Phage–Antibiotic Combinations Against Mature Multidrug-Resistant Biofilms: A Critical Narrative Review of Synergy Determinants, Treatment Sequencing, and Translation

Background: Phage–antibiotic combinations (PACs) are increasingly proposed for difficult biofilm infections, but planktonic synergy does not reliably predict activity in mature multidrug-resistant (MDR) biofilms. Objective: To identify the biological, pharmacological, evolutionary, methodological, and translational determinants that govern whether phage–antibiotic synergy (PAS) persists in mature MDR biofilms. Methods: This critical narrative review used a structured evidence map updated through 21 August 2026. Fifty-four primary studies met the final operational core criteria after endpoint-eligibility and publication-status verification and were evaluated for biofilm maturity, phage and antibiotic exposure, treatment sequence, resistance evolution, assay choice, and translational level. Main Results: Twenty of 54 studies (37.0%) included at least one qualifying biofilm/PAC condition aged 48 h or longer, and 14 directly compared treatment order. Interaction direction depended on phage identity, bacterial strain, matrix, absolute phage exposure, antibiotic concentration, timing, and endpoint; the schedule maximizing immediate killing did not necessarily best suppress resistance. Nine core studies reached animal models and four human cases met the defined translational criteria, but uncontrolled cases support feasibility rather than comparative efficacy. Negative, antagonistic, and indeterminate outcomes were retained, and CFU, biomass, metabolic, and lysis-based assays could classify the same regimen differently. Conclusions: PAS should be treated as a context-dependent phenotype requiring direct mature-biofilm validation, factorial dose-sequence testing, longitudinal resistance assessment, and site-matched translational confirmation.