Tehran University of Medical Sciences Iranian Journal of Microbiology 2008-3289 18 4 2026 08 04 460 472 Farah Badakshi Health Sciences Division, Higher Colleges of Technology, Abu Dhabi, United Arab Emirates Kiran Zahid Health Sciences Division, Higher Colleges of Technology, Abu Dhabi, United Arab Emirates 2025 12 08 2026 06 11 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. https://ijm.tums.ac.ir/index.php/ijm/article/view/5998 https://ijm.tums.ac.ir/index.php/ijm/article/download/5998/1906