JAC Advance Access originally published online on September 22, 2006
Journal of Antimicrobial Chemotherapy 2006 58(5):1097-1099; doi:10.1093/jac/dkl365
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Correspondence |
Carriage of OXA-58 but not of OXA-51 ß-lactamase gene correlates with carbapenem resistance in Acinetobacter baumannii
1 Department of Microbiology, Medical School, University of Athens 115 27 Athens, Greece 2 Department of Clinical Microbiology, University of Thessalia Mezourlo, Larissa, Greece
*Corresponding author: Tel: +30-210-746-2140; Fax: +30-210-746-1489; E-mail: atsakris{at}med.uoa.gr
Keywords: imipenem , meropenem , carbapenemase , oxacillinase , ISAbA1 , ISAbA3, , Greece
Sir,
Acinetobacter baumannii is recognized as playing a significant role in the colonization and infection of hospitalized patients, especially those in critical care environments. The carbapenems, such as imipenem and meropenem, have been widely used to treat infections caused by multidrug-resistant A. baumannii clinical isolates. However, increasing rates of carbapenem resistance have been described among A. baumannii in several regions worldwide. Such strains owe their resistance to various combined mechanisms, including target inaccessibility or drug inactivation by carbapenemases such as class B metallo-ß-lactamases and two subgroups of class D OXA-type enzymes. Recently, two novel subgroups of class D oxacillinases with carbapenemase properties, formed by OXA-51 variants and OXA-58, have been additionally described in A. baumannii.1 However, the latter enzymes exhibit relatively weak hydrolytic activities against carbapenems compared with the metallo-ß-lactamases and it is likely that other combined mechanisms contribute mostly to the observed resistance.2 In Greece both subgroups of oxacillinases have been commonly detected among selected A. baumannii clinical isolates with various susceptibility profiles to carbapenems.3,4 In the present study, in a large series of clinical A. baumannii isolates from different Greek hospitals, we determined the incidence of OXA-51-like and OXA-58 ß-lactamase genes and their correlation with resistance to carbapenems.
From April 2002 to May 2006, 252 A. baumannii isolates were randomly collected from multiple infection sites at several hospitals in four major Greek regions. The isolates were re-identified using the API 20NE system (bioMerieux API, Marcy l'Etoile, France) and a simplified identification scheme. Imipenem and meropenem MICs were determined using an agar dilution method and Pseudomonas aeruginosa ATCC 27853 as control. Among these isolates, the MIC50/90s of imipenem and meropenem were 8/64 and 4/16 mg/L, respectively; 66.7% of the isolates were imipenem resistant and 42.5% were meropenem-resistant (defined according to the British Society for Antimicrobial Chemotherapy as an MIC 
8 mg/L; Table 1). The isolates belonged to as many as 12 major genotypes according to PFGE analysis (data not shown). PCR testing for carbapenemase-encoding genes (blaIMP, blaVIM, blaSPM, blaOXA-23-like, blaOXA-24-like, blaOXA-51-like, blaOXA-58) was carried out using consensus primers that were specific for each gene group.3 Insertion sequences ISAbA1 and ISAbA3 were amplified as described previously.5,6 The genetic elements carrying the blaOXA-51-like and blaOXA-58 genes were investigated by PCR mapping using ISAbA1 forward/OXA-51-like reverse and ISAbA3 forward/OXA-58 reverse primers, respectively.
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The isolates were negative for the blaIMP, blaSPM, blaOXA-23-like and blaOXA-24-like genes, whereas the blaVIM gene was detected in three isolates. However, the vast majority of the isolates carried the blaOXA-51-like (n = 229, 90.9%) and the blaOXA-58 gene (n = 165, 65.5%). No significant difference in the predominance of these genes among the four geographic regions was detected (data not shown). The incidence of imipenem or meropenem resistance was higher in A. baumannii strains carrying the blaOXA-58 gene (142/165 and 95/165, respectively) than in strains carrying the blaOXA-51-like gene (160/229 and 98/229, respectively; P = 0.0003 and P = 0.0052, respectively). In addition, resistance to either imipenem or meropenem was very significantly associated with carriage of the blaOXA-58 gene (P < 0.0001 and P = 0.0035, respectively), while carriage of the blaOXA-51-like gene had no apparent association with resistance (P = 0.51 and P = 0.98, respectively).
Carbapenem-resistant A. baumannii clinical isolates have become more prevalent and the OXA-type ß-lactamases associated with them have continued to increase. Recently, it has been suggested that enzymes of the OXA-51-like subgroup are very poor carbapenemases and may be natural and chromosomally encoded in the vast majority of A. baumannii isolates, regardless of their susceptibility or resistance to carbapenems.7 In the present study >90% of a large series of unrelated A. baumannii isolates were blaOXA-51-like-producers and the gene was equally distributed among carbapenem-susceptible and carbapenem-resistant isolates. However, Turton et al. have shown that blaOXA-51-like genes may be associated with carbapenem resistance in isolates with an adjacent copy of ISAbA1.5 In representative isolates of our imipenem- or meropenem-resistant A. baumannii clones that were OXA-51-like-positive but OXA-58-negative, we attempted to determine whether ISAbA1 was adjacent to the blaOXA-51-like gene. Although three of the five representatives were ISAbA1-positive, the insertion sequence was not found upstream of the blaOXA-51-like gene in any of the tested isolates. This might suggest that other mechanisms are responsible for carbapenem resistance in our OXA-51-like-positive/OXA-58-negative isolates.
OXA-58 is also a widespread enzyme, mostly plasmid encoded, which exhibits weak carbapenemase activity and may play a role in carbapenem resistance in A. baumannii, particularly when blaOXA-58 is activated by insertion sequences.2,6 A study conducted in one of our units has shown that the blaOXA-58 gene is highly expressed by most of the A. baumannii carriers and inhibition of the oxacillinase may considerably reduce carbapenem MICs.3 The statistical data in the present report further support the hypothesis that carriage of blaOXA-58 is significantly associated with high rates of carbapenem resistance in A. baumannii. Moreover, in representative isolates of our blaOXA-58-bearing carbapenem-resistant A. baumannii clones we tested the linkage of the oxacillinase gene to the insertion sequence ISAbA3, which may supply it with strong promoter sequences.6 In all eight cases, the isolates were ISAbA3-positive and the insertion sequence was adjacent to the blaOXA-58 gene, confirming the contribution of the OXA-58 enzyme to carbapenem resistance, although it cannot be excluded that other secondary mechanisms may additionally affect the activity of carbapenems in our isolates.
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References
1
Brown S and Amyes S. (2006) OXA ß-lactamases in Acinetobacter: the story so far. J Antimicrob Chemother 57:1–3.
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Walther-Rasmussen J and Høiby N. (2006) OXA-type carbapenemases. J Antimicrob Chemother 57:373–83.
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Pournaras S, Markogiannakis A, Ikonomidis A, et al. (2006) Outbreak of multiple clones of imipenem-resistant Acinetobacter baumannii isolates expressing OXA-58 carbapenemase in an intensive care unit. J Antimicrob Chemother 57:557–61.
4 Tsakris A, Ikonomidis A, Pournaras S, et al. (2006) VIM-1 metallo-ß-lactamase in Acinetobacter baumannii. Emerg Infect Dis 12:981–3.[Web of Science][Medline]
5 Turton JF, Ward ME, Woodford N, et al. (2006) The role of ISAba1 in expression of OXA carbapenemase genes in Acinetobacter baumannii. FEMS Microbiol Lett 258:72–7.[CrossRef][Web of Science][Medline]
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Poirel L and Nordmann P. (2006) Genetic structures at the origin of acquisition and expression of the carbapenem-hydrolyzing oxacillinase gene blaOXA-58 in Acinetobacter baumannii. Antimicrob Agents Chemother 50:1442–8.
7
Héritier C, Poirel L, Fournier PE, et al. (2005) Characterization of the naturally occurring oxacillinase of Acinetobacter baumannii. Antimicrob Agents Chemother 49:4174–9.
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