IMPORTANCEChildhood community-acquired pneumonia (CAP) is usually treated with 10 days of antibiotics. Shorter courses may be effective with fewer adverse effects and decreased potential for antibiotic resistance.OBJECTIVE To compare a short (5-day) vs standard (10-day) antibiotic treatment strategy for CAP in young children. DESIGN, SETTING, AND PARTICIPANTS Randomized double-blind placebo-controlled clinical trial in outpatient clinic, urgent care, or emergency settings in 8 US cities. A total of 380 healthy children aged 6 to 71 months with nonsevere CAP demonstrating early clinical improvement were enrolled from December 2, 2016, to December 16, 2019. Data were analyzed from January to September 2020.INTERVENTION On day 6 of their originally prescribed therapy, participants were randomized 1:1 to receive 5 days of matching placebo or 5 additional days of the same antibiotic.
MAIN OUTCOMES AND MEASURESThe primary end point was the end-of-treatment response adjusted for duration of antibiotic risk (RADAR), a composite end point that ranks each child's clinical response, resolution of symptoms, and antibiotic-associated adverse effects in an ordinal desirability of outcome ranking (DOOR). Within each DOOR rank, participants were further ranked by the number of antibiotic days, assuming that shorter antibiotic durations were more desirable. Using RADAR, the probability of a more desirable outcome was estimated for the short-vs standard-course strategy. In a subset of children, throat swabs were collected between study days 19 and 25 to quantify antibiotic resistance genes in oropharyngeal flora.RESULTS A total of 380 children (189 randomized to short course and 191 randomized to standard course) made up the study population. The mean (SD) age was 35.7 (17.2) months, and 194 participants (51%) were male. Of the included children, 8 were Asian, 99 were Black or African American, 234 were White, 32 were multiracial, and 7 were of unknown or unreported race; 33 were Hispanic or Latino, 344 were not Hispanic or Latino, and 3 were of unknown or unreported ethnicity. There were no differences between strategies in the DOOR or its individual components. Fewer than 10% of children in either strategy had an inadequate clinical response. The short-course strategy had a 69% (95% CI, 63-75) probability of a more desirable RADAR outcome compared with the standard-course strategy. A total of 171 children were included in the resistome analysis. The median (range) number of antibiotic resistance genes per prokaryotic cell (RGPC) was significantly lower in the short-course strategy compared with the standard-course strategy for total RGPC (1.
The phenylalanine residues 300 and 309 in the enzyme tyrosine hydroxylase are known to aid in the positioning and binding of tetrahydrobiopterin (BH4) to the enzyme active site. The residues phenylalanine 254 and tyrosine 325 similarly aid in binding BH4 in phenylalanine hydroxylase. BH4 is a cofactor necessary for enzyme function, and mutations in these residues have been shown to cause a decrease in enzyme function. We examine the pairwise interactions between each aromatic residue and BH4 using second-order Moller Plesset theory and density functional theory to determine the amount of binding due to these aromatic residues. Further, we perform in silico point mutations of these residues to determine if several likely mutations can cause a decrease in protein function. Our results show that dispersion dominates these interactions, and electrostatics alone is not enough to bind the BH4.
Multisystem inflammatory syndrome in children (MIS-C) has been reported to cause significant gastrointestinal symptoms. In this case series, we present four patients with MIS-C with documented acute appendicitis, which strengthens the association between SARS-CoV-2, MIS-C, and acute appendicitis.
Antibiotic resistance is a major threat to public health. Treatment strategies involving shorter antibiotic courses have been proposed as a strategy to lower the potential for antibiotic resistance.
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