Corticosteroids in the Management of Infectious Keratitis: A Concise Review

Abstract

Microbial keratitis is devastating corneal morbidity with a variable spectrum of clinical manifestations depending on the infective etiology. Irrespective of the varied presentation delayed treatment can lead to severe visual impairment resulting from corneal ulceration, possible perforation, and subsequent scarring. Corticosteroids with a potent anti-inflammatory activity reduce host inflammation, thus minimizing resultant scarring while improving ocular symptoms. These potential effects of corticosteroids have been applied widely to treat various corneal diseases ranging from vernal keratoconjunctivitis to dry eye disease. However, antimicrobial therapy remains the mainstay of treatment in microbial keratitis, whereas the use of adjunctive topical corticosteroid therapy remains a matter of debate. Understandably, the use of topical corticosteroids is a double-edged sword with pros and cons in the treatment of microbial keratitis. Herein we review the rationale for and against the use and safety of topical corticosteroids in the treatment of infective keratitis. Important considerations, including type, dose, efficacy, the timing of initiation of corticosteroids, use of concomitant antimicrobial agents, and duration of corticosteroid therapy while prescribing corticosteroids for microbial keratitis, have been discussed. This review intends to provide new insights into the therapeutic utility of steroids as adjunctive treatment of corneal ulcer.

Introduction

Microbial keratitis is devastating corneal morbidity characterized by cellular infiltration, edema, and subsequent necrosis caused by varied pathogens. The severity, spectrum of clinical features, and outcomes vary with the type of organism. It is one of the leading causes of preventable blindness in the world with varied incidence from 10/100,000 persons per year in the United States to 799/100,000 persons per year in developing countries.^1,2 The World Health Organization (WHO) has recognized microbial keratitis as an emerging cause of visual disability,³ with over 90% of the disease load in the developing countries.⁴

Being a preventable and treatable condition, it is imperative to be informed about all potential and approved treatment modalities of infective keratitis. The mainstay of treatment in infective keratitis is targeted against specific causative organisms by way of broad-spectrum topical and systemic antimicrobial agents. Adjunctive treatment comprises lubricants, cycloplegics, and antiglaucoma drugs to support ocular healing and mitigate complications.

The use of corticosteroids in the treatment of corneal ulcers is not backed by a clear consensus and harbors contradictory views on various aspects relating to corneal wound healing and visual outcome. Although judicious use of corticosteroids is hypothesized to limit the inflammatory component of bacterial keratitis, it can delay healing and potentiate pathogens. Corticosteroids reduce host inflammation, minimize resultant scarring, and improve ocular symptoms.^5–9 However, they can cause relative immunosuppression, a decrease in inflammation, and delayed epithelization, which may further aggravate the infection due to increased bacterial survival and proliferation and subsequently corneal melting and poor visual outcomes.¹⁰

Understandably corticosteroids remain a double-edged sword with pros and cons in the treatment of infective keratitis. Practicing ophthalmologists frequently face the need for a standard guideline for the administration of corticosteroids in selected cases. This review provides a comprehensive analysis of current literature and summarizes evidence on the use of corticosteroids in microbial keratitis and its outcome. Furthermore, it presents the classical understanding of the role of steroids in corneal diseases and various studies conducted over the years. This would impart a clearer perspective on the judicious and safer use of corticosteroids in human patients and allow researchers to develop newer therapeutics for treating and preventing infective keratitis.

Corneal Wound Healing Mechanisms

Infective pathologies of the cornea in the acute phase attract activated immune cells which release an array of cytokines, proteinases, and growth factors that lead to stromal remodeling involving keratocyte apoptosis and obliteration of collagens.^11–13 Corticosteroids are known to initiate an anti-inflammatory cascade on the targeted tissues by virtue of their inherent properties. Corticosteroids likely reduce inflammatory response, including reduced expression of pro-inflammatory cytokines and immune cell infiltration. They inhibit neutrophil chemotaxis, thereby reducing the collagenase and cytokine-induced ulceration and scarring.^13–19 As these immune cells are the major defending cells, there would be an increase in the bacterial burden, which causes further tissue damages by the virulent factors. In addition, they suppress corneal infiltrate and decrease anterior chamber reaction.²⁰ Later on, as a secondary response the viable keratocytes are transformed to activated fibroblasts (myofibroblasts) that function to restore the tissue loss.^12,21,22 However, they can initiate irregular deposition of collagen and extracellular matrix with subsequent corneal haze and scarring, which in most part remain irreversible, if not disappear timely and adequately.^22,23

Corticosteroids through multiple mechanisms can favorably modify wound healing in the inflamed cornea of infectious keratitis and, therefore, have the potential to reduce stromal melting, neovascularization, corneal scarring, and endothelial decompensation. The mechanisms postulated to facilitate this include inhibition of polymorphonuclear leukocytes, inhibition of pro-inflammatory cytokines, chemotactic factors, neutrophil chemotaxis and decreased collagenase burden,^{15,18,19,24–27} inhibition of epithelial cytokines leading to downregulation of matrix metalloproteinase production, facilitation, and enhanced reepithelialization secondary to reduced inflammation,²⁸ and enhanced stromal clarity secondary to the elimination of polymorphonuclear leukocytes from the stroma.²⁹

Contrary to the above declarations, there are arguments against the use of corticosteroids in infectious keratitis for a cautious use. For example, topical corticosteroid use, especially in compromised corneas like preexisting corneal and ocular surface diseases, may act as a predisposing factor toward infectious keratitis if used without concomitant antibiotic coverage.^30,31 The use of topical corticosteroids in bacterial keratitis delays epithelial healing; inhibition of neutrophil chemotaxis may further exacerbate the infection severity, particularly in absence of adequate antimicrobial cover.^13,14 Furthermore, the administration of topical corticosteroids is associated with a considerably increased chance of antibiotic failure.^30,32,33 These may interfere with corneal repair mechanisms in an event of uncontrolled infection and hence exacerbate stromal collagenolysis, which predisposes the cornea to progressive ulceration, thinning, and/or perforation.²⁹

Steroids as Anti-Inflammatory Agent in Corneal Diseases

Various in vivo and in vitro studies have been conducted widely to evaluate the action of corticosteroids on corneal tissues.^34,35 In experimental corneal wounds cortisone has been shown to inhibit the formation of the fibrinous coagulum, cellular infiltration, fibroblastic repair, and endothelial regeneration.^36,37 Apart from the effect in reducing corneal scarring, their major use lies in the suppression of corneal inflammation. These potential effects of corticosteroids have been applied widely to treat various corneal diseases.

Topical corticosteroids play an important role in controlling acute exacerbations in allergic eye diseases with predominant corneal manifestations such as vernal keratoconjunctivitis and atopic keratoconjunctivitis. Supratarsal injection of steroids is effective in refractory, severe, and advanced cases of allergic eye diseases.³⁸ However, corticosteroids should be restricted for long-term use, due to their potentially serious side effects such as secondary glaucoma.³⁹

The effectiveness of topical corticosteroids in corneal neovascularization with distinct benefits is well documented in the literature.^40–44 Pathological blood vessels in corneal neovascularization are immature and lack structural integrity, with a potential to predispose the cornea to lipid exudation, inflammation, and scarring. Topical corticosteroids are the mainstay of treatment for the suppression of these early proliferating corneal vessels.^40–44 Mechanism of action is primarily the suppression of inflammation associated with neovascularization and not angioregressive per se.⁴⁵

Several randomized clinical trials have demonstrated that short-term topical corticosteroid use improves signs and symptoms of dry eye disease (DED).⁴⁵ In addition, short-term corticosteroid treatment has shown to improve symptoms and the majority of signs of DED in tandem with a lowering of tear cytokine levels and improved filamentary keratitis.^46,47 The “Tear Film and Ocular Surface Society Dry Eye Workshop II (TFOS DEWS II)” recommends the use of topical steroids; typically, with low-strength corticosteroids in the management of keratoconjunctivitis sicca.⁴⁸

Corneal involvement of Graft Versus Host Disease (GVHD) may cause an acute or chronic immune-mediated inflammatory manifestation of the ocular surface. Systemic corticosteroids are the mainstay of treating the acute exacerbations of chronic GVHD; adjunctive topical steroids are often used to promote tapering and cessation of systemic immunosuppression. Topical corticosteroids are the mainstay of management of acute graft rejection after corneal transplantation. Nevertheless, pulsed intravenous and/or oral steroids have been shown to improve the percentage of graft survival in cases of endothelial and high-risk rejection cases.^49,50

Rationale for Use of Steroids in Corneal Ulcer

Pathogenic invasion of corneal tissue is accompanied by cellular destruction and the consecutive reparative response of cellular components. This infection, inflammation, and subsequent repair determine the course of bacterial keratitis. The host inflammatory response is the major determinant of outcome. Mild corneal ulcers heal without corneal opacity, while moderate-to-severe cases may progress to perforation sloughing and subsequent scar formation of varying degree, depth, and size. The inflammatory response is mediated by interleukins, cytokines such as interleukin-1, and tumor necrosis factor to facilitate neutrophil migration and degranulation causing further necrosis. In addition, platelet-activating factor upregulates metalloproteinases, which can cause further stromal necrosis.⁵¹

The treatment goal in infective keratitis is to eliminate the infectious organism, thereby limiting the cellular damage in addition to reducing the inflammatory response, which can be a cause of further destruction of corneal tissues. Corticosteroids being potent anti-inflammatory agents have been used for the same in the treatment of corneal haze following refractive procedures and the treatment of herpes simplex virus keratitis.^52–54

Corticosteroids can cause suppression of prostaglandin mediated inflammation; therefore, in theory, by virtue of their anti-inflammatory effect can decrease subsequent tissue necrosis neovascularization and scarring.⁹ This control of inflammation-mediated damage serves as a main driver in salvaging useful visual acuity.

Important Considerations While Prescribing Steroids for Microbial Keratitis

Having gained important insights, as described above, on different aspects of corticosteroid use, it is prudent to study important determinants of corneal wound healing as a correlate of steroid prescription. Following is a description of factors affecting the outcome of microbial keratitis with concurrent use of steroids.

Type and dose

Appropriate selection of corticosteroid formulation and dosage of administration are important considerations for optimized therapeutic effects while minimizing the potential risk of impaired tissue healing. Topical administration in the appropriate dosage remains useful in the reduction of corneal inflammation. The acetate derivatives of various corticosteroids have been shown to be the most effective commercially available anti-inflammatory agents. McDonald et al.⁵⁵ studied the effect of various steroid formulations (dexamethasone alcohol, dexamethasone acetate, and dexamethasone phosphate) on corneal wound healing in rabbits, which showed a linear association of wound tensile strength with time in control eyes. No steroid preparation had an inhibitory effect on wound healing after 72 h of treatment. In a study by Sugar and Chandler,⁵⁶ dexamethasone 0.1% administered thrice a day on rabbit eyes having partial-thickness linear corneal wounds caused a decrease in tensile wound strength when administered during the first postoperative week. However, it did not cause any reduction in corneal tensile wound strength when initiated at the third postoperative week. Gritz et al.¹⁶ noted an increased rate of recurrent keratitis after subconjunctival corticosteroid treatment in patients with Pseudomonas keratitis.

Topical corticosteroids in the form of dexamethasone and prednisolone have been reported by various authors. However, the outcome as reported does not deviate much in terms of final visual acuity and corneal ulcer treatment. Carmichael et al. randomized 40 eyes of 39 bacterial keratitis patients who received dexamethasone 0.1% or placebo 4 times a day along with antimicrobial treatment.⁵⁷ Dexamethasone 0.1% was continued until complete healing for at least 2 weeks. Another study by Blair et al. included 30 randomized participants with bacterial keratitis who received either dexamethasone 0.1% or placebo 4 times a day.⁵⁸ Dexamethasone 0.1% was given 4 times a day for 3 weeks, then it was tapered 2 times a day for a week and then once daily for the 5th week. Both studies reported no statistically significant differences in terms of best-corrected vision, ulcer healing rate, and adverse events at a mean follow-up of 2.5 months between the 2 groups of patients.

Use of prednisolone eye drops as adjunctive treatment in bacterial keratitis has been reported in a pilot study by Srinivasan et al.⁵⁹ Patients were administered topical prednisolone sodium phosphate 1% or placebo 4 times a day for 1 week, 2 times a day for 1 week, and once a day for the 3rd week. There was no difference in corneal scar size, best-corrected visual acuity (BCVA), and adverse effects between the 2 patient groups. However, a statistically significant delay in corneal reepithelialization was noted in the corticosteroid-treated group. Subsequently, the Steroids for Corneal Ulcers Treatment Trial (SCUT) utilized prednisolone sodium phosphate 1% as the study drug while accessing the outcome of cases in the study group in comparison to placebo as adjunctive therapy. This was not indicative of any additional advantage in healing ulcers and improving visual outcome.⁶⁰ However, the prednisolone treated group showed delayed epithelial healing.⁶⁰

Efficacy against possible pathogens

The anti-infective efficacy of steroids lacks uniformity in varied pathogens and thus accords a potential risk of progression and complication in certain pathogens such as Pseudomonas, fungi, and Nocardia.^61–65 Various studies which have been conducted on the potential efficacy of topical steroids in corneal ulcer were composed of specific utility against the particular pathogen as one of the terms of reference.^62,63–65 Steroids have been found to be relatively efficacious against gram positive infection with central ulcers up to 4 mm with resultant post treatment improvement in visual acuity without any significant deleterious effects.⁶⁰ In contrast, steroids are contraindicated in a possible fungal infection and patients who with a history of trauma as a predisposing factor.^60,61,66

Animal studies suggest that topical corticosteroids may have a beneficial effect in cases of bacterial keratitis involving Pseudomonas aeruginosa, Streptococcus pneumoniae, or Staphylococcus aureus.^{15,16,25–27,67–69} The virulence of pathogens like Pseudomonas carries a justifiable hesitancy toward the use of steroids. Wilhelmus et al.³⁰ reviewed cases of 19 studies and found 3 studies with adverse outcomes, 6 studies with beneficial outcomes, and 10 studies with neutral outcomes. It is to note that studies showing adverse outcomes were flawed for reasons of antibiotic resistance,⁷⁰ while other studies used an inadequate antibiotic dosage⁷¹ and long-acting subconjunctival injection of a corticosteroid.¹⁶ Likewise, in HSV stromal keratitis topical steroids have a known benefit for reducing the inflammation.⁷²

Aronson and Moore⁷³ reported rapid clinical recovery after the initiation of corticosteroids in infective keratitis, caused by bacterial, viral, and fungal etiologies. Visual acuity outcomes and corneal healing rates were similar between the groups stratified as per the pathogens, suggesting a possible outcome benefit for worse ulcers treated with corticosteroids in addition to antibiotics.⁵⁸ There have been reports of recurrence of Pseudomonas keratitis after initiation of steroids.⁷⁴ Experimental data, mainly in rabbits, suggest no adverse effects so long as an appropriate antibiotic is given concurrently with steroids. This has been shown for Pseudomonas and S. aureus infections. However, Smolin et al. suggested that wound healing may be delayed, and there may be prolonged replication of organisms in Pseudomonas infections.⁷⁵ Special care should be exercised while treating S. pneumoniae and P. aeruginosa infections, as they can reactivate after an initial positive response to antibiotics.

The use of corticosteroids is an absolute contraindication in the treatment of fungal keratitis and a relative contraindication in the treatment of Acanthamoeba keratitis (AK).^62,76 Fungal infections seem to be adversely affected by the use of steroids owing to the fungistatic action of available antifungal agents on the cornea. It is believed that steroid treatment should be delayed for 24 h to account for rapidly deteriorating cases and fungal infections. It seems prudent to reduce or discontinue steroid treatment if healing is delayed. To demonstrate identifiable benefits of steroids, a large sample size prospective study would be needed, perhaps multicentric trials involving objectively curated assessment techniques.

Optimal timing

Evidence in favor of the timing of initiation of steroids has different perspectives. It is important to be informed about when to supplement the standard antimicrobial therapy with steroids, once the infection is controlled. Corticosteroids limit the inflammatory response through decreased expression of pro-inflammatory cytokines and reduced collagenase activity, subsequently leading to decreased scarring.^6,14 However, in the presence of active infection steroids, it can render a deleterious effect on the healing process. Furthermore, it is difficult to ascertain when the lesion gets sterile. Thus, the initiation of steroids for the treatment of infective keratitis remains a contentious issue. Early institution of topical corticosteroids in bacterial keratitis has been argued to reduce the severity of corneal stromal melt, neovascularization, and subsequent scarring, which occur as a result of the host inflammatory and immune responses to the bacterial infection.¹⁹ Reportedly, early addition of steroids to the antimicrobial therapy for corneal ulcer does not seem to be harmful when used in a closely monitored clinical setting.⁵⁸

The timing of the institution of steroid therapy mainly depends on the type of keratitis and clinical parameters. In the SCUT corticosteroids were found to be beneficial when administered early showing 1.3 lines of improvement at 3 months compared with placebo and neutral when given later.⁶⁰ Early initiation of corticosteroids resulted in the improvement in visual acuity by at least one-line across ulcers of all severities compared with a placebo. Furthermore, subgroup analysis of SCUT reported that the efficacy of topical corticosteroids depends upon early administration for more central corneal ulcers with poorer visual acuity at presentation, for invasive Pseudomonas strains, and for non-Nocardia ulcers.^62,63 Thus, early administration of corticosteroids may be beneficial, while late administration seems associated with limited improvement.^77,78

Concomitant antibiotics

Concomitant use of antimicrobial agents along with corticosteroid therapy is an important aspect with regard to good control of infection complimented by the anti-inflammatory effect of steroids. Wilhelmus et al.³⁰ comprehensively summarized 24 studies in which corticosteroids and antibiotics were concomitantly started after bacterial inoculation of the cornea, typically within 48 h. The authors noted a beneficial effect of topical corticosteroids in 37.5% of studies, a neutral effect in 50%, and an adverse effect in 12.5%. Moreover, animal studies have demonstrated the efficacy of bactericidal antibiotics in killing the most virulent bacteria, including S. aureus, when used simultaneously with steroids.^{15,16,24–27,69,70}

In a study involving 75 patients with the active central stromal disease, 17 patients were administered intensive topical corticosteroid in addition to topical antibiotic therapy.⁷³ Eight of these patients received 7–10 days of antimicrobial therapy before the institution of steroids, and 9 received antibiotics along with concurrent corticosteroids. Authors reported that the use of steroids enhanced the resolution of the disease process and, in some cases, resulted in a favorable response when the use of antibiotics alone had been clinically ineffective. However, results differed significantly in relation with location of ulcer, with favorable visual outcomes observed in patients with paracentral lesions while severe central lesions ultimately underwent penetrating keratoplasty. Hence the study lacked clarity on whether the final outcome was improved by the use of corticosteroids. In addition, recurrence was observed in 2 patients after discontinuation of therapy.⁷³

Patient compliance is reported to be better with topical steroids in conjunction with frequent instillation of fortified antibiotics by decreasing pain and discomfort. Several randomized controlled trials have been conducted to assess the effect of concurrent use of corticosteroids with antibiotics on bacterial keratitis.^57–60

Studies have compared vision, ulcer healing rate, and time to reepithelialization and adverse events in 2 groups: administration of topical antibiotics alone versus antibiotic plus corticosteroid therapy. Broadly, these studies did not report any definitive advantages or disadvantages from the adjunctive use of topical corticosteroid drops in bacterial keratitis.

Duration of therapy

Duration of corticosteroid administration in corneal ulcers remains an important consideration while managing such cases. In a double-blinded randomized clinical trial, Blair et al. evaluated the benefit of early addition of topical corticosteroids to antibiotics in the treatment of corneal ulcers.⁵⁸ Out of 30 participants, 15 received a topical antibiotic (gatifloxacin) or a masked placebo, while the other 15 received a similar antibiotic along with a masked topical corticosteroid (dexamethasone 0.1%). No conclusive differences were observed in both primary (residual ulcer size at 10 weeks based on digital photographs) and secondary (residual ulcer area by clinician estimate, visual acuity, VF-14 score, and time to healing) outcome measures. Carmichael et al. studied the effect of dexamethasone 0.1% 4 times a day in conjunction with fortified cefazolin 32 g/L and gentamicin 14 g/L hourly for 24 h. Dexamethasone 0.1% was continued until complete healing with a minimum of 2 weeks. They reported no statistically significant difference in terms of best-corrected vision, ulcer healing rate, and adverse events at a mean follow-up of 2 or 2.5 months.⁵⁷ In a pilot study ahead of SCUT, patients were pretreated with moxifloxacin 0.5% hourly (while awake) for 48 h before the initiation of either topical corticosteroid (prednisolone sodium phosphate 1%) or placebo 4 times a day.⁵⁹ Patients were given topical corticosteroids 4 times a day for 1 week, 2 times a day for 1 week, and once a day for the 3rd week. The topical antibiotic was given every 2 h while awake until reepithelialization, and it was then reduced to 4 times a day until the end of the 3rd week. There was no difference in corneal scar size, BCVA, and adverse effects between the 2 patient groups. However, a statistically significant delay in reepithelialization was noted in the corticosteroid-treated group.⁵⁹

Steroids in Corneal Ulcer: Evidences Till Date

Several randomized controlled trials with at least one large sample-sized trial (the SCUT) have been conducted to provide new insights into the therapeutic utility of steroids as adjunctive treatment of corneal ulcer (Table 1).^{33,57–60,62,63} Adjunctive topical corticosteroids initiated after at least 48 h of appropriate antimicrobial therapy with demonstrable signs of ulcer healing in culture-proven cases appear to be of benefit in the treatment of some pathogens while of limited benefit to others.

Table 1.

Compendium of Prospective Clinical Studies on the Adjunctive Use of Topical Corticosteroids for Infectious Keratitis

Sr No	Author/Year	No of cases/eyes	Group	Treatment and control arm	Parameters	Follow-up	Conclusion/Inferences
1	Carmichael et al. 1990⁵⁷	40	Bacterial corneal ulcer	Antibiotic (fortified Cefazolin 32 g/L and fortified gentamicin 14 g/L) + Steroid (topical dexamethasone 0.1%) group: 21 eyes Only Antibiotic (fortified Cefazolin 32 g/L and fortified gentamicin 14 g/L) group: 19 eyes	(1) Complications; (2) Healing rates (mm² of ulcer per day); (3) Visual acuity	2 months	Insignificant differences in BCVA, healing rate, and complications between 2 arms
2	Srinivasan et al. 2008⁵⁹	42	Bacterial corneal ulcer	Antibiotic (topical moxifloxacin 0.5%) + Steroid (topical prednisolone phosphate) group: 20 eyes Antibiotic (topical moxifloxacin) + Placebo group: 22 eyes	(1) The primary outcome was best spectacle-corrected visual acuity (BSCVA) at 3 months Other prespecified outcomes included: (1)Reepithelialization time, (2)Infiltrate/scar size, and (3)Adverse events	3 Weeks and 3 Months	Compared with placebo, patients in the steroid group reepithelialized more slowly. No significant difference in BSCVA or infiltrate/scar size and adverse events at 3 weeks or 3 months between 2 groups. To have 80% power to detect a 2-line difference in acuity, 360 cases would be required for conducting a larger clinical trial.
3	Blair et al. 2011⁵⁸	30	Bacterial corneal ulcer	Antibiotic (topical gatifloxacin) and a masked placebo group: 15 eyes Antibiotic (topical gatifloxacin) and masked steroid (topical dexamethasone 0.1%): 15 eyes	Primary outcome was: (1) Residual ulcer size at 10 weeks based on digital photographs Secondary outcomes were: (2) Residual ulcer area by clinician estimate (3) Visual acuity (4) VF-14 score (5) Time to healing	10 weeks	No significant difference between the 2 arms in both primary and secondary outcome measures Early addition of steroids to the antibiotic treatment of bacterial corneal ulcers does not seem to be harmful when used in a closely monitored clinical setting.
4	Srinivasan et al. 2012⁶⁰	500	Bacterial corneal ulcer	Antibiotic (topical moxifloxacin 0.5%) plus Steroid (Prednisolone phosphate 1%): 250 eyes vs Antibiotic (topical moxifloxacin 0.5%) plus Placebo (0.9% sodium chloride): 250 eyes	Primary outcome measure was (1) BSCVA at 3 months from enrolment Secondary outcome, measures were (2) Infiltrate/scar size, (3) Duration for reepithelialization, (4) BSCVA at 3 weeks and 12 months, and (5) Adverse events, including corneal perforation	3 weeks, 3 months, and 12 months	No significant difference between the 2 arms in both primary and secondary outcome measures
Subgroup analysis
4a	Lalitha et al. 2012⁶³	55	Nocardia corneal ulcer	—	BSCVA and infiltrate or scar size at 3 months from enrolment	3 months	Steroid treated cases have significantly larger infiltrate or scar sizes at 3 months but without any difference in BSCVA
4b	McClintic et al. 2014³³	50	Bacterial corneal ulcer	—	BSCVA at 12 months and 4 years	4 Years	No significant difference in BSCVA between 12 months and 4 years Bacterial keratitis cases treated with steroids may continue to demonstrate improvements in visual acuity up to 12 months following diagnosis, but further improvements are unlikely
4c	Aileen Sy et al. 2012⁶²	99	Pseudomonas aeruginosa corneal ulcer	—	(1) BSCVA at 3 months (2) Scar/infiltrate size (3) Rate of adverse events	3 months	No statistically significant difference in either BSCVA and size of scar at 3 months or in the rate of adverse events. P. aeruginosa corneal ulcers have a more severe presentation; they appear to respond better to treatment than other bacterial ulcers.

BCVA, best-corrected visual acuity; BSCVA, best spectacle-corrected visual acuity.

Bacterial keratitis

The recent past has witnessed an increasing trend in the use of topical steroids in the management of bacterial keratitis. Some studies have reported favorable outcomes. In a retrospective study, comparing changing trends in clinical course and outcome of bacterial keratitis, researchers evaluated the treatment group to a cohort of patients in years 1995 and 2005. In presence of clinical evidence of a favorable clinical response, topical corticosteroid therapy was initiated after 48 h in confirmed Gram-positive keratitis and after 72 h in confirmed mixed Gram-positive and Gram-negative keratitis. There was a significant increase in the use of topical corticosteroid in 2005 in addition to almost similar topical fortified antibiotic regimens, and statistically significant improvements in the clinical outcome of cases of bacterial keratitis (mainly severe keratitis), compared to those admitted in 1995.⁷⁹ Improved pharmacological intervention, particularly the use of adjunctive anti-inflammatory therapy, may have contributed to the better results (shortened inpatient duration and improved final visual outcome) observed in this study.

Topical corticosteroid therapy in the treatment of bacterial keratitis warrants strict adherence to appropriate protocols to avoid potential complications.⁸⁰ Miedziak et al. in a case–control study compared the outcome of microbial ulcer based on medical therapy alone versus penetrating keratoplasty. They reported topical corticosteroids as one of the risk factors for poor outcome.⁸¹ Results indicated that early use of topical corticosteroids is not only an independent risk factor for the microbial ulcer requiring penetrating keratoplasty but also is correlated significantly with the delay in referral of subjects to a tertiary center or cornea specialist.⁸¹ Indiscriminate use of corticosteroids by general ophthalmologists is reported as a potential risk factor for a poor visual prognosis in a corneal ulcer.⁸²

The limited number of studies, diverse cohorts, treatment bias, follow-up attrition, and multiple inherent confounding factors associated with retrospective studies make the concluding statements equivocal and disputable.

Acanthamoeba keratitis

AK is usually seen to be associated with severe corneal inflammation and pain.⁸³ Theoretically, topical corticosteroids can help alleviate the acute symptoms by relieving pain and inflammation. However, with the potential to downregulate immune responses and thus aggravate infection, the use of corticosteroids remains a matter of concern in treating AK. Results from many previous studies supported the fact that it is the timing of the institution of corticosteroids that plays a major role in AK outcomes.

Early institution of corticosteroids has been observed to be associated with poorer outcomes in AK, but the majority of such cases are deemed to be complicated by lengthy diagnostic delay. Cohen et al. in series of 7 patients with AK that received corticosteroids for initial incorrect diagnosis and/or treatment⁸⁴ reported treatment failure in 5 out of 7 cases requiring penetrating keratoplasty; however, all of these had a diagnostic delay of ≥6 weeks. Rabinowitch et al. on 14 cases of AK concluded that topical corticosteroid use was the single most important factor predicting failure of medical treatment.⁸⁵ Stern et al. reviewed retrospectively the available research in 1991 and recommended that corticosteroid use was relatively contraindicated for AK.⁸⁰ However, these observations were biased by the less effective anti-amoebic regimens available before the introduction of biguanide therapy in 1992 and might have contributed to poorer outcomes.⁸⁶ Corticosteroid use was observed to be associated with suboptimal outcomes before the initiation of anti-amoebic therapy.⁸⁷

Arguably in cases with early diagnosis and timely institution of anti-amoebic therapy, the use of corticosteroids does not appear to be associated with treatment failure. Three out of 5 cases with a shorter diagnostic period achieved resolution with a final visual acuity of 20/20 when topical corticosteroids were used.⁸⁸ In a retrospective analysis of 38 patients with AK, authors concluded that topical corticosteroids were not associated with a higher rate of medical treatment failure.⁸⁹ Instead, prudent use of corticosteroids in selected patients with severe pain—not responding to analgesics and cases with severe corneal or anterior chamber inflammation—appears justified. In one of the largest retrospective cohort study of 196 cases with AK, Carnt et al. observed substantial evidence to support the potential benefits of topical corticosteroid therapy for treating pain and discomfort.⁹⁰ Use of corticosteroids was not associated with worse outcomes when initiated after starting standard anti-amoebic therapy.

These observations support the use of well-timed administration of topical corticosteroids in AK; however, other potential benefits, especially in terms of resolution of inflammatory complications, need a carefully designed randomized clinical trial to provide a substantial outcome in favor of corticosteroids.

Mycotic keratitis

The addition of topical corticosteroids as adjunctive therapy in fungal keratitis is associated with progression and increased risk of complications, as there is no convincing evidence of benefit. There is rather a significant potential to interfere with the efficacy of antifungal agents, since corticosteroids may enhance fungal replication.^64,65,91,92 Therapeutic benefits also remain a contentious issue owing to inadequate evidence in favor of corticosteroids in the management of mycotic keratitis. Moreover, an initial misdiagnosis of the condition and consequent treatment with topical antibiotics and corticosteroids is a frequent occurrence. Kuntsson et al., in a small case series, observed a rebound inflammation after few days of discontinuing the corticosteroids in a cohort of mycotic keratitis patients receiving corticosteroids before diagnosis.⁶⁷ Results of this study as well as previous reports suggest that abrupt corticosteroid discontinuation may lead to the development of unpredictable consequences requiring rapid medical or surgical care.^67,76

Nocardia keratitis

With an emerging prevalence in South Asia, Nocardia spp has been observed to be a commonly associated cause of infectious keratitis.^93,94 With an established role of amikacin in the treatment of Nocardia keratitis, and better visual outcomes in comparison to other infectious keratitis, only sparse literature is available to support the utility of topical corticosteroids in its management.

Prospective subanalysis of a SCUT demonstrated that the use of corticosteroids resulted in larger infiltrate/scar sizes in Nocardia keratitis. These cases were observed to have significantly less improvement in visual outcomes and infiltrate/scar size at 3 months than the ulcers due to all other bacteria.⁶³ Results indicated that there may not have been room for dramatic improvement with the addition of topical corticosteroids, as seen in ulcers of other etiologies.⁶²

SCUT: a landmark study

A pilot study was conducted by Srinivasan et al. as a preliminary clinical trial to assess whether adjunctive topical corticosteroid therapy improves outcome in bacterial keratitis and to determine the feasibility and sample size necessary for conducting a larger clinical trial to address this controversial issue.⁵⁹ This single-center, double-masked clinical trial included 42 patients from South India with culture-confirmed bacterial keratitis. Patients were randomized to receive either topical corticosteroids (prednisolone phosphate) or placebo in addition to topical antibiotics (moxifloxacin). The authors observed no significant difference in the best spectacle-corrected visual acuity (BSCVA) at 3 months. In comparison to the placebo group, patients in the steroid group took a longer time for corneal reepithelialization. The study concluded that corticosteroid as adjunctive treatment resulted in a statistically significant delay in corneal reepithelialization without affecting BSCVA, infiltrate size, or adverse events. This highlights the need for further trials with larger sample size.⁵⁹

The aforementioned pilot study with its indicative results provided the platform for the first largest randomized clinical trial. SCUT enrolled 500 participants for a multicenter, prospective, randomized, placebo-controlled, double-masked clinical trial.⁹⁵ The primary outcome measure was BSCVA at 3 months from enrolment, while secondary outcome measure included infiltrate/scar size, the duration for corneal reepithelialization, and adverse event particularly corneal perforation. At 3 months, there was no significant difference between patients receiving topical corticosteroid or placebo as adjunctive therapy concerning BSCVA, infiltrate/scar size, and time to resolution of corneal epithelial defect. No obvious benefits and no serious safety concerns were observed while using corticosteroids in the overall study population.⁹⁵

Subsequent subgroup analysis put forth an intriguing observation that corticosteroid treatment was found to be associated with significant benefit in BSCVA at 3 months compared with the placebo group in a subset of patients with severe grades of corneal ulcer with impaired visual acuity and large-deep and centrally located ulcers involving the pupil. However, ulcer location was the only baseline characteristic that significantly differed across the 2 treatment arms. Results showed, although not statistically significant, that BSCVA was better in the corticosteroid group compared to the placebo group with non-Nocardia ulcers. This particular observation might be of significance as it is quite consistent with the 12-month SCUT results and may indicate a potential long-term benefit of corticosteroids in non-Nocardia ulcers.^33,60,77

To elicit expert opinion on the use of adjunctive corticosteroid therapy in bacterial corneal ulcers, a Bayesian analysis, using the questionnaire data as a prior probability and the primary outcome of SCUT as a likelihood involving Indian and North American experts, produced results similar to those produced by the SCUT primary analysis and had similar expectations on the effectiveness of corticosteroids in bacterial corneal ulcers; that corticosteroids would markedly improve visual outcomes.⁹⁶

Complications of Steroid Therapy in Infectious Keratitis

Topical corticosteroids can be a cause of significant deleterious ocular effects which can get potentiated in the setting of compromised corneal integrity. The steroid-treated corneas have a substantial probability to worsen the infection and subsequent corneal thinning, melting, and perforation. Topical corticosteroids can predispose to decreased corneal wound strength as demonstrated in few animal studies.^55,56 Potentiation of infection can occur consequent to a decrease in absorption of topical antibiotics due to the corticosteroid potentiation of the vasoconstrictive effect of local catecholamines. In addition, corticosteroid induced inhibition of neutrophils compromises the local ocular defense and can worsen infections or cause recurrences in absence of inadequate antibiotic cover.^15,16 Moreover, topical corticosteroid use is considered as a single independent risk factor for ulcer development, and its use along with bandage soft contact lens has the greatest effect for the development of infectious keratitis per se.³¹

Delayed corneal epithelial healing from adjunctive corticosteroid therapy has always been a matter of concern. Topical corticosteroids were found to decrease the migration of corneal epithelial cells and delayed epithelial healing in patients after refractive surgery, as well as in experimental animals with alkali burns.^13,14 The results of various prospective clinical trials showed no significant difference in the rate of corneal reepithelialization among the patients receiving topical corticosteroids as adjunctive therapy.^57–60

A possible association of corticosteroid to corneal thinning in patients has been a concern for a majority of treating ophthalmologists. However, to date, there is no compelling evidence to support or prove a risk of corneal thinning directly attributable to corticosteroid use. Various prospective clinical studies on bacterial keratitis revealed no significant risk of corneal thinning with the use of topical corticosteroids. Moreover, various studies done on postpenetrating keratoplasty, postcataract surgery, and patients of uveitis treated with topical corticosteroids for a longer period do not report corneal thinning from the use of topical corticosteroids.^97–101

Elevation of intraocular pressure (IOP) and development of cataract^102,103 are well-proven adverse effects associated with the use of topical corticosteroids for ocular use. The risk of increased IOP is seen in about 30% of cases and is largely dependent on the duration of therapy and potency of the particular agent used. However, the prospective studies have failed to demonstrate an increase in Intraocular pressure (IOP) with the use of topical corticosteroids as adjunctive therapy in bacterial keratitis.

Contraindications of Steroids in Corneal Ulcer

The role of corticosteroids has always been a controversial issue in the management of keratitis.^62,65 Furthermore, its use is absolutely contraindicated in certain specific conditions like corneal ulcers of unknown origin carrying a significant risk for rapid progression to an advanced stage. It is important to emphasize that all study participants in the SCUT were started on topical corticosteroids after 48 h of antibiotic use in proven bacterial keratitis. However, even for microbiologically confirmed bacterial keratitis, it is imperative to closely monitor the clinical picture to prevent secondary fungal superinfection in patients with predisposing factors like poor contact lens hygiene, history of trauma, preexisting chronic ocular surface disease, and in the tropical climate.

However, in the absence of substantial evidence in support of steroid use, possible severe clinical course for use of corticosteroids in conditions which predispose to fungal growth is contraindicated, in addition to Acanthamoeba and/or Nocardia keratitis before starting specific antimicrobial therapy.

Summary

The undisputable knowledge supported by evidence has indicated that the judicious use of topical corticosteroids in conjunction with the appropriate antibiotics as per the sensitivity pattern is effective for limiting corneal damage in bacterial keratitis. However, it is important to be apprised of the following considerations while instituting steroids for the treatment of corneal ulcer;

(1)

Corticosteroids should be started only when culture and sensitivity reports are available. They are contraindicated in noncultured ulcers.

(2)

Corticosteroids are contraindicated for all fungal etiology.

(3)

Corticosteroids should be started only under the cover of appropriate broad-spectrum antibiotics in combination with frequent administration and fortification if deemed. Antibiotics should be continued till such time the steroids are in use.

(4)

It is prudent to start steroids when there is clear evidence of resolution of ulcer reflected by improvement in clinical features.

(5)

Prednisolone phosphate 1%, or prednisolone acetate 1%, and dexamethasone 0.3% 3–4 times daily can be started with tailored treatment wherever necessary.

(6)

Response to treatment should be evaluated every 24 h to assess any improvement or worsening of clinical condition subsequently to modify the treatment.

(7)

Corticosteroids are not indicated for healing corneal ulcers and when not involving the pupillary axis. In addition, they should be avoided in the 67 mk presence of stromal thinning, progressive ulcers, poor wound healing, diabetes, or immunosuppression.

(8)

Subconjunctival administration should be avoided owing to their bolus dose causing prolonged action.

Conclusion

Despite the potent anti-inflammatory effect of topical corticosteroids, relative safety, and lack of adverse events in many clinical trials, the use of this therapy remains contentious. Earlier similar ambiguity existed regarding the use of topical corticosteroids in the treatment of herpes simplex stromal keratitis. However, multiple randomized clinical trials put forth important recommendations based on the outcome of trials importantly, the herpetic eye disease study. Similar prospective randomized trials are warranted to better understand the positive and negative impact of topical corticosteroid treatment in the management of infective keratitis. We expect that such a study would provide definitive guidance to clinicians in this contentious matter for the ultimate benefit of the patients.

Method of Literature Search

A literature review was performed within PubMed, MedlinePlus, and Google Scholar using the following keywords: corticosteroids, topical corticosteroids, infectious keratitis, microbial keratitis, bacterial keratitis, corneal ulcer, corticosteroids and keratitis, corticosteroids and corneal ulcer, treatment, trials in corneal ulcer, the role of corticosteroids, and eye. One keyword/phrase from each cluster was used, unless repeated. All reports consisting of ≥10 patients, published before October 2020, were screened and evaluated with relevant studies and then included. Reference lists of these articles were also searched to be included if clinically relevant.

Footnotes

Author Disclosure Statement

No competing financial interests exist.

Funding Information

No funding was received for this article.

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