Gut microbiome alteration in MORDOR I: a community-randomized trial of mass azithromycin distribution.

The MORDOR I trial1, conducted in Niger, Malawi and Tanzania, demonstrated that mass azithromycin distribution to preschool children reduced childhood mortality1. However, the large but simple trial design precluded determination of the mechanisms involved. Here we examined the gut microbiome of preschool children from 30 Nigerien communities randomized to either biannual azithromycin or placebo. Gut microbiome γ-diversity was not significantly altered (P = 0.08), but the relative abundances of two Campylobacter species, along with another 33 gut bacteria, were significantly reduced in children treated with azithromycin at the 24-month follow-up. Metagenomic analysis revealed functional differences in gut bacteria between treatment groups. Resistome analysis showed an increase in macrolide resistance gene expression in gut microbiota in communities treated with azithromycin (P = 0.004). These results suggest that prolonged mass azithromycin distribution to reduce childhood mortality reduces certain gut bacteria, including known pathogens, while selecting for antibiotic resistance.

Improvement in corneal scarring following bacterial keratitis.

AIM: Bacterial keratitis results in corneal scarring and subsequent visual impairment. The long-term evolution of corneal scars has not been well described. In this case series, we identified patients who had improvement in corneal scarring and visual acuity from a clinical trial for bacterial keratitis. METHODS: We searched the records of the Steroids for Corneal Ulcers Trial (SCUT) for patients who had improvement in vision between the 3-month and 12-month visits and reviewed their clinical photographs. RESULTS: Of the 500 patients enrolled in SCUT, five patients with large central corneal scars due to bacterial keratitis are presented. All experienced improvement in rigid contact lens-corrected visual acuity from months 3 to 12. All patients also had marked improvement in corneal opacity during the same time period. None of the patients opted to have penetrating keratoplasty. CONCLUSIONS: Corneal scars may continue to improve even many months after a bacterial corneal ulcer has healed. The corneal remodeling can be accompanied by considerable improvement in visual acuity, such that corneal transplantation may not be necessary.

Predictors of outcome in fungal keratitis.

PURPOSE: To analyse predictors of clinical outcome in fungal keratitis. METHODS: Data was collected during a prospective, randomized, controlled, double-masked clinical trial of treatment for fungal keratitis. Clinical features at presentation and demographics were collected at the enrollment visit for all patients. Pre-specified clinical outcomes included 3-month visual acuity and infiltrate/scar size, time to re-epithelialization, and corneal perforation. A separate multivariable model with each outcome as the dependent variable included all predictor variables. RESULTS: Predictors for worse 3-month visual acuity include older age (P=0.024), worse presentation visual acuity (P<0.001), larger infiltrate size at presentation (P<0.001), and pigmented ulcer (P=0.030). Larger infiltrate size at presentation was a significant predictor of worse 3-month infiltrate/scar size (P<0.001). Larger epithelial defect size was a significant predictor of perforation (P=0.0013). Predictors of longer time to re-epithelialization include infiltrate size at presentation (P<0.001) and older age (P=0.025). CONCLUSION: Ulcer severity at presentation is highly predictive of worse outcomes. Presentation of clinical characteristics such as baseline acuity and infiltrate scar can provide important information to clinicians about prognosis, and may help guide management and treatment decisions. Prevention of corneal ulcer remains important, as it is difficult to change the course of the ulcer once it has begun.

American College of Rheumatology classification criteria for Sjögren's syndrome: a data-driven, expert consensus approach in the Sjögren's International Collaborative Clinical Alliance cohort.

OBJECTIVE: We propose new classification criteria for Sjögren's syndrome (SS), which are needed considering the emergence of biologic agents as potential treatments and their associated comorbidity. These criteria target individuals with signs/symptoms suggestive of SS. METHODS: Criteria are based on expert opinion elicited using the nominal group technique and analyses of data from the Sjögren's International Collaborative Clinical Alliance. Preliminary criteria validation included comparisons with classifications based on the American­European Consensus Group (AECG) criteria, a model-based "gold standard"obtained from latent class analysis (LCA) of data from a range of diagnostic tests, and a comparison with cases and controls collected from sources external to the population used for criteria development. RESULTS: Validation results indicate high levels of sensitivity and specificity for the criteria. Case definition requires at least 2 of the following 3: 1) positive serum anti-SSA and/or anti-SSB or (positive rheumatoid factor and antinuclear antibody titer >1:320), 2) ocular staining score >3, or 3) presence of focal lymphocytic sialadenitis with a focus score >1 focus/4 mm2 in labial salivary gland biopsy samples. Observed agreement with the AECG criteria is high when these are applied using all objective tests. However, AECG classification based on allowable substitutions of symptoms for objective tests results in poor agreement with the proposed and LCA-derived classifications. CONCLUSION: These classification criteria developed from registry data collected using standardized measures are based on objective tests. Validation indicates improved classification performance relative to existing alternatives, making them more suitable for application in situations where misclassification may present health risks.

Microbiological cure times in acanthamoeba keratitis.

AIMS: The purpose of this study was to estimate the duration of treatment necessary for sequential acanthamoeba laboratory tests from corneal scrapings to become negative, and to assess predictors that affect this duration period. METHODS: We included all patients with at least one positive acanthamoeba culture or Giemsa stain at the F.I. Proctor Foundation Microbiology Laboratory from 1996 to 2009. A parametric survival analysis was performed among patients with repeat cultures to assess significant predictors for extended clearance time. Simulations were performed to estimate clearance time in the entire patient population, assuming imperfect sensitivity. RESULTS: Thirty-seven patients with laboratory evidence of acanthamoeba had testing at 69 time points. The median clearance time among eyes with repeat cultures was 42.5 days (interquartile range (IQR) 22.0-82.0 days; unadjusted parametric model). Initial visual acuity was the only predictor significantly associated with clearance time in univariate analyses (P<0.0001). Using initial visual acuity as a predictor for clearance time among the entire patient population, the estimated clearance time decreased to 38.7 days (95% confidence interval (CI) 27.9-53.5 days). When the imperfect sensitivity of the culture technique was also taken into account, the estimated clearance time was 44.1 days (95% CI 31.9-61.0 days). CONCLUSION: The duration of infection with acanthamoeba keratitis undergoing treatment has not been well characterized. In this report we estimate a median clearance time of approximately 6 weeks, with an IQR of 22-82 days.

Activity of antibiotics against Fusarium and Aspergillus.

BACKGROUND/AIMS: To study the susceptibility of Fusarium and Aspergillus isolated from keratitis to amoxicillin, cefazolin, chloramphenicol, moxifloxacin, tobramycin and benzalkonium chloride (BAK). METHODS: 10 isolates of Fusarium and 10 isolates of Aspergillus from cases of fungal keratitis at Aravind Eye Hospital in South India were tested using microbroth dilution for susceptibility to amoxicillin, cefazolin, chloramphenicol, moxifloxacin, tobramycin and BAK. The minimum inhibitory concentration (MIC) median and 90th percentile were determined. RESULTS: BAK had the lowest MIC for both Fusarium and Aspergillus. Chloramphenicol had activity against both Fusarium and Aspergillus, while moxifloxacin and tobramycin had activity against Fusarium but not Aspergillus. CONCLUSIONS: The susceptibility of Fusarium to tobramycin, moxifloxacin, chloramphenicol and BAK and of Aspergillus to chloramphenicol and BAK may explain anecdotal reports of fungal ulcers that improved with antibiotic treatment alone. While some of the MICs of antibiotics and BAK are lower than the typically prescribed concentrations, they are not in the range of antifungal agents such as voriconazole, natamycin and amphotericin B. Antibiotics may, however, have a modest effect on Fusarium and Aspergillus when used as initial treatment prior to identification of the pathological organism.

Corticosteroids for bacterial corneal ulcers.

AIMS: The aim of the study was to conduct a preliminary clinical trial to assess whether adjunctive topical corticosteroids improve outcomes in bacterial keratitis and, if no difference was found, to determine the feasibility and sample size necessary for conducting a larger trial to answer this question. METHODS: In this single centre, double-masked clinical trial, 42 patients with culture-confirmed bacterial keratitis at Aravind Eye Hospital in India were randomised to receive either topical prednisolone phosphate or placebo. All patients received topical moxifloxacin. The primary outcome was best spectacle-corrected visual acuity (BSCVA) at 3 months, adjusting for enrolment BSCVA and arm. Other pre-specified outcomes included re-epithelialisation time, infiltrate/scar size and adverse events. RESULTS: Compared with placebo, patients in the steroid group re-epithelialised more slowly (hazard ratio 0.47, 95% CI 0.23 to 0.94). There was no significant difference in BSCVA or infiltrate/scar size at 3 weeks or 3 months. To have 80% power to detect a two-line difference in acuity, 360 cases would be required. CONCLUSIONS: Although corticosteroid treatment resulted in a statistically significant delay in re-epithelialisation, this did not translate to a significant difference in visual acuity, infiltrate/scar size or adverse events. To assess the effect of steroids on acuity, a larger trial is warranted and feasible.

Mooren''s ulcer following extracapsular cataract extraction.

PURPOSE: Prior cataract surgery is a recognized risk factor for the development of Mooren''s ulcer, but the demographic and clinical features of a large cohort of such patients have not been described. METHODS: The authors performed a retrospective review of demographic and clinical data from 14 eyes in 13 patients who developed Mooren's ulcer following extracapsular cataract extraction at Aravind Eye Hospital in Madurai, South India. RESULTS: Eight (62%) of the 13 patients were men and 5 (39%) were women. The median age in our population was 65 years, with a range of 45 to 85 years. The median number of months from surgery to the onset of Mooren's ulcer was 19, with a range of 4 to 156 months. Of the 14 eyes with prior cataract surgery, the location of the ulcer was at or contiguous with the wound in 10 eyes (71%), which was 2.5 times more likely than other circumlimbal locations, and only one patient (8%) had bilateral disease. CONCLUSIONS: Mooren''s ulcer may occur following extracapsular cataract extraction and when it does it is most likely to be unilateral and contiguous with the wound. These findings support the notion that exposure of normally concealed corneal antigens may contribute to the pathogenesis of Mooren''s ulcer in some patients.

The Antioxidants in Prevention of Cataracts Study: effects of antioxidant supplements on cataract progression in South India.

AIM: To determine if antioxidant supplements (beta carotene and vitamins C and E) can decrease the progression of cataract in rural South India. METHODS: The Antioxidants in Prevention of Cataracts (APC) Study was a 5 year, randomised, triple masked, placebo controlled, field based clinical trial to assess the ability of interventional antioxidant supplements to slow cataract progression. The primary outcome variable was change in nuclear opalescence over time. Secondary outcome variables were cortical and posterior subcapsular opacities and nuclear colour changes; best corrected visual acuity change; myopic shift; and failure of treatment. Annual examinations were performed for each subject by three examiners, in a masked fashion. Multivariate modelling using a general estimating equation was used for analysis of results, correcting for multiple measurements over time. RESULTS: Initial enrolment was 798 subjects. Treatment groups were comparable at baseline. There was high compliance with follow up and study medications. There was progression in cataracts. There was no significant difference between placebo and active treatment groups for either the primary or secondary outcome variables. CONCLUSION: Antioxidant supplementation with beta carotene, vitamins C and E did not affect cataract progression in a population with a high prevalence of cataract whose diet is generally deficient in antioxidants.

Topical ocular antibiotics induce bacterial resistance at extraocular sites.

AIM: To compare the prevalence of antibiotic resistance found in nasopharyngeal Streptococcus pneumoniae between villages treated with topical tetracycline or systemic azithromycin as part of a trachoma control programme. METHODS: All children aged 1-10 years were offered either single dose oral azithromycin treatment (20 mg/kg) or a course of topical 1% tetracycline ointment, depending on the area. Treatment was given annually for 3 years. Six months after the third annual treatment in each village, children were surveyed for nasopharyngeal carriage of S pneumoniae and resistance was determined using broth dilution MIC technique. Children in two additional villages, which had not yet been treated, were also surveyed. RESULTS: Nasopharyngeal carriage of S pneumoniae was similar in the tetracycline treated, azithromycin treated, and untreated areas (p=0.57). However, resistance to tetracycline and azithromycin was distributed differently between the three areas (p=0.004). The village treated with topical tetracycline had a higher prevalence of tetracycline resistance than the other villages (p=0.010), while the oral azithromycin treated village had a higher prevalence of macrolide resistance than the other villages (p=0.014). CONCLUSIONS: Annual mass treatment with oral azithromycin may alter the prevalence of drug resistant S pneumoniae in a community. Surprisingly, topical tetracycline may also increase nasopharyngeal pneumococcal resistance. Topical antibiotics may have an effect on extraocular bacterial resistance.

Pesky trachoma suspect finally caught.

AIM: Face seeking flies have long been thought to transmit Chlamydia trachomatis, the causative agent of trachoma, but this has never been proven. The four criteria proposed by Barnett, previously used to incriminate other arthropods suspected of transmitting disease, were examined. One of these criteria remains unmet: the repeated demonstration of the presence of C trachomatis on flies. The authors used polymerase chain reaction (PCR) to look for the presence of C trachomatis DNA on flies in the Gurage Zone of Ethiopia. METHODS: Using sticky paper, one fly was collected from the face of each of 103 children aged 1-10 years. The piece of fly paper to which the fly was attached was cut out, followed by the collection of an empty piece from an arbitrary area of the fly paper, which served as control. Roche Amplicor PCR kits were used to detect C trachomatis DNA. RESULTS: Evidence of C trachomatis by PCR was found on 15 of 103 flies versus 0 of 103 controls (p = 0.0001). CONCLUSION: These results meet the final criterion needed to incriminate flies as a vector of trachoma. However, interventional studies will be needed to show the importance of fly control.

Community treatment with azithromycin for trachoma is not associated with antibiotic resistance in Streptococcus pneumoniae at 1 year.

AIMS: To determine if macrolide resistant Streptococcus pneumoniae will be a major concern in areas that receive annual mass azithromycin distributions for trachoma. METHODS: A cross sectional survey was conducted of nasopharyngeal S pneumoniae isolates for susceptibility to azithromycin 1 year after administering a single dose of azithromycin to treat trachoma in a village in Nepal. RESULTS: S pneumoniae was isolated from 50 (86%) of 57 nasopharyngeal cultures and no resistance to azithromycin was detected. CONCLUSION: The authors were unable to demonstrate that mass azithromycin therapy for trachoma produced macrolide resistant S pneumoniae that persists until the next scheduled annual treatment.

Adverse and beneficial secondary effects of mass treatment with azithromycin to eliminate blindness due to trachoma in Nepal.

Mass administration of azithromycin to eliminate blindness due to trachoma has raised concerns regarding the emergence of antimicrobial resistance. During 2000, we compared the antimicrobial resistance of nasopharyngeal pneumococcal isolates recovered from and the prevalence of impetigo, respiratory symptoms, and diarrhea among 458 children in Nepal before and after mass administration of azithromycin. No azithromycin-resistant pneumococci were isolated except from 4.3% of children who had received azithromycin during 2 previous mass treatments (P<.001). There were decreases in the prevalence of impetigo (from 14% to 6% of subjects; adjusted odds ratio [OR], 0.41; 95% confidence interval [CI], 0.21-0.80) and diarrhea (from 32% to 11%; adjusted OR, 0.26; 95% CI, 0.14-0.43) 10 days after azithromycin treatment. The absence of macrolide-resistant isolates after 1 mass treatment with azithromycin is encouraging, although the recovery of azithromycin-resistant isolates after 2 mass treatments suggests the need for resistance monitoring when multiple rounds of antimicrobial treatment are given.

Biotypes and serotypes of Haemophilus influenzae ocular isolates.

AIM: To determine which subtypes of Haemophilus influenzae are most commonly associated with ocular disease, and whether the site of ocular H influenzae infection is correlated with specific subtypes of the organism. METHODS: The biotypes and serotypes of ocular H influenzae isolates collected at the Francis I Proctor Foundation between March 1989 and January 2000 were examined. A total of 62 ocular isolates were retrieved from frozen storage and plated on chocolate agar. Biotypes were assigned based upon the ability of the isolates to produce indole, urease, and ornithine decarboxylase. Capsular subtypes a-f were determined by slide agglutination using commercially available subtype specific antisera. Identified biotypes and serotypes were then analysed with regard to site of infection. RESULTS: Patient age ranged from 1 to 92 years with a median age of 45 years. 38 (61%) of the isolates were biotype II, 23 (37%) were biotype III, and one (2%) was biotype VII. All of the isolates were non-encapsulated and thus serologically non-typable. H influenzae biotype II was found in 28 of 48 (58%) conjunctivitis cases, five of eight (63%) keratitis cases, and two of two (100%) endophthalmitis cases. Biotype III was found in 20 of 48 (42%) conjunctivitis cases, two of eight (25%) keratitis cases, and a single case of dacryocystitis. Biotype VII was associated with one of eight (13%) keratitis cases. CONCLUSION: Most ocular H influenzae isolates appear to be serologically non-typable strains from biotypes II and III, less virulent subtypes that frequently colonise the nasopharynx. In addition, the site of ocular H influenzae infections appears to be largely independent of species subtype.