Anti-inflammatory treatments in microbial keratitis

Abstract

Infectious keratitis remains a leading cause of corneal blindness worldwide. The role of topical anti-inflammatory agents such as corticosteroids, calcineurin inhibitors, and other steroid-sparing therapies in the management of infectious keratitis has not been clearly defined and remains controversial. The benefit of corticosteroids in the treatment of infectious keratitis varies depending on the causal organism. While one large randomized-controlled trial supports their use in some cases of bacterial keratitis, high-quality evidence for their use in fungal or amoebic keratitis is not well-established. There are few case reports and no randomized control trials evaluating the safety and efficacy of steroids in the treatment of fungal or amoebic keratitis, although generally steroids are avoided in fungal keratitis and used judiciously in amoebic keratitis. Topical steroid-sparing anti-inflammatory treatments such as calcineurin inhibitors may especially have a role in the treatment of fungal keratitis, where topical corticosteroid use is generally avoided. Emerging adjunctive therapies, including amniotic membrane transplantation, photoactivated chromophore cross-linking, and experimental immunomodulators, show preclinical or early clinical promise but lack robust human data. Large, multicenter trials are needed to establish evidence-based protocols for infectious keratitis treatment that balance infection eradication with control of host inflammation. While judicious anti-inflammatory use appears beneficial in many cases, optimal timing, dosing, and combination strategies remain uncertain. This review summarizes current evidence on topical anti-inflammatory therapy for infectious keratitis, focusing on bacterial, fungal and amoebic infections, and highlights key gaps in knowledge.

INTRODUCTION

Infectious keratitis is a potentially blinding condition that often results in visual disability as a result of significant corneal inflammation, destruction, and eventually scar. Cases may exceed 2 million cases per year worldwide, and etiologies vary depending on geography, contact lens wear, trauma, and other factors.[1] Organism-specific factors aid in the ability of the to penetrate, invade, and destroy corneal tissue. Tissue invasion incites a host immune cascade, which adds to tissue destruction, inhibits healing, and potentiates corneal scar formation.

The use of anti-inflammatory agents in the management of microbial keratitis is controversial. While anti-inflammatory agents reduce the inflammatory destruction of tissue, they also suppress the host’s immune response to infection, potentially delaying healing and eradication of the infection.

Anti-inflammatory treatments vary in their efficacy depending on the concomitant and preceding anti-infectious treatment as well as the causal organism. This article will focus on a review of the current literature on the use of steroids and steroid-sparing anti-inflammatory treatments in bacterial, parasitic, and fungal keratitis.

TOPICAL CORTICOSTEROIDS

Topical corticosteroids bind the glucocorticoid receptor, altering transcription to suppress cytokines/chemokines, stabilize lysosomes, and inhibit phospholipase A2 and downstream prostaglandins. Clinically, corticosteroids reduce inflammatory cytokines responsible for cell infiltration and corneal neovascularization and reduce destructive collagenases.[2,3,4,5]

Because they dampen both adaptive and innate responses, premature steroids can convert a localized lesion into a rapidly progressive ulcer. In addition, topical corticosteroids have been shown to delay epithelial healing in patients after refractive surgery, a finding that could translate to delayed epithelial healing with their use in microbial keratitis.[6]

Bacterial keratitis

Bacterial keratitis is a sight- and eye-threatening condition that is a leading cause of blindness worldwide.[7] Trauma, contact lens wear, and ocular surface disease are major risk factors for infection, and the causal infectious organism varies depending on these and other risk factors, as well as geography.[1,8]

Bacterial invasion incites host-driven inflammatory cascades[9,10,11] including an influx of inflammatory cells, including T-cells and macrophages. Subsequent release of inflammatory factors such as interleukin-1 (IL-1), tumor necrosis factor, transforming growth factor-beta, and platelet-activating factor[10,11] upregulate metalloproteinases, which result in tissue degradation and scar.[11,12]

Initial treatment involves broad-spectrum topical antibiotic coverage with subsequent changes to therapy based on results of corneal culture and antibiotic sensitivity results.

There have been four randomized controlled trials (RCTs) on the use of corticosteroids in bacterial keratitis, one of which demonstrated high-level evidence. Two trials showed no benefit in final visual acuity with the addition of corticosteroid drops to antimicrobial therapy (Blair et al. with 30 patients and Srinivasan et al. with 42 patients).[13,14] Blair et al. found no difference in time to healing with corticosteroids, although Srinivasan et al. saw slower epithelialization in patients in the corticosteroid group.

The largest randomized, double-masked, placebo-controlled trial on corticosteroids in bacterial keratitis, the Steroids for Corneal Ulcers Trial (SCUT), provided Level 1 evidence for a small benefit with the use of steroids in culture-proven non-Nocardia bacterial keratitis.[15,16,17,18] In SCUT, topical prednisolone phosphate 1% was initiated at least 48 h after starting appropriate antibiotics in culture-proven bacterial keratitis. Dosing for the topical corticosteroid was four times daily for 1 week, followed by twice daily for 1 week, and then once daily for 1 week. The pilot study showed a longer epithelialization time in the steroid group, but the larger RCT found no difference in best corrected visual acuity between the steroid and placebo groups at 3-months.[14,15] There was also no significant difference between the groups in scar size, time to re-epithelialization, or perforation. Patients with severe ulcers (counting fingers vision or worse) and central corneal ulcers had nearly 2 lines better visual acuity at 3 months in the corticosteroid group compared to placebo.[15] Non-Nocardia ulcers in the corticosteroid group maintained one line better visual acuity than the placebo group at one year, with no significant difference in scar size.[17] A subset of patients with invasive pseudomonas aeruginosa keratitis (vs. cytotoxic or atypical based on polymerase chain reaction [PCR]) in the corticosteroid group had 2.5-lines more visual improvement at 3 months compared to the placebo group.[19] Importantly, patients with Nocardia ulcers in the steroid group had larger infiltrates or scars at 3 months compared to those in the control group, with no difference in best spectacle-corrected visual acuity.[16] Furthermore, steroids are not recommended in the treatment of Nocardia keratitis.

While SCUT was a large RCT that provided useful clinical data, some limitations exist. Ulcer etiology varies widely depending on geography, and 97% of patients in SCUT were in India. Therefore, the results may not be generalizable to other population groups.[17]

Topical steroids in bacterial keratitis are not without some risk, and cautious use should be employed. In some cases, corticosteroid drops could potentiate bacterial invasion, reduce host immune response to the infection, and delay overall healing.[9] There are also some corneal infections that are known to worsen with corticosteroid administration, including fungal keratitis and nocardia keratitis, so before initiation of corticosteroids, an organism must be identified with culture or PCR or response to anti-infective treatment must be noted.[15] One study evaluating the risk of developing endophthalmitis following infectious keratitis found a low risk (0.5%), but 75% of those that developed endophthalmitis were on topical steroids as well as antibiotics.[20]

For these reasons, it is advisable to initiate corticosteroids after appropriate treatment of the bacterial ulcer with antibiotics is initiated, and the efficacy of treatment is confirmed with clinical improvement or sensitivity results from culture. Patients should be followed closely after initiating corticosteroids, and potential risks and complications of treatment must be discussed to prompt close follow-up.

More studies exploring the optimal dosing for corticosteroids in the management of bacterial keratitis are needed. The RCTs that have been done all use steroids 4 times per day with a taper over the subsequent weeks.[13,14,15] One retrospective review of 328 evaluated the effect of high-dose steroid drops in patients with bacterial keratitis, with high-dose defined as 6 or more corticosteroid drops per day started within 1 week of corneal scraping.[21] High-dose steroid treatment was associated with a 5.5x chance of a better visual outcome. Further study to elucidate optimal dosage and timing of therapy is needed.

Acanthamoeba keratitis

Acanthamoeba is an opportunistic unicellular free-living protist found ubiquitously in water, air, and soil, including swimming pools, hot tubs, and ponds. It is also found frequently on contact lenses, especially when not correctly sanitized.[22] Organisms have a two-stage life cycle: active trophozoites and quiescent double-walled cysts. Exposure to stress results in encystment. Cysts are resistant to harsh conditions and require prolonged use of cysticidal medications to fully treat. Trophozoites are typically well-treated with most anti-Acanthamoeba therapies available.

Acanthamoeba keratitis is thought to occur primarily in contact lens wearers due to microtrauma from contact lens wear. Increased expression of epithelial glycoproteins allows Acanthamoeba to adhere to corneal tissue and release enzymes and toxins that degrade the stroma.[23,24]

Topical corticosteroid use in the treatment of Acanthamoeba keratitis is controversial.[25] In vitro studies have shown that steroids result in excystment of Acanthamoeba as well as proliferation of trophozoites.[26] Corticosteroid use before initiation of antiamoebic therapy is associated with increased trophozoite expression and worse outcomes; however, corticosteroid use following the initiation of antiamoebic therapy has not.[27,28,29] Topical corticosteroids have been shown to control pain in patients with Acanthamoeba keratitis, and several case series have shown noninferior outcomes in patients who received delayed topical corticosteroids.[28,30] Topical steroids and systemic immunosuppression have also been shown to be effective in the management of patients with Acanthamoeba sclerokeratitis.[31] Topical steroids are also often used in conjunction with oral miltefosine, an alkylphosphocholine that has been shown to be a successful treatment in case series for refractory AK. Topical or oral steroids are often needed to treat the profound inflammatory response that often follows the initiation of miltefosine.[32] Further RCTs are needed to support timing, dosage, and specific cases for which corticosteroids may be beneficial in the treatment of AK.

Fungal keratitis

Fungal keratitis, or keratomycosis, is a severe, vision-threatening corneal infection and a major cause of corneal blindness worldwide.[33,34] Recent estimates suggest that more than a million new cases occur annually, with the highest prevalence in tropical and subtropical regions where agricultural work, ocular trauma, and delayed access to care are common.[35] The most common pathogens responsible for keratomycosis are Fusarium, Aspergillus, Curvularia, Bipolaris, and Candida.[36] The disease often presents insidiously, leading to delayed diagnosis and treatment, and its clinical course can be protracted and difficult to control. Management remains challenging as currently available antifungal medications are largely fungistatic, not fungicidal, and exhibit poor corneal penetration. Even with aggressive medical therapy, eradication of the pathogen is frequently incomplete.[34,37] As a result, treatment failure is common. Multiple studies report that up to 44% of cases ultimately require therapeutic penetrating keratoplasty (PK) or, in advanced cases, enucleation for infection control.[33,38]

The therapeutic value of topical antifungal agents such as natamycin, voriconazole, and amphotericin has been explored extensively, with numerous randomized trials and large observational series defining dosing regimens, penetration profiles, and visual outcomes in fungal keratitis.[36,37,39] In contrast, the literature on topical anti-inflammatory agents, including corticosteroids, calcineurin inhibitors, and other steroid-sparing immunomodulators in mycotic keratitis remains relatively sparse. This disparity underscores that while the antifungal arm of therapy is well established and evidence-based, strategies for topical anti-inflammatories in fungal keratitis are poorly defined and lack consensus.

While topical corticosteroids can limit destructive host inflammation, they also suppress local immune defenses and may enhance fungal proliferation, deep stromal invasion, and recurrence.[34,40] Persistent or uncontrolled inflammation can induce stromal melt and lead to visually significant scarring. In general, corticosteroids are believed to be contraindicated in fungal keratitis, although no randomized trials have assessed their role.[25] Support for avoiding corticosteroids in fungal keratitis is primarily on the based on in vitro studies, animal studies, and observational human studies showing prediagnosis steroid exposure associated with deeper infiltrates and increased risk of surgical intervention.[41] A retrospective study reviewing 16 patients with fungal keratitis treated with the addition of corticosteroids following an average of 42 days of topical antifungals found recurrence of infection in only 1 patient.[42,43] While high-quality evidence is limited, most clinicians avoid corticosteroids in the management of fungal keratitis.

TOPICAL CALCINEURIN INHIBITORS (CYCLOSPORINE A, TACROLIMUS)

The therapeutic tension of balancing infection control with suppression of damaging inflammation has spurred interest in alternative topical immunomodulatory agents that can temper inflammatory responses without markedly promoting microbial growth.[44,45]

Calcineurin inhibitors such as cyclosporine and tacrolimus, nonsteroidal anti-inflammatory agents, and other steroid-sparing approaches have emerged as potential adjuncts to anti-infectious treatment, but their efficacy and safety remain incompletely defined.

Calcineurin inhibitors selectively suppress T-cell activation by blocking calcineurin-mediated dephosphorylation of NFAT, thereby reducing IL-2 transcription and clonal expansion.[40,46] Cyclosporine A (CsA) binds cyclophilin while tacrolimus binds FKBP12; both complexes inhibit calcineurin. These agents suppress T-cell-mediated inflammation while preserving innate defenses, providing a critical anti-inflammatory response while minimizing the risk of fueling recurrent infection.

Ophthalmic preparations of these agents at the desired therapeutic concentrations may be a logistical challenge, as they are not commercially available and require compounding. However, calcineurin inhibitors do not induce ocular hypertension or cataract formation and may have some advantages over corticosteroids in some infections.

There is a paucity of published literature on the use of topical calcineurin inhibitors in the treatment of bacterial and Acanthamoeba keratitis.

The use of systemic immunosuppression with cyclosporine and other agents has been reported for the management of Acanthamoeba-induced sclerokeratitis,[31] although topical therapy has not been reported. More high-quality evidence is needed to establish the efficacy and safety of topical steroid-sparing anti-inflammatories in bacterial and amoebic keratitis.

The use of steroid-sparing anti-inflammatory agents in fungal keratitis is of interest, as the use of corticosteroids in the treatment of fungal corneal infections is generally avoided. Laboratory data suggest CsA and tacrolimus may interfere with fungal calcineurin signaling, potentially exerting direct or synergistic antifungal effects with natamycin or azoles in models.[47,48,49]

Topical CsA has accumulated the most supportive clinical experience. Practical considerations include the need for compounding to achieve higher concentrations, as doses of 1%–2% may be necessary to meaningfully suppress T-cell activity, which is below most agents commercially available.

There are a few small reports of CsA use for infectious keratitis in corneal transplant patients, though interpretation of response is complex when considering and delineating the effects of treatment on the active infection vs immunomodulation in these keratoplasty patients. One published case report described the clinical course of a case of methicillin-resistant Staphylococcus aureus keratitis in a corneal transplant where CsA was used to control inflammation after the addition to antimicrobial therapy and topical prednisolone acetate 1%.[50] The authors published worsening of the infectious infiltrate after initiating topical CsA 0.5%. This anecdotal report, while valuable, was complicated by the complex nature of the case with multiple anti-inflammatory modalities used. Small series in post-PK fungal keratitis describe early postoperative CsA (2%) in lieu of steroids with acceptable safety, improved clear graft rates, and low recurrence of fungus.[45]

Topical tacrolimus (0.03%–0.1%) provides a similar mechanism with higher potency by weight. Preclinical models demonstrate synergy with natamycin or voriconazole, with reduced corneal inflammation and fungal burden.[47,48,51] In fungal keratitis, tacrolimus is favored when CsA is not tolerated or available, although ophthalmic suspensions may not be readily available.[44]

NON-STEROIDAL ANTI-INFLAMMATORY DRUGS

Topical non-steroidal anti-inflammatory drugs (NSAIDs) (e.g., diclofenac 0.1%, ketorolac 0.4%) inhibit COX-1/2, lowering prostaglandins and providing analgesia and mild anti-inflammatory effects. They are generally avoided in active infectious ulcers due to concerns for delayed epithelialization and rare associations with stromal melt.[39] Given the limited anti-rejection effect and potential epithelial toxicity, NSAIDs are not recommended for primary inflammation control in infectious keratitis and have no evidence of improving outcomes.

EMERGING APPROACHES

Targeted modulation seeks to blunt select pathways while preserving host defense. Animal studies investigating cytokines (e.g., IL-17, interferon-gamma) reveal that some inflammatory axes are protective, cautioning against indiscriminate blockade. Experimental nuclear factor kappa B pathway inhibition (e.g., fenretinide) and host-response modifiers show preclinical promise but lack human data.[39] Nonpharmacologic adjuncts such as amniotic membrane transplantation have proven valuable in promoting corneal healing. Amniotic membrane therapies can reduce pain, mitigate inflammation, and stabilize areas of stromal thinning, but they are best considered supportive rather than definitive treatment. In keratitis, they can promote epithelial healing and provide a biologic bandage that delivers anti-inflammatory cytokines and growth factors. Consequently, amniotic membrane placement is generally considered an adjunct to primary antimicrobial and anti-inflammatory strategies.[52,53] Riboflavin-mediated photoactivated chromophore cross-linking (PACK-CXL), most commonly used to increase stromal tensile strength in keratoconic eyes, has also been used to treat microbial ulcers. PACK-CXL accelerates the healing of fungal keratitis by reducing pathogen load and conferring anti-inflammatory effects, though randomized trials in fungal keratitis have not shown consistent superiority over antifungals alone.[37,39,54,55,56,57,58]

In mouse models, topical oxidized chondroitin sulfate drops conferred anti-inflammatory activity by halting the recruitment of neutrophils. Another report showed that topical administration of umbilical cord mesenchymal cells reduced corneal scar formation area and corneal opacity by downregulating fibrotic-related factors to exert antifibrotic effects, but findings have not been validated in human clinical studies.[59,60] Human corneal stromal stem cells may also prove beneficial in reducing corneal inflammation and preventing fibrosis.[61] Finally, pentoxifylline, a methylxanthine, has been found to have anti-inflammatory properties in fungal keratitis, reducing the production of proinflammatory factors by stimulating the Nrf2/HO1 pathway, although further research is warranted.[62]

CONCLUSION

Adjunctive anti-inflammatory treatment in conjunction with appropriate anti-microbial therapy in the management of infectious keratitis can hasten and improve corneal recovery and improve visual acuity in select cases. During the acute infection phase, effective and sufficient antimicrobial therapy remains the priority. Establishing the etiology of infection and if possible the sensitivities of the organism to the employed treatment of choice are important steps in determining the safety and utility of initiating anti-inflammatory therapy. Few case series and even fewer randomized-controlled trials are available to support these therapies, and more studies are needed to further establish their safety and the optimal timing and dosing strategies.

Corticosteroid use in infectious keratitis is controversial, but may show some benefit in non-Nocardial bacterial ulcers that are large, deep, central, or classically invasive Pseudomonas aeruginosa. Corticosteroids are generally avoided in fungal infections. Their use in Acanthamoeba keratitis treatment algorithms is controversial, though judicious use for pain control may be supported. Corticosteroid use with miltefosine is generally recommended to control the increased inflammation associated with initiation of this agent.

In fungal keratitis, corticosteroids are avoided in the acute infectious stage, as premature immunosuppression can accelerate fungal proliferation and worsen stromal invasion.[41,63] Selective introduction of a topical calcineurin inhibitor such as CsA or tacrolimus may be considered once there is convincing clinical improvement or immediately after a therapeutic PK, if the infected tissue has been fully excised. While calcineurin inhibitors are especially promising in the treatment of fungal keratitis, they pose a logistical challenge in that effective ophthalmic preparations must be compounded, which may be entirely unavailable in some countries where fungal keratitis is the most common. Expanding commercial production of higher-dose cationic or nanoemulsion formulations with validated sterility and long shelf-life could improve equity and adherence, particularly in low-resource settings where the burden of disease is greatest.

Looking ahead, several future directions hold particular promise. Advances in drug-delivery technology, including cationic emulsions, nano- or microcarriers, drug-eluting contact lenses, and intracorneal or intracameral depots, could enhance corneal penetration of both anti-infective agents and immunomodulators, shorten the sterilization window, and permit earlier safe introduction of anti-inflammatory therapy.[37,39] Sustained-release calcineurin platforms would reduce dosing frequency and improve adherence, offering a critical advantage.[44]

A deeper understanding of corneal innate and adaptive immune networks will enable target-specific modulation, identifying molecular nodes where transient inhibition reduces tissue damage without compromising microbial clearance. Parallel exploration of host-defense augmentation, such as topical cell-penetrating peptides or granulocyte-macrophage colony-stimulating factor analogs, could accelerate sterilization and indirectly reduce the need for prolonged immunosuppression.[36,39]

Personalized medicine will likely play an increasing role. Pathogen-specific inflammatory patterns, host comorbidities, and individual immune phenotypes may guide customized timing, dosing, and agent selection. Incorporating point-of-care diagnostics such as rapid PCR, confocal microscopy criteria for fungal and Acanthamoeba keratitis, and risk-scoring systems could standardize and refine individualized care.

Ultimately, topical anti-inflammatory therapy for infectious keratitis requires a delicate balance: suppress destructive host inflammation without enabling infection persistence or recurrence.

Calcineurin inhibitors (e.g. CsA and tacrolimus) offer a selective, steroid-sparing alternative that can be introduced early to temper T-cell-mediated responses while preserving innate antifungal defenses.[45,64] Their use in antibacterial and antiamoebic infections is less supported. Advances in targeted immunotherapy, innovative delivery platforms, and personalized management paired with wider international access are essential to lessen the worldwide burden of infectious keratitis.

Conflicts of interest

There are no conflicts of interest.

Funding Statement

Nil.