Emergence and Distribution of Plasmids Bearing the blaOXA-51-Like Gene with an Upstream ISAba1 in Carbapenem-Resistant Acinetobacter baumannii Isolates in Taiwan

The bla_OXA-51-like gene with an upstream ISAba1 (ISAba1-bla_OXA-51-like gene) was originally found on the chromosomes of carbapenem-resistant or -susceptible Acinetobacter baumannii isolates. However, a plasmid-borne ISAba1-bla_OXA-51-like gene has recently been identified in Acinetobacter genomic species 13TU and several A. baumannii isolates in Taiwan, and all of the isolates are carbapenem resistant. This study aimed to characterize the plasmids bearing the ISAba1-bla_OXA-51-like gene and their significance in A. baumannii. Among the 117 ISAba1-bla_OXA-51-like-harboring isolates collected from 10 hospitals in Taiwan, 58 isolates (49.6%) from 24 clones had the genes located on plasmids that likely originated from a common progenitor. Among the 58 isolates, four had additional copy of the ISAba1-bla_OXA-51-like gene on their chromosomes. Based on the analysis of these four isolates, the plasmid-located ISAba1-bla_OXA-51-like gene appeared to be acquired via one-ended transposition (Tn6080). The isolates with a plasmid bearing the ISAba1-bla_OXA-51-like gene had higher rates of resistance to imipenem (98% versus 46.6%; P < 0.001) and meropenem (98% versus 69%; P = 0.019) than those with the genes chromosomally encoded, which is most likely due to increased gene dosage provided by the higher copy number of associated plasmids. Transformation with a recombinant plasmid harboring only the ISAba1-bla_OXA-51-like gene was enough to confer a high level of carbapenem resistance to A. baumannii, eliminating the possible contribution of other factors on the original plasmids. This study demonstrated that the carbapenem resistance-associated plasmids carrying the ISAba1-bla_OXA-51-like gene are widespread in A. baumannii strains in Taiwan.Acinetobacter baumannii has emerged as a major pathogen of nosocomial infections in immunocompromised patients and is associated with a high mortality rate (7). The management of this pathogen has become a significant challenge due to the increased emergence of carbapenem-resistant strains (19, 22). It has been shown that most of the carbapenem resistance in A. baumannii is due to the production of carbapenemases, especially those belonging to carbapenem-hydrolyzing class D beta-lactamases (CHDLs), which are encoded by the bla_OXA-51-like, bla_OXA-23-like, bla_OXA-24-like, and bla_OXA-58-like genes (19). Among these CHDL genes, the bla_OXA-51-like gene is intrinsic to and was originally located on the chromosome of A. baumannii (7, 18, 24).The CHDLs have only a weak carbapenem-hydrolyzing activity (1, 19). However, overexpression of these CHDL genes, driven mostly by promoters provided by their upstream insertion sequences (ISs), is one of the means by which A. baumannii acquires a high level of carbapenem resistance. For example, ISAba1 upstream of the bla_OXA-51-like gene is associated with the overexpression of the bla_OXA-51-like gene and carbapenem resistance in A. baumannii (12, 23). However, some isolates harboring the bla_OXA-51-like gene with an upstream ISAba1 (ISAba1-bla_OXA-51-like gene) are still susceptible to carbapenem (9, 14, 16). The reason for this discrepancy in carbapenem susceptibility levels in isolates harboring the ISAba1-bla_OXA-51-like gene has not been completely clarified. In some isolates, the high level of resistance might be due to interplay between the overexpression of the bla_OXA-51-like gene and other mechanisms, such as overexpression of an efflux pump (12, 19). However, the overexpression of the CHDL genes by themselves can occasionally confer a high level of carbapenem resistance, especially when the resistance determinants are located on a plasmid, and this is likely due to the higher gene dosage provided by the higher copy number associated with plasmids (3). Recently, we have identified several A. baumannii isolates in Taiwan that harbor plasmid-borne ISAba1-bla_OXA-51-like genes (ISAba1-bla_OXA-82) (GenBank accession no. {"type":"entrez-nucleotide","attrs":{"text":"GQ352402","term_id":"255076961","term_text":"GQ352402"}}GQ352402). Moreover, a plasmid bearing the ISAba1-bla_OXA-51-like gene (ISAba1-bla_OXA-138) has also been indentified in an Acinetobacter genomic species 13TU isolate (15). The mobilization of the ISAba1-bla_OXA-51-like gene to plasmids and dissemination of these plasmids will further complicate the management of A. baumannii infections. This study aimed to characterize the spread of these plasmids and their significance in A. baumannii isolates in Taiwan.