Abstract
Multidrug-resistant (MDR) Pseudomonas aeruginosa infections pose a serious health threat. Bacteriophage–antibiotic combination therapy is a promising candidate for combating these infections. A 5-phage P. aeruginosa cocktail, PAM2H, was tested in combination with antibiotics (ceftazidime, ciprofloxacin, gentamicin, meropenem) to determine if PAM2H enhances antibiotic activity. Combination treatment in vitro resulted in a significant increase in susceptibility of MDR strains to antibiotics. Treatment with ceftazidime (CAZ), meropenem, gentamicin, or ciprofloxacin in the presence of the phage increased the number of P. aeruginosa strains susceptible to these antibiotics by 63%, 56%, 31%, and 81%, respectively. Additionally, in a mouse dorsal wound model, seven of eight mice treated with a combination of CAZ and PAM2H for three days had no detectable bacteria remaining in their wounds on day 4, while all mice treated with CAZ or PAM2H alone had ~107 colony forming units (CFU) remaining in their wounds. P. aeruginosa recovered from mouse wounds post-treatment showed decreased virulence in a wax worm model, and DNA sequencing indicated that the combination treatment prevented mutations in genes encoding known phage receptors. Treatment with PAM2H in combination with antibiotics resulted in the re-sensitization of P. aeruginosa to antibiotics in vitro and a synergistic reduction in bacterial burden in vivo.
Highlights
The discovery of penicillin as an antimicrobial in 1928 by Alexander Fleming launched the world into a new era of treating infectious diseases [1]
In order to determine the level of susceptibility to antibiotics, phages or combination treatment, minimum inhibitory concentrations (MICs) and fractional inhibitory concentrations (FICs) were measured for PAO1, PAO1::lux and 14 phylogenetically diverse MDR
256-fold in the presence of PAM2H. We hypothesized that this significant increase in invitro efficacy would result in increased efficacy in vivo in a mouse dorsal wound model compared to antibiotic treatment alone
Summary
The discovery of penicillin as an antimicrobial in 1928 by Alexander Fleming launched the world into a new era of treating infectious diseases [1]. The emergence of multidrug-resistant (MDR) bacteria coupled with the waning of the antibiotic development pipeline has moved society back into an era where bacterial infections pose a serious threat to human health [3,4]. Pharmaceuticals 2021, 14, 184 increasingly resistant to antibiotics and cause the bulk of nosocomial infections in hospital settings [5,6]. The ESKAPE pathogens have become a top target for novel antimicrobial therapies. Among these species is P. aeruginosa, a gram-negative, opportunistic bacterium that can cause complex recurrent infections, in immunocompromised groups [7]
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