Synergistic antibacterial efficacy of early combination treatment with tobramycin and quorum-sensing inhibitors against Pseudomonas aeruginosa in an intraperitoneal foreign-body infection mouse model

J Antimicrob Chemother. 2012 May;67(5):1198-206. doi: 10.1093/jac/dks002. Epub 2012 Feb 1.

Abstract

Objectives: Quorum sensing (QS)-deficient Pseudomonas aeruginosa biofilms formed in vitro are more susceptible to tobramycin than QS-proficient P. aeruginosa biofilms, and combination treatment with a QS inhibitor (QSI) and tobramycin shows synergistic effects on the killing of in vitro biofilms. We extended these results to an in vivo P. aeruginosa foreign-body biofilm model. The effect of treatment initiated prophylactically was compared with treatment initiated 11 days post-insertion.

Methods: Silicone tube implants pre-colonized with wild-type P. aeruginosa were inserted into the peritoneal cavity of BALB/c mice. Mice were treated with intraperitoneal or subcutaneous injections of the QSIs furanone C-30, ajoene or horseradish juice extract in combination with tobramycin. Mice were euthanized on day 1, 2, 3 or 14 post-infection for the estimation of quantitative bacteriology, histopathology and cytokine measurements.

Results: Combination treatment of P. aeruginosa resulted in a significantly lower cfu per implant as compared with the placebo groups for all QSIs tested. For early-initiated treatment, a significant difference in clearing was also observed between the combination group and the single-treatment groups, and between the placebo group and the single-treatment groups. In one case a significant difference in clearing was found between the two single-treatment groups.

Conclusions: Synergistic antimicrobial efficacy could be achieved when treating mice with both a QSI and tobramycin, resulting in an increased clearance of P. aeruginosa in a foreign-body infection model. Our study highlights the important prospects in developing an early combinatory treatment strategy for chronic infections.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Anti-Bacterial Agents / administration & dosage*
  • Bacterial Load
  • Disease Models, Animal
  • Drug Synergism*
  • Drug Therapy, Combination / methods
  • Female
  • Foreign Bodies / complications*
  • Histocytochemistry
  • Mice
  • Mice, Inbred BALB C
  • Peritonitis / drug therapy*
  • Peritonitis / microbiology
  • Peritonitis / pathology
  • Peritonitis / prevention & control
  • Pseudomonas Infections / drug therapy*
  • Pseudomonas Infections / microbiology
  • Pseudomonas Infections / pathology
  • Pseudomonas Infections / prevention & control
  • Pseudomonas aeruginosa / drug effects
  • Quorum Sensing / drug effects*
  • Tobramycin / administration & dosage*

Substances

  • Anti-Bacterial Agents
  • Tobramycin