scholarly journals In vivo Emergence of Colistin and Tigecycline Resistance in Carbapenem-Resistant Hypervirulent Klebsiella pneumoniae During Antibiotics Treatment

2021 ◽  
Vol 12 ◽  
Author(s):  
Jiawei Chen ◽  
Yu Zeng ◽  
Rong Zhang ◽  
Jiachang Cai
Keyword(s):  
Klebsiella Pneumoniae ◽  
Galleria Mellonella ◽  
Survival Rates ◽  
Fold Increase ◽  
Conjugative Plasmid ◽  
Virulence Plasmid ◽  
Carbapenem Resistant ◽  
Antimicrobial Resistance Genes

Three carbapenem-resistant Klebsiella pneumoniae (CRKP; strains KP-426, KP-C76, and KP-CT77) were isolated from a patient with severe burns during the treatment of colistin and tigecycline. Single-nucleotide polymorphism typing showed that three ST11 CRKP were clonally related. Three isolates harbored the same set of antimicrobial resistance genes. blaKPC-2, blaSHV-12, blaTEM-1, and rmtB genes were located on the same 128,928-bp IncFII/IncR plasmid. Tet(A), catA2, sul2, and dfrA14 genes were located on a plasmid with an unknown Inc-type. blaSHV-11, fosA, and aadA2 were chromosomal genes. An IS1 and an ISKpn14 were found in the promoter region of the mgrB gene of two colistin-resistant CRKP, K. pneumoniae KP-C76, and KP-CT77, respectively. A novel amino acid substitution, G300E, was identified in the type 1 Tet(A) variant of K. pneumoniae KP-CT77 which exhibited high-level tigecycline resistance compared to strains KP-426 and KP-C76 (MIC of 32, 4, and 4mg/l, respectively). Conjugation and cloning experiments confirmed that the mutated Tet(A) resulted in a 4-fold increase in tigecycline minimal inhibitory concentration (MIC) of Escherichia coli. Three CRKP belonged to the K64 serotype and possessed a similar IncHI1B/repB virulence plasmid carrying rmpA, rmpA2, and iucABCDiutA. The survival rates of Galleria Mellonella injected with K. pneumoniae KP-426, KP-C76, and KP-CT77 were 4.2, 20.8, and 8.3%, respectively. The emergence of colistin and tigecycline resistance in carbapenem-resistant hypervirulent K. pneumoniae posed a serious threat to clinical anti-infective therapy. The type 1 Tet(A) variant carrying G300E mutation, which conferred significantly elevated tigecycline MIC and was located on a conjugative plasmid, needs attention.

scholarly journals An Outbreak of Carbapenem-Resistant Klebsiella Pneumoniae of K57 Capsular Serotype in an Emergency Intensive Care Unit of a Teaching Hospital in China

2020 ◽  
Author(s):  
Chunhong Shao ◽  
Yan Jin ◽  
Shuang Liu ◽  
Meijie Jiang ◽  
Shuping Zhao
Keyword(s):  
Intensive Care Unit ◽  
Intensive Care ◽  
Klebsiella Pneumoniae ◽  
Teaching Hospital ◽  
Galleria Mellonella ◽  
Pulse Field ◽  
Carbapenem Resistant ◽  
Surrounding Environment ◽  
Antimicrobial Resistance Genes ◽  
Broth Microdilution Method

Abstract Background: Klebsiella pneumoniae is a common causative pathogen of nosocomial infections. The emergence of carbapenem-resistant hypervirulent K. pneumoniae (CR-hvKP) strains has further increased the threat posed by this bacterium. Here, we described an outbreak of 32 CR-hvKP isolates from the emergency intensive care unit (EICU) of a teaching hospital in China. Methods: From January 29, 2019 to March 11, 2019, 32 CRKp isolates were collected from 6 patients and their surrounding environment in EICU. Patient information including age, gender, length of EICU stay, diagnosis, treatment, and outcomes were obtained from electronic medical records. The isolates were identified using Vitek-MS system. The hypermucoviscosity phenotype was determined by the “string test”. Antimicrobial susceptibility testing was performed using VITEK 2 compact system, E-test or the broth microdilution method. All isolates were serotyped for K1, K2, K5, K20, K54, and K57 serotypes, antimicrobial resistance genes and twelve virulence-associated genes were screened using PCR and DNA sequencing. Multilocus sequence typing (MLST) and pulse-field gel electrophoresis (PFGE) were employed to characterize the genetic relationships among the CPKP isolates. The virulence capability of 11 CRKp isolates from 6 patients was evaluated through Galleria mellonella larva infection assay. Results: This outbreak involved 6 patients and lasted for 40 days. All 32 CR-hvKp isolates were obtained from 6 patients and their surrounding environment. PFGE showed that all 32 isolates belonged to one cluster, and MLST revealed that belonged to ST11. All isolates exhibited high resistance to β-lactam antibiotics, quinolones, and aminoglycosides. They were susceptible to ceftazidime/averbatan, tigecycline, and colistin. All 32 isolates harbored multiple resistance determinants, including blaKPC-2, blaSHV-11, blaTEM-1, rmtB, and qnrD. The serotype of all 32 isolates was K57 that was rarely reported. In the virulence gene analysis, all 32 isolates contained 6 virulence genes, namely, fimH, iucB, mrkD, rmpA, uge, and wabG. Infection assays demonstrated high mortality in the Galleria mellonella model. Following measures implemented by the hospital, the outbreak was controlled. The mortality rate was 83.3%.Conclusions: The epidemiology of CR-hvKP should be monitored closely to detect early indications of this emerging public health threat.

scholarly journals Aerobactin Seems To Be a Promising Marker Compared With Unstable RmpA2 for the Identification of Hypervirulent Carbapenem-Resistant Klebsiella pneumoniae: In Silico and In Vitro Evidence

2021 ◽  
Vol 11 ◽  
Author(s):  
Chaitra Shankar ◽  
Soumya Basu ◽  
Binesh Lal ◽  
Sathiya Shanmugam ◽  
Karthick Vasudevan ◽  
...  
Keyword(s):  
High Risk ◽  
Antimicrobial Resistance ◽  
Klebsiella Pneumoniae ◽  
In Silico ◽  
Fitness Cost ◽  
Virulence Plasmid ◽  
Virulence Determinants ◽  
Carbapenem Resistant ◽  
Antimicrobial Resistance Genes

BackgroundThe incidence of hypervirulent (hv) carbapenem-resistant (CR) Klebsiella pneumoniae (Kp) is increasing globally among various clones and is also responsible for nosocomial infections. The CR-hvKp is formed by the uptake of a virulence plasmid by endemic high-risk clones or by the uptake of plasmids carrying antimicrobial resistance genes by the virulent clones. Here, we describe CR-hvKp from India belonging to high-risk clones that have acquired a virulence plasmid and are phenotypically unidentified due to lack of hypermucoviscosity.MethodsTwenty-seven CRKp isolates were identified to possess rmpA2 by whole-genome sequencing; and resistance and virulence determinants were characterized. By in silico protein modeling (and validation), protein backbone stability analysis, and coarse dynamics study, the fitness of RmpA, RmpA2, and aerobactin-associated proteins-IucA and IutA, were determined to establish a reliable marker for clinical identification of CR-hvKp.ResultsThe CR-hvKp belonged to multidrug-resistant (MDR) high-risk clones such as CG11, CG43, ST15, and ST231 and carried OXA-232 as the predominant carbapenemase followed by NDM. The virulence plasmid belonged to IncHI1B replicon type and carried frameshifted and truncated rmpA and rmpA2. This resulted in a lack of hypermucoviscous phenotype. However, functional aerobactin was expressed in all high-risk clones. In silico analysis portrayed that IucA and IutA were more stable than classical RmpA. Furthermore, IucA and IutA had lower conformational fluctuations in the functional domains than the non-functional RmpA2, which increases the fitness cost of the latter for its maintenance and expression among CR-hvKp. Hence, RmpA and RmpA2 are likely to be lost among CR-hvKp owing to the increased fitness cost while coding for essential antimicrobial resistance and virulence factors.ConclusionIncreasing incidence of convergence of AMR and virulence is observed among K. pneumoniae globally, which warrants the need for reliable markers for identifying CR-hvKp. The presence of non-functional RmpA2 among high-risk clones highlights the significance of molecular identification of CR-hvKp. The negative string test due to non-functional RmpA2 among CR-hvKp isolates challenges phenotypic screening and faster identification of this pathotype. This can potentially be counteracted by projecting aerobactin as a stable, constitutively expressed, and functional marker for rapidly evolving CR-hvKp.

scholarly journals Mobilization of the nonconjugative virulence plasmid from hypervirulent Klebsiella pneumoniae

2021 ◽  
Vol 13 (1) ◽  
Author(s):  
Yanping Xu ◽  
Jianfeng Zhang ◽  
Meng Wang ◽  
Meng Liu ◽  
Guitian Liu ◽  
...  
Keyword(s):  
Klebsiella Pneumoniae ◽  
In Silico ◽  
In Silico Analysis ◽  
Conjugative Plasmid ◽  
Virulence Plasmid ◽  
E Coli ◽  
Virulence Plasmids ◽  
Carbapenem Resistant ◽  
Helper Plasmids ◽  
Silico Analysis

Abstract Background Klebsiella pneumoniae, as a global priority pathogen, is well known for its capability of acquiring mobile genetic elements that carry resistance and/or virulence genes. Its virulence plasmid, previously deemed nonconjugative and restricted within hypervirulent K. pneumoniae (hvKP), has disseminated into classic K. pneumoniae (cKP), particularly carbapenem-resistant K. pneumoniae (CRKP), which poses alarming challenges to public health. However, the mechanism underlying its transfer from hvKP to CRKP is unclear. Methods A total of 28 sequence type (ST) 11 bloodstream infection-causing CRKP strains were collected from Ruijin Hospital in Shanghai, China, and used as recipients in conjugation assays. Transconjugants obtained from conjugation assays were confirmed by XbaI and S1 nuclease pulsed-field gel electrophoresis, PCR detection and/or whole-genome sequencing. The plasmid stability of the transconjugants was evaluated by serial culture. Genetically modified strains and constructed mimic virulence plasmids were employed to investigate the mechanisms underlying mobilization. The level of extracellular polysaccharides was measured by mucoviscosity assays and uronic acid quantification. An in silico analysis of 2608 plasmids derived from 814 completely sequenced K. pneumoniae strains available in GenBank was performed to investigate the distribution of putative helper plasmids and mobilizable virulence plasmids. Results A nonconjugative virulence plasmid was mobilized by the conjugative plasmid belonging to incompatibility group F (IncF) from the hvKP strain into ST11 CRKP strains under low extracellular polysaccharide-producing conditions or by employing intermediate E. coli strains. The virulence plasmid was mobilized via four modes: transfer alone, cotransfer with the conjugative IncF plasmid, hybrid plasmid formation due to two rounds of single-strand exchanges at specific 28-bp fusion sites or homologous recombination. According to the in silico analysis, 31.8% (242) of the putative helper plasmids and 98.8% (84/85) of the virulence plasmids carry the 28-bp fusion site. All virulence plasmids carry the origin of the transfer site. Conclusions The nonconjugative virulence plasmid in ST11 CRKP strains is putatively mobilized from hvKP or E. coli intermediates with the help of conjugative IncF plasmids. Our findings emphasize the importance of raising public awareness of the rapid dissemination of virulence plasmids and the consistent emergence of hypervirulent carbapenem-resistant K. pneumoniae (hv-CRKP) strains.

scholarly journals Microcin MccI47 selectively inhibits enteric bacteria and reduces carbapenem-resistant Klebsiella pneumoniae colonization in vivo when administered via an engineered live biotherapeutic

2021 ◽  
Author(s):  
Benedikt M Mortzfeld ◽  
Jacob D Palmer ◽  
Shakti K Bhattarai ◽  
Haley L Dupre ◽  
Regino Mercado-Lubo ◽  
...  
Keyword(s):  
Klebsiella Pneumoniae ◽  
Genetically Modify ◽  
Enteric Bacteria ◽  
Probiotic Bacterium ◽  
Multicopy Plasmid ◽  
Gi Tract ◽  
Carbapenem Resistant ◽  
Antimicrobial Resistance Genes

Background: The gastrointestinal (GI) tract is the reservoir for multidrug-resistant (MDR) pathogens, specifically carbapenem-resistant (CR) Klebsiella pneumoniae and other Enterobacteriaceae, which often lead to the spread of antimicrobial resistance genes, severe extraintestinal infections, and lethal outcomes. Selective GI decolonization has been proposed as a new strategy for preventing transmission to other body sites and minimizing spreading to susceptible individuals. Results: Here, we purify the to-date uncharacterized class IIb microcin I47 (MccI47) and demonstrate potent inhibition of numerous Enterobacteriaceae, including MDR clinical isolates, in vitro at concentrations resembling those of commonly prescribed antibiotics. We then genetically modify the probiotic bacterium Escherichia coli Nissle 1917 (EcN) to produce MccI47 from a stable multicopy plasmid by using MccI47 toxin production in a counterselection mechanism to engineer one of the native EcN plasmids, which renders provisions for inducible expression and plasmid selection unnecessary. We then test the clinical relevance of the MccI47-producing engineered EcN in a murine CR K. pneumoniae colonization model and demonstrate significant MccI47-dependent reduction of CR K. pneumoniae abundance after seven days of daily oral live biotherapeutic administration without disruption of the resident microbiota. Conclusions: This study provides the first demonstration of MccI47 as a potent antimicrobial against certain Enterobacteriaceae, and its ability to significantly reduce the abundance of CR K. pneumoniae in a preclinical animal model, when delivered from an engineered live biotherapeutic product. This study serves as the foundational step towards the use of engineered live biotherapeutic products aimed at the selective removal of MDR pathogens from the GI tract.

scholarly journals Komodo-dragon cathelicidin-inspired peptides are antibacterial against carbapenem-resistant Klebsiella pneumoniae

2020 ◽  
Vol 69 (11) ◽  
pp. 1262-1272
Author(s):  
Samantha J. Hitt ◽  
Barney M. Bishop ◽  
Monique L. van Hoek
Keyword(s):  
Antimicrobial Activity ◽  
Klebsiella Pneumoniae ◽  
Antimicrobial Peptides ◽  
Galleria Mellonella ◽  
Content Type ◽  
Carbapenem Resistant ◽  
Level Of Activity ◽  
Improvement In Survival ◽  
Synthetic Antimicrobial Peptides

Introduction. The rise of carbapenem-resistant enterobacteriaceae (CRE) is a growing crisis that requires development of novel therapeutics. Hypothesis. To this end, cationic antimicrobial peptides (CAMPs) represent a possible source of new potential therapeutics to treat difficult pathogens such as carbapenem-resistant Klebsiella pneumoniae (CRKP), which has gained resistance to many if not all currently approved antibiotics, making treatment difficult. Aim. To examine the anti-CRKP antimicrobial activity of the predicted cathelicidins derived from Varanus komodoensis (Komodo dragon) as well as synthetic antimicrobial peptides that we created. Methodology. We determined the minimum inhibitory concentrations of the peptides against CRKP. We also characterized the abilities of these peptides to disrupt the hyperpolarization of the bacterial membrane as well as their ability to form pores in the membrane. Results. We did not observe significant anti-CRKP activity for the predicted native Komodo cathelicidin peptides. We found that the novel peptides DRGN-6,-7 and -8 displayed significant antimicrobial activity against CRKP with MICs of 4–8 µg ml−1. DRGN-6 peptide was the most effective peptide against CRKP. Unfortunately, these peptides showed higher than desired levels of hemolysis, although in vivo testing in the waxworm Galleria mellonella showed no mortality associated with treatment by the peptide; however, CRKP-infected waxworms treated with peptide did not show an improvement in survival. Conclusion. Given the challenges of treating CRKP, identification of peptides with activity against it represents a promising avenue for further research. Given DRGN-6′s similar level of activity to colistin, DRGN-6 is a promising template for the development of novel antimicrobial peptide-based therapeutics.

scholarly journals Acquisition of the Conjugative Virulence Plasmid From a CG23 Hypervirulent Klebsiella pneumoniae Strain Enhances Bacterial Virulence

2021 ◽  
Vol 11 ◽  
Author(s):  
Dongxing Tian ◽  
Weiwen Wang ◽  
Meng Li ◽  
Wenjie Chen ◽  
Ying Zhou ◽  
...  
Keyword(s):  
Klebsiella Pneumoniae ◽  
Biofilm Formation ◽  
Evidence Base ◽  
Serum Resistance ◽  
Virulence Plasmid ◽  
E Coli ◽  
Virulence Plasmids ◽  
Carbapenem Resistant ◽  
High Level

The emergence of hypervirulent and carbapenem-resistant Klebsiella pneumoniae (hv-CRKP) has become a hot topic and confounding problem for clinicians and researchers alike. Conjugative virulence plasmids have the potential to cause more threatening dissemination of hv-CRKP strains. We previously identified K2606, a CG23 clinical hypervirulent strain of Klebsiella pneumoniae harboring a conjugative virulence plasmid designated pK2606. In this study we examined hypervirulence levels using assays of biofilm formation, serum resistance, and wax larvae and mouse in vivo infection models. Moreover, to define the transfer ability of pK2606 and whether this confers hypervirulence to other strains we performed plasmid transconjugation experiments between K2606 and the ST11 CRKP strain HS11286 along with E. coli J53. We found that although biofilm formation and serum resistance were not significantly increased, the transconjugants acquired the ability of produce high level of siderophores and also caused high mortality of wax larvae and mice. Furthermore, we identified pK2606-like conjugative virulence plasmids in GenBank, providing evidence that such plasmids may have begun to spread throughout China. These findings provide an evidence base for the possible mechanisms of the emergence of hv-CRKP strains and highlight the potential of pK2606-like conjugative virulence plasmids to spread worldwide.

scholarly journals Prevalence of Carbapenem-Resistant Klebsiella pneumoniae Co-Harboring blaKPC-Carrying Plasmid and pLVPK-Like Virulence Plasmid in Bloodstream Infections

2021 ◽  
Vol 10 ◽  
Author(s):  
Fang-ling Du ◽  
Qi-sen Huang ◽  
Dan-dan Wei ◽  
Yan-fang Mei ◽  
Dan Long ◽  
...  
Keyword(s):  
Klebsiella Pneumoniae ◽  
Galleria Mellonella ◽  
Bloodstream Infections ◽  
Multi Drug Resistance ◽  
Virulence Plasmid ◽  
E Coli ◽  
Plasmid Gene ◽  
Carbapenem Resistant ◽  
Large Plasmids ◽  
Serotype K2

This study aimed to characterize carbapenem-resistant Klebsiella pneumoniae (CR-KP) co-harboring blaKPC-2-carrying plasmid and pLVPK-like virulence plasmid. Between December 2017 and April 2018, 24 CR-KP isolates were recovered from 24 patients with bacteremia. The mortality was 66.7%. Pulsed-field gel electrophoresis and multilocus sequence typing results indicated four clusters, of which cluster A (n = 21, 87.5%) belonged to ST11 and the three remaining isolates (ST412, ST65, ST23) had different pulsotypes (cluster B, C, D). The blaKPC-2-carrying plasmids all belonged to IncFIIK type, and the size ranged from 100 to 390 kb. Nineteen strains (79.2%) had a 219-kb virulence plasmid possessed high similarity to pLVPK from CG43 with serotype K2. Two strains had a 224-kb virulence plasmid resembled plasmid pK2044 from K. pneumoniae NTUH-K2044(ST23). Moreover, three strains carried three different hybrid resistance- and virulence-encoding plasmids. Conjugation assays showed that both blaKPC-2 and rmpA2 genes could be successfully transferred to E. coli J53 in 62.5% of the strains at frequencies of 4.5 × 10−6 to 2.4 × 10−4, of which three co-transferred blaKPC-2 along with rmpA2 in large plasmids. Infection assays in the Galleria mellonella model demonstrated the virulence level of these isolates was found to be consistently higher than that of classic Klebsiella pneumoniae. In conclusion, CR-KP co-harboring blaKPC-2-carrying plasmid and pLVPK-like virulence plasmid were characterized by multi-drug resistance, enhanced virulence, and transferability, and should, therefore, be regarded as a real superbug that could pose a serious threat to public health. Hence, heightened efforts are urgently needed to avoid its co-transmission of the virulent plasmid (gene) and resistant plasmid (gene) in clinical isolates.

scholarly journals Roles of ramR and tet(A) Mutations in Conferring Tigecycline Resistance in Carbapenem-Resistant Klebsiella pneumoniae Clinical Isolates

2017 ◽  
Vol 61 (8) ◽  
Author(s):  
Sheng-Kang Chiu ◽  
Li-Yueh Huang ◽  
Hsi Chen ◽  
Yu-Kuo Tsai ◽  
Ci-Hong Liou ◽  
...  
Keyword(s):  
Klebsiella Pneumoniae ◽  
Synergistic Effects ◽  
Fold Increase ◽  
Amplicon Sequencing ◽  
Resistance Mechanisms ◽  
Content Type ◽  
Carbapenem Resistant ◽  
A Site

ABSTRACT Tigecycline is regarded as a last-resort treatment for carbapenem-resistant Klebsiella pneumoniae (CRKP) infections, but increasing numbers of tigecycline-resistant K. pneumoniae isolates have been reported. The tigecycline resistance mechanisms in CRKP are undetermined. This study aimed to elucidate the mechanisms underlying tigecycline resistance in 16 tigecycline- and carbapenem-resistant K. pneumoniae (TCRKP) isolates. Mutations in tigecycline resistance determinant genes [ramR, acrR, oqxR, tet(A), tet(L), tet(X), tet(M), rpsJ] were assessed by PCR amplicon sequencing, and mutations in ramR and tet(A) exhibited high prevalences individually (81%) and in combination (63%). Eight functional ramR mutation profiles reducing tigecycline sensitivity were verified by plasmid complementation of wild-type and mutant ramR. Using a site-specific mutant, the most frequent RamR mutation, A19V (60%), had no significant effect on tigecycline susceptibility or the upregulation of ramA and acrA. Two tet(A) variants with double frameshift mutations, type 1 and type 2, were identified; type 2 tet(A) is novel. A parent strain transformed with a plasmid carrying type 1 or type 2 tet(A) increased the tigecycline MIC by 8-fold or 4-fold, respectively. Synergistic effects were observed in strains harboring no ramR gene and a mutated tet(A), with an 8-fold increase in the tigecycline MIC compared with that in strains harboring only mutated tet(A) being seen. Overall, mutations in the ramR and tet(A) efflux genes constituted the major tigecycline resistance mechanisms among the studied TCRKP isolates. The identification of strains exhibiting the combination of a ramR deficiency and widespread mutated tet(A) is concerning due to the possible dissemination of increased tigecycline resistance in K. pneumoniae.

Emergence of ceftazidime/avibactam resistance in KPC-3-producing Klebsiella pneumoniae in vivo

2019 ◽  
Vol 74 (11) ◽  
pp. 3211-3216 ◽  
Author(s):  
Stephan Göttig ◽  
Denia Frank ◽  
Eleonora Mungo ◽  
Anika Nolte ◽  
Michael Hogardt ◽  
...  
Keyword(s):  
Combination Therapy ◽  
Klebsiella Pneumoniae ◽  
Selection Pressure ◽  
Galleria Mellonella ◽  
Phenotypic Characterization ◽  
Infection Model ◽  
Development Of Resistance ◽  
Time Kill

Abstract Objectives The β-lactam/β-lactamase inhibitor combination ceftazidime/avibactam is active against KPC-producing Enterobacterales. Herein, we present molecular and phenotypic characterization of ceftazidime/avibactam resistance in KPC-3-producing Klebsiella pneumoniae that emerged in vivo and in vitro. Methods Sequence analysis of blaKPC-3 was performed from clinical and in vitro-generated ceftazidime/avibactam-resistant K. pneumoniae isolates. Time–kill kinetics and the Galleria mellonella infection model were applied to evaluate the activity of ceftazidime/avibactam and imipenem alone and in combination. Results The ceftazidime/avibactam-resistant clinical K. pneumoniae isolate revealed the amino acid change D179Y in KPC-3. Sixteen novel mutational changes in KPC-3 among in vitro-selected ceftazidime/avibactam-resistant isolates were described. Time–kill kinetics showed the emergence of a resistant subpopulation under selection pressure with either imipenem or ceftazidime/avibactam. However, combined selection pressure with imipenem plus ceftazidime/avibactam prevented the development of resistance and resulted in bactericidal activity. Concordantly, the G. mellonella infection model revealed that monotherapy with ceftazidime/avibactam is prone to select for resistance in vivo and that combination therapy with imipenem results in significantly better survival. Conclusions Ceftazidime/avibactam is a valuable antibiotic against MDR and carbapenem-resistant Enterobacterales. Based on time–kill kinetics as well as an in vivo infection model we postulate a combination therapy of ceftazidime/avibactam and imipenem as a strategy to prevent the development of ceftazidime/avibactam resistance in KPC-producing Enterobacterales in vivo.

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