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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.

Background Infectious keratitis secondary to fungus or acanthamoeba often has a poor outcome despite receiving the best available medical therapy. In vitro rose bengal photodynamic therapy (RB-PDT) appears to be effective against fungal and acanthamoeba isolates (Atalay HT et al., Curr Eye Res 43:1322–5, 2018, Arboleda A et al. Am J Ophthalmol 158:64-70, 2014). In one published series, RB-PDT reduced the need for therapeutic penetrating keratoplasty in severe bacterial, fungal, and acanthamoeba keratitis not responsive to medical therapy. Methods This international, randomized, sham and placebo controlled 2-arm clinical trial randomizes patients with smear positive fungal and acanthamoeba and smear negative corneal ulcers in a 1:1 fashion to one of two treatment arms: 1) topical antimicrobial plus sham RB-PDT or 2) topical antimicrobial plus RB-PDT. Discussion We anticipate that RB-PDT will improve best spectacle-corrected visual acuity and also reduce complications such as corneal perforation and the need for therapeutic penetrating keratoplasty. This study will comply with the NIH Data Sharing Policy and Policy on the Dissemination of NIH-Funded Clinical Trial Information and the Clinical Trials Registration and Results Information Submission rule. Our results will be disseminated via ClinicalTrials.gov website, meetings, and journal publications. Our data will also be available upon reasonable request. Trial registration NCT, NCT05110001 , Registered on November 5, 2021.  Key messages Fungal or acanthamoeba keratitis often has a poor outcome despite receiving the best available medical therapy. Rose bengal photodynamic therapy (RB-PDT) may directly kill infectious organisms and strengthen the cornea, reducing the risk of perforation or need for therapeutic penetrating keratoplasty. This protocol describes the first large, NIH-funded, randomized clinical trial to study this therapy in patients and will determine whether RB-PDT is a beneficial adjunctive therapy for infectious 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 enrolment 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.

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

Childhood mortality remains high in sub-Saharan Africa. In this cluster-randomized, placebo-controlled trial, mortality among children younger than 5 years of age was lower among those who received azithromycin than among those who received placebo.

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.

Aim: To determine if antioxidant supplements (β 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 β 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.

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.Trial registration number:NCT00324168

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.

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.