O86 | Combination of antibiotic and bacteriophages to prevent the selection of resistant <i>Pseudomonas aeruginosa</i>

International audience

English. Introduction: Pseudomonas aeruginosa is an opportunistic pathogen, naturally resistant to many antibiotics. The development of additional drug resistance after repeated antibiotic treatments can lead to therapeutic gaps. Among alternative therapeutic strategies to antibiotics, bacteriophages (phages), antibacterial viruses that have the particular ability to self-amplify at the site of infection, were proposed. Nevertheless, as with antibiotics, bacteria have developed several ways to resist phages. However, as the molecular mechanisms involved in drug and phage resistance do not overlap, their combination in cocktails or with antibiotics has been proposed to improve treatment efficacy. Here, we tested the combination of ciprofloxacin and phages on P. aeruginosa by mimicking the pharmacokinetic profiles of ciprofloxacin in patients over several days.Methods: Using a hollow fiber infection model (HFIM) inoculated with P. aeruginosa, we simulated the pharmacokinetics of ciprofloxacin in the lungs during oral treatment of patients for 72 h. A single local inhalation treatment with phages was mimicked with one phage or a cocktail of two phages directly inoculated in the extracapillary space of the HFMI cartridge. Ciprofloxacin and phages alone and in combination were tested on a standard bacterial inoculum of 5.5 log10 CFU/mL and a high inoculum of 8.5 log10 CFU/mL. For the combinations, the first dose of ciprofloxacin was injected into the HFMI at the same time as the phages or 4 h after them.Results: Ciprofloxacin alone, a single phage, or a cocktail of two phages were unable to inhibit the growth of antibiotic- or phage-resistant P. aeruginosa within 30 h. With the standard inoculum, the combination of ciprofloxacin and phages eradicated bacteria regardless of the timing of ciprofloxacin administration. For the high inoculum, bacterial regrowth and resistance selection were prevented by the combination when the first dose of ciprofloxacin was added in the HFIM 4 h after phage inoculation.Conclusion: Our data, demonstrating the eradication of bacteria and the prevention of resistance by the combination of ciprofloxacin and phages, call for in vivo experiments to probe their clinical translation. These results constitute a proof-of-concept for innovative therapeutic strategies against Gram-negative pathogens in veterinary medicine, combining phages and veterinary antimicrobials.