Topical Anti-inflammatory Agents in an Animal Model of Microbial Keratitis

Infectious keratitis is a major global cause of visual impairment and blindness, often affecting marginalized populations. Proper diagnosis of the causative organism is critical, and while culture remains the prevailing diagnostic tool, newer techniques such as in vivo confocal microscopy are helpful for diagnosing fungal keratitis and Acanthameoba. Next generation sequencing holds the potential for early and accurate diagnosis even for organisms that are difficult to culture by conventional methods. Topical antibiotics remain the best treatment for bacterial keratitis, and a recent review found all commonly prescribed topical antibiotics to be equally effective. However outcomes remain poor secondary to corneal melting, scarring and perforation. Adjuvant therapies aimed at reducing the immune response responsible for much of the morbidity associated with keratitis include topical corticosteroids. The large, randomized controlled Steroids for Corneal Ulcers trial found that while steroids provided no significant improvement overall, they did appear beneficial for ulcers that were central, deep or large, non-Nocardia or classically invasive P. aeruginosa, patients with low baseline vision, and when started early after the initiation of antibiotics. Fungal ulcers often have worse clinical outcomes than bacterial ulcers, with no new treatments since the 1960’s when topical natamycin was introduced. The randomized controlled Mycotic Ulcer Treatment Trial showed a benefit of topical natamycin over topical voriconazole for fungal keratitis, particularly among those caused by Fusarium. The second Mycotic Ulcer Treatment Trial showed that oral voriconazole did not improve outcomes overall although there may have been some effect among Fusarium ulcers. Given an increase in non-serious adverse events the authors concluded that they could not recommend oral voriconazole at this time. Viral keratitis differs from bacterial and fungal cases in that is often recurrent and is common in developed countries. The first Herpetic Eye Disease Study (HEDS) showed a significant benefit of topical corticosteroids and oral acyclovir for stromal keratitis. HEDS II showed that oral acyclovir decreased the recurrence of any type of HSV keratitis by approximately half. Future strategies to reduce the morbidity associated with infectious keratitis are likely to be multidimensional with adjuvant therapies aimed at modifying the immune response to infection holding the greatest potential to improve clinical outcomes.

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“…49–52 However, others argue that corticosteroids delay epithelial healing and may even worsen infection. 53–56 …”

Section: Bacterial Keratitismentioning

confidence: 99%

Update on the Management of Infectious Keratitis

2017

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“…Topical corticosteroids are capable of inhibiting leukocytes and pro-inflammatory cytokines, thereby potentially favorably modifying wound healing in the inflamed cornea and potentially reducing corneal scarring [23][24][25][26][27][28][29][30][31][32][33][34][35][36]. Indirect benefits of reduced inflammation may also include facilitation of reepitheliazation [37,38] and subsequent down-regulation of metalloproteinase production through inhibition of stimulatory epithelial cytokines [39] and exclusion of polymorphonuclear leukocytes from the stroma [40].…”

Section: Discussionmentioning

confidence: 99%

Changing trends in the clinical course and outcome of bacterial keratitis at King Khaled Eye Specialist Hospital

2008

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“…[76,89,123, 12S-13I] Some steroids, such as prednisolone (1.0%), have demonstrated an anti-inflammatory effect when administered topically in combination with antibacterial agents for experimental P aeruginosa keratitis.l126-129] Other studies found no decrease in inflammation following steroid use, and no inhibition of bactericidal action of agents such as gentamicin (1.4%), tobramycin (0.3% and 1.4%), neomycin (0.5%), ofloxacin (0.3%), or carbenicillin (40.0% ). [76,87,125,128,129,131] Pseudomonal infection has been shown to recur following administration of steroid and antibacterial therapy, but only upon discontinuation of the antibacterial. [123] Several studies have demonstrated that administration of an NSAID without concomitant antibacterial therapy can worsen pseudomonal keratitis.…”

Section: Adjuvant Therapymentioning

confidence: 99%

Pharmacokinetic Considerations in the Treatment of Bacterial Keratitis

Callegan

O’Callaghan

Hill

1994

Clinical Pharmacokinetics

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The eye is relatively impermeable to micro-organisms and other environmental elements. However, if corneal integrity is breached by trauma, a sight-threatening bacterial infection can result. Staphylococcus aureus, Pseudomonas aeruginosa, and Streptococcus pneumoniae are the most common bacterial pathogens associated with infection of compromised corneas. Bacterial enzymes and toxins, as well as factors associated with the host immune response, can lead to tissue destruction during corneal infection. For successful therapy, an antibacterial agent must be active against the pathogen and must be able to overcome the permeability barrier of the cornea. Topical application of antibacterial agents adequately delivers drugs to the cornea and aqueous humour. However, drug concentrations at the site of infection are not always sufficient to rapidly kill infective organisms. Infections with antibiotic-resistant strains present an even greater therapeutic challenge. In addition, sterilisation of the cornea by antibacterial agents does not eliminate inflammation and corneal scarring that accompany infection. Steroidal and non-steroidal antiinflammatory agents limit corneal scarring during experimentally induced bacterial keratitis. However, although promising, concomitant use of these drugs with antibacterial agents remains controversial. Two ocular drug delivery systems that provide high and sustained concentrations of drug to ocular tissues are corneal collagen shields and transcorneal iontophoresis. The collagen shield, originally designed as a bandage lens, prolongs drug contact with the cornea. Chemotherapeutic studies of experimental bacterial keratitis demonstrate that shields hydrated with antibacterial agents reduce bacteria in the cornea as well as or better than frequent applications of fortified antibacterial drops. Transcorneal iontophoresis uses an electric current to drive charged drugs into the cornea. In experimentally induced bacterial keratitis, transcorneal iontophoresis of antibacterial agents is superior to topically administered ocular drops for reducing the numbers of bacteria in the cornea. Although both drug delivery systems appear to be well tolerated and nontoxic in animal models, clinical trials in patients are required to determine the usefulness of these drug delivery systems in clinical trials. Based on present experimental results, future therapy of bacterial keratitis will involve efficient drug delivery devices, the use of new antibacterial agents or combinations of presently available antibacterial agents, and careful use of adjuvant anti-inflammatory agents.

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Topical Anti-inflammatory Agents in an Animal Model of Microbial Keratitis

Cited by 35 publications

References 19 publications

Update on the Management of Infectious Keratitis

Update on the Management of Infectious Keratitis

Changing trends in the clinical course and outcome of bacterial keratitis at King Khaled Eye Specialist Hospital

Pharmacokinetic Considerations in the Treatment of Bacterial Keratitis

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