Effectiveness Of Continuous Lavage Of Voriconazole In The Management Of Moderate To Severe Fungal Keratitis:a Randomized Trial

Purpose:To evaluate the efficacy and safety of continuous lavage of voriconazole in the management of moderate to severe fungal keratitis.Methods:31 eyes from 31 patients with moderate to severe fungal keratitis were randomized to the continuous lavage group(n=15)or the topical group(n=16).The patients of continuous lavage group received4-hour continuous lavage of 1%voriconazole every day but it lasted no more than six days.The usage of topical drugs in the continuous lavage group was the same as in the topical group when the continuous lavage was not undergoing.The patients of topical group received 5%natamycin and 1%voriconazole eye drops hourly.If there was inflammation in the anterior chamber,0.5%tropicamide phenylephrine eye drops were added.Both groups was examined every day.If the corneal ulcer was obviously healing,the patient was discharged with topical antifungal drugs at three days after treatment.If the corneal ulcer got worse or unimproved at six days after treatment,surgical treatment was recommended.The primary outcome was treatment success rate.The secondary outcomes were“improved”rate,“unimproved”rate and“deteriorated”rate at six days after treatment,infiltrated size,central corneal thickness and the epithelial defect size at three days and six days after treatment,the degree of uncomfortable feelings and the degree of clinical signs after each continuous lavage.Results:There were no significant difference in baseline demographic and clinical characteristics between the continuous lavage group and the topical group.The most causative organism was Fusarium species(12/31),followed by Aspergillus.spp(5/31).The treatment success rate was 53.3%(8/15)in continuous lavage group and 31.3%(5/16)in topical group.There was no significantly different between the two groups(p=0.21).Further analysis showed that in moderate patients,the treatment success rate was 66.7%(4/6)in the continuous lavage group and62.5%(5/8)in the topical group,respectively.It did not reach statistically difference(p=1.0).But in sever patients,we surprisingly found 4(44.4%)severe patients healed in the continuous lavage group while none(0%)of patients cured in the topical group.However,it still didn’t reach significant difference(p=0.08)due to the small simple size.The risk factors for treatment failure were presence of hypopyon,endothelial plaque or the patients with severe fungal keratitis at enrollment by Cox proportional hazard models.At six days after treatment,the“improved”rate and“unimproved”rate were comparable between the two groups.But the“deteriorated”rate was obviously lower in the continuous lavage group compared to the topical group and it reach significant difference(p<0.05).After controlling for baseline infiltrated size,the infiltrated size in the continuous lavage group was 4.48mm~2less than the topical group at three days after treatment and this was statistically significant(95%CI,2.71 to 6.25;p=0.02).The infiltrated size in the continuous lavage group was 5.36mm~2less than the topical group at six days after treatment and this was also statistically significant(95%CI,3.46 to 7.26;p<0.01).After controlling for baseline values,there was no significant difference in the central corneal thickness or epithelial defect size at three days and six days after treatment.In continuous lavage group,the degree of conjunctival hyperemia and edema was temporarily increased at two days and three days after continuous lavage,respectively(p<0.05).But there was no significant difference between the two groups at other time points.After each continuous lavage,we didn’t find any increased degree of uncomfortable feelings and other clinical signs.Conclusion:In our study,continuous lavage of voriconazole was an effective,safe,convenient and noninvasive method to treat funal keratitis,especially in severe fungal keratitis.By continuous lavage,it was beneficial to reduce the occurrence of deteriorative events,control the progress of the disease and reduce the size of lesion.For patients who eventually need to undergo corneal transplantation,it may help reduce the rates of recurrence and immune rejection caused by large-diameter graft.But it need a large scale of clinical samples to demonstrate in the furture.