" class=\"CitationRef\"\u003e27\u003c/span\u003e]\u003c/sup\u003e。\u003c/p\u003e\u003cdiv id=\"Sec15\" class=\"Section2\"\u003e\u003ch2\u003eStrengthen and limitation\u003c/h2\u003e\u003cp\u003eOur study has several limitations. Firstly, the single-center retrospective study design may introduce selection bias. Secondly, molecular mechanisms such as porin loss and overexpression of efflux pumps were not thoroughly explored. Moreover, the limited sample size restricted the detection of rare resistance subtypes.\u003c/p\u003e\u003c/div\u003e"},{"header":"Conclusions","content":"\u003cp\u003eThis study demonstrates that CZA-resistant CRKP in our hospital is driven primarily by metalloenzyme production\u0026mdash;especially KPC-2/NDM-1 co-producers\u0026mdash;while KPC mutations and over-expression are additional key mechanisms. Renal replacement therapy and a history of previous CZA exposure are identified as independent risk factors for CZA-resistant CRKP.\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eEthics approval\u003c/strong\u003e\u003cp\u003e This retrospective study was conducted in accordance with the Declaration of Helsinki and was approved by the Medical Ethics Committee of the First Affiliated Hospital of Xi\u0026rsquo;an Jiaotong University, which waived pan-informed consent.\u003c/p\u003e\u003c/p\u003e\u003cp\u003e\u003cstrong\u003eConsent for publication\u003c/strong\u003e\u003cp\u003eNot applicable.\u003c/p\u003e\u003c/p\u003e\u003cp\u003e\u003cstrong\u003eCompeting interests\u003c/strong\u003e\u003cp\u003eThe authors declare no competing interests.\u003c/p\u003e\u003c/p\u003e\u003ch2\u003eFunding\u003c/h2\u003e\u003cp\u003eThis work was supported by the Shaanxi Provincial natural science basic research Project (S2024JC-YBQN-0836, S2024JC-YBQN-0986).\u003c/p\u003e\u003ch2\u003eAuthor Contribution\u003c/h2\u003e\u003cp\u003eXiaqin He and Meng Liu carried out the medical records database search, statistical analysis, and drafted the manuscript.Xiaoqian Wang, Sijia Li,Yi Zhang，Zhe Liu and Xiaoqin Wang participated in the design and coordination of the study and helped to draft the manuscript. All authors read and approved the final manuscript.\u003c/p\u003e\u003ch2\u003eData Availability\u003c/h2\u003e\u003cp\u003eAll data generated or analyzed in the study are included in the article and further inquiries can be directly contacted with the corresponding author Xiaoqin Wang via e-mail.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\u003cli\u003e\u003cspan\u003eHe J, Shi Q, Chen Z et al. Opposite evolution of pathogenicity driven by in vivo wzc and wcaJ mutations in ST11-KL64 carbapenem-resistant \u003cem\u003eKlebsiella pneumoniae\u003c/em\u003e[J]. Drug Resist Updat,2023,66:100891.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eLiu E, Jia P, Li X, et al. In vitro and in vivo Effect of Antimicrobial Agent Combinations Against Carbapenem-Resistant \u003cem\u003eKlebsiella pneumoniae\u003c/em\u003e with Different Resistance Mechanisms in China[J]. Infect Drug Resist. 2021;14:917\u0026ndash;28.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eWang YY, Jiang M, Liu SJ et al. The synergistic effect of imipenem combined with ceftazidime-avibactam against \u003cem\u003eKlebsiella pneumoniae\u003c/em\u003e with alternating resistance to CZA and carbapenem[J]. J Microbiol Immunol Infect,2025.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eSanz HF. Ceftazidime-avibactam[J]. Rev Esp Quimioter 2022 35 Suppl 1(Suppl 1):40\u0026ndash;2.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eXiong L, Wang X, Wang Y et al. Molecular mechanisms underlying bacterial resistance to ceftazidime/avibactam[J]. WIREs Mech Dis 2022,14(6):e1571.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eJean SS, Chang HT, Huang CL et al. Distributions of plasmidic genes encoding extended-spectrum and AmpC beta-lactamases, and susceptibilities of global non-carbapenemase-producing meropenem-resistant Enterobacterales to ceftazidime-avibactam, meropenem-vaborbactam, and aztreonam-avibactam, 2017\u0026ndash;2022[J]. J Infect,2025,90(2):106380.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eLiu X, Chu Y, Yue H, et al. Risk factors for and clinical outcomes of ceftazidime-avibactam-resistant carbapenem-resistant \u003cem\u003eKlebsiella pneumoniae\u003c/em\u003e nosocomial infections: a single-center retrospective study[J]. Volume 50. Infection; 2022. pp. 1147\u0026ndash;54. 5.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eDing L, Shen S, Chen J et al. \u003cem\u003eKlebsiella pneumoniae\u003c/em\u003e carbapenemase variants: the new threat to global public health[J]. 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Risk factors for infection and mortality caused by carbapenem-resistant \u003cem\u003eKlebsiella pneumoniae\u003c/em\u003e: A large multicentre case-control and cohort study[J]. J Infect. 2022;84(5):637\u0026ndash;47.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eLiu SY, Chou SH, Chuang C, et al. Clinical and Microbiological characteristics of patients with ceftazidime/avibactam-resistant \u003cem\u003eKlebsiella pneumoniae\u003c/em\u003e carbapenemase (KPC)-producing K. pneumoniae strains[J]. Ann Clin Microbiol Antimicrob. 2025;24(1):26.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eZhang J, Xu J, Shen S et al. Comparison of three colloidal gold immunoassays and GeneXpert Carba-R for the detection of \u003cem\u003eKlebsiella pneumoniae\u003c/em\u003e bla(KPC-2) variants[J]. J Clin Microbiol 2024,62(7):e15424.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eChou SH, Chuang C, Juan CH, et al. 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Ceftazidime-Avibactam in Combination with Imipenem as Salvage Therapy for ST11 KPC-33-Producing \u003cem\u003eKlebsiella pneumoniae\u003c/em\u003e[J]. Antibiotics (Basel),2022,11(5).\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eYang W, Xu H, Zhao Y, et al. Identification of bla(KPC-90) in \u003cem\u003eKlebsiella pneumoniae\u003c/em\u003e associated with ceftazidime-avibactam resistance and the translocation \u0026amp; truncation of resistant genes mediated by IS26[J]. Int J Antimicrob Agents. 2025;65(1):107388.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eNelson K, Hemarajata P, Sun D et al. Resistance to Ceftazidime-Avibactam Is Due to Transposition of KPC in a Porin-Deficient Strain of \u003cem\u003eKlebsiella pneumoniae\u003c/em\u003e with Increased Efflux Activity[J]. Antimicrob Agents Chemother,2017,61(10).\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eTiseo G, Falcone M, Leonildi A et al. Meropenem-Vaborbactam as Salvage Therapy for Ceftazidime-Avibactam-, Cefiderocol-Resistant ST-512 \u003cem\u003eKlebsiella pneumoniae\u003c/em\u003e-Producing KPC-31, a D179Y Variant of KPC-3[J]. Open Forum Infect Dis 2021,8(6):ofab141.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eZhou P, Gao H, Li M, et al. Characterization of a novel KPC-2 variant, KPC-228, conferring resistance to ceftazidime-avibactam in an ST11-KL64 hypervirulent \u003cem\u003eKlebsiella pneumoniae\u003c/em\u003e[J]. Int J Antimicrob Agents. 2025;65(3):107411.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eVenditti C, Butera O, Meledandri M et al. Molecular analysis of clinical isolates of ceftazidime-avibactam-resistant \u003cem\u003eKlebsiella pneumoniae\u003c/em\u003e[J]. Clin Microbiol Infect 2021,27(7):1040\u0026ndash;1.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eGong Y, Feng Y, Lv X. Identification of a Novel KPC Variant, KPC-204, Conferring Resistance to Both Carbapenems and Ceftazidime-Avibactam in an ST11 \u003cem\u003eKlebsiella pneumoniae\u003c/em\u003e Strain[J]. Microorganisms,2024,12(6).\u003c/span\u003e\u003c/li\u003e\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":true,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"bmc-research-notes","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"resn","sideBox":"Learn more about [BMC Research Notes](http://bmcresnotes.biomedcentral.com)","snPcode":"","submissionUrl":"https://www.editorialmanager.com/resn/default.aspx","title":"BMC Research Notes","twitterHandle":"@BMC_series","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"em","reportingPortfolio":"BMC Series","inReviewEnabled":true,"inReviewRevisionsEnabled":true},"keywords":"ceftazidime-avibactam resistance, carbapenem-resistant Klebsiella pneumoniae, resistance mechanisms, risk factors","lastPublishedDoi":"10.21203/rs.3.rs-7507415/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-7507415/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003e\u003cb\u003eObjective\u003c/b\u003e To investigate the molecular epidemiological characteristics of carbapenem-resistant \u003cem\u003eKlebsiella pneumoniae\u003c/em\u003e(CRKP),elucidate the resistance mechanisms to ceftazidime-avibactam (CZA) and identify the risk factors associated with CZA resistance. Clinical and microbiological data from 293 hospitalized patients with CRKP infections were retrospectively collected at the First Affiliated Hospital of Xi'an Jiaotong University from January 2024 to March 2025. Based on CZA susceptibility results, patients were divided into the CZA-sensitive CRKP group (n\u0026thinsp;=\u0026thinsp;228) and the CZA-resistant CRKP group (n\u0026thinsp;=\u0026thinsp;64). The colloidal gold detection method was used to identify five carbapenemase genes(\u003cem\u003ebla\u003c/em\u003eKPC, \u003cem\u003ebla\u003c/em\u003eNDM, \u003cem\u003ebla\u003c/em\u003eVIM, \u003cem\u003ebla\u003c/em\u003eIMP, and \u003cem\u003ebla\u003c/em\u003eOXA)and their subtypes were determined through PCR amplification and sanger sequencing. The relative expression of the \u003cem\u003ebla\u003c/em\u003eKPC gene was measured using real-time quantitative PCR (RT-qPCR). Multivariate logistic regression analysis was performed to identify risk factors for CZA-resistant CRKP infections.\u003c/p\u003e\u003cp\u003e\u003cb\u003eResults\u003c/b\u003e The primary resistance mechanisms for CZA-resistant CRKP in our hospital are the production of metal enzymes, especially KPC-2 and NDM-1 co-producing strains. Some strains exhibit resistance to CZA due to blaKPC-2 mutations and increased gene expression. Multivariate logistic regression analysis revealed that renal replacement therapy (\u003cem\u003eOR\u003c/em\u003e\u0026thinsp;=\u0026thinsp;2.611, 95% \u003cem\u003eCI\u003c/em\u003e 1.192\u0026ndash;5.721) and prior CZA exposure (\u003cem\u003eOR\u003c/em\u003e\u0026thinsp;=\u0026thinsp;2.749, 95% \u003cem\u003eCI\u003c/em\u003e 1.269\u0026thinsp;~\u0026thinsp;5.953) were independent risk factors for CZA-resistant CRKP infections.\u003c/p\u003e","manuscriptTitle":"The resistance mechanisms and risk factors of carbapenem-resistant Klebsiella pneumoniae to ceftazidime-avibactam","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2025-10-27 14:25:24","doi":"10.21203/rs.3.rs-7507415/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"decision","content":"Revision requested","date":"2026-04-23T07:18:34+00:00","index":"","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2026-04-02T12:29:31+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"99499449074176596702571405828054067865","date":"2026-03-30T09:15:28+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"160136450098106507589713830898275206728","date":"2026-03-27T16:54:39+00:00","index":"hide","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2025-11-23T06:19:41+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"190425467924963511571752684359552249411","date":"2025-11-23T04:48:55+00:00","index":"hide","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2025-10-13T16:37:43+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"3464365045675327266551560358990164199","date":"2025-10-12T12:21:55+00:00","index":"hide","fulltext":""},{"type":"reviewersInvited","content":"","date":"2025-10-12T11:43:36+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2025-09-11T08:53:33+00:00","index":"","fulltext":""},{"type":"editorInvited","content":"","date":"2025-09-11T08:37:36+00:00","index":"","fulltext":""},{"type":"checksComplete","content":"","date":"2025-09-11T08:25:53+00:00","index":"","fulltext":""},{"type":"submitted","content":"BMC Research Notes","date":"2025-09-11T08:21:00+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"bmc-research-notes","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"resn","sideBox":"Learn more about [BMC Research Notes](http://bmcresnotes.biomedcentral.com)","snPcode":"","submissionUrl":"https://www.editorialmanager.com/resn/default.aspx","title":"BMC Research Notes","twitterHandle":"@BMC_series","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"em","reportingPortfolio":"BMC Series","inReviewEnabled":true,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"638f2a9a-a6c7-45da-98c3-28705cc0e60f","owner":[],"postedDate":"October 27th, 2025","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"under-review","subjectAreas":[],"tags":[],"updatedAt":"2026-05-07T09:39:52+00:00","versionOfRecord":[],"versionCreatedAt":"2025-10-27 14:25:24","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-7507415","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-7507415","identity":"rs-7507415","version":["v1"]},"buildId":"8U1c8b4HqxoKbykW_rLl7","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}