Citation: Atshan, S.S.; Hamat, R.A.; Aljaberi, M.A.; Chen, J.-S.; Huang, S.-W.; Lin, C.-Y.; Mullins, B.J.; Kicic, A. Phage Therapy as an Alternative Treatment Modality for Resistant Staphylococcus aureus Infections. Antibiotics 2023, 12, 286. https:// doi.org/10.3390/antibiotics12020286 Academic Editor: Magdalena Plotka Received: 19 December 2022 Revised: 25 January 2023 Accepted: 30 January 2023 Published: 1 February 2023 Copyright: © 2023 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https:// creativecommons.org/licenses/by/ 4.0/). antibiotics Review Phage Therapy as an Alternative Treatment Modality for Resistant Staphylococcus aureus Infections Salman Sahab Atshan 1,2,3,4 , Rukman Awang Hamat 4, * , Musheer A. Aljaberi 5 , Jung-Sheng Chen 6, * , Shih-Wei Huang 7,8 , Chung-Ying Lin 9 , Benjamin J. Mullins 2 and Anthony Kicic 2,3,10,11 1 Department of Medical Science, Collage of Dentistry, University of Basrah, Basrah 61004, Iraq 2 School of Population Health, Curtin University, Perth, WA 6152, Australia 3 Wal-yan Respiratory Research Centre, Telethon Kids Institute, The University of Western Australia, Perth, WA 6009, Australia 4 Department of Medical Microbiology, Faculty of Medicine and Health Sciences, Universiti Putra Malaysia, Serdang 43400, Selangor, Malaysia 5 Faculty of Medicine and Health Sciences, Taiz University, Taiz 6803, Yemen 6 Department of Medical Research, E-Da Hospital, I-Shou University, Kaohsiung 824, Taiwan 7 Institute of Environmental Toxin and Emerging Contaminant, Cheng Shiu University, Kaohsiung 833, Taiwan 8 Center for Environmental Toxin and Emerging-Contaminant Research, Cheng Shiu University, Kaohsiung 833, Taiwan 9 Institute of Allied Health Sciences, College of Medicine, National Cheng Kung University, Tainan 701, Taiwan 10 Department of Respiratory and Sleep Medicine, Perth Children’s Hospital, Nedlands, WA 6009, Australia 11 Centre for Cell Therapy and Regenerative Medicine, School of Medicine and Pharmacology, The University of Western Australia, Perth, WA 6009, Australia * Correspondence: rukman@upm.edu.my (R.A.H.); ed113187@edah.org.tw (J.-S.C.) Abstract: The production and use of antibiotics increased significantly after the Second World War due to their effectiveness against bacterial infections. However, bacterial resistance also emerged and has now become an important global issue. Those most in need are typically high-risk and include individuals who experience burns and other wounds, as well as those with pulmonary infections caused by antibiotic-resistant bacteria, such as Pseudomonas aeruginosa, Acinetobacter sp, and Staphylococci. With investment to develop new antibiotics waning, finding and developing alternative therapeutic strategies to tackle this issue is imperative. One option remerging in popularity is bacteriophage (phage) therapy. This review focuses on Staphylococcus aureus and how it has developed resistance to antibiotics. It also discusses the potential of phage therapy in this setting and its appropriateness in high-risk people, such as those with cystic fibrosis, where it typically forms a biofilm. Keywords: phage therapy; antibiotics resistant; S. aureus; biofilms; infection 1. Introduction Bacterial infections are the cause of major health problems, but after the advent of antibiotics, there was the view that the issue was resolved. However, one pathogen of current global importance, Staphylococcus aureus (S. aureus), has developed drug resistance mechanisms to the currently available antibiotics, including cloxacillin, vancomycin, dapto- mycin, and others, and is resultantly responsible for over two million infections and over 23,000 deaths in the United States alone each year [1–3]. With antibiotic development by the pharmaceutical industry waning, there are many unanswered questions, including what alternatives are being developed and whether bacteriophages could be a solution. Bacteriophages (phages) are found in all habitats, and their interaction with bacteria has attracted greater attention from scientists for almost a decade [4]. Bacteriophage therapy or phage therapy (PT) that consists of specific virulent bacteriophages can be used for targeting multidrug-resistant bacteria and can mimic the action of an antibacterial Antibiotics 2023, 12, 286. https://doi.org/10.3390/antibiotics12020286 https://www.mdpi.com/journal/antibiotics