Specialists address challenges of microbial keratitis management

Microbial keratitis is a diverse and changing landscape.

The type and prevalence of pathogens vary according to location and climate, while human mobility and global warming, with their multiple implications, are bringing unforeseen changes and new phenomena. Antimicrobial resistance, with the rise of aggressive organisms that do not respond to conventional treatment, is a global threat that challenges the established methods of managing infections.

However, the community of cornea specialists is moving fast and proactively. Numerous study groups and research partnerships across continents are working together to gain a deeper understanding of the complex geography and evolution of corneal infections and to develop new diagnostic tools and more powerful, targeted treatments.

“I see a future wherein technology is going to make our approach to corneal infections easier and more effective,” N. Venkatesh Prajna, DO, DNB, consultant at Aravind Eye Hospital, Madurai, India, said.

Rapid and simple point-of-care diagnostics with lateral flow devices, deep learning algorithms, selective immunomodulators and the use of light as an alternative or adjunct to medications will soon become the new gold standard.

“I would make a very strong statement that the world will laugh at the simplistic, almost barbaric way we are treating an infection today,” he said.

Diverse geography of corneal infections

The environment has a huge impact on the presentation of corneal infections, and their distribution and determinants differ significantly according to location and climate.

“In the Western world, approximately 95% of infections are caused by bacteria and 5% by fungi. In the past, we used to treat infections according to the epidemiology of the Western world, but over the past 20 years, we have developed our own very strong microbiology surveillance, and we showed that in India, the proportion of fungi and bacteria is 50-50,” Prajna said.

In the U.S., the humid subtropical climate of Florida favors the proliferation of fungal species that are not seen so frequently in the rest of the country.

“In Miami, about 80% of our infections are bacterial, but 20% are fungal, while in the Northeast, in Cleveland, in Wisconsin, fungal infections are much less common,” Anat Galor, MD, MSPH, professor at Bascom Palmer Eye Institute, University of Miami, said.

Australia has a wide variety of climates with significant microbial diversity.

“In East Australia, the most common cause of keratitis is gram-positive organisms, particularly coagulase-negative staphylococci, while in Western Australia, Pseudomonas, a gram-negative organism, has been found to be the most common,” Stephanie Watson, OAM Bsc(Med), MBBS, PhD, FRANZCO, professor at the University of Sydney, said.

Changes in the world

Human mobility and climate change are favoring the spread of infectious diseases and will inevitably have an impact on the disease patterns and microbial profile of keratitis. Flooding, often occurring because of heavier rainfall in many regions of the world, has shown to be connected with the outbreak of uncommon infections, according to Watson.

“There have been reports in a number of countries of less common organisms after flooding, such as microsporidia,” she said.

In addition, patients who experience extreme weather events often have delayed presentation and therefore more severe disease due to the disruption of health care services and transportation.

“Pollution is also thought to make the surface of the eye more vulnerable to infection, and extreme UV can cause inflammations on the surface of the eye,” she said.

An emerging presentation has been reported in association with the widespread adoption of endothelial keratoplasty.

“There is this new entity, called Candida-associated keratitis, where you get spots of Candida in the interface between the endothelial graft and the host. We rarely saw Candida infection when we were doing penetrating keratoplasty. With the increasing adoption of endothelial keratoplasty, this new entity is on the rise, and we are trying to figure out how to best prevent it from occurring and managing it when it does,” Galor said.

Antimicrobial resistance

Between 2022 and 2023, a rare, virulent strain of drug-resistant Pseudomonas aeruginosa was transferred from India through contaminated over-the-counter eye drops that caused permanent vision loss and even death in some cases.

“We had a severe outbreak here in Florida and were among the first to alert the CDC. We took care of many of those patients, and it was terrible, but the source was found, and the spread of infection was eventually controlled,” Guillermo Amescua, MD, professor at Bascom Palmer Eye Institute, said.

He reported seeing an increasing number of keratitis cases, more fungal infections and more aggressive organisms in recent years.

“We see about 1,000 corneal ulcers every year. Of those, about 30% are gram-negative bacteria, and 20% are gram-positive. About 20% are fungal, and the rest are atypical organisms such as Acanthamoeba and mycobacteria. Of our gram-positive isolates, 33% are resistant to the fourth-generation fluoroquinolone antibiotics, and we have started to see a low-grade resistance of some of the gram-negatives too,” he said.

A systematic review of antibiotic resistance data from U.S.-based studies, published by Bispo and colleagues, found compelling evidence of high in vitro resistance among Staphylococcus aureus and coagulase-negative staphylococci to fluoroquinolones, macrolides and methicillin/oxacillin.

Another review of international studies by Watson’s group found that resistance to fluoroquinolones has increased particularly in Asia and North America, while methicillin-resistance and multidrug resistance are emerging.

“In Australia, resistance to fluoroquinolones is lower compared to North America, but over time, we’ve seen some increases in resistance, particularly of methicillin-resistant Staphylococcus aureus to gentamicin and cephalothin and of coagulase-negative staphylococci to cephalothin,” Watson said.

Prajna was one of the principal investigators in the Asia Cornea Society Infectious Keratitis Study (ACSIKS), which involved centers in India, Hong Kong, Singapore and Thailand. The highest rate of resistance to antibiotics, up to 47.5% for moxifloxacin and 39.8% for ciprofloxacin, was found in isolates from India, whereas the other centers involved had a rate of less than 10%.

“In India and Hong Kong, there were a lot more fungi as compared to Singapore or Taiwan, so there is a country-wise difference in that factor. Surprisingly, we found a lot more resistance in Indian bugs, especially with Pseudomonas. We have multidrug-resistant Indian bugs to an extent that is almost scary,” Prajna said.

How organisms become resistant

There are several mechanisms by which organisms become resistant. Widespread systemic use of antibiotics, antibiotic overuse in food-producing animals, and contamination of soil and water are some of the most common causes. In order to survive, microbes modify their genes and pass on the drug-resistant genes to one another within a localized area.

“This explains why there are local patterns in resistance,” Watson said.

In India, the Aravind Eye Hospital in Madurai and the LV Prasad Eye Institute in Hyderabad are located more than 600 miles apart. What do they have in common to justify such a similar high resistance to the same antibiotics?

“In India, you are not required to have a doctor’s prescription to buy any drugs, even antibiotics, and that is causing an increased resistance systemically,” Prajna said.

Although this is a matter of concern, he said that the topical administration of antibiotics still holds advantages because the eye is flooded with the drug and rarely does not respond to the therapy. As a matter of fact, a specific method for assessing resistance in ophthalmology has not yet been found.

In her study, Watson explained that the assessment of microbial resistance is based on minimum inhibitory concentrations (MICs), “that is, the lowest concentration of an antimicrobial that will inhibit growth of a given organism within strictly controlled conditions of incubation time and temperature.” MICs calculation is based on serum concentration and does not truly represent drug resistance at the ocular level.

“In the ACSIKS study, we demonstrated very high resistance for moxifloxacin in India, but even today, if you put moxifloxacin eye drops, the ulcer will heal. It does not translate exactly like a systemic disease,” Prajna said.

However, ophthalmologists have been cautioned against overuse of antibiotics in some cases of conjunctivitis and keratitis, as well as procedures such as intravitreal injections and cataract surgery.

“For many years, patients getting intravitreal injections were placed on topical fluoroquinolones with a high frequency, even monthly, and for extremely long periods of time. Nowadays, this is no longer a common practice, but that might have contributed to resistance. The role of antibiotics before cataract surgery is another topic of discussion,” Amescua said.

Watson emphasized the need for more collaborative antimicrobial stewardship programs in ophthalmology as a first-line defense strategy to curb the phenomenon of antibiotic resistance.

“We need to find out what current antibiotics are in use in what locations. We need to collaborate with microbiologists to figure out what are the most common bugs causing keratitis and what is their resistance patterns. With this information, we need to create guidelines for clinicians to make sure the antibiotics are used appropriately and then keep monitoring and evaluating what’s happening in the clinics, what is being prescribed and what’s emerging in terms of different patterns of infection and resistance,” she said.

Basis of good diagnostics

Improving diagnosis and looking into new treatment pathways are key to the future management of corneal infections.

“My first recommendation is to know the landscape where you’re working because the types of infections you see in Chicago are going to be different from the ones you see in San Francisco or Miami. Also, infections in a farming community will be different than in a city,” Galor said.

A study by the Corneal Ulcer Image Interpretation Study Group showed that locality was the strongest predictor of correct interpretation of corneal photography in differentiating bacterial from fungal keratitis. Indian experts largely outperformed international experts because they were more familiar with the presentation of fungal infections.

“The fundamental thing, before you treat any infectious keratitis in your region, is that you should know your local epidemiology,” Prajna said.

He also emphasized that differentiating between fungi and bacteria is paramount, and an efficient microbiological surveillance system is needed particularly in developing countries.

“In many institutions there is no access to good microbiology facilities, and so you tend to toss the coin using clinical features to differentiate whether the infection is caused by bacteria or fungi. Here, you have a 50% chance of getting it right because the ratio is 50-50. But the more experienced you are, the more doubtful you become because you see multiple variations of the same clinical presentation, and you become more aware of how you must rely on microbiology,” he said.

Future developments in the pipeline

Prajna believes that technological advancements will make microbiology simpler in the near future. Lateral flow immunoassay will take testing out of the laboratory and provide simple point-of-care diagnostics. A study that his group conducted at Aravind showed high diagnostic accuracy in identifying microbial keratitis caused by Aspergillus species.

Other newer methods include confocal microscopy, which generally works best for Acanthamoeba, and molecular diagnostics for fungi, Watson said.

“PCR is an effective and rapid method for diagnosing fungal keratitis but is not universally available. The biggest burden of microbial keratitis is often in low-resource settings or developing countries where a simple trauma leads to infection due to delays or inappropriate management, and in these settings, there’s no PCR,” she said.

However, molecular diagnostics continue to improve, with probes able to identify multiple molecular targets, Amescua said.

“We are starting a study here where we have a probe that targets 18 of the most common organisms. We take a sample of either corneal tissue or tears, and then we run it, and within hours we have a potential diagnosis. I think that the future is in the use of molecular diagnosis for infectious keratitis,” he said.

AI applied to corneal imaging will also help make rapid and possibly more accurate diagnoses of corneal infections in the future.

A study conducted by Prajna’s group showed that image interpretation without microbiological support — the real-world situation in many hospitals — is correct 35% to 50% of the time in differentiating infections caused by bacteria or fungi.

“AI technology is able to come up with the right answer 78% of the time. The devices are still learning, but it’s just a matter of time. The whole area of diagnosis is going to go outside the hands of the doctors,” Prajna said.

Phototherapy strategies for treatment

A recent WHO report on the state of development of antibacterials underlined the “pressing need for new, innovative agents for serious infections” but pointed out that “not only are there too few antibacterials in the pipeline, given how long is needed for R&D and the likelihood of failure, there is also not enough innovation.”

However, alternative ways of fighting corneal infections are showing promise. One method, developed at Bascom Palmer Eye Institute through the joint efforts of Amescua and Jean-Marie Parel, is the use of rose bengal photodynamic antimicrobial therapy (RB-PDAT).

“We have done a lot of in vitro studies by killing samples that we get from our patients. We grow them in the media, and then we shine green fluorescent light after adding rose bengal as a photosensitizer. We have shown in multiple laboratory studies that we can successfully kill many of the bacteria and fungi,” Amescua said.

A clinical trial is currently ongoing in collaboration with Aravind Eye Hospital and the Proctor Foundation in San Francisco. It is a NIH-sponsored prospective randomized clinical trial in which one group is treated by the standard of care for fungal keratitis and Acanthamoeba and the other group by standard of care plus RB-PDAT. The results may be presented at the World Cornea Congress in March.

“The study has been completed, and we are currently just waiting for the follow-up of the last group of patients that were enrolled, so we can have at least 6 months of follow-up in 300 patients,” Amescua said.

A similar concept, initially developed by the group of Theo Seiler, MD, PhD, is corneal cross-linking using yellow UV light and riboflavin.

“We haven’t been very successful treating that way, and that’s why we migrated toward the use of rose bengal, but there are other groups in the world, like the group of Farhad Hafezi in Switzerland, doing very good research on using higher energy levels to kill the organisms,” Amescua said.

Galor has been using RB-PDAT in the clinic with excellent outcomes.

“I have saved eyeballs and vision because of it,” she said.

The advantage of the use of light as an alternative nonmedical therapy is that no resistance is developed, and there is a lot of interest in that sphere, according to Prajna.

“I believe that light is going to be the future. In the retina, we have gone from light to drugs as the primary treatment. For infectious keratitis, it’s going to be the reverse, from drugs to light,” he said.

Addressing host-pathogen interactions

One of the new frontiers in corneal infection management is to gain a deeper understanding of how the pathogens interact with the host. Galor is part of a team that is working on defining the ocular surface microbiome in healthy eyes and examining how the microbiome varies with different environments and exposures.

“Our hypothesis is that it’s not just the presence of pathological organisms but also the host ocular surface microbiome that may predispose some individuals to infection. Commensals interact with harmful pathogens, and some commensals likely inhibit pathogenic organisms and prevent infection. We are interested in understanding the mechanisms through which the microbiome helps prevent infection and whether the microbiome can be manipulated and optimized to make the eye more infection resistant,” she said.

Other lines of research aim at learning how to treat the host response, which often goes overboard, causing damage.

“When you get an infection, the body sends the immune cells to the site, but these cells can also be destructive and start damaging the tissue. So, we need to also learn how to modulate the host response. Generally, we do that with topical steroids, but they can also have a downside if you have a fungal infection. So, we need more specific ways to modulate the immune response to infection,” Watson said.

Infections often result in corneal scars, which can lead to permanent vision loss. New treatments are also needed to deal with the scars.

“We are looking toward mesenchymal stem cell therapies and stem cell-based factors to try to modulate or treat the scar,” Watson said.

The current ways of treating infections are aimed only at killing the organism, but a more comprehensive approach is needed to kill the organism and also keep the host immune system in check, Prajna said.

“Selective immunosuppression, which is now being used in cancer and in many systemic autoimmune diseases, will definitely come into the picture in ophthalmology in the years to come,” he said.

He believes that the future treatment algorithm for infectious keratitis is going to include light, topical treatment and selective immunosuppression.

“It will be light of different intensities for superficial infections and light plus topical medication and selective immunosuppression for deeper infections,” Prajna said.

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• For more information:
• Guillermo Amescua, MD, of Bascom Palmer Eye Institute in Miami can be reached at gamescua@med.miami.edu.
• Anat Galor, MD, MSPH, of Bascom Palmer Eye Institute in Miami, can be reached at agalor@med.miami.edu.
• N. Venkatesh Prajna, DO, DNB, of Aravind Eye Hospital in Tamil Nadu, India, can be reached at prajna@aravind.org.
• Stephanie Watson, OAM Bsc(Med), MBBS, PhD, FRANZCO, of the Save Sight Institute at the University of Sydney, Australia, can be reached at stephanie.watson@sydney.edu.au.

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