Thursday, June 8, 2023
| Carbapenemases (no. isolates) | Geographic location (no. isolates) | Sequence types (no. isolates) |
|---|---|---|
| KPCs (50) | ||
| KPC-2 (35) | Argentina (4), Brazil (5), Colombia (8), Greece (1), Guatemala (4), Israel (2), Puerto Rico (2), United States (4), Venezuela (1), Vietnam (4) | ST10 (3), ST46 (2), ST69 (2), ST95 (3), ST131 (7), ST349 (1), ST405 (3), ST410 (3), ST538 (1), ST540 (1), ST607 (1), ST617 (1), ST648 (1), ST1193 (1), ST1196 (1), ST2172 (1), ST2279 (1), ST3580 (1) |
| KPC-3 (14) | Colombia (1), Israel (1), Italy (8), United States (4) | ST12 (1), ST73 (1), ST131 (7), ST141 (1), ST191 (1), ST617 (1), ST973 (1), ST1148 (1) |
| KPC-18 (1) | United States (1) | ST131 (1) |
| NDMs (66) | ||
| NDM-1 (19) | Egypt (3), Guatemala (2), Kuwait (1), Morocco (4), Philippines (1), Romania (1), Russia (3), Serbia (1), Thailand (2), Vietnam (1) | ST38 (1), ST44 (1), ST69 (1), ST95 (1), ST131 (4), ST167 (3), ST345 (1), ST361 (1), ST617 (2), ST1193 (1), ST1434 (1), ST1470 (1), ST4553 (1), |
| NDM-4 (1) | Vietnam (1) | ST405 (1) |
| NDM-5 (40) | Canada (1), Egypt (16), Italy (2), Jordan (4), Lebanon (1), Thailand (8), United Kingdom (2), Vietnam (6) | ST131 (1), ST156 (1), ST167 (11), ST361 (4), ST405 (3), ST410 (12), ST448 (2), ST648 (4), ST2003 (2) |
| NDM-6 (1) | Guatemala (1) | ST38 (1) |
| NDM-7 (5) | Philippines (4), Vietnam (1) | ST156 (2), ST410 (1), ST448 (1), ST5229 (1) |
| OXA-48–like (96) | ||
| OXA-48 (40) | Austria (1), Belgium (2), Egypt (3), Georgia (3), Israel (1), Lebanon (2), Mexico (1), Morocco (2), Saudi Arabia (1), Spain (2), Thailand (1), Tunisia (1), Turkey (15), United Kingdom (1), Vietnam (4) | ST10 (2), ST12 (1), ST34 (1), ST38 (8), ST58 (1), ST131 (2), ST224 (1), ST349 (1), ST354 (6), ST361 (1), ST405 (4), ST410 (2), ST624 (1), ST648 (1), ST1431 (1), ST11260 (6) |
| OXA-181 (48) | Egypt (6), Germany (1), Jordan (15), Kuwait (1), Lebanon (1), Malaysia (1), South Africa (2), Taiwan (1), Thailand (2), Turkey (18) | ST46 (1), ST131 (1), ST167 (2), ST205 (1), ST354 (1), ST410 (21), ST648 (1), ST1284 (18), ST1487 (1), ST6802 (1) |
| OXA-232 (5) | Malaysia (1), Mexico (3), Thailand (1) | ST127 (1), ST131 (1), ST361 (3) |
| OXA-244 (3) | Egypt (3) | ST58 (1), ST648 (1), ST1722 (1) |
| VIMs (4) | ||
| VIM-1 (2) | Greece (1), Spain (1) | ST88 (1), ST404 (1) |
| VIM-23 (2) | Mexico (2) | ST410 (2) |
| IMPs (2) | ||
| IMP-59 (2) | Australia (2) | ST357 (2) |
| Two carbapenemases (11) | ||
| NDM-1 + VIM-1 (1) | Egypt (1) | ST131 (1) |
| NDM-1 + OXA-181 (2) | Egypt (2) | ST46 (2) |
| NDM-5 + OXA-48 (1) | Egypt (1) | ST167 (1) |
| NDM-5 + OXA-181 (5) | Egypt (3), South Korea (1), Vietnam (1) | ST410 (4), ST448 (1) |
| NDM-5 + OXA-232 (2) | United Kingdom (2) | ST2083 (2) |
Table. Global molecular epidemiology of 229 carbapenemase-producing Escherichia coli isolates, 36 countries, 2015–2017*
*KPC, Klebsiella pneumoniae carbapenemase; NDM, New Delhi metallo-β-lactamase; OXA, oxacillinase; ST, sequence type ; VIM, Verona integron‒encoded metallo-β-lactamase.
This activity is intended for infectious disease clinicians, epidemiologists, public health officials, geneticists, internists, and other clinicians who treat and manage patients with or at risk for carbapenemase-producing Escherichia coli.
The goal of this activity is to describe the geographic distribution of different carbapenemase genes (including associations with dominant sequence types, clades, and underlying mobile genetic elements), other β-lactamases, antibiotic resistance genes, and virulence factors, based on short read whole genome sequencing of 229 carbapenemase-producing Escherichia coli (2015-17) from 36 countries (including 20 lower- and middle-income countries).
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A World Health Organization report showed the lack of adequate surveillance programs in many parts of the world, especially from lower- and middle-income countries (LMICs)[38]. That report identified bacteria, including carbapenem-resistant E. coli, where global surveillance data are urgently required. LMICs bear a considerable share of the disease burden attributable to MDR E. coli but lack adequate genomic surveillance systems[39]. Our study aimed to describe the global molecular epidemiology of 229 carbapenemase-producing E. coli obtained from 36 countries (including 20 LMICs) during 2015–2017. Isolates with multiple AMR genes dominated the population. The most common carbapenemase group was the OXA-48-like carbapenemases (44%), followed by NDMs (32%), KPCs (21%), VIMs (2%), and IMPs (1%). OXA-48-like carbapenemases were numerous in Egypt, Jordan, and Turkey; NDMs were numerous in Egypt, Thailand, and Vietnam, and KPCs were numerous in Colombia, Italy, and the United States.
We identified 5 dominant STs and their respective clades and subclades; 4 were global: ST410 subclades B3/H24Rx and B4/H24RxC; ST131 clade A/H41, subclades C1_nonM27/H30, C1_M27/H30, and C2/H30; ST167 subclades B1, B2, and B3; and ST405 clades A and B (Appendix Figure). ST1284 (1 clade) was limited to Turkey, and the ST167-A clade was limited to Guatemala. Dominant STs and their respective clades and subclades were associated with different underlying mobile genetic elements: ST410 was linked with NDM-5 and OXA-181; ST131 was linked with KPCs, ST1284 was linked with OXA-181, ST167 was linked with NDM-5, and ST405 was linked with various carbapenemases.
A recent survey of global carbapenemase-producing E. coli for the period 2002–2017 included 343 carbapenem-resistant isolates obtained mainly from the United States[40]. KPC (16%), NDM (16%), and OXA-48–like (13%) carbapenemases were common. The study screened for different E. coli phylogroups and certain STs (ST131, ST648, and ST405). Phylogroup B2 isolates were common, and phylogroup A was dominant in Asia. Global ST131 with bla KPCs was the most common ST, followed by ST648 with bla OXA-48-like and ST405 with bla NDMs.
The most frequent individual carbapenemases in our survey were OXA-181 (23%), NDM-5 (20%), OXA-48 (17%), KPC-2 (15%), and NDM-1 (10%). This result was different from carbapenemase-producing K. pneumoniae and Enterobacter cloacae complex with carbapenemases obtained from the same surveillance programs[14,41]. The K. pneumoniae population was dominated by ST258 with KPC-2 from Greece and KPC-3 from the United States[41]. The E. cloacae complex isolates (various STs) were dominated by VIM-1 from Greece and Italy[14]. K. pneumoniae[42] and E. cloacae complex[43] are mainly hospital pathogens, whereas E. coli was mainly a community pathogen[6], which could partly be responsible for the different carbapenemase types among these species.
Molecular-based surveillance studies have shown that OXA-48–like enzymes are common among global carbapenemase-producing Enterobacterales[4,5]. OXA-48 is currently the most common OXA-48–like derivative and OXA-181 the second most common derivative[44]. OXA-48 is endemic in North Africa, Middle East, and Turkey[44]. E. coli with blaOXA-48 is linked to various STs[44]. In our study, OXA-48 was identified among 18 STs from 15 countries. E. coli with bla OXA-48 was common in Turkey, where it was linked with ST11260.
OXA-181 is linked with certain E. coli STs, especially ST410[44]. E. coli ST410 belongs to phylogroup A and is divided into 2 clades (A/H53 and B/H24). Clade B is divided into subclades B1/H24, B2/H24R, B3/H24Rx, and B4/H24RxC[21]. The B2/H24R subclade is associated with fluroquinolone resistance, B3/H24Rx with blaCTX-M-15, and B4/H24RxC with blaOXA-181[21]. In our survey, OXA-181 was identified among 11 different STs obtained from 12 countries. All the OXA-181 genes were situated within Tn2013 harbored on near identical IncX3 plasmids (≈100% similarly to p72_X3_OXA181). K. pneumoniae ST307 with p72_X3_OXA181 was previously responsible for large outbreaks in South Africa[13,37]. E. coli with bla OXA-181 was frequent in Jordan, Egypt (linked with ST410- B4/H24RxC subclade), and Turkey (linked with ST1284). The ST410-B4/H24RxC subclade with bla OXA-181 was also found in Thailand and South Korea. The ST410-B3/H24Rx subclade with bla OXA-181 was present in South Africa and Kuwait.
Molecular-based surveillance studies have shown that NDMs are often the most common carbapenemase in certain regions (e.g., the Indian subcontinent)[4,5]. NDM-1 is the most frequent NDM enzyme and associated with various STs within diverse plasmid platforms[45]. In our survey, NDM-1 was identified among 14 different STs obtained from 10 countries. E. coli with bla NDM-1 was not linked with a specific ST and was evenly distributed among the different countries.
E. coli with NDM-5 is numerous among E. coli with NDMs from India, China, and sub-Saharan Africa[45]. NDM-5, in our survey, was found among 9 different STs from 9 countries. It was common in Egypt (linked with ST410 [B4/H24RxC] and ST167 [B1 and B3]), Thailand (linked with ST410 [B4/H24RxC] and ST167 [B2]), and Vietnam (linked with ST448). ST167 belongs to phylogroup A and is an emerging carbapenemase clone associated with blaNDM-5[46]. We divided ST167 into 2 clades (A and B) and 3 subclades (B1, B2, and B3). Subclade B3 was the most dominant clade and associated with bla NDM-5 obtained from Egypt and Italy. Other subclades were less common and linked with bla NDM-5, bla NDM-1, and bla OXA-181 obtained in Guatemala (clade A), Egypt (subclades B1 and B2), and Thailand (subclade B2).
E. coli with blaKPC is associated with ST131[47] on diverse plasmid platforms[48]. E. coli ST131 is global MDR high-risk clone associated with fluoroquinolone resistance and blaCTX-Ms[49]. ST131 belongs to clades A/H41, B/H22, and C/H30[50]. C/H30 is divided into subclades C0, C1_nonM27, C1_M27, and C2. In our survey, KPC genes were found among 26 different STs from 11 countries. E. coli with blaKPC was common in Colombia linked with various STs. ST131 was responsible for 32% of KPC isolates and obtained from Italy, Israel, Guatemala, Puerto Rico, and the United States (including Puerto Rico). ST131 with blaKPC was dominated by the C1_nonM27 subclade. This dominance is different from that observed by Johnson et al. study[40], where the C2 subclade was common. The ST131-C1_M27 subclade in our survey was positive for bla NDM-1 and bla OXA-232.
Among this study’s strengths is that it included a large global collection of recent isolates representing multiple LMICs. We characterized all isolates using short-read WGS and provided novel information regarding the geographic distribution and MDR determinants of dominant STs and their respective clades and subclades (e.g., global ST410 was linked with bla OXA-181, ST131 with bla KPCs, ST167 with bla NDM-5, and ST405 with various carbapenemases).
We showed that the underlying molecular epidemiology within the same carbapenemase groups were very different (e.g., NDM-1 was linked with various STs, including ST131-C2/H30, whereas NDM-5 was linked with ST167-B and ST410B4/H24Rx). The geographic distribution of isolates with NDM-1 and NDM-5 was different (e.g., NDM-1 showed global distribution whereas those with NDM-5 were numerous in Egypt, Thailand, and Vietnam). Similar differences were described for isolates with OXA-48 (various STs) and OXA-181 (linked with ST410B4/H24Rx). Future genomic surveys should use methodologies that characterize individual carbapenemases.
We also showed that global bla OXA-181 was harbored on near identical IncX3 plasmids (irrespective of the ST or geographic location). This finding suggests that highly similar IncX3 plasmids were mainly responsible for the global distribution of OXA-181 genes, the most common carbapenemase in this collection. The control of such IncX3 plasmids should be a public health priority.
Limitations of this study include the fact that flanking regions and plasmids harboring carbapenemases were not fully reconstructed because of the limitations of short-read sequencing[30]. The characterization of plasmids is vital to fully comprehend the molecular epidemiology of global carbapenemase-producing E. coli, and a follow-up study using long-read sequencing is under way. Several countries included only few isolates (Table) and therefore may not be fully representative of what carbapenemase-producing E. coli dominates in that region.
In summary, the global carbapenemase-producing E. coli population is dominated by diverse STs with different characteristics and varied geographic distributions. This characterization was especially apparent within certain carbapenemases groups (i.e., NDM-1 vs. NDM-5 or OXA-48 vs. OXA-181). Ongoing genomic surveillance to characterize individual carbapenemases will assist in designing management and prevention strategies to help curtail the spread of AMR bacteria.
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