Synergistic Antibacterial Effect of Phage pB3074 in Combination with Antibiotics Targeting Cell Wall against Multidrug-Resistant Acinetobacter baumannii In Vitro and Ex Vivo

Abstract

Combined application of phages and antibiotics cannot only effectively inhibit the appearance of phage-resistant bacteria, but also reduce the effective use concentration of antibiotics, and even make some bacteria regain sensitivity to some resistant antibiotics. Therefore, phage-antibiotic combination (PAC) could improve the antibacterial activity of individual drug, providing a new choice for clinical treatment of multidrug-resistant bacterial infections. Synergistic effects of phages in combination with antibiotics have received increasing attention. In this present study, we isolated a new phage pB3074 against clinically isolated multidrug-resistant Acinetobacter baumannii . Phage pB3074 combined with cell wall-targeting antibiotics could produce synergistic antibacterial effect in vitro bactericidal activities. Further research indicates that the bacteriophage dose is critical to synergistic antimicrobial effect of phage and antibiotic combination. Cefotaxime and meropenem were selected as the representative cell wall-targeting antibiotics for further synergistic antibacterial study. Results illustrated that phage pB3074 and cefotaxime or meropenem combination was very effective for the removal of mature biofilm and inhibition of biofilm formation. In a pig skin explant model, results also showed that phage pB3074 and cefotaxime or meropenem combination was very effective for the treatment of wound infection ex vivo . Subsequent studies showed that some extent recovery of drug sensitivity to cell wall-targeting antibiotics might be vital mechanism of synergistic antibacterial effect between bacteriophage pB3074 and these antibiotics. The existence of antibiotics could promote phage adsorption and proliferation, which might also be potential mechanism for synergistic antibacterial activities and have been observed in cefotaxime and meropenem application. In summary, results in the current study demonstrated that phage pB3074 has the potential to be developed as an antibacterial agent and combined application of phages and antibiotics might be a new choice for the treatment of current multidrug-resistant bacterial infections. IMPORTANCE Combined application of phages and antibiotics cannot only effectively inhibit the appearance of phage-resistant bacteria, but also reduce the effective use concentration of antibiotics, and even make some bacteria regain sensitivity to some resistant antibiotics. Therefore, phage-antibiotic combination (PAC) could improve the antibacterial activity of individual drug, providing a new choice for clinical treatment of multidrug-resistant bacterial infections.