Ocular surface infections: Strengthening defenses, withstanding attacks
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The eye is well adept at protecting itself against pathogens. There are antimicrobial proteins in tears, and the intact epithelium on the surface of the eye shields it efficiently from external assaults.
However, when these barriers are breached and defenses are weakened, microbes gain entry, causing infection.
Source: Bascom Palmer Eye Institute microbiology research team
Two of the most typical cases of patients with at-risk eyes are dry eye patients and contact lens wearers, and dry eye contact lens wearers are a bad combination, according to OSN Cornea/External Disease Board Member Francis S. Mah, MD.
“Dry eye patients have punctate areas where the epithelium is weakened or disrupted, and contact lenses cause some amount of hypoxia, which weakens the ability of the cornea to defend itself. Pathogens, specifically bacteria, fungi and parasites, adhere to the contact lens and through these open areas or hypoxic areas of the epithelium gain access into the cornea,” he said.
There are underlying conditions that cause chronic alterations of the epithelium and tear film, such as Sjögren’s syndrome and graft-versus-host disease, and another obvious cause of epithelial disruption is trauma, accidental or induced by surgery, Anat Galor, MD, an ocular surface expert at Bascom Palmer Eye Institute, said.
“In general, things heal quickly, but anytime your skin is compromised, you are at higher risk of infection. So, we want to, as much as possible, try to reduce the risk of our eye coming into contact with a potentially infectious organism,” she said.
Commercial products causing infection
Infections of a rare strain of drug-resistant Pseudomonas aeruginosa were recently identified by the CDC in different and distant locations in the United States. Cases of permanent vision loss and even death were reported. Investigators linked the infections to EzriCare artificial tears, Delsam Pharma’s artificial tears and Delsam Pharma’s artificial eye ointment, over-the-counter products manufactured by Global Pharma Healthcare. The FDA issued a warning to consumers not to purchase and immediately stop using these products, and the company agreed to recall them.
“These events are rare, but they do happen. And when they happen, as a community, I think we need to pause. We need to try to understand whether the problem was in the delivery process, in the lack of preservatives, in a bottle that maybe was not meant for that purpose. Every single link of the chain needs to be examined to make sure that people are safe when they go to Walgreens or CVS and buy artificial tears and that they know they’re getting a product that doesn’t contain harmful microbes,” Galor said.
“Kudos to the researchers who identified the connection with those artificial tears,” Mah said. “Fortunately, it has not been extremely common, but there has been a history where commercial products have been linked to causing infections. This one has gained a lot of spotlight because of not only the risk to the eye but the risk of death.”
Beginning in 2004, outbreaks of Fusarium keratitis were reported in various parts of the world among contact lens wearers. The infections were traced to the ReNu MultiPlus solution (Bausch + Lomb), and the product was ultimately withdrawn from the market.
In 2007, the Complete Moisture Plus multipurpose contact lens solution (Advanced Medical Optics) was linked to an outbreak of Acanthamoeba keratitis. There was no evidence of contamination at the source, but the company voluntarily recalled the product.
“These were not cases of contamination, but contact lens solutions used to be tested with one type of contact lens, and as long as they worked in that one contact lens and met USP standards, then they were FDA approved. In the association of ReNu with Fusarium, it turned out that the preservative contained in the solution lost efficacy with certain types of contact lens materials, leading to increased risk for Fusarium. And that highlighted the fact that contact lens solutions should be tested with various different materials instead of just one before they get approved. The same could apply to the association between the Complete Moisture Plus solution and Acanthamoeba. Contamination may happen, but it is rare, and most cases are associations due to various circumstances and interactions that often involve patients’ behaviors,” Mah said.
Incorrect behaviors
“The keys to decreasing the risk of infection are, No. 1, decrease the risk of your epithelium being unhealthy, and No. 2, decrease the risk of coming in contact with microbes. And if you’re in contact with them, avoid wearing contact lenses because they prolong that contact,” Galor said.
Using expired drops and not following storage recommendations are mistakes that people make quite frequently.
“It is probably not the best idea to take an eye drop from 2 years ago that’s been opened and stored outside in the sun and put it in the eye. Or, with preservative-free drops, open the small single-use vial, use half of the content, and then use the other half 1 week later,” she said.
Most bacteria cannot penetrate into the eye and start an infection if the epithelium is intact, but even a small breach in the barrier may allow them to invade, with sometimes devastating consequences.
Wearing contact lenses (CLs) is one of biggest risk factors for microbial keratitis, responsible for about 30% of all infections, according to Jennifer Craig, OD, professor and head of the Ocular Surface Laboratory at the University of Auckland, New Zealand.
“Obviously, something in such close contact with the eye increases the risk of damage on the ocular surface, presenting an opportunity for infection to take hold. And by not looking after our contact lenses as well as we should, we increase the risk even further,” she said.
Poor contact lens disinfection, not using proper contact lens solutions, poor hand hygiene, sleeping in contact lenses, not replacing contact lenses appropriately, swimming while wearing contact lenses and exposing contact lenses to tap water are among the most common risk factors.
“I am not sure people know they should never use tap water with CLs and shower while wearing them. Even more scary than just general tap water is the hot water of spa pools. Tap water contains Acanthamoeba, and if there’s any breach in the epithelium, the Acanthamoeba is allowed access to the eye. And, even worse than doing nothing, if you wear a CL, you are protecting the bugs, creating a closed, warm, humid environment in which they can grow well,” Craig said.
According to instructions
Most vision care specialists would nowadays recommend daily disposable contact lenses.
“They are the safest because they are worn for 1 day and then thrown out. All the potentially hazardous steps of cleaning and storing are avoided. But then you get people who rewear their disposable lenses, and that’s a massive risk because they are not designed to be cleaned and reused,” Craig said.
With reusable contact lenses, the most highly recommended solutions are peroxide-based products, which are the most efficient in removing all microbes, including Acanthamoeba. However, they must be used mindfully, Galor said.
“Those products are meant to let the CL sit for at least 6 hours before you can wear it again. We love those products, but they are not meant for an hour in and then back in the eye. If not neutralized properly, they cause painful reactions,” she said.
Multipurpose solutions are more popular but need to be used according to the instructions.
“You need to rub and rinse the lens to dislodge anything that’s adhering to it and then store it. And fresh solution must be used every day. Some people have the dangerous habit of keeping the solution from the day before and just adding a little bit more. That should never be done,” Craig said.
Solutions today are more biocompatible. The toxic first-generation preservatives are no longer used and have been replaced by newer compounds that disappear when they are exposed to light.
“But they must be used according to instructions because otherwise they wouldn’t have the same anti-infective properties,” she said.
Patients should be educated to look for the expiration date and beyond-use date and to use any product and device according to instructions.
“There are drugs that are toxic beyond the expiration date, such as doxycycline, and there are products that lose sterility. A lot of the products lose efficacy. Expiration dates are there for a reason, and it is common sense to follow them,” Mah said.
The same applies to contact lenses, which, according to manufacturers’ instructions, must be disposed of after a specific number of hours or days.
“Some people will try to extend the use of their contact lenses. So, for example, instead of getting rid of them after 2 weeks or a month, they will wear them for an extra day. Since nothing bad happens, they wear them for an extra week, and then again nothing bad happens, and they wear them for an extra month. Only when their eyes start getting irritated or red, they decide it’s time to get rid of the lenses. Again, I think common sense tells us that there’s probably a reason why the eyes are getting irritated or red. There’s probably a reason why there’s a time limit as far as recommendations,” he said.
Hazards of everyday habits
People tend to be even more careless with cosmetics, which can also be a source of infection. Again, most of the time, the user is to blame rather than the product itself.
“We have bugs all around our eyes, and when we use a mascara brush over and over again, we continue to collect microbes from our eyelashes and put them back into the container, ready for tomorrow. Cosmetics should be replaced regularly, should be good quality and should have an expiry date on them,” Craig said.
Also, cosmetics should never be shared.
“Younger people often like to try everybody’s makeup out, and that’s not a good idea. Limit the bugs you are exposed to — don’t expose yourself to other people’s,” she said.
Mascara brushes, pencils and eyeliners are also potentially the cause of eye injury and should never be used in situations where the hands are not stable, such as in a moving car.
“Even a small abrasion, which is not in itself a big damage, can let bugs enter the eye and risk causing an infection,” she said.
Other daily activities such as gardening can present a risk, and Craig’s advice is to wear eye protection.
“Yucca plants, which are quite commonly found in our gardens or homes, have sharp leaves, and just a little scratch on the eye’s surface can increase the risk of infection. Fungal infections from vegetative matters are not so rare,” she said.
Pathogens involved
Infections in non-contact lens wearers, which include stye, conjunctivitis and blepharitis, are more often caused by gram-positive bacteria such as Staphylococcus aureus and Streptococcus pneumoniae.
In contact lens wearers, gram-negative bacteria often come into play.
“Pseudomonas aeruginosa is the most feared, the one that causes the most damage the most quickly, and then we have Serratia and Moraxella,” Mah said.
“Acanthamoeba is a serious cause of keratitis and is hard to treat. It is very common in domestic tap water and very diffused in open waters like in lakes and streams, but also in swimming pools,” Ashok Kumar, PhD, associate professor of ophthalmology, microbiology and immunology at Wayne State University School of Medicine in Detroit, said.
And as shown during the COVID-19 pandemic, the eyes are a gateway for respiratory infection.
“It is just my guess, not supported by data, that the people who died after the eyes got infected by the artificial tears had the pulmonary function affected by penetration of Pseudomonas through the eye. Maybe these people were immunocompromised and died because of lung complications,” Kumar said.
Staphylococcus aureus, Streptococcus pneumoniae and Klebsiella pneumoniae are all pathogens that can affect the eye and also the lungs. Acinetobacter baumannii can be the cause of severe pneumonia.
“It is also called ‘Iraqibacter’ because it came for the first time to the U.S. with soldiers fighting the Iraq war. In hospital settings, it has a history of appearing in ICUs, where patients, because of high sedation, cannot blink and have the eyes permanently open. By swabbing on the conjunctiva, we found very severe colonization of these bacteria and also found that they were highly resistant to more than 18 antibiotics. In a study, we demonstrated that intravitreal injections may carry these bacteria inside the eyes and cause endophthalmitis,” Kumar said.
First-line and adjuvant therapies
Ocular surface infections are diagnosed clinically by the presence of infiltrates and, typically, epithelial defects and stromal loss.
“At Bascom Palmer, 80% of the infections we diagnose are bacterial and 20% are fungal, and within the bacteria, about half are gram positive, most often MRSA, and half are gram negative, typically Pseudomonas. But we see a plethora of different microbes, and we also see parasites, such as Acanthamoeba. The first-line treatment is with topical medications, either antibiotics, antifungals or antiparasitic drugs, but we also have adjuvant therapies,” Galor said.
A device created by two doctors at Bascom Palmer, Guillermo Amescua, MD, and Jean-Marie Parel, IngETS-G, PhD, uses rose bengal activated by green light to release reactive oxygen species that neutralize bacteria, fungi and Acanthamoeba. In studies, clinical resolution of infectious keratitis refractory to standard medical therapy was achieved in more than 77% of patients.
“Rose bengal photodynamic antimicrobial therapy (RB-PDAT) has revolutionized my practice, and to me, it is the most exciting innovation that has happened in microbial keratitis in the last 10 years. A lot of the difficult cases that don’t respond to other therapies are doing well with it,” Galor said. “The interesting thing is that it is a broad-spectrum treatment. You don’t need to know what the underlying organism is. Also, in eyes that have undergone transplantation later on, outcomes seem better, suggesting that the treatment is not just killing organisms but may be stiffening the cornea and changing the immune response.”
Craig is involved in studies on another light-based method for treating infections, based on UV-C irradiation.
“In very low doses, UV-C doesn’t cause significant damage to corneal cells but works very well on microbes. We have tested it on fungi and bacteria, including antibiotic-resistant bacteria, and so far it has proved effective on all species tested. It messes with the DNA of infective organisms, such that they die when they undergo cell division,” she said.
Antibiotic resistance
Antibiotic resistance is on the rise and has become a concern with fluoroquinolones, the most preferred class of antibiotics to treat ocular infections.
“Since the action of fluoroquinolones and aminoglycosides is concentration dependent, in eye care with topical administration, we can overcome resistance to a certain degree with frequent dosing. This still helps us addressing ocular surface infections to a degree broadening the efficacy, but toxicity and compliance may be issues of failed topical administration and limit how much can be used when intravitreal or systemic administration is required,” Mah said.
“In New Zealand, our judicious use of antibiotics means there is less antibiotic resistance. The benefit of this is that second-generation fluoroquinolones are still effective. Ciprofloxacin is still our go-to antibiotic as a first-line drug for microbial keratitis,” Craig said.
Among the many strategies under investigation to address the problem of antibiotic resistance, drug repurposing looks promising and more approachable because it involves pharmacotherapies that have already been approved.
“Basically, it involves the investigation of existing drugs for new indications. In a study, we used the Connectivity Map (CMap) database, which comprises more than 7,000 genomic profiles corresponding to 1,309 small bioactive molecules and FDA-approved drugs to rapidly identify molecules able to reverse genes/pathways dysregulated during bacterial endophthalmitis. The same process could potentially be applied to other infectious diseases,” Kumar said.
In addition, science is making progress toward new and more precise diagnostic methods.
“We are really poor in terms of diagnosing infections. We identify organisms by taking swabs and culturing them, but this is a slow process with a high percentage of false negatives,” Kumar said.
Metabolomics methods are a promising approach.
“When organisms infect the eye, they release certain metabolites, sort of signature molecules, that change the metabolism of the host,” Kumar said. “By detecting these signatures, we can see, as a first step, if there is an infection and, as a second step, if the infection is bacterial or fungal, and address it with the appropriate therapy.”
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- For more information:
- Jennifer Craig, OD, of the University of Auckland, can be reached at jp.craig@auckland.ac.nz.
- Anat Galor, MD, of Bascom Palmer Eye Institute, can be reached at agalor@med.miami.edu.
- Ashok Kumar, PhD, of Wayne State University, can be reached at akuma@med.wayne.edu.
- Francis S. Mah, MD, of Scripps Clinic Torrey Pines, can be reached at mah.francis@scrippshealth.org.
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