Contact lens associated corneal infections ... - Wiley Online Library

OPTOMETRY REVIEW

Contact lens associated corneal infections. Where do we go from here? Clin Exp Optom 2002; 85: 3: 141-148 Michael J Giese OD PhD FAAO*+ BarryA Weissman OD PhD FAAO' * The Ocular Inflammatory Disease Center and tJules Stein Eye Institute and Department of Ophthalmology, UCLA School of Medicine

Accepted for publication: 21 March 2002

Key words: contact lens, infectious keratitis

Direct microbial corneal infection is one of the most serious known complications of contact lens wear. Pseudomonasspp. and Staphylococcusspp. are the most commonly isolated microbes from corneal infections during cosmetic contact lens wearl-y (Table l ) , followed by protozoa (for example, Acanthamoeba spp.) lo and rarely, fungi. Viral corneal infections, especially herpetic and adenoviral, occur but do not seem to be specific complications of contact lens wear. We have reviewed the pertinent literature regarding contact lenses and our purpose is to suggest a direction for future research based on current findings. ~

RISK FACTORS Close to three decades of concern and study have led to almost universal acceptance of several risk factors for contact lens

associated corneal infection. Principal among these are poor contact lens care compliance and contact lens wear extended through one or more sleep cycles before cleaning and 'disinfection.' Other proposed risk factors include contact lens related hypoxia, foreign travel, warm weather, tobacco smoking, concomitant use of topical steroids and systemic immunosuppression (diabetes and HIV infection as examples) .'I Contact lens associated corneal infections were relatively rare until the introduction of extended-wear contact lenses. Only 14 cases of 'lost or blinded' eyes could be documented by Dixon and colleagues' in 1966. Several small case in the late 1970s suggested that there might be an increase in corneal infections with the evolution from PMMA to hydrogel contact lenses. Ruben'* concluded from his own experiences at Moorfields Eye Hospital in London that the overall incidence of infection with the use of hydrogel contact lenses was low when patients complied with hygiene and lens care regimes, although the rate might be somewhat greater than that found with PMMA lenses. Wilson, Schlitzer and Ahern5 documented eight corneal ulcers in seven patients who were using hydrogel contact lenses with home-made saline for the care solution. They identified the same Pseudomonas serotypes in corneal ulcers as in the contact lens care systems used by four of their seven patients. It is important to note that all of these patients used homeClinical and Experimental Optometry 85.3 May 2002

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BACTERIA Gram-negative (aerobic and anaerobic) Cocci and rods Pseudomonas aeruginosa Serratia marcescens Gram-positive Cocci Staphylococcusaureus Coagulase-negative Staphylococci (eg, S.epidermidis) Streptococcuspneumoniae Rods Bacillus spp. Propionibacterium spp. Corynebacteriumspp. Mycobacterium spp. PROTOZOA Acanthamoeba spp. FUNGI VIRUSES Herpes simplex Herpes zoster Adenovirus spp. Table 1. Microbes of concern for corneal infection during contact lens w e a P

made saline inappropriately as a wetting agent, eye drop or bath, after thermal disinfection of their contact lenses. Microbial contamination of care solutions was thereby linked with microbial infection of the cornea. OthersIsJ4have since verified these results. For example, Donzis and

Contact lenses: where next? Giese and Weisman

colleagues” suggested Acanthamoeba spp. studies of very large populations (of the infections, in particular, may be associated order of thousands) and long-term studwith poor contact lens care. ies will be necessary to statistically prove Cooper and Constable3 reported eight that new contact lens designs, material or cases of infectious keratitis in wearers of other interventional strategy may or may hydrogel contact lenses. Four of these not affect the corneal infection rate. eight patients appeared to have no preIn one such study, Chalupa and co-workdisposing factors, except that they were ersmobserved corneal infection associated using their lenses for ‘continuous’ or with contact lens wear over a two-year ‘extended’ wear. Cooper and Constable’s period in a large population (estimated report introduced the modern concerns at 35,000 to 40,000) of contact lens wearregarding microbial infection associated ers in Gothenberg, Sweden. They found with extended contact lens wear. an incidence rate of about one per 15,000 It is important to emphasise that all types for daily wear and one per 3,000 for exof contact lenses, including refractive, cos tended wear of hydrogel lenses. MacRae metic (soft, hard, hybrid and gas permeable) and colleagues2’summarised the experiand therapeutic, have been associated with ence collected from 48 FDA-controlled corneal infection at one time or ~10ther.l~ studies of new contact lenses between 1980 The scope of clinical studies may change and 1988. These data represented the exin the future as safety concerns of clini- periences of 22,739 patients. There were 159 serious adverse reactions reported to cians, patients and the contact lens industhe FDA and among these 28 were ‘cortry evolve. Case reports and patient series, neal ulcers’. From these data, MacRae and which dominate the contact lens literature, are valuable in stimulating curiosity colleagues2’calculated an infection rate of about one per 1,500 (eventdpatientand interest and provide important information on the natural history and re- years) overall for daily wear of contact lenses, one per 244 for cosmetic hydrogel sponse to treatment. However, they are of extended wear and one per 185 for aphalimited value in assessing pathogenesis, the kic hydrogel extended wear. Unforturelative importance of possible treatments nately, these particular studies rely on and risk factors, and the absolute scope of disease. SharmaI6has suggested that clini- retrospective reports of many clinicians and not all adverse reactions or corneal cians use five ‘levels of evidence’ in considering new information from the evolv- infections may have been reported. ing literature. Single case reports provide evidence at ‘level 5’ and a small series at EXTENDED-WEAR CONTACT LENSES ‘level 4.’ Studies at ‘level 3’ consist of nonrandomised but controlled trials. ‘Level 1’ Approximately 70 million people throughstudies consist of either randomised clini- out the world now wear contact lenses,22 often for extended wear, so it is not surcal trials with low statistical error rates or prising that there is concern about conwell-done meta-analysis. Such research tact lens related microbial keratitis becomoften has major and immediate impact on ing an important, worldwide, public health clinical care. Both the Early Treatment of problem. The first large prospective studDiabetic Retinopathy StudyI7 and the Collaborative Ocular Melanoma StudyI8 ies of corneal infection with both daily and extended cosmetic hydrogel lens wear are examples of level 1 research. were conducted by the CLI and published Two large case control studies funded by the Contact Lens Institute (CLI)’5*19in- in the New England Journal of Medicine in late 1989.I5J9 vestigated contact lens associated corneal Two companion studies first estimated infection in the New England states and the relative risk of infection in a prospecshowed that the annualised incidence for tive, case-control study and then atsuch events with extended wear was about tempted to estimate the incidence of ultwo per 1,000. Restricting use of contact cerative keratitis for both modes of contact lenses to daily wear reduced this incidence lens use.15J9Schein and associate^'^ idenby about 75 per cent. Such data mean that Clinical and Experimental Optometry 85.3 May 2002

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tified 86 patients with corneal infections associated with contact lens wear and matched them with controls. Use of either daily or extended wear hydrogel contact lenses under closed eye (extended wear) conditions resulted in a statistically significant increase in risk of infection (nine-fold for daily wear and 10- to 15-fold for extended wear). Moreover, the risk of infection appeared to increase with each additional night of contact lens wear. Poggio and co-w~rkers’~ surveyed all practising ophthalmologists in a five-state area (in New England) to identify all new cases of corneal infection with contact lens wear over a four-month period. The denominator of the fraction was estimated from a telephone survey of 4,178 households in the same geographic area. The annualised incidence of corneal infection was found to be 20.9 per 10,000 for extended wear and 4.1 per 10,000 for daily wear. A decade later, Cheng and colleaguesz3 provided almost identical data and conclusions in a European study. About 30 per cent of all corneal ulcers treated at three US ophthalmic centres in the mid-1980s were found to be related to contact lens Extended wear was associated with the majority of these infections at all centres. WilhelmusQsuggested that the incidence of contact lens associated microbial keratitis was increasing, when he found that more than 40 per cent of corneal ulcers treated in 1988 and 1989 at his facility were associated with contact lens wear. Of those using contact lenses for cosmesis, 21 (48 per cent) of 44 used their lenses for extended wear in this study. Another more recent follow-up study by Rattanatam and associatesz7has come to a different conclusion. They found that the incidence of contact lens associated microbial keratitis was decreasing and suggested that this may be due to a more conservative approach to extended wear on the part of clinicians providing contact lenses.

DIAGNOSTIC CONSIDERATIONS There are many contact lens related complications (Table 2) but corneal infection is considered the complication of most concern. Clinical signs of microbial cor-

Contact lenses: where next? Giese and Weissman

Lids Toxicity Allergy: papillary conjunctivitis Ptosis Blepharitis Bulbar conjunctiva Injection Oedema Staining Corneal epithelium 3 to 9 stain Pancorneal stain Superior epithelial arcuate lesion (SEAL) Inferior arcuate stain Foreign body tracks Cluster stain Inferior band (exposure) stain Abrasion Dimple veil Infiltration Oedema Corneal stroma Oedema: stromal striae Infiltrates Neovascularlsatlon 3 to 9: pseudopterygium Pannus Deep stromal vessels Corneal endothelium Blebs Polymegathism

FEATURE

BACTERIAL KERATITIS

NON-INFECTIOUS KERATITIS

Onset

usually acute

subacute or acute

Predisposing factors

various: trauma, contact lens wear, and prior ocular surface disease

various: including corneal foreign bodies, soft lens wear, blepharoconjunctivitis, herpetic eye disease, topical medications, etc.

Symptoms

moderate to severe, increasing pain and light sensitivity

variable, usually initial mild discomfort or foreign body sensation

Eyelids

lid oedema

pseudoptosis

Conjunctiva

marked hyperaemia with episcleral injection and mucopurulent discharge

mild hyperaemia with mucoid discharge

Corneal eplthellum

usually ulcerated

usually intact, with punctate staining

Corneal stroma

white-yellow suppurative infiltrate with blurred margins and surrounding inflammatory cells and oedema, > 1.5 mm enlarges of 24 to 36 hours

white-gray superficial infiltrates usually c1 to 1.5 mm (tend to remain small)

Corneal endothelium

pseudoguttata with occasional inflammatory plaque or ring under stromal infiltrate

minimal changes

Anterlor chamber

variable, hypopyon common

mild cells and flare, hypopyon uncommon

Fluorescein stalnlng

moderate to extreme

none to minimal

Table 3. Clinical comparison between infectious and non-infectiouskeratitis9

Mlcroblal corneal infection Bacterial, amoebic, fungal Table 2. Physiological complications of contact lens wear

neal infection include an epithelial (and perhaps stromal) defect and associated keratitis (corneal infiltrates and oedema) . Conjunctival oedema and injection often accompany severe keratitis, as does lid inflammation, anterior chamber reaction (seen as cells and flare in the aqueous humour) and hypopyon. Subjectivesymp toms include ocular pain, photophobia and decreased vision, owing to involvement of the corneal visual axis and anterior chamber reaction. Mild or early keratitis may have minimal subjective

symptoms.9.zR Neovascularisation, scarring and corneal thinning may result following episodes of acute or chronic keratitis. Stein and colleaguesz8studied 50 patients who presented with corneal infiltrates associated with contact lens wear to determine which clinical signs and symp toms were most important in predicting the results of microbial culture. Twenty patients were found to have culturepositive corneal infections; 20 had ‘sterile’ infiltrates and the remaining 10 patients had corneal infiltrates with negative cultures that appeared to be infectious in origin. Positive culture results were statistically associated with increased pain, discharge, epithelial staining and anterior chamber reactions. Lesions that did not yield positive cultures (sterile infiltrates) Clinical and Experimental Optometry 85.3 May 2002

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were usually smaller (70 per cent measured less than one millimetre in diameter), multiple, showed minimal superficial punctate epithelial stain and presented without s u b stantial pain, discharge or anterior chamber reaction. It is also important to recognise that studies of corneal infection always include substantial numbers of patients who clinically appear to have microbial keratitis and respond to treatment but who also yield negative culture results for any of a number of reasons, including previous antibiotic therapy and sampling err~r.~.~r~ Distinguishing, non-infectious sterile keratitis and infiltrate^,^^.^ such as contact lens induced peripheral ‘ulcers’ (CLPU), from active microbial corneal infection can be difficult (Table 3). The issue of

Contact lenses: where next? Gkse and Weissman

precise definition has led to much controversy and confusion, both clinically and in the research literature. The appearance of early lesions can be diagnostically inconclusive and positive or negative culture results, while compelling, are also far from definitive. Aggressive use of antibiotics and withholding steroids comprises the standard treatment approach to active infection. Some cliniciansbelieve thatjudicious use of topical steroids for contact lens associated ‘sterile’infiltrates may be of value?’ We believe it is important to emphasise that size, corneal location and positive culture results could be suggestive but are not necessarily the only distinguishingfeatures of infectious lesions. All infections begin as small infiltrates and/or epithelial defects. Mondino and colleagues6 found that only 23 (58per cent) of 40 clinically diagnosed corneal infections associated with contact lens wear were central ulcers, whereas the remainder were peripheral. Considering the risk/benefit of treating a sterile infiltrate versus not treating an infectious keratitis, it is probably better to have a high clinical index of suspicion and to over-treat rather than under-treat. As is evident from these data, most of our current understanding has come from observational case series and the occasional casecontrol study. These studies are of limited value in assessing pathogenesis, the relative importance of possible treatments and risk factors, and the absolute scope of disease. Other problems include limited numbers, poor or absent controls and heterogeneous populations. Therefore, current clinical studies fail to absolutely establish which risk factors are most important and how they interact to allow bacterial infection to occur. We believe that further elucidation of this issue, including risk, prevention and improved treatment, requires more rigorous epidemiological studies and basic science investigations, involving immunology and microbiology in particular. BACTERIAL STUDIES ~

~~~

~

Three decades ago the most feared corneal pathogen was Streptococcuspteumoniae,

a gram-positive bacterium that caused elastase and alkaline protease are severe corneal ulcers with hypopyon~.~-~* examples.3441Engel and associates42have The introduction of antibiotics has tamed also shown that Pseudomonm protease W this particular beast to a great degree and mediates keratitis in an animal model. it is now believed that herpes is the most Ocular and non-ocular models of S. aureus frequent pathogen of direct corneal infec- infection have shown that staphylococcal tion in the developed world.3sWhether exoproteins such as alpha haemolysin are contact lenses are worn for daily or ex- important in the disease proces~.’~ These tended wear, Pseudomonas aeruginosa, a bacterial products also induce the producgram-negative bacterium, is known to be tion, release and activation of host factors the most common cause of contact lens such as complement, leucocyte lysosomal related keratitis. constituents and metalloproteinases.y Bacterial corneal infection develops These hostderived soluble mediators also when host defences are overcome by bacplay roles in corneal tissue destruction. terial virulence factors. Some conditions The complex interactions between baccreated by wearing contact lenses, perhaps teria and host have been studied extenhypoxia, either inhibit normal ocular desively in animal models of corneal infecfences or enhance a particular bacterium’s tion caused by Pseudonwnas and S. aureus virulence mechanisms. in rats,44 rabbit^,^^^^^ guinea pigs47and Research from in vitm and noncontact mice.48These models have provided inforlens related animal models have contribmation relative to the in uivo mechanisms of corneal ulcer development and progresuted significant information regarding the sion. Cole and c o - ~ o r k e r have s ~ ~ identified pathogenesis of infectious keratitis (for that different strains of Pseudomonas are reviews see Wilhelmusgand O’Brien and associated with varying degrees of corneal HazlettS4).The first step in an infection is damage. One keratitis isolate produced bacterial attachment. Numerous studies have shown that bacteria possess many dif- ulceration and neutrophil infiltration, ferent mechanisms to adhere to and in- while the other, a contact lens-induced acute red eye isolate, was non-invasive and vade the injured c ~ r n e a .Adherence ~!~~ is non-cytotoxic. Studies in animal models mediated through the binding of bactehave identified strains of Ps. w g i n o s a is@ rial cell surface adhesins and receptor lated from corneal infections that are eimolecules on the corneal surface or extracellular matrix. Pseudomonas,for exarn- ther cytotoxic or inwive.%These findings may explain why eradication of this organple, has been shown to bind to basement ism is often difficult. When genetically membrane proteins in a mouse corneal altered strains of bacteria, deficient in the infection m0de1,5~.~~ however, the specific production of toxins and other compobinding molecules and mechanisms of nents, were used to create an infection in attachment have not yet been fully elucimouse models, the contribution of these dated. bacterial products to the infection procProgression of keratitis is dependent on ess was clearly demonstrated. For examboth bacterial replication and invasion and ple, experiments using an alphaproduction of bacterial and host products. haemolysin deficient strain of S. aureus Some bacteria are able to prevent their confirmed its significance in the establishremoval by producing an IgA protease, ment of corneal infection^.'^ Additionally, which cleaves and inactivates host antibody protein A and beta-toxin were shown to molecules.37Other bacteria are able to prevent activation of the alternate comple- be less important in the infection process, ment cascade via their capsular polysac- but they still contributed to disease.q3 Given all the data derived from these in charide, thus avoiding recognition by the vitm and in uivo studies, many questions innate immune system. still are unanswered but we are heading Bacterial endotoxin, exotoxins and enin the right direction. Future research zymes have all been shown to be key in needs to determine how contact lenses the initiation and progression of corneal and bacteria alter the corneal surface and/ infection^.^" Pseudomonas exotoxin A, Clinical and Experimental Optometry 85.3 May 2002

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or the extracellular matrix to predispose the cornea to infection. Additional research needs to identify and characterise the specific binding epitopes of bacterial membranes, corneal cells, basement membranes and the extracellular matrix, as well as the molecular mechanisms of attachment and invasion. Clearly, bacterial strains that produce toxins can cause more severe corneal inflammation. The exact bacterial and host products responsible for induction and progression of corneal infections need to be identified and characterised. HOST RESPONSE Direct microbial invasion of the intact cornea is relatively rare in healthy individuals because the anterior ocular segment is well provided with immunological defences-mechanical, humoral and cellular. Some physical protection is provided by the bones of the orbit and brow and by the eyelashes. The blinking action of the lids and flushing of tears across the ocular surface mechanically remove free-floating particles and microbes. Constant shedding of epithelial cells removes microbes that have attached to receptors on the cell membrane. Tears are relatively cool and nutrient poor and contain various nonspecific antibacterial substances, such as complement, lysozyme, beta-lysin and lactoferrin. Phospholipase Az, has been detected in rabbit tears and has been shown to be important in preventing S. aureusinfection.51Tears also contain other protective proteins, such as angiostatin, which may have a role in preventing corneal neovascularisation.5* Immunoglobulinsand elements of complement have been identified in tears and in the corneal ~ t r o m aTear . ~ ~complement activation has been documented in both uncomplicated and complicated contact lens wear.54In particular, C3 and its cleavage products (critical elements in the activated complement cascade) have been detected in patients with corneal inflammation after overnight contact lens wear.55 Complement component C3 has been shown to be important in host resistance in experimental Pseudomonas ocular dis-

ease.56Increased levels of C1, C3, C4 and C5 have also been detected in patients with of both dicorneal ~ l c e r a t i o n Because .~~ rect and bystander effects associated with complement activation, complement regulatory proteins (for example, decay accelerating factor [DAF]) are essential in controlling tissue damage. DAF has been shown to be decreased in patients with contact lens associated inflammatory conditions, such as giant papillary conjunctivitis and infectious k e r a t i t i ~Mucus, . ~ ~ produced by the conjunctival goblet cells, not only enables tears to adhere to the ocular surface, but may envelop microbes and deliver them to the inner canthus for removal. Neutrophils and macrophages patrol the tears and eradicate bacteria. Unlike the cornea, the conjunctiva contains both blood and lymphatic vessels and large numbers of immunologically active cells-mast cells, neutrophils and lymphocytes-and can be termed conjunctivalassociated lymphoid tissue.58The conjunctiva can be thought of as a ‘lymph node turned inside out.’59It contains all of the components necessary to generate a complete immune response and for this reason, it belongs to the secretory immune system. The role of the conjunctiva in contact lens wear or ulceration, if any, needs to be investigated. Once the corneal infection processes have been activated, a series of interconnected reactions occur. Cytokines are produced which mediate inflammation and the infiltration of inflammatory cells. Pseudomonas infections have been shown to induce the release of tumour necrosis factor-alpha and interleukin-1 from human monocytes“ and in u Z V O . ~ ~ Interestingly, non-toxic doses of Pseudomonas exotoxin A have been shown to inhibit the production of these cytokines, suggesting that exotoxin A is able to suppress the immune response.60Animal studies have shown that neutrophils are the major inflammatory cells responding to PseuThese cells domonas infection.44.45*49.w.62.65 are important in elimination of the bacteria but they are also destructive to host preventing the return of a clear cornea.9 Antigen presenting cells (Langerhans Clinical and Experimental Optometry 85.3 May 2002

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cells) have been shown to be present in the conjunctival epithelium adjacent to the cornea. Following extended-wear conor Pseudomonas infection, tact lens these cells migrate into the central cornea.” Hazlett and associates7ohave hypothesised that these antigen presenting cells in the cornea ‘prime’ the lens wearer’s eye for a rapid response to insults during extended-wear contact lens use. In a genetically susceptible mouse scarification model of Pseudomonas keratitis, CD4t T lymphocytes were shown to be the mediators of the inflammatory response.72 Hazlett and associates72propose that a CD4+ Th-1 dominated response results in corneal perforation and blindness. Despite all the data derived from host immune response studies, we have only started to investigate these enormous and interconnected fields. We know that corneal inflammation results from both bacterial and host derived products. However, the exact host derived soluble mediators (for example, immunoglobulins, vasoactive amines, eicosinoids and cytokines) have not been fully described. The role of complement and adhesion molecule expression has not been completely charact e r i ~ e d The . ~ ~ molecular changes of the corneal surface or extracellular matrix that predispose the cornea to bacterial infection remain to be elucidated. The importance of humoral and cellular immunity during corneal infections needs to be better described and the functional importance of antigen presenting cells needs to be clarified.

FUTURE RESEARCH Given the research into bacterial pathogenesis and host immune responses to bacterial corneal infection, we still need to better define all of the components and mechanisms involved in the disease process. Because these events occur in a living organism, the processes may be difficult to elucidate but we are clearly heading in the right direction. The aetiology of contact lens related corneal infection (‘ulcers’) is multifactorial. The process depends, in part, on the characteristics of the micro-organism


namely, inoculum size, virulence, adherence and the production of biofilm on contact lenses and storage cases. The organism's resistance to disinfection systems and patient compliance issues, such as inappropriate lens wear (for example, wearing time) and care regimens are important contributing factors. Host immune issues, such as defects in mechanical protection mechanisms and humoral and cellular defence mechanisms, are also involved. The consequences of contact lens wear on the cornea, such as hypoxia, stagnation of the tear film, deposits on the lens surface and the effect of the contact lens on the closed eye environment are also involved in the development of kerati tis. Clinicians need to understand how contact lens wear impacts ocular defences and contributes to increased pathogenicity of micro-organisms. Future research should: 1. define the scope of the problem more precisely, identify risk factors (to aid in prevention) and provide more precise diagnostic and treatment tools 2. exploit advances in molecular biology, immunology and microbiology. Enhanced understanding of ocular immune defences will allow us to strengthen the activity of the system components that extended contact lens wear suppresses. In addition, we need to learn how to more effectively treat corneal ulcers, while minimising collateral host-tissue damage. Strategiesaimed at precluding infection and more effectively utilising immunological responses, once infection has been diagnosed, undoubtedly will need to be pursued. If the mechanisms of corneal ulcer pathogenesis can be elucidated, it may be possible to pharmacologically interrupt the process. New treatment strategies are being developed that may eliminate the effects of naturally occurring enzymes and subsequent secondary host responses that can lead to additional damage. Such agents include several classes of matrix metalloproteinase inhibitor^,^**^^ as well as inhibitors of leucocyte and bacterial substances, and inhibitors of inflammatory mediators. Monoclonal antibodies designed to regulate the infiltration of inflammatory cells may help decrease tissue

damage76and blocking the expression of inflammatory genes may be possible.77 Maybe a combination of all of these new therapies will allow us to customise ideal treatment regimes. The emergence of methacillin resistant strains of S. a u w necessitates the development of alternative treatment strategies such as vaccines. Pseudomonas and S. a u m corneal infections may also be approachable in this manner. Immunisation with Pseudomonas outer membrane proteins (OMP) has been shown to confer protection against Pseudomonas bacteraemia in bum patients.'* Vaccination with monocle nal antibodies against OMP has been shown to confer some protection against keratiti~.?~ Numerous vaccination strategies have been attempted for S. a u w but have had limited success.8oA novel a p proach that targets virulence has been suggested recently!' Additionally, Hume and colleagues**have shown that immunisation with alpha-toxin toxoid protects the cornea against tissue damage during experimental S. aureus keratitis.

CONCLUSION ~~~

~

Clearly, the risk of infection while wearing contact lenses is low but a substantial increase in risk occurs when the lenses are used on an extended wear basis. Clinicians who prescribe contact lenses, patients who wear them and the industry that produces them have a vested interest in research enhancing the safety and efficacy of contact lenses. Certainly, minimising complications that may lead to visual loss, particularly microbial infection, is a priority. Now that the field of contact lens research has.matured, it is appropriate to consider the directions our research should take to enhance safe contact lens wear. REFERENCES 1. DixonJM,YoungCAJr, BaldoneJA, Halberg GP, Sampson W, Stone WJr. Complications associated with the wearing of contact lenses.J A M 1966; 195: 901-903. 2. Freedman H, Sugar J. Pseudomonas keratitis followingcosmetic soft contact lens wear. Contact LensJ1976; 10: 21-25. 3. Cooper RL, Constable IJ. Infective keratitis in soft contact lens wearers. Br J

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Ophthalmoll977;61: 250-254. 4. KrachmerJH, PurcellJJr. Bacterial corneal ulcers in cosmetic soft contact lens wearers. Arch Ophthalmoll978;9 6 57-61. 5. Wilson LA, Schlitzer RL, Ahearn DG. Pseudomonos corneal ulcers associated with soft contact lens wear. AmJOphthalmoll981;92: 548554. 6. Mondino BJ, Weissman BA, Farb MD, Pettit TH. Corneal ulcers associated with dailywear and extended-wear contact lenses. Am J OPhthalmoll986 102: 5865. 7. Asbell P, Stenson S. Ulcerative keratitis: a survey of 30 years' laboratory experience. Arch Ophthalmoll982; 100: 77-80. 8. Wilhelmus KR. Review of clinical experience with microbial keratitis associated with contact lenses. CLAOJ 1987; 13: 21 1-214. 9. Wilhelmus KR. Bacterial keratitis. In: PeposeJS, Holland GN, Wilhemus KR, eds. Ocular Infection and Immunity. St Louis: Mosby-Year Book Inc. 1996; 970-1031. 10. Donzis PB, Mondino BJ, Weissman BA, Bruckner DA. Microbial analysis of contact lens care systems contaminated with Acanthamoeba. Am J Ophthalmol 1989; 108: 53-56. 11. Weissman BA, Giese MJ, Mondino BJ: Ulcerative bacterial keratitis. In: SilbertJA, ed. Anterior Segment Complications of Contact Lens Wear, 2nd e d . Boston: Butterworth-Heinemann, 2000: 225250. 12. Ruben M. Acute eye disease secondary to contact-lens wear. Lancet 1976; 1: 138-140. 13. Donzis PB, Mondino BJ, Weissman BA, Bruckner DA. Microbial contamination of contact lens care systems. Am J Ophthalmol 1987; 1 0 4 325333. 14. Garwood PC. Complicationswith daily-wear disposable contact lenses. Contact Lens J 1991; 19: 137-141. 15. Schein OD, Glynn RJ, Poggio EC, Seddon JM, Kenyon KR. The relative risk of ulcerative keratitis among users of daily-wearand extended-wear soft contact lenses: a case control study. Microbial Keratitis Study Group. NEngl JMed 1989; 321: 773-778. 16. Sharma S. Levels of evidence. EvidenceBased Eye Care 2000; 1: 67-68. 17. Early treatment diabetic retinopathy study design and baseline patient characteristics. ETDRS report number 7. Ophthalmology 1991; 98 (SUPPI5): 741-756. 18. Design and methods of a clinical trial for a rare condition: the Collaborative Ocular Melanoma Study. COMS Report number 3. Control Clin rials 1993; 14: 362-391. 19. Poggio EC, Glynn RJ, Schein OD, Seddon JR, Schannon MJ, Scardino VA, Kenyon KR. The incidence of ulcerative keratitis among users of daily-wear and extended-wear soft contact lenses. NEnglJMed 1989; 321: 7 7 4 783. 20. Chalupa E, Swarbrick HA, Holden BA,


Sjdstrand J. Severe corneal infections associated with contact lens wear. Ophthalmology 1987; 94: 17-22. 21. MacRae S, Herman C, Stulting RD, Lippman R, Whipple D, Cohen E, Egan D, Wilkinson CP, Scott C, Smith R, Phillips D. Corneal ulcer and adverse reaction rates in premarket contact lens studies. Am J Ophthalmoll991; 111: 457-465. 22. Barr J. The 1997 report on contact lenses. Contact Lens Spectrum 1998; 1: 23-33. 23. Cheng KH, Leung SL, Hoekman HW, Beekhuis WH, Mulder PC, Geerards AT, Kijlstra A. Incidence of contact-lensassociated microbial keratitis and its related morbidity. Lancet 1999; 354: 181-185. 24. Koidou-TsiligianniA, Alfonso E, Forster RK. Ulcerative keratitis associated with contact lens wear. Am J Ophthalmol 1989; 108: 6 4 67. 25. Donnenfeld ED, Cohen EJ, Arentsen J, Genvert GI, Laibson PR. Changing trends in contact lens associated corneal ulcers: an overview of 116 cases. CLAOJ1986; 12: 145-149. 26. Schein OD, Ormerod LD, Barraquer E, Alfonso E, Egan KM, Paton BG, Kenyon KR. Microbiology of contact lens related keratitis. Cornea 1989; 8: 281-285. 27. Rattanatam T, Heng WJ, Rapuano CJ, Laibson PR, Cohen EJ. Trends in contact lens-related corneal ulcers. Cornea 2001; 20: 290-294. 28. Stein RM, Clinch TE, Cohen EJ, Genvert GI, Arentsen J,Laibson PR. Infected vs sterile corneal infiltrates in contact lens wearers. AmJOphthalmoll988; 105: 632-636. 29. Mondino BJ, Groden LR. Conjunctival hyperemia and corneal infiltrates with chemically disinfected soft contact lenses. Arch Ophthalmoll980; 98: 1767-1770. 30. Gordon A, Kracher GP. Corneal infiltrates and extended-wear contact lenses. J A m Optom Assoc 1985; 56: 198-201. 31. Baum J, Dabezies OH Jr. Pathogenesis and treatment of ‘sterile’ midperipheral corneal infiltrates associated with soft contact lens use. Cornea 2000; 19: 777-781. 32. Vaughn DG Jr. Corneal ulcers. Surv Ophthalmoll958; 3: 203-215. 33. Hyndiuk RA, Glasser DB. Herpes Simplex Keratitis. In: Tabbara KF, Hyndiuk RA, eds. Infections of the Eye, 2nd ed. Boston: Little Brown and Co, 1996: 361. 34. O’Brien TP, Hazlett LD. Pathogenesis of ocular infection. In: Pepose JS, Holland GN, Wilhemus KR, eds. Ocular Infection and Immunity. St. Louis: Mosby-Year Book Inc. 1996; 200-214. 35. Hazlett LD, Masinick S. Lacrimal Gland, Tear Film, and Dry Eye Syndromes,2nd ed. New York, Plenum Press, 1998: 567-574. 36. Chen LD, Hazlett LD. Perlecan in the basement membrane of corneal epithelium

serves as a site of I? aeruginosa binding. Cuw Eye Res 2000; 20: 260-267. 37. Kilian M, ReinholdtJ, Lomholt H, Poulsen K, Frandsen EV. Biological significance of IgAl protease in bacterial colonization and pathogenesis: critical evaluation of experimental evidence. APMIS 1996; 104: 321338. 38. O’Callaghan RJ. Role of exoproteins in bacterial keratitis: the Fourth Annual Thygeson Lecture, presented at the Ocular Microbiology and Immunology Group meeting, November 7, 1998. Cornea 1999; 18: 532-537. 39. Hazlett LD, Iglewski BH, Berk RS. Experimental Pseudomonas exotoxin A mediated ocular damage in mouse pups: microscopic observations, Ophthalmic Res 1982; 14: 401408. 40. Ohman DE, Burns RP, Iglewski BH. Corneal infections in mice with toxin A and elastase mutants of Pseudomonas aeruginosa. J Infect Dis 1980; 142: 547-555. 41. Howe TR, Iglewski BH. Isolation and characterization of alkaline proteasedeficient mutants of Pseudomonas aeruginosa in vitro and in a mouse eye model. Infect Immun 1984: 43: 1058-1063. 42. Engel LS, Hill JM, Moreau JM, Green LC, Hobden JA, O’Callaghan RJ. Pseudomonas aeruginosa protease Iv produces corneal damage and contributes to bacterial virulence. Invest Ophthalmol Vis Sci 1998; 39: 662665. 43. O’Callaghan RJ, Callegan MC, Moreau JM, Green LC, Foster TJ, Hartford OM, Engel LS, Hill JM. Specific roles of alpha-toxin and beta-toxin during Staphylococcus aureus cornea infection. Infect Immun 1997; 65: 1571-1578. 44. Twining SS, Lohr KM, Moulder JE. The immune system in experimental Pseudomonas keratitis. Model and early effects. Invest Ophthalmol Vis Sci 1986 27: 507-515. 45. Van Horn DL, Davis SD, Hyndiuk RA, Pederson HJ. Experimental Pseudomonas keratitis in the rabbit: bacteriologic, clinical, and microscopic observations. Invest Ophthalmol Vis Sci 1981; 20: 213-221. 46. Hume EB, DajcsJ, Moreau JM, Sloop GD, Willcox MD, O’Callaghan RJ. Staphylococcus corneal virulence in a new topical model of infection. Invest Ophthalmol Vis Sci 2001: 42: 29042908. 47. Van Horn DL, Davis SD, Hyndiuk RA, Alpren TV. Pathogenesis of experimental Pseudomonas keratitis in the guinea pig: bacteriologic, clinical, and microscopic observations. Invest Ophthalml Vis Sci 1978; 17: 10761086. 48. Cowell BA, Wu C, Fleiszig SMJ. Use of animal model in studies of bacterial corneal infection. IZAR J 1999; 40: 43-50. 49. Cole N, Willcox MD, Fleiszig SM, Stapleton


147

F, Bao B, Tout S, Husband A. Different strains of Pseudomonas aeruginosa isolated from ocular infections or inflammation display distinct corneal pathologies in an animal model. Cuw Eye Res 1998; 17: 730-735. 50. Fleiszig SMJ, Zaidi TS, Preston MJ, Grout M, Evans DJ, Pier GB. Relationship between cytoxicity and corneal epithelial cell invasion by clinical isolates of Pseudomonas aeruginosa. Infect Immun 1996; 64: 22882294. 51. Moreau JM, Girgis DO, Hume EB, DajcsJ, Austin MS, O’Callaghan RJ. Phospholipase A, in rabbit tears: A host defence against Staphylococcus aureus. Invest Ophthalmol Vis Sci 2001; 42: 2347-2354. 52. Sack RA, Beaton AR,Sathe S. Diurnal variations in angiostatin in human tear fluid: a possible role in prevention of corneal neovascularization. Cum Eye Res 1999; 18: 186-193. 53. Waldrep JC, Mondino BJ. Humoral immunity and the eye. In: PeposeJS, Holland GN, Wilhemus KR, eds. Ocular Infection and Immunity. St. Louis: Mosby-Year Book Inc. 1996; 33-49. 54. Szczotka LB, Cocuzzi E, Medof ME. Decayaccelerating factor in tears of contact lens wearers and patients with contact lens associated complications. Optom Vis Sci 2000; 77: 586591, 55. Sack RA, Sathe S, Hackwood LA, Willcox MD, Holden BA, Morris CA.The effect of eye closure on protein and complement composition on Group IV hydrogel lenses: relationship to tear flow dynamics. CurrEye R ~ 1996 s 15: 1092-1100. 56. Cleveland RP, Hazlett LD, Leon MA, Berk RS.Role of complement in murine cornea1 infection caused by Pseudomonas aeruginosa. Invest Ophthalmol Vis Sci 1983; 24: 237-242. 57. Mondino BJ, Zaidman GW. Hemolytic complement in tears. Ophthalmic Res 1983; 15: 208-211. 58. Knop N, Knop E. Conjunctiva associated lymphoid tissue in the human eye. Invest Ophthalmol Vis Sci 2000; 41: 1270-1279. 59. Allensmith MR. Immunology of the eye. In: The Eye and Immunology. St Louis, MO: CV Mosby Co, 1982: 82. 60. Staugus RE, Harvey DP, Ferrante A, Nandoskar M, Allison AC. Induction of tumor necrosis factor (TNF) and interleukin-1 (IL-1) by Pseudomonas aeruginosa and exotoxin A-induced suppression of lymphoproliferation and TNF, lymphotoxin, gamma interferon, and I L l production in human leukocytes. Infect Immun 1992; 60: 3162-3168. 61. Kernacki KA, Berk RS. Characterization of the inflammatory response induced by corneal infection with Pseudomonas. J Ocul Phannucol1994; 10: 281-288 62. Mondino BJ, Rabin BS, Kessler E, Gallo J,


Brown SI. Corneal rings with gram-negative bacteria. Amh Ophthalmol 1977; 95: 22222225. 63. Hazlett LD, Rosen DD, Berk RS. Pseudomonas eye infection in cyclophosphamide-treated mice. Invest Ophthalmol Vis Sci 1977; 16: 649-652. 64. Weiss SJ. Tissue destruction by neutrophils. New EnglJMed 1989; 321: 327-329. 65. Steuhl KP, Ddring G, Henni A, Thiel HJ, Botzenhart K. Relevance of hostderived and bacterial factors in Pseudomonas aeruginosa corneal infections. Invest Ophthalmol Vis Sci 1987; 28: 1559-1568. 66. Chusid MJ, Nelson DB, Meyer LA. The role of the polymorphonuclear leucocyte in the induction of corneal edema. Invest Ophthalmol Vis Sci 1986; 27: 14661469. 67. Hobden JA, Engel LS, Callegan MC, Hill JM, Gebbardt BM, O’Callaghan RJ. Pseudomonas amginosa keratitis in leukopenic rabbits. Curr Eye Res 1993; 12: 461-467. 68. Hazlett LD, Zucker M, Berk RS.Distribution and kinetics of the inflammatory cell response to ocular challengewith Pseudmnonar amginosa in susceptible versus resistant mice. Ophthalmic Res 1992; 2 4 32-39. 69. Kessler E, Mondino BJ, Brown SI. The corneal response to Pseudomonas amginosa: histopathologicaland enzymaticcharacterization. Invest Ophthalmol Vis Sci 1977; 1 6 116125. 70. Hazlett LD, McClellan SM, Hume EBH, Dajcs JJ, O’Callaghan RJ, Willcox MDP. Extended-wear contact lens usage induces Langerhan’scell migration into cornea. Exp Eye Res 1999; 69: 575-577. 71. Hazlett LD, Moon M, Dawisha S, Berk RS. Age alters ADPase positive dendritic (Langerhans) cell response to I! amginosa ocular challenge. CurrEyeRes 1986; 5: 343-355. 72. Kwon B, Hazlett LD. Association of CD4+T celldependent keratitis with genetic susceptibility to Pseudomonas m g i n o s a ocular infection. JImmunoll997; 159: 6283-6290. 73. Verhagen C, Breebaart AC, Kijlstra A. The effects of complement depletion on corneal inflammation in rats. Invest Ophthalmol Vis Sci 1992: 33: 273-279. 74. Galardy RE, Cassabonne ME, Giese C, GilbertJH, Lapierre F, Lopez H, Schaefer ME, Stack R, Sullivan M, Summers B et al. Low molecular weight inhibitors in corneal ulceration. Ann NYAcad Sci 1994: 732: 3 1 5 323. 75. Gray RD, Paterson CA. Application of peptide-based matrix metalloproteinase inhibitors in corneal ulceration. Ann Ny Acad Sci 1994 732: 206216. 76. Welsh NH, Rauch AJ, Gaffin SL. Topical immunotherapy for Pseudomunas keratitis in rabbits: use of antilipopolysaccharide plasma. BrJ Ophthalmol1984: 68: 828-832. 77. Cho-Chung YS, Park YG, Lee YN.

Oligonucleotides as transcription factor decoys. Curr Opin Mol Ther1999: 1: 386392. 78. Kim DK, KimJJ, Kim JH, Woo YM, Kim S, Yoon DW, Choi CS, Kim I, Park WJ,Lee N, Jung SB, Ahn BY, Nam SW,Yoon SM, Choi WJ. Comparison of two immunization schedules for a Pseudomonas aeruginosa outer membrane proteins vaccine in burn patients. Vaccine 2001; 19: 12741283. 79. Moon MM, Hazlett LD, Hancock RE, Berk RS, Barrett R. Monocloncal antibodies provide protection against Pseudomonas amuginosa infection. Invest Ophthalmol Vis Sci 1988: 29: 1277-1284. 80. Lee JC. An experimental vaccine that targets staphylococcal virulence. Trends Mimbiol1998; 6: 461-463. 81. Balaban N, Collins LV, CullorJS, Hume EB, Medina-Acosta E, Viera d a Motta 0, O’Callaghan R, Rossitto PV, Shirtliff ME, Serafim da Silveira L, Tarkowski A, Torres JV.Prevention of diseases caused by Staphylococcus aureus using the peptide RIP. Peptides 2000; 21: 1301-1311. 82. Hume EB, Dajcs JJ, Moreau JM, O’Callaghan RJ. Immunization with alphatoxin toxoid protects the cornea against tissue damage during experimental Staphylococcus a u m keratitis. Infect Immun 2000; 68: 6052-6255. Author’s address:

Dr Michael J Giese 100 Stein Plaza, DSERC 3-143 Jules Stein Eye Institute UCLA School of Medicine Los Angeles CA 900957000 USA


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