Optometry & Vision Science:
Effect of Antibiotic Drops on Adverse Events During Extended Lens Wear
Ozkan, Jerome*; Willcox, Mark D. P.†; Rathi, Varsha M.‡; Srikanth, Dumpati§; Zhu, Hua∥; de la Jara, Percy Lazon∥; Naduvilath, Thomas∥; Holden, Brien A.**
†PhD, FBCLA, FAAO, MASM
**PhD, DSc, FAAO
Brien Holden Vision Institute (JO, HZ, PLdlJ, TN, BAH); and School of Optometry and Vision Science, University of New South Wales (JO, MDPW, HZ, PLdlJ, BAH), Sydney, New South Wales, Australia; and LV Prasad Eye Institute (VR, DS), Hyderabad, India.
Jerome Ozkan Brien Holden Vision Institute Rupert Myers Building University of New South Wales Sydney NSW 2052 Australia e-mail: email@example.com
Purpose: Overnight lens wear is associated with increased lens contamination and risk of developing a corneal infiltrate or infectious event. Antibacterial lenses have been proposed as a potential strategy for reducing lens contamination. A proof-of-principle study was conducted to investigate what effect control of potential pathogens, through the use of antibiotic eye drops, would have on the incidence of corneal infiltrative events (CIEs) and on the ocular microbiota and lens contamination.
Methods: This is a prospective, open-label, controlled, parallel-group, 1-month clinical study in which 241 subjects were dispensed with lotrafilcon A silicone hydrogel lenses for 30 days of continuous wear. Subjects were randomized into either test (moxifloxacin 0.5%) or control (rewetting solution) group. One drop was instilled into each eye on waking and before sleeping, while lenses were on-eye. Follow-ups were conducted after one night and 1 month. Lid margin swabs were taken at baseline and at 1 month and worn lenses were aseptically collected at 1 month.
Results: The incidence of CIEs was not significantly different between the test (2.6%) and control (3.9%) groups (p = 0.72). Microorganism levels from the test group swabs were significantly lower than those from the control group (p = 0.001). Gram-positive bacteria were less frequently recovered from lower lid swabs from the test group (39.6% vs. 66.0% [p < 0.001], test vs. control, respectively) or from contact lens samples (1.9% vs. 10.5% [p = 0.015], test vs. control, respectively), but there was no difference in gram-negative bacteria (GNB). Corneal infiltrative events were associated with higher levels of lens contamination (p = 0.014) and contamination of lenses with GNB (CIE: 7.3% vs. 0.6% [p = 0.029], GNB contamination vs. no GNB contamination, respectively).
Discussion: Twice-daily antibiotic instillation during continuous wear of lenses did not significantly influence the rate of inflammatory events. Corneal infiltrative events were associated with higher levels of lens contamination in general and with contamination by GNB specifically.
Despite improvements in lens materials and designs, the possibility of complications with contact lens wear remains an issue for lens wearers. The most severe complication, with the potential for permanent reduction or loss of sight, is microbial keratitis (MK). Although rare, the rate of contact lens–related MK has remained relatively unchanged for the past 20 years.1 The risk of developing an inflammatory event during contact lens wear is increased with continuous wear2,3 in contrast to daily disposable wear that has a lower risk than daily wear.4 Bacterial contamination and increased bacterial load on the lens surface have also been identified as risk factors associated with inflammatory adverse events.5–8 Although inflammatory events have not been associated with increased risk of developing MK,9 inflammatory events can sometimes progress to an infective event.10 Inflammatory events can serve as indicators of wear modality safety and ocular health.11,12 This suggests that reducing adhesion and preventing multiplication of pathogenic bacteria on lenses are critical in decreasing the incidence of these adverse events. Preventing and reducing these adverse events remain a significant challenge for practitioners and the industry.
Numerous factors influence bacterial adhesion to contact lenses including lens wear, bacterial species/strains, and the physical and chemical properties of the lens material.13,14 Preventative methods for minimizing lens contamination include greater patient education regarding maintenance of hygiene, lens disinfection, and adherence to lens and case cleaning/replacement schedule. Potential strategies that may reduce contact lens contamination include development of contact lenses surfaces with bacteriostatic/bactericidal surfaces. Investigations have examined silver,15,16 selenium,17,18 fimbrolides,19 and melimine20,21 as potential antimicrobials. Other studies have also been conducted to investigate the impact of daily lens replacement during continuous wear on ocular adverse events, the hypothesis being that exposing the eye to a new lens surface would reduce adverse events.22 Although the number of inflammatory events was trending lower with morning lens replacement, the overall reduction in adverse events was driven primarily by a reduction in mechanical adverse events. Perhaps lens contamination during handling overwhelmed the benefit offered by a new lens surface.22
Prolonged antibiotic use is thought to increase the risk of eliminating commensal bacterial microbiota while simultaneously permitting development of resistance in pathogenic bacteria. Dave et al.23 have found rapid development of resistant Staphylococcus epidermidis after repeated exposure of ocular microbiota to macrolide or fluoroquinolone (including moxifloxacin) antibiotics. By contrast, another study showed no significant difference in the resistance profile of isolates against moxifloxacin during a 2-year period.24 Before the current proof-of-principle study, we conducted a 3-month pilot study to investigate whether daily antibiotic drop (tobramycin, 0.3%) use during continuous wear of a silicone hydrogel lens would have any deleterious effects on resident ocular microbiota and ocular physiology.25 Microbiology results showed that significantly fewer microbes were recovered from lower eyelid swabs from the antibiotic group, but no differences were observed in the numbers and types of microbes recovered from contact lens samples between the antibiotic and saline (control) drop groups. There was no change in the resistance profiles of microbes in the lid margin or throat.25
The purpose of the current study was to investigate what effect control of potential pathogens, through the use of antibiotic eye drops, would have on the incidence of lens-related adverse events and on the ocular microbiota and lens contamination. Sleep is known to promote an increase in ocular bacteria,26 and many of the adverse events seen during overnight lens wear occur during sleep and are produced as direct results of bacteria, often in large numbers, contaminating contact lens surfaces.8,27 For these reasons, instilling an antibiotic around the critical period surrounding eye closure, i.e., before sleeping and on waking, may have potentially the most benefit by reducing the likelihood of microbial colonization of the lens surface. This research is proof-of-principle and in no way intended to instigate off-label prophylactic antibiotic use in healthy eyes but as a reference point for further research into the utility of pursuing development of contact lens materials with antimicrobial properties.
The study was conducted at the LV Prasad Eye Institute in Hyderabad, Andhra Pradesh, India. The design was a prospective, open-label, controlled, parallel-group, 1-month clinical study using commercially available silicone hydrogel lenses (lotrafilcon A, NIGHT & DAY; CIBA VISION, Duluth, GA) worn bilaterally on a 30-day continuous wear schedule. Participants were randomized to either using a control drop (contact lens rewetting solution; Refresh, Optics Laboratories, El Monte, CA) or the test drop (ocular antibiotic; moxifloxacin 0.5%; Moxicip, CIPLA, Verna, Goa). To eliminate issues related to epithelial toxicity, both solutions were unpreserved. The control drop was used in single-use containers.
The protocols and informed consent were reviewed and approved by an independent ethics committee; this research followed the tenets of the Declaration of Helsinki, and informed consent was obtained before enrollment. The studies were registered with the Australian and New Zealand Clinical Trial Registry before subject enrolment (ACTRN12610000920099).
Based on historical data (previously conducted trial at the same site using the same lens type and wear schedule),28 the expected incidence of corneal inflammatory events was 7 per 100 participant-eyes in the first month of wear. A minimum of 120 participants (240 participant-eyes) per study arm were required to determine a significant decrease in these events to 1.4% (80% reduction) at the 5% level of significance and 80% power after adjusting for a 5% dropout rate and 15% correlation of adverse events between eyes of the same participant.
Inclusion and Exclusion Criteria
Only subjects who met the inclusion and exclusion criteria were enrolled into the study. Inclusion criteria required subjects to be a minimum of 18 years old, require bilateral contact lens correction between −0.75 and −6.00, and have no ocular or systemic findings that would prevent safe wear of lenses. Exclusion criteria were allergy to moxifloxacin, use of any ocular or systemic medication known to affect ocular physiology up to 12 weeks prior, or previous corneal refractive surgery. Prior history of an inflammatory event increases the rates of recurrence.29,30 To minimize this bias, subjects with a prior history of severe (MK) or significant (contact lens–induced peripheral ulcer [CLPU], contact lens–induced acute red eye [CLARE], or infiltrative keratitis [IK]) ocular adverse event were excluded from the trial.
A full ocular examination was conducted at the baseline visit, and subjects were randomized into either the antibiotic drop (test) or lens rewetting solution (control) group. Once lenses were dispensed, subjects were instructed in compliance with overnight wear schedule (30 nights continuous wear) and the proper instillation technique (drop into inferior cul de sac) and dosage (one drop, into both eyes, on waking each morning and before sleeping each night, while lenses on-eye). In the event that lenses were removed during wear, subjects were instructed to either disinfect the lenses in the supplied contact lens care solution (Complete Multipurpose Solution Easy Rub Formula; Abbott Medical Optics, Abbott Park, IL) or replace the lenses before reinserting lenses. Subjects returned for follow-up scheduled visits after one night and 1-month overnight wear. Neophytes and those unadapted to lens wear were required to attend an additional visit after 1 week of daily wear (from the baseline) before proceeding to the overnight lens wear stage of 1 month of overnight wear (including a scheduled visit after one night). No drops were required to be instilled during the daily wear adaptation period. Use of contact lens rewetting drops was permitted for both groups as required, but to avoid dilution of the treatment, test group subjects were asked to avoid using the provided in-eye rewetting drop a minimum of 1 hour before and after antibiotic drop instillation.
At each scheduled visit, slit lamp biomicroscopy was performed to assess lens surface characteristics and fitting performance and ocular physiology, ocular redness (bulbar, limbal, palpebral), palpebral roughness, and corneal and conjunctival fluorescein staining using a standardized grading scale.31
At the baseline and 1-month visits, an area of the lower lid margin was swabbed with a calcium alginate swab, and the swab was then placed into 2.5-mL sterile phosphate-buffered saline containing 1% (wt/vol) sodium hexametaphosphate to dissolve the alginate. At the 1-month visit or during adverse events, worn lenses were aseptically removed and placed into 2-mL sterile phosphate-buffered saline. All swab and lens samples were transported to the microbiology laboratory for immediate analysis. The methodology for processing contact lenses and eyelid swabs has previously been described elsewhere.25
Subjects were advised to immediately inform the clinic if they experience any adverse ocular symptoms (redness, pain, blurred vision, excessive tearing, and photophobia). Subjects were reviewed in the clinic if required and monitored until full resolution of the condition. In the event of an adverse event, ocular swabs (upper palpebral and lower lid margin) were taken. If resumption of lens wear was not appropriate, subjects were permanently discontinued.
Demographic factors were compared between the two study groups to ensure comparability. The incidence of adverse events was compared between study groups using the Fisher exact test for participants and logistic regression with robust estimate of variance for participant-eyes. The robust estimate of variance accounts for the lack of independence of the eyes of subjects. Survival distributions using participant data were compared using log-rank test and Cox proportional hazard model. Contact lens contamination data were recorded in colony-forming units (CFUs) per lens format and were also converted to binary units for analysis. Lens-specific contamination data were aggregated for each participant before data analysis. Contamination rates were compared using the Fisher exact test. Contamination levels were log-transformed before analysis and compared using t-test. Association of contamination with adverse events was analyzed using Fisher exact test and t-test. The level of statistical significance was set at 5%.
A total of 241 subjects were enrolled into the study and dispensed with lenses. Sex (83% male), age (mean, 23.7 years), refractive power (mean spherical equivalent, −2.85D), and prior contact lens experience (neophyte, 55%) were not significantly different between the two groups.
There were no serious adverse events in the study. The incidence of corneal infiltrative events (CIEs) was not different between the test and control groups (2.6% vs. 3.9% of participants [p = 0.708; Fig. 1] and 1.7% vs. 2.0% of participant-eyes [p = 0.869], test vs. control, respectively). The test group had a lower incidence of mechanical events compared to the control group, although this did not reach significance (0.9% vs. 4.9% of participants [p = 0.100; Fig. 2] and 0.4% vs. 2.5% of participant-eyes [p = 0.109], test vs. control, respectively). The total incidence of adverse events between the test and control groups, combining inflammatory and mechanical events, was 3.4% versus 8.8% of participants (p = 1.50; Fig. 3) and 2.2% versus 4.4% of participant-eyes (p = 0.240). The probability of a subject surviving any adverse event at the end of 31 days was 98% for the test group and 94% for the control group (p = 0.183, log-rank test). The relative risk of failure of a subject due to any adverse event in the control group compared to the test group was 2.6 (95% confidence interval, 0.8 to 8.2; p = 0.108). Of the three types of significant CIEs, CLPU had the highest incidence (2.9%), and there was no incidence of CLPU in the test group. The incidence and distribution of adverse events for each study group are shown in Fig. 4. The bacterial types isolated during CIE events are shown in Fig. 5.
Microorganisms Recovered From Eye Swabs
Swabs were taken from a section of the lower lid margin of the test (n = 121) and control (n = 119) groups at the baseline and at 1-month visits. After 1 month, there was a greater percentage of sterile swabs obtained from participants in the test group compared to the control group (55.0% vs. 30.9% [p = 0.001], test vs. control, respectively; Fig. 6). The mean levels of microorganisms recovered from swabs after 1 month were significantly lower in the test group compared to those in the control group (mean [SD], 198  vs. 399  CFU/swab [p = 0.001], test vs. control, respectively; Fig. 7). Gram-positive bacteria (GPB) were less frequently recovered from swab samples from the test group compared to those from the control group (39.6% vs. 66.0% [p < 0.001], test vs. control, respectively; Fig. 8). There was no significant difference between the two subject groups in the frequency of gram-negative bacteria (GNB; 8.1% vs. 7.2% [p = 1.000], test vs. control, respectively, Fig. 8), and fungi were never isolated from eye swabs.
Microorganism species recovered from the lower lid margins of the test and control groups are summarized in Table 1.
Microorganisms Recovered From Worn Contact Lenses
Lenses were collected from 199 subjects at the 1-month visit, of which 104 were from the test group and 95 were from the control group. After 1 month, there was no significant difference in the rates of sterile lenses between the two groups (76.9% vs. 69.5% [p = 0.263], test vs. control, respectively). The difference in the mean levels of microorganisms recovered from contact lens samples of the test and control groups was also not significantly different (mean [SD], 437  vs. 481  CFU/lens [p = 0.540], test vs. control, respectively). Gram-positive bacteria were less frequently recovered from contact lens samples from the test group compared to the control group (1.9% vs. 10.5% [p = 0.015], test vs. control, respectively; Fig. 9). There was no significant difference between the two subject groups in the frequency of GNB (20.2% vs. 21.1% [p = 1.000], test vs. control, respectively; Fig. 9) or fungus (1.0% vs. 0% [p = 1.000], test vs. control, respectively) isolated from worn lenses. Corneal infiltrative events were, however, associated with contamination of lenses with GNB (CIE events: 7.3% vs. 0.6% [p = 0.029], GNB contamination vs. no GNB contamination; Fig. 10). Furthermore, higher levels of GNB contamination on lenses were also associated with CIE events (5.7 ± 3.8 vs. 1.8 ± 3.1 log CFU/lens [p = 0.014], CIE event vs. no CIE event; Fig. 11).
The microorganism species recovered from the worn contact lenses of test and control groups are summarized in Table 2.
The study was designed as a proof-of-principle investigation to assess whether in vivo bacterial reduction through antimicrobial drops has the potential to reduce the incidence of adverse events, specifically bacterially driven corneal inflammatory events. The fourth-generation fluoroquinolone, moxifloxacin, was chosen because of its broad spectrum of activity against GNB and GPB, low toxicity,32 and low rate of bacterial resistance.24
The study did not show a significant reduction in inflammatory adverse events in the group instilling antibiotic drops. Previous studies have shown GNB contamination of lenses to be associated with inflammatory adverse events of IK and CLARE8,27,33 and lens contamination by GPB associated with the development of CLPU events.28,29 The results of the current study seem to indicate that, in the group instilling antibiotic drops, there was reduced incidence of adverse events related to GPB (CLPU) but not for adverse events associated with GNB (CLARE and IK). Antibiotic instillation resulted in a reduction in the rate and levels of GPB being recovered from the lower lid margin, and this reduction in levels of GPB on lids was also seen in a similar study using 42 subjects who instilled tobramycin drops twice daily during lens wear.25 As with ocular swabs, GPB were less frequently recovered from the lenses of subjects in the test group compared to those in the control group. A concomitantly lower rate of GPB contamination on lenses and eyelid in the subjects instilling antibiotic drops might account for the relatively low incidence of CLPU and asymptomatic infiltrates in the test group.
Antibiotic instillation in the current study did not seem to influence the colonization of GNB on the lenses and the eyelid. Although moxifloxacin has a broad spectrum of activity, it has been shown to be more effective against GPB than against GNB.32,34 The lack of change to GNB or microbially driven adverse events such as CLARE or IK often caused by GNB but the apparent reduction in CLPU and asymptomatic infiltrates, which are more often associated with GPB,35,36 might indicate a different timing for the contamination of lenses. It may be that GNB colonization of lenses occurs randomly at any time during the day, whereas GPB contamination may occur more frequently in the mornings or evenings, when antibiotic drops were instilled. A study that examined contact lens contamination during increasing duration of lens wear demonstrated that GPB contamination was common but GNB contamination was sporadic.37 The sporadic nature of GNB contamination suggests that, even if an alternative antibiotic with better GNB efficacy had been used, this may not have affected the event rates in the test group. This suggests that, to control microbial contamination of lenses, there needs to be the continuous presence of an antimicrobial drops, such as would be given with silver, fimbrolide, selenium or melimine-coated lenses.17,19,21
The Indian environment imposes a more challenging climate and environmental condition, with a previous study also reporting more frequent contact lens contamination in an Indian population.38 This could explain the higher rates of inflammatory events after 1 month in the control group (2.0% of participant-eyes) compared to the first-month incidence rates in studies conducted in the United States using the same lens and wear schedule (0.6% [Donshik et al.30] and 1.0% [McNally et al.29]). Furthermore, the population of the current study was predominantly male (83%), young (23.7 years), and neophyte contact lens wearers (55%), which is different from the broader international contact lens wearing population, which is female (67%), older (31.7 years), and experienced (approximately 66%).39 These differences (climate, environment, and demographic) may limit the ability to generalize the results from the current study to other parts of the world where contact lenses are worn.
Another interesting finding was the notably lower incidence of corneal erosion in the subjects using antibiotic drops, with one event in the test group versus four events in the control group. The erosions were observed after 1 night of wear (two events) and after 30 nights of wear (two events), with most events resulting in a central to paracentral surface defect. Extended wear has been shown to increase the level of collagen-degrading enzymes (such as matrix metalloproteinase 9) in tears.40 Elevation of these enzymes has been associated with recurrent corneal erosions.41 Orally administered antibiotic (doxycycline) is an established treatment for recurrent erosions, and its efficacy has been attributed to its ability to inhibit these degrading enzymes.42 However, the present study found reduced erosions although we used an antibiotic that has been shown to increase protease activity.43 Therefore, it may be possible that the activity of moxifloxacin on corneal erosion is likely related to antimicrobial activity, that is, there is a reduction in bacterial proteases. A lower rate of mechanical events (driven primarily by corneal erosions) was also observed in a study in which lenses were replaced each morning during a 30-day extended wear, and this was attributed to the elimination of overnight debris accumulation behind the lenses after waking.22 Data analysis by Willcox et al.44 of trials conducted over a 7-year period found that the rate of MK is comparable to the rate of corneal erosions during lens wear coupled with GNB contamination of lenses. They suggested that contact lens manufacturers should design lenses that minimize corneal erosions, particularly during extended wear, to reduce the incidence of MK. However, the cause of development of corneal erosion during extended lens wear remains unclear.
A limitation of this study was its short duration of 1-month extended wear. A study of longer duration might have showed stronger adverse event trends between study groups, but it was important to minimize the potential for complications related to prophylactic antibiotic use. Offsetting this limitation was a previous extended wear study that showed that 40% of infiltrates occurred in the first month of wear.29 Although there have been reports on the emergence of moxifloxacin resistance,45,46 this is not likely to have been an issue in this short-term study because numerous investigations have shown no diminution of moxifloxacin activity against ocular isolates.24,32,47,48
Another limitation was that neither subjects nor examiners were masked to the treatment arm. To minimize bias, all clinicians followed the diagnostic categories of the Cornea and Contact Lens Research Unit/LV Prasad Eye Institute’s Guide to Infiltrative Conditions. Once the examiner had made a preliminary diagnosis, a study ophthalmologist reviewed the case to confirm or amend the final diagnosis. At the conclusion of the study, all adverse event cases were presented masked to the study clinicians, and a consensus was reached as to the final diagnosis of each event.
Another limiting factor, necessary to minimize the potential for complications related to prophylactic antibiotic use, was the limited antibiotic application, which occurred on waking and before sleeping. Although the study used two drops daily, whereas the therapeutic dosage of moxifloxacin is three drops daily, the slight retention of antibiotic solution into the lens material after each instillation provided an increased dosage of antibiotic to a therapeutic level through the sustained release of antibiotic from the lens material. Preliminary investigation showed that the antimicrobial was absorbed into the lens material and showed that the retention of the antibiotic drop in the lens material after drop instillation was present approximately 1 minute after drop instillation but was absent after 10 minutes (Fig. 12). Greater antibiotic retention into the lens material was observed in the pilot study, in which four drops of tropicamide were instilled daily (two drops on waking and two drops before sleeping).
An effective antibacterial contact lens would minimize or eliminate microbial contamination of the lens surface throughout the lens wear period. The current study partially simulated the actions of an antibacterial lens in reducing lens contamination after waking and before sleeping. This intervention seemed to have a limited impact on the complication rate, particularly with regard to inflammatory events driven by lens contamination with GNB. This would imply that, to reduce inflammatory complications, there would need to be sustained minimization of bacterial contamination, particularly against GNB, of the lens surface throughout the wear cycle.
Brien Holden Vision Institute
Rupert Myers Building
University of New South Wales
Sydney NSW 2052
Received May 12, 2013; accepted September 2, 2013.
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extended wear; silicone hydrogel lenses; adverse events; antibiotic; contamination
© 2014 American Academy of Optometry
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