Bacteriophage cocktails and bacterial coevolution: a systematic review of resistance prevention strategies against multidrug-resistant pathogens in sewage water.

BACKGROUND AND OBJECTIVES: This systematic review aimed to determine whether phage cocktails and co-evolutionarily trained phages prevent or delay the emergence of resistance in multidrug-resistant (MDR) bacteria more effectively than single-phage therapy in sewage and wastewater-derived systems, and to characterize the underlying mechanisms and the maturity of the current evidence base. MATERIALS AND METHODS: Following PRISMA guidelines, a systematic review was performed using the PubMed and Scopus databases, with screening conducted via Rayyan Premium. RESULTS: Among 4,795 records, 20 studies (≈0.4%) fulfilled the inclusion criteria; this low fraction reflects a deliberately broad search combined with strict eligibility criteria targeting original experimental studies of phage activity against MDR pathogens specifically isolated from sewage or wastewater. Phage cocktails showed a wider range of host coverage, a delay in resistance development, and improved penetration of biofilms, particularly when paired with depolymerases or antibiotics. Phage co-evolution training resulted in a more prolonged suppression of multidrug-resistant bacteria. CONCLUSION: Phage cocktails, especially those that are co-evolved and enhanced with enzymes, show potential for applications in wastewater; however, additional long-term and large-scale research is necessary.