Synergistic antibacterial efficacy of early combination treatment with tobramycin and quorum-sensing inhibitors against Pseudomonas aeruginosa in an intraperitoneal foreign-body infection mouse model.
OBJECTIVE
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.
Department of International Health, Immunology and Microbiology, Faculty of Health Sciences,  University of Copenhagen, DK-2200 Copenhagen,  Denmark.
Louise D
LD
Christensen
Maria
M
van Gennip
Tim H
TH
Jakobsen
Morten
M
Alhede
Hans Petter
HP
Hougen
Niels
N
Høiby
Thomas
T
Bjarnsholt
Michael
M
Givskov
D000818:Animals; D000900:Anti-Bacterial Agents / Q000008:administration & dosage*; D058491:Bacterial Load; D004195:Disease Models, Animal; D004357:Drug Synergism; D004359:Drug Therapy, Combination / Q000379:methods; D005260:Female; D005547:Foreign Bodies / Q000150:complications*; D006651:Histocytochemistry; D051379:Mice; D008807:Mice, Inbred BALB C; D010538:Peritonitis / Q000188:drug therapy* / Q000382:microbiology / Q000473:pathology / Q000517:prevention & control; D011552:Pseudomonas Infections / Q000188:drug therapy* / Q000382:microbiology / Q000473:pathology / Q000517:prevention & control; D011550:Pseudomonas aeruginosa / Q000187:drug effects; D053038:Quorum Sensing / Q000187:drug effects*; D014031:Tobramycin / Q000008:administration & dosage*
D000900:Anti-Bacterial Agents; D014031:Tobramycin