Genomic Characterization of Carbapenem-Non-susceptible Pseudomonas aeruginosa Clinical Isolates From Saudi Arabia Revealed a Global Dissemination of GES-5-Producing ST235 and VIM-2-Producing ST233 Sub-Lineages

Abstract

Carbapenem-resistant P. aeruginosa has become a major clinical problem due to limited treatment options. However, studies assessing the trends in the molecular epidemiology and mechanisms of antibiotic resistance in this pathogen are lacking in Saudi Arabia. Here, we reported the genome characterization in a global context of carbapenem non-susceptible clinical isolates from a nationally representative survey. The antibiotic resistance profiles of the isolates (n = 635) collected over 14 months between March 2018 and April 2019 from different geographical regions of Saudi Arabia showed resistance rates to relevant β-lactams, aminoglycosides and quinolones ranging between 6.93 and 27.56%. Overall, 22.52% (143/635) of the isolates exhibited resistance to both imipenem and meropenem that were mainly explained by porin loss and efflux overexpression. However, 18.18% of resistant isolates harbored genes encoding GES (69.23%), VIM (23.07%), NDM (3.85%) or OXA-48-like (3.85%) carbapenemases. Most common GES-positive isolates produced GESs −5, −15 or −1 and all belonged to ST235 whereas the VIM-positive isolates produced mainly VIM-2 and belonged to ST233 or ST257. GES and VIM producers were detected at different sampling periods and in different surveyed regions. Interestingly, a genome-wide comparison revealed that the GES-positive ST235 and VIM-2-positive ST233 genomes sequenced in this study and those available through public databases from various locations worldwide, constituted each a phylogenetically closely related sub-lineage. Profiles of virulence determinants, antimicrobial resistance genes and associated mobile elements confirmed relatedness within each of these two different sub-lineages. Sequence analysis located the blaGES gene in nearly all studied genomes (95.4%) in the same integrative conjugative element that also harbored the acc(6′)-Ib, aph(3′)-XV, aadA6, sul1, tet(G), and catB resistance genes while blaVIM–2 in most (98.89%) ST233-positive genomes was co-located with aac(6′)-I1, dfrB-5, and aac(3′)-Id in the same class I integron. The study findings revealed the global spread of GES-5 ST235 and VIM-2 ST233 sub-lineages and highlighted the importance of routine detection of rare β-lactamases.

Genomic Study of Chromosomally and Plasmid-Mediated Multidrug Resistance and Virulence Determinants in Klebsiella Pneumoniae Isolates Obtained from a Tertiary Hospital in Al-Kharj, KSA

“…The presence of ESBLs genes ( bla OXA-1 , bla CTX-M-3 and bla OXA-232 ) in the K6 isolate is consistent with the phenotypic finding in which the isolate was highly resistant to third- and fourth-generations of cephalosporins. Consistent with our findings, Doumith et al [ 25 ] recently reported the presence of the plasmid p ColKP3 carrying bla OXA-232 in Pseudomonas aeruginosa clinical isolates from Saudi Arabia, which may indicate the exchange of plasmids among different microbial strains and the circulation of such plasmids in our region. ARGs residing in extrachromosomal plasmid DNA tend to disseminate more into different niches, and the replication initiator protein (Rep) is required for the replication initiation of this plasmid [ 26 ].…”

Global genomic epidemiology ofblaGES-5carbapenemase-associated integrons

“…The overrepresentation of Pseudomonas spp. is consistent with previously reported bla GES-5 distribution 62 . Assembled contigs containing bla GES-5 varied dramatically in length (median=4,900bp, range=960-7,086,823bp), reflecting the fact that assembly of integron regions from short reads can lead to short contigs.…”

“…To date, bla GES-5 has been linked to several clinical outbreaks in Japan 58 , Korea 59 , the UK 60 , and the Czech Republic 61 . Moreover, bla GES-5 has been identified globally across a range of species, both on the chromosome (most notably Pseudomonas aeruginosa ST235 62 ) and plasmids (for example, the Q-type plasmid pHPRU111 found across several Enterobacterales spp . 60 ).…”

Prevalence of Carbapenem Non-susceptible Gram-Negative Bacteria at Tertiary Care Hospitals in Saudi Arabia

“…Resistance to third-generation cephalosporins, fluoroquinolones, and aminoglycosides has increased due to the spread of antimicrobial-resistant Gramnegative bacteria. In particular, the dramatic increase and spread of carbapenem-resistant-Gram-negative bacteria (CRGNB) has become a serious global public health concern, including in Saudi Arabia [5][6][7][8]. The World Health Organization (WHO) has classified CRGNB as a critical pathogen, indicating that it poses significant threats to human health and necessitates immediate research and development of novel antimicrobials [9][10][11].…”