Adjunctive S100A8/A9 Immunomodulation Hinders Ciprofloxacin Resistance in Pseudomonas aeruginosa in a Murine Biofilm Wound Model.

Abstract

Objective:

Pseudomonas aeruginosa is known to contribute to the pathogenesis of chronic wounds by biofilm-establishment with increased tolerance to host response and antibiotics. The neutrophil-factor S100A8/A9 has a promising adjuvant effect when combined with ciprofloxacin, measured by quantitative bacteriology, and increased anti- and lowered pro-inflammatory proteins. We speculated whether a S100A8/A9 supplement could prevent ciprofloxacin resistance in infected wounds.

Method:

Full-thickness 2.9cm2-necrosis was inflicted on 32 mice. On day 4, P.aeruginosa in seaweed alginate was injected sub-eschar to mimic a mono-pathogenic biofilm. Mice were randomized to receive ciprofloxacin and S100A8/A9 (n=14), ciprofloxacin (n=12) or saline (n=6). Half of the mice in each group were euthanized day 6 and the remaining day 10 post-infection. Mice were treated until sacrifice. Primary endpoint was the appearance of ciprofloxacin resistant P.aeruginosa. The study was further evaluated by genetic characterization of resistance, means of quantitative bacteriology, wound-size and cytokine-production.

Results:

Three mice receiving ciprofloxacin monotherapy developed resistance after 14 days. None of the mice receiving combination therapy changed resistance pattern. Sequencing of fluoroquinolone-resistance determining regions in the ciprofloxacin resistant isolates identified two high-resistant strains mutated in gyrA C248T (MIC>32µg/ml) and a gyr B mutation was found in the sample with low level resistance (MIC=3µg/ml). Bacterial densities in wounds were lower in the dual treated group compared to the placebo group on both termination days.

Conclusion:

This study supports the ciprofloxacin augmenting effect and indicates a protective effect in terms of hindered ciprofloxacin resistance of adjuvant S100A8/A9 in P.aeruginosa biofilm infected chronic wounds.

• Authors: Anne S Laulund, Franziska Schwartz, Hannah Trøstrup, Kim Thomsen, Lars Christophersen, Henrik Calum, Oana Ciofu, Niels Høiby, Claus Moser
• Journal: Frontiers in cellular and infection microbiology (Front Cell Infect Microbiol) Vol. 11 Pg. 652012 ( 2021) ISSN: 2235-2988 [Electronic] Switzerland
• PMID: 33912476 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2021 Laulund, Schwartz, Trøstrup, Thomsen, Christophersen, Calum, Ciofu, Høiby and Moser.

Chemical References

• Anti-Bacterial Agents
• Ciprofloxacin

Topics

• Animals
• Anti-Bacterial Agents
• Biofilms
• Ciprofloxacin
• Immunomodulation
• Mice
• Microbial Sensitivity Tests
• Pseudomonas Infections
• Pseudomonas aeruginosa
• Wound Infection