iAlthough ampicillin is the most commonly used drug in neonates, developmental pharmacokinetic (PK) data to guide dosing are lacking. Ampicillin is primarily renally eliminated, and developmental changes are expected to influence PK. We conducted an open-label, multicenter, opportunistic, prospective PK study of ampicillin in neonates stratified by gestational age (GA) (<34 or >34 weeks) and postnatal age (PNA) (<7 or >7 days). Drug concentrations were measured by tandem mass spectrometry. PK data were analyzed using population nonlinear mixed-effects modeling in NONMEM 7.2. Monte Carlo simulations were conducted to determine the probability of target attainment for the time in which the total steady-state ampicillin concentrations remained above the MIC (T>MIC) for 50%, 75%, and 100% of the dosing interval. A total of 142 PK samples from 73 neonates were analyzed (median [range] GA, 36 [24 to 41] weeks; PNA, 5 [0 to 25] days). The median ampicillin dose was 200 (100 to 350) mg/kg/day. Postmenstrual age and serum creatinine were covariates for ampicillin clearance (CL). A simplified dosing regimen of 50 mg/kg every 12 h for GA of <34 weeks and PNA of <7 days, 75 mg/kg every 12 h for GA of <34 weeks and PNA of >8 and <28 days, and 50 mg/kg every 8 h for GA of >34 weeks and PNA of <28 days achieved the prespecified surrogate efficacy target in 90% of simulated subjects. Ampicillin CL was associated with neonatal development. A simplified dosing regimen stratified by GA and PNA achieves the desired surrogate therapeutic target in the vast majority of neonates.

Objective To identify characteristics differentiating the node-first presentation of Kawasaki disease (NFKD) from bacterial cervical lymphadenitis (BCL) and typical Kawasaki disease (KD). Study design From our prospectively collected database, we compared clinical, laboratory, and imaging characteristics of NFKD and BCL cohorts and performed multivariable logistic regression to identify variables that distinguish NFKD from BCL. We then compared outcomes of NFKD and patients with typical KD treated during the same period. Results Over 7 years, 57 patients were hospitalized for NFKD, 78 for BCL, and 287 for typical KD. Patients with NFKD were older and had more medical encounters and longer duration of illness prior to correct diagnosis than patients with BCL. Of patients with NFKD, 33% had an admission diagnosis of bacterial adenitis or abscess. Compared with patients with BCL, patients with NFKD had lower leukocyte (WBC), hemoglobin, and platelet counts and higher absolute band counts (ABC), C-reactive protein (CRP), alanine transaminase and γ-glutamyl transpeptidase levels, and erythrocyte sedimentation rates. In the multivariable analysis, smaller nodes, lower WBC, and higher ABC and CRP were independently associated with NFKD. Patients with NFKD had multiple enlarged solid nodes and comparable rates of retropharyngeal edema. Compared with patients with typical KD, patients with NFKD were older, had more severe inflammation, and had similar rates of coronary artery abnormalities and resistance to intravenous immune globulin. Conclusions High ABC and CRP values and multiple enlarged solid nodes in febrile patients with cervical adenopathy should prompt consideration of NFKD to prevent delayed diagnosis of KD. Retropharyngeal edema on radiography should not dissuade from the diagnosis of NFKD.

Objectives To characterize the clinical presentation and outcome in infants <6 months of age with Kawasaki disease (KD) and to describe the use of newer anti-inflammatory therapies in this young population. Study design We evaluated 88 infants < 6 months old and 632 ≥ 6 months old treated for KD. We compared differences in laboratory data, response to treatment, and coronary artery outcomes between the two cohorts. Fisher exact test was used to analyze categorical variables, while the Wilcoxon Rank Sum test was used for continuous variables. Results The majority of children in both cohorts were diagnosed and treated within the first 10 days of illness (median illness day 6 in both cohorts). For patients treated within the first 10 days after fever onset, a larger proportion of infants < 6 months old had a dilated or aneurysmal coronary artery on the initial echocardiogram compared with those ≥ 6 months old (43.4% vs. 19.5%). 18.6% of infants < 6 months old who had a normal echocardiogram at diagnosis, developed a dilated or aneurysmal coronary artery on a subsequent echocardiogram within 8 weeks of diagnosis. Twenty-eight infants < 6 months old received a single dose of infliximab without any untoward effects. Conclusions Despite treatment in the first 10 days, infants < 6 months old with acute KD are more likely to develop coronary artery abnormalities. Thus, the development of adjunctive therapies to reduce coronary artery damage should target this population.

Background— Kawasaki disease (KD) is an acute pediatric vasculitis in which host genetics influence both susceptibility to KD and the formation of coronary artery aneurysms. Variants discovered by genome-wide association studies and linkage studies only partially explain the influence of genetics on KD susceptibility. Methods and Results— To search for additional functional genetic variation, we performed pathway and gene stability analysis on a genome-wide association study data set. Pathway analysis using European genome-wide association study data identified 100 significantly associated pathways ( P <5×10 − 4 ). Gene stability selection identified 116 single nucleotide polymorphisms in 26 genes that were responsible for driving the pathway associations, and gene ontology analysis demonstrated enrichment for calcium transport ( P =1.05×10 − 4 ). Three single nucleotide polymorphisms in solute carrier family 8, member 1 ( SLC8A1 ), a sodium/calcium exchanger encoding NCX1, were validated in an independent Japanese genome-wide association study data set (meta-analysis P =0.0001). Patients homozygous for the A (risk) allele of rs13017968 had higher rates of coronary artery abnormalities ( P =0.029). NCX1, the protein encoded by SLC8A1 , was expressed in spindle-shaped and inflammatory cells in the aneurysm wall. Increased intracellular calcium mobilization was observed in B cell lines from healthy controls carrying the risk allele. Conclusions— Pathway-based association analysis followed by gene stability selection proved to be a valuable tool for identifying risk alleles in a rare disease with complex genetics. The role of SLC8A1 polymorphisms in altering calcium flux in cells that mediate coronary artery damage in KD suggests that this pathway may be a therapeutic target and supports the study of calcineurin inhibitors in acute KD.

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