What We Can Do in Infectious Keratitis, Except for Conventional Antimicrobial‐Based Therapies: Major Narrative Review

ABSTRACT

Background and Aims

Infectious keratitis (IK) is classified as a critical ophthalmic emergency, with the potential to result in vision‐impairing complications. The treatment approach involves the use of pharmacological antimicrobial agents in combination with surgical interventions. Traditionally, the management of IK has relied on conventional antimicrobial agents, although the specific treatment regimen may vary based on the underlying causative agent. The growing antimicrobial resistance, along with the less favorable outcomes in most cases, emphasizes the urgent need for adjunctive or novel therapies. This report aims to provide a thorough overview of the current clinical and experimental non‐antimicrobial therapies, encompassing both medical and surgical options, whether they serve as adjuncts to antimicrobial treatments or function as independent therapies for IK.

Methods

A comprehensive search on PubMed was undertaken to identify relevant articles. Articles that described conventional antimicrobial‐based treatments were excluded from the review. Additionally, case reports and non‐English publications were not considered.

Results

Various therapeutic options, including medical‐based therapies (povidone‐iodine, matrix metalloproteinases inhibitors, corticosteroids, host defense peptides, novel small molecules, formaldehyde releasers, synthetic polymers, antioxidants, and bacteriophages), laser/light‐based therapies (photodynamic therapy, ultraviolet C light, thermal lasers, photothermal therapy, phototherapeutic keratectomy, and blue light), surgical‐based therapies (conjunctival flap and Tenon graft, corneal gluing, amniotic membrane transplantation, and keratoplasty), and miscellaneous therapies (nanomedicine and contact lens, plasma ablation, debridement, and cryotherapy) were included and discussed.

Conclusion

The conventional approach to managing IK involves the use of topical antimicrobial agents. Most instances can be effectively addressed with empirical treatment using antimicrobial eye drops, yielding satisfactory results. However, it seems the rise in antimicrobial resistance and insufficient response in some cases, especially fungal keratitis, necessitates ophthalmologists to utilize all currently available options in their toolbox more efficiently and intensify research efforts aimed at developing alternative therapeutic strategies.

1. Introduction

Infectious keratitis (IK), also known as infectious corneal ulcer, is classified as a major ophthalmic emergency, posing the potential for vision‐impairing complications, even blindness [1, 2, 3, 4, 5]. IK ranks as the fifth primary cause of blindness, accounting for 3.5% (36 million) of the blindness cases by 2015 [6, 7]. The incidence of IK has been estimated to range from 2.5 to 799 cases per 100,000 population per year [8], with a notably higher prevalence in low‐income nations. Prior studies on IK in the United States indicated an estimated incidence of 2.5–27.6 per 100,000 population‐year [9], while in the United Kingdom, the incidence ranged from 2.6 to 40.3 per 100,000 population‐year [10]. Conversely, a significantly elevated incidence of IK has been documented in resource‐limited countries, such as South India, where it stands at 113 per 100,000 population‐year [11]. In the United States, IK accounts for approximately 1 million consultations with healthcare providers and 58,000 visits to emergency rooms each year, costing the healthcare system 175 million dollars in direct medical expenses [12].

Based on etiology, IK can be classified as bacterial, viral, fungal, and protozoal. For the diagnosis, the standard initial test involves culturing corneal scrapings [3]. Other diagnostic techniques include polymerase chain reaction and in vivo confocal microscopy [6]. The therapeutic approach typically involves the utilization of pharmacological antimicrobial agents in conjunction with surgical intervention. The primary objective for most clinicians is to provide a cure through medical treatment. Traditionally, the medical management of corneal ulcers has involved the use of conventional antimicrobial agents (e.g., antibacterial, antifungal, antiparasitic, and antiviral drugs). However, the specific regimen may differ based on the underlying causative agent [6]. The increasing resistance to antimicrobial agents, coupled with the poor outcomes in most cases, highlights the urgent necessity for adjunctive or novel therapies.

In addition to conventional antimicrobials, several pharmacological agents can be added to the treatment regimen to control inflammation. Moreover, surgical approaches are necessary for severe cases that show progressive stromal thinning, descemetocele development, and localized perforation [13, 14, 15]. In recent years, considerable efforts have been directed toward the development of novel therapeutic modalities and alternatives. Novel small molecules, laser/light‐, contact lens‐, and nanotechnology‐based innovations are among the latest progress in the field (Figure 1). The goal of this report is to provide a comprehensive overview on the current clinical and experimental nonantimicrobial‐based therapies, including both medical and surgical options, whether they act as adjuncts to conventional antimicrobials or as standalone options for IK. This report is designed to serve as a benchmark for clinicians and researchers.

Figure 1.

Therapeutic options in infectious keratitis.

2. Methodology of Search

A comprehensive search on PubMed was undertaken to identify relevant articles using the search terms: “keratitis” or “corneal ulcer” combined with “treatment,” “therapy,” “therapeutic,” or “management.” Articles that described conventional antimicrobial‐based treatments were excluded from the review. Additionally, case reports and non‐English publications were not considered. This search was conducted on November 1, 2024, and was restricted to literature published after January 1, 2000.

3. Medical‐Based Therapies

3.1. Povidone‐Iodine

The compound known as polyvinyl pyrrolidone‐iodine (PVP‐I) exerts bactericidal, fungicidal, and virucidal effects by releasing free iodine gradually at the site of application. The free iodine quickly infiltrates microbial cell membranes and interacts with various cellular components, leading to rapid cell death [16].

In a randomized clinical trial (RCT), Isenberg and colleagues compared the efficacy of a 1.25% PVP‐I ophthalmic solution against topical antibiotics in bacterial keratitis (BK). The results revealed no significant differences in treatment outcomes between the 1.25% PVP‐I and common topical antibiotics [17]. As a result, the 1.25% PVP‐I solution is considered a practical treatment option for BK when the use of antibiotics is not possible [15]. This result was also achieved in animal studies [18, 19]. Furthermore, a prospective study was conducted to assess the safety and efficacy of applying topical PVP‐I during the interval required for pathogen identification and susceptibility testing. The findings suggested that the use of 0.66% PVP‐I during this timeframe is a safe approach and can frequently eliminate the necessity for broad‐spectrum antimicrobials [20]. An in vitro study evaluated the cytotoxic activity of three common antimicrobials against Acanthamoeba keratitis (AK): 1% PVP‐I, 0.04% chlorhexidine, and 5% natamycin. The findings revealed that 1% PVP‐I has a significantly superior potency relative to both 0.04% chlorhexidine and 5% natamycin [21].

3.2. Matrix Metalloproteinases (MMPs) Inhibitors

The primary feature of ulceration is the destruction of the stromal tissue. The corneal stroma represents over 90% of the corneal thickness. Its architecture is predominantly formed by the extracellular matrix (ECM), which is primarily comprised of collagen and proteoglycans [22].

MMPs play an essential role in the degradation of ECM and are associated with various diseases and inflammatory processes, notably IK [23]. The corneas of patients afflicted with keratitis exhibit significantly elevated concentrations of proinflammatory cytokines, cell adhesion molecules, and MMPs compared to healthy corneas [24]. It has been proposed that the inhibition of MMPs could play a significant role in the healing of corneal ulcers. Within the MMP family, MMP‐2 (gelatinase A) and MMP‐9 (gelatinase B) are secreted by numerous cell types. It is important to note that MMP‐9 expression markedly rises in the context of keratitis, while MMP‐2 levels remain low after injury or infection [25]. The activity of MMP‐9 is regulated by mechanisms that facilitate the conversion of pro‐MMP‐9 into its active form, MMP‐9. This process is modulated by tissue inhibitor of metalloproteinase 1 (TIMP‐1), which acts as an inhibitor by binding to pro‐MMP‐9 and obstructing its interaction with the converting enzyme [26]. The investigation by Neidhart et al. [27] focused on the application of a cyclic TIMP peptidomimetic to inhibit MMP‐9 activity in IK models. The results demonstrated that the treatment significantly decreased the levels of MMP‐9 and proinflammatory markers. Furthermore, in vitro assessments indicated the potential of this compound to alleviate scar formation. The findings collectively indicate that the TIMP peptidomimetic holds significant promise as a new adjunctive treatment for IK [27]. Clinically, the most well‐known and used MMP inhibitors are tetracyclines, which show properties independent of their antimicrobial potency [28].

3.3. Corticosteroids

The application of adjuvant corticosteroids in the management of BK has been a subject of considerable debate. Some experts state that these agents mitigate inflammation and minimize complications such as scarring, neovascularization, and stromal melting [29]. Conversely, critics believe that corticosteroids may delay epithelial repair and extend the duration of infection [30]. The Steroids for Corneal Ulcers Trial (SCUT) stands out as the largest RCT investigating the use of adjunctive steroids for BK, enrolling 500 participants with culture‐confirmed ulcers. After adjusting for baseline best‐corrected visual acuity (BCVA), a multiple linear regression analysis indicated that corticosteroids did not yield a significant enhancement in 3‐month BCVA. Furthermore, no differences were observed in the rates of re‐epithelialization, infiltrate or scar size, or the incidence of perforations. Notably, the use of corticosteroids did not correlate with an increase in adverse events [31]. Post hoc subgroup analysis has indicated that the early intervention for large, central, non‐Nocardia ulcers is associated with superior visual acuity (VA) outcome compared to treatment with antibiotics alone [32]. A 12‐month analysis from the SCUT trial, which excluded Nocardia ulcers, found that participants who received topical steroids experienced a one‐line improvement in VA [33]. Moreover, it was determined that those who were treated with steroids within 2–3 days of antibiotic therapy had a one‐line enhancement in VA at the 3‐month follow‐up [32, 34]. SCUT II study can robust the literature in this regard [30].

3.4. Host Defense Peptides (HDPs)

HDPs, previously known as antimicrobial peptides, are short chains of amino acids, typically consisting of 12–50 residues. These peptides exhibit a wide range of antimicrobial properties primarily due to the presence of cationic amino acids such as arginine and lysine [35, 36, 37, 38, 39]. Peptides are generally divided into two categories: natural peptides and synthetic peptides. Synthetic/semi‐synthetic peptides are often developed to mitigate the drawbacks of naturally sourced HDPs, which include host toxicity, degradation by proteases, and a reduction in antimicrobial activity when exposed to physiological salt levels [40]. The advantages of short synthetic peptides include their high selectivity and cost‐effectiveness in production [41].

Various HDPs are expressed by the cornea and other components of the ocular surface. Defensins, liver‐expressed antimicrobial peptide, LL‐37/cathelicidin, the S‐100 protein family or calgranulins, human neutrophil peptides, RNAse, lactoferrin, lysozyme, transferrin, calprotectin, and lipocalin are among these HDPs, which collectively play a crucial role in preventing infections [41, 42, 43, 44, 45, 46].

Several investigations have revealed that the application of HDPs can exert immunomodulatory effects and provide protection against IK [47, 48, 49]. For example, Brilcidin (PMX30063), a defensin mimetic, has shown in vitro effectiveness against Gram‐positive bacteria isolated from ocular samples of patients suffering from keratitis. In vivo studies revealed that a 0.5% concentration of Brilcidin was as effective as vancomycin in diminishing methicillin‐resistant Staphylococcus aureus (MRSA) in the eyes of rabbits [50]. HDPs can be delivered using contact lenses (CLs), nanoparticles (NPs), hydrogels, and liposomes to combat the instability of these agents in physiological environments [51, 52]. In an in vivo rabbit model, melimine‐coated CLs were found to significantly mitigate IK caused by Pseudomonas aeruginosa [53]. However, the presence of corneal staining associated with the melimine‐coated lenses led researchers to formulate Mel4, a shorter variant of the melimine peptide [54].

The application of exogenous HDPs along with the enhancement of endogenous HDP production may represent a significant therapeutic strategy against multidrug resistance. HDPs offer numerous advantages as an alternative treatment, including broad‐spectrum antimicrobial activity, rapid killing capabilities, effectiveness against biofilms, lower risk of developing resistance, and reduced cytotoxicity to the host [55]. However, additional studies are essential to determine their therapeutic efficacy.

3.5. Novel Small Molecules

The other subject of interest in advancing the field is novel small molecules. The research conducted by Dajcs et al. [56] highlights the effectiveness of lysostaphin in combating Staphylococcus aureus‐induced keratitis. In vivo studies utilizing rabbit models demonstrated that lysostaphin treatment resulted in a significantly higher reduction of both methicillin‐resistant and methicillin‐sensitive S. aureus (MRSA and MSSA) compared to vancomycin treatment or no treatment groups [56]. Sharma et al. [42] further demonstrated that INP0341 effectively mitigated Pseudomonas infections in a murine keratitis model. This class of compounds has shown broad‐spectrum activity against several pathogens, including Yersinia pseudotuberculosis and Chlamydia trachomatis [57, 58]. Pseudolipasin A, which inhibits ExoU of Pseudomonas aeruginosa, was found to promote healing and reduce cell death in corneal epithelial cells during infection [59]. Furthermore, glycyrrhizin significantly diminished the adherence of Pseudomonas aeruginosa to corneal epithelial cells and inhibited bacterial growth in a mouse model, both alone and in combination with antibiotics [60]. Lastly, suberoylanilide hydroxamic acid was reported to significantly reduce inflammation and expression of pro‐inflammatory cytokines in a murine model of Fusarium solani keratitis [41].

3.6. Formaldehyde Releasers (FARs)

Compounds classified as FARs, such as sodium hydroxymethyl glycinate (SMG), are recognized for their antimicrobial properties and have demonstrated the ability to induce tissue cross‐linking effects [61]. Therapeutic tissue cross‐linking using SMG may influence infectious processes in the cornea similarly to the riboflavin photochemical cross‐linking (CXL) technique, yet it does not require de‐epithelialization, exposure to ultraviolet light, or the use of expensive UV light sources. The findings of a study by Rapuano et al. [62] revealed that the SMG solution possesses a dose‐dependent bactericidal activity against MSSA, MRSA, and Pseudomonas aeruginosa.

3.7. Synthetic Polymers

Synthetic polymers represent a novel class of antimicrobial agents characterized by their unique amphiphilic structures [63]. In contrast to the antibiotic resistance that arises from rapid genetic mutations, synthetic antimicrobial polymers are less susceptible to bacterial resistance [64]. Lignin, the most plentiful biopolymer of aromatic substances, is extracted from the cell walls of wood and herbaceous plants [65]. This compound is noted for its considerable properties, including biodegradability, antioxidant capabilities, and antimicrobial activity [66]. A study was conducted in which a series of cationic lignin‐based hyperbranched polymers were formulated and assessed for their effectiveness against keratitis caused by Pseudomonas aeruginosa in a rabbit model. The results demonstrated that the copolymers were successful in lowering bacterial counts and corneal edema, leading to the complete elimination of the bacteria [67].

3.8. Antioxidants

The production of reactive oxygen species (ROS) by corneal epithelial cells plays a crucial role in protecting the cornea against microbial infections. Nevertheless, an overproduction of ROS can lead to corneal inflammation, ultimately resulting in irreversible corneal opacification and vision impairment. Antioxidants mitigate the effects of free radicals by donating electrons, thereby reducing inflammatory damage. Numerous studies have highlighted the efficacy of antioxidants in shielding the cornea from inflammation caused by microbial agents. Various antioxidants such as resveratrol, tempol, asiatic acid, quercetin, baicalein, epigallocatechin gallate, and vincamine have been investigated in this regard. However, these investigations were experimental [41, 68, 69, 70, 71, 72, 73].

3.9. Bacteriophages

Viruses known as bacteriophages are ubiquitous in the environment and have the capacity to eliminate bacteria without harming mammalian cells. In studies involving phage therapy, the Pseudomonas phage has proven effective in treating Pseudomonas aeruginosa infections in animal models of keratitis [74]. As a result, the use of eye drops containing bacteriophages is suggested as a promising supplementary or alternative approach for managing keratitis [74].

4. Laser/Light‐Based Therapies

4.1. Photodynamic Therapy (PDT)

PDT involves the activation of a designated photosensitizer (PS) that absorbs light at a specific wavelength in the presence of oxygen in the tissue [75, 76]. Antimicrobial PDT (aPDT) has exhibited considerable efficacy in the management of drug‐resistant infectious diseases. aPDT presents numerous advantages; it functions as a localized intervention with minimal systemic adverse effects. Notably, there have been no reported cases of resistance to PDT, and it is effective against both planktonic and biofilm‐forming microorganisms. Interestingly, bacteria that survive PDT exhibit reduced resistance to antibiotics [76, 77, 78]. Up to now, various PSs have been tested to treat IK [76, 79, 80, 81, 82].

In ophthalmology, the most well‐known variant of PDT is riboflavin‐mediated CXL, which is extensively employed to enhance corneal stiffness. Since its introduction in 2003, the application of CXL has been expanded to address IK [83]. In the process of CXL, riboflavin is utilized in drop form, functioning as a chromophore that is photoactivated by UV‐A radiation at wavelengths between 365 and 370 nm. Theoretically, riboflavin's role, in conjunction with UV‐A light, extends to the inactivation of pathogens through the induction of DNA damage in both bacteria and viruses, as well as enhancing the cornea's resistance to protein‐digesting enzymes [84, 85]. Following the 2013 International Congress of Corneal Cross‐Linking held in Dublin, the treatment technique for keratoconus was termed CXL, and the technique for IK was labeled as photoactivated chromophore‐corneal cross‐linking (PACK‐CXL) [86].

PACK‐CXL is mainly applied as an adjuvant to antimicrobial therapy [87]. However, in a couple of clinical studies, it was tested as the primary therapy [88, 89, 90]. The proposed advantages of PACK‐CXL include financial savings, as well as a reduction in the frequency of follow‐up visits and hospital admissions [91, 92]. Interestingly, there is evidence suggesting that prior PACK‐CXL can exert a beneficial effect on corneal graft survival, possibly due to the regression of blood and lymphatic vessels induced by apoptosis in vascular endothelial cells [93, 94, 95]. However, this technique is not without disadvantages [96, 97, 98, 99]. It is important to highlight that fluorescein and riboflavin exhibit similar UV‐A absorbance spectra. Consequently, the presence of fluorescein diminishes the quantity of UV‐A energy that can interact with riboflavin, which in turn lessens the antimicrobial efficacy of the treatment. Therefore, if a patient has undergone fluorescein staining, it is advisable to postpone the PACK‐CXL procedure [91, 100].

The efficacy of PACK‐CXL seems to be controversial, which can be related to the difference in the inclusion criteria and heterogeneity in the studies. A study indicated that PACK‐CXL mitigated corneal melting, with effectiveness observed in the following descending order: Gram‐negative bacteria, Gram‐positive bacteria, Acanthamoeba, and fungi [97, 101, 102]. The severity of the disease appears to play a crucial role in determining clinical outcomes. One investigation indicated that patients afflicted with deep stromal fungal keratitis (FK) did not exhibit a favorable response to treatment, presumably due to inadequate penetration and intensity of UV‐A light [103]. Conversely, cases of early and superficial FK demonstrated a favorable response to PACK‐CXL [104, 105]. Evidence from different clinical trials suggests that adjuvant PACK‐CXL failed to diminish the size of corneal epithelial defects at the 1‐week assessment in cases of fungal and BK [89, 106]. Regarding the size of corneal infiltrates, trials demonstrated that adjuvant PACK‐CXL failed to decrease the size of fungal infiltrates at 1 week. However, the results for BK were less clear‐cut [89, 106, 107]. In the only trial assessing the ulcer depth, no reduction with the administration of PACK‐CXL was found [107]. Also, findings from clinical trials suggest that adjuvant PACK‐CXL does not provide any benefits in terms of VA and could possibly result in diminished VA [89, 90, 103, 107, 108, 109]. Nevertheless, Hafezi and colleagues recommended in their RCT to consider PACK‐CXL as an alternative to antimicrobial drugs for first‐line and standalone treatment of early to moderate IK of bacterial or fungal origin [91].

Meta‐analyses, as the highest level of evidence, also show a significant controversy [110]. Table 1 summarizes recent meta‐analyses on the topic.

Table 1.

A summary of meta‐analysis studies on the application of photoactivated chromophore‐corneal cross‐linking (PACK‐CXL).

First author	Year of study	Included studies	Main results	Ref.
Papaioannou	2016	Twenty‐five studies, including two randomized clinical trials	* PACK‐CXL shows promising results, except for herpetic keratitis. * A higher likelihood of success was detected in bacterial and Acanthamoeba cases compared to fungal infections.	[111]
Ting	2019	Forty‐six studies, including four randomized clinical trials	* PACK‐CXL led to a shorter average healing time and faster clearance of corneal infiltration compared to standard antibiotic treatment alone.	[112]
Davis	2020	Three trials (two randomized clinical trials and one quasi‐ randomized clinical trial)	* The degree of effectiveness of PACK‐CXL combined with standard antibiotic treatment versus standard antibiotic treatment alone for re‐epithelialization and complete healing in bacterial keratitis is uncertain.	[113]
Liu	2023	Seven randomized clinical trials	* Adjuvant PACK‐CXL effectively reduces the duration of corneal healing in fungal keratitis compared to standard antibiotic treatment alone. * Adjuvant PACK‐CXL could not reduce adverse events in both fungal and bacterial keratitis. * It seems that the application of PACK‐CXL is still controversial, and ophthalmologists should consider the type and severity of the disease, the drug regimens associated with standard antibiotic treatment, and the PACK‐CXL protocol in their clinical practice.	[110]

It should be mentioned that a transient increase in the size of hypopyon has been reported after PACK‐CXL, which is thought to result from riboflavin's penetration into the anterior chamber, thereby causing an increase in inflammatory response [114, 115]. Regarding the safety and effectiveness of repeated PACK‐CXL sessions, a study reported a success rate of 90% after four sessions of PACK‐CXL, a greater efficacy in managing resistant BK compared to a single session, with minimal complications [116].

4.2. Ultraviolet C Light

UV light is categorized by its wavelength, which spans from 100 to 400 nm, and is divided into three segments: UVA (long wavelengths > 315 nm), UVB (middle wavelengths 280–315 nm), and UVC (short wavelengths < 280 nm) [117]. CXL utilizes 365 nm UVA at a dosage of 5.4 J/cm². Nonetheless, this procedure is time‐consuming and has logistical challenges [118].

UVC light possesses natural antimicrobial activity, attributed to its efficient absorption by microbial nucleic acids. This property has led to the application of UVC as an antimicrobial agent across diverse fields, with studies indicating its capability to inactivate bacteria responsible for keratitis at doses that are confirmed to be safe for the cornea [119]. The maximum efficacy has been reported at a wavelength of 265 ± 5 nm [119]. An investigation has revealed that doses between 1.93 and 57.9 mJ/cm² are non‐lethal to human cells while being lethal to microorganisms [120]. Therefore, UVC may be a promising candidate for treating IK. However, its short wavelength and high scattering characteristics suggest that even a thin layer can quickly obstruct UVC, potentially reducing its antimicrobial effectiveness [121].

An experimental investigation on corneal infection revealed a significant growth inhibition associated with UVC treatment. A dose‐dependent effect was particularly evident, with 15 s of UVC exposure yielding optimal bactericidal results. Additionally, it was confirmed that multiple exposures of 15 s of UVC are non‐harmful to human corneal DNA [118, 119]. Interest in UVC as an antimicrobial agent is on the rise; however, the safety of this treatment has garnered significant critical attention, primarily due to the acknowledged risk of genotoxicity [122].

4.3. Thermal Lasers

The application of green thermal lasers in the management of retinal diseases is well‐established. These lasers are absorbed by pigments in tissues, leading to thermal damage characterized by temperature elevations exceeding 90°C [123]. The introduction of thermal lasers in treating corneal pathologies, particularly neovascularization, dates back nearly half a century. Recent investigations have provided evidence supporting the use of green thermal lasers as an adjunctive therapy for resistant IK [124, 125]. Table 2 shows evidence in this regard.

Table 2.

Main results of studies applied thermal lasers in the management of infectious keratitis.

Study settings	Main results	Ref.
* Retrospective case series of 150 patients with resistant keratitis	* Green thermal laser is a safe and effective adjunctive treatment option. * Three cases experienced corneal micro‐perforations, which could be linked to repeated laser application at the same site or unintentional movements of the patient's eye. * Eleven cases presented with significant corneal thinning and descemetocele formation, primarily due to excessive laser treatment and subsequent necrotic tissue sloughing.	[124]
* Clinical interventional case series involving 20 eyes with resistant keratitis * Ten patients were treated with laser therapy as an adjunct (10 patients received antimicrobials alone).	* All patients in the laser group achieved complete epithelial healing and resolution of stromal infiltrates within 4 weeks. * The duration of healing was significantly shorter in the laser group. * No adverse effects were reported in the laser group. * One patient in the laser group and four patients in the control group required amniotic membrane transplantation.	[125]
* The effectiveness of laser photocoagulation compared to intrastromal voriconazole injection as adjunctive therapy for resistant mycotic corneal ulcers	* The laser group achieved superior results concerning the time required for complete healing and the occurrence of complications.	[126]
* The clinical outcomes of amniotic membrane transplantation paired with either laser photocoagulation or simple tissue debridement in treating resistant fungal corneal ulcers	* The combination of laser treatment and amniotic membrane transplantation led to enhanced treatment duration and visual results.	[127]

4.4. Photothermal Therapy (PTT)

In PTT, photothermal transduction agents (PTAs) are employed to convert light into heat energy, which subsequently raises the temperature of the surrounding environment, facilitating the elimination of pathogenic microorganisms [128]. The extensive bactericidal capabilities and the relatively simple sterilization process of PTT have attracted considerable attention. Irradiated PTAs can increase local temperatures to over 50°C, resulting in microbial death [129]. Polydopamine (PDA) stands out among various photothermal agents (PTAs) due to its superior photothermal conversion efficiency and excellent biocompatibility. With photothermal conversion efficiency reaching 40%, PDA is particularly advantageous for applications aimed at managing bacterial infections [130, 131]. Additionally, the process of synthesizing PDA is notably straightforward. Fan et al. [132] engineered EPL‐modified PDA NPs to implement a targeted antibacterial strategy mediated by PTT against MRSA‐induced keratitis. Upon exposure to near‐infrared lasers, these NPs successfully increased the temperature, effectively eliminating the bacteria through a photothermal conversion process [132].

4.5. Phototherapeutic Keratectomy (PTK)

At present, numerous anterior corneal conditions are effectively managed through PTK. The advantages of PTK include precise control, ease of use, and the possibility for repeated surgical interventions [133]. Evidence suggests that PTK yields positive results in treating various types of keratitis [134, 135, 136, 137]. It is hypothesized that the ablation and remodeling effects inherent in PTK can successfully eradicate infected corneal tissue and organisms, while also aiding in the restoration of a more regular corneal surface during the healing phase [138]. The treatment outcomes of PTK for clinically suspected FK were investigated in a study. Forty‐seven eyes were treated with PTK, with all corneal lesions found in the anterior stroma and resistant to pharmacological therapy for at least 1 week. Following the PTK procedure, complete removal of infected corneal lesions and resolution of clinical symptoms occurred in 41 cases, accounting for 87.2% of the participants. The mean duration for epithelial defect healing was 8.8 ± 5.6 days. Additionally, 34 eyes (82.9%) demonstrated an improvement in BCVA by two or more lines, indicating that PTK is a promising therapeutic alternative for superficial IK [138].

4.6. Blue Light

Antimicrobial blue light (aBL) represents a novel light‐based method for combating microbial infections, attracting growing interest due to its inherent antimicrobial capabilities that do not rely on external PSs [139]. It is also postulated that pathogens are less likely to develop resistance to aBL [139]. A study was conducted to evaluate the efficacy of aBL (415 nm) in the treatment of IK, employing both ex vivo rabbit and in vivo mouse models [140]. The results demonstrated a significant and rapid reduction in bacterial populations after a single exposure to aBL in both models. Additionally, the retinal toxicity of aBL was found to be largely dependent on the transmission of aBL through the cornea. The findings suggest that aBL could be a potential alternative or supplementary treatment for IK. However, successful treatment outcomes with aBL require optimal timing, careful management of exposure levels, and appropriate adjuvant antibacterial therapy [140].

5. Surgical‐Based Therapies

5.1. Conjunctival Flap and Tenon Graft

The application of a conjunctival flap has been reported as a viable method for managing progressive corneal thinning associated with IK. This technique promotes healing by introducing superficial blood vessels to the corneal area, thereby aiding in the recovery of corneal ulcers and reducing associated pain [141, 142]. Successful outcomes have been observed with this procedure in cases with deep ulcers, descemetocele, corneal perforation, and failed medical treatment [143]. A flap can be constructed to either cover the entire cornea, referred to as the Gundersen flap, or to address only the diseased portion of the cornea [141]. When comparing the effectiveness of conjunctival flap versus amniotic membrane transplantation (AMT), research indicates that there are no significant differences in success rates, epithelialization durations, or improvements in VA [143]. However, AMT offers potential advantages, such as permitting corneal evaluations, preserving limbal stem cells that could influence the efficacy of subsequent PK, and maintaining conjunctival integrity, which may be critical for future ocular interventions, including glaucoma filtering surgery [143].

Tenon tissue is recognized for its ability to produce autologous fibroblasts, which facilitate corneal healing. This property has been effectively utilized for sealing perforations that are less than 3 mm in diameter [144]. Upon the removal of all necrotic tissue, Tenon's tissue is harvested from the superotemporal or superonasal quadrant. The dimensions of the harvested Tenon tissue must exceed the defect area by 1 mm. The graft is then either sutured into position or secured using cyanoacrylate glue [141].

5.2. Corneal Gluing

The main function of tissue adhesive is to offer structural support to the globe in cases of minor corneal perforations (< 3 mm) and significant stromal thinning. Its use should be restricted to an adjunctive role alongside antimicrobial therapy, and only after an initial positive response to treatment has been established [141]. The classification of ocular adhesives encompasses two main categories: synthetic adhesives and those formulated from natural polymers [145]. The predominant synthetic adhesives in use today are cyanoacrylates. The efficacy of this type of adhesives is reported to range between 29% and 86% [13]. Notably, one more important advantage of cyanoacrylate glue is its marked antibacterial and antifungal properties, which may assist in the resolution of IK [146, 147]. Cyanoacrylate‐based adhesives, commonly referred to as “superglues,” lack FDA approval and are utilized off‐label for a range of ophthalmic applications. Upon contact with alcohols, water, or amino acids found in living tissues, these substances quickly polymerize, typically within 10–30 s [145]. On the other hand, naturally sourced polymer‐based adhesives include protein‐based varieties such as fibrin, collagen, and serum albumin, in addition to polysaccharide‐based adhesives. Fibrin‐based adhesives are notable for their FDA approval and are the most widely employed and available in the market [141]. They function by mimicking the natural clot formation process. These adhesives are made up of two components that, when combined, produce a final insoluble adhesive. After applying to the targeted ocular tissue, the adhesive undergoes polymerization and cross‐links with the collagen in the corneal stroma, resulting in a whitish translucent membrane that forms within 30–120 s [148].

A variety of surgical approaches have been outlined for the use of cyanoacrylate and fibrin glue [141]. It is important to highlight that, regardless of the technique employed, debridement of 1–2 mm of surrounding necrotic epithelium and ensuring a dry surface before application are critical steps [149]. The comparison between cyanoacrylate glue and fibrin glue indicates that cyanoacrylate remains adherent to the application site for a significantly longer time than fibrin glue. Additionally, cyanoacrylate glue has been linked to a higher incidence of giant papillary conjunctivitis, inflammatory reactions, corneal neovascularization, foreign body reactions, and tissue necrosis. In contrast, fibrin glue is associated with faster healing, although it requires a significantly longer period for adhesive plug formation [150].

5.3. Amniotic Membrane (AM) Transplantation

AM, the innermost layer of the placenta, is composed of a single layer of metabolically active epithelial cells, a thick basement membrane, and an avascular stromal matrix. Studies have highlighted the extensive biological properties of AM, such as wound healing, anti‐inflammatory effects, antimicrobial activity, and anti‐angiogenic properties. Additionally, the ready availability of donor AM tissues, lack of graft rejection, and improvements in preservation methods have contributed to the increasing popularity of AMT for treating ocular surface diseases, including IK [151, 152].

The existing literature lacks clear recommendations regarding the optimal timing for the application of AMT in IK. However, it is advisable to perform AMT after observing an initial positive response to antimicrobial therapy or once the infection has been effectively controlled, given that the AM itself can act as a source of infection [141]. To address the significance of integrating AMT with antimicrobial treatment during the active phase of IK, Ting et al. [153] conducted a systematic review on 28 RCTs, non‐randomized controlled studies, and case series, which collectively involved 861 eyes diagnosed with IK. Among these, 666 eyes underwent a combined treatment of AMT with standard antimicrobial treatment, while 195 eyes were treated with standard antimicrobial treatment alone [153]. The findings from their meta‐analysis involving only RCTs (cases with BK, FK, and mixed bacterial/FK) suggest that early adjuvant AMT resulted in a reduction of approximately 4 days in the duration required for complete corneal healing. Additionally, patients who received adjuvant AMT demonstrated an improvement of 2–3 Snellen lines in uncorrected distance visual acuity (UDVA) during the 1‐month follow‐up. There was no significant difference observed regarding the incidence of adverse events [153]. The antimicrobial properties of AMT in IK can be attributed to the diverse antimicrobial agents found in amniotic fluid, along with the role of AM as a potent reservoir for antibiotics when used in combination with antibiotics, facilitating prolonged drug release [151, 154]. Although there is an absence of RCTs specifically addressing the advantages of AMT in herpetic keratitis, evidence suggests that AMT plays a crucial role in achieving complete corneal healing in such cases. Furthermore, AMT has demonstrated positive outcomes in the treatment of AK and polymicrobial cases [153].

5.4. Keratoplasty

Perforated corneal ulcers and nonhealing and refractory corneal ulcers characterized by significant thinning are indications for keratoplasty in IK. Various keratoplasty techniques, including penetrating keratoplasty (PK), lamellar keratoplasty (LK), and corneal patch grafts, are employed based on factors such as the size, depth, location, and etiology of the perforation [141, 155, 156, 157]. However, in cases of active ulceration, postoperative inflammatory response and vascularization are markedly pronounced, resulting in diminished graft survival and an elevated likelihood of rejection. Factors impacting graft survival include the type of microorganism involved, the timing of the surgical intervention, the severity of inflammation, the quality of the donor tissue, the medical management provided preoperatively and postoperatively, the degree of corneal involvement and perforation, and ultimately, the size of the graft [158]. A study was conducted in which patients were divided into two groups based on the timing of PK. Group 1 consisted of patients who received surgery within 15 days of the onset of keratitis, while Group 2 included those who were operated on at least 15 days after the initial symptoms emerged. The results indicated that early surgical intervention may yield better clinical outcomes, especially when performed before the development of perforation or limbal/scleral extension [159]. The success rates for achieving a clear graft at the 1‐year mark exhibit considerable variation, ranging from 48% to 54% in cases of BK, 50% to 55% in FK, 60% to 80% in AK, and 50% to 70% in viral keratitis. Furthermore, the probability of graft survival diminishes by approximately 50% after 4 years when inflammation or corticosteroid administration is present during the grafting procedure [15]. It is imperative to underscore that the risk of reinfection remains at levels between 20% and 30% in both FK and AK [156].

Due to the natural contour of the cornea, in which its horizontal diameter is larger than the vertical diameter, the involvement of the corneal limbus is almost inevitable when a conventional circular trephine is used for patients with total corneal infections or large, elliptical corneal ulcers. This issue may increase the risk of postoperative immune rejection. Additionally, making incisions and suturing in the limbus can lead to intraoperative bleeding, which increases the overall difficulty of the procedure, as well as disrupting the anterior chamber angle's structure, and raising the likelihood of postoperative anterior synechia and secondary glaucoma. To counter these challenges, a research group suggested a manual fusiform corneal transplantation method that employs multiple trephines of different sizes [160].

Surgical intervention plays a crucial role in the management of FK, with approximately 50% of affected individuals necessitating therapeutic keratoplasty to effectively control the infection [161]. This highlights the inherent limitations of pharmacological treatment alone in the management of FK. Notably, the presence of hypopyon, along with the dimensions and depth of infiltrates, has been significantly associated with the necessity for therapeutic keratoplasty in FK. Furthermore, infiltrates that extend into the posterior third of the cornea were linked to a 71.4% likelihood of perforation or the necessity for PK [162]. LK is becoming a prominent option in the treatment of FK. In a research study that included 55 cases of FK unresponsive to traditional treatments, LK achieved a success rate of 92.7% (n = 51) and a recurrence rate of merely 7.3% (n = 4). Comparable findings have been documented in other investigations [163, 164, 165]. During therapeutic keratoplasty, it is critical that the trephination size accommodates a 1–1.5 mm zone of clinically uninvolved cornea. The corneal region encircling the trephination must be devoid of any residual fungal infection to mitigate the risk of recurrence. Interrupted sutures should be employed, utilizing slightly longer bites to prevent cheese wiring at the recipient's edge. Anterior chamber irrigation is performed to remove any residual exudates or organisms. It is advisable to refrain from contacting the lens to mitigate the risk of disseminating infection to the posterior segment [166, 167].

6. Miscellaneous Therapies

6.1. Nanomedicine and Contact Lens

Nanotechnology is an innovative discipline that is increasingly gaining attention in medicine [168]. The application of nanotechnology in ocular therapeutics can mitigate tissue irritation, boost the bioavailability of medications, and enhance the compatibility of drugs with eye cells, effectively addressing the challenges posed by direct ocular drug delivery [169]. It should be emphasized that most recent literature highlights nanotechnology/contact lens‐based therapies that include antimicrobial substances; however, such therapies are not covered in this section. The focus here is solely on therapies that lack antimicrobial agents, consistent with the parameters established by the title and scope of this research.

Nanozymes are defined as nanomaterials that possess enzyme‐like activities, allowing them to catalyze substrate reactions efficiently under physiological conditions [170]. The inherent advantages of nanomaterials enable nanozymes to surpass the limitations of conventional enzymes, such as complicated production methods, high expenses, and limited permeability [171]. Metal‐organic frameworks (MOFs) are recognized as a promising type of biomedical material, notable for their unique characteristics. These MOFs are regarded as potential enzyme mimics. [172]. A team of researchers has successfully developed iron‐doped nanozymes characterized by their antibacterial and anti‐inflammatory capabilities for the management of BK [172]. These nanozymes mimic the activity of peroxidase, thus eliminating bacteria without fostering drug resistance [172].

NPs are characterized by their small size, customizable shapes, and diverse physiochemical properties [173, 174]. Several classifications of NPs are noteworthy for their intrinsic therapeutic capabilities.

Recent studies have increasingly concentrated on the utilization of CLs for the prompt treatment of IK. Essential characteristics of these therapeutic lenses include their ability to inhibit microbial growth and their capacity to transmit visible light. Various strategies exist for the development of CLs with antibacterial properties, such as incorporation of nanomaterials and addition of peptides. Silver nanoparticles (Ag NPs) have garnered significant attention as therapeutic NPs for combating infectious diseases, attributed to their broad‐spectrum antimicrobial efficacy against a variety of infectious agents [175]. However, the potential toxicity of Ag NPs in ocular use warrants careful consideration [176]. Notably, the results from existing studies have not provided definitive conclusions, necessitating further exploration into the effectiveness of Ag NPs‐based CLs for the management of IK [177, 178, 179, 180]. Gold nanoparticles (Au NPs) and zinc oxide nanoparticles (ZnO NPs) are also of considerable interest in research, primarily due to their diverse antibacterial capabilities [181, 182]. Moreover, according to the findings of Sahadan et al. [183], the coating of CLs with phomopsidione NPs has been shown to markedly reduce the severity of keratitis caused by Gram‐negative bacteria. Another research has demonstrated a notable amoebicidal effect of Au NPs linked to chlorhexidine on Acanthamoeba castellanii [184]. Furthermore, Ag NPs associated with tannic acid have been identified as a potential therapeutic agent against Acanthamoeba species [185]. It was also found that chitosan NPs and Nigella sativa, both individually and in combination, can effectively treat experimentally induced AK [186].

Alongside the loading of nanomaterials and peptides into CLs, the method of generating ROS in a controlled and sustained manner emerges as a beneficial strategy for the treatment of IK [187, 188]. Furthermore, these methods do not contribute to the development of drug resistance and help mitigate the misuse of antibiotics [181]. Nitric oxide (NO) is an endogenous molecule that plays a vital role in various physiological processes and exhibits broad‐spectrum antimicrobial activity against both Gram‐negative and Gram‐positive bacteria. It functions as an antimicrobial agent by engaging with endogenous ROS. Moreover, NO is effective against both planktonic bacteria and biofilms. Nevertheless, the application of NO is limited by its gaseous free radical nature and a short half‐life of less than 10 s, which restricts its safety and practicality. To overcome these limitations, the use of NO donors is essential for enabling controlled and sustained delivery of NO to infection sites [189, 190]. Aveyard and his team conducted a study in which they successfully developed CL gels capable of releasing NO. These gels demonstrated remarkable optical and mechanical characteristics, maintaining a sustained release of NO for over 16 h under physiological conditions. Furthermore, the gels exhibited significant antimicrobial efficacy against Staphylococcus aureus and Pseudomonas aeruginosa, while showing minimal cytotoxic effects on a human corneal epithelial cell line [191].

6.2. Plasma Ablation

Plasma serves as a vital surgical tool, significantly impacting the processes of cutting, cauterizing, drying, and coagulating blood and tissues. However, in electrosurgery, the high temperatures produced by conventional thermal plasma can result in excessive tissue damage [192]. The emergence of microplasma, which is generated at low temperatures within a small‐volume cavity, is beginning to shift the current treatment landscape. Operating at an average temperature of 25°C–28°C, this microplasma achieves an ablation depth of about 50 μm, effectively minimizing the risk of tissue harm [193]. The application of atmospheric pressure low‐temperature plasma technology in ophthalmology has been relatively slow. The antibacterial efficacy of plasma against various ocular pathogens has been documented [194]. In a clinical study, the efficacy of low‐temperature plasma ablation combined with pharmacological therapy in treating FK was evaluated. They included 34 FK patients with an infiltration depth not exceeding 50% of the corneal thickness. The treatment led to effective infection control in 30 cases, yielding an 88% success rate. There were no reported cases of infection recurrence during the follow‐up period of 1–6 months. Additionally, VA improved in 23 eyes (68%) compared to the initial vision [194].

6.3. Debridement

Aggressive debridement significantly improves the outcome of FK [195]. A study involving patients with FK randomized participants into two groups. The first group received diagnostic corneal scraping performed with a Kimura spatula, while the second group underwent surgical debridement using a motorized drill with a diamond burr attachment. Findings revealed that those who underwent aggressive debridement experienced a significant reduction in the time required for re‐epithelialization and resolution of keratitis, averaging 9.4 days, compared to 17.1 days for the scraping group. The mean UCVA in the surgical group was 1.02 logMAR before the procedure and improved to 0.43 logMAR afterward. In contrast, the Kimura spatula group had a mean UCVA of 1.20 logMAR preoperatively and 0.58 logMAR postoperatively [195]. In line with this study, an assessment was conducted on the treatment outcomes and financial implications of early keratectomy for moderate Fusarium keratitis. The findings indicated that early keratectomy not only lowered the rates of complications in both the short and long term but also required a reduced allocation of financial resources for the management of FK [196]. The process of aggressive debridement removes corneal epithelium, thus enhancing topical drug penetration and also aids in the removal of necrotic tissue and hyphae‐laden debris.

6.4. Cryotherapy

In an experimental study, Chen and colleagues investigated the combined use of cryotherapy and antifungal agents in treating FK [197]. The results revealed that cryotherapy significantly improves fungal ulcers. The authors theorized that the rapid cooling effect leads to the formation of intracellular ice crystals, which disrupt the integrity of the cell membrane and cause denaturation and degradation of proteins within the fungal cells. The subsequent re‐warming after the procedure may further compromise the cell membrane and activate the immune system, resulting in the production of interferon by the infected corneal cells [197].

7. Limitations and Concerns

Table 3 provides a summary of limitations and concerns of the therapies discussed.

Table 3.

Limitations and concerns of non‐conventional antimicrobial‐based therapies.

Therapeutic option	Is there any clinical evidence?	Limitations and concerns	Ref.
Povidone‐iodine	Yes	Risk of allergic reactions Ocular irritation Corneal toxicity Limited effectiveness against some pathogens	[16]
Matrix metalloproteinases inhibitors	Yes	Systemic side effects Low oral bioavailability and tolerance Lack of specificity (broad‐spectrum inhibition)	[198, 199]
Corticosteroids	Yes	Risk of delayed epithelial repair Risk of prolonged duration of infection Risk of deterioration of disease Not suitable for all cases and pathogens	[31, 32, 33]
Host defense peptides	No	Poor stability in vivo condition Potential toxicity Cost	[35, 37, 38]
Novel small molecules	No	Poor bioavailability Delivery challenges Formulation difficulty Narrow spectrum of activity Cost	[41]
Formaldehyde releasers	No	Toxicity Risk of allergic reactions Narrow spectrum of activity	[61, 62]
Synthetic polymers	No	Toxicity Immunogenicity and inflammatory responses Cost	[63, 66]
Antioxidants	No	Interference with the host's immune responses Poor bioavailability and delivery Formulation and stability difficulty	[41]
Bacteriophages	No	Narrow spectrum of activity Immunogenicity and inflammatory responses Storage and stability issues	[74]
Photodynamic therapy	Yes	Limited penetration depth Potential ocular side effects Spectrum of activity and pathogen variability Technical and procedural complexity Cost	[77, 87, 96]
Ultraviolet C light	No	Ocular toxicity Limited penetration depth Safety profile issues	[118, 119]
Thermal lasers	Yes	Lack of specificity Risk of collateral damages Visual impairment and scarring Limited penetration depth	[124, 125, 126, 127]
Photothermal therapy	No	Lack of specificity Risk of collateral damages Limited penetration Safety and biocompatibility issues Cost	[128, 129, 130, 131, 132]
Phototherapeutic keratectomy	Yes	Limited to superficial infections Risk of superinfection Risk of corneal haze and scarring Risk of thinning and ectasia Postop discomfort and prolonged healing Non‐specificity	[138]
Blue light	No	Risk of ocular damages Variable efficacy and specificity	[139, 140]
Conjunctival flap and tenon graft	Yes	Compromising vision Poor cosmesis Infection monitoring issues Limiting drug penetration Surgical complications	[141]
Corneal gluing	Yes	Masking of underlying infection Limited efficacy for large defects Toxicity and inflammation Compromising vision Poor cosmesis Limiting drug penetration Adhesion‐related complications	[141, 150]
Amniotic membrane transplantation	Yes	Infection monitoring issues Compromising vision Variability in effectiveness Cost	[141, 153]
Keratoplasty	Yes	Risk of rejection and failure Risk of infection recurrence Surgical challenges and complications Variable and often guarded visual prognosis	[15, 158, 159, 160]
Nanomedicine and contact lens	No	Safety and toxicity concerns Delivery challenges Not suitable for all patients Cost	[171, 172, 173, 174, 175, 185, 186, 187, 188, 189, 190]
Plasma ablation	Yes	Risk of tissue damage Precision and targeting challenges Cost	[192, 193, 194]
Debridement	Yes	Pain and discomfort Further trauma and damage Limited efficacy in deep infections Not suitable for all cases and pathogens	[195, 196]
Cryotherapy	No	Risk of tissue damage Ocular discomfort and inflammation Limited penetration depth Variable efficacy	[197]

8. Conclusion

The conventional approach to managing IK involves the use of topical antimicrobial agents. Most instances can be effectively addressed with empirical treatment using antimicrobial eye drops, yielding satisfactory results. However, it seems the rise in antimicrobial resistance and insufficient response in some cases, especially FK, necessitates ophthalmologists to utilize all currently available options in their toolbox more efficiently and intensify research efforts aimed at developing alternative therapeutic strategies. This review highlights alternative adjuvant treatment options that do not contain antimicrobials, which, despite being less recognized, warrant greater attention in future clinical applications.

Author Contributions

Kasra Cheraqpour: conceptualization, methodology, writing – original draft, writing – review and editing, supervision.

Ethics Statement

The author has nothing to report.

Conflicts of Interest

The author declares no conflicts of interest.

Transparency Statement

The lead author, Kasra Cheraqpour, affirms that this manuscript is an honest, accurate, and transparent account of the study being reported; that no important aspects of the study have been omitted; and that any discrepancies from the study as planned (and, if relevant, registered) have been explained.

Data Availability Statement

Data sharing not applicable to this article as no datasets were generated or analysed during the current study. The author confirms that the data supporting the findings of this study are available within the article.