Heleen H DeCory

Advances in Corticosteroid Therapy for Ocular Inflammation: Loteprednol Etabonate

Topical corticosteroids are effective in reducing anterior segment inflammation but are associated with adverse drug reactions (ADRs) including elevation of intraocular pressure (IOP) and cataract formation. Retrometabolic drug design has advanced the development of new corticosteroids with improved therapeutic indices. Engineered from prednisolone, loteprednol etabonate (LE) has a 17α-chloromethyl ester, in lieu of a ketone group, and a 17β-etabonate group. LE is highly lipophilic and binds with high affinity to the glucocorticoid receptor; any unbound LE is metabolized to inactive metabolites. LE has been studied in several anterior segment inflammatory conditions (giant papillary conjunctivitis, allergic conjunctivitis, anterior uveitis, and keratoconjunctivitis sicca), and in postoperative ocular inflammation and pain. Combined with tobramycin, it is effective in blepharokeratoconjunctivitis. Elevations in IOP are infrequent with LE, and the absence of a C-20 ketone precludes formation of Schiff base intermediates with lens proteins, a common first step implicated in cataract formation with ketone steroids.

Efficacy of two once-daily methylphenidate formulations compared across dose levels at different times of the day: preliminary indications from a secondary analysis of the COMACS study data.

BackgroundMethylphenidate (MPH) is commonly prescribed in the treatment of Attention-Deficit/Hyperactivity Disorder or ADHD. Concerta and Metadate CD are once-daily formulations of MPH using different delivery mechanisms resulting in different pharmacokinetic profiles. A recent study (COMACS) showed that for near-milligram (mg) equivalent daily doses, Metadate CD provides greater symptom control in the morning (1.5 through 4.5 hours post-dose), while Concerta provides greater control in the early evening (12 hours post-dose). Non-inferential comparison of effects for different dose levels of the two formulations suggested that equivalent levels of morning symptom control could be obtained with lower daily doses of Metadate CD than Concerta; the situation being reversed in the evening. The current paper presents a secondary analysis that provides a statistical test of these observations.MethodThe COMACS study was a multi-center, double-blind crossover study of Metadate CD, Concerta and placebo with each treatment administered for 1 week. Children were assigned on the basis of their pre-trial dosage to either high (Metadate CD 60 mg; Concerta 54 mg), medium (Metadate CD 40 mg; Concerta 36 mg) or low doses (Metadate CD 20 mg; Concerta 18 mg) of MPH, and attended a laboratory school on the 7th day for assessment at 7 sessions across the day. For the post-hoc comparisons across dose levels presented here, total SKAMP scores with the active treatments (adjusted for placebo response) were analyzed using an analysis of covariance, with a combined measure modeling placebo response across all time period as the covariate.ResultsSymptom control from 1.5 through 6.0 hours post-dose was as good with lower doses of Metadate CD (20 and 40 mg) as with higher doses of Concerta (36 and 54 mg, respectively). Lower daily doses of Concerta (18 and 36 mg) and higher doses of Metadate CD (40 and 60 mg, respectively) gave equivalent control at 7.5 and 12 hours with Metadate CD giving better control from1.5 through 6.0 hours post-dose.ConclusionsDifferent delivery profiles of Metadate CD and Concerta can be exploited to limit total daily exposure to MPH while at the same targeting a specific, especially clinically significant, period of the day. These results need to be confirmed in a study in which children are randomly allocated to different dose levels of the two formulations and plasma MPH concentrations are assessed simultaneously.

Integrated analysis of three bacterial conjunctivitis trials of besifloxacin ophthalmic suspension, 0.6%: etiology of bacterial conjunctivitis and antibacterial susceptibility profile

Background 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 increasing. Patient age and local antibiotic resistance trends should be considered in the treatment of this ocular infection. Besifloxacin showed broad-spectrum in vitro activity and was particularly potent against multidrug-resistant staphylococcal isolates.

Development of a non-settling gel formulation of 0.5% loteprednol etabonate for anti-inflammatory use as an ophthalmic drop

The eye has protective barriers (ie, the conjunctival and corneal membranes) and defense mechanisms (ie, reflex tearing, blinking, lacrimal drainage) which present challenges to topical drug delivery. Topical ocular corticosteroids are commonly used in the treatment of anterior segment diseases and inflammation associated with ocular surgery, and manufacturers continually strive to improve their characteristics. We describe the development of a novel ophthalmic gel formulation of loteprednol etabonate (LE), a C-20 ester-based corticosteroid with an established safety profile, in the treatment of ocular inflammatory conditions. The new LE gel formulation is non-settling, eliminating the need to shake the product to resuspend the drug, has a pH close to that of tears, and a low preservative concentration. The rheological characteristics of LE gel are such that the formulation is instilled as a drop and transitions to a fluid upon instillation in the eye, yet retains sufficient viscosity to prolong ocular surface retention. The new formulation provides consistent, uniform dosing as evidenced by dose extrusion studies, while pharmacokinetic studies in rabbits demonstrated rapid and sustained exposure to LE in ocular tissues following instillation of LE gel. Finally, results from two clinical studies of LE gel in the treatment of postoperative inflammation and pain following cataract surgery indicate that it was safe and effective. Most patients reported no unpleasant drop sensation upon instillation, and reports of blurred vision were rare.

Besifloxacin ophthalmic suspension 0.6% in the treatment of bacterial conjunctivitis patients with Pseudomonas aeruginosa infections

Background 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 with P. aeruginosa infections with besifloxacin ophthalmic suspension 0.6% led to bacterial eradication of P. aeruginosa by the first follow-up visit and high rates of clinical resolution.

Antibacterial efficacy of prophylactic besifloxacin 0.6% and moxifloxacin 0.5% in patients undergoing cataract surgery.

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 inhibitory concentration (MIC90) of besifloxacin against methicillin-resistant S. epidermidis (MRSE) was eightfold lower than that of moxifloxacin. Conclusion Besifloxacin appeared more effective in reducing bacterial counts on eyelids of patients undergoing cataract surgery, with significant reductions as early as 1 hour postdose, compared with moxifloxacin. Besifloxacin was more active in vitro against MRSE.

Clinical outcomes with besifloxacin ophthalmic suspension 0.6% in the treatment of bacterial conjunctivitis due to potentially consequential pathogens

Purpose: 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 conse quential 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 (ciprofloxacinresistant [CipR]-MRSA n=24; CipR-MRSE n=32). The MIC 90 (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 treated with besifloxacin were 100% by the first follow-up visit for infections due to P. aeruginosa, S. marcescens, and Neisseria spp. and 87.8% by the second follow-up visit for infections due to MRSA and MRSE. Conclusion: The use of besifloxacin ophthalmic suspension 0.6% in the treatment of conjunc tival infections due to potentially consequential pathogens resulted in high rates of bacterial

Integrated analysis of three bacterial conjunctivitis trials of besifloxacin ophthalmic suspension, 0.6%: microbiological eradication outcomes.

Purpose 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 strain isolated at baseline; these eradication failures were not associated with a lower antimicrobial susceptibility at the follow-up visit. Conclusion Treatment with besifloxacin ophthalmic suspension, 0.6%, administered TID for 5 days resulted in microbiological eradication rates that were ≥ 90% across the three clinical studies for the common pathogens of bacterial conjunctivitis. The few eradication failures were not due to fluoroquinolone resistance at baseline and/or resistance development during treatment.

Antibiotic susceptibility of bacterial pathogens isolated from the aqueous and vitreous humor in the Antibiotic Resistance Monitoring in Ocular Microorganisms (ARMOR) surveillance study

Bacterial endophthalmitis is a rare but serious complication of ocular surgery, with infection often arising from a patients own bacterial flora introduced during surgery. Perioperative local antibacterial prophylaxis is a key strategy to minimize the risk for endophthalmitis but may be compromised by antibiotic resistance. We examined susceptibility profiles of bacterial pathogens isolated from the aqueous and vitreous humor to antibiotics routinely used in ophthalmic practice. Aqueous and vitreous humor bacterial isolates were obtained from January 1, 2009, through December 31, 2015, as part of the ongoing Antibiotic Resistance Monitoring in Ocular Microorganisms (ARMOR) surveillance program. Study methods and 5-year results have been reported. Briefly, minimum inhibitory concentrations (MICs) of various antibiotics and the MIC that inhibits the growth of 90% of indicated isolates (MIC90) were determined by broth microdilution, and systemic breakpoints were used to categorize isolates as susceptible, intermediate, or resistant. A total of 182 presumed endophthalmitis isolates (aqueous, n Z 61; vitreous, n Z 121) were obtained from 35 clinical sites including 105 coagulase-

Antibiotic resistance among bacterial conjunctival pathogens collected in the Antibiotic Resistance Monitoring in Ocular Microorganisms (ARMOR) surveillance study

The Antibiotic Resistance Monitoring in Ocular Microorganisms (ARMOR) surveillance study evaluates in vitro antibiotic resistance among Staphylococcus aureus, coagulase-negative staphylococci (CoNS), Streptococcus pneumoniae, Pseudomonas aeruginosa, and Haemophilus influenzae isolates from ocular infections. Here we report resistance rates and trends among conjunctival-sourced ocular isolates collected across the US from 2009 through 2016. A total of 1198 conjunctival isolates (483 S. aureus, 305 CoNS, 208 H. influenzae, 118 S. pneumoniae, and 84 P. aeruginosa) were collected from patients with presumed bacterial conjunctivitis from 57 sites across 40 states. A large proportion of staphylococci demonstrated resistance to oxacillin and azithromycin, while resistance was low against the majority of antibiotics tested for S. pneumoniae, P. aeruginosa, and H. influenzae. Multidrug resistance (≥3 antibiotic classes) was found in 30.2% of S. aureus and 39.0% of CoNS isolates, and methicillin resistance more than doubled the rate of multi-drug resistance (methicillin-resistant S. aureus [MRSA], 76.5%; methicillin-resistant CoNS isolates, 72.8%). There was a pattern of increasing mean percent resistance with increasing age by decade of life among S. aureus, MRSA, and CoNS (P≤0.038). Over the eight-year study period, there were small yet significant decreases in resistance rates among S. aureus to azithromycin, ciprofloxacin, tobramycin, trimethoprim, and oxacillin (P≤0.003), and among CoNS and P. aeruginosa (both P<0.05) to ciprofloxacin. These data indicate that antibiotic resistance is high, but did not increase, among conjunctival-sourced isolates collected in the US from 2009 through 2016. For certain antibiotic/pathogen combinations, there was a trend of decreased resistance, including a decrease in oxacillin resistance among S. aureus.