Acanthamoeba keratitis - A review.

This is a comprehensive review after a thorough literature search in PubMed-indexed journals, incorporating current information on the pathophysiology, clinical features, diagnosis, medical and surgical therapy, as well as outcomes of Acanthamoeba keratitis (AK). AK is a significant cause of ocular morbidity, and early diagnosis with timely institution of appropriate therapy is the key to obtaining good outcomes. The varied presentations result in frequent misdiagnosis, and co-infections can increase the morbidity of the disease. The first line of therapy continues to be biguanides and diamidines, with surgery as a last resort.

A 5-Year Review of Coinfections in Acanthamoeba keratitis From South India.

PURPOSE: To ascertain the frequency of coinfections in Acanthamoeba keratitis, the nature of copathogens involved, and to analyze the implications in the context of current research on amoebic interactions. METHODS: A retrospective case review from a Tertiary Care Eye Hospital in South India. Smear and culture data for coinfections in Acanthamoeba corneal ulcers were collected from records over a 5-year period. The significance and relevance of our findings in the light of current research on Acanthamoeba interactions were analyzed. RESULTS: Eighty-five cases of culture-positive Acanthamoeba keratitis were identified over a 5-year period (43 of them being coinfections). Fusarium was most commonly identified species, followed by Aspergillus and the dematiaceous fungi. Pseudomonas spp was the commonest bacterial isolate. CONCLUSION: Coinfections with Acanthamoeba are common at our centre, and account for 50% of Acanthamoeba keratitis. The diverse nature of the organisms involved in coinfections suggest that such amoebic interactions with other organisms are probably more widespread than recognized. To the best of our knowledge, this is the first documentation from a long-term study of pathogen diversity in Acanthamoeba coinfections. It is possible that Acanthamoeba itself may be virulence enhanced and secondary to the co-organism, breaching the ocular surface defenses in an already compromised cornea. However, observations from the existing literature on Acanthamoeba interactions with bacteria and certain fungi are based mainly on nonocular or nonclinical isolates. It would be illuminating if such studies are performed on Acanthamoeba and coinfectors from corneal ulcers-to ascertain whether interactions are endosymbiotic or virulence enhanced through amoebic passage.

Characteristics and Outcomes of Sepsis Presenting in Inpatient Pediatric Settings.

OBJECTIVE: The pediatric sepsis literature lacks studies examining the inpatient setting, yet sepsis remains a leading cause of death in children's hospitals. More information is needed about sepsis arising in patients already hospitalized to improve morbidity and mortality outcomes. This study describes the clinical characteristics, process measures, and outcomes of inpatient sepsis cases compared with emergency department (ED) sepsis cases within the Improving Pediatric Sepsis Outcomes data registry from 46 hospitals that care for children. METHODS: This retrospective cohort study included Improving Pediatric Sepsis Outcomes sepsis cases from January 2017 to December 2019 with onset in inpatient or ED. We used descriptive statistics to compare inpatient and ED sepsis metrics and describe inpatient sepsis outcomes. RESULTS: The cohort included 26 855 cases; 8.4% were inpatient and 91.6% were ED. Inpatient cases had higher sepsis-attributable mortality (2.0% vs 1.4%, P = .025), longer length of stay after sepsis recognition (9 vs 5 days, P <.001), more intensive care admissions (57.6% vs 54.1%, P = .002), and greater average vasopressor use (18.0% vs 13.6%, P <.001) compared with ED. In the inpatient cohort, >40% of cases had a time from arrival to recognition within 12 hours. In 21% of cases, this time was >96 hours. Improved adherence to sepsis treatment bundles over time was associated with improved 30-day sepsis-attributable mortality for inpatients with sepsis. CONCLUSIONS: Inpatient sepsis cases had longer lengths of stay, more need for intensive care, and higher vasopressor use. Sepsis-attributable mortality was significantly higher in inpatient cases compared with ED cases and improved with improved sepsis bundle adherence.

A case of stromal microsporidiosis: medical strategies employed for successful resolution.

We describe the diagnosis and successful management of a case of stromal microsporidiosis, an important emerging ocular disease. Stromal microsporidiosis is recalcitrant and very often requires therapeutic keratoplasty for effective eradication. We successfully managed a steroid-treated case diagnosed only after 9 months, with a combination of polyhexamethyl biguanide 0.04%, chlorhexidine 0.04% and fluconazole 0.3% eye drops supplemented with tablet albendazole. However, complete resolution was achieved only after epithelial debridement. Toxicity due to the drugs was not noted. Diagnostic delays, steroid use and inappropriate therapy are commonly observed in stromal microsporidiosis. In spite of these potential disadvantages, our case responded well with complete eradication of the infection. The disease being fairly indolent and slowly progressive, medical therapy should be continued, in the absence of progression or other complications. Epithelial debridement may facilitate healing.

Voriconazole in the successful management of a case of Acanthamoeba-Cladosporium keratitis.

PURPOSE: Acanthamoeba and fungal infections can be recalcitrant to therapy - more so when the deeper layers of the corneas are involved. We describe the diagnosis and successful management strategies employed in a case of deep keratitis due to co-infection with Acanthamoeba and Cladosporium sp. OBSERVATIONS: Once the diagnosis of co-infection with both Acanthamoeba and Cladosporium was made, treatment was initiated with a combination of PHMB, chlorhexidine, natamycin, and voriconazole; to which the response was favorable. Signs of relapse with spread of the infection to the deeper plane and the presence of endothelial exudates were noted at 5 weeks. This was attributed to poor compliance. Though the response to re-initiation of therapy under direct supervision was once again favorable; it was only after the introduction of intrastromal voriconazole repeated at timely intervals that rapid and complete resolution was obtained. CONCLUSIONS: Severe keratitis due to fungi or Acanthamoeba very often requires surgical intervention. Complete resolution with medical therapy was obtained only after the introduction of intrastromal voriconazole; thereby avoiding a therapeutic keratoplasty. The addition of voriconzole both topically and particularly intrastromally facilitated faster resolution as well as restricted the duration of therapy with more toxic drugs such as phmb and chlorhexidine.

Pediatric keratoconus - Current perspectives and clinical challenges.

Keratoconus is an ectatic corneal disease characterized by progressive stromal thinning, irregular astigmatism, and defective vision. It can be unilateral or bilateral with asymmetric presentation. It starts at puberty and either progresses rapidly to an advanced stage of the disease or stops in case of delayed onset and slow progression. Pediatric keratoconus is more aggressive than in adults and the management protocols differ because of various rationales such as accelerated progression, advanced stage of disease at the time of diagnosis and co-morbidities. It poses a burden to the society as it affects the quality of life, social, and educational development in children. Hence early diagnosis, recognition of progression, and timely intervention with collagen crosslinking is imperative to arrest the worsening. Association with systemic syndromes and ocular comorbidities can be of concern in pediatric keratoconus. Severe ocular allergy when associated hastens progress and complicates timely intervention of crosslinking treatment and compliance to contact lens wear. Keratoplasty in pediatric keratoconus has good outcomes but can encounter frequent suture-related concerns. This article discusses the epidemiology, etiopathogenesis, clinical challenges, and current perspectives of management of pediatric keratoconus.

Cluster of Post-Operative Endophthalmitis Caused by Acanthamoeba T10 Genotype - A First Report.

PURPOSE: To report a cluster of postoperative Acanthamoeba endophthalmitis after routine cataract surgeries. METHODS: A brief summary of sentinel events leading to the referral of 4 patients of postoperative endophthalmitis to our hospital is followed by clinical descriptions and the various diagnostic approaches and interventions used. Genotyping and phylogenetic analysis are also discussed. RESULTS: Four cases of postoperative cluster endophthalmitis, presumed to be bacterial and treated as such, were referred to our hospital. The presence of an atypical ring infiltrate in the first case facilitated the diagnosis of Acanthamoeba endophthalmitis. All patients had vitritis, corneal involvement, and scleral inflammation. Multiple diagnostic methods, such as corneal scrapings, confocal microscopy, aqueous and vitreous taps, scleral abscess drainage, histopathological studies, polymerase chain reaction, and genotyping and phylogenetic analyses of isolated Acanthamoeba, were used to confirm the diagnosis of endophthalmitis and to establish the extent of ocular involvement. Various medical and therapeutic interventions used to control the infections were also documented. The isolated Acanthamoeba were confirmed as belonging to the T10 genotype, an environmentally and clinically rare variety. CONCLUSIONS: This is the first report of a cluster of postoperative T10 genotype Acanthamoeba endophthalmitis, occurring after routine cataract surgery in immunocompetent individuals. Contrary to current perceptions, a rapidly evolving infection can occur with Acanthamoeba.

Conidiobolus, a hitherto unidentified pathogen in microbial keratitis.

Fungal infections are a significantly increasing cause of ocular and systemic morbidity; the vast majority of cases being ascribed to a handful of species. Fungal keratitis, unlike systemic infections, usually occur in immunocompetent individuals. Rarely, systemic infections can be associated with ocular involvement (e.g., Candida, Mucor, Pythium), or a fungus that predominantly causes systemic disease can affect the eye. One such fungus is Conidiobolus which is known to cause muco-cutaneous infections. We report the identification and successful treatment of a case of Conidiobolus corneal ulcer in an immunocompetent individual, who had no co-existing muco-cutaneous disease. Identification of this particular fungus and awareness of its potential to cause systemic disease is especially relevant, given its potential for chronic indolent infection of the subcutaneous tissues. To the best of our knowledge, this is the first reported case of a Conidiobolus corneal ulcer.

Fulminant Acanthamoeba Endophthalmitis After Cataract Surgery-A Case Report.

PURPOSE: To report a case of Acanthamoeba endophthalmitis after an uneventful cataract surgery. METHODS: Description, management, and outcomes of a biopsy-proven case of Acanthamoeba endophthalmitis. RESULTS: Two days after a routine cataract surgery elsewhere, the patient presented with acute endophthalmitis diagnosed as a bacterial infection based on timing and severity. When conventional methods of management failed, the patient was referred to us. Only the presence of an atypical ring infiltrate suggested Acanthamoeba as a probable cause. Subsequent diagnostic evaluations confirmed the initial suspicion. Management with topical antiamoebics and intracameral and intravitreal voriconazole was attempted. Systemic voriconazole and metronidazole were also administered. However, because of relentless disease progression, the eye had to be eviscerated. The cornea, aqueous, vitreous, and sclera were positive by culture and/or polymerase chain reaction and histopathology. CONCLUSIONS: Acanthamoeba usually causes a chronic smoldering keratitis and, very rarely, scleritis. This report, which is the first of its kind, emphasizes the fact that fulminant endophthalmitis with associated scleritis can occur after ocular surgery in an immunocompetent individual, with no significant ophthalmic history.

The Acanthamoeba-Fungal Keratitis Study.

PURPOSE: To ascertain the incidence of Acanthamoeba keratitis and the coexistence of Acanthamoeba and fungi in microbial keratitis. DESIGN: Prospective cross-sectional study. METHODS: Patients presenting with stromal keratitis were additionally tested for Acanthamoeba irrespective of the clinical diagnosis. Culture positivity was the gold standard. RESULTS: Of the 401 cases included in the study, 40 were positive for Acanthamoeba (10%); of these 40, 16 were positive for both Acanthamoeba and fungi (4.5% of the study group was Acanthamoeba and fungal keratitis positive); 5 were positive for Acanthamoeba and bacteria; and 2 had triple infection with Acanthamoeba, fungi, and bacteria. Ring infiltrates and stromal edema are frequently associated with Acanthamoeba keratitis, as well as in Acanthamoeba coinfections. Ring infiltrates in particular were more frequently seen in the Acanthamoeba and fungal keratitis group (8/16) and they were often yellowish with hyphate edges (vs ring infiltrates only, which are seen in the patients with Acanthamoeba alone). Only 2 patients were contact lens wearers: however, they presented with history of trauma. CONCLUSIONS: Acanthamoeba coinfections are much more frequent and are not restricted to contact lens users. Anticipating coinfections is necessary for establishing a diagnosis as well as for appropriate and timely therapeutic interventions.

Pythium insidiosum and Acanthamoeba keratitis in a contact lens user.

The oomycete Pythium and the protozoan Acanthamoeba can cause fulminant and recalcitrant keratitis, respectively. These infections are not only sight-threatening but can also threaten the structural integrity of the eye. A high index of suspicion is required to identify Pythium keratitis given its uncommon occurrence. Acanthamoeba keratitis is most commonly associated with contact lens wear. However, its coexistence with Pythium has not been reported. We present the successful management of a case of contact lens-related keratitis, coinfected with Pythium and Acanthamoeba.

Diagnostic Evaluation of Co-Occurrence of Acanthamoeba and Fungi in Keratitis: A Preliminary Report.

PURPOSE: To test the hypothesis that the coexistence of Acanthamoeba with other forms of microbial keratitis, especially fungal keratitis (FK), is more prevalent than suspected. METHODS: A prospective diagnostic study whereby patients presenting with stromal keratitis were additionally tested for Acanthamoeba, irrespective of the initial diagnosis. In addition to the routine workup with Gram stain, KOH mount, and cultures on blood agar and potato dextrose agar, nonnutrient agar was included. Confocal microscopy was performed where feasible. Samples for polymerase chain reaction studies were also obtained. We present the preliminary report of the first 100 culture-positive cases. The primary outcome measured was the number of coexistent Acanthamoeba and FK. The secondary outcomes were the total number of Acanthamoeba cases detected and the correlation between clinical diagnosis and microbiological observations. RESULTS: Of the first 100 cases, 22 were culture positive for Acanthamoeba, of which 9 were associated with concurrent FK, 5 with bacterial keratitis, and 8 in isolation. However, only 2 cases were diagnosed clinically as Acanthamoeba, whereas 5 were Acanthamoeba suspects. An additional 4 cases of fungal/Acanthamoeba coexistence in keratitis were revealed purely by confocal microscopy. CONCLUSIONS: Acanthamoeba can coexist with other forms of microbial keratitis. The frequency of infection coexistent or otherwise is higher than reported, and the possibility of coinfection must be considered especially in unresponsive cases. Including nonnutrient agar and confocal microscopy in all cases of keratitis would perhaps translate into better treatment strategies and outcomes.

Effect of pretreatment with antifungal agents on clinical outcomes in fungal keratitis.

BACKGROUND: To determine if pretreatment with antifungal agents is predictive of worse clinical outcome in a fungal keratitis clinical trial. DESIGN: Non-pre-specified subgroup analysis of a randomized controlled trial in a tertiary hospital. PARTICIPANTS: Three hundred twenty-three fungal ulcer cases with an enrolment visual acuity of 20/40 to 20/400. METHODS: The Mycotic Ulcer Treatment Trial I was a randomized, double-masked trial to determine the optimal treatment for filamentous fungal keratitis at the Aravind Eye Care System, India. Enrolled cases were randomized to receive topical natamycin or voriconazole. Prior antifungal medication use, dose and duration were collected at enrolment. A subgroup analysis was performed to determine if patients using natamycin or azoles at presentation have worse clinical outcomes compared with those who were not pretreated. MAIN OUTCOME MEASURES: Three-month visual acuity (primary), 3-month infiltrate or scar size, corneal perforation and/or transplant and re-epithelialization time. RESULTS: Of the 323 patients enrolled, 44% presented on an antifungal agent. Pretreated patients had larger mean baseline infiltrate size (P < 0.001) and epithelial defect size (P = 0.02). Multivariate regression analysis demonstrated that pretreatment was associated with significantly worse 3-month visual acuity (P = 0.006), larger 3-month scar size (P < 0.001) and increased odds of corneal perforation and/or transplant (P = 0.001). CONCLUSIONS: Fungal keratitis that is smear-positive despite being pretreated with appropriate antifungal agents appears to be a risk factor for worse outcomes, likely a result of initial ulcer severity and treatment failure. These patients may benefit from more aggressive multimodal therapy at a tertiary centre.

Changing Azole Resistance: A Secondary Analysis of the MUTT I Randomized Clinical Trial.

IMPORTANCE: The development of multiple triazole resistance in pathogenic filamentous fungi has become an increasing clinical concern and has been shown to increase the risk for treatment failure. OBJECTIVE: To determine whether antifungal resistance increased during the Mycotic Ulcer Treatment Trial I (MUTT I), as measured by minimum inhibitory concentrations (MICs) in baseline cultures. DESIGN, SETTING, AND PARTICIPANTS: This secondary analysis of a double-masked, multicenter, randomized clinical trial included patients with culture- or smear-positive filamentous fungal corneal ulcer and a baseline visual acuity of 20/40 to 20/400. Culture-positive samples with susceptibility testing were included in this analysis. The patients were treated at multiple locations of the Aravind Eye Care Hospital system in South India. Data were collected from April 3, 2010, to December 31, 2011, and analyzed from July 15 to September 1, 2015. INTERVENTIONS: Corneal smears and cultures were obtained from all study participants at baseline. Susceptibility testing was performed for each culture-positive specimen. MAIN OUTCOMES AND MEASURES: Minimum inhibitory concentration of voriconazole and natamycin in baseline cultures. RESULTS: Of 323 participants with smear-positive specimens (183 men [56.7%]; 140 women [43.3%]; median [interquartile range] age, 47 [38-56] years), fungal-positive cultures were obtained for 256 (79.3%). The MIC data were available for 221 of 323 participants (68.4%), because 35 samples had no growth during susceptibility testing. A 2.14-fold increase per year (95% CI, 1.13-4.56; P = .02) in voriconazole MICs after controlling for the infectious organism was found. This association was not found when looking at natamycin MICs of baseline cultures after controlling for the infectious organism (1.26; 95% CI, 0.13-12.55; P = .85). CONCLUSIONS AND RELEVANCE: Susceptibility to voriconazole appeared to decrease during the relatively short enrollment period of the clinical trial. This decrease may be more related to increased resistance of environmental fungi rather than previous treatment with azoles, because presenting with azole treatment was not a risk factor for resistance. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT00996736.

Risk factors for low vision related functioning in the Mycotic Ulcer Treatment Trial: a randomised trial comparing natamycin with voriconazole.

BACKGROUND/AIMS: The Mycotic Ulcer Treatment Trial I (MUTT I) was a double-masked, multicentre, randomised controlled trial, which found that topical natamycin is superior to voriconazole for the treatment of filamentous fungal corneal ulcers. In this study, we determine risk factors for low vision-related quality of life in patients with fungal keratitis. METHODS: The Indian visual function questionnaire (IND-VFQ) was administered to MUTT I study participants at 3 months. Associations between patient and ulcer characteristics and IND-VFQ subscale score were assessed using generalised estimating equations. RESULTS: 323 patients were enrolled in the trial, and 292 (90.4%) completed the IND-VFQ at 3 months. Out of a total possible score of 100, the average VFQ score for all participants was 81.3 (range 0-100, SD 23.6). After correcting for treatment arm, each logMAR line of worse baseline visual acuity in the affected eye resulted in an average 1.2 points decrease on VFQ at 3 months (95% CI -1.8 to 0.6, p<0.001). Those who required therapeutic penetrating keratoplasty had an average of 25.2 points decrease on VFQ after correcting for treatment arm (95% CI -31.8 to -18.5, p<0.001). Study participants who were unemployed had on average 28.5 points decrease on VFQ (95% CI -46.9 to -10.2, p=0.002) after correcting for treatment arm. CONCLUSIONS: Monocular vision loss from corneal opacity due to fungal keratitis reduced vision-related quality of life. Given the relatively high worldwide burden of corneal opacity, improving treatment outcomes of corneal infections should be a public health priority. TRIAL REGISTRATION NUMBER: Clinicaltrials.gov Identifier: NCT00996736.

Topical 5% Natamycin With Oral Ketoconazole in Filamentous Fungal Keratitis: A Randomized Controlled Trial.

PURPOSE: To assess the role of additive oral antifungal therapy in deep keratitis caused by filamentous fungi. DESIGN: A randomized, masked, double-blind clinical trial. METHODS: All patients presenting with culture-positive fungal keratitis with a size measuring 2 to 60 mm2 and involving more than 50% of stromal depth were enrolled in 1 of the 2 treatment arms. Group A received 5% natamycin, whereas Group B was given 200mg of oral ketoconazole twice a day in addition to 5% natamycin. Patients were followed up for 4 weeks. Liver function was assessed at baseline and at exit. Tests for significance included t test to compare the means of continuous variables, chi-square and Fisher's exact tests for comparing categorical variables and Kaplan-Meier procedure to estimate the survival rate. RESULTS: Of the 115 patients enrolled, 108 completed the study. Fifty-eight patients were in group A and 57 in group B. There was no significant difference in baseline characteristics or in ulcer characteristics between the 2 groups. In group A, 68.5% of the patients responded favorably to medical therapy, whereas in group B, 72.2% responded favorably. There was no statistically significant difference in healing between the 2 groups (P = -0.618). All patients had normal liver functions during the study. CONCLUSIONS: Although safe, oral ketoconazole did not add significant benefit to topical natamycin therapy in treating deep fungal keratitis. The efficacy of newer antifungal agents and drug delivery routes needs to be explored.

Vision-Related Quality-of-Life Outcomes in the Mycotic Ulcer Treatment Trial I: A Randomized Clinical Trial.

IMPORTANCE: Given the limitations in health care resources, quality-of-life measures for interventions have gained importance. OBJECTIVE: To determine whether vision-related quality-of-life outcomes were different between the natamycin and voriconazole treatment arms in the Mycotic Ulcer Treatment Trial I, as measured by an Indian Vision Function Questionnaire. DESIGN, SETTING, AND PARTICIPANTS: Secondary analysis (performed October 11-25, 2014) of a double-masked, multicenter, randomized, active comparator-controlled, clinical trial at multiple locations of the Aravind Eye Care System in South India that enrolled patients with culture- or smear-positive filamentous fungal corneal ulcers who had a baseline visual acuity of 20/40 to 20/400 (logMAR of 0.3-1.3). INTERVENTIONS: Study participants were randomly assigned to topical voriconazole, 1%, or topical natamycin, 5%. MAIN OUTCOMES AND MEASURES: Subscale score on the Indian Vision Function Questionnaire from each of the 4 subscales (mobility, activity limitation, psychosocial impact, and visual function) at 3 months. RESULTS: A total of 323 patients were enrolled in the trial, and 292 (90.4%) completed the Indian Vision Function Questionnaire at 3 months. The majority of study participants had subscale scores consistent with excellent function. After adjusting for baseline visual acuity and organism, we found that study participants in the natamycin-treated group scored, on average, 4.3 points (95% CI, 0.1-8.5) higher than study participants in the voriconazole-treated group (P = .046). In subgroup analyses looking at ulcers caused by Fusarium species and adjusting for baseline best spectacle-corrected visual acuity, the natamycin-treated group scored 8.4 points (95% CI, 1.9-14.9) higher than the voriconazole-treated group (P = .01). Differences in quality of life were not detected for patients with Aspergillus or other non-Fusarium species as the causative organism (1.5 points [95% CI, -3.9 to 6.9]; P = .52). CONCLUSIONS AND RELEVANCE: We found evidence of improvement in vision-related quality of life among patients with fungal ulcers who were randomly assigned to natamycin compared with those randomly assigned to voriconazole, and especially among patients with Fusarium species as the causative organism. Incorporation of quality-of-life measures in clinical trials is important to fully evaluate the effect of the studied interventions. TRIAL REGISTRATION: clinicaltrials.gov Identifier:NCT00996736.

Clinical features and management of ocular lesions after stings by hymenopteran insects.

We describe the ocular alterations and the management after stings from Hymenopteran insects. In all the five patients, the insect was identified as bee. The patients presented with significant corneal edema, which resolved dramatically in three of them after removal of stingers. Among the other two one went for permanent corneal decompensation and the other developed Intumuscent cataract with increased intraocular pressure. Although a rare occurrence, ocular trauma caused by Hymenopteran insects has a potential to cause severe ocular damage in humans. A high level of clinical suspicion and immediate removal of the stingers along with administration of high doses of topical and systemic steroids is a must to prevent chances of permanent corneal damage and intraocular complications.

The mycotic ulcer treatment trial: a randomized trial comparing natamycin vs voriconazole.

OBJECTIVE: To compare topical natamycin vs voriconazole in the treatment of filamentous fungal keratitis. METHODS: This phase 3, double-masked, multicenter trial was designed to randomize 368 patients to voriconazole (1%) or natamycin (5%), applied topically every hour while awake until reepithelialization, then 4 times daily for at least 3 weeks. Eligibility included smear-positive filamentous fungal ulcer and visual acuity of 20/40 to 20/400. MAIN OUTCOME MEASURES: The primary outcome was best spectacle-corrected visual acuity at 3 months; secondary outcomes included corneal perforation and/or therapeutic penetrating keratoplasty. RESULTS: A total of 940 patients were screened and 323 were enrolled. Causative organisms included Fusarium (128 patients [40%]), Aspergillus (54 patients [17%]), and other filamentous fungi (141 patients [43%]). Natamycintreated cases had significantly better 3-month best spectacle-corrected visual acuity than voriconazole-treated cases (regression coefficient=0.18 logMAR; 95% CI, 0.30 to 0.05; P=.006). Natamycin-treated cases were less likely to have perforation or require therapeutic penetrating keratoplasty (odds ratio=0.42; 95% CI, 0.22 to 0.80; P=.009). Fusarium cases fared better with natamycin than with voriconazole (regression coefficient=0.41 logMAR; 95% CI,0.61 to 0.20; P<.001; odds ratio for perforation=0.06; 95% CI, 0.01 to 0.28; P<.001), while non-Fusarium cases fared similarly (regression coefficient=0.02 logMAR; 95% CI, 0.17 to 0.13; P=.81; odds ratio for perforation=1.08; 95% CI, 0.48 to 2.43; P=.86). CONCLUSIONS: Natamycin treatment was associated with significantly better clinical and microbiological outcomes than voriconazole treatment for smear-positive filamentous fungal keratitis, with much of the difference attributable to improved results in Fusarium cases. APPLICATION TO CLINICAL PRACTICE: Voriconazole should not be used as monotherapy in filamentous keratitis. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT00996736

Expert prior elicitation and Bayesian analysis of the Mycotic Ulcer Treatment Trial I.

PURPOSE: To perform a Bayesian analysis of the Mycotic Ulcer Treatment Trial I (MUTT I) using expert opinion as a prior belief. METHODS: MUTT I was a randomized clinical trial comparing topical natamycin or voriconazole for treating filamentous fungal keratitis. A questionnaire elicited expert opinion on the best treatment of fungal keratitis before MUTT I results were available. A Bayesian analysis was performed using the questionnaire data as a prior belief and the MUTT I primary outcome (3-month visual acuity) by frequentist analysis as a likelihood. RESULTS: Corneal experts had a 41.1% prior belief that natamycin improved 3-month visual acuity compared with voriconazole. The Bayesian analysis found a 98.4% belief for natamycin treatment compared with voriconazole treatment for filamentous cases as a group (mean improvement 1.1 Snellen lines, 95% credible interval 0.1-2.1). The Bayesian analysis estimated a smaller treatment effect than the MUTT I frequentist analysis result of 1.8-line improvement with natamycin versus voriconazole (95% confidence interval 0.5-3.0, P = 0.006). For Fusarium cases, the posterior demonstrated a 99.7% belief for natamycin treatment, whereas non-Fusarium cases had a 57.3% belief. CONCLUSIONS: The Bayesian analysis suggests that natamycin is superior to voriconazole when filamentous cases are analyzed as a group. Subgroup analysis of Fusarium cases found improvement with natamycin compared with voriconazole, whereas there was almost no difference between treatments for non-Fusarium cases. These results were consistent with, though smaller in effect size than, the MUTT I primary outcome by frequentist analysis. The accordance between analyses further validates the trial results. (ClinicalTrials.gov number, NCT00996736.).