An Overview of Infectious Keratitis
Author: James Lai, BS, MS2 | University of Miami Miller School of Medicine
Global Burden
The fifth leading cause of blindness and the most common cause of non-trachomatous corneal opacification is a microbial infection of the cornea, known as infectious keratitis. Caused by bacteria, fungi, parasites, or herpes viruses, infectious keratitis disproportionately affects poor, rural, and agricultural populations. The incidence of microbial keratitis varies worldwide, with higher rates in developing countries in Asia. Specifically, studies have shown that there may be nearly 1 million cases of microbial keratitis in India alone each year, almost 10 times that of the US.[1] Although the incidence of infectious keratitis in the US is between 11.0-27.6 per 100,000 person-years, it still leads to a significant number of visits to health professionals and emergency departments, costing the healthcare system over 150 million dollars in healthcare expenditure annually. [2] That said, the true global burden of the disease is challenging to determine, but it disproportionately affects poor rural and agricultural populations. [3] Effective treatments for infectious keratitis are limited by diagnostic accuracy, access to antimicrobial drops, and the most severe cases often require surgical intervention by replacing damaged corneal tissue via a therapeutic penetrating keratoplasty. Here, we examine where we are and where we should be headed with respect to some of the most serious infections of the eye.
Bacterial Keratitis
The most common cause of infectious keratitis in the United States are bacterial in origin, by which the standard of care is addressed by topical antibiotics after proper culture and staining is performed as per AAO’s preferred practice guidelines.[4] When choosing an antibiotic regimen, clinicians consider factors such as broad-spectrum coverage, toxicity, availability, cost, and regional epidemiology of pathogens and resistance patterns. A Cochrane review of clinical trials on the management of bacterial keratitis found no significant difference in treatment success or time to cure when comparing different topical antibiotics. Minor adverse events were more common with aminoglycoside-cephalosporin, but serious complications were similar across antibiotics. Unfortunately, antibiotic overuse has contributed to a rise of antibiotic-resistant strains, such as methicillin-resistant Staphylococcus aureus (MRSA). As a result, corneal culture and sensitivity testing is recommended for all corneal ulcers to guide treatment and practice antibiotic stewardship. That said, it is equally important to monitor and mitigate the inflammatory response to infection present in bacterial keratitis as it can lead to corneal melting and permanent scarring. [5]
Fungal and Acanthamoeba Keratitis
Unlike bacterial keratitis which is currently well managed, fungal and acanthamoeba keratitis continues to pose a daunting question to both researchers and clinicians with poorer outcomes and limited solutions. While it represents a smaller proportion of cases in temperate climates, these infections can account for up to 50% of infectious ulcers in tropical regions. For fungal keratitis, there have been no new FDA-approved treatments since the introduction of topical natamycin in the 1960s. The effectiveness of topical natamycin is hindered by its limited penetration into the corneal stroma. An alternative option is topical amphotericin B, but its use is restricted due to the need for compounding pharmacies and concerns about toxicity. Voriconazole, a newer generation triazole, has gained popularity for its excellent ability to penetrate the eye and its susceptibility against commonly implicated fungal isolates in keratitis. However, in the first Mycotic Ulcer Treatment Trial (MUTT 1), where topical natamycin was compared against topical voriconazole, the trial had to be stopped due to a statistically significant increase in the rate of corneal perforation and therapeutic penetrating keratoplasty in those receiving topical voriconazole. [6-8] In acanthamoeba keratitis, infection typically predominates with cysts and trophozoites both within the corneal stroma. [9] Cultivating cysts typically takes one week to grow in culture but requires monitoring for 13 days. [10] In this form of keratitis, cationic antiseptics and diamidines are the standard of care – but their efficacy against the cystic form of acanthamoeba is questionable. As a result, it is common to see acanthamoeba and fungal forms of keratitis become refractory to first-line medical treatment and progress to rapid vision loss. [11] Interestingly, acanthamoeba keratitis is commonly misdiagnosed as HSV (herpes simplex virus) keratitis given identical clinical presentations of dendritic ulcers but coinfection is extremely rare. More commonly, acanthamoeba may present secondary or opportunistic to HSV infections. [12, 13] However, in HSV keratitis, confirmatory testing with multiplex PCR can determine infection within 4-8 hours instead of the much longer culture period required to detect acanthamoeba. [4] Additionally, standard of care is oral or topical administration of acyclovir, valacyclovir or famciclovir for 10-14 days. [14]
New Directions
Promisingly, an adjunctive therapy known as photodynamic antimicrobial therapy is coming to the fore. Specifically known as rose bengal photodynamic antimicrobial (RB-PDAT) therapy, this process involves the application of a topically safe dye, a photosensitive chemical called rose bengal – to the ulcer. Subsequently, exposure of the chemical to green light generates free radicals in the form of reactive singlet oxygen species which then produces its antimicrobial effect. [15] Although not FDA approved, one pilot clinical study by Amescua et al. in 2019 demonstrated that in the setting of progressively infectious keratitis, 13 of 17 patients that initially failed first line medical treatment responded to RB-PDAT. [16] Of the refractory cases, it was shown that almost uniformly, the deepest penetrating infections were resistant to both topical treatment as well as RB-PDAT. This suggests that penetration depth is the next largest obstacle that needs to be tackled in the development of this new therapy.
Another avenue that is yet to be explored from a therapeutic standpoint is the ocular surface microbiome. Over the past few decades, exploration of dysbiosis in the human gut microbiome has been shown to be associated with a plethora of systemic diseases and the ocular microbiome is only now starting to receive the same attention. While the eye itself is considered to be immune privileged, ocular surface microbiome analysis has recently revealed interesting patterns relating to dysbiosis and the development of keratitis. One study by Prashanthi et al. in 2019 revealed 11 distinct genera present in greater abundance in the microbiomes of those who developed fungal keratitis and this finding is backed by myriad of studies performing ocular surface analysis. [17-19] Unfortunately, there is yet to be concordance among studies or therapeutic avenues proposed with the given investigations, but continued research in these domains show promise for more effective treatments over time.
References
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