Abstract
Methicillin-resistant Staphylococcus aureus (MRSA) increasingly undermines the effectiveness of topical fluoroquinolone monotherapy in ophthalmic infections. We present a theoretical evaluation of rotational fluoroquinolone therapy, in which moxifloxacin and trovafloxacin are alternated to enhance bacterial suppression and mitigate resistance. Experimental time-kill data were fit using Bayesian parameter estimation via Markov Chain Monte Carlo (MCMC) to derive drug-specific growth and kill parameters, which were integrated into spatiotemporal pharmacodynamic models. These models incorporate radial anterior chamber geometry, intraocular diffusion, and aqueous humor pharmacokinetics governed by a circadian clearance function. Structural docking simulations of topoisomerase IV mutants reveal that common resistance mutations disrupt moxifloxacin binding while preserving trovafloxacin affinity, supporting a collateral-sensitivity mechanism. Under high-resistance conditions, rotational therapy improves bacterial clearance compared to monotherapy by increasing heterogeneity in antimicrobial exposure fronts and reducing overall bacterial burden. By alternating fluoroquinolones with complementary resistance profiles, rotational therapy leverages physiological clearance rhythms and spatial drug gradients to enhance anterior-segment efficacy, providing a quantitative foundation for its use as a rational alternative to monotherapy in ocular MRSA management.