Antibiotic combination therapy can select for broad-spectrum multidrug resistance in Pseudomonas aeruginosa

Martin Vestergaard, Wilhelm Paulander, Rasmus L. Marvig, Julie Clasen, Nicholas Jochumsen, Søren Molin, Lars Jelsbak, Hanne Ingmer, Sven Anders Folkesson

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Abstract

Combination therapy with several antibiotics is one strategy that has been applied in order to limit the spread of antimicrobial resistance. We compared the de novo evolution of resistance during combination therapy with the β-lactam ceftazidime and the fluoroquinolone ciprofloxacin with the resistance evolved after single-drug exposure. Combination therapy selected for mutants that displayed broad-spectrum resistance, and a major resistance mechanism was mutational inactivation of the repressor gene mexR that regulates the multidrug efflux operon mexABoprM. Deregulation of this operon led to a broad-spectrum resistance phenotype that decreased susceptibility to the combination of drugs applied during selection as well as to unrelated antibiotic classes. Mutants isolated after single-drug exposure displayed narrow-spectrum resistance and carried mutations in the MexCD–OprJ efflux pump regulator gene nfxB conferring ciprofloxacin resistance, or in the gene encoding the non-essential penicillin-binding protein DacB conferring ceftazidime resistance. Reconstruction of resistance mutations by allelic replacement and in vitro fitness assays revealed that in contrast to single antibiotic use, combination therapy consistently selected for mutants with enhanced fitness expressing broad-spectrum resistance mechanisms.
Original languageEnglish
JournalInternational Journal of Antimicrobial Agents
Volume47
Pages (from-to)48-55
Number of pages8
ISSN0924-8579
DOIs
Publication statusPublished - 2016

Keywords

  • Antibiotics
  • Combination therapy
  • Multidrug resistance
  • β-Lactams
  • Fluoroquinolones
  • Drug efflux

Cite this

Vestergaard, Martin ; Paulander, Wilhelm ; Marvig, Rasmus L. ; Clasen, Julie ; Jochumsen, Nicholas ; Molin, Søren ; Jelsbak, Lars ; Ingmer, Hanne ; Folkesson, Sven Anders. / Antibiotic combination therapy can select for broad-spectrum multidrug resistance in Pseudomonas aeruginosa. In: International Journal of Antimicrobial Agents. 2016 ; Vol. 47. pp. 48-55.
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abstract = "Combination therapy with several antibiotics is one strategy that has been applied in order to limit the spread of antimicrobial resistance. We compared the de novo evolution of resistance during combination therapy with the β-lactam ceftazidime and the fluoroquinolone ciprofloxacin with the resistance evolved after single-drug exposure. Combination therapy selected for mutants that displayed broad-spectrum resistance, and a major resistance mechanism was mutational inactivation of the repressor gene mexR that regulates the multidrug efflux operon mexAB–oprM. Deregulation of this operon led to a broad-spectrum resistance phenotype that decreased susceptibility to the combination of drugs applied during selection as well as to unrelated antibiotic classes. Mutants isolated after single-drug exposure displayed narrow-spectrum resistance and carried mutations in the MexCD–OprJ efflux pump regulator gene nfxB conferring ciprofloxacin resistance, or in the gene encoding the non-essential penicillin-binding protein DacB conferring ceftazidime resistance. Reconstruction of resistance mutations by allelic replacement and in vitro fitness assays revealed that in contrast to single antibiotic use, combination therapy consistently selected for mutants with enhanced fitness expressing broad-spectrum resistance mechanisms.",
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author = "Martin Vestergaard and Wilhelm Paulander and Marvig, {Rasmus L.} and Julie Clasen and Nicholas Jochumsen and S{\o}ren Molin and Lars Jelsbak and Hanne Ingmer and Folkesson, {Sven Anders}",
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Antibiotic combination therapy can select for broad-spectrum multidrug resistance in Pseudomonas aeruginosa. / Vestergaard, Martin; Paulander, Wilhelm; Marvig, Rasmus L.; Clasen, Julie; Jochumsen, Nicholas; Molin, Søren; Jelsbak, Lars; Ingmer, Hanne; Folkesson, Sven Anders.

In: International Journal of Antimicrobial Agents, Vol. 47, 2016, p. 48-55.

Research output: Contribution to journalJournal articleResearchpeer-review

TY - JOUR

T1 - Antibiotic combination therapy can select for broad-spectrum multidrug resistance in Pseudomonas aeruginosa

AU - Vestergaard, Martin

AU - Paulander, Wilhelm

AU - Marvig, Rasmus L.

AU - Clasen, Julie

AU - Jochumsen, Nicholas

AU - Molin, Søren

AU - Jelsbak, Lars

AU - Ingmer, Hanne

AU - Folkesson, Sven Anders

PY - 2016

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N2 - Combination therapy with several antibiotics is one strategy that has been applied in order to limit the spread of antimicrobial resistance. We compared the de novo evolution of resistance during combination therapy with the β-lactam ceftazidime and the fluoroquinolone ciprofloxacin with the resistance evolved after single-drug exposure. Combination therapy selected for mutants that displayed broad-spectrum resistance, and a major resistance mechanism was mutational inactivation of the repressor gene mexR that regulates the multidrug efflux operon mexAB–oprM. Deregulation of this operon led to a broad-spectrum resistance phenotype that decreased susceptibility to the combination of drugs applied during selection as well as to unrelated antibiotic classes. Mutants isolated after single-drug exposure displayed narrow-spectrum resistance and carried mutations in the MexCD–OprJ efflux pump regulator gene nfxB conferring ciprofloxacin resistance, or in the gene encoding the non-essential penicillin-binding protein DacB conferring ceftazidime resistance. Reconstruction of resistance mutations by allelic replacement and in vitro fitness assays revealed that in contrast to single antibiotic use, combination therapy consistently selected for mutants with enhanced fitness expressing broad-spectrum resistance mechanisms.

AB - Combination therapy with several antibiotics is one strategy that has been applied in order to limit the spread of antimicrobial resistance. We compared the de novo evolution of resistance during combination therapy with the β-lactam ceftazidime and the fluoroquinolone ciprofloxacin with the resistance evolved after single-drug exposure. Combination therapy selected for mutants that displayed broad-spectrum resistance, and a major resistance mechanism was mutational inactivation of the repressor gene mexR that regulates the multidrug efflux operon mexAB–oprM. Deregulation of this operon led to a broad-spectrum resistance phenotype that decreased susceptibility to the combination of drugs applied during selection as well as to unrelated antibiotic classes. Mutants isolated after single-drug exposure displayed narrow-spectrum resistance and carried mutations in the MexCD–OprJ efflux pump regulator gene nfxB conferring ciprofloxacin resistance, or in the gene encoding the non-essential penicillin-binding protein DacB conferring ceftazidime resistance. Reconstruction of resistance mutations by allelic replacement and in vitro fitness assays revealed that in contrast to single antibiotic use, combination therapy consistently selected for mutants with enhanced fitness expressing broad-spectrum resistance mechanisms.

KW - Antibiotics

KW - Combination therapy

KW - Multidrug resistance

KW - β-Lactams

KW - Fluoroquinolones

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