Abstract
Given the global rise of antibiotic resistance, there has been a resurgence of interest in bacteriophage therapy, typically administered concomitantly with antibiotics and currently used as a last resort treatment. In this study, we use the Galleria mellonella model to investigate the treatment outcomes and dynamics of joint therapy against a toxigenic and pathogenic strain of Staphylococcus aureus . While our previous research demonstrated that single-agent therapy, whether using bactericidal or bacteriostatic antibiotics or lytic phage, could suppress infections below a critical threshold, it rarely achieved complete bacterial eradication. Here, we show that the coadministration of a phage PYO (Sa) with antibiotics generally enhances clearance, regardless of the antibiotic class. Joint therapy with daptomycin resulted in the complete clearance of infecting bacteria in the majority of larvae. Notably, even when combined with ampicillin, to which the bacteria are highly resistant, approximately half of the larvae achieved infection clearance. Taken together, these results demonstrate that joint therapy with phage and antibiotics enhances clearance beyond what either agent achieves alone, while underscoring that treatment timing and drug-specific pharmacodynamics remain critical determinants of therapeutic outcome. SIGNIFICANCE STATEMENT: The global rise of antibiotic resistance has renewed interest in bacteriophage therapy, which is almost universally administered concomitantly with antibiotics in clinical practice. Using Galleria mellonella (the wax moth larvae), which possess an innate immune response functionally similar to that of mammals, we demonstrate that coadministration of bacteriophages and antibiotics significantly enhances infection clearance compared with single-agent therapies. Critically, this joint action of antibiotics and phage can achieve bacterial eradication even when employing antibiotics to which the bacteria are resistant. We also find that therapeutic efficacy is sensitive to treatment timing and the specific pharmacodynamics of each drug. These factors are not captured by standard in vitro assessments of antimicrobial activity. Together, these results motivate further quantitative study of clinically relevant dosing regimens to determine the impact of host-pathogen-drug interactions on treatment outcome.