Antimicrobial Drug–Drug Interactions in the Treatment of Infectious Keratitis

Abstract

Purpose: Infectious keratitis is a serious disease requiring immediate, intensive, and broad-spectrum empiric treatment to prevent vision loss. Given the diversity of organisms that can cause serious corneal disease, current guidelines recommend treatment with several antimicrobial agents simultaneously to provide adequate coverage while awaiting results of microbiology cultures. However, it is currently unknown how the use of multiple ophthalmic antimicrobial agents in combination may affect the efficacy of individual drugs. Methods: Using a panel of 9 ophthalmic antibiotics, 3 antifungal agents, and 2 antiacanthamoeba therapeutics, fractional inhibitory concentration testing in the standard checkerboard format was used to study 36 antibiotic–antibiotic combinations, 27 antibiotic–antifungal combinations, and 18 antibiotic–antiacanthamoeba combinations against both Staphylococcus aureus and Pseudomonas aeruginosa for synergistic, additive, neutral, or antagonistic drug–drug interactions. Results: We demonstrate that while most combinations resulted in no change in antimicrobial efficacy of individual components, the combination of erythromycin + polyhexamethylene biguanide was found to be antagonistic toward P. aeruginosa. Conversely, 18 combinations toward S. aureus and 15 combinations toward P. aeruginosa resulted in additive or synergistic activity, including 4 with improved activity toward both species. Conclusions: Understanding how drug–drug interactions may affect drug efficacy is critical to selecting the appropriate combination therapy and improving clinical outcomes of this blinding disease.