Treating Infectious Keratitis

Infectious keratitis is a potentially blinding corneal condition caused by a diverse array of organisms, including bacteria, viruses, fungi, protozoa, and parasites.^1–3 Prompt antimicrobial therapy offers the best hope for recovery with limited vision loss.^3–5 For bacterial and fungal keratitis, initial broad-spectrum antimicrobial coverage should be followed by targeted, culture and sensitivity-directed treatment – the immediate and long-term goals of which are microbial elimination, re-epithelialization, and structural repair. In addition, a number of ancillary treatments for microbial keratitis have been explored,^4,5 such as adjunctive use of topical corticosteroids and several routes of enhanced delivery of antimicrobial agents, including iontophoresis, intrastromal or intracameral injection, and drug-releasing contact lenses and corneal shields. Studies have also investigated the use of corneal collagen cross-linking with ultraviolet photoactivation of riboflavin—both to inactivate pathogens and to structurally stabilize the cornea.^6–8 Even with these established and emerging approaches, however, corneal infections remain a therapeutic challenge. Three original articles^9–11 in this issue of Ocular Immunology & Inflammation (OII) address adjunctive approaches to the treatment of infectious keratitis.

Accorinti et al.⁹ described the clinical features and outcomes of a series of 20 consecutive patients who presented to the emergency department at the Sapienza University of Rome, Italy, with severe, unilateral central, or paracentral bacterial corneal ulcers associated with dense and deep corneal stromal infiltration and moderate to severe (≥2+) anterior chamber reaction, hence keratouveitis. All were treated with combined intensive topical levofloxacin (5 mg/mL) and tobramycin (0.3%) plus oral levofloxacin (1 g daily). Patients also received topical atropine (1%) twice daily in the affected eye. Following corneal re-epithelialization, 12 patients received prolonged treatment with a drop containing both topical tobramycin (0.3%) and dexamethasone (0.1%). Identified risk factors in the cohort included contact lens use (70.0%), prior corneal trauma (15.0%), previous ocular surgery (5.0%), and preceding viral infection (5.0%). While all eyes had moderate to severe uveitis, nine (45.5%) had hypopyon. Intraocular pressure (IOP) at presentation was not reported. Positive corneal, conjunctival, and/or contact lens cultures were obtained in 11 subjects (55.0%), nine of which (81.8%) showed Pseudomonas either alone or together with Staphylococcus aureus, Klebsiella, Corynebacterium, or Acynetobacterium. Culture of one subject revealed Staphylococcus aureus and of a second subject Serratia marcescens. The mean time to corneal re-epithelialization was approximately 3 weeks (20 ± 12.6 days; range: 8–64 days) and the mean time on topical levofloxacin and tobramycin was about 1 month (29.7 ± 14.4 days; range: 12–64 days). Among the 12 subjects treated with topical tobramycin/dexamethasone four times daily following re-epithelialization, this treatment was continued for a mean of 29.9 ± 12.5 days (range: 14–55 days). Over the variable follow-up in the study (mean = 12.6 months; median = 13 months; range: 4–20 months) best-corrected visual acuity (BCVA) improved in all but one eye (95.0%). While the sample size was small, follow-up variable, and the authors did not describe adjusting the reported p values for multiple testing, their retrospective analyses suggested that vision at last visit tended to be better in patients <60 years of age, independent of the location of the ulcer. No mention was made of attempts to control for other potential confounders, such as the presence or absence of an identified Gram-negative pathogen. Of note, the high rate of keratouveitis in patients with Gram-negative infections, including Pseudomonas, has been confirmed by others.^12,13 The authors concluded that combined use of topical and systemic antibiotics in patients with moderate to severe keratouveitis resulted in re-epithelialization and stabilization or improvement of BCVA in the vast majority of their subjects. While the investigators chose not to use topical corticosteroids early in the course of treatment in their patients, it should be noted that a pre-specified subgroup analysis from the Steroids for Corneal Ulcers Trial (SCUT), a 500-patient, NIH-sponsored, randomized, controlled study,^14–16 demonstrated an improvement in mean vision in eyes with central bacterial ulcers that were treated with a 3-week taper of topical 1% prednisolone phosphate started 2–3 days after initiation of intensive topical antibiotics. This therapeutic benefit of early, adjunctive topical corticosteroids increased with ulcer severity, but was not observed in eyes with Nocardia keratitis.^17,18 The investigators in SCUT also noted that early, adjunctive topical corticosteroid use was associated with improved patient comfort and a five-fold lower rate of infection-induced ocular hypertension, a complication known to occur in nearly one-third of patients with active microbial keratitis.¹⁹ Debate continues, however, whether, when, and how best to use topical corticosteroids in eyes with infectious keratitis.^20–22

Kesavan et al.¹⁰ compared the therapeutic effectiveness of an ion-activated mucoadhesive hydrogel containing gatifloxacin to commercially available topical gatifloxacin solution (both 0.3%) in the treatment of experimental Staphylococcus aureus stromal keratitis in rabbits. Treatment began 24 h after infection and included either twice daily application of a gatifloxacin-containing mucoadhesive hydrogel (n = 6) or four times daily application of gatifloxacin drops (n = 3) for 5 days. Hydrogels contained gellan or sodium alginate, either alone or with sodium carboxymethylcellulose. Both treatments were well-tolerated, with no signs of conjunctival inflammation in any of the animals. While the authors did not report precise p values or state that they corrected these p values for multiple comparisons, they reported less redness, tearing, mucus discharge, eyelid swelling, and sensitivity to touch in eyes treated with the hydrogel as compared with drops at days 4 and 5 of the study (two-tailed Student’s t-tests, nominal p values <0.05). The authors ascribed the enhanced efficacy of their experimental hydrogels to improved pre-corneal residence time of gatifloxacin, and noted the added benefit of decreased dosing frequency. Others have explored the therapeutic use of antibiotic-loaded soft contact lenses to achieve comparable benefits.^23,24

Sharma et al.¹¹ reported the results of a randomized clinical trial in 45 eyes with microscopically-confirmed fungal keratouveitis with hypopyon seen at a tertiary eye center in New Delhi, India. The three treatment arms (n = 15) included: intensive topical natamycin (5%) and amphotericin B (0.15%) – both hourly while awake and every other hour while sleeping; plus oral ketoconazole (200 mg, twice daily); the same topical and oral antifungal agents together with intracameral amphotericin B (5 μg/0.1 mL of 5% dextrose); or the same topical, oral and intracameral antifungal agents administered following hypopyon aspiration and anterior chamber irrigation. Intracameral amphotericin B injections were repeated up to three times, each separated by at least 72 h, in eyes with clinical progression. Nine eyes were culture-positive, seven with Aspergillus flavus and two with Fusarium solani. While the subgroup sizes were small, the authors saw no absolute or trend in difference between the three groups in the overall rate of treatment success, which the authors defined as resolution of stromal infiltrates, healing of the corneal epithelium, and resolution of an endothelial plaque if present – and which ranged from 60.0% to 73.3% across the treatment arms. Similarly, there was no difference in time to healing or BCVA at last visit. Given the small sample size and correspondingly limited statistical power, the authors recommended larger randomized clinical trials to help resolve the roles of both intracameral antifungal administration and anterior chamber irrigation in the management of severe keratomycosis.^25–29

Together, these studies highlight both the challenges of treating infectious keratitis and the promise and importance of novel therapeutic approaches. For now, intensive, topical antimicrobial therapy remains the mainstay of treatment.^3–5

Declaration of Interest

The authors report no conflicts of interest. The authors alone are responsible for the content and writing of the paper.

Funding

Supported in part by The Pacific Vision Foundation (ETC) and The San Francisco Retina Foundation (ETC).