Nosocomial infections by Pseudomonas aeruginosa continue to be a widespread problem in Asia, North and South America, and Europe. Carbapenems are the most potent β-lactams against P. aeruginosa because its strong affinity to penicillin binding proteins, stability against most serine β-lactamases and high permeability across the outer membrane (7,8). However, intensive use of the carbapenems facilitated the emergence of carbapenem-resistant P. aeruginosa. Low level resistance to imipenem (MIC, 8 to 32 µg/ml) in P. aeruginosa is mostly due to reduced uptake of the drug as a result of loss of the porin OprD (8). This mechanism correlates with continued expression of AmpC β-lactamase. Resistance to meropenem but not imipenem may also arise via overexpression of the MexA-MexBOprM efflux pump (14). High level resistance to carbapenems (MICϾ32 µg/ml) can be caused by the presence of metallo-β-lactamase, which exhibits a broadspectrum resistance to β-lactams including carbapenems. Metallo-β-lactamase-producing P. aeruginosa Abstract: Pseudomonas aeruginosa showing resistance to imipenem were found in 100 of 1,058 strains (9.5%) from six hospitals (a-f) in Hiroshima City, Japan. Of the 100 strains, 14 (14%) were double disk synergy test positive using sodium mercaptoacetic acid disks, and 18 (18%) were bla IMP-1 or blaVIM-2 allele positive by polymerase chain reaction (PCR). Among 100 imipenem-resistant strains, 32 were categorized into multi-drug resistant strains, in which 13 were positive for the metallo--lactamase gene. Fifty-one strains (51%) among the 100 imipenem-resistant strains had elevated RND efflux pump activity against levofloxacin. But only 6 of 51 strains were classified as multi-drug resistant strains. The pulsed field gel electrophoresis analysis of the SpeI-digested DNA from the 100 isolates suggested not only clonal spread but spread of heterogeneous clones started to contribute to the prevalence of metallo--lactamase producing P. aeruginosa strains in Japanese hospitals.
A 9-year surveillance for multidrug-resistant (MDR) Pseudomonas aeruginosa in the Hiroshima region showed that the number of isolates harboring the metallo--lactamase gene bla IMP-1 abruptly increased after 2004, recorded the highest peak in 2006, and showed a tendency to decline afterwards, indicating a history of an epidemic. PCR mapping of the variable regions of the integrons showed that this epidemic was caused by the clonal persistence and propagation of an MDR P. aeruginosa strain harboring the bla IMP-1 gene and an aminoglycoside 6=-N-acetyltransferase gene, aac(6=)-Iae in a class I integron (In113), whose integrase gene intl1 was disrupted by an IS26 insertion. Sequence analysis of the representative strain PA058447 resistance element containing the In113-derived gene cassette array showed that the element forms an IS26 transposon embedded in the chromosome. It has a Tn21 backbone and is composed of two segments sandwiched by three IS26s. In Japan, clonal nationwide expansion of an MDR P. aeruginosa NCGM2.S1 harboring chromosomally encoded In113 with intact intl1 is reported. Multilocus sequence typing and genomic comparison strongly suggest that PA058447 and NCGM2.S1 belong to the same clonal lineage. Moreover, the structures of the resistance element in the two strains are very similar, but the sites of insertion into the chromosome are different. Based on tagging information of the IS26 present in both resistance elements, we suggest that the MDR P. aeruginosa clone causing the epidemic in Hiroshima for the past 9 years originated from a common ancestor genome of PA058447 and NCGM2.S1 through an IS26 insertion into intl1 of In113 and through IS26-mediated genomic rearrangements. P seudomonas aeruginosa is an opportunistic human pathogen and a leading cause of nosocomial infections. It also causes mastitis in dairy cows as mild chronic persistent inflammation (1). Carbapenems have been used to treat P. aeruginosa infections; however, P. aeruginosa isolates resistant to carbapenems are reported in many countries and an acquired resistance to carbapenems by metallo--lactamase (MBL) genes causes a serious therapeutic problem in clinical settings. Carbapenem-resistant P. aeruginosa strains producing MBLs were first discovered in Japan (2, 3) and have since been reported in many countries all over the world (4).Specifically, IMP, VIM, SPM, and NDM are the most important types of MBL with worldwide distribution, and their genes are frequently carried on class 1 integrons (4, 5). Class 1 integrons are often found on plasmids or as a part of transposons or resistance genetic elements that are able to integrate into chromosomal elements, resulting in an increase in the number of resistant Gramnegative bacilli (6). MBL-producing P. aeruginosa strains often behave as multidrug-resistant (MDR) strains. The recent increase of nosocomial infections caused by MDR P. aeruginosa has raised a serious concern.In the Hiroshima prefecture, we have conducted a multihospital surveillance for drug-resistant P. aeruginosa i...
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