Abstract
It is well-established that the spread of many multidrug-resistant (MDR) bacteria is predominantly clonal. Interestingly the international clones/sequence types (STs) of most pathogens emerged and disseminated during the last three decades. Strong experimental evidence from multiple laboratories indicate that diverse fitness cost associated with high-level resistance to fluoroquinolones contributed to the selection and promotion of the international clones/STs of hospital-associated methicillin-resistant Staphylococcus aureus (HA-MRSA), extended-spectrum β-lactamase-(ESBL)-producing Klebsiella pneumoniae, ESBL-producing Escherichia coli and Clostridioides difficile. The overwhelming part of the literature investigating the epidemiology of the pathogens as a function of fluoroquinolone use remain in concordence with these findings. Moreover, recent in vitro data clearly show the potential of fluoroquinolone exposure to shape the clonal evolution of Salmonella Enteritidis. The success of the international clones/STs in all these species was linked to the strains’ unique ability to evolve multiple energetically beneficial gyrase and topoisomerase IV mutations conferring high-level resistance to fluorquinolones and concomittantly permitting the acquisition of an extra resistance gene load without evoking appreciable fitness cost. Furthermore, by analyzing the clonality of multiple species, the review highlights, that in environments under high antibiotic exposure virulence factors play only a subsidiary role in the clonal dynamics of bacteria relative to multidrug-resistance coupled with favorable fitness (greater speed of replication). Though other groups of antibiotics should also be involved in selecting clones of bacterial pathogens the role of fluoroquinolones due to their peculiar fitness effect remains unique. It is suggested that probably no bacteria remain immune to the influence of fluoroquinolones in shaping their evolutionary dynamics. Consequently a more judicious use of fluoroquinolones, attuned to the proportion of international clone/ST isolates among local pathogens, would not only decrease resistance rates against this group of antibiotics but should also ameliorate the overall antibiotic resistance landscape.
Highlights
We have been witnessing a genuine metamorphosis in the clonal spectra of many multidrug-resistant (MDR) pathogens during the last three decades
The advent of the nowadays principal MDR clones commenced with the widespread dissemination of the first international sequence types (STs) of hospital-associated methicillin-resistant Staphylococcus aureus (HA-MRSA) the New York-Japan clone (ST5) in the 1990s (Oliveira et al, 2001) which was followed by the emergence of the ribotype 027 clone of Clostridioides difficile (Kuijper et al, 2006), the international STs of vancomycin-resistant Enterococcus faecium (VRE) (Willems et al, 2005), and the major STs/lineages of ESBL-producing Klebsiella pneumoniae (Damjanova et al, 2008) and ESBL-producing Escherichia coli (Nicolas-Chanoine et al, 2008)
We have seen how MRSA, MDR K. pneumoniae, MDR E. coli and C. difficile responded to the challenge: exclusively strains from a few international/global clones/STs proved capable of developing favorable quinolone-resistance determining regions (QRDR) mutations and emerged commanding superior fitness and replacing minor clone/ST strains in fluoroquinolone environments
Summary
We have been witnessing a genuine metamorphosis in the clonal spectra of many multidrug-resistant (MDR) pathogens during the last three decades. A comparative genomic analysis demonstrated that strains from the important sequence types, ST405, ST648, and ST38, which were not tested by Ciesielczuk et al (2015) carried considerably more virulence factors than ST131 isolates (Shaik et al, 2017) Despite this lower virulence gene load compared with some STs, it is wellestablished, that ST131 H30R remains the most prevalent group among MDR E. coli in most countries. To MRSA and MDR K. pneumoniae, the proportion of the major ST131 H30 group remains much lower among fluoroquinolone susceptible E. coli strains relative to other STs (Hertz et al, 2016; Yamaji et al, 2018) arguing strongly for a dominant role for fluoroquinolone resistance-associated fitness relative to virulence in promoting dissemination. The involvement of fluoroquinolone resistance-associated fitness cost in the selection of the global/international clones of MDR A. baumannii, Enterobacter cloacae and MDR Pseudomonas aeruginosa would deserve a thorough investigation
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