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Frank A Bucci Jr,1 Ruth E Evans,1 Loretta M Amico,1 Timothy W Morris,2 Angel T Fluet,1 Christine M Sanfilippo,3 Heleen H DeCory,3 Timothy L Comstock3 1Bucci Laser Vision Institute, Wilkes-Barre, PA, USA; 2Microbiology and Sterilization Sciences, Bausch and Lomb, Rochester, NY, USA; 3Medical Affairs, Bausch and Lomb, Rochester, NY, USA Background: The purpose of this study was to investigate the ocular bacterial flora in patients scheduled to undergo cataract surgery and compare the antibacterial effects of besifloxacin ophthalmic suspension 0.6% and moxifloxacin ophthalmic solution 0.5% in these patients. Methods: This was a prospective, randomized, laboratory-masked clinical trial. Patients received besifloxacin or moxifloxacin “quater in die” or QID (four times a day) for 3 days before cataract surgery in the surgical eye and 1 hour before surgery in the nonsurgical fellow eye. Conjunctival and eyelid swabs were obtained from both eyes at baseline and after treatment, on the day of surgery (Visit 2). Swabs were processed for bacterial colony counts (in terms of colony-forming units) and species identification. In vitro antibiotic susceptibilities of isolates were determined using Clinical and Laboratory Standards Institute breakpoints. Results: Fifty-nine patients (n=28 besifloxacin, n=31 moxifloxacin) completed the study. The majority (73%) of conjunctival samples were culture negative at baseline. The most frequent isolates were coagulase-negative staphylococci (CoNS, 89%), specifically Staphylococcus epidermidis (72%). Both fluoroquinolones reduced the lid CFU values when administered QID for 3 days (P≤0.019), but only besifloxacin reduced the lid CFU estimate 1 hour following instillation of a single drop (P=0.039). Fewer besifloxacin-treated eyes had lids that were culture positive for CoNS at Visit 2 compared with moxifloxacin-treated eyes regardless of dosing regimen (P≤0.03). The minimum inhibito

Timothy L Comstock,1 Timothy W Morris,2 Lynne S Gearinger,2 Heleen H DeCory11Medical Affairs, 2Department of Microbiology and Sterilization Sciences, Bausch + Lomb, Rochester, NY, USAPurpose: Besifloxacin is a chlorofluoroquinolone approved for use in the treatment of bacterial conjunctivitis. This study assessed the clinical efficacy of besifloxacin ophthalmic suspension 0.6% against conjunctivitis infections caused by potentially consequential pathogens.Design: Post hoc analysis of clinical outcomes for patients with conjunctival infections due to Pseudomonas aeruginosa, Serratia marcescens, Neisseria spp., methicillin-resistant Staphylococcus aureus (MRSA), and methicillin-resistant Staphylococcus epidermidis (MRSE) who were treated with besifloxacin in four multicenter, double-masked, randomized clinical trials.Methods: Minimum inhibitory concentrations (MICs) of besifloxacin against potentially consequential pathogens were pooled. Clinical outcome data for patients treated with besifloxacin with baseline infections due to these pathogens were pooled and summarized. Bacterial eradication was defined as the absence of ocular bacterial species present at or above threshold at baseline.Results: A total of 1,317 patients had culture-confirmed bacterial conjunctivitis across the four studies, and 151 infections were due to the aforementioned pathogens (P. aeruginosa n=9; S. marcescens n=10; Neisseria spp. n=16; MRSA n=35; MRSE n=81). Among MRSA and MRSE infections, 48.3% demonstrated concurrent ciprofloxacin resistance (ciprofloxacin-resistant [CipR]-MRSA n=24; CipR-MRSE n=32). The MIC90 (MIC for 90% of isolates) for besifloxacin was 1 µg/mL for S. marcescens, 0.25 µg/mL for Neisseria spp., 0.06 µg/mL for both ciprofloxacin-sensitive MRSA and ciprofloxacin-sensitive MRSE, and 4 µg/mL for both CipR-MRSA and CipR-MRSE. Against P. aeruginosa, the MIC range was 1–4 µg/mL. Bacterial eradication rates in patients

Wolfgang Haas, Christine M Sanfilippo, Christine K Hesje, Timothy W Morris Department of Microbiology and Sterilization Sciences, Bausch + Lomb, Inc, Rochester, NY, USA Introduction: Previous work has shown that besifloxacin, an 8-chloro-fluoroquinolone, has more potent activity against gram-positive pathogens than moxifloxacin and gatifloxacin, which carry an 8-methoxy group. This study was conducted to determine the contribution of the R7 and R8 substituent to fluoroquinolone antibacterial activity. Materials and methods: Besifloxacin, moxifloxacin, gatifloxacin, their R8 structural analogs, and ciprofloxacin were tested against representative isolates of various gram-positive and gram-negative species and previously characterized fluoroquinolone-resistant mutants of Staphylococcus aureus. Minimum inhibitory and minimum bactericidal concentrations were determined according to Clinical and Laboratory Standards Institute (CLSI) guidelines. Reserpine was used to determine the effect of efflux pumps on antibacterial activity. Results: In general, exchanging the R8 residue in besifloxacin slightly reduced the molecule's potency, while introducing an 8-chloro group in moxifloxacin increased its potency. A similar change in gatifloxacin had little to no effect. Substituting the R8 residues did not increase the susceptibility to the efflux pump inhibitor reserpine or result in a loss of bactericidal activity. In contrast, the positive control, ciprofloxacin, was shown to be a substrate for reserpine and lost bactericidal activity against some fluoroquinolone-resistant isolates of S. aureus. Conclusion: The data presented here show that, depending on the R7 substituent, replacing an 8-methoxy group with an 8-chloro substituent can improve potency or can have little-to-no effect. These findings highlight the importance of the interplay between the R7 and R8 substituents in determining antibacterial potency. Keywords: moxifloxacin, besifloxacin, fluoroquinolone analo

Bruce E Silverstein,1 Timothy W Morris,2 Lynne S Gearinger,2 Heleen H DeCory,2 Timothy L Comstock21Shasta Eye Medical Group Inc, Redding, CA, 2Bausch and Lomb Inc, Rochester, NY, USABackground: The purpose of this study was to determine the efficacy of besifloxacin ophthalmic suspension 0.6% when used in the treatment of bacterial conjunctivitis infections due to Pseudomonas aeruginosa.Methods: We undertook a post hoc analysis of clinical outcomes in patients with bacterial conjunctivitis due to P. aeruginosa across four prospective, multicenter, double-masked, randomized, controlled, clinical studies of besifloxacin ophthalmic suspension 0.6%. Efficacy outcomes included bacterial eradication and clinical resolution of the baseline infection at follow-up visits. Bacterial eradication was defined as the absence of ocular bacterial species present at or above threshold at baseline, while clinical resolution was defined as grade 0 ocular discharge and bulbar conjunctival injection. Safety outcomes included the incidence of adverse events, changes in visual acuity, and biomicroscopy and ophthalmoscopy findings. Patient outcomes were summarized and bacterial eradication and clinical resolution rates integrated.Results: Of 1317 patients with culture-confirmed bacterial conjunctivitis across four clinical studies, nine (0.7%) were infected with P. aeruginosa at baseline, and of these, five were randomized to treatment with besifloxacin ophthalmic suspension 0.6%. Bacterial eradication of the baseline infection was observed at both follow-up visits in all five patients. Clinical resolution was achieved in two of five patients by the first follow-up visit and four of five patients by the second follow-up visit. There were no adverse events reported in these patients. There were no clinically meaningful biomicroscopy findings or changes in ophthalmoscopy or visual acuity.Conclusion: The incidence of bacterial conjunctivitis due to P. aeruginosa was low. Treatment of patients

Wolfgang Haas1, Lynne S Gearinger1, Dale W Usner2, Heleen H DeCory3, Timothy W Morris11Microbiology and Sterilization Sciences, 2Clinical Affairs, 3Global Pharmaceutical Medical Affairs, Bausch and Lomb Inc, Rochester, NY, USABackground: The purpose of this paper is to report on the bacterial species isolated from patients with bacterial conjunctivitis participating in three clinical trials of besifloxacin ophthalmic suspension, 0.6%, and their in vitro antibacterial susceptibility profiles.Methods: Microbial data from three clinical studies, conducted at multiple clinical sites in the US and Asia were integrated. Species were identified at a central laboratory, and minimum inhibitory concentrations were determined for various antibiotics, including β-lactams, fluoroquinolones, and macrolides.Results: A total of 1324 bacterial pathogens representing more than 70 species were isolated. The most common species were Haemophilus influenzae (26.0%), Streptococcus pneumoniae (22.8%), Staphylococcus aureus (14.4%), and Staphylococcus epidermidis (8.4%). H. influenzae was most frequently isolated among patients aged 1–18 years, while S. aureus was most prevalent among those >65 years. Drug resistance was prevalent: Of H. influenzae isolates, 25.3% were β-lactamase positive and 27.2% of S. pneumoniae isolates were penicillin-intermediate/resistant; of S. aureus isolates, 13.7% were methicillin-resistant (MRSA), and of these, 65.4% were ciprofloxacin-resistant, while 45.9% of S. epidermidis isolates were methicillin-resistant (MRSE), and, of these, 47.1% were ciprofloxacin-resistant. Besifloxacin was more potent than comparator fluoroquinolones overall, and particularly against Gram-positive bacteria. Against ciprofloxacin-resistant MRSA and MRSE, besifloxacin was four-fold to ≥ 128-fold more potent than other fluoroquinolones.Conclusions: While the pathogen distribution in bacterial conjunctivitis has not changed, drug resistance is

Timothy W Morris1, Lynne S Gearinger1, Dale W Usner2, Michael R Paterno2, Heleen H DeCory3, Timothy L Comstock3, Wolfgang Haas11Microbiology and Sterilization Sciences, 2Clinical Affairs, 3Global Pharmaceutical Medical Affairs, Bausch & Lomb, Rochester, NY, USAPurpose: To assess clinical antimicrobial efficacy results obtained with besifloxacin ophthalmic suspension, 0.6%, administered three times a day (TID) for 5 days, integrated across three clinical trials of bacterial conjunctivitis and to investigate any microbiological eradication failures.Methods: Clinical microbiological eradication data from three randomized, double-masked, parallel group studies of patients with bacterial conjunctivitis (two vehicle controlled; one active controlled with moxifloxacin ophthalmic solution, 0.5%) were integrated. All bacterial samples isolated at baseline above the species-specific threshold value were subjected to antimicrobial susceptibility testing. Samples isolated at subsequent visits were subjected to susceptibility testing and pulsed-field gel electrophoresis (PFGE) to investigate the cause of eradication failures and the potential for drug resistance development.Results: Visit 2 (day 4 or 5) and visit 3 (day 8) overall microbiological eradication rates were 92.2% and 88.4% for besifloxacin ophthalmic suspension compared with 61.4% and 72.5% for vehicle and 91.6% and 85.7% for moxifloxacin ophthalmic solution. Visit 2 and visit 3 microbiological eradication rates for Gram-positive and Gram-negative isolates and for individual species were consistent with the overall eradication rates. The majority of observed eradication failures in any treatment group were due to the persistence of the pathogen isolated at baseline. Eradication failures in the besifloxacin treatment group were not associated with lower antimicrobial susceptibility at baseline. PFGE data showed that the majority of bacterial strains in eyes with eradication failures were identical to the strai

Timothy L Comstock1, Paul M Karpecki2, Timothy W Morris3, Jin-Zhong Zhang41Global Medical Affairs, Pharmaceuticals, Bausch and Lomb, Inc., Rochester, NY, USA; 2Koffler Vision Group, Lexington, KY, USA; 3Research and Development Microbiology and Sterilization Sciences, Bausch and Lomb, Inc., Rochester, NY, USA; 4Global Preclinical Development, Bausch and Lomb, Inc., Rochester, NY, USAAbstract: Bacterial conjunctivitis, commonly known as pink eye, is demographically unbiased in its prevalence and can be caused by a variety of aerobic and anaerobic bacteria. Timely empiric treatment with a broad-spectrum anti-infective, such as a topical fluoroquinolone, is critical in preventing potentially irreversible ocular damage. However, the rise in ocular methicillin-resistant Staphylococcus aureus isolates and the patterns of fluoroquinolone resistance for patients with other ocular bacterial infections mandate the need for new agents targeted for ocular use. Besifloxacin, a novel broad-spectrum fluoroquinolone, is approved for the treatment of bacterial conjunctivitis. It has a uniquely balanced dual-targeting activity that inhibits both DNA gyrase and topoisomerase IV and is associated with a lower incidence of resistance development. Besifloxacin is not marketed in other formulations, ensuring that its exposure is limited to bacterial populations in and around the eye. This specifically precludes any bacterial exposure to besifloxacin resulting from systemic use, which further reduces the likelihood of emergence of bacterial resistance. In vitro, besifloxacin has demonstrated equivalent or superior activity compared with other commonly used topical antibiotics. In clinical trials, besifloxacin has consistently demonstrated efficacy and safety in the treatment of patients with bacterial conjunctivitis. Besifloxacin is considered safe and is well tolerated with no observed contraindications.Keywords: conjunctivitis, fluoroquinolones, besifloxacin, besivance, bacterial conjunc