The Global Ascendency of OXA-48-Type Carbapenemases

Abstract

Surveillance studies have shown that OXA-48-like carbapenemases are the most common carbapenemases in Enterobacterales in certain regions of the world and are being introduced on a regular basis into regions of nonendemicity, where they are responsible for nosocomial outbreaks. OXA-48, OXA-181, OXA-232, OXA-204, OXA-162, and OXA-244, in that order, are the most common enzymes identified among the OXA-48-like carbapenemase group. OXA-48 is associated with different Tn1999 variants on IncL plasmids and is endemic in North Africa and the Middle East. OXA-162 and OXA-244 are derivatives of OXA-48 and are present in Europe. OXA-181 and OXA-232 are associated with ISEcp1, Tn2013 on ColE2, and IncX3 types of plasmids and are endemic in the Indian subcontinent (e.g., India, Bangladesh, Pakistan, and Sri Lanka) and certain sub-Saharan African countries. Overall, clonal dissemination plays a minor role in the spread of OXA-48-like carbapenemases, but certain high-risk clones (e.g., Klebsiella pneumoniae sequence type 147 [ST147], ST307, ST15, and ST14 and Escherichia coli ST38 and ST410) have been associated with the global dispersion of OXA-48, OXA-181, OXA-232, and OXA-204. Chromosomal integration of bla_OXA-48 within Tn6237 occurred among E. coli ST38 isolates, especially in the United Kingdom. The detection of Enterobacterales with OXA-48-like enzymes using phenotypic methods has improved recently but remains challenging for clinical laboratories in regions of nonendemicity. Identification of the specific type of OXA-48-like enzyme requires sequencing of the corresponding genes. Bacteria (especially K. pneumoniae and E. coli) with bla_OXA-48, bla_OXA-181, and bla_OXA-232 are emerging in different parts of the world and are most likely underreported due to problems with the laboratory detection of these enzymes. The medical community should be aware of the looming threat that is posed by bacteria with OXA-48-like carbapenemases.

Keywords: Enterobacteriaceae; OXA-48-like; carbapenemases.

FIG 1

UPGMA (unweighted pair group method using average linkages) phylogenetic tree of OXA-48-producing Enterobacterales using amino acid alignments. The tree calculation was performed with the ClustalW2 multiple-sequence alignment program.

FIG 2

Origin and evolution of OXA-48-like carbapenemases, namely, OXA-48, OXA-162, OXA-181, OXA-204, OXA-232, and OXA-244.

FIG 3

Global distribution of Enterobacterales with OXA-48.

FIG 4

Similarities between Tn1999 with bla_OXA-48 within the pOXA-48a plasmid and the Shewanella xiamenensis chromosome. Genes from background plasmids are indicated with cyan, and chromosomal genes of Shewanella are indicated with green. Yellow triangles indicate target site duplications.

FIG 5

Genetic environments of Tn1999 and its variants within pOXA-48a-like plasmids. Mobile elements are indicated with black (e.g., IS1999) or gray (others). Genes from background plasmids are indicated with cyan. Yellow triangles indicate target site duplications.

FIG 6

Genetic environments of Tn1999 within pOXA-48a, Tn1999.2 in pOXA-48_4963, inverted Tn1999.2 in pRA35, and Tn6237 containing inverted ΔTn1999.2 in the E. coli chromosome. In the E. coli EC15 chromosome, Tn6237 was inserted into a gene coding histidine kinase-like ATPase (ECP4571 in E. coli 536 [GenBank accession number CP000247]). Mobile elements are indicated with black (e.g., IS1999) or gray (others). Genes from background plasmids are indicated with cyan, and those from the chromosome are indicated with green. Yellow triangles indicate target site duplications.

FIG 7

Global distribution of Enterobacterales with OXA-181.

FIG 8

Similarities between S. xiamenensis chromosome with bla_OXA-181 and Tn2013 within the pKP3-A plasmid. Genes from background plasmids are indicated with cyan, and chromosomal genes of Shewanella are indicated with green. Yellow triangles indicate target site duplications.

FIG 9

Genetic environments of bla_OXA-181 in the K. pneumoniae chromosome, IncT plasmid, Tn2013 (pKP3-A plasmid), IncX3 plasmid, and IncN1 plasmid. Tn6361 with bla_NDM-1 in the IncN1 plasmid pNDM-BTR was also shown for comparison with Tn6360 in the IncN1 plasmid pMR3-OXA181. Mobile elements are indicated with black (ISEcp1) or gray (others). Genes from background plasmids are indicated with cyan, and those from the chromosome are indicated with green. Yellow triangles indicate target site duplications.

FIG 10

Genetic environments of bla_OXA-204 in the S. xiamenensis chromosome, Tn2016 (p204-B plasmid), and Tn2016 variants. Only partial sequences of Tn2016 ISEcp1 intact type (pKP49) and Tn2016 IS903B type (pEC25) were available (GenBank accession numbers KP027886 and KP027885, respectively), but the whole structures of the transposons are drawn. Mobile elements are indicated with black (ISEcp1) or gray (others). Genes from background plasmids are indicated with cyan, and those from the chromosome are indicated with green. Yellow triangles indicate target site duplications.

FIG 11

Genetic environments of bla_OXA-244 in Tn51098 (E. coli chromosome) and bla_OXA-48 in Tn6237 (E. coli chromosome). Mobile elements are indicated with black (IS1999) or gray (others). The upstream regions of Tn51098 and Tn6237 in isolate 2 are identical, whereas the downstream regions are different. The Tn6237 flanking regions in isolate 2 and EC15 are different. Genes from background plasmids are indicated with cyan, and those from the chromosome are indicated with green. Yellow triangles indicate target site duplications.