Genomics and Susceptibility Profiles of Extensively Drug-Resistant (XDR) Pseudomonas aeruginosa from Spain [PublishAheadOfPrint]

This study assessed the molecular epidemiology, resistance mechanisms and susceptibility profiles of a collection of 150 XDR P. aeruginosa clinical isolates obtained from a 2015 Spanish multicenter study, with a particular focus on resistome analysis in relation to ceftolozane/tazobactam susceptibility. Broth microdilution MICs revealed that nearly all (>95%) of the isolates were nonsusceptible to piperacillin/tazobactam, ceftazidime, cefepime, aztreonam, imipenem, meropenem and ciprofloxacin. Most of them were also resistant to tobramycin (77%), whereas nonsusceptibility rates were lower for ceftolozane/tazobactam (31%), amikacin (7%) and colistin (2%). PFGE-MLST analysis revealed that nearly all of the isolates belonged to previously described high-risk clones. ST175 was detected in all 9 participating hospitals and accounted for 68% (n=101) of the XDR isolates, distantly followed by ST244 (n=16), ST253 (n=12), ST235 (n=8) and ST111 (n=2) detected only in 1-2 hospitals. Through phenotypic and molecular methods, the presence of horizontally-acquired carbapenemases was detected in 21% of the isolates, mostly including VIM (17%) and GES enzymes (4%). At least two representative isolates from each clone and hospital (n=44) were fully sequenced on an Illumina MiSeq®. Classical mutational mechanisms, such as those leading to the overexpression of the β-lactamase AmpC or efflux pumps, OprD inactivation, and/or QRDR mutations, were confirmed in most isolates and correlated well with the resistance phenotypes in the absence of horizontally-acquired determinants. Ceftolozane/tazobactam resistance was not detected in carbapenemase-negative isolates, in agreement with sequencing data showing the absence of ampC mutations. The unique set of mutations responsible for the XDR phenotype of ST175 clone documented 7 years earlier were found to be conserved, denoting the long-term persistence of this specific XDR lineage in Spanish hospitals. Finally, other potentially relevant mutations were evidenced, including those in PBP3, involved in β-lactam (including ceftolozane/tazobactam) resistance, and FusA1, linked to aminoglycoside resistance.

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