Rapid evolution of pan-β-lactam resistance in Enterobacterales co-producing KPC and NDM: insights from global genomic analysis after the COVID-19 pandemic

Enterobacterales co-producing Klebsiella pneumoniae carbapenemase (KPC) and New Delhi metallo-β-lactamase (NDM) enzymes are rapidly emerging worldwide.1Thomas GR Corso A Pasterán F et al.Increased detection of carbapenemase-producing Enterobacterales bacteria in Latin America and the Caribbean during the COVID-19 pandemic.Emerg Infect Dis. 2022; 28: 1-8Crossref PubMed Scopus (25) Google Scholar, 2Seo H Kim HJ Kim MJ et al.Comparison of clinical outcomes of patients infected with KPC- and NDM-producing Enterobacterales: a retrospective cohort study.Clin Microbiol Infect. 2021; 27: 1167.e1-1167.e8Summary Full Text Full Text PDF PubMed Scopus (0) Google Scholar, 3Vásquez-Ponce F Dantas K Becerra J et al.Detecting KPC-2 and NDM-1 coexpression in Klebsiella pneumoniae complex from human and animal hosts in South America.Microbiol Spectr. 2022; 10e0115922Crossref Scopus (5) Google Scholar, 4Bianco G Boattini M Comini S et al.Occurrence of multi-carbapenemases producers among carbapenemase-producing Enterobacterales and in vitro activity of combinations including cefiderocol, ceftazidime-avibactam, meropenem-vaborbactam, and aztreonam in the COVID-19 era.Eur J Clin Microbiol Infect Dis. 2022; 41: 573-580Crossref PubMed Scopus (0) Google Scholar, 5Gao H Liu Y Wang R Wang Q Jin L Wang H The transferability and evolution of NDM-1 and KPC-2 co-producing Klebsiella pneumoniae from clinical settings.EBioMedicine. 2020; 51102599Summary Full Text Full Text PDF Scopus (73) Google Scholar In some countries, this emergence has been linked to the empirical use of antimicrobials for potential bacterial infections associated with COVID-19 during the pandemic period.1Thomas GR Corso A Pasterán F et al.Increased detection of carbapenemase-producing Enterobacterales bacteria in Latin America and the Caribbean during the COVID-19 pandemic.Emerg Infect Dis. 2022; 28: 1-8Crossref PubMed Scopus (25) Google Scholar,3Vásquez-Ponce F Dantas K Becerra J et al.Detecting KPC-2 and NDM-1 coexpression in Klebsiella pneumoniae complex from human and animal hosts in South America.Microbiol Spectr. 2022; 10e0115922Crossref Scopus (5) Google Scholar, 4Bianco G Boattini M Comini S et al.Occurrence of multi-carbapenemases producers among carbapenemase-producing Enterobacterales and in vitro activity of combinations including cefiderocol, ceftazidime-avibactam, meropenem-vaborbactam, and aztreonam in the COVID-19 era.Eur J Clin Microbiol Infect Dis. 2022; 41: 573-580Crossref PubMed Scopus (0) Google Scholar, 5Gao H Liu Y Wang R Wang Q Jin L Wang H The transferability and evolution of NDM-1 and KPC-2 co-producing Klebsiella pneumoniae from clinical settings.EBioMedicine. 2020; 51102599Summary Full Text Full Text PDF Scopus (73) Google Scholar, 6AlBahrani S Almogbel F Alanazi W et al.Carbapenem use correlates with percentage of patients with COVID-19 in intensive care units.Infection. 2023; 51: 331-336Crossref PubMed Scopus (3) Google Scholar Concurrently, Latin American and Caribbean countries reported the occurrence and rapid dissemination of carbapenemase combinations, predominantly associated with KPC and NDM, to PAHO/WHO, triggering the issuance of an epidemiological alert.7Pan American Health Organization (PAHO)Epidemiological alert: emergence and increase of new combinations of carbapenemases in Enterobacterales in Latin America and the Caribbean.https://www.paho.org/en/documents/epidemiological-alert-emergence-and-increase-new-combinations-carbapenemasesDate: Oct 22, 2021Date accessed: December 5, 2023Google Scholar Carbapenemase co-production can hydrolyse all β-lactams, such as penicillins, monobactams, cephamycins, cephalosporins, carbapenems, and novel β-lactam–β-lactamase inhibitor combinations, including ceftolozane–tazobactam, ceftazidime–avibactam, meropenem–vaborbactam, and imipenem–relebactam.4Bianco G Boattini M Comini S et al.Occurrence of multi-carbapenemases producers among carbapenemase-producing Enterobacterales and in vitro activity of combinations including cefiderocol, ceftazidime-avibactam, meropenem-vaborbactam, and aztreonam in the COVID-19 era.Eur J Clin Microbiol Infect Dis. 2022; 41: 573-580Crossref PubMed Scopus (0) Google Scholar Considering the emergence of bacteria co-producing KPC and NDM, strengthening the genomic surveillance and analysing the global distribution and genomic background of these strains are urgently needed. In this Comment, we present the results of our analysis of 35 761 publicly available KPC-positive bacterial genomes or NDM-positive bacterial genomes, or both, in the National Database of Antibiotic Resistant Organisms.8National Institutes of HealthNational Database of Antibiotic Resistant Organisms (NDARO).https://www.ncbi.nlm.nih.gov/pathogens/antimicrobial-resistanceDate accessed: August 18, 2023Google Scholar Among the analysed genomes, 249 (0·7%) Enterobacterales strains harbouring KPC and NDM were identified, with the majority belonging to the Klebsiella genus (73·8%), including the K pneumoniae species complex, Klebsiella michiganensis, and Klebsiella aerogenes. This coexistence was also observed in Escherichia coli, the Enterobacter cloacae complex, Citrobacter spp, Morganella morganii, and Raoultella spp (appendix pp 2–9). Between 2013 and 2023, dual-carbapenemase producers have been isolated primarily from humans (94·0%), with smaller proportions identified from environmental sources such as sludge and wastewater from wastewater treatment plants and hospital surfaces (5·6%) and food sources such as retail pork (0·4%) in some countries of the Americas (Brazil, Chile, Colombia, Peru, the USA, and Uruguay), Asia (Bangladesh, China, Israel, Malaysia, Oman, Singapore, South Korea, and Türkiye), and Europe (France, Germany, Italy, Poland, Russia, Slovakia, Switzerland, and the UK). However, genomes co-harbouring KPC and NDM have mainly been reported in China (45·1%) and the USA (23·0%; appendix pp 2–9), reinforcing the need for a closer look at this emerging problem in low-income and middle-income countries. The temporal analysis revealed a 3·5-fold increase in the emergence of strains co-producing KPC and NDM from 2018 to 2022, evidencing a linear upward trend worldwide, particularly during the COVID-19 period (appendix p 10). From an epidemiological standpoint, K pneumoniae sequence type (ST) 11 emerged as the most predominant clone (25·4%), whereas the clonal group (CG) 258 (comprising ST11, ST258, ST340, and ST512) dominated (36·3%) among all the bacterial genomes studied. These lineages, recognised as successful nosocomial clones, have contributed towards the global dissemination of KPC-type carbapenemases.9Rojas LJ Weinstock GM De La Cadena E et al.An analysis of the epidemic of Klebsiella pneumoniae carbapenemase-producing K. pneumoniae: convergence of two evolutionary mechanisms creates the "perfect storm".J Infect Dis. 2017; 217: 82-92Crossref PubMed Scopus (54) Google Scholar Among other bacterial species, E coli ST410, Enterobacter hormaechei subsp steigerwaltii ST93, and Citrobacter freundii ST107 were the most prevalent. Additionally, a great diversity of carbapenemase-harbouring STs was identified, highlighting health-care-associated or international high-risk clones of K pneumoniae (ST11, ST15, ST258, ST307, and ST340), E coli (ST44, ST167, ST410, ST617, and ST658), Enterobacter hormaechei subsp xiangfangensis (ST114 and ST171), and C freundii (ST107, ST116, and ST256; appendix pp 2–8). Moreover, different associations of KPC and NDM variants were identified, with KPC-2 plus NDM-1 (53·6%), KPC-2 plus NDM-5 (18·5%), and KPC-3 plus NDM-1 (14·1%) being the most prevalent (appendix p 11). Notably, the KPC and NDM co-production in K pneumoniae appears to have originated from global KPC-positive high-risk clones that subsequently acquired NDM-harbouring plasmids. This evolutionary pathway could be elucidated by analysing KPC-positive strains harbouring plasmids with a high degree of homology to NDM-carrying plasmids.5Gao H Liu Y Wang R Wang Q Jin L Wang H The transferability and evolution of NDM-1 and KPC-2 co-producing Klebsiella pneumoniae from clinical settings.EBioMedicine. 2020; 51102599Summary Full Text Full Text PDF Scopus (73) Google Scholar Various single and multireplicon plasmids carrying KPC or NDM were identified, with their co-localisation identified on the IncL/M and IncFII/IncR/IncN plasmids in clinical K pneumoniae strains from China. The chromosomal integration of KPC and NDM was also observed (appendix pp 2–5). These findings highlight that the evolution of bacterial resistance, leading to the co-production of carbapenemases, can arise from different genetic events and that KPC-bearing and NDM-bearing multireplicon plasmids emerge as an important mechanism for pan-β-lactam resistance. In summary, the global genomic data analysis of Enterobacterales co-producing KPC and NDM highlights a temporal increase of double carbapenemase-positive pandemic clones, which constitutes an urgent and serious public health threat. Notably, the high prevalence of K pneumoniae strains within CG 258 co-producing KPC and NDM indicates a novel resistance trend, revealing an evolutionary pathway leading to the acquisition of NDM by successful KPC-positive clones. The stress induced by the selective pressure resulting from the extensive use of antimicrobials, polymicrobial infections, and multiple colonisation during the COVID-19 pandemic is hypothesised to have contributed to the evolutionary adaptation of epidemic clones towards co-production of carbapenemases worldwide.10Emamalipour M Seidi K Zununi Vahed S et al.Horizontal gene transfer: from evolutionary flexibility to disease progression.Front Cell Dev Biol. 2020; 8: 229Crossref PubMed Scopus (63) Google Scholar,11Bedenić B Luxner J Car H et al.Emergence and spread of Enterobacterales with multiple carbapenemases after COVID-19 pandemic.Pathogens. 2023; 12: 677Crossref PubMed Scopus (4) Google Scholar However, more genomic surveillance studies are required to validate these findings and provide insights into the origin and evolution of carbapenemase co-production in clinically relevant bacterial pathogens. We declare no competing interests. This work was funded by the National Council for Scientific and Technological Development (CNPq; 304905/2022-4, 314336/2021-4, and 150712/2022-7) and the Coordination for the Improvement of Higher Education Personnel (CAPES; 88887.463868/2019-00 and Finance Code 001). Download .pdf (.61 MB) Help with pdf files Supplementary appendix