The steroids for corneal ulcers trial: study design and baseline characteristics.

OBJECTIVES: To provide comprehensive trial methods and baseline data for the Steroids for Corneal Ulcers Trial and to present epidemiological characteristics such as risk factors, causative organisms, and ulcer severity. METHODS: Baseline data from a 1:1 randomized, placebo-controlled, double-masked clinical trial comparing prednisolone phosphate, 1%, with placebo as adjunctive therapy for the treatment of bacterial corneal ulcers. Eligible patients had a culture-positive bacterial corneal ulcer and had been taking moxifloxacin for 48 hours. The primary outcome for the trial is best spectacle-corrected visual acuity at 3 months from enrollment. This report provides comprehensive baseline data, including best spectacle-corrected visual acuity, infiltrate size, microbiological results, and patient demographics, for patients enrolled in the trial. RESULTS: Of 500 patients enrolled, 97% were in India. Two hundred twenty patients (44%) were agricultural workers. Median baseline visual acuity was 0.84 logMAR (Snellen, 20/125) (interquartile range, 0.36-1.7; Snellen, 20/50 to counting fingers). Baseline visual acuity was not significantly different between the United States and India. Ulcers in India had larger infiltrate/scar sizes (P = .04) and deeper infiltrates (P = .04) and were more likely to be localized centrally (P = .002) than ulcers enrolled in the United States. Gram-positive bacteria were the most common organisms isolated from the ulcers (n = 366, 72%). CONCLUSIONS: The Steroids for Corneal Ulcers Trial will compare the use of a topical corticosteroid with placebo as adjunctive therapy for bacterial corneal ulcers. Patients enrolled in this trial had diverse ulcer severity and on average significantly reduced visual acuity at presentation. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT00324168.

Corticosteroids for bacterial keratitis: the Steroids for Corneal Ulcers Trial (SCUT).

OBJECTIVE: To determine whether there is a benefit in clinical outcomes with the use of topical corticosteroids as adjunctive therapy in the treatment of bacterial corneal ulcers. METHODS: Randomized, placebo-controlled, double-masked, multicenter clinical trial comparing prednisolone sodium phosphate, 1.0%, to placebo as adjunctive therapy for the treatment of bacterial corneal ulcers. Eligible patients had a culture-positive bacterial corneal ulcer and received topical moxifloxacin for at least 48 hours before randomization. MAIN OUTCOME MEASURES: The primary outcome was best spectacle-corrected visual acuity (BSCVA) at 3 months from enrollment. Secondary outcomes included infiltrate/scar size, reepithelialization, and corneal perforation. RESULTS: Between September 1, 2006, and February 22, 2010, 1769 patients were screened for the trial and 500 patients were enrolled. No significant difference was observed in the 3-month BSCVA (-0.009 logarithm of the minimum angle of resolution [logMAR]; 95% CI, -0.085 to 0.068; P = .82), infiltrate/scar size (P = .40), time to reepithelialization (P = .44), or corneal perforation (P > .99). A significant effect of corticosteroids was observed in subgroups of baseline BSCVA (P = .03) and ulcer location (P = .04). At 3 months, patients with vision of counting fingers or worse at baseline had 0.17 logMAR better visual acuity with corticosteroids (95% CI, -0.31 to -0.02; P = .03) compared with placebo, and patients with ulcers that were completely central at baseline had 0.20 logMAR better visual acuity with corticosteroids (-0.37 to -0.04; P = .02). CONCLUSIONS: We found no overall difference in 3-month BSCVA and no safety concerns with adjunctive corticosteroid therapy for bacterial corneal ulcers. APPLICATION TO CLINICAL PRACTICE: Adjunctive topical corticosteroid use does not improve 3-month vision in patients with bacterial corneal ulcers. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT00324168.

Bilateral effect of unilateral ranibizumab in patients with uveitis-related macular edema.

PURPOSE: To describe an observed therapeutic effect of ranibizumab in untreated contralateral eyes of patients with bilateral uveitis-related cystoid macular edema. METHODS: The authors conducted an open-label, prospective, nonrandomized, interventional study to evaluate the effect of intravitreal ranibizumab injections for the off-label treatment of persistent uveitic cystoid macular edema. Patients were given 3 monthly injections of 0.5 mg intravitreal ranibizumab in the eye with worse vision. Subsequent monthly ranibizumab injections were administered based on macular thickness measurements. Best-spectacle corrected visual acuity measurements and optical coherence tomography scans were performed on both eyes at baseline and at monthly follow-up visits. RESULTS: Three of the seven patients in our nonrandomized consecutive case series presented with controlled uveitis and cystoid macular edema bilaterally. Two of the three patients demonstrated a significant improvement in visual acuity and a reduction in macular edema in both eyes after three monthly injections to the study eye. One patient experienced limited effect bilaterally possibly because of the presence of epiretinal membranes in both eyes. CONCLUSION: The authors observed a beneficial effect of ranibizumab in both eyes of patients who were treated unilaterally for uveitis-related cystoid macular edema. This warrants further investigation of the pharmacokinetics and systemic availability of ranibizumab, particularly in patients with uveitis.

Comparison of natamycin and voriconazole for the treatment of fungal keratitis.

OBJECTIVE: To conduct a therapeutic exploratory clinical trial comparing clinical outcomes of treatment with topical natamycin vs topical voriconazole for fungal keratitis. METHODS: The multicenter, double-masked, clinical trial included 120 patients with fungal keratitis at Aravind Eye Hospital in India who were randomized to receive either topical natamycin or topical voriconazole and either had repeated scraping of the epithelium or not. MAIN OUTCOME MEASURES: The primary outcome was best spectacle-corrected visual acuity (BSCVA) at 3 months. Other outcomes included scar size, perforations, and a subanalysis of BSCVA at 3 months in patients with an enrollment visual acuity of 20/40 to 20/400. RESULTS: Compared with those who received natamycin, voriconazole-treated patients had an approximately 1-line improvement in BSCVA at 3 months after adjusting for scraping in a multivariate regression model but the difference was not statistically significant (P = .29). Scar size at 3 months was slightly greater with voriconazole after adjusting for scraping (P = .48). Corneal perforations in the voriconazole group (10 of 60 patients) were not significantly different than in the natamycin-treated group (9 of 60 patients) (P >.99). Scraping was associated with worse BSCVA at 3 months after adjusting for drug (P = .06). Patients with baseline BSCVA of 20/40 to 20/400 showed a trend toward a 2-line improvement in visual acuity with voriconazole (P = .07). CONCLUSIONS: Overall, there were no significant differences in visual acuity, scar size, and perforations between voriconazole- and natamycin-treated patients. There was a trend toward scraping being associated with worse outcomes. Application to Clinical Practice The benefit seen with voriconazole in the subgroup of patients with baseline visual acuity of 20/40 to 20/400 needs to be validated in a confirmatory clinical trial. Trial Registration clinicaltrials.gov Identifier: NCT00557362.

Travel and implications for the elimination of trachoma in ethiopia.

PURPOSE: Trachoma is the leading infectious cause of blindness. The World Health Organization has set a goal of reducing the trachoma disease burden to a level where it is no longer a public health concern by the year 2020. Some investigators feel that local elimination of ocular chlamydia infection is possible, but little has been done to study the likelihood of reintroduction of infection from neighboring areas. Mass administration of azithromycin has been shown to dramatically reduce the prevalence of infection in many villages in central Ethiopia. However, after treatment is discontinued, infection returns. Reintroduction of infection could occur from the few remaining infected cases in a treated community or from outside the community. People traveling between villages might be responsible thus complicating the elimination of trachoma. METHODS: We conducted a survey to assess the travel pattern of the Gurage zone residents in Ethiopia. Seven hundred and seventeen households with at least one child aged 1-5 years in 48 villages were surveyed to collect the details of travel in 1 month prior to the survey. RESULTS: Seventy-eight percent of the surveyed households had at least one traveler, with the majority being women. Pre-school children, the main reservoir of clinically active infection, rarely traveled. Most travel was to the market or to school, and most for less than 1 day. CONCLUSIONS: Travel routinely takes place in these villages. Trachoma control programs in this area might consider treating areas with the same markets and schools in the same period to increase the efficacy of mass treatment.

Importance of coverage and endemicity on the return of infectious trachoma after a single mass antibiotic distribution.

BACKGROUND: As part of the SAFE strategy, mass antibiotic treatments are useful in controlling the ocular strains of chlamydia that cause trachoma. The World Health Organization recommends treating at least 80% of individuals per community. However, the role of antibiotic coverage for trachoma control has been poorly characterized. METHODOLOGY/PRINCIPAL FINDINGS: In a collection of cluster-randomized clinical trials, mass oral azithromycin was administered to 40 villages in Ethiopia. The village prevalence of ocular chlamydia was determined before treatment, and at two and six months post-treatment. The mean prevalence of ocular chlamydia was 48.9% (95% CI 42.8 to 55.0%) before mass treatments, decreased to 5.4% (95% CI 3.9 to 7.0%) at two months after treatments (p<0.0001), and returned to 7.9% (95% CI 5.4 to 10.4%) by six months after treatment (p = 0.03). Antibiotic coverage ranged from 73.9% to 100%, with a mean of 90.6%. In multivariate regression models, chlamydial prevalence two months after treatment was associated with baseline infection (p<0.0001) and antibiotic coverage (p = 0.007). However, by six months after treatment, chlamydial prevalence was associated only with baseline infection (p<0.0001), but not coverage (p = 0.31). CONCLUSIONS/SIGNIFICANCE: In post-hoc analyses of a large clinical trial, the amount of endemic chlamydial infection was a strong predictor of chlamydial infection after mass antibiotic treatments. Antibiotic coverage was an important short-term predictor of chlamydial infection, but no longer predicted infection by six months after mass antibiotic treatments. A wider range of antibiotic coverage than found in this study might allow an assessment of a more subtle association.

Ranibizumab for refractory uveitis-related macular edema.

PURPOSE: To evaluate the effect of intravitreal ranibizumab injections (Lucentis; Genentech Inc, South San Francisco, California, USA) on refractory cystoid macular edema (CME) in patients with controlled uveitis who have failed oral and regional corticosteroid treatment, the mainstays of current medical therapy. DESIGN: Prospective, noncomparative, interventional case series. METHODS: Seven consecutive patients with controlled uveitis and refractory CME who had failed corticosteroid treatment were studied. One eligible patient chose not to participate and another did not complete follow-up for nonmedical reasons. Intravitreal ranibizumab injections (0.5 mg) were given monthly for 3 months, followed by reinjection as needed. The primary outcome was the mean change in best spectacle-corrected visual acuity (VA) from baseline to 3 months, and the secondary objective was the mean change in central retinal thickness (CRT) on ocular coherence tomography. Six-month outcomes were also assessed. RESULTS: At 3 months, the mean increase in acuity for the 6 patients who completed follow-up was 13 letters (2.5 lines), and the mean decrease in CRT was 357 mum. Both VA and CRT improved significantly between baseline and 3 months (P = .03 for each). Although most patients required reinjection, this benefit was maintained at 6 months. There were no significant ocular or systemic adverse effects. CONCLUSIONS: Intravitreal ranibizumab led to an increase in VA and regression of uveitis-associated CME in patients refractory to or intolerant of standard corticosteroid therapy. Further studies of this promising treatment are warranted.

Assessment of herd protection against trachoma due to repeated mass antibiotic distributions: a cluster-randomised trial.

BACKGROUND: Trachoma-control programmes distribute oral azithromycin to treat the ocular strains of chlamydia that cause the disease and to control infection. Theoretically, elimination of infection is feasible if untreated individuals receive an indirect protective effect from living in repeatedly treated communities, which is similar to herd protection in vaccine programmes. We assessed indirect protection against trachoma with mass azithromycin distributions. METHODS: In a cluster randomised trial, 24 subkebeles (government-defined units) in Amhara, Ethiopia, were randomised, with use of a simple random sample, to distribution four times per year of single-dose oral azithromycin to children aged 1-10 years (12 subkebeles, 4764 children), or to delayed treatment until after the study (control; 12 subkebeles, 6014 children). We compared the prevalence of ocular chlamydial infection in untreated individuals 11 years and older between baseline and 12 months in the treated subkebeles, and at 12 months between the treated and control subkebeles. Health-care and laboratory personnel were blinded to study group. Analysis was intention to treat. The study is registered with clinicaltrials.gov, number NCT00322972. FINDINGS: At 12 months, 637 children aged 1-10 years and 561 adults and children aged 11 years and older were analysed in the children-treated group, and 618 and 550, respectively, in the control group. The mean prevalence of infection in children decreased from 48.4% (95% CI 42.9-53.9) to 3.6% (0.8-6.4) after four mass treatments. At 12 months, the mean prevalence of infection in the untreated age group (>/=11 years) was 47% (95% CI 33-57) less than baseline (p=0.002), and 35% (95% CI 1-57) less than that in untreated communities (p=0.04). INTERPRETATION: Frequent treatment of children, who are a core group for transmission of trachoma, could eventually eliminate infection from the entire community. Herd protection is offered by repeated mass antibiotic treatments, providing a strategy for elimination of a bacterial disease when an effective vaccine is unavailable. FUNDING: National Institutes of Health.

Reduction and return of infectious trachoma in severely affected communities in Ethiopia.

BACKGROUND: Antibiotics are a major tool in the WHO's trachoma control program. Even a single mass distribution reduces the prevalence of the ocular chlamydia that causes trachoma. Unfortunately, infection returns after a single treatment, at least in severely affected areas. Here, we test whether additional scheduled treatments further reduce infection, and whether infection returns after distributions are discontinued. METHODS: Sixteen communities in Ethiopia were randomly selected. Ocular chlamydial infection in 1- to 5-year-old children was monitored over four biannual azithromycin distributions and for 24 months after the last treatment. FINDINGS: The average prevalence of infection in 1- to 5-year-old children was reduced from 63.5% pre-treatment to 11.5% six months after the first distribution (P<0.0001). It further decreased to 2.6% six months after the fourth and final treatment (P = 0.0004). In the next 18 months, infection returned to 25.2%, a significant increase from six months after the last treatment (P = 0.008), but still far lower than baseline (P<0.0001). Although the prevalence of infection in any particular village fluctuated, the mean prevalence of the 16 villages steadily decreased with each treatment and steadily returned after treatments were discontinued. CONCLUSION: In some of the most severely affected communities ever studied, we demonstrate that repeated mass oral azithromycin distributions progressively reduce ocular chlamydial infection in a community, as long as these distributions are given frequently enough and at a high enough coverage. However, infection returns into the communities after the last treatment. Sustainable changes or complete local elimination of infection will be necessary. TRIAL REGISTRATION: ClinicalTrials.gov NCT00221364.

Detection of Chlamydia trachomatis ocular infection in trachoma-endemic communities by rRNA amplification.

PURPOSE: Trachoma remains the leading infectious cause of blindness worldwide. The World Health Organization (WHO) recommends mass antibiotic distributions in its strategy to eliminate blinding trachoma. To determine the most effective antibiotic treatment strategy, it is essential to have a diagnostic test that can correctly measure the true status of ocular Chlamydia trachomatis infection in individuals, particularly after treatment. A newer ribosomal ribonucleic acid (rRNA)-based amplification test was compared with the current DNA-based polymerase chain reaction (PCR) for the detection of C. trachomatis. METHODS: An rRNA-based assay and PCR were performed on swab specimens taken from the right upper tarsal conjunctiva of 240 children aged 1 to 5 years living among 16 endemic villages in the Gurage Zone, Ethiopia. RESULTS: The rRNA-based test detected ocular C. trachomatis infection in 142 (59%) subjects compared with 67 (28%) detected by PCR (McNemar's test, P < 0.0001). The rRNA-based test gave positive results for all subjects who were positive by PCR and detected infection in 75 (31%) additional subjects. CONCLUSIONS: The rRNA-based test appears to have significantly greater sensitivity than PCR for the detection of ocular C. trachomatis infection in children in trachoma-endemic villages. The increased sensitivity of the rRNA-based test may be due to its ability to detect low levels of C. trachomatis infection in individuals, which can occur especially after antibiotic treatment. Data from past studies in which PCR was used to assess the prevalence of infectious trachoma after community-wide antibiotic treatments could have underestimated the true prevalence of infection.

Complete elimination is a difficult goal for trachoma programs in severely affected communities.

The World Health Organization has distributed millions of doses of azithromycin to control the ocular chlamydial infection that causes trachoma. Theoretically, a loftier goal of elimination is feasible. Here, we demonstrate that, although local elimination of infection in the most severely affected communities is difficult, it is possible with biannual antibiotic distributions.

PERIOD-TIMELESS interval timer may require an additional feedback loop.

In this study we present a detailed, mechanism-based mathematical framework of Drosophila circadian rhythms. This framework facilitates a more systematic approach to understanding circadian rhythms using a comprehensive representation of the network underlying this phenomenon. The possible mechanisms underlying the cytoplasmic "interval timer" created by PERIOD-TIMELESS association are investigated, suggesting a novel positive feedback regulatory structure. Incorporation of this additional feedback into a full circadian model produced results that are consistent with previous experimental observations of wild-type protein profiles and numerous mutant phenotypes.

A rationale for continuing mass antibiotic distributions for trachoma.

BACKGROUND: The World Health Organization recommends periodic mass antibiotic distributions to reduce the ocular strains of chlamydia that cause trachoma, the world's leading cause of infectious blindness. Their stated goal is to control infection, not to completely eliminate it. A single mass distribution can dramatically reduce the prevalence of infection. However, if infection is not eliminated in every individual in the community, it may gradually return back into the community, so often repeated treatments are necessary. Since public health groups are reluctant to distribute antibiotics indefinitely, we are still in need of a proven long-term rationale. Here we use mathematical models to demonstrate that repeated antibiotic distributions can eliminate infection in a reasonable time period. METHODS: We fit parameters of a stochastic epidemiological transmission model to data collected before and 6 months after a mass antibiotic distribution in a region of Ethiopia that is one of the most severely affected areas in the world. We validate the model by comparing our predicted results to Ethiopian data which was collected biannually for two years past the initial mass antibiotic distribution. We use the model to simulate the effect of different treatment programs in terms of local elimination of infection. RESULTS: Simulations show that the average prevalence of infection across all villages progressively decreases after each treatment, as long as the frequency and coverage of antibiotics are high enough. Infection can be eliminated in more villages with each round of treatment. However, in the communities where infection is not eliminated, it returns to the same average level, forming the same stationary distribution. This phenomenon is also seen in subsequent epidemiological data from Ethiopia. Simulations suggest that a biannual treatment plan implemented for 5 years will lead to elimination in 95% of all villages. CONCLUSION: Local elimination from a community is theoretically possible, even in the most severely infected communities. However, elimination from larger areas may require repeated biannual treatments and prevention of re-introduction from outside to treated areas.

Antimicrobial susceptibility of Fusarium, Aspergillus, and other filamentous fungi isolated from keratitis.

OBJECTIVE: To characterize the susceptibility of filamentous fungi isolated from keratitis to amphotericin B, natamycin, caspofungin acetate, itraconazole, voriconazole, and posaconazole. METHODS: Ninety isolates from fungal keratitis cases at Aravind Eye Hospital in South India were tested using macrobroth dilution for susceptibility to amphotericin B, natamycin, caspofungin, itraconazole, voriconazole, and posaconazole. The minimum inhibitory concentration (MIC) median and 90th percentile were determined. RESULTS: The 90 isolates included 41 Aspergillus species, 38 Fusarium species, and 11 others. The triazoles and caspofungin had the lowest MICs against Aspergillus species; voriconazole, amphotericin B, and posaconazole had the lowest MICs against Fusarium species, and none of the Fusarium species were inhibited by itraconazole or caspofungin. Amphotericin B had significantly lower MICs compared with natamycin, but after correcting for the typical prescription dose, natamycin was superior. CONCLUSION: No single agent was universally most effective, but voriconazole and other triazoles demonstrated the broadest spectrum. Itraconazole and caspofungin were not effective against Fusarium species. CLINICAL RELEVANCE: Fungal ulcers are commonly treated empirically; drugs are typically selected without regard to susceptibility data. The nonocular infectious disease literature suggests modern fungal susceptibility methods are clinically relevant, but ocular studies are limited. Our results suggest antifungal therapy might be tailored to individual organisms.

Comparison of an rRNA-based and DNA-based nucleic acid amplification test for the detection of Chlamydia trachomatis in trachoma.

BACKGROUND/AIM: The World Health Organisation (WHO) hopes to achieve global elimination of trachoma, still the leading cause of preventable blindness worldwide, in part through mass antibiotic treatment. DNA-based nucleic acid amplification tests (NAATs) are currently used to evaluate the success of treatment programmes by measuring the prevalence of C trachomatis infection. Some believe that newer ribosomal RNA (rRNA)-based tests may be much more sensitive since bacterial rRNA is present in amounts up to 10 000 times that of genomic DNA. Others believe that rRNA-based tests are instead less sensitive but more specific, due to the presence of dead or subviable organisms that the test may not detect. This study compares an rRNA-based test to a DNA-based test for the detection of ocular C trachomatis infection in children living in trachoma-endemic villages. METHODS: An rRNA-based amplification test and DNA-based polymerase chain reaction (PCR) were performed on swab specimens taken from the right upper tarsal conjunctiva of 56 children aged 0-10 years living in two villages in Amhara, Ethiopia. RESULTS: The rRNA-based test detected ocular C trachomatis infection in 35 (63%) subjects compared with 22 (39%) detected by PCR (McNemar's test, p = 0.0002). The rRNA-based test gave positive results for all subjects that were positive by PCR, and also detected infection in 13 (23%) additional subjects. CONCLUSION: The rRNA-based test appears to have significantly greater sensitivity than PCR for the detection of ocular chlamydial infection in children in trachoma-endemic villages. Using the rRNA-based test, we may be able to detect infection that was previously missed with PCR. Past studies using DNA-based tests to assess prevalence of infectious trachoma following antibiotic treatment may have underestimated the true prevalence of infection.