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Bacterial keratitis is a leading cause of corneal blindness worldwide. The treatment goal is to eradicate the infection by delivering sufficient levels of antibiotics to the infected cornea. The standard of care—commercial antibiotic eye drops–have limited ability to overcome anatomical and physiological barriers, and consequently may not achieve therapeutic concentrations within the cornea, particularly for drug-resistant infections. Here, we describe a moxifloxacin-eluting therapeutic contact lens (M-TCL) that provides sustained drug release to test the hypothesis that continuous delivery of high levels of antibiotics to infected tissues can overcome antimicrobial resistance. M-TCLs contained a thin moxifloxacin-polymer film encapsulated within the periphery of a contact lens hydrogel. Pharmacokinetic studies in rabbits compared M-TCL to the peak concentration from an intensive regimen of moxifloxacin eye drops and found that M-TCLs maintained significantly higher drug concentrations at all tested time points over 24 hours (p= 0.03) and a 32-fold higher peak drug concentration. When these treatments were tested in a rabbit model of methicillin-resistant Staphylococcus aureus (MRSA) keratitis derived from a clinical isolate that displayed in vitro resistance to moxifloxacin (minimum inhibition concentration= 8 µg/ml), M-TCLs demonstrated a bactericidal effect with a 3.86 log-unit reduction in colony-forming units (p< 0.0001), and mitigated keratitis-associated inflammation with less aqueous humor protein (p= 0.01). M-TCL safety was demonstrated in healthy rabbit eyes through Draize testing and histological analysis. M-TCLs may be an effective …