The contact lens is a medical device widely used as an alternative to spectacles in order to correct refractive vision problems, although it may also be employed as a drug delivery device, an ocular ‘bandage’ or for cosmetic effect. There are estimated to be 125 million contact lens wearers globally. As with all medical devices, contact lenses can be associated with a number of complications, the most serious of which is infection.
Microbial keratitis is a potentially sight-threatening adverse event associated with contact lens wear, where the corneal tissue is invaded by replicating microbes. It is estimated that there are approximately 1,200 new cases of contact lens-related microbial keratitis each year in the UK out of almost 3 million wearers.
The condition ranges in severity from a painful episode that resolves quickly with intensive antimicrobial therapy to an infection requiring long periods of hospitalisation and surgery for restoration of vision. An unfortunate consequence of microbial keratitis is that the patient may be unsuitable for future lens wear, and more seriously, loss of vision is reported to occur in 11–13% of cases.
Development and treatment of microbial keratitis
It has been proposed that the first step in the development of microbial keratitis is bacterial adhesion to the contact lens. The most frequently isolated microorganism is Pseudomonas aeruginosa, but other pathogens such as coagulase negative staphylococci (Staphylococcus epidermidis), Staphylococcus aureus, Serratia marcescens and Acanthamoeba species have also been identified as causative microorganisms. Figure 1 details the stages involved in the development of bacterial microbial keratitis.
Bacterial adhesion to contact lenses is influenced by many factors, including lens type, surface chemistry and charge, bacterial hydrophobicity/hydrophilicity, the presence of an adsorbed tear film layer and water content of the lens.
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Bacterial adhesion to a contact lens is initially reversible, but becomes irreversible in time through the secretion of exopolymeric substances by the bacteria. Bacterial growth under these conditions eventually leads to the formation of a mature biofilm, in which the bacterial cells have significantly greater resistance to antimicrobial agents than their planktonic counterparts.
Therapy should be initiated, usually in the form of fortified broad-spectrum antibiotics or fluoroquinolone agents, as soon as microbial keratitis is suspected as it is an ocular emergency requiring prompt and appropriate treatment to ensure the best visual outcome for the patient.
Current treatment options require long-term administration of eye-drops and a cure is not always achieved. Initial treatment should be intensive with hourly application of antibiotic so that the corneal tissue is rapidly saturated with a high antibiotic concentration. A high concentration can be achieved within a few hours, so that 48 hours of sustained high concentrations is usually enough to eliminate most bacterial infections, sometimes even those organisms only partially sensitive to the antibiotic.
Sustained intensive treatment day and night for the first 48 hours, then hourly by day for the next two to three days allows for more than an adequate chance of sterilising the cornea.
Following this initial treatment phase, the antibiotic application is reduced to four times a day to allow for epithelial healing. This treatment programme is intensive and expensive, often requiring hospital admission; it has been reported that 30% of patients require admission to hospital for treatment.
Fortified antibiotics and fluoroquinolones are effective for the treatment of microbial keratitis, with each mode of therapy providing good cover for the most frequently encountered bacteria causing keratitis, although combination fortified antibiotics provide superior coverage against Gram-positive organisms.
Fluoroquinolone antibiotics, however, are more convenient to use due to their commercial availability and longer shelf-life.
Greater short-term epithelial toxicity occurs with fortified antibiotics, particularly the aminoglycosides, but there is a more serious potential for corneal perforation with ofloxacin.
Furthermore, with the fluoroquinolones, clinical and laboratory reports show emerging resistance and gaps in the spectrum of activity for organisms that commonly cause keratitis, while aminoglycosides cannot penetrate the corneal cell membrane, leaving an intracellular sanctuary of infection that increases the likelihood of a more adverse outcome.
Additionally, treatment for Acanthamoeba infection may often be delayed due to misdiagnosis resulting in a more negative outcome. The treatments for microbial keratitis are not without their disadvantages, and it is therefore preferable that steps are taken to prevent bacterial adhesion to the contact lens from the offset.
Novel approaches are required in order to prevent bacterial adhesion and subsequent biofilm formation on contact lenses. Such approaches may involve improving patient compliance with lens care hygiene, removing modifiable risk factors such as delays in receiving appropriate therapy, or developing contact lens materials that prevent bacterial binding or kill any adhered bacteria.
Second-generation fluoroquinolones such as ciprofloxacin and ofloxacin have been examined as prophylactic antibiotics for the prevention of Staphylococcus aureus keratitis, and the effectiveness of the fourth-generation fluoroquinolone gatifloxacin in the prevention of multi-drug-resistant S. aureus keratitis after lamellar keratectomy in a rabbit model and for prevention of Staphylococcus epidermidis keratitis has also been investigated.
A number of strategies for prevention of contact lens-related microbial keratitis have involved development of antimicrobial surfaces and materials for contact lenses; Mathews et al evaluated contact lenses coated with covalently attached selenium in a rabbit model and demonstrated that a selenium coating decreased bacterial colonisation in vitro while not adversely affecting the corneal health in vivo.
Danion et al investigated the antibacterial activity of contact lenses bearing surface-immobilised layers of intact liposomes loaded with levofloxacin, and found that this method of drug delivery could provide a sustained release of antibiotics over a six-day period.
However, the authors concluded that in vivo studies were needed to confirm these results, as well as to demonstrate that contact lenses bearing surface-immobilised layers of intact liposomes loaded with levofloxacin may constitute a promising approach for controlling drug release to maintain a topical antibacterial activity for a long period of time.
Treatment of contact lenses with furanones, an example of quorum-sensing blockers, is also being examined. Quorum-sensing blockers exert their antibacterial effect by interfering, in part, with bacteria-signalling systems. One study has examined contact lenses soaked in synthetic furanone with equivocal results, highlighting the need for additional research in this area.
Further to contamination of the lens itself, it has been observed that microbial keratitis may also be due to bacterial contamination of contact lens storage cases. Studies have therefore examined impregnation of contact lens cases with silver, a broad-spectrum antimicrobial agent which when present on the surface of medical devices retards the adherence and colonisation of microorganisms.
Amos & George examined the performance of silver-impregnated lens cases compared to conventional lens cases and reported results from in vitro and in vivo studies. The in vitro study demonstrated significantly lower numbers of recovered microbes (Ps. aeruginosa, Serratia marcescens, Citrobacter amalonaticus, Klebsiella pneumoniae, Enterobacter cloacae, Acinetobacter calcoacetus and Escherichia coli) from silver-impregnated cases than from control cases, with the greatest reductions in microbial recovery observed for Ps. aeruginosa, the main causative microorganism for microbial keratitis. In the in vivo clinical studies, silver-impregnated cases had a statistically lower proportion of bacterial contamination than control cases.
Vermeltfoort et al also examined the effect of silver incorporation on planktonic and biofilm-associated bacteria grown in contact lens storage cases; their results were in accordance with Amos & George. However, in addition they examined the killing efficacy of a range of multipurpose lens care solutions against biofilm and planktonic bacteria; the rationale for this being that bacteria detaching from biofilms on a lens case surface will become planktonic in the lens care solution and are subsequently available to colonise the contact lens.
The authors demonstrated that a lens care solution containing a polyquat (polymeric quarternary ammonium compound) and a cationic amidoamine (myristamidopropyl dimethylamine) as antimicrobials was more effective against Ps. aeruginosa and S. aureus than one containing polyaminopropyl biguanide and poloxamine (a non-ionic surfactant which disrupts microbial membranes) or a solution containing the antiseptic agent polyhexanide.
Improvement of lens materials and lens care systems that avoid or decrease contact lens-associated infections such as microbial keratitis are important aspects of contact lens research. Table 1 provides a brief summary of additional methods employed in the prevention of microbial keratitis. It is in the context of this research that we are examining the use of light-activated photosensitising agents as a novel method of killing bacteria adhering to the surface of contact lenses.
In 2007 we reported the potential use of this treatment paradigm for killing bacteria on the surface of an intraocular lens, and such an approach may potentially be employed in the contact lens industry as a novel approach to preventing bacterial adhesion to contact lenses.
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