Evaluating the potential efficacy and limitations of a phage for joint antibiotic and phage therapy of <i>Staphylococcus aureus</i> infections

Abstract

In response to increasing frequencies of antibiotic-resistant pathogens, there has been a resurrection of interest in the use of bacteriophage to treat bacterial infections: phage therapy. Here we explore the potential of a seemingly ideal phage, PYO^Sa, for combination phage and antibiotic treatment of <i>Staphylococcus aureus</i> infections. This K-like phage has a broad host range; all 83 tested clinical isolates of S.aureus tested were susceptible to PYO^Sa Because of the mode of action of PYO^Sa, <i>S. aureus</i> is unlikely to generate classical receptor-site mutants resistant to PYO^Sa; none were observed in the 13 clinical isolates tested. PYO^Sa kills <i>S. aureus</i> at high rates. On the downside, the results of our experiments and tests of the joint action of PYO^Sa and antibiotics raise issues that must be addressed before PYO^Sa is employed clinically. Despite the maintenance of the phage, PYO^Sa does not clear populations of <i>S. aureus</i> Due to the ascent of a phenotyically diverse array of small-colony variants following an initial demise, the bacterial populations return to densities similar to that of phage-free controls. Using a combination of mathematical modeling and in vitro experiments, we postulate and present evidence for a mechanism to account for the demise-resurrection dynamics of PYO^Sa and <i>S. aureus</i> Critically for phage therapy, our experimental results suggest that treatment with PYO^Sa followed by bactericidal antibiotics can clear populations of <i>S. aureus</i> more effectively than the antibiotics alone.