Emerging Ocular Pathogen Resistance and Clinically Used Solutions: A Problem That Is More than Meets the Eye

<b>Background/Objectives:</b> Antimicrobial resistance (AMR) in ocular infections has become a serious concern with major implications for vision preservation. Bacterial AMR contributed to 4.71 million deaths worldwide in 2021, and ophthalmology mirrors these trends with multidrug resistance rates as high as 66% documented in some regions and persistently high methicillin resistance among common ocular pathogens. Across regions and care settings, traditional empiric therapies are losing effectiveness against an expanding range of pathogens, resulting in slower recovery, more complications, and, in many cases, permanent vision loss. This review aims to synthesize recent clinical, microbiologic, and pharmacologic evidence on ocular AMR, focusing on recent studies to capture current resistance patterns, therapeutic challenges, and evolving management strategies. <b>Methods:</b> Most included papers were published between 2020 and 2025, with additional foundational studies referenced where appropriate. Reports and systematic reviews addressing bacterial, viral, fungal, and parasitic ocular pathogens were evaluated to characterize current resistance mechanisms and management strategies across ocular pathogens. <b>Results:</b> The eye's anatomic and physiologic barriers limit drug penetration, often promoting resistance and reducing therapeutic efficacy. Resistance mechanisms vary by pathogens; <i>Pseudomonas</i> keratitis is driven mainly by efflux pumps and biofilm formation, while CMV retinitis' mutations in UL97 and UL54 are linked with clinical failure, and in MRSA associated <i>Staphylococcus</i> keratitis, the presence of mecA necessitates vancomycin-based therapy across bacterial, viral, fungal, and parasitic infections, with mechanisms such as β-lactamase production, efflux pump overexpression, target-site mutation, and biofilm formation contributing to poor response to standard therapy. MDR <i>Pseudomonas</i> keratitis remains the leading cause of rapidly progressive corneal infection with high risk of perforation and vision loss, while resistant CMV retinitis continues to threaten sight in immunocompromised patients despite antiviral advances. MDR organisms are recalcitrant to treatment and may lead to longer treatment courses and potentially worse outcomes and are discussed in detail within the manuscript. <b>Conclusions:</b> Ocular AMR represents an urgent and expanding clinical challenge. This review centers on the two most encountered multidrug-resistant organisms and their corresponding ocular sites, <i>Pseudomonas aeruginosa</i> (anterior segment) and CMV (posterior segment), while contextualizing them within the broader spectrum of resistant bacterial, viral, fungal, and parasitic pathogens. Despite growing awareness of AMR in ophthalmology, comprehensive surveillance data and longitudinal epidemiologic studies remain limited, making it difficult to track evolving resistance trends or guide region-specific therapy. Preserving vision in the AMR era will require faster diagnostics, improved ocular drug-delivery systems, and pathogen-specific therapies.