Managing Corneal Infections: Out with the old, in with the new?

There have been multiple reports of eye infections caused by antibiotic-resistant bacteria, with increasing evidence of ineffective treatment outcomes from existing therapies. With respect to corneal infections, the most commonly used antibiotics (fluoroquinolones, aminoglycosides, and cephalosporines) are demonstrating reduced efficacy against bacterial keratitis isolates. While traditional methods are losing efficacy, several novel technologies are under investigation, including light-based anti-infective technology with or without chemical substrates, phage therapy, and probiotics. Many of these methods show non-selective antimicrobial activity with potential development as broad-spectrum antimicrobial agents. Multiple preclinical studies and a limited number of clinical case studies have confirmed the efficacy of some of these novel methods. However, given the rapid evolution of corneal infections, their treatment requires rapid institution to limit the impact on vision and prevent complications such as scarring and corneal perforation. Given their rapid effects on microbial viability, light-based technologies seem particularly promising in this regard.

Preclinical confirmation of UVC efficacy in treating infectious keratitis.

PURPOSE: Preclinical evaluation of the therapeutic potential of antimicrobial 265 nm UVC for infectious keratitis. METHODS: Four experiments explored UVC: 1) impact on bacterial and fungal lawns on agar, in individual or mixed culture, 2) bacterial inactivation dose in an in vitro deep corneal infection model, 3) dose validation in an ex vivo porcine keratitis model and 4) efficacy in a masked, randomised, controlled murine keratitis trial using bioluminescent Pseudomonas aeruginosa. RESULTS: Minimum effective UVC exposures ranged between 2 s and 5 s for lawn bacteria and fungi in individual or mixed culture. Significant P. aeruginosa growth inhibition in the in vitro infection model was achieved with 15 s UVC, that resulted in a >3.5 log10 reduction of bacteria in a subsequent ex vivo keratitis model (p < 0.05). Bioluminescence fell below baseline levels in all treated animals, within 8 h of treatment (p < 0.05), in the in vivo study. Re-epithelialisation with corneal clarity occurred within 24 h in 75% of UVC-treated cases, with no relapse at 48 h. On plating, bacteria were recovered only from untreated controls. CONCLUSIONS: UVC inhibited all tested bacteria and fungi, including mixed culture and strains linked to antibiotic resistance, in vitro, with exposures of ≤ 5 s. In vitro and ex vivo testing confirmed therapeutic potential of 15 s UVC. In vivo, 15 s UVC administered in two doses, 4 h apart, proved effective in treating murine bacterial keratitis.

Blinking and upper eyelid morphology.

PURPOSE: To explore blinking patterns and sagittal eyelid misalignment in the East Asian eye. METHODS: Forty-four participants (22 females; age 26 ± 5 years; 52% of East Asian ethnicity) were enrolled in this pilot study and subdivided, based on upper eyelid crease presence and extent, into single (n = 10), partial (n = 11) or double (n = 23) eyelid crease groups. Blinking was filmed surreptitiously with high-speed video simultaneously from an inferior temporal and frontal view. Spontaneous blink rate and type (incomplete, almost complete, or complete) were assessed over a 30 s period. Sagittal misalignment of the lids on closure was graded during complete spontaneous blinks, voluntary lid closure and voluntary maximal lid contraction (squeezing). A 0.15 µL drop of lissamine green was placed on the central lower lid margin and the number and type of blinks required to eliminate the drop informed complete palpebral apposition during blinking. RESULTS: Mean ± SD blink rates averaged 16.9 ± 10.5 blinks/minute. The proportion of incomplete blinks was 83 ± 22% in single, 58 ± 35% in partial and 59 ± 30% in double eyelid crease groups. The sagittal misalignment of the lid margins during blinking was limited to approximately one-third of the lid margin width; this was similar for all lid morphologies and blink types. The lissamine green drop was eliminated only by voluntary maximal lid contraction, and was similar in all groups (p = 0.97). CONCLUSIONS: Incomplete blinking and sagittal lid misalignment of the central eyelid margin predominate in habitual blinking, irrespective of lid morphology.

Five-year results of a prospective, randomised, contralateral eye trial of corneal crosslinking for keratoconus.

BACKGROUND: Few studies have evaluated corneal crosslinking (CXL) in a prospective, randomised fashion. This study aimed to determine the efficacy and safety of CXL to reduce the progression of keratoconus. METHODS: Prospective, unmasked, randomised, contralateral eye controlled trial at a tertiary eye centre. PARTICIPANTS: Individuals with bilateral progressive keratoconus. One eye from each subject was randomised to CXL and the contralateral, untreated eye acted as the control. PRIMARY OUTCOME MEASURE: change in maximum keratometry. SECONDARY OUTCOME MEASURES: uncorrected distance visual acuity, spectacle corrected distance visual acuity, spherical equivalent refraction, simulated keratometry, corneal astigmatism, minimum pachymetry and complications. RESULTS: Thirty-eight individuals (mean age 21.1 ± 6.7 years) were enrolled with one eye treated with CXL. At 5 years, there was a mean decrease in maximum keratometry of treated eyes (-1.45 ± 2.25 D) compared to an increase among the controls (1.71 ± 2.46 D; p < 0.001). There were significant differences between the treated and control groups in the mean change of Steep SimK (-1.07 ± 1.22 vs. 0.96 ± 1.97 D; p < 0.001), Flat SimK (-0.61 ± 1.34 vs. 0.43 ± 1.12 D; p < 0.001), corneal astigmatism (-0.45 ± 1.31 vs. 0.63 ± 1.52 D; p < 0.01) and minimum pachymetry (-32.49 ± 26.32 vs. -13.57 ± 24.11 µm; p < 0.01). Complications included sterile infiltrates (n = 2), microbial keratitis (n = 1), persistent corneal haze/scarring at 5 years (n = 4) and loss of ≥2 lines of corrected distance visual acuity (n = 3). CONCLUSIONS: CXL is an effective and relatively safe intervention to halt or reduce the progression of keratoconus in the majority of eyes for at least 5 years.

Safety and efficacy of UV application for superficial infections in humans: A systematic review and meta-analysis.

BACKGROUND: Ultraviolet (UV) light is naturally antimicrobial, but risks associated with UV overexposure have limited its clinical application. This systematic review evaluates the safety and efficacy of UV light treatment of superficial human infections. METHODS: MEDLINE, Embase, Cochrane CENTRAL, ANZCTR and US National Library of Medicine were searched (March 25, 2020). Clinical studies applying UV light (200-400 nm) for superficial infections and non-clinical studies evaluating the antimicrobial effects of UV light on human samples were included. Randomised controlled trials (RCTs) and non- RCTs were appraised using the Cochrane risk of bias and the ROBINS-I tools, respectively. RESULTS: Eleven RCTs, seven non-RCTs, 24 case studies, and 11 in vitro studies were included. Most clinical studies (34/42) evaluated UVA treatment for microbial keratitis (MK) using cross-linking (UVA-CXL) methods. Six clinical studies assessed UVC; one, UVB; and one, broadband UV for chronic skin infections. Pooled data analysis showed no difference in the time to wound resolution with UVA-CXL relative to standard treatment (mean difference [MD]: -18.20 [95% CI: -39.04 to 2.65] days; p = 0.09). Adverse event incidence was similar to control for UVA-CXL in MK (RR: 0.70 [95%CI: 0.32-1.79]; 5 RCTs) and UVC in skin infections (RR: 0.63 [95%CI: 0.25-1.54]; 2 RCTs). CONCLUSION: Alone or as an adjunct to standard therapy, UV light shows promise as a safe and effective treatment for a wide range of infections. Applications of UV light as an anti-infective agent are deserving of further evaluation, especially in the context of growing antibiotic resistance. REGISTRATION: PROSPERO registration number CRD42020176510.

Effect of therapeutic UVC on corneal DNA: Safety assessment for potential keratitis treatment.

PURPOSE: Antimicrobial ultraviolet C (UVC) has proven efficacy in vitro against keratitis isolates and has potential to treat corneal infection if safety can be confirmed. METHOD: Safety of 265 nm, 1.93 mW/cm2 intensity UVC (15-300 s exposures) was investigated in vitro via cyclobutane pyrimidine dimer (CPD) formation in DNA of human cultured corneal epithelial cells; ex vivo, by evaluating UVC transmissibility as a function of porcine corneal thickness; and in vivo, by evaluating CPD induction in the mouse cornea following UVC exposure. RESULTS: A single exposure of 15 s UVC did not induce significant CPD formation (0.92 ± 1.45%) in vitro relative to untreated control (p = 0.93) whereas 300 s exposure caused extensive CPD formation (86.8 ± 13.73%; p < 0.0001). Cumulative exposure to 15 s UVC daily for 3 days induced more CPD (14.6 ± 8.2%) than a single equivalent 45 s exposure (8.3 ± 4.0%) (p < 0.001) but levels returned to baseline within 72 h (p = 0.29), indicating highly efficient DNA repair. Ex vivo, UVC transmission decreased sharply with increasing corneal thickness, confirming UVC effects are limited to the superficial corneal layers. In vivo evaluations demonstrated no detectable CPD after three consecutive daily 15 s UVC exposures, whereas a single 300 s exposure induced extensive CPD formation in superficial corneal epithelium. CONCLUSION: Up to three daily doses of 15 s UVC, in vivo, appear safe with respect to CPD formation. Ongoing research exploring UVC as a possible treatment for microbial keratitis is warranted.

Microdroplet and spatter contamination during phacoemulsification cataract surgery in the era of COVID-19.

IMPORTANCE: Determine phacoemulsification cataract surgery risk in a Covid-19 era. BACKGROUND: SARS-CoV-2 (Covid-19) transmission via microdroplet and aerosol-generating procedures presents risk to medical professionals. As the most common elective surgical procedure performed globally; determining contamination risk from phacoemulsification cataract surgery may guide personal protection equipment use. DESIGN: Pilot study involving phacoemulsification cataract surgery on enucleated porcine eyes by experienced ophthalmologists in an ophthalmic operating theatre. PARTICIPANTS: Two ophthalmic surgical teams. METHODS: Standardized phacoemulsification of porcine eyes by two ophthalmologists accompanied by an assistant. Fluorescein incorporated into phacoemulsification irrigation fluid identifying microdroplets and spatter. Contamination documented using a single-lens reflex camera with a 532 nm narrow bandpass (fluorescein) filter, in-conjunction with a wide-field blue light and flat horizontal laser beam (wavelength 532 nm). Quantitative image analysis using Image-J software. MAIN OUTCOME MEASURES: Microdroplet and spatter contamination from cataract phacoemulsification. RESULTS: With phacoemulsification instruments fully within the eye, spatter contamination was limited to <10 cm. Insertion and removal of the phacoemulsification needle and bimanual irrigation/aspiration, with irrigation active generated spatter on the surgeons' gloves and gown extending to >16 cm below the neckline in surgeon 1 and > 5.5 cm below the neckline of surgeon 2. A small tear in the phacoemulsification irrigation sleeve, presented a worse-case scenario the greatest spatter. No contamination above the surgeons' neckline nor contamination of assistant occurred. CONCLUSIONS AND RELEVANCE: Cataract phacoemulsification generates microdroplets and spatter. Until further studies on SARS-CoV-2 transmission via microdroplets or aerosolisation of ocular fluid are reported, this pilot study only supports standard personal protective equipment.

Comparison between endoscopic and external dacryocystorhinostomy by using the Lacrimal Symptom Questionnaire: A pilot study.

BACKGROUND: Epiphora has a significant impact on the patient's quality of life and is commonly caused by nasolacrimal duct obstruction. Dacryocystorhinostomy (DCR) has traditionally been performed via an external approach, which involves a skin incision. With the advent of endoscopes, the endonasal approach to DCR has gained significant popularity. METHOD: To prospectively compare the quality of life of adult patients who underwent either an endonasal or an external DCR for acquired nasolacrimal duct obstruction, the Lacrimal Symptom Questionnaire (Lac-Q) was administered before and after surgery. The treatment group assignment was nonrandom and performed based on patient preference. The Lac-Q is a validated questionnaire that assesses the subjective perception of one's well-being from an eye-specific symptom and social impact standpoint. Total scores range from 0 (no concerns) to 33 (maximal degree of ocular symptoms and social impact). RESULTS: Sixty patients (22 in the endonasal group, 38 in the external group) were recruited between January 1, 2014, and January 1, 2016. Postoperative assessment was performed at 3 and 6 months. Patients who underwent external DCR reported a median 7.0-point improvement (interquartile range [IQR], 3.0-11.0) in total Lac-Q scores. A 12.0-point improvement (IQR, 10.0-18.5) was seen in the endonasal group (p = 0.005). The median change in the social impact score was 3.0 and 4.0 in the external group and the endoscopic group, respectively (p = 0.029). Changes in the median lacrimal symptom score were 4.0 in the external group and 8.0 in the endoscopic group (p = 0.014). The anatomic patency rate was lower in the external group (60.0%) when compared with the endonasal group (90.4%). Patients in the external DCR group were significantly older (median age, 51 versus 41 years). CONCLUSION: Our study indicated that both endonasal and external DCR can lead to improvement in quality of life by using a validated questionnaire. Although there are differences in age and anatomic success rates between the two groups, subgroup analyses indicated that the differences in the Lac-Q scores persisted when age and anatomic patency were removed as potential confounding factors. Further larger, randomized studies would be helpful.

Current dilemmas and controversies in allergic contact dermatitis to ophthalmic medications.

Identifying contact allergens in ophthalmic medications can be a challenging and daunting experience. We summarize data on topical ophthalmic medications with the potential to cause periorbital contact dermatitis and allergic conjunctivitis, highlighting current dilemmas and controversies in this area. The following groups of allergens are reviewed: preservatives, antiglaucoma medications (prostaglandin analogues, ß-blockers, carbonic anhydrase inhibitors, parasympathomimetics, sympathomimetics), antiinflammatory medications (nonsteroidal antiinflammatory drugs, corticosteroids), antibiotics, antivirals, antiallergic medications (antihistamines, cromones), anaesthetics, mydriatics, and cycloplegics.

Efficacy and safety assessment of a novel ultraviolet C device for treating corneal bacterial infections.

BACKGROUND: A prototype solid-state Ultraviolet-C (UVC) LED device may be useful in the treatment of corneal microbial infections, as UVC is commonly used for eradicating bacteria, fungi and viruses in other settings. This study assessed the efficacy of 265 nm UVC from this LED, on four different bacterial strains, and investigated the consequences of corresponding exposures on human corneal epithelial cells in vitro. METHODS: Agar plate lawns of Staphylococcus aureus, Escherichia coli, Pseudomonas aeruginosa and Streptococcus pyogenes were exposed to a 4.5 mm diameter 265 nm UVC beam at a fixed intensity and distance, for 30, 5, 4, 2 and 1 seconds. Growth inhibition was assessed with a BioRad Gel imager, and the diameter of lucent areas of bacterial inhibition recorded. Human corneal epithelial cells cultured on glass cover-slips were exposed to corresponding doses of UVC from the same device. Live/dead staining was performed and the results quantified. RESULTS: There was 100% inhibition of growth for all bacteria tested, at all exposure times. A 30-second exposure of human corneal epithelium to UVC gave no statistically significant decrease (P = 0.877) in the ratio of live to dead cells when compared to control cultures. CONCLUSION: The results confirmed that a 1 second exposure to germicidal UVC from this LED source was sufficient to inhibit microbial proliferation in the four bacterial strains tested in vitro. The literature suggests UVC at this dose could potentially be beneficial in treating corneal surface infections, without causing significant adverse effects, supported by our findings in human corneal epithelium exposed to UVC.

Contrasting décollement and prism properties over the Sumatra 2004-2005 earthquake rupture boundary.

Styles of subduction zone deformation and earthquake rupture dynamics are strongly linked, jointly influencing hazard potential. Seismic reflection profiles across the trench west of Sumatra, Indonesia, show differences across the boundary between the major 2004 and 2005 plate interface earthquakes, which exhibited contrasting earthquake rupture and tsunami generation. In the southern part of the 2004 rupture, we interpret a negative-polarity sedimentary reflector approximately 500 meters above the subducting oceanic basement as the seaward extension of the plate interface. This predécollement reflector corresponds to unusual prism structure, morphology, and seismogenic behavior that are absent along the 2005 rupture zone. Although margins like the 2004 rupture zone are globally rare, our results suggest that sediment properties influence earthquake rupture, tsunami hazard, and prism development at subducting plate boundaries.

Effects of some ophthalmic medications on pupil size: a literature review.

Ophthalmological pharmacology is a rapidly expanding field aimed at achieving the safest and most effective treatment results. Physicians must be aware of the side-effect profiles, both beneficial and harmful, of medications currently used. This review highlights the available data on the effect of some ophthalmic medications on pupil size; it was limited to all reports or studies describing topical ophthalmic agents not originally designed or indicated to alter pupil diameter. This awareness will protect patients from unwanted drug-induced side effects and will improve clinical management and patient care.

Difficulties imaging herpes simplex keratitis with fluorescein isothiocynate-labeled anti-HSV-1 antibodies in an ex vivo model.

AIM: The aim of this study was to attempt to visualize herpes simplex keratitis in an ex vivo model using currently available ophthalmological equipment and anti-herpes simplex virus 1 (HSV-1) fluorescein isothiocynate-labeled antibody. METHODS: Sixteen donor human corneas were included in this study. Eight corneas were infected with HSV-1, whereas 8 remained uninfected. Abrasions were made on 2 infected and 2 uninfected corneas to assess a possible nonspecific absorption of antibodies in the sites of corneal epithelial defects. Corneas were examined before and after antibody application using a slit lamp, the fluorescein enhancing filter settings of fundus camera, and Confoscan 3. All corneas were further imaged using multiphoton laser confocal microscopy. RESULTS: Before anti-HSV-1 antibody application, no fluorescence was detected in donor corneas with the blue light of the slit lamp and fundus camera at fluorescein enhancing filter settings. Examination with the fundus camera after antibody application detected increased background fluorescence in all the corneas with more highlighted areas of epithelial defects in abraded infected and uninfected corneas. Confoscan 3 did not show a significant difference between the appearances of HSV-1-infected and control corneas with and without application of the antibody. However, specific staining was confirmed by multiphoton laser confocal microscopy in all infected corneas. CONCLUSION: Further refinement of currently available ophthalmological tools is required to aid in vivo visualization of herpes simplex keratitis using fluorescein isothiocynate-labeled antibodies.

The use of voriconazole in the treatment of cylindrocarpon keratomycosis.

PURPOSE: To describe a rare form of fungal keratitis due to Cylindrocarpon lichenicola. METHOD: A 56-year-old woman presented with an atypical corneal ulcer that did not respond to broad- spectrum antibiotics. RESULTS: Additional diagnostic tests such as confocal microscopy and corneal biopsy were useful aids in establishing the diagnosis of fungal keratitis. The ulcer healed completely after the initiation of antifungal therapy. CONCLUSIONS: To the best of our knowledge, this is the first case of C. lichenicola keratomycosis in the United Kingdom. Our case demonstrates that prompt recognition and effective treatment of this condition can lead to a good visual outcome.

Documentation of corneal epithelial defects with fluorescein-enhanced digital fundus camera photography.

The advent of digital photography in the ophthalmic setting has provided not only a means of documenting pathology, but with instantaneous results, it is possible to aid clinical diagnosis and management. This study was designed to demonstrate the ability to image corneal epithelial lesions stained with fluorescein, with a digital fundus camera set on fluorescein angiography settings. The contrast of this technique demonstrated both gross and subtle corneal epithelial lesions better than traditional methods. The results obtained demonstrated the high sensitivity and high contrast images this technique can facilitate in every ophthalmic practice equipped with a fundus camera with digital fluorescein angiography capability.