BackgroundAntibiotic resistance is rising in important bacterial pathogens. Phage therapy (PT), the use of bacterial viruses infecting the pathogen in a species-specific way, is a potential alternative.MethodT4-like coliphages or a commercial Russian coliphage product or placebo was orally given over 4 days to Bangladeshi children hospitalized with acute bacterial diarrhea. Safety of oral phage was assessed clinically and by functional tests; coliphage and Escherichia coli titers and enteropathogens were determined in stool and quantitative diarrhea parameters (stool output, stool frequency) were measured. Stool microbiota was studied by 16S rRNA gene sequencing; the genomes of four fecal Streptococcus isolates were sequenced.FindingsNo adverse events attributable to oral phage application were observed (primary safety outcome). Fecal coliphage was increased in treated over control children, but the titers did not show substantial intestinal phage replication (secondary microbiology outcome). 60% of the children suffered from a microbiologically proven E. coli diarrhea; the most frequent diagnosis was ETEC infections. Bacterial co-pathogens were also detected. Half of the patients contained phage-susceptible E. coli colonies in the stool. E. coli represented less than 5% of fecal bacteria. Stool ETEC titers showed only a short-lived peak and were otherwise close to the replication threshold determined for T4 phage in vitro. An interim analysis after the enrollment of 120 patients showed no amelioration in quantitative diarrhea parameter by PT over standard care (tertiary clinical outcome). Stool microbiota was characterized by an overgrowth with Streptococcus belonging to the Streptococcus gallolyticus and Streptococcus salivarius species groups, their abundance correlated with quantitative diarrhea outcome, but genome sequencing did not identify virulence genes.InterpretationOral coliphages showed a safe gut transit in children, but failed to achieve intestinal amplification and to improve diarrhea outcome, possibly due to insufficient phage coverage and too low E. coli pathogen titers requiring higher oral phage doses. More knowledge is needed on in vivo phage–bacterium interaction and the role of E. coli in childhood diarrhea for successful PT.FundingThe study was supported by a grant from . The trial was registered with Identifier NCT00937274 at ClinicalTrials.gov.

Decentralized on-site production of hydrogen peroxide (H 2 O 2 ) relies on efficient, robust, and inexpensive electrocatalysts for the selective two-electron (2e − ) oxygen reduction reaction (ORR). Here, we combine computations and experiments to demonstrate that cobalt pyrite (CoS 2 ), an earth-abundant transition-metal compound, is both active and selective toward 2e − ORR in the acidic solution. CoS 2 nanomaterials drop-casted on the rotating ring-disk electrode (RRDE) showed selective and efficient H 2 O 2 formation in 0.05 M H 2 SO 4 at high catalyst loadings, with their operational stability evaluated by structural and surface analyses. CoS 2 nanowires directly grown on the high-surface-area carbon fiber paper electrode boosted the overall performance of bulk ORR electrolysis and the H 2 O 2 product was chemically quantified to yield a ∼70% H 2 O 2 selectivity at 0.5 V vs reversible hydrogen electrode (RHE), in good agreement with the RRDE results. Computations suggested the modest binding of OOH* adsorbate on the single Co site of CoS 2 and the kinetically disfavored O−O bond scission due to the lack of active site ensembles in the crystal structure, consistent with the experimentally observed activity and selectivity. CoS 2 also catalyzes 2e − ORR with less activity and selectivity in the noncorrosive neutral solution. This work opens up the exploration of diverse earth-abundant transition-metal compounds in search of highly active and selective electrocatalysts for efficient H 2 O 2 production.

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A T4-like coliphage cocktail was given with different oral doses to healthy Bangladeshi children in a placebo-controlled randomized phase I safety trial. Fecal phage detection was oral dose dependent suggesting passive gut transit of coliphages through the gut. No adverse effects of phage application were seen clinically and by clinical chemistry. Similar results were obtained for a commercial phage preparation (Coliproteus from Microgen/Russia). By 16S rRNA gene sequencing, only a low degree of fecal microbiota conservation was seen in healthy children from Bangladesh who were sampled over a time interval of 7 days suggesting a substantial temporal fluctuation of the fecal microbiota composition. Microbiota variability was not associated with the age of the children or the presence of phage in the stool. Stool microbiota composition of Bangladeshi children resembled that found in children of other regions of the world. Marked variability in fecal microbiota composition was also seen in 71 pediatric diarrhea patients receiving only oral rehydration therapy and in 38 patients receiving coliphage preparations or placebo when sampled 1.2 or 4 days apart respectively. Temporal stability of the gut microbiota should be assessed in case-control studies involving children before associating fecal microbiota composition with health or disease phenotypes.