Complications related to contact lens wear include inflammatory and mechanical adverse events (AEs), most of which are self-limiting and easily managed by practitioners and patients. The least common but potentially most serious complication is microbial keratitis. However, in developed countries, contact lens wear is associated with a significant proportion of microbial keratitis,1–3 occurring at a higher rate with extended wear (EW) or continuous wear (CW) compared with daily wear.4,5 Climate and geographical location have also been implicated in increased risk6 and severity7 of microbial keratitis.
Compared with daily wear, CW is associated with a five times greater risk of developing an ocular infection6 and has been shown to significantly alter the microbiological environment (ie, reduced sterility of the conjunctiva) of the eye.8 Fleiszig and Evans9 have postulated that EW provides more time for bacteria to colonize the lens and thereby adapt to the ocular environment and become appropriately virulent and adept at infecting the cornea. In contrast, fewer complications result from a daily disposable wear schedule.10–12 Practitioners, aware of this increased risk, have reservations in recommending overnight wear with this potential for increased complication. In contrast, contact lens wearers reveal a preference for the convenience and simplicity of extended lens wear.13 Effective control of adverse responses during contact lens wear is a goal of the contact lens industry, and the development of strategies to significantly reduce the number of ocular AEs would be of benefit to contact lens wearers.
Although silicone hydrogel contact lenses have eliminated complications of contact lens wear associated with hypoxia, other nonhypoxic problems, such as ocular inflammation caused by bacterial contamination, remain. Previous studies have found that bacterial colonization occurs during lens wear,14–16 and this contamination of the lens surface by bacteria has been associated with inflammation and infection of the ocular surface.17–22 In vitro studies have shown that bacterial adhesion to silicone hydrogel materials is higher compared with bacterial adhesion to conventional hydrogels,23,24 although lens wear is known to decrease bacterial adhesion25 and lens handling–induced contamination.26 Minimizing lens contamination is also linked to disinfection solution efficacy, patient compliance, and the inherent defense mechanisms of the eye.27 Other avenues for reducing lens contamination include antimicrobial surfaces in lens cases and lenses. Several manufacturers offer silver-impregnated lens cases, and studies have shown a reduced level of contamination (including the number of colonies and type of species isolated) with use of these cases.28–30 Current investigations into the development of antimicrobial surfaces for lenses include lenses containing silver that have been shown to exhibit antimicrobial efficacy31,32 and to not significantly alter the ocular microbiota33; lenses coated with selenium covalently bonded to the surface that have exhibited decreased bacterial colonization in an animal model34 and acceptable safety in small-scale human studies35; fimbrolide-coated lenses that have demonstrated efficacy in reducing bacterial adhesion in vitro and found to be safe in an animal model and in short-term human clinical evaluation36; and a novel synthetic peptide (melimine) has been investigated in vitro and in an in vivo animal model as a potential antibacterial compound for use in contact lenses.37,38
The literature also suggests that bacterial load on lenses can be reduced by variations to cleaning routines or other interventions. A recent study has shown that inclusion of a rub-and-rinse step into the cleaning routine is effective at removing pathogenic organisms.39,40 Studies using antibiotics have shown that lenses presoaked with antibiotic retained antimicrobial activity for up to 12 hours,41 and that a higher proportion of sterile lenses seemed to be recovered if subjects instilled antibiotics during continuous lens wear.42 The aim of the present proof-of-concept studies was to assess the impact on ocular AEs when lenses are replaced in the morning and night during a CW schedule.
Two concurrent clinical studies were conducted at the L. V. Prasad Eye Institute in Hyderabad in the state of Andhra Pradesh, India. The studies were of an interventional open-labeled design and commenced on March 2008 and concluded on September 2009. The protocols and informed consent were reviewed and approved by an independent ethics committee, and this research followed the tenets of the Declaration of Helsinki.
For both studies, subjects were dispensed with commercially available silicone hydrogel contact lenses (lotrafilcon A; CIBA VISION, Duluth, Ga) on a 30-day/night CW schedule. Lens replacement was varied for each study as follows. Night lens replacement study: worn lenses were discarded each evening before sleep and immediately replaced with a new lens; morning lens replacement study: worn lenses were discarded each morning after waking and immediately replaced with a new lens. This replacement schedule also included a subset of subjects who instilled ocular lubricant bilaterally immediately after lens removal and before replacement with a new lens. The studies were registered with the Australian and New Zealand Clinical Trial Registry before subject enrollment (ACTRN12608000036314, ACTRN12609000220268). The results of the studies were compared with those of a historical control study conducted at the same site in 2005 to 2006, in which the same lens types were replaced after 30-day/night CW.
A sample size of 220 eyes was estimated to determine a fourfold reduction (odds ratio, 0.25) in any AE (mechanical and infiltrative) rate for the new replacement schedules when compared with the historical control rate of approximately 9%. This sample size was estimated based on a 5% level of significance, with 80% power, 5% dropout rate for 1 month, and a correlation of 0.15 for AEs between the eyes of the same participant.
For the two studies, subjects were dispensed with lenses at the baseline visit, and follow-up visits were scheduled at 1 week and 1 month. For adaptation purposes, neophytes to lens wear were required to wear lenses for 1 week as daily wear and attend a visit before commencing an overnight wear schedule. Anterior eye examination with a biomicroscope was conducted at all visits. The baseline visit included history, keratometry, subjective refraction, and visual acuity. In the event of an AE, ocular swabs (upper palpebral and lower lid margin) were taken and worn lenses (if available at presentation) were collected aseptically for microbiological analysis (refer to Adverse Events).
Subjects were required to be older than 18 years, have ocular health findings that would not prevent them from safely wearing lenses, and not have a concurrent need for ocular or systemic medication. Subjects with a previous history of severe or significant contact lens–related ocular AE(s), including microbial keratitis, infiltrative keratitis (IK), contact lens–induced acute red eye (CLARE), and/or contact lens–induced peripheral ulcer (CLPU), were excluded from enrolling into the studies.
Unworn Lens Collection at Baseline
To provide an estimate of hand-to-lens bacterial transference during the lens insertion process, at the baseline visit of the night replacement study, the first 20 subjects were required, after hand washing with liquid soap, to remove a lens from the original packaging and transfer it directly into a sterile vial containing 2 mL sterile phosphate-buffered saline for microbiological analysis without being inserted on the eye. The vial was then transported within 30 minutes to the microbiology laboratory. Aspects of the microbiological analysis of samples have been described elsewhere.43
Adverse events were classified as per Table 1. Subjects were instructed to advise the clinic immediately if they experienced any adverse symptoms (red eye, pain, excessive tearing, persistent irritation). Most AEs in the study required temporary discontinuation from lens wear and regular monitoring until the condition had resolved to the satisfaction of the clinician. At this stage, subjects resumed lens wear as per the study protocol. If resumption of lens wear was inappropriate, subjects were permanently discontinued from the study.
The study was designed based on the 1-month data of a historical study (refer to Study Design). The frequency of AEs (corneal inflammatory event [CIE] and any AE) that occurred in the first month of wear in the historical control sample is shown in Tables 2 and 3. There was only one (0.5%) subject who had a CIE in both eyes. The κ level of agreement for CIE between the two eyes in the first month of wear was 0.152. The McNemar paired test was significant (p = 0.021), suggesting a difference between the eyes. When any AE was considered, there were three (1.6%) subjects who had an AE in both eyes. The κ level of agreement for any AE between the two eyes in the first month of wear was 0.148. The McNemar paired test had a value of p = 0.093. Based on the above historical data, it was assumed that the correlation of AEs between the eyes within the first month of wear was low (0.15).
All participants who were successfully enrolled in the trials were included in the analysis. As an initial step, demographic variables were retrospectively compared between study groups and the historical controls using t tests and Fisher exact tests based on the scale of the variable. Demographic variables that were significant between groups were included in the multiple logistic regression analysis as a possible confounder. Adverse event data were obtained from both scheduled and unscheduled visits. Rates were reported as the number of first AEs per 100 participant eyes. Because subjects who experience a first event have a greater likelihood of developing a second event,44 only first events were considered in the analysis. Adverse event rates were compared between study groups using multiple logistic regression with a robust estimator of variance.45 The robust estimate of variance takes into account the within-subject correlation caused by the two-eye data, where it considers each subject as a cluster of two observations. Analysis of AE types that resulted in zero frequency cells used Fisher exact test. Any significant result from a Fisher exact test was considered as a trend. A value of p ≤ 0.05 was considered statistically significant. Analysis was performed using STATA version 10.46
Demographic variables, namely age, refractive error, and lens wear experience were not significantly different between the two studies and historical control samples (p ≥ 0.21). However, the distribution of sex was different between the groups (p < 0.01). Sex was therefore included as a possible confounder in the multiple logistic regression. Subject demographics for the studies are detailed in Table 4.
Fig. 1 compares the AE rate between the lubricant instillation and no lubricant instillation subgroups that formed the morning lens replacement study. No significant differences in individual AEs were observed between these two subgroups. As a result, the subgroups were combined when comparing between the three studies.
After adjusting for sex, logistic regression analysis revealed that at the 1-month scheduled visit (Table 5), there were significantly fewer mechanical events when lenses were replaced each morning compared with being replaced monthly (1.2 vs 5.2%, p = 0.02). Considering all AEs at the 1-month time point, the rate was significantly lower with morning lens replacement compared with that of the historical control (4 vs 8.9%, p = 0.04). Night lens replacement had an overall AE rate of 7.9%, which was not significantly different from that of the historical control.
Fig. 2 shows the rate and distribution of AEs across the three study groups. Participants in the morning replacement group had a lower incidence of superior epithelial arcuate lesion (SEAL), asymptomatic IK (AIK), and corneal erosion (CE). Incidence was significantly lower at the 5% level for SEAL (0 vns 2.1%, p = 0.03, morning replacement vs historical control) and AIK (0 vs 2.2%, p = 0.03, morning vs night replacement) but did not achieve significance for CE (0.8 vs 3.1%, p = 0.08, morning replacement vs historical control; 0.8 vs 3.4%, p = 0.07, morning vs night replacement). Night replacement had a significantly higher rate of AIK compared with that of the historical control (2.2 vs 0%, p = 0.05). Analysis of AEs between experienced wearers and neophytes across all studies showed that neophytes in the night lens replacement group had a higher incidence of CEs compared with that of experienced wearers, although this did not reach significance (5.7 vs 0%, p = 0.08).
Handled-Only Lens Contamination
The distribution of colony-forming units (CFU) per lens for isolated organisms on handled-only lenses is shown in Fig. 3. The mean bacterial count for the handled-only lenses was 813 CFU/lens. Staphylococcus aureus was isolated from the lenses of 35% of subjects, and 65% of subjects had more than 1000 CFU/lens of gram-positive bacterial contamination. Gram-negative bacteria were isolated from the lens of 5% of subjects.
This study investigated the impact of morning and night lens replacement during CW on ocular AEs. As overnight wear increases the risk and rate of AEs6,47 and, by contrast, daily disposable lens wear is associated with the lowest risk of experiencing a severe microbial keratitis,6 the hypothesis of the current study was exposing the eye to a new lens would reduce AEs. This study indicates that regularly replacing lenses each morning, compared with overnight replacement or monthly lens replacement (control), seems to reduce the overall rate of contact lens–related ocular AEs. Although total CIEs were trending lower with the morning lens replacement modality compared with those of the historical control and had a contributory effect in reducing the overall AE rate, the reduction was driven primarily by mechanical events. The lower mechanical events with morning lens replacement might be related to elimination of overnight debris accumulation behind the lenses soon after waking. Although night lens replacement had a similar trend for lower mechanical events compared with that in the historical control, there seemed to be a higher rate of erosions among neophytes compared with that in experienced wearers in the night replacement group. Stapleton et al. has shown that neophytes have significantly higher levels of lid biota compared with those in experienced wearers and attributed these to increased lid manipulation in neophytes.48 Perhaps neophytes inflicted a minor corneal abrasion during the insertion process, which, coupled with overnight lens wear, resulted in a more marked discrete epithelial loss.
Compared with that in the control group, the incidence of corneal inflammatory AEs in the morning and night replacement schedules showed similar trends for a reduction in events of IK/CLARE and an increase in CLPU. Gram-negative contamination of lenses is frequently involved in IK and CLARE events.20,21 Because increased bacterial load on lenses is one of the risk factors for corneal inflammation, perhaps regular lens replacement refreshes the contact lens surface sufficiently to minimize bacteria becoming more adept at infecting the cornea.9 By contrast, CLPU events are associated with increased gram-positive contamination of lenses17,22,49 associated with an epithelial defect.50 The apparent increase in CLPU events in both replacement groups compared with the control might be caused by the increased handling necessitated by both replacement schedules compared with the minimal handling of the control group. Contact lens–induced peripheral ulcer might be caused by specific members of the normal microbiota that become pathogenic at elevated levels.49 Furthermore, AIK was only recorded in the night replacement group. Sankaridurg51 has suggested that AIK is a precursor to CLARE because similar organisms were isolated with both AIK and CLARE. Perhaps if the lenses were not replaced each evening, there might instead have been an increase in acute red eye responses. In any case, lens contamination related to handling lenses in the evening, just before overnight eye closure, overwhelms the benefit offered by exposing the eye to a new lens.
The rates of lens contamination14 and AEs5 have been observed to be higher in the Indian population compared with those in other population groups. This has been attributed to multiple factors, including higher rates of microbial load, environmental irritants (dust, pollution), and tropical climate.52,53 A recent study has also shown that hand carriage of S. aureus in the Indian child population can be as high as 44%.54 Although lens handling contributes to contact lens contamination,26,27,55 the biological environment of the ocular surface has effective antimicrobial systems to swiftly combat this type of contamination.26 A subset of subjects, after hand washing, briefly handled lenses at the baseline visit to provide an estimate of likely microbial contamination of lenses during the study. To replicate real-world conditions, subjects were not given specific instructions with regard to hand washing technique, although the presence of the clinician in the room may have motivated the subjects to be more thorough in their technique than usual. Although the cultured microbes were predominantly commensal nonpathogenic bacteria, just more than one-third of subjects had S. aureus on their lenses after handling and elevated levels (>10 CFU/lens16) of gram-positive bacterial contamination. This could explain the increase in CLPU events in the morning and night replacement studies, which involved daily handling, compared with that in the control group that involved none (or minimal) handling. By contrast, gram-negative bacteria were isolated in only 5% of the sample, which concurs with findings by Willcox et al.56 and Keay et al.15 (<2%) and Szczotka-Flynn et al.57 (7.4%). This might explain why there was no increase in events of CLARE and IK in the morning and night replacement groups compared with that of the monthly replacement control group.
A previous study showed a reduction in the total counts and frequency of isolation of bacteria recovered from eye swabs of subjects instilling saline drops on waking and before sleep compared with baseline.42 The authors speculated that regular saline and/or lubricant instillation acted as a kind of ocular flush, removing stagnant tears and reducing the levels of microorganisms. In the current study, instillation of lubricant after morning lens replacement compared with no saline instillation did not seem to confer any benefit in terms of reducing the incidence of AEs.
The primary limitation of the study was its short duration of 1-month EW. Although the correlation of AEs between the two eyes was low and was based on the 1-month data of the historical control, we accept that this may not be true if the duration of the study was of a longer duration. However, a previous study has shown that more than 40% of infiltrates occurred in the first month of wear.44 The short trial duration also meant that subjects in the current studies remained highly motivated and, coupled with regular follow-up, permitted documentation of all AEs that occurred during the trial period. An obvious improvement to the study design would be to conduct a year-long trial using an active control, which would control for seasonal variations that might have influenced the rates of bacterially driven AEs. In terms of the analysis, logistic regression has one limitation, that it cannot handle cells with zero frequency. In all such situations, the Fisher exact test was used instead. This was the case for specific events, such as SEAL, IK, and AIK. The p values arising from Fisher exact tests could only be considered as trends and not conclusive.
This study supported the hypothesis that replacing lenses after waking reduces contact lens wear–related complications related to CW. Although AEs are higher with EW, they have not been established as an accurate predictor of risk of microbial keratitis; however, it would be interesting to test whether morning replacement reduces the incidence or severity of microbial keratitis with EW of contact lenses. Unfortunately, replacing lenses at night does not seem to have any beneficial effect perhaps because of the side effects of handling lenses just before overnight eye closure. Lens wearers on an EW/CW schedule should be advised to minimize lens handling before sleep to reduce the risk of complications.6
Brien Holden Vision Institute
Rupert Myers Bldg
University of New South Wales
Sydney, New South Wales 2052
Received May 2, 2012; accepted August 10, 2012.
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