Clinical application prospects and challenges of preservative-free anti-glaucoma drugs

PurposeWe previously reported the presence of multidrug-resistant staphylococci on the ocular surface of glaucoma patients using prostaglandin analog drops for more than 1 year. Here, we investigated the effect of benzalkonium chloride (BAC) on these multidrug-resistant staphylococci.MethodsStaphylococcus epidermidis was isolated from the conjunctival sacs of 32 eyes of 32 patients comprised of 13 eyes treated with 0.005% latanoprost (Xalatan; Xa group) and 19 eyes treated with 0.004% travoprost (Travatan Z; Tz group). The minimum inhibitory concentrations (MICs) of prostaglandin analogs and BAC were measured. The presence of efflux pump genes was analyzed using polymerase chain reaction.ResultsNo difference was found in the MIC values of prostaglandin analogs. In contrast, the MIC values of BAC were significantly higher for the isolates from the Xa group than for those from the Tz group (2.02 vs. 1.02 µg/mL; P = 0.001). One proton-motive efflux gene, qacC/smr, was detected more frequently in the Xa isolates than in the Tz isolates (P < 0.001). The prevalence of methicillin resistance was correlated with the presence of qacC/smr (P = 0.010), and the MIC of BAC was significantly correlated with the detection of qacA/B and qacC/smr sequences (P = 0.03 and P < 0.001, respectively).ConclusionsThe long-term use of eye drops containing BAC might select BAC-resistant S. epidermidis harboring qacC/smr.Translational RelevanceThese findings suggest that the long-term use of eye drops containing BAC might be inappropriate in terms of avoiding antimicrobial resistance.

To investigate the protective effects of sodium hyaluronate on ocular surface toxicity induced by a prolonged use of benzalkonium chloride-preserved Brimonidine eye drops. Experimental study. Thirty adult female New Zealand rabbits were divided into three groups with randomized numbers design. Ten rabbits were treated with 0.2% Brimonidine eye drops and PBS (PBS group), the other ten rabbits with 0.2% Brimonidine combined with sodium hyaluronate eye drops (SH group), and control group received no treatment for 60 days. Schirmer test, fluorescein (FL) and Rose Bengal (RB) staining, conjunctival impression cytology specimens collecting were performed on day 0, 31, and 61. Apoptosis of conjunctival epithelium was detected by in situ terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) assay on day 61. Conjunctival inflammation was observed by hematoxylin eosin staining. Histomorphological changes of cornea and conjunctiva were observed by light microscopy, and scanning and transmission electron microscopy at day 61. Fluorescein and Rose Bengal scores were analysed by Kruskal-Wallis test. Schirmer scores, goblet cell density and inflammatory cells infiltration were analysed by repeated measures analysis of variance. There were significant differences in fluorescein and Rose bengal (H = 22.031, 15.303, P < 0.01) staining among the groups on day 61. Compared with the control group (FL: 0, 0-1, RB: 0, 0-1), fluorescein and Rose Bengal scores were significantly (P < 0.001) increased in PBS group (FL: 1.5, 1-2, RB: 1, 1-2), whereas was significantly (P < 0.001) decreased in SH group (FL:0, 0-1 RB:1, 0-1) when compared to PBS group. There were significant differences in aqueous tear production and goblet cell density (F = 7.980, 14.545, both P < 0.01) among the groups on day 61. Compared with the control group [(9.43 ± 0.57) mm, (87.73 ± 2.34/HP)], Schirmer scores and goblet cell density were significantly (P < 0.01) reduced in PBS-treated group [(6.61 ± 0.38) mm, (68.06 ± 3.61)/HP], but significantly (P < 0.05) increased in SH-treated group [(8.75 ± 0.57) mm, (82.31 ± 1.64)/HP] compared with PBS-treated group. The number of inflammatory cells was significant difference (F = 56.306, P < 0.001) among the groups on day 61. Compared with the control group [(39.89 ± 2.03)/HP], inflammatory cells infiltration was significantly (P < 0.01) increased in both PBS [(73.18 ± 2.17)/HP] and SH groups [(48.79 ± 2.64)/HP], however, SH-treated group was significantly lowered when compared with PBS-treated group. In addition, decrease in apoptosis, complete microvilli and cell organelles were found in the corneal and conjunctival epithelial cells in SH-treated group. Our results demonstrate that topical application of SH reduces the ocular toxicity and protect the ocular surface in the long term anti-glaucomatous medical therapies and may be considered as a vehicles or neutralizing material for future ocular application.

Is it time for a moratorium on the use of benzalkonium chloride in eyedrops?

Within the corneal limbal epithelium there exist limbal stem cells (LSC) which under suitable conditions can regenerate their population or differentiate into corneal epithelial cells. However, upon limbal damage, the cells differentiate irreversibly and do not self-renew. One of the causes of the damage of progenitor cells and their niche is a long-term use of eye drops containing preservatives. While the side effects are related to the antimicrobial activity of such eye drops, damage to cellular and cytoplasmic membranes as well as enzymatic reactions can concurrently cause disorders of normal ocular surface tissue. The aim of this study was to evaluate the toxic effects of the preservative used in eye drops - benzalkonium chloride (BAK) - on human corneal limbal epithelial cells in vitro, and to define the mechanisms of acute limbal cell damage caused by the action of BAK. Ten corneoscleras rims, which were not qualified for transplantation by the Eye Tissue Bank, were obtained from 5 deceased donors aged 39 to 43 years. The tissue fragments (explants) containing corneal limbal epithelial cells were immediately after the explantation subjected to the action of the experimental substance being benzalkonium chloride (BAK) in concentrations of 0.005% and 0.01%. The qualitative analysis of microscopic images of the corneal limbus specimens was performed on tissue sections stained with hematoxylin and eosin using the immunohistochemical method for vimentin and with the use of a transmission electron microscope. The structure of the area of corneal limbus, as well as the morphological characteristics and the ultrastructure of the very limbal cells were evaluated with careful attention to the basal epithelial cells of the limbus. The BAK-treated groups of explants in sections stained by H &amp; E featured characteristics of severe structural disorders of the corneal limbus area. Depletion of the epithelial cells was visible and involved both superficial and deep layers. Immunohistochemical staining for vimentin did not show the expression of this protein. This might have been connected with the damage to the cytoskeleton of limbal epithelial cells and large depletion of cells reaching down to the basement membrane. The images obtained with electron microscopy demonstrate serious defects of cell ultrastructure and, indirectly, abnormal cellular metabolism, including water and electrolyte balance and energy metabolism.This experiment confirmed the significant adverse effect of benzalkonium chloride on the limbal epithelial cells and the possibility of their damage.

Understanding the Dual Dilemma of Dry Eye and Glaucoma: An International Review.

To explore the impact of pre-intervention ultrasound diagnosis results of PFO and evaluation criteria on the success rate of surgery, intraoperative ultrasound monitoring methods, and postoperative ultrasound follow-up results, and to analyse the results of ultrasound-related examinations and the evaluation value of the success rate of surgery and interventional efficacy. A total of 1617 patients with related symptoms who were diagnosed and treated in our hospital from January 2022 to March 2023 were selected for screening, and transthoracic echocardiography (TTE), contrast transthoracic echocardiography (cTTE), and contrast-enhanced Transcranial Doppler (cTCD) were performed. Positive patients were selected for transesophageal Echocardiography (TEE). And interventional surgery for patent foramen ovale in 70 of these patients. cTTE was performed 3 months and 6 months respectively after surgery to evaluate the therapeutic efficacy. Among the 1617 cases of cTTE, 938 cases were positive, including 538 cases of grade 1, 198 cases of grade 2, and 202 cases of grade 3. TEE was performed in 317 patients with positive cTTE, and 228 patients were diagnosed as PFO with definite shunt. Then selected 76 patients of grade 2-3 in cTTE with positive TEE to perform the closure surgery of the PFO, and 70 cases were successfully operated, with a success rate of 92.11%. cTTE、cTCD and TEE results are correlated with the success rate of interventional surgery. Evaluation using multiple ultrasound techniques can provide guidance for rational selection of treatment in clinical application.

AIM: To analyze the effect of ocular massage on patients after glaucoma filtering surgery. METHODS: Databases including the China National Knowledge Infrastructure (CNKI), VIP Information, WanFang and Chinese Biomedical Literature (CBM) were electronically searched for all randomized controlled trials (RCTs) about comparing the intraocular pressure (IOP), forming efficiency of functional filtering blebs and success rate of filtering surgery between patients with and without ocular massage after receiving filtering surgery. Two reviewers independently screened literature according to the inclusion and exclusion criteria, and evaluated the included studies. Then, Meta-analysis was performed using RevMan5.3 software. RESULTS: Totally 20 eligible studies involving 1757 eyes of 1 750 individuals were included to investigate the effect of ocular massage on patients after glaucoma filtering surgery. Ten of the studies were related with IOP. The results of Meta-analysis showed that IOP was better controlled in patients with ocular massage in the postoperative 2wk, 1mo and 3mo [(WMD=-0.96, 95%CI (-1.83, -0.09), P&lt;0.05], [WMD=-2.68, 95%CI (-3.81, -1.55), P&lt;0.05] and [WMD= -3.98, 95%CI (-5.00, -2.96), P&lt;0.05], respectively). Fourteen of the studies were related with the forming efficiency of functional filtering blebs. The results of Meta-analysis showed that patients with ocular massage act better in forming functional blebs [RR=1.33, 95%CI (1.23, 1.44), P&lt;0.05)]. Nine of the studies were related with the success rate of surgery. The results of Meta-analysis showed that patients with ocular massage had higher rate of surgery success [(RR=1.41, 95%CI (1.28, 1.55), P&lt;0.05)]. CONCLUSION: Ocular massage can help patients after filtering surgery to control IOP more effectively and promote the formation of functional filtering blebs, so as to improve the success rate of surgery.

Background: A dacryolith mainly contains organic material, but its specific protein content is unknown. We observed a unique dacryolith formation in patients with long-term use of rebamipide eye drops and tried to identify the differences in protein compositions of dacryoliths from patients with or without use of rebamipide eye drops using novel proteomic analysis. Methods: Dacryolith samples were obtained from 7 patients (4 samples were without rebamipide usage, 3 were with rebamipide usage) who underwent endo-dacryocystorhinostomy or lacrimal endoscopic surgery and were subjected to protein identification and metaproteomic analysis. Results: The proteomic analysis revealed that most core proteins of dacryoliths are involved in immune and inflammatory responses and rebamipide-related proteins participated in several biological processes, including immune response, receptor-mediated endocytosis, and negative regulation of endopeptidase activity. Metaproteomic analysis of taxonomic diversity of dacryolith proteomes suggested less involvement of bacterial infections in dacryoliths from patients with long-term use of rebamipide. Conclusion: This is the first report to clinically detect the different features of dacryoliths related with long-term use of rebamipide eye drops with proteomic analysis. It is possible that lacrimal protein alteration may be accelerated by topical rebamipide treatment with less bacterial infection involvement, but this requires further study. Long-term rebamipide eye drop use may be restricted in patients with nasolacrimal duct obstruction.

A parallel, randomized, double-blind study was performed in 30 healthy subjects to investigate the effects on the nasal mucosa of a 1-month treatment with nasal sprays. Ten subjects received oxymetazoline nasal spray; 10 subjects used a nasal spray containing the preservative benzalkonium chloride, and the others were treated with a placebo nasal spray. The three variables that were studied --nasal mucosal swelling, symptom scores, and nasal reactivity-- were estimated by histamine challenge before and after 28 days of treatment. Rhinostereometry was used to measure nasal mucosal swelling and nasal reactivity. After 28 days of use, benzalkonium chloride spray alone induced an increase in nasal mucosal swelling. At the end of the month, the score for nasal stuffiness was significantly higher for the group treated with oxymetazoline than for those treated with benzalkonium chloride. Oxymetazoline nasal spray induced a pronounced increase in nasal reactivity, which was significantly greater than that induced in the placebo group. Long-term use of placebo and benzalkonium chloride nasal sprays also caused an increase in nasal reactivity, but not to the same extent as with the nasal sprays containing oxymetazoline. The authors concluded that long-term use of oxymetazoline induces a sensation of nasal stuffiness, which may be due to unconscious exaggeration of the degree of nasal stuffiness, induced nasal hyperreactivity, or a combination of both. These factors are probably the main reasons for the prolonged use of nasal decongestive sprays and the development of rhinitis medicamentosa. Benzalkonium chloride induces mucosal swelling, which explains why the presence of this preservative in a decongestant spray aggravates rhinitis medicamentosa.

The aim of this study was to compare, in vivo on a rat model, two different preservatives- benzalkonium chloride (BAC) and polyquaternium-1 (PQ-1)-using new experimental approaches. Thirty (30) eyes of 15 male Lewis rats were used in this study. Rats were randomly divided into five groups instilled twice a day for 11 days with eye drops containing different concentrations of preservatives, 0.1% BAC, 0.5% BAC, 0.1% PQ-1, 0.5% PQ-1, and balanced salt solution (BSS) as a control. The ocular surface toxicity of these two preservatives was investigated using new in vivo experimental approaches. Slit-lamp examination, the fluorescein test, the red phenol test, impression cytology, and in vivo corneal confocal microscopy were used to evaluate the rat ocular surface after preservative instillation. Histology sections and immunohistochemistry were also examined to confirm these results. Compared to PQ-1, BAC consistently and dramatically altered the corneoconjunctival surface as evaluated by slit-lamp examination, the fluorescein test, impression cytology, in vivo confocal microscopy, and histology. The 0.5% BAC solution also significantly decreased tear production compared to the control. Although 0.5% PQ-1 significantly decreased goblet cell density in comparison to the control, and some abnormalities were observed with in vivo confocal microscopy, no statistically significant differences were observed between these two groups using the tear production test, slit-lamp and fluorescein evaluation, or histology. Using an acute rat model of ocular toxicity by comparing preservatives at high concentrations, we demonstrated in vivo that high doses of PQ-1 were much less toxic than BAC. In vivo confocal microscopy and impression cytology are new promising experimental approaches to studying the rat corneoconjunctival surface, particularly in the field of ocular surface toxicity.

PurposeTo identify the risk factors associated with fluoroquinolone resistance in patients undergoing cataract surgery.MethodsA total of 1,125 patients (1,125 eyes) who underwent cataract surgery at Veterans Health Service Medical Center from May 2011 to July 2012 were enrolled in this study. Conjunctival cultures were obtained from the patients on the day of surgery before instillation of any ophthalmic solutions. The medical records of patients with positive coagulase negative staphylococcus (CNS) and Staphylococcus aureus (S. aureus) cultures were reviewed to determine factors associated with fluoroquinolone resistance.ResultsOf 734 CNS and S. aureus cultures, 175 (23.8%) were resistant to ciprofloxacin, levofloxacin, gatifloxacin, or moxifloxacin. Use of fluoroquinolone within 3 months and within 1 year before surgery, topical antibiotic use other than fluoroquinolone, systemic antibiotic use, recent hospitalization, ocular surgery, intravitreal injection and use of eyedrops containing benzalkonium chloride were significantly more frequent in resistant isolates than in susceptible isolates. In multivariable logistic regression analysis, ocular surgery (odds ratio [OR], 8.457), recent hospitalization (OR, 6.646) and use of fluoroquinolone within 3 months before surgery (OR, 4.918) were significant predictors of fluoroquinolone resistance, along with intravitreal injection (OR, 2.976), systemic antibiotic use (OR, 2.665), use of eyedrops containing benzalkonium chloride (OR, 2.323), use of fluoroquinolone within 1 year before surgery (OR, 1.943) and topical antibiotic use other than fluoroquinolone (OR, 1.673).ConclusionsRecent topical fluoroquinolone use, hospitalization and ocular surgery were significantly associated with fluoroquinolone resistance in CNS and S. aureus isolates from ocular culture.

Benzalkonium chloride (BAC) is the most commonly used preservative in ophthalmic preparations.So far large bodies of clinical and experimental studies have shown that use of topical drugs containing BAC can induce a series of ocular surface diseases, such as apoptosis.However, recently, some clinical studies have shown that ocular toxicity in patients treated with eye drops containing BAC has not apparent correlated with BAC.Some scholars consider that the limitations of the research lead people to recognize the BAC toxicity exaggeratedly.Here we summarize numerous clinical and experimental studies of BAC in the past few years, and focus on reviewing recent researches of the toxic effect of BAC on ocular surface.

ObjectiveTo explore the impact of AI-assisted computing systems on the effects of surgery, stereoscopic vision, and quality of life in patients with intermittent exotropia after treatment.MethodsData from a total of 108 children with intermittent exotropia were collected and randomly divided into Group A and Group B. Group A used the traditional prism calculation method, whereas Group B used the AI-assisted calculation system method. The success rate of surgery, the strabismus correction effect, postoperative stereoscopic function, far strabismus, near strabismus, horizontal and vertical perceptual eye positions, externally skewed deviation, and quality of life (Child-IXTQ score) were compared between the two groups.ResultsAt different time points (1 day, 1 month, 3 months, and 6 months after surgery), the success rate of surgery in Group B was significantly higher than that in Group A, with an average difference in the success rate of 8.47 ± 1.92% (all P < 0.05). Compared with those at 1 day after surgery, the incidence rates of 6-m strabismus and 33-cm strabismus in the two groups of children were significantly lower at 1, 3, and 6 months after surgery (all P < 0.05). Compared with the preoperative conditions, the central stereoscopic vision of the two groups of children significantly increased at 1, 3, and 6 months after surgery, whereas the proportion of children without stereoscopic vision significantly decreased (all P < 0.05). Moreover, compared with preoperative conditions and 1 month postoperatively, the proportion of far-standing stereopsis gradually increased in both groups of patients at 3 and 6 months postoperatively (all P < 0.05). However, in terms of both central and far-standing stereoscopic vision, the rate of increase displayed by children in Group B was significantly greater than that in Group A (all P < 0.05). At various postoperative time points, the Child-IXTQ score of Group B was higher than that of Group A. At 6 months after surgery, the Child-IXTQ score of Group B reached its highest value (84.57 ± 5.32) (all P < 0.05).ConclusionAI-assisted computing systems can effectively improve the success rate of paediatric surgery, enhance the establishment of stereoscopic vision function, improve visual quality, and significantly improve quality of life.

Background:Long-term use of benzalkonium chloride (BAC)-preserved drugs is often associated with ocular surface toxicity. Ocular surface symptoms had a substantial impact on the glaucoma patients’ quality of life and compliance. This study aimed to investigate the effects of sodium hyaluronate (SH) on ocular surface toxicity induced by BAC-preserved anti-glaucoma medications treatment.Methods:Fifty-eight patients (101 eyes), who received topical BAC-preserved anti-glaucoma medications treatment and met the severe dry eye criteria, were included in the analysis. All patients were maintained the original topical anti-glaucoma treatment. In the SH-treated group (56 eyes), unpreserved 0.3% SH eye drops were administered with 3 times daily for 90 days. In the control group (55 eyes), phosphate-buffered saline were administered with 3 times daily for 90 days. Ocular Surface Disease Index (OSDI) questionnaire, break-up time (BUT) test, corneal fluorescein staining, corneal and conjunctival rose Bengal staining, Schirmer test, and conjunctiva impression cytology were performed sequentially on days 0 and 91.Results:Compared with the control group, SH-treated group showed decrease in OSDI scores (Kruskal-Wallis test: H = 38.668, P < 0.001), fluorescein and rose Bengal scores (Wilcoxon signed-ranks test: z = −3.843, P < 0.001, and z = −3.508, P < 0.001, respectively), increase in tear film BUT (t-test: t = −10.994, P < 0.001) and aqueous tear production (t-test: t = −10.328, P < 0.001) on day 91. The goblet cell density was increased (t-test: t = −9.981, P < 0.001), and the morphology of the conjunctival epithelium were also improved after SH treatment.Conclusions:SH significantly improved both symptoms and signs of ocular surface damage in patients with BAC-preserved anti-glaucoma medications treatment. SH could be proposed as a new attempt to reduce ocular surface toxicity, and alleviate symptoms of ocular surface damage in BAC-preserved anti-glaucoma medications treatment.

Effects of benzalkonium chloride on histamine H1 receptor mRNA expression in nasal epithelial cells.