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Background: An overlooked factor in the efficacy of topical antibiotics to treat bacterial keratitis is the state of the corneal epithelium. Recently, we evaluated topical cefiderocol for the treatment of extensively drug-resistant (XDR) Pseudomonas aeruginosa (PA) keratitis in eyes with the corneal epithelium abraded. The goal of this study was to use the same model with the corneal epithelium left intact to evaluate the efficacy of cefiderocol and other antibiotics and compare the results to those of the previous study. Methods: NZW rabbit corneas with intact epithelium were inoculated with XDRPA. After 16 h, the rabbits were topically treated with cefiderocol 50 mg/mL, ciprofloxacin 0.3%, tobramycin 14 mg/mL, or saline. Following 8 h of treatment, the corneas were harvested for CFU determinations and cefiderocol concentrations. Results: Only cefiderocol significantly decreased CFU of the XDRPA strain compared with saline. The CFU in the cefiderocol and tobramycin-treated corneas for the XDRPA strain with initially intact epithelium were 1.83–1.4 Log10 greater than those produced in corneas with the abraded epithelium (p < 0.05). Cefiderocol concentrations were 5.02× less in corneas with initially intact epithelium. Conclusions: The efficacy of cefiderocol and tobramycin to treat experimental XDRPA keratitis is dependent on the state of the corneal epithelium.

Abstract We employed the mechanical effect from 40 kHz ultrasound (US) to improve the delivery of riboflavin into corneal stroma for collagen crosslinking, which can benefit the treatment of keratoconus and other corneal ectasias. Experiments were conducted, first with porcine corneas ex vivo and then with New Zealand white rabbits in vivo, at varying mechanical index (MI) and sonication time. Results showed that 15 min of US applied on the cornea at MI = 0.8 in the presence of 0.5% of riboflavin solution enabled its delivery to deeper corneal stroma. Excessive heat was removed by a cooling setup to negate the thermal effect. The corneal absorption amount and penetration of riboflavin through cornea as detected by fluorotron, as well as the enhancement of corneal stiffness as measured by Young's modulus, were comparable to the conventional approach that requires complete corneal epithelium debridement. Histological analysis revealed minor exfoliation of superficial cell layers of corneal epithelium and loss of ZO‐1 tight junctions immediately after US. Full recovery of the corneal epithelium and restoration of tight junctions occurred in 3–4 days. The study shows that low‐intensity low‐frequency ultrasound (LILF US) is a less invasive alternative to the conventional epithelium‐off method for delivering riboflavin into the corneal stroma.

Purpose: Systemic doxycycline has been prescribed to reduce inflammation and enhance corneal healing in bacterial keratitis. Topical autologous serum drops (ASD) containing doxycycline following oral supplementation may additionally confer an anti-bacterial effect. The potential of this supplementation was evaluated by determining the in vitro susceptibility of bacterial keratitis isolates to doxycycline. Methods: The minimum inhibitory concentrations (MICs) of doxycycline against 100 bacterial keratitis isolates were determined using Etests. Twenty-seven Staphylococcus aureus, ten coagulase-negative Staphylococci, six Streptococcus pneumoniae, seven viridans group streptococci, seven other Gram-positive bacteria, nineteen Pseudomonas aeruginosa, eight Serratia marcescens, four Moraxella spp., two Haemophilus spp., and ten other Gram-negative bacteria isolates were tested. MICs of doxycycline were compared to a serum standard concentration of doxycycline (SSCD) of 4 µg/mL and concentrations that would be found in 50% and 20% serum component clinical preparations of ASD, corresponding to 50% SSCD (2 µg/mL) and 20% SSCD (0.8 µg/mL), respectively. MICs equal to or less than these values were used to deem a bacterial isolate susceptible. Results: For Gram-positive bacteria, susceptibilities to SSCD, 50% SSCD, and 20% SSCD were 86%, 65%, and 60%, respectively. For Gram-negative bacteria, susceptibilities to SSCD, 50% SSCD, and 20% SSCD were 37.2%, 23.3%, and 11.6%, respectively. Chi-squared analyses comparing Gram-positive and Gram-negative susceptibilities showed significantly greater susceptibility of Gram-positive bacteria at all three tested MICs (

Corneal opacification is the fourth most common cause of blindness globally behind cataracts, glaucoma, and age-related macular degeneration. The standard treatment of serious corneal scarring is corneal transplantation. Though it is effective for restoring vision, the treatment outcome is not optimal, due to limitations such as long-term graft survival, lifelong use of immunosuppressants, and a loss of corneal strength. Regulation of corneal stromal wound healing, along with inhibition or downregulation of corneal scarring is a promising approach to prevent corneal opacification. Pharmacological approaches have been suggested, however these are fraught with side effects. Tissue healing is an intricate process that involves cell death, proliferation, differentiation, and remodeling of the extracellular matrix. Current research on stromal wound healing is focused on corneal characteristics such as the immune response, angiogenesis, and cell signaling. Indeed, promising new technologies with the potential to modulate wound healing are under development. In this review, we provide an overview of cell-free strategies and some approaches under development that have the potential to control stromal fibrosis and scarring, especially in the context of early intervention.

The treatment of eye infections is very different than treating other body infections that require systemic anti-infectives. Endophthalmitis, keratitis, conjunctivitis, and other ocular infections are treated with direct injection and with topical drops directly to the infection site. There are no anti-infective susceptibility standards to interpret treatment success, but the systemic standards can be used to guide ocular therapy if the concentration of anti-infective in the ocular tissue is assumed to be higher than the concentration in the blood serum. This Perspective describes: (1) eye infections, (2) diagnostics of eye infections, (3) anti-infective treatment of eye infections, (4) anti-infective resistance of ocular pathogens, and (5) alternative anti-infective delivery and therapy. The data, based on years of clinical and laboratory research, support the premise that ocular infections are less problematic if etiologic agents are laboratory-diagnosed and if prompt, potent, anti-infective therapy is applied. Anti-infective susceptibility should be monitored to assure continued therapeutic success and the possibility of new-found resistance. New delivery systems and therapies may be helpful to better treat future ocular infections.

Abstract Primary Sjögren’s syndrome is an autoimmune disease characterized by dry eye and dry mouth. We systematically reviewed all the randomized controlled clinical trials published in the last 15 years that included ocular outcomes. We found 22 trials involving 9 topical, 10 oral, 2 intravenous and 1 subcutaneous modalities of treatment. Fluoromethalone eye drops over 8 weeks were more effective than topical cyclosporine in the treatment of dry eye symptoms and signs; similarly, indomethacin eye drops over 1 month were more efficacious than diclofenac eye drops. Oral pilocarpine 5 mg twice daily over 3 months was superior to use of lubricants or punctal plugs for treating dry eye, but 5% of participants had gastrointestinal adverse effects from pilocarpine, though none discontinued treatment. In contrast, etanercept, a TNF-alpha blocking antibody, administered as subcutaneous injections twice weekly, did not improve dry eye significantly compared to placebo injections. In conclusion, topical corticosteroids have been shown to be effective in dry eye associated with Sjögren’s syndrome. As some topical non-steroidal anti-inflammatory drugs may be more effective than others, these should be further evaluated. Systemic secretagogues like pilocarpine have a role in Sjögren’s syndrome but the adverse effects may limit their clinical use. It is disappointing that systemic cytokine therapy did not produce encouraging ocular outcomes but participants should have assessment of cytokine levels in such trials, as those with higher baseline cytokine levels may respond better. (229 words)

Coagulase-negative staphylococci (CoNS) are frequently occurring ocular opportunistic pathogens that are not easily identifiable to the species level. The goal of this study was to speciate CoNS and document antibiotic susceptibilities from cases of endophthalmitis (n = 50), keratitis (n = 50), and conjunctivitis/blepharitis (n = 50) for empiric therapy. All 150 isolates of CoNS were speciated using (1) API Staph (biochemical system), (2) Biolog GEN III Microplates (phenotypic substrate system), and (3) DNA sequencing of the sodA gene. Disk diffusion antibiotic susceptibilities for topical and intravitreal treatment were determined based on serum standards. CoNS identification to the species level by all three methods indicated that S. epidermidis was the predominant species of CoNS isolated from cases of endophthalmitis (84–90%), keratitis (80–86%), and conjunctivitis/blepharitis (62–68%). Identifications indicated different distributions of CoNS species among endophthalmitis (6), keratitis (10), and conjunctivitis/blepharitis (13). Antibiotic susceptibility profiles support empiric treatment of endophthalmitis with vancomycin, and keratitis treatment with cefazolin or vancomycin. There was no clear antibiotic choice for conjunctivitis/blepharitis. S. epidermidis was the most frequently found CoNS ocular pathogen, and infection by other CoNS appears to be less specific and random. Antibiotic resistance does not appear to be a serious problem associated with CoNS.