Efficacy of Ophthalmic Antimicrobials in Combination Therapeutic Approaches
Rachel AF Wozniak, William Johnson, Elianna Dunster
Department of Ophthalmology, University of Rochester, Rochester, New York
Purpose: In the treatment of severe ocular infections, it is common clinical practice to utilize multiple anti-infective agents for broad spectrum coverage as well as overcome circulating antibiotic resistance. However, drugs may either potentiate or antagonize one another with respect to antimicrobial efficacy when used in combination. Thus, using a suite of common ophthalmic antimicrobial agents, we studied how drug-drug interactions impact antimicrobial efficacy toward both Staphylococcus aureus and Pseudomonas aeruginosa to aid clinicians in selecting appropriate combination therapies.
Methods: Using standard in vitro growth conditions, we first measured the minimum inhibitory concentrations (MICs) of 8 antibiotics (vancomycin, tobramycin, gentamicin, moxifloxacin, polymyxin B/trimethoprim (PT), ceftazidime, cefazolin, and erythromycin), 3 antifungals (voriconazole, amphotericin B, and natamycin) and 2 anti-acanthamoeba agents (chlorhexidine and polyhexamethylene biguanide (PHMB)) using S. aureus and P. aeruginosa. Next, every drug was evaluated in combination with every antibiotic using standard checkerboard Fractional Inhibitory Concentration (FIC) testing. The formula: [(MIC Drug A in combination/MIC Drug A alone) + (MIC Drug B in combination/MIC Drug B alone) = FICI] was used to classify drug-drug interactions as antagonistic (FICI>4), indifferent (FICI=1-4), additive (FICI=0.5-1) or synergistic (FICI<0.5).
Results: A total of 136 combinations were evaluated (68 toward S. aureus and 68 toward P. aeruginosa). Towards S. aureus, 24 combinations did not result in an FICI value due to an unmeasurable MIC for one or both drugs. However, 30 combinations were indifferent (efficacy was similar alone vs combination), 12 combinations demonstrated additive activity in combination, 2 displayed synergistic activity (improved activity beyond what may be expected), and none were antagonistic. Against P. aeruginosa, 41 combinations had no measurable FICI, however, 17 were indifferent, 5 additive, 4 synergistic and 1 displayed antagonism. In general, results were specific to S. aureus or P. aeruginosa. However, ceftazidime + gentamicin and tobramycin + gentamicin displayed additive activity towards both species. PT + PHMB was synergistic towards P. aeruginosa and simultaneously additive towards S. aureus.
Conclusions: Drug-drug interactions are well known in medicine yet have not been specifically studied with respect to ophthalmic antimicrobial agents. Our data suggest that there are several combinations that displayed improved antimicrobial efficacy including 3 that improved towards both S. aureus and P. aeruginosa, as well as a combination that resulted in reduced efficacy. Thus, for empiric, multi-drug treatment of severe ocular infections, our data may help guide clinicians in the selection of appropriate combination therapies.
Disclosure: S (NIH EYE9012, Research to Prevent Blindness Career Dev, Award)