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In Vitro Emergence of High Persistence upon Periodic Aminoglycoside Challenge in the ESKAPE Pathogens

Joran Elie Michiels1, Bram Van den Bergh1, Natalie Verstraeten1

  • 1Centre of Microbial and Plant Genetics, KU Leuven, Leuven, Belgium.

Antimicrobial Agents and Chemotherapy
|May 18, 2016
PubMed

Insights

The study reveals that common hospital pathogens, known as ESKAPE bugs, can develop increased persistence, a tolerance to antibiotics, when exposed to high-dose, intermittent therapy. This persistence can hinder treatment and may promote antibiotic resistance.

Area of Science:

  • Microbiology
  • Infectious Diseases
  • Pharmacology

Background:

  • Health care-associated infections (HAIs) pose a significant threat, often caused by multidrug-resistant pathogens.
  • The ESKAPE pathogens (Enterococcus faecium, Staphylococcus aureus, Klebsiella pneumoniae, Acinetobacter baumannii, Pseudomonas aeruginosa, and Enterobacter spp.) are major contributors to HAIs.
  • Bacterial persistence, a non-heritable tolerance to antibiotics, is an underappreciated factor in treatment failure and resistance development.

Purpose of the Study:

  • To investigate the phenomenon of bacterial persistence in ESKAPE pathogens.
  • To determine if high-dose, extended-interval aminoglycoside therapy promotes persistence in these bacteria.
  • To explore the impact of increased persistence on antibiotic tolerance and biofilm formation.

Main Methods:

  • Concentration- and time-dependent aminoglycoside killing assays were performed on ESKAPE pathogens.
  • Experimental evolution was used to simulate adaptation to high-dose, extended-interval aminoglycoside therapy in vitro.
  • Persistence levels were quantified, and cross-tolerance to other antibiotics was assessed in planktonic and biofilm states.

Main Results:

  • ESKAPE pathogens demonstrated biphasic killing kinetics, indicating the formation of persister cells.
  • In vitro adaptation to intermittent high-dose aminoglycoside therapy resulted in a significant (37- to 213-fold) increase in persistence without the emergence of genetic resistance.
  • Elevated persistence was observed in biofilms and conferred cross-tolerance to various clinically relevant antibiotics.

Conclusions:

  • Intermittent, high-dose antibiotic therapy may inadvertently promote bacterial persistence, potentially complicating infection eradication.
  • Persistence in ESKAPE pathogens can increase tolerance to multiple antibiotics and is exacerbated by simulated clinical dosing regimens.
  • Clinical strategies and diagnostics should consider bacterial persistence as a critical factor in managing HAIs and combating antibiotic resistance.

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