MICROBES & LENS WEAR

Microbiology and Contact Lens Wear

Take a look back at what's changed—and what hasn't—over the past 10 years.

By Mark D. P. Willcox, PhD

While contact lens wear remains relatively safe, microbial colonization of lenses and the subsequent interplay between the microbes and the cornea can lead to adverse responses. Microbial keratitis, or frank infection of the cornea, is the most serious of these responses. At the beginning of 2011, it is perhaps useful to examine what has changed in our understanding of the interplay between microbes, lenses, and the cornea, and what still needs to be done to reduce incidence of microbial keratitis.

Contact Lenses: Risk Factors

By 2000 to 2001, we knew that contact lens wear was one of the major risk factors for developing microbial keratitis. Table 1 (Erie et al, 1988; Pachigolla et al, 2007; Dart et al, 1991; and others—full list available at www.clspectrum.com/references.asp) gives the frequency of contact lenses as a cause of microbial keratitis in people attending various hospitals around the world. Differences in the rates associated with contact lens wear in different geographical regions are largely a consequence of the overall rate of contact lens use. Contact lenses remain one of the most frequent causes of keratitis. In the United States, the cases of ulcerative keratitis associated with contact lens wear increased from 0 percent in the 1950s and 1960s to 32 percent in the 1970s to 52 percent in the 1980s (Erie et al, 1988), and dropped to 27 percent in the 2000s (Pachigolla et al, 2007). The apparent decrease from the 1980s to the 2000s may be partially explained by changes in referring patterns and treatment over that time frame in the United States.

For contact lens-related microbial keratitis (CLMK), Table 2 lists the reported risk factors in studies performed before 2000 (Dart et al, 1991; Poggio et al, 1989; Stapleton et al, 1993; and others). Studies reported from 2001 onward show many of the same risk factors (Table 2). Risk factors that are not modifiable—for example, gender—would obviously not change. Removal of chlorine disinfection and cessation of heat disinfection has removed some of these modifiable factors, but most other modifiable factors remain a problem.

Before 2000 to 2001, the incidence of CLMK was reported to be remarkably constant, from the first report in 1987 from the United States of 4.1 per 10,000 wearers of soft daily wear lenses and 20.9 per 10,000 wearers of soft extended wear lenses, to 3.1 per 10,000 wearers of soft daily wear and 9.3 per 10,000 wearers of soft extended wear lenses in 1997 to 1998 from Hong Kong (Poggio et al, 1989; Lam et al, 2002).

The first report for the incidence of CLMK after 2001 gave the incidence of CLMK for both soft and silicone hydrogel lenses (Morgan et al, 2005): 6.9 per 10,000 for soft daily wear, 96.4 per 10,000 for soft extended wear (much higher than all other reports), and 0 per 10,000 for silicone hydrogel daily wear and 19.8 per 10,000 for silicone hydrogel extended wear. Another study from 2005 gave an incidence of 18.0 per 10,000 for CLMK of silicone hydrogel extended wear (Schein et al, 2005).

More recently a study from Australia (Stapleton et al, 2008) has given incidence rates for soft and silicone hydrogel lenses as well as, for the first time, the rate for soft lenses prescribed on a daily disposable basis: 2.0 per 10,000 for soft daily disposable, 1.9 per 10,000 for soft daily wear, 11.9 per 10,000 for silicone hydrogel daily wear, 19.5 per 10,000 for soft extended wear, and 25.4 per 10,000 for silicone hydrogel extended wear. In other words, and very disappointingly, new modalities or new lens materials such as silicone hydrogels have failed to have any effect on the incidence of CLMK.

A study of the incidence of British military personnel stationed in Iraq, most of whom wore “soft” lenses on an extended wear or daily disposable wear basis, indicated an incidence of CLMK regardless of wear modality of 35 per 10,000 (Musa et al, 2010).

Looking to the next 10 years, it would be informative if the incidence of CLMK with newer contact lenses and modalities, as well as newer multipurpose disinfecting solutions, was examined and reported.

Microbes in the Last Decade

Have the types of microbes that cause the disease changed in the past 10 years? Perhaps over the years there have been changes in causative organisms. Perhaps the new lens types or modalities have allowed different pathogens to cause the disease. Studies reported in 1980 (Liesegang et al) and 1997 (Wong et al) had shown that if the risk factor for MK was confirmed as being contact lens wear, then the causative organism was between six to 20 times more likely to be a bacterium than a fungus. This preponderance for bacteria causing CLMK had certainly not decreased from data reported in 2007 from India (Bharathi et al) or 2008 from Thailand (Sirikul et al).

By 2001, we knew that the most common causative microorganism of CLMK was Pseudomonas aeruginosa, followed by coagulase-negative staphylococci, Staphylococcus aureus, other gram negatives (including Serratia marcescens, Klebsiella sp.) and streptococci (Tabbara et al, 2000; Galentine et al, 1984; and others). Fungi and Acanthamoeba were much less frequently isolated. Data spanning 2002 to 2008 from the United Kingdom, Ireland, Holland, Thailand, Taiwan, Hong Kong, Brazil, and Australia have continued to report that Pseudomonas sp. (usually aeruginosa), coagulase-negative staphylococci, Serratia marcescens, Klebsiella sp., Staphylococcus aureus, and other gram positive bacteria (including streptococci) are the most common causative organisms (van der Meulen et al, 2008; Preechawat et al, 2007; and others). There is little evidence that the bacterial types that cause CLMK are changing, although climatic differences may slightly alter the rates for the major types (Stapleton et al, 2007). Generally fungi (2 percent) and Acanthamoeba (3 percent to 6 percent) are still rare causes, although it has been reported that a staggering 36 percent of CLMK cases between 2002 to 2007 in Brazil may have been caused by Acanthamoeba sp. (Moriyama et al, 2008).

Indeed, we all know of the sporadic increases in fungal and Acanthamoeba sp. CLMK that were caused by failures of two multipurpose disinfecting solutions (MPDSs) and their recall in 2006 and 2007. Prior to those events, the rates of Acanthamoeba keratitis had been reported to be relatively low (Table 3; Seal et al, 1999; Lam et al, 2002; and others). During the period 2006 to 2007, this incidence increased an apparent six times in Australia (Ku et al, 2009), and three to four times in Chicago (Joslin et al, 2006). Much has been reported from epidemiological and microbiological studies on these events and I will not detail these further. Suffice it to say that the problems were most likely associated with the solution formulation and user compliance with instructions for use (failure of the solution to kill Fusarium if the solution was “topped-off” in the lens case; the solution promoting encystment of Acanthamoeba [Levy et al, 2006; Kilvington et al, 2008]).

For the fungal CLMK caused by Fusarium sp., most publications indicate that incidence of this disease after the recall of the MPDS returned to the low levels that occurred before its availability (Gower et al, 2010; Grant et al, 2007), although there have been suggestions that there may be a continued higher incidence of this disease or other fungal CLMK even after the recall (Gower et al, 2010; Jurkunas et al, 2009). Similarly for Acanthamoeba-induced CLMK—while the incidence of the disease decreased dramatically after the recall of the MPDS—there may still be an underlying trend for the incidence to be increasing (Joslin et al, 2010; Patel et al, 2010).

Not only were there dramatic changes in lenses that people wore in the past 10 years, there also was an increase in wearers using MPDSs. For example, in the United Kingdom, use of MPDSs increased from 56 percent in 1997 to 93 percent in 2007 (Efron and Morgan, 2008). Market leaders of MPDSs containing polyhexanide (PHMB) or the dual disinfecting system of polyquaternium-1 (Polyquad) and myristamidopropyldimethylamine (Aldox) were already on the market in 2000 to 2001. During 2001 to 2011, the two MPDSs that caused the increase in Fusarium and Acanthamoeba CLMK were released and withdrawn. Another Polyquad/Aldox product was also launched (Figure 1).

Figure 1. Rates of MK with daily wear lenses and key dates relating to lenses and solutions.

Storage Case Contamination

The ISO microbiological disinfecting standards that MPDSs need to meet or exceed have not changed for many years, and interestingly the level of contamination of contact lens storage cases has also not changed. As hygiene of contact lens cases has been associated with increased risk of CLMK during daily wear of lenses (Stapleton et al, 2008), it is important that MPDSs and instructions to lens wearers reduce microbial colonization of cases.

By 2000 to 2001, microbial contamination of storage cases had been reported to range from 53 percent to 83 percent (Kanpolat et al, 1992; Wilson et al, 1990; Devonshire et al, 1993). The most recent studies on the rate of contamination of cases when using silicone hydrogel lenses and a range of MPDSs or a hydrogen peroxide disinfecting solution still report a range from 58 percent to 92 percent (Willcox et al, 2010; Wu et al, 2010). What I believe may be a major advance for the safety of lenses during wear has been the release of silver impregnated lens cases during 2001 to 2011. Several manufactures now supply this antimicrobial lens case, and the cases have been shown to reduce colonization by bacteria in vitro (Amos and George, 2006; Dantam et al, 2011) and in vivo (Amos and George, 2006).

Looking forward to 2011 and beyond, I will be interested to see the performance of the new dual disinfecting solutions being launched and whether the introduction of mandatory testing of MPDSs against Acanthamoeba sp. has any effect on the overall incidence of CLMK or of Acanthamoeba MK as well as on contamination of contact lenses and cases.

Lens Colonization

Not only do lens cases get contaminated by microbes during use, but so do contact lenses. It is probably bacterial colonization of lenses that is the first step in the production of CLMK. Prior to 2000 to 2001, we knew that during asymptomatic wear of soft HEMA-based lenses the lids and conjunctiva were colonized by gram positive bacteria (mainly coagulase-negative staphylococci, Corynebacterium sp., and Propionibacterium sp. [Stapleton et al, 1995; Hovding, 1981; Fleiszig et al, 1992]), and that colonization by gram negative rods or fungi was rare. The types of microbes on the lids and conjunctiva were also shown to colonize contact lenses during asymptomatic wear at approximately the same rates (Baleriola-Lucas et al, 1997). We also knew that the rate of colonization of HEMA lenses was greater in the Indian and Australian populations, but the types of microbes were similar (Gopinathan et al, 1997).

Examination of the types of microbes that colonized the lids, conjunctiva, and lenses during silicone hydrogel wear has shown that they were essentially the same as microbes colonizing those surfaces during HEMA-based wear (Willcox et al, 2000). This was confirmed in 2001 to 2002 (Keay et al, 2001; Willcox et al, 2002) and later in 2009 (Szczotka-Flynn et al, 2009a).

Adverse events (non-MK) during HEMA-based wear were associated with increased lens colonization by Streptococcus pneumoniae and gram negative bacteria (Sankaridurg et al, 2000; Sankaridurg et al, 1999; Sankaridurg et al, 1996). This finding was essentially repeated for silicone hydrogels (Szczotka-Flynn et al, 2010).

By 2000 to 2001 we knew that Pseudomonas aeruginosa adhered in higher numbers to a variety of HEMA-based lenses compared to staphylococci in laboratory studies (Bruinsma et al, 2001; Taylor et al, 1998; Ahanotu et al, 2001). The ability of P. aeruginosa to adhere in higher numbers compared to staphylococci was also shown on silicone hydrogel lenses (Borazjani et al, 2004; Henriques et al, 2005; Kodjikian et al, 2005), as was their increased ability to form biofilms on these lenses (Szczotka-Flynn et al, 2009b). Indeed, some studies have shown that adhesion of P. aeruginosa or staphylococci to silicone hydrogel lenses is greater than to HEMA-based lenses (Kodjikian et al, 2005; Willcox et al, 2001; Giraldez et al, 2010).

There have been no reports on whether P. aeruginosa strains have changed pathogenic traits over the years. That doesn't mean there haven't been increases in our knowledge of virulence factors of P. aeruginosa and the host defenses involved in MK—there have (Hazlett, 2005; Willcox, 2007; Evans et al, 2007). However, there are no reports of these changing during that time. There have been many reports on the antibiotic susceptibilities of P. aeruginosa isolates from keratitis (not only CLMK) for many years, and this has been reviewed recently (Willcox, 2010).

In brief, P. aeruginosa isolates from MK from the United States were essentially all sensitive (<10 percent of isolates resistant) to ciprofloxacin (or other fluoroquinolones) between 1990 and 2003. This contrasts with the case of these isolates from India, where resistance increased up to >20 percent between 1993 and 2006 (Willcox, 2010; Chawla et al, 2010). While the susceptibility/resistance criteria for antibiotics are based on the amount that can be achieved in serum, the amount that can be achieved during antimicrobial therapy for MK may be different. However, Kaye et al (2010) found that there is a linear relationship between clinical outcome and MIC for Pseudomonas sp., Staphylococcus aureus, and Enterobacteriaceae. With the relatively high resistance rate of P. aeruginosa to fluoroquinolones in India, there is an obvious risk of the rate increasing elsewhere. It is therefore encouraging that newer antimicrobials are being investigated as therapies for MK, including meropenem to which most P. aeruginosa MK from the United Kingdom are susceptible (Sueke et al, 2010).

Conclusion

“Plus ça change, plus c'est la même chose” springs to mind after reading the above! However, the information also points to areas changing for the better, including in the next few years ISO standards manufacturers must meet to sell MPDSs in many markets. These will probably include activity against Acanthamoeba and testing uptake of MPDS into lenses. The development availability of antimicrobial cases may be shown to have effects on bacterially driven adverse events during daily wear.

Another area is the development of antimicrobial contact lenses. Some have been reviewed (Willcox, 2007; Weisbarth et al, 2007), and more is being published on their efficacy and safety (Mathews et al, 2006; Cole et al, 2010; and others). Let us hope that research, development, and regulatory hurdles can be overcome so that these are available soon.

Advances in our understanding of the interplay between microbial virulence factors and host defense systems may lead to new therapies. Monitoring strains of microbes cultured from MK cases for changes to their virulence characteristics may be important. Surveillance of resistance rates to currently available antibiotics certainly is important. Still, while there are some new antibiotics to treat CLMK, lack of development of new generations of antimicrobials, as well as the paucity of antimicrobials that are effective against the rarer cases of CLMK caused by fungi and Acanthamoeba, remain a concern. CLS

For references, please visit www.clspectrum.com/references.asp and click on document #185.

Professor Willcox is professor at the School of Optometry and Vision Science, University of New South Wales, CSO of the Brien Holden Vision Institute, and Deputy CEO of the Vision CRC, Sydney, Australia. He is also a consultant or advisor to and has received research funds from Alcon, Ciba, B+L, and AMO.