Background
Acute Bacterial Conjunctivitis
Acute conjunctivitis, an inflammation of the conjunctiva with symptoms lasting 7-14 days,[1,2] is the most frequently treated eye disorder in primary care.[3] One in eight children develops the signs and symptoms of acute conjunctivitis every year, and up to 18% of young children are brought to their primary-care physician at least once a year because of an episode of acute conjunctivitis.[1]
Red eye, ocular discharge, and discomfort are the symptoms of acute conjunctivitis,[4] which can be viral or bacterial in etiology. Clinically, it is difficult to distinguish between the two microbes.[1,5,6] As many as 78% of children with acute conjunctivitis may have bacterial conjunctivitis,[5] which in children may be caused by Haemophilus influenzae, Streptococcus pneumoniae, Staphylococcus aureus, S. epidermidis, and Moraxella catarrhalis. H. influenzae alone is estimated to cause 58% of all cases of bacterial conjunctivitis in children.[7] The adenoviruses and picornaviruses are most often responsible for acute viral conjunctivitis in children.[5]
Acute bacterial conjunctivitis is highly contagious, with outbreaks commonly reported in schools and daycare centers.[1] Most state departments of health in the US, as well as the medical literature, recommend that children with bacterial conjunctivitis be kept home until they are symptom-free, which could be as soon as 24 hours after the start of treatment.[8]
Although acute bacterial conjunctivitis is most often self-limiting,[4,5] treatment with an antibacterial agent has been shown to improve clinical and microbial remission rates, decrease the spread of infection, reduce the likelihood of relapses, and prevent sight-threatening complications, such as corneal ulceration.[3,5,9]
Topical fluoroquinolones have become the treatment of choice for bacterial conjunctivitis because of their broad-spectrum potency and low toxicity.[8,10] However, a limitation of most ophthalmic fluoroquinolones is their high frequency of dosing. The recommended dosing for ophthalmic fluoroquinolones, with the exception of moxifloxacin ophthalmic solution, is eight times daily for the first 2 days, then four times daily thereafter for 1 week, a regimen that challenges patient compliance.[11] Another limitation is resistance by bacteria to older fluoroquinolones and emerging resistance to newer fluoroquinolones.[10,12,13] Hence, there is a need for new fluoroquinolones with improved activity against resistant strains.
Besifloxacin
Besifloxacin is a new fluoroquinolone, specifically a chlorofluoroquinolone, recently approved for the topical treatment of bacterial conjunctivitis in the US. It is also the first fluoroquinolone developed exclusively for topical ophthalmic use. For this reason, selection pressure for resistance stemming from systemic use of besifloxacin is not possible, although cross-resistance stemming from bacterial pathogens resistant to other fluoroquinolones may still occur. The recommended dosage of besifloxacin ophthalmic suspension 0.6% is three times daily, 4-12 hours apart. Besifloxacin ophthalmic suspension 0.6% is formulated in a mucoadhesive polymer (DuraSite® ; InSite Vision, Inc., Alameda, CA, USA) that was designed to increase the ocular surface residence time of the drug.[14] This formulation also includes the preservative benzalkonium chloride 0.01%, which has been shown in in vitro studies to have its own antimicrobial activity[15] and to enhance the antimicrobial effect of fluoroquinolone anti-infectives when tested in combination.[16,17] Data from in vitro studies show that the inhibitory activity of besifloxacin against its targets of topoisomerase IV and DNA gyrase in S. pneumoniae occur at concentrations lower than that seen with ciprofloxacin and moxifloxacin.[18] Besifloxacin has a relatively balanced activity against both of these enzymes, resulting in a low frequency of occurrence of spontaneous mutants resistant to this agent (<1 × 10-10 at four times the minimum inhibitory concentration [MIC]).[18] These studies demonstrate that notable resistance to besifloxacin would emerge only after multiple mutations, rather than one single mutation.[18] Consistent with this premise, emergence of resistance during clinical trials of besifloxacin was not observed.[19]
Besifloxacin has been shown to be a potent antibacterial agent against more than 2500 isolates of Gram-positive and Gram-negative pathogens of bacterial conjunctivitis, including drug-resistant isolates.[20] The minimum concentration required to inhibit the growth of 90% of organisms (MIC90 ) for the common bacterial conjunctivitis pathogens S. aureus (including 21% methicillin-resistant isolates), S. pneumoniae, and H. influenzae were 0.12, 0.06, and 0.03 μg/mL, respectively; the minimum concentration required to inhibit the growth of 50% of organisms (MIC50 ) for S. epidermidis (including 44% methicillin-resistant isolates) was 0.03 μg/mL. Other studies have also demonstrated potency against isolates resistant to methicillin, ciprofloxacin, penicillin, and ampicillin, as well as multidrug-resistant isolates.[21,22] Besifloxacin retained activity against ciprofloxacin-resistant staphylococcal isolates with MIC90 values 8-, 16-, and 64-fold lower than moxifloxacin, gatifloxacin, and ciprofloxacin or levofloxacin, respectively.[23] Rapid bactericidal activity of besifloxacin has been demonstrated against the major Gram-positive and Gram-negative conjunctivitis pathogens S. aureus, S. pneumoniae, and H. influenzae, with minimum bactericidal concentrations being within one dilution of the MIC.[21,24,25]
The results of three previously reported clinical trials demonstrated that besifloxacin was safe and effective in the treatment of bacterial conjunctivitis in patients ranging in age from 1 to 98 years.[26-28] Because acute bacterial conjunctivitis most commonly affects younger patients,[1,4,29] the present analysis examined the efficacy and safety of besifloxacin in pediatric subjects aged 1-17 years who participated in these three studies.
Methods
Clinical Studies
Data for this post hoc analysis were extracted from three previously reported, randomized, double-masked, parallel-group, multicenter clinical trials evaluating the efficacy and safety of besifloxacin in the treatment of bacterial conjunctivitis. Besifloxacin ophthalmic suspension 0.6% (Besivance® ; Bausch & Lomb, Inc., Rochester, NY, USA) was compared with vehicle in two studies,[26,27] while the third trial compared besifloxacin ophthalmic suspension 0.6% with moxifloxacin hydrochloride ophthalmic solution 0.5% as base.[28]
Patients in these studies were aged 1-100 years and had a clinical diagnosis of bacterial conjunctivitis in at least one eye based on the presence of grade 1 or greater purulent conjunctival discharge and conjunctival injection, and pin-hole visual acuity (VA) of at least 20/200 in both eyes using age-appropriate testing. If VA was unobtainable in children, it was at the investigator's discretion whether the child exhibited behaviors suggesting they met the inclusion criteria. The results of patients aged 1-17 years are included in the current analysis.
For all three treatment groups, treatment consisted of one drop in the affected eye(s) three times daily, at approximately 6-hourly intervals during waking hours, for a total of 5 days, starting on day 1. Efficacy assessments included clinical resolution of baseline conjunctivitis and eradication of baseline infection at visit 2 (day 4 ± 1 in one study and day 5 ± 1 in the other two studies) and visit 3 (day 8 or 9). Clinical resolution was defined as the absence of conjunctival discharge and conjunctival bulbar injection, while microbial eradication was defined as the absence of all ocular bacterial species present at or above threshold levels according to the Cagle list (summarized in Liebowitz)[30] at baseline, based on samples taken from the cul-de-sac of the affected eyes at each visit.[26-28] Microbial eradication rates of selected ocular pathogens in the modified, intent-to-treat population were also evaluated.
Safety was assessed based on an analysis of both ocular and non-ocular adverse events.
Data Analysis
Efficacy outcomes of the three studies were evaluated in all patients whose baseline bacterial cultures in at least one eye showed levels that were at or above defined thresholds for any of the accepted ocular species (culture-confirmed [as-treated], modified intent-to-treat patients). Clinical resolution and microbial eradication endpoints were analyzed using the exact Pearson chi-squared (χ2 ) test, with missing data and discontinued patients imputed as failures. In addition, 95% confidence intervals (CIs) were calculated for the differences in percentages for besifloxacin minus the comparator (vehicle or moxifloxacin). Outcomes for subgroups aged 1 year and 1-5 years are also reported.
The safety analysis included all randomized patients who received at least one drop of study medication (safety population). The frequencies and percentages of treated eyes with adverse events were tabulated for each treatment group.
Results
Patients
Demographic information for the cohort of patients is listed in table I. A total of 407 patients received besifloxacin treatment, 241 received vehicle, and 167 received moxifloxacin treatment. Bacterial conjunctivitis was confirmed by culture in 447 of the 815 pediatric patients. The mean (±SD) age of the patients was 7.6 (±4.9) years in the besifloxacin group, 7.8 (±4.8) years in the vehicle group, and 7.6 (±5.1) years in the moxifloxacin-treated group. Age distribution and other characteristics were similar among the three groups.
Table I. Demographics of pediatric patients aged 1-17 years from three clinical trials of besifloxacin ophthalmic suspension 0.6% (safety population) [Table omitted.]
Clinical Resolution and Microbial Eradication in Vehicle-Controlled Studies
Rates of clinical resolution and microbial eradication for patients aged 1 year, 1-5 years, and 1-17 years in the vehicle-controlled studies (integrated data) are shown in table II.
Table II. Clinical resolution and microbial eradication in baseline-designated study eyes at visits 2 and 3 with besifloxacin ophthalmic suspension 0.6% or vehicle by age group[superscript] a[/superscript] [Table omitted.]
The percentage of study eyes with clinical resolution was significantly higher (p < 0.05) in the besifloxacin-treated group than in the vehicle-treated group for both visit 2 (53.7% vs 41.3%) and visit 3 (88.1% vs 73.0%) in the group aged 1-17 years (figure 1). Greater percentages of study eyes showed clinical resolution with besifloxacin in the subgroups aged 1 year and 1-5 years, but the difference was not statistically significant, likely due to the small sample size.
Fig. 1 Clinical resolution at visits 2 and 3 with besifloxacin ophthalmic suspension 0.6% or vehicle in patients aged 1-17 years. p-Values are derived from exact Pearson chi-squared (χ2 ) test. [Figure omitted.]
Similarly, microbial eradication was significantly better (p < 0.05) with besifloxacin than with vehicle at visit 2 (85.8% vs 56.3%) and visit 3 (82.8% vs 68.3%) in the group aged 1-17 years (figure 2). In the subgroups aged 1 year and 1-5 years, higher rates of microbial eradication were seen with besifloxacin than with vehicle at both visits, but the difference was statistically significantly different only at visit 2 for these younger age subgroups (72.2% vs 33.3% and 79.5% vs 45.2%, respectively, for the subgroups aged 1 year and 1-5 years).
Fig. 2 Microbial eradication at visits 2 and 3 with besifloxacin ophthalmic suspension 0.6% or vehicle in patients aged 1-17 years. p-Values are derived from exact Pearson chi-squared (χ2 ) test. [Figure omitted.]
Clinical Resolution and Microbial Eradication in the Comparator-Controlled Study: Besifloxacin vs Moxifloxacin
High rates of clinical resolution and microbial eradication were seen in both the besifloxacin- and moxifloxacin-treated patients for all three age groups (table III), with rates ranging from 69.9% to 89.8% for clinical resolution and from 66.7% to 94.2% for microbial eradication. There were no significant differences between the two treatments in any age group.
Table III. Clinical resolution and microbial eradication in baseline-designated study eyes at visits 2 and 3 with besifloxacin 0.6% or moxifloxacin 0.5% by age group[superscript] a[/superscript] [Table omitted.]
Treatment Efficacy by Organism
Table IV presents the data on microbial eradication by the organisms that were most commonly associated with bacterial conjunctivitis in the three clinical studies: S. aureus, S. epidermidis, H. influenzae, and S. pneumoniae. At both visits 2 and 3, the rates of microbial eradication were higher in besifloxacin-treated eyes than in eyes receiving vehicle, except in those with S. epidermidis infections where seven of eight subjects treated with besifloxacin ophthalmic suspension 0.6% had their infections eradicated compared with three of three subjects treated with vehicle. In the comparator-controlled study, eradication rates exceeding 78% were achieved in both treatment groups for all organisms.
Table IV. Efficacy of treatment (subjects with microbial eradication) as a function of select ocular pathogens in patients aged 1-17 years[superscript] a[/superscript] [Table omitted.]
Safety
Table V presents a summary of treatment-emergent ocular adverse events in all treated eyes. The overall incidence of adverse events was similar between treatment groups (besifloxacin 11.0%; vehicle 14.2%; moxifloxacin 10.6%). Rates of individual ocular adverse events were low in all treatment groups. The most commonly reported ocular adverse events among all besifloxacin-treated eyes, i.e. conjunctivitis (2.9%), bacterial conjunctivitis (2.1%), and eye pain (1.8%), were consistent with the underlying condition being treated. The only non-ocular adverse event reported in more than 1% of patients was headache, occurring in 1-2% of patients in each treatment group.
Table V. Treatment-emergent ocular adverse events (AEs) occurring in ≥0.5% of all treated eyes of patients aged 1-17 years in any treatment group (safety population)[superscript] a[/superscript] [Table omitted.]
Discussion
This analysis of pediatric patients aged 1-17 years who had participated in three randomized, double-blind, controlled trials showed that besifloxacin ophthalmic suspension 0.6% is safe and effective for the treatment of bacterial conjunctivitis in this age group. Clinical resolution rates were significantly better in the besifloxacin-treated group than in the vehicle-treated group in patients aged 1-17 years at both visits 2 and 3, and similar to those with moxifloxacin. Similarly, microbial eradication rates in patients aged 1-17 years treated with besifloxacin at both visits were significantly better than with vehicle alone, and similar to those with moxifloxacin. The incidence of adverse events among those treated with besifloxacin was low and was similar to those observed with vehicle and moxifloxacin.
The results for clinical resolution and microbial eradication in pediatric patients in this study are similar to the overall results for patients of all ages in the three clinical trials.[26-28] Significantly higher rates of clinical resolution (p < 0.01) were seen in the two vehicle-controlled studies at the primary analysis visits: 73.3% versus 43.1%[26] and 45.2% versus 33.0%.[27] Similarly, the rates of bacterial eradication were also significantly different: 88.3% versus 60.3% and 91.5% versus 59.7% at these timepoints. In the comparator study,[28] the rates of clinical resolution and microbial eradication for besifloxacin versus moxifloxacin were comparable (58.3% vs 59.4% and 93.3% vs 91.1%, respectively, at the primary analysis visit). Despite the small number of patients aged 1 year and 1-5 years, results for the subgroups aged 1 year and 1-5 years in the current analysis paralleled the results of patients aged 1-17 years by showing a trend of improved rates, and in some cases significantly higher rates, of clinical resolution and microbial eradication for besifloxacin versus vehicle, and comparable rates for besifloxacin versus moxifloxacin.
The most frequently isolated pathogens in the three original studies were H. influenzae, S. pneumoniae, S. aureus, and S. epidermidis.[19] In the current analysis, microbial eradication rates of besifloxacin at both visits were generally better than those of vehicle for the first three pathogens, and similar to those of moxifloxacin for all four pathogens. Overall, the results show that besifloxacin exhibited efficacy for the common ocular pathogens in the pediatric age group. These results are consistent with the previously reported eradication rates for these four species at visit 2 in besifloxacin-treated eyes from the three studies, encompassing all ages: rates of 80-100% in the vehicle-controlled studies and 85-95% in the comparator-controlled study.[19]
The safety analyses of the original clinical studies identified no significant concerns, a finding that was supported by the current subgroup analysis. The only significant difference between besifloxacin and moxifloxacin in the comparator controlled overall clinical study analysis was the greater incidence of eye irritation in eyes receiving moxifloxacin.[28] That difference was not noted among pediatric patients in the current analysis.
Only a few studies have examined the efficacy of fluoroquinolones in the treatment of acute bacterial conjunctivitis among study populations restricted to children and adolescents. A comparison of the efficacy of ciprofloxacin 0.3% and tobramycin 0.3% in 257 patients aged ≤12 years with culture-positive acute bacterial conjunctivitis found no significant differences between the two agents.[9] On day 7, clinical cure rates were 87.0% for ciprofloxacin and 89.9% for tobramycin, with bacterial eradication rates of 90.1% for ciprofloxacin and 84.3% for tobramycin. In a subset analysis of 167 patients ranging in age from 1 to 16 years who participated in two clinical studies comparing levofloxacin 0.5% ophthalmic solution with ofloxacin 0.3% ophthalmic solution administered over a 5-day treatment course,[29] the clinical cure rates were 81% for levofloxacin and 86% for ofloxacin at the last visit (days 6-10); however, bacterial eradication rates were higher with levofloxacin (85%) than with ofloxacin (68%). Among children 2-11 years of age, levofloxacin resulted in significantly higher bacterial eradication (87%) than ofloxacin (62%) on days 6-10. These results are similar to those obtained in the current analysis, with clinical resolution rates ranging from 70-90% and microbial eradication rates ranging from 67-94% in the comparison of besifloxacin and moxifloxacin.
As with other topical ophthalmic treatments for bacterial conjunctivitis, besifloxacin ophthalmic suspension 0.6% should have particular advantages for young patients and their caregivers. The rapid bactericidal effect that has been demonstrated for besifloxacin[21,25] should provide rapid and effective eradication and cure of the infection. This could reduce time lost from school and, in turn, allay parents' anxiety. Furthermore, parents of patients can return to work faster when their children return to school sooner, an aspect that has been shown to have socioeconomic benefits.[1]
Limitations of the current analysis include its post hoc design and the small number of patients in the subgroups aged 1 year and 1-5 years. The latter limitation makes it difficult to draw conclusions about the efficacy of besifloxacin in these subgroups. Nevertheless, higher efficacy rates, in some cases statistically significant despite the small samples, compared with vehicle were seen in these younger age groups.
Conclusions
This analysis of the results for pediatric patients from three large, randomized, double-masked, vehicle or comparator-controlled trials of besifloxacin ophthalmic suspension 0.6% demonstrates the safety and efficacy of this anti-infective in children and adolescents with bacterial conjunctivitis.
Acknowledgments
This work was sponsored by Bausch & Lomb, Inc., Rochester, NY, USA. Timothy Comstock, Michael Paterno, and Dale Usner are employees of Bausch & Lomb. Michael Pichichero did not receive any compensation as an author and has no conflicts of interest that are directly relevant to the content of this study. All of the authors had full access to the data in the study and take responsibility for the integrity and accuracy of the data. The authors thank Anthony Shardt, MD, of Churchill Communications for writing, and Heleen H. DeCory, PhD, of Bausch & Lomb for editorial assistance.
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[Author Affiliation]
1. Timothy L Comstock, Medical Affairs, Global Pharmaceutical, Bausch & Lomb, Inc., Rochester, New York, USA
2. Michael R Paterno and Dale W Usner, Clinical Affairs, Global Pharmaceutical, Bausch & Lomb, Inc., Rochester, New York, USA
3. Michael E Pichichero, Rochester General Research Institute, Center for Infectious Disease and Immunology, Rochester General Hospital, Rochester, New York, USA
Correspondence: Dr Timothy L. Comstock, Director, Medical Affairs, Global Pharmaceutical, Bausch & Lomb, Inc., 1400 N Goodman St, Rochester, NY 14609, USA.
