ulcers are often thought to respond poorly to treatment and have worse clinical outcomes than other bacterial ulcers.1,9,10
However, in this subanalysis of a large clinical trial, we found that, when compared with other bacterial ulcers of the same presentation severity, P. aeruginosa
corneal ulcers responded significantly better to treatment, with approximately 1.5 lines greater improvement in visual acuity from presentation to 3-month follow-up that was not attributable to ulcer enrollment characteristics (BSCVA, infiltrate/scar size, depth, and location). In fact, even though they have significantly worse clinical presentations, P. aeruginosa
ulcers do not have significantly worse overall visual outcomes at 3 months when compared with all other bacterial ulcers. There was also no evidence of a significant difference in adverse events between P. aeruginosa
ulcers and other bacterial ulcers, including perforations. These findings suggest that P. aeruginosa
ulcers may not be as difficult to treat or may not result in worse clinical outcomes, as had been previously thought.
The use of adjunctive corticosteroid therapy is particularly controversial for P. aeruginosa
corneal ulcers. Corticosteroids have been shown to reduce the host inflammatory response, which may be damaging to the cornea.14,20,21
However, corticosteroids may also significantly slow the process of corneal wound healing, prolong infection, and predispose to stromal thinning and perforation, especially in P. aeruginosa
infections, which are known to be more invasive and to cause rapid systemic tissue destruction.1,9,10,13,22
Patients receiving corticosteroid treatment before
presentation for corneal infection have been reported to be at triple the risk for complications, including treatment failure.22
Additionally, animal studies have found corticosteroid treatment in the absence of antibiotic treatment to be associated with increased bacterial growth and recurrence of P. aeruginosa
keratitis in rabbit corneas.11,12
However, other animal studies have demonstrated that corticosteroid treatment given concurrently with appropriate antibiotic therapy reduces inflammation but does not interfere with the bactericidal action of antibiotics and does not lead to increased bacterial growth.23,24
The results of this study indicate there is no significant difference, either benefit or harm, in 3-month BSCVA or infiltrate/scar size among P. aeruginosa ulcers treated with adjunctive corticosteroids compared with placebo. Although multivariate analysis suggested a slight benefit with corticosteroid treatment over placebo for both 3-month BSCVA and infiltrate/scar size, these findings were not statistically significant. The large number of P. aeruginosa ulcers from SCUT allowed for the detection of small changes in visual acuity: a priori power calculations estimated >80% power to detect approximately a 2-line difference in visual acuity; post hoc, the 95% CI of the interaction term was approximately ±2 lines of visual acuity, suggesting that a large true effect would not be missed. Subgroup analysis did not find any differential effect for corticosteroid efficacy dependent on baseline clinical characteristics.
This study also found no evidence of an increase in adverse events with corticosteroid treatment. Corneal perforation, increased intraocular pressure, and delayed corneal healing are recognized potential adverse events associated with corticosteroid therapy, particularly in P. aeruginosa
One previous prospective study was discontinued after a patient with a P. aeruginosa
ulcer worsened following the addition of corticosteroid treatment and required a penetrating keratoplasty for a large central scar.13
However, we found no difference in the number of perforations between corticosteroid and placebo-treated P. aeruginosa
ulcers with one patient in each treatment arm. Although corticosteroids may increase IOP, patients with P. aeruginosa
ulcers receiving corticosteroid treatment in SCUT were not more likely to have elevated IOP than those receiving placebo; in fact, there were more patients with elevated IOP in the placebo arm than in the corticosteroid arm.
Delayed corneal wound healing is also a recognized potential adverse effect of corticosteroid therapy.11,12,22
The pilot study for SCUT found adjunctive corticosteroid treatment to be associated with a significant delay in the reepithelialization of corneal ulcers secondary to all bacterial organisms.17
However, though there were more reported cases of epithelial defects at 21 days and beyond in the corticosteroid arm, time to reepithelialization was not significantly different between the two treatment arms in SCUT.18
In this substudy, within the P. aeruginosa
subgroup, there were more patients who had an epithelial defect at 21 days or beyond in the corticosteroid arm than in the placebo arm, but this difference was not statistically significant. Cox regression analysis also demonstrated that time to reepithelialization was not significantly different between the two study arms. Recurrence of epithelial defect can be another measure of corticosteroid effect on corneal healing. Only one patient with a P. aeruginosa
ulcer experienced a recurrence of epithelial defect. Although this patient was treated with corticosteroids, there was no significant difference between the two treatment arms. Therefore, our present study did not find a significant delay in the measures of healing time and recurrence of epithelial defect for P. aeruginosa
ulcers treated with corticosteroids.
This study has a few potential limitations. Because most patients were enrolled at the Aravind Eye Care System in India, it is possible that differences in risk factors, bacteriology, and response to treatment in this population may make these results not generalizable to other populations. P. aeruginosa
infections are most common among contact lens wearers in the United States.1
In SCUT, although most contact lens wearers had P. aeruginosa
infection, a low proportion of the total P. aeruginosa
cases occurred in contact lens wearers because contact lens use is less common in India.2,19
This difference in associated risk factors may reflect genotypic variation in P. aeruginosa
strains between the two countries. Variations of pathogenicity between P. aeruginosa
strains could contribute to differing outcomes and responses to adjunctive corticosteroid therapy. Sensitivity analysis demonstrated no effect of study site on outcome; nevertheless, results may be biased toward P. aeruginosa
strains found in India. The SCUT criteria for a positive bacterial culture, defined as growth of the organism on one solid medium at the site of inoculation (with more stringent criteria for coagulase-negative Staphylococcus
and diphtheroids), may differ from microbiologic criteria in other studies. The choice of treatment regimen in SCUT, both antibiotic and corticosteroid, might also have affected outcomes because choice of agent, number of agents used, concentration, and administration timing and route are all factors in treatment efficacy. Because of potential safety concerns, a more aggressive corticosteroid regimen was not chosen. The treating physician did have the option of adding or changing antibiotics during the trial if deemed necessary. Within the P. aeruginosa
subgroup, the number of antibiotic changes was greater in the placebo treatment arm than in the corticosteroid treatment arm.
Although P. aeruginosa ulcers in SCUT had a more severe presentation than the other bacterial ulcers, this subanalysis suggests that P. aeruginosa ulcers respond better to treatment than previously thought. There appears to be no definite benefit for visual outcome and infiltrate/scar size with corticosteroid treatment in P. aeruginosa ulcers. However, the lack of any significant difference in adverse events with corticosteroid therapy suggests that adjunctive corticosteroid therapy may be used according to clinical judgment that takes into account the specific features of an individual case.