O cular Microbiology and Immunology Group
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2023 Harry Hirsch Leiter Award Recipient:

Efficacy of a Novel Antibiotic Drug Combination Towards Multi-Drug Resistant Ocular Pathogens

Rachel Wozniak^1,2, Gowtham Lakshminarayanan³, Paul Dunman², Esther Sheba³, Joveeta Jospeh³,
and Prashant Garg<sup>3

1</sup>University of Rochester, Department of Ophthalmology; Rochester, NY; ²University of Rochester, Department of Microbiology and Immunology; Rochester, NY; ³LV Prasad Eye Institute, Hyderabad, India

Purpose: Staphylococcus aureus and Pseudomonas aeruginosa are major causes of severe bacterial corneal infections (keratitis). Unfortunately, current therapeutics are increasingly ineffective in the face of significant multi (MDR)-drug resistance, and novel treatments are urgently needed. We sought to evaluate the in vitro efficacy of the novel drug combination polymyxin B/trimethoprim (PT) + rifampin to eradicate MDR clinical keratitis isolates.

Methods: 20 S. aureus, and 19 P. aeruginosa clinical keratitis isolates were collected from the LV Prasad Eye Institute and underwent extensive minimum inhibitory concentration (MIC) testing. S. aureus isolates were tested against 22 antibiotics from 11 distinct classes, while P. aeruginosa isolates were tested with 25 antibiotics from 16 classes. MDR was defined as resistance to > 3 classes. Fractional inhibitory concentration (FIC) testing was performed with PT + rifampin. The FIC index (FICI) was calculated: FICI = (MIC drug A in combination/MIC drug A alone) + (MIC drug B in combination/MIC drug B alone). The averaged FICI from three biological replicates was defined as synergistic (FICI < 0.5), additive (0.5-1), indifference (1-4), or antagonistic (FICI> 4).

Results: Among P. aeruginosa isolates, 100% were classified as MDR. Among S. aureus isolates, 100% were resistant to at least 1 antibiotic class, 12 (60%) were MDR, and 14 (70%) were classified as methicillin-resistant (MRSA). FIC testing revealed that PT + rifampin was effective at eradicating 100% of all isolates, displaying additive or synergistic activity towards approximately 70% of strains. Mean FICI values were
0.753 + 0.311 and 0.833 + 0.392 for S. aureus and P. aeruginosa isolates, respectively, and a >2-fold reduction in MICs was measured for both PT and rifampin when tested in combination vs alone.

Conclusions: High levels of circulating antibiotic resistance continue to be a major threat to the effective treatment of corneal infections. Our data demonstrates the ability of PT + rifampin to eradicate all isolates tested, even those conferring multi- drug resistance, highlighting the promise of this drug combination for the treatment of bacterial keratitis.

Disclosure:

S