Biological Markers of Pseudomonas aeruginosa Epidemic High-Risk Clones

Abstract

T he increasing prevalence of nosocomial infections produced by multidrug-resistant (MDR) or extensively drug-resistant (XDR) Pseudomonas aeruginosa strains severely compromises the selection of appropriate treatments and is therefore associated with significant morbidity and mortality (1-3). This growing threat results from the interplay of the extraordinary capacity of this pathogen for developing resistance to nearly all available antibiotics by the selection of mutations in chromosomal genes and from the increasing prevalence of transferable resistance determinants, particularly those encoding class B carbapenemases (metallo-␤-lactamases [MBLs]) or extended-spectrum ␤-lactamases (ESBLs), frequently cotransferred with genes encoding aminoglycoside-modifying enzymes (4). Over the last decade, multiple reports have warned about the epidemic dissemination of XDR/ MDR strains in multiple hospitals (5-10). Even more concerning are recent reports which have provided evidence of the existence of MDR/XDR clones of P. aeruginosa disseminated in multiple institutions worldwide, denominated epidemic highrisk clones (11). Among them, are the most widespread (12-18). Moreover, in a recent multicenter study of P. aeruginosa bloodstream infections, we showed that all XDR isolates (10.5% of all isolates) and some MDR isolates belonged to the epidemic high-risk clones, which were not detected among susceptible isolates (19); the specific genetic resistance markers of these clones, which may include multiple combinations of chromosomal mutations and/or horizontally acquired resistance elements, were also described in detail for the first time (19).The global success of bacterial pathogens is expected to be determined by a complex interplay between pathogenicity, epidemicity, and antibiotic resistance (20). The fitness cost of antibiotic resistance mechanisms (21), the existence of regulatory networks interconnecting resistance and virulence (22,23), and natural genetic engineering linking antibiotic resistance determinants and clonal success through genetic capitalism (24) are thought to be the main elements of this intricate equation (25). While the impacts on virulence and fitness of several individual antibiotic resistance mechanisms of P. aeruginosa have been evaluated (26-28), the specific adaptive traits that may explain the global success of epidemic high-risk clones remains unexplored. Since understanding the reasons for the success of these clones could be crucial for designing specific treatment and infection control strategies (29), the objective of this work was to determine the potential underlying biological parameters. For this purpose, using a large collection of well-characterized strains with different resistance profiles from a Spanish multicenter study of bloodstream infections (19,30) and control

Evolution of Pseudomonas aeruginosa Antimicrobial Resistance and Fitness under Low and High Mutation Rates

“…In vitro competition experiments between each of the resistant mutants and a gentamicin-tagged (att intergenic neutral chromosomal locus) wild-type PAO1 were performed (23,24). Exponentially growing cells were mixed in a 1:1 ratio and diluted in 0.9% saline solution.…”

Pseudomonas aeruginosa Ceftolozane-Tazobactam Resistance Development Requires Multiple Mutations Leading to Overexpression and Structural Modification of AmpC

“…In vitro competition experiments between each of the resistant mutants and a gentamicin-tagged (att intergenic neutral chromosomal locus) wild-type PAO1 were performed (29,30). Exponentially growing cells were mixed in a 1:1 ratio and diluted in 0.9% saline solution.…”

High-Resolution Analysis by Whole-Genome Sequencing of an International Lineage (Sequence Type 111) of Pseudomonas aeruginosa Associated with Metallo-Carbapenemases in the United Kingdom

“…As a result, it has become clear that (i) high-risk clones of various Gram-negative bacteria, including Pseudomonas aeruginosa, can be found in many disparate locations, often with no obvious epidemiological links between the affected patients, and (ii) many of these clones are adept at acquiring various antibiotic resistance determinants (1,2). These clones are commonly referred to as international lineages since they have been described in many countries across the globe.…”