"Two Is Better Than One": The Multifactorial Nature of Phage-Antibiotic Combinatorial Treatments Against ESKAPE-Induced Infections.

Phage-antibiotic synergy (PAS) has been extensively explored over the past decade, with the aim of developing more effective treatments against multidrug-resistant organisms. However, it remains unclear how to effectively combine these two approaches. To address this uncertainty, we assessed four main aspects of PAS interactions in this review, seeking to identify commonalities of combining treatments within and between bacterial species. We examined all literature on PAS efficacy toward ESKAPE pathogens and present an analysis of the data in papers focusing on: (1) order of treatment, (2) dose of both phage and antibiotics, (3) mechanism of action, and (4) viability of transfer from or animal model trials to clinical applications. Our analysis indicates that there is little consistency within phage-antibiotic therapy regimens, suggesting that highly individualized treatment regimens should be used. We propose a set of experimental studies to address these research gaps. We end our review with suggestions on how to improve studies on phage-antibiotic combination therapy to advance this field.