Ocular Microbiology and Immunology Group
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2013 OMIG Abstract 17

The In Vitro and In Vivo Evaluation of RPX-978 (Tigecycline) as an
Ocular Antibacterial
EG Romanowski, KA Yates, K O’Connor, TA Kowalski, FS Mah, LV Raju, RMQ Shanks, RP Kowalski.
The Charles T. Campbell Ophthalmic Microbiology Laboratory, UPMC Eye Center, University of Pittsburgh, Pittsburgh, PA

Purpose: Tigecycline (TIG) is a glycylcycline antibiotic indicated for the IV treatment of systemic infections. RPX-978 is a topical ophthalmic formulation of TIG in development for the treatment of ocular infections. The goals of the current study were to determine the in vitro activity of TIG against multiple clinically relevant ocular pathogens and compare the efficacy of 0.5% TIG to topical vancomycin (VAN) using a methicillin-resistant Staphylococcus aureus (MRSA) keratitis model.

Methods: In vitro: Minimum Inhibitory Concentrations (MIC) using broth dilution were determined for 110 clinical conjunctivitis isolates based on incidence at the Campbell Lab. In addition, MICs were performed on 26 keratitis isolates of Pseudomonas aeruginosa (PA) and 10 endophthalmitis isolates each of MRSA, MSSA, methicillin-resistant and susceptible coagulase-negative Staphylococcus (CNS). A total of 176 isolates were tested. In vivo: In 32 NZW rabbits, corneal epithelial defects were created OS using an Amoils epithelial scrubber (abraded corneas), while the epithelia OD remained intact (intact corneas) to determine if corneal abrasion affected drug efficacy by enhancing penetration. The corneas were intrastromally injected with 1000 CFU of MRSA. Rabbits were separated into 4 groups (n=8): A) TIG 0.5%, B) VAN 5%, C) saline (SAL), and D) no treatment (euthanized before treatment for baseline CFU). 4h after MRSA challenge, topical treatment of one drop every 15’ for 5h was initiated. 1 hr after treatment the corneas were harvested for CFU. The data were non-parametrically analyzed.

Results: In vitro: Data is expressed as MIC₅₀, MIC₉₀ and Range of MICs in μg/ml respectively. Conjunctivitis: SA (0.25, 0.5, 0.125-0.5); CNS (0.25, 0.5, 0.05-1.0); Pneumococcus (<0.03, 0.125, <0.03-0.25); other Gram Pos (0.125, 0.5, <0.03-1.0); Haemophilus sp. (2.0, 4.0, 2.0-4.0); other Gram Neg (1.0, 4.0, 0.5-8.0). Keratitis: PA (4.0, 8.0, 0.5-8.0). Endophthalmitis: MRSA (0.5, 0.5, 0.25-0.5); MSSA (0.125, 0.5, 0.125-8.0); MRCNS (0.25, 0.25, 0.125-0.25); MSCNS (0.25, 0.5, 0.125-0.5). In vivo: VAN and TIG produced similar reductions in CFU, and were less than saline (P<0.05, K-W) in abraded and intact corneas. TIG and VAN demonstrated 99.9% reductions compared to baseline CFU (P<0.05, K-W) in intact and abraded corneas. The comparable reduction in CFU of abraded and intact corneas (P>0.05, M-W) by TIG suggest high penetration through the corneal epithelium. For TIG and VAN, the CFU of abraded and intact corneas were equivalent suggesting that TIG penetrated through the corneal epithelium as well as VAN.

Conclusions: TIG demonstrated broad spectrum in vitro activity against clinically relevant ocular pathogens. TIG was equally efficacious as VAN in this MRSA keratitis model. Additional studies are warranted to determine the potential of TIG in the treatment of ocular infections due to other bacteria.

Disclosure code:  S   Support: Rempex Pharmaceuticals, San Diego, CA

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