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1.  Early Addition of Topical Corticosteroids in the Treatment of Bacterial Keratitis 
JAMA ophthalmology  2014;132(6):737-741.
Scarring from bacterial keratitis remains a leading cause of visual loss.
To determine whether topical corticosteroids are beneficial as an adjunctive therapy for bacterial keratitis if given early in the course of infection.
The Steroids for Corneal Ulcers Trial (SCUT) was a randomized, double-masked, placebo-controlled trial that overall found no effect of adding topical corticosteroids to topical moxifloxacin hydrochloride in bacterial keratitis. Here, we assess the timing of administration of corticosteroids in a subgroup analysis of the SCUT. We define earlier administration of corticosteroids (vs placebo) as addition after 2 to 3 days of topical antibiotics and later as addition after 4 or more days of topical antibiotics.
We assess the effect of topical corticosteroids (vs placebo) on 3-month best spectacle-corrected visual acuity in patients who received corticosteroids or placebo earlier vs later. Further analyses were performed for subgroups of patients with non-Nocardia keratitis and those with no topical antibiotic use before enrollment.
Patients treated with topical corticosteroids as adjunctive therapy within 2 to 3 days of antibiotic therapy had approximately 1-line better visual acuity at 3 months than did those given placebo (−0.11 logMAR; 95% CI, −0.20 to −0.02 logMAR; P = .01). In patients who had 4 or more days of antibiotic therapy before corticosteroid treatment, the effect was not significant; patients given corticosteroids had 1-line worse visual acuity at 3 months compared with those in the placebo group (0.10 logMAR; 95% CI, −0.02 to 0.23 logMAR; P = .14). Patients with non-Nocardia keratitis and those having no topical antibiotic use before the SCUT enrollment showed significant improvement in best spectacle-corrected visual acuity at 3 months if corticosteroids were administered earlier rather than later.
There may be a benefit with adjunctive topical corticosteroids if application occurs earlier in the course of bacterial corneal ulcers.
PMCID: PMC4174411  PMID: 24763755
2.  Antibiotic Use as a Tragedy of the Commons: A Cross-Sectional Survey 
Background. Many believe antibiotic use results in a tragedy of the commons, since overuse may lead to antibiotic resistance and limiting use would benefit society. In contrast, mass antibiotic treatment programs are thought to result in community-wide benefits. A survey was conducted to learn the views of infectious disease experts on the individual- and societal-level consequences of antibiotic use. Methods. The survey instrument was designed to elicit opinions on antibiotic use and resistance. It was sent via SurveyMonkey to infectious disease professionals identified through literature searches. Descriptive statistics were used to analyze the data. Results. A total of 1,530 responses were received for a response rate of 9.9%. Nearly all participants believed antibiotic use could result in a tragedy of the commons, at least in certain circumstances (96.0%). Most participants did not believe mass antibiotic treatment programs could produce societal benefits in an antibiotic-free society (91.4%) or in the United States (94.2%), though more believed such programs would benefit antibiotic-free societies compared to the United States (P < 0.001). Conclusions. The experts surveyed believe that antibiotic use can result in a tragedy of the commons and do not believe that mass treatment programs benefit individuals or society.
PMCID: PMC3920666  PMID: 24587818
4.  Expert Prior Elicitation and Bayesian Analysis of the Mycotic Ulcer Treatment Trial I 
To perform a Bayesian analysis of the Mycotic Ulcer Treatment Trial I (MUTT I) using expert opinion as a prior belief.
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.
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.
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. ( number, NCT00996736.)
We elicited the opinions of corneal specialists on treating filamentous fungal keratitis, to perform a Bayesian analysis of the Mycotic Ulcer Treatment Trial I. The Bayesian analysis result was consistent with, but suggested a smaller treatment effect than, the frequentist result.
PMCID: PMC3684218  PMID: 23702779
fungal keratitis; corneal ulceration; clinical trial; Bayesian; statistics
5.  Acanthamoeba, fungal, and bacterial keratitis: a comparison of risk factors and clinical features 
American journal of ophthalmology  2013;157(1):10.1016/j.ajo.2013.08.032.
To determine risk factors and clinical signs that may differentiate between bacterial, fungal, and acanthamoeba keratitis among patients presenting with presumed infectious keratitis.
Hospital-based cross-sectional study.
We examined the medical records of 115 patients with laboratory-proven bacterial keratitis, 115 patients with laboratory-proven fungal keratitis, and 115 patients with laboratory-proven acanthamoeba keratitis seen at Aravind Eye Hospital, Madurai, India, from 2006–2011. Risk factors and clinical features of the three organisms were compared using multinomial logistic regression.
Of 95 patients with bacterial keratitis, 103 patients with fungal keratitis, and 93 patients with acanthamoeba keratitis who had medical records available for review, 287 (99%) did not wear contact lenses. Differentiating features were more common for acanthamoeba keratitis than for bacterial or fungal keratitis. Compared to patients with bacterial or fungal keratitis, patients with acanthamoeba keratitis were more likely to be younger and to have a longer duration of symptoms, and to have a ring infiltrate or disease confined to the epithelium.
Risk factors and clinical examination findings can be useful for differentiating acanthamoeba keratitis from bacterial and fungal keratitis.
PMCID: PMC3865075  PMID: 24200232
risk factors; disease attributes; India; corneal ulcer
6.  Fluoroquinolone Treatment and Susceptibility of Isolates From Bacterial Keratitis 
JAMA ophthalmology  2013;131(3):10.1001/jamaophthalmol.2013.1718.
To analyze the relationship between fluoroquinolone use at presentation and minimum inhibitory concentration in bacterial keratitis.
The Steroids for Corneal Ulcers Trial was a randomized, double-masked, placebo-controlled trial assessing the effect of adjunctive topical corticosteroid treatment on outcomes in bacterial keratitis. After presentation, all patients were treated with moxifloxacin hydrochloride, 0.5%. We compare antibiotic use at presentation with minimum inhibitory concentration against moxifloxacin for all isolates. Separate analyses accounted for organism species and fluoroquinolone generation.
Topical fluoroquinolone use at presentation was reported in 92 of 480 cases (19.2%). Causative organisms in the 480 cases included Streptococcus pneumoniae (247 cases [51.5%]), Pseudomonas aeruginosa (109 cases [22.7%]), and Nocardia species (55 cases [11.5%]). Isolates from patients who reported fluoroquinolone use at presentation had a 2.01-fold–higher minimum inhibitory concentration (95% CI, 1.39-fold to 2.91-fold; P <.001). Fourth-generation fluoroquinolones were associated with a 3.48-fold–higher minimum inhibitory concentration than those isolates that were not exposed to pretreatment at enrollment (95% CI, 1.99-fold to 6.06-fold; P <.001).
This study provides evidence that prior use of fluoroquinolones is associated with antibiotic resistance.
PMCID: PMC3833086  PMID: 23307105
8.  Prior Elicitation and Bayesian Analysis of the Steroids for Corneal Ulcers Trial 
Ophthalmic epidemiology  2012;19(6):10.3109/09286586.2012.735332.
To elicit expert opinion on the use of adjunctive corticosteroid therapy in bacterial corneal ulcers. To perform a Bayesian analysis of the Steroids for Corneal Ulcers Trial (SCUT), using expert opinion as a prior probability.
The SCUT was a placebo-controlled trial assessing visual outcomes in patients receiving topical corticosteroids or placebo as adjunctive therapy for bacterial keratitis. Questionnaires were conducted at scientific meetings in India and North America to gauge expert consensus on the perceived benefit of corticosteroids as adjunct treatment. Bayesian analysis, using the questionnaire data as a prior probability and the primary outcome of SCUT as a likelihood, was performed. For comparison, an additional Bayesian analysis was performed using the results of the SCUT pilot study as a prior distribution.
Indian respondents believed there to be a 1.21 Snellen line improvement, and North American respondents believed there to be a 1.24 line improvement with corticosteroid therapy. The SCUT primary outcome found a non-significant 0.09 Snellen line benefit with corticosteroid treatment. The results of the Bayesian analysis estimated a slightly greater benefit than did the SCUT primary analysis (0.19 lines verses 0.09 lines).
Indian and North American experts had similar expectations on the effectiveness of corticosteroids in bacterial corneal ulcers; that corticosteroids would markedly improve visual outcomes. Bayesian analysis produced results very similar to those produced by the SCUT primary analysis. The similarity in result is likely due to the large sample size of SCUT and helps validate the results of SCUT.
PMCID: PMC3830548  PMID: 23171211
Bacterial keratitis; Corneal ulcer; Clinical trial; Statistics; Prior distribution
10.  The Mycotic Ulcer Treatment Trial 
JAMA ophthalmology  2013;131(4):422-429.
To compare topical natamycin vs voriconazole in the treatment of filamentous fungal keratitis.
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.
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%]). Natamycin-treated 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).
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 Identifier: NCT00996736
PMCID: PMC3769211  PMID: 23710492
12.  Moxifloxacin Susceptibility Mediates the Relationship between Causative Organism and Clinical Outcome in Bacterial Keratitis 
Bacterial keratitis is a sight-threatening infection of the cornea that is one of the leading causes of blindness globally. In this report, we analyze the role of moxifloxacin susceptibility in the relationship between causative organisms and clinical outcome in bacteria keratitis.
A mediation analysis is used to assess the role of moxifloxacin susceptibility in the relationship between causative organisms and clinical outcome in bacterial keratitis using data collected in a randomized, controlled trial.
In the Steroids for Corneal Ulcers Trial (SCUT), 500 corneal infections were treated with topical moxifloxacin. The outcome of 3-week best spectacle-corrected visual acuity was significantly associated with an organism (Streptococcus pneumoniae, Pseudomonas aeruginosa, etc., P = 0.008). An indirect effects mediation model suggests that MIC accounted for approximately 13% (95% confidence interval, 3%–24%, P = 0.015) of the effect of the organism on 3-week visual acuity.
Moxifloxacin mediates the relationship between causative organisms and clinical outcome in bacterial keratitis, and is likely on the causal pathway between the organism and outcome. ( number, NCT00324168.)
Different etiologic organisms are thought to result in different clinical outcomes. Here, we found that moxifloxacin susceptibility mediates this relationship, suggesting it is on the causal pathway.
PMCID: PMC4136376  PMID: 23385795
13.  Optimal Seasonal Timing of Oral Azithromycin for Malaria 
Mass administration of azithromycin for trachoma has been shown to reduce malarial parasitemia. However, the optimal seasonal timing of such distributions for antimalarial benefit has not been established. We performed numerical analyses on a seasonally forced epidemic model (of Ross-Macdonald type) with periodic impulsive annual mass treatment to address this question. We conclude that when azithromycin-based trachoma elimination programs occur in regions of seasonal malaria transmission, such as Niger, the optimal seasonal timing of mass drug administration (MDA) may not occur during the season of maximum transmission.
PMCID: PMC4228890  PMID: 25223942
14.  Visual Outcomes in Treated Bacterial Keratitis: Four Years of Prospective Follow-up 
We described the change in visual acuity experienced by eyes successfully treated for bacterial keratitis.
This was a prospective cohort study of a subset of study participants who had previously enrolled in the Steroids for Corneal Ulcers Trial (SCUT). All study participants had been diagnosed with culture-proven bacterial keratitis before enrollment in SCUT and subsequently were randomized to adjunctive topical corticosteroids or placebo. During SCUT, we monitored study participants at enrollment, 3 weeks, 3 months, and 12 months. We invited a subset to complete a comprehensive eye examination approximately 4 years after enrollment in SCUT. Certified refractionists assessed best spectacle-corrected visual acuity (BSCVA) using the same protocol at each study visit.
We examined 50 SCUT participants at 4 years after enrollment. Among those in this cohort, mean logMAR BSCVA at enrollment was 0.85 (Snellen equivalent, 20/160; 95% confidence interval [CI], 0.71–0.99). On average, visual acuity improved by 2.9 logMAR lines from enrollment to 3 weeks (P < 0.001), 1.2 lines from 3 weeks to 3 months (P = 0.002), and 0.8 lines from 3 to 12 months (P = 0.01). The BSCVA did not change significantly between 12 months and 4 years (0.04-line improvement, P = 0.88). After controlling for visual acuity at enrollment, BSCVA was not significantly different between the corticosteroid and placebo groups at 4 years (P = 0.53).
Cases of bacterial keratitis may continue to demonstrate improvements in visual acuity up to 12 months following diagnosis, but further improvements are unlikely. These findings may guide the appropriate timing of surgical intervention in these patients. ( number, NCT00324168.)
In a subset of study participants from the Steroids for Corneal Ulcers trial (SCUT), best spectacle corrected visual acuity improved from enrollment to the 3-month study visit, and from the 3- to 12-month study visits, but not from the 12-month to 4-year study visits.
PMCID: PMC4010363  PMID: 24618327
prospective; visual acuity; long-term; outcomes; keratitis; clinical trial
15.  Organism, MIC, and Outcome in a Fungal Corneal Ulcer Clinical Trial 
Cornea  2012;31(6):662-667.
To analyze the minimum inhibitory concentration (MIC) of isolates from fungal keratitis to natamycin and voriconazole, and to assess the relationship between organism, MIC, and clinical outcome.
Data were collected as part of a randomized, controlled, double-masked clinical trial. Main outcome measures included best spectacle-corrected visual acuity (BSCVA), infiltrate/scar size, time to re-epithelialization, and perforation. Speciation and analysis of MIC to natamycin and voriconazole was done according to NCCLS standards. The relationship between MIC and organism, organism and outcome measure, and each outcome measure and MIC was assessed.
Of 120 samples obtained in the trial, 84 isolates had an identifiable organism and were available for further analyses. Fusarium spp and Aspergillus spp were the most commonly-isolated organisms. MIC was significantly different across the groups of organisms (P=0.0001). A higher MIC was significantly associated with an increased likelihood of perforation (OR 2.03, 95%CI 1.02 to 4.04, P=0.04). There was no significant association between MIC and 3-week visual acuity (0.058, 95%CI -0.01 to 0.13, P=0.11), 3-month visual acuity (0.01, 95%CI -0.08 to 1.04, P=0.79), 3-week infiltrate/scar size (0.12, 95% CI -0.02 to 0.27, P=0.10), 3-month infiltrate/scar size (0.12, 95%CI -0.02 to 0.25, P=0.09), or time to re-epithelialization (HR 1.19, 95%CI 0.98 to 1.45, P=0.08).
A higher MIC was associated with an increased odds of perforation. The results of this study suggest that resistance to antifungal medication may be associated with worse outcomes in fungal keratitis.
PMCID: PMC3695737  PMID: 22333662
fungus; keratitis; susceptibility; voriconazole; natamycin
16.  The Association between Latrine Use and Trachoma: A Secondary Cohort Analysis from a Randomized Clinical Trial 
Latrine use has been promoted as a component of an integrated strategy for trachoma control. As part of a randomized trial in Ethiopia, 12 communities received a mass azithromycin distribution followed by a latrine promotion intervention. A random sample of children ages 0–9 years in each community was monitored longitudinally for ocular chlamydia. After latrine construction ended, those communities with a higher proportion of households using latrines were more likely to experience a reduction in the prevalence of ocular chlamydia. Specifically, for each 10% increase in latrine use, there was a 2.0% decrease (95% confidence interval = 0.2–3.9% decrease) in the community prevalence of ocular chlamydia over the subsequent year (P = 0.04).
PMCID: PMC3795102  PMID: 24002488
17.  Relationship of In Vitro Susceptibility to Moxifloxacin and In Vivo Clinical Outcome in Bacterial Keratitis 
The role of antibiotic susceptibility testing on clinical outcome is unclear. In a randomized, controlled trial of bacterial keratitis, a higher minimum inhibitory concentration to moxifloxacin was significantly associated with worse visual acuity.
Background. For bacterial infections, the susceptibility to antibiotics in vitro has been associated with clinical outcomes in vivo, although the importance of minimum inhibitory concentration (MIC) has been debated. In this study, we analyzed the association of MIC on clinical outcomes in bacterial corneal ulcers, while controlling for organism and severity of disease at presentation.
Methods. Data were collected as part of a National Eye Institute–funded, randomized, controlled trial (the Steroids for Corneal Ulcers Trial [SCUT]). All cases enrolled in SCUT had a culture-positive bacterial corneal ulcer and received moxifloxacin. The MIC to moxifloxacin was measured by E test. Outcomes included best spectacle-corrected visual acuity, infiltrate/scar size, time to re-epithelialization, and corneal perforation.
Results. Five hundred patients with corneal ulcers were enrolled in the trial, and 480 were included in this analysis. The most commonly isolated organisms were Streptococcus pneumoniae and Pseudomonas aeruginosa. A 2-fold increase in MIC was associated with an approximately 0.02 logMAR decrease in visual acuity at 3 weeks, approximately 1 letter of vision loss on a Snellen chart (0.019 logMAR; 95% confidence interval [CI], .0040–.033; P = .01). A 2-fold increase in MIC was associated with an approximately 0.04-mm larger infiltrate/scar size at 3 weeks (0.036 mm; 95% CI, .010–.061; P = .006). After controlling for organism, a higher MIC was associated with slower time to re-epithelialization (hazards ratio, 0.92; 95% CI, .86–.97; P = .005).
Conclusions. In bacterial keratitis, a higher MIC to the treating antibiotic is significantly associated with worse clinical outcomes, with approximately 1 line of vision loss per 32-fold increase in MIC.
Clinical Trials Registration: NCT00324168.
PMCID: PMC3334362  PMID: 22447793
18.  Does Mass Azithromycin Distribution Impact Child Growth and Nutrition in Niger? A Cluster-Randomized Trial 
Antibiotic use on animals demonstrates improved growth regardless of whether or not there is clinical evidence of infectious disease. Antibiotics used for trachoma control may play an unintended benefit of improving child growth.
In this sub-study of a larger randomized controlled trial, we assess anthropometry of pre-school children in a community-randomized trial of mass oral azithromycin distributions for trachoma in Niger. We measured height, weight, and mid-upper arm circumference (MUAC) in 12 communities randomized to receive annual mass azithromycin treatment of everyone versus 12 communities randomized to receive biannual mass azithromycin treatments for children, 3 years after the initial mass treatment. We collected measurements in 1,034 children aged 6–60 months of age.
Principal Findings
We found no difference in the prevalence of wasting among children in the 12 annually treated communities that received three mass azithromycin distributions compared to the 12 biannually treated communities that received six mass azithromycin distributions (odds ratio = 0.88, 95% confidence interval = 0.53 to 1.49).
We were unable to demonstrate a statistically significant difference in stunting, underweight, and low MUAC of pre-school children in communities randomized to annual mass azithromycin treatment or biannual mass azithromycin treatment. The role of antibiotics on child growth and nutrition remains unclear, but larger studies and longitudinal trials may help determine any association.
Author Summary
Recent studies suggest that antibiotic use could have an effect on growth in humans. Azithromycin is an antibiotic used for trachoma control, and hence, may have an unintended benefit of improving child growth. Niger is a trachoma-endemic country where mass antibiotic distributions for trachoma take place and where malnutrition is widespread among children. In addition, azithromycin may have an effect on common childhood diseases associated with malnutrition, such as diarrhea, pneumonia, and malaria. In a community-randomized trachoma trial in Matameye, Niger, we assessed child growth by measuring height, weight, and mid-upper arm circumference of pre-school children who have received 3 years of annual or biannual mass azithromycin treatment. While these measures were better in the biannually treated communities, the difference was not statistically significant. Thus, further research will help determine the impact of antibiotics on child growth and nutrition.
PMCID: PMC4161345  PMID: 25210836
19.  Comparison of an rRNA‐based and DNA‐based nucleic acid amplification test for the detection of Chlamydia trachomatis in trachoma 
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.
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.
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.
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.
PMCID: PMC1857674  PMID: 17050583
21.  Emerging moxifloxacin resistance in Pseudomonas aeruginosa keratitis isolates in South India 
Ophthalmic epidemiology  2013;20(3):155-158.
To describe temporal trends in Pseudomonas aeruginosa resistance to moxifloxacin in keratitis isolates from South India.
The Steroids for Corneal Ulcers Trial (SCUT) was a randomized, double-masked, placebo-controlled trial assessing outcomes in patients with culture positive bacterial corneal ulcers randomized to receive prednisolone phosphate or placebo. All patients received moxifloxacin, and susceptibility to moxifloxacin was measured at baseline using Etest. We investigated trends in moxifloxacin susceptibility of P. aeruginosa during 2007, 2008, and 2009 isolated in SCUT in South India.
There were 89 P. aeruginosa isolates during 2007, 2008, and 2009 in SCUT that were eligible for this study. There was an increase in the proportion of resistant isolates from 19% in 2007 to 52% in 2009 (P=0.02, Chi-square test for trend). Logistic regression showed that there was a 2-fold increase in odds of resistance per one year increase during the study period (OR 2.16, 95% CI 1.09 to 4.26, P=0.027).
We found a sharp increase in the proportion of isolates that were resistant to moxifloxacin from 2007 to 2009. Further work needs to be done to characterize the nature of this increase.
PMCID: PMC3746029  PMID: 23662986
22.  Reliability of Trachoma Clinical Grading—Assessing Grading of Marginal Cases 
Clinical examination of trachoma is used to justify intervention in trachoma-endemic regions. Currently, field graders are certified by determining their concordance with experienced graders using the kappa statistic. Unfortunately, trachoma grading can be highly variable and there are cases where even expert graders disagree (borderline/marginal cases). Prior work has shown that inclusion of borderline cases tends to reduce apparent agreement, as measured by kappa. Here, we confirm those results and assess performance of trainees on these borderline cases by calculating their reliability error, a measure derived from the decomposition of the Brier score.
Methods and Findings
We trained 18 field graders using 200 conjunctival photographs from a community-randomized trial in Niger and assessed inter-grader agreement using kappa as well as reliability error. Three experienced graders scored each case for the presence or absence of trachomatous inflammation - follicular (TF) and trachomatous inflammation - intense (TI). A consensus grade for each case was defined as the one given by a majority of experienced graders. We classified cases into a unanimous subset if all 3 experienced graders gave the same grade. For both TF and TI grades, the mean kappa for trainees was higher on the unanimous subset; inclusion of borderline cases reduced apparent agreement by 15.7% for TF and 12.4% for TI. When we assessed the breakdown of the reliability error, we found that our trainees tended to over-call TF grades and under-call TI grades, especially in borderline cases.
The kappa statistic is widely used for certifying trachoma field graders. Exclusion of borderline cases, which even experienced graders disagree on, increases apparent agreement with the kappa statistic. Graders may agree less when exposed to the full spectrum of disease. Reliability error allows for the assessment of these borderline cases and can be used to refine an individual trainee's grading.
Author Summary
Trachoma is the leading infectious cause of blindness and the World Health Organization plans to eliminate it as a public health concern worldwide by the year 2020. This effort in large part involves mass oral antibiotic distributions to communities. A simplified trachoma grading scale is used to assess presence of active infection. Field workers must be properly trained and certified to perform these eye exams because their findings inform when to start and stop community-wide antibiotic treatments. Certification involves measuring agreement in trachoma grades between a trainee and an experienced grader on a test-set of trachoma photographs. Often, these test-sets have hard-to-grade cases of trachoma removed. We found that removing these borderline cases inflates agreement. Including these borderline cases in the test-set allows a more realistic estimate of agreement, but it is still difficult to assess a trainee's grades for cases which even experts disagree on. We found that reliability error, a measure derived from the decomposition of the Brier score (the mean squared error of a set of forecasts), can be used to assess a trainee's evaluation of these borderline cases.
PMCID: PMC4006735  PMID: 24784355
23.  Cytotoxic clinical isolates of Pseudomonas aeruginosa identified during the Steroids for Corneal Ulcers Trial show elevated resistance to fluoroquinolones 
BMC Ophthalmology  2014;14:54.
To determine the relationship between type three secretion genotype and fluoroquinolone resistance for P. aeruginosa strains isolated from microbial keratitis during the Steroids for Corneal Ulcers Trial (SCUT) and for two laboratory strains, PA103 and PAO1.
Confirmed P. aeruginosa isolates from the SCUT were divided into exoU(+) or exoU(−). The exoU(+) strains contained the gene encoding ExoU, a powerful phospholipase toxin delivered into host cells by the type three secretion system. Isolates were then assessed for susceptibility to fluoroquinolone, cephalosporin, and aminoglycoside antibiotics using disk diffusion assays. Etest was used to determine the MIC of moxifloxacin and other fluoroquinolones. Laboratory isolates in which the exoU gene was added or deleted were also tested.
A significantly higher proportion of exoU(+) strains were resistant to ciprofloxacin (p = 0.001), gatifloxacin (p = 0.003), and ofloxacin (p = 0.002) compared to exoU(−) isolates. There was no significant difference between exoU(+) or exoU(−) negative isolates with respect to susceptibility to other antibiotics except gentamicin. Infections involving resistant exoU(+) strains trended towards worse clinical outcome. Deletion or acquisition of exoU in laboratory isolates did not affect fluoroquinolone susceptibility.
Fluoroquinolone susceptibility of P. aeruginosa isolated from the SCUT is consistent with previous studies showing elevated resistance involving exoU encoding (cytotoxic) strains, and suggest worse clinical outcome from infections involving resistant isolates. Determination of exoU expression in clinical isolates of P. aeruginosa may be helpful in directing clinical management of patients with microbial keratitis.
PMCID: PMC4008435  PMID: 24761794
P. aeruginosa; Microbial keratitis; SCUT; Fluoroquinolone resistance; ExoU
24.  How Reliable Are Tests for Trachoma?—A Latent Class Approach 
Latent class analysis allows the estimation of test sensitivities and specificities in the absence of a gold standard. PCR outperformed clinical examination and intense trachomatous inflammation (TI) appeared much more specific than follicular trachomatous inflammation (TF).
Tests for ocular Chlamydia trachomatis have not been well characterized, because there is no gold standard test. Latent class analysis (LCA) was performed to estimate the sensitivity and specificity of laboratory and clinical tests for trachoma in the absence of a gold standard.
Individual data from pretreatment, hyperendemic areas in Ethiopia were used. A clustered LCA was performed for three diagnostic tests: PCR and WHO simplified criteria grades of follicular trachoma (TF) and intense trachomatous inflammation (TI).
Data from 2111 subjects in 40 villages were available. TF was estimated to be 87.3% (95% CI, 83.3–90.1) sensitive and 36.6% (95% CI, 23.6–40.3) specific; TI was estimated to be 53.6% (95% CI, 46.1–88.0) sensitive and 88.3% (95% CI, 83.3–92.0) specific, and PCR was estimated to be 87.5% (95% CI, 79.9–97.2) sensitive and 100% (95% CI 69.3–100) specific.
LCA allows for an estimate of test characteristics without prior assumption of their performance. TF and TI were found to act in a complementary manner: TF is a sensitive test and TI is a specific test. PCR is highly specific but lacks sensitivity. The performance of these tests may be due to the time course of ocular chlamydial infection, and for this reason, results may differ in areas of low prevalence or recent mass treatment ( number, NCT00221364).
PMCID: PMC3176003  PMID: 21685340
25.  Association between Cytotoxic and Invasive Pseudomonas aeruginosa and Clinical Outcomes in Bacterial Keratitis 
JAMA ophthalmology  2013;131(2):147-153.
Clinical isolates of Pseudomonas aeruginosa can be characterized as cytotoxic or invasive, based on their differing effects on host cells. Previous studies have shown that strain type influences pathology in animal models. The aim of this study was to determine if invasive and cytotoxic strains differentially impact clinical presentation, outcome, or therapeutic response in bacterial keratitis.
P.aeruginosa isolates from the NEI-funded Steroids for Corneal Ulcers Trial (SCUT) were subtyped as invasive or cytotoxic strains. The main outcome measure compared between the two subtypes was change in visual acuity at three months using Huber robust regression, adjusting for topical corticosteroid treatment.
Of the 101 confirmed P.aeruginosa isolates from the SCUT, 74 had a classically invasive or cytotoxic genotype. While corneal ulcers caused by genotypically invasive P.aeruginosa strains presented with significantly better visual acuity than those caused by genotypically cytotoxic P.aeruginosa strains when adjusting for the effect of ulcer location (p=0.008), invasive ulcers improved significantly less than cytotoxic ulcers at three months (0.35 logMAR (three and a half line difference), 95% CI 0.04 to 0.66 p=0.03). When compared with topical moxifloxacin alone, adjunctive treatment with topical corticosteroids was associated with significantly more improvement in visual acuity in the invasive subgroup (p=0.04), but was associated with less improvement in vision in the cytotoxic subgroup (p=0.07).
The results of this study suggest that rational profiling of differentially expressed virulence determinants, e.g. cytotoxicity and invasiveness for P.aeruginosa, could be used as a tool for decision making in management of infections to optimize outcome.
PMCID: PMC3796098  PMID: 23411878
Pseudomonas aeruginosa; bacterial keratitis; virulence; type III secretion

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