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

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 Staphylococcus aureus 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), S. aureus is unlikely to generate classical receptor-site mutants resistant to PYO(Sa); none were observed in the 13 clinical isolates tested. PYO(Sa) kills S. aureus 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 S. aureus. 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 S. aureus. Critically for phage therapy, our experimental results suggest that treatment with PYO(Sa) followed by bactericidal antibiotics can clear populations of S. aureus more effectively than the antibiotics alone.