A Phase 3, Randomized, Double-Blind Study Comparing Tedizolid Phosphate and Linezolid for Treatment of Ventilated Gram-Positive Hospital-Acquired or Ventilator-Associated Bacterial Pneumonia.

BACKGROUND: Hospital-acquired bacterial pneumonia (HABP) and ventilator-associated bacterial pneumonia (VABP) are associated with high mortality rates. We evaluated the efficacy and safety of tedizolid (administered as tedizolid phosphate) for treatment of gram-positive ventilated HABP/VABP. METHODS: In this randomized, noninferiority, double-blind, double-dummy, global phase 3 trial, patients were randomized 1:1 to receive intravenous tedizolid phosphate 200 mg once daily for 7 days or intravenous linezolid 600 mg every 12 hours for 10 days. Treatment was 14 days in patients with concurrent gram-positive bacteremia. The primary efficacy end points were day 28 all-cause mortality (ACM; noninferiority margin, 10%) and investigator-assessed clinical response at test of cure (TOC; noninferiority margin, 12.5%) in the intention-to-treat population. RESULTS: Overall, 726 patients were randomized (tedizolid, n = 366; linezolid, n = 360). Baseline characteristics, including incidence of methicillin-resistant Staphylococcus aureus (31.3% overall), were well balanced. Tedizolid was noninferior to linezolid for day 28 ACM rate: 28.1% and 26.4%, respectively (difference, -1.8%; 95% confidence interval [CI]: -8.2 to 4.7). Noninferiority of tedizolid was not demonstrated for investigator-assessed clinical cure at TOC (tedizolid, 56.3% vs linezolid, 63.9%; difference, -7.6%; 97.5% CI: -15.7 to 0.5). In post hoc analyses, no single factor accounted for the difference in clinical response between treatment groups. Drug-related adverse events occurred in 8.1% and 11.9% of patients who received tedizolid and linezolid, respectively. CONCLUSIONS: Tedizolid was noninferior to linezolid for day 28 ACM in the treatment of gram-positive ventilated HABP/VABP. Noninferiority of tedizolid for investigator-assessed clinical response at TOC was not demonstrated. Both drugs were well tolerated. CLINICAL TRIALS REGISTRATION: NCT02019420.

Putative association between UBE2E2 polymorphisms and the risk of gestational diabetes mellitus.

We hypothesized that ubiquitin-conjugating enzyme E2 E2 (UBE2E2) may be associated with gestational diabetes mellitus (GDM) and conducted association analyses. A total of 2071 subjects were recruited for the study, with 1104 cases and 967 controls. Two UBE2E2 single-nucleotide polymorphisms rs6780569 and rs7612463, and their haplotypes were analyzed for the study. As a result, rs7612463 showed a significant association with GDM in the recessive model. In addition, the regression analyses for the phenotypes showed that rs6780569. rs7612463 and ht2 showed significant associations with fasting plasma glucose (FPG) in recessive models, while ht1 showed an association in the dominant model. Our results show that the genetic variants of UBE2E2 are associated with GDM and FPG, which could be an important preliminary result for future studies.

Melatonin receptor 1 B polymorphisms associated with the risk of gestational diabetes mellitus.

BACKGROUNDS: Two SNPs in melatonin receptor 1B gene, rs10830963 and rs1387153 showed significant associations with fasting plasma glucose levels and the risk of Type 2 Diabetes Mellitus (T2DM) in previous studies. Since T2DM and gestational diabetes mellitus (GDM) share similar characteristics, we suspected that the two genetic polymorphisms in MTNR1B may be associated with GDM, and conducted association studies between the polymorphisms and the disease. Furthermore, we also examined genetic effects of the two polymorphisms with various diabetes-related phenotypes. METHODS: A total of 1,918 subjects (928 GDM patients and 990 controls) were used for the study. Two MTNR1B polymorphisms were genotyped using TaqMan assay. The allele distributions of SNPs were evaluated by x2 models calculating odds ratios (ORs), 95% confidence intervals (CIs), and corresponding P values. Multiple regressions were used for association analyses of GDM-related traits. Finally, conditional analyses were also performed. RESULTS: We found significant associations between the two genetic variants and GDM, rs10830963, with a corrected P value of 0.0001, and rs1387153, with the corrected P value of 0.0008. In addition, we also found that the two SNPs were associated with various phenotypes such as homeostasis model assessment of beta-cell function and fasting glucose levels. Further conditional analyses results suggested that rs10830963 might be more likely functional in case/control analysis, although not clear in GDM-related phenotype analyses. CONCLUSION: There have been studies that found associations between genetic variants of other genes and GDM, this is the first study that found significant associations between SNPs of MTNR1B and GDM. The genetic effects of two SNPs identified in this study would be helpful in understanding the insight of GDM and other diabetes-related disorders.

Safety and Efficacy of Oral and/or Intravenous Tedizolid Phosphate From a Randomized Phase 3 Trial in Adolescents With Acute Bacterial Skin and Skin Structure Infections.

BACKGROUND: Tedizolid phosphate is an oxazolidinone prodrug approved in 2014 for treatment of adults with acute bacterial skin and skin structure infections (ABSSSIs); however, efficacy has not previously been evaluated in children. This study compared the safety and efficacy of tedizolid (administered as tedizolid phosphate) with active antibacterial comparators for the treatment of ABSSSIs in adolescents. METHODS: This was a randomized, assessor-blind, global phase 3 study of tedizolid versus active comparators for the treatment of Gram-positive ABSSSIs in adolescents (12 to <18 years of age; NCT02276482). Enrolled participants were stratified by region and randomized 3:1 to receive tedizolid phosphate 200 mg (oral and/or intravenous) once daily for 6 days or active comparator, selected by investigator from an allowed list per local standard of care, for 10 days. The primary endpoint was safety; blinded investigator's assessment of clinical success at the test-of-cure visit (18-25 days after the first dose) was a secondary efficacy endpoint. Statistical comparisons between treatment groups were not performed. RESULTS: Of the 121 participants enrolled, 120 were treated (tedizolid, n = 91; comparator, n = 29). Treatment-emergent adverse events were balanced between treatment groups (tedizolid, 14.3%; comparator, 10.3%). Overall, 3 participants (3.3%) in the tedizolid group and 1 (3.4%) in the comparator group experienced a single drug-related TEAE. Clinical success rates were high in both treatment groups: 96.7% and 93.1% at the test-of-cure visit for the tedizolid and comparator groups, respectively. CONCLUSIONS: Tedizolid demonstrated safety and efficacy similar to comparators for the treatment of ABSSSIs in adolescents.

Pharmacokinetics and Safety of Single-dose Tedizolid Phosphate in Children 2 to <12 Years of Age.

BACKGROUND: Infections with Gram-positive bacteria, including acute bacterial skin and skin structure infections (ABSSSIs), are common in children. We describe a single-dose pharmacokinetics and safety study of tedizolid phosphate, a new oxazolidinone under investigation for the treatment of ABSSSIs in children, in hospitalized participants 2 to <12 years of age. METHODS: This open-label, multicenter, phase 1 trial (NCT02750761) enrolled hospitalized children 2 to <12 years of age receiving treatment for a confirmed/suspected Gram-positive bacterial infection. Participants were stratified by age (2 to <6 years and 6 to <12 years) to receive a single oral or intravenous dose of tedizolid phosphate. Evaluations included safety and pharmacokinetics of tedizolid phosphate and its active metabolite, tedizolid. Palatability of the oral suspension was also evaluated. RESULTS: Thirty-two participants were enrolled and received 3-6 mg/kg of study medication. For both routes of administration, tedizolid phosphate was rapidly converted to tedizolid; median time to maximum tedizolid plasma concentration was 1-2 hours after initiation of the 1-hour intravenous infusion and 2-3 hours after oral dosing. The tedizolid mean terminal half-life was 5-6 hours and 6-7 hours for the intravenous and oral administration groups, respectively. The oral tedizolid phosphate suspension demonstrated high bioavailability comparable to that of the parenteral administration. A single dose of intravenous or oral tedizolid phosphate was well tolerated; no unexpected safety findings were observed. CONCLUSIONS: Pharmacokinetic and safety observations provide the information necessary for the continued development of tedizolid phosphate for the treatment of Gram-positive infections in children, particularly ABSSSIs.

Effects of highly active antiretroviral therapy (HAART) on cholesterol in HIV-1 infected children: a retrospective cohort study.

OBJECTIVE: To determine the extent to which different highly active antiretroviral therapy (HAART) regimens pose risks for hypercholesterolemia in children with perinatal HIV-1. METHODS: A single center, retrospective cohort study examined different HAART regimens and total cholesterol (TC) levels. The primary outcomes were TC levels > 180, > 200 mg/dl. HAART was defined as multiple nucleoside analog reverse transcriptase inhibitors (NRTI), NRTI and protease inhibitor (PI) combinations (NRTI/PI), and NRTI and non-nucleoside analog reverse transcriptase inhibitor (NNRTI) combinations (NRTI/NNRTI). Controls were HIV-1 infected children while on no medications (No MED). Univariate and multivariable Cox regression models generated hazard ratios for each of the primary outcomes with duration of therapy in the model. RESULTS: Of the 178 HIV-1 infected children eligible for study, 72.4% had TC > 180 mg/dl, 53.4% had TC > 200 mg/dl. For TC > 200, the multivariable analysis showed increased risk with NRTI/NNRTI (HR: 1.86, 95%CI: 1.34-2.19) and NRTI/PI (HR: 3.45, 95%CI: 2.65-4.51) when compared to No MED. Compared to NRTI/NNRTI, NRTI/PI increased the risk for TC > 200 mg/dl (HR: 1.86, 95%CI: 1.45-2.39) in the multivariable model. CONCLUSIONS: In vertically acquired HIV-1 infected children, HAART elevates the risk of hypercholesterolemia. NRTI/PI increased risk of TC levels threefold, while NRTI/NNRTI increased risk twofold over No MED.

Hospitalization for underage drinkers in the United States.

PURPOSE: Underage drinking is common in the United States. This article presents nationally representative data on hospitalizations for alcohol use disorder (AUD) in youth. METHODS: Using the Nationwide Inpatient Sample database, discharge records of individuals between 15 and 20 years diagnosed with AUD were identified. Incidence rates of these hospitalizations were calculated based on population estimates from the US Census Bureau. RESULTS: In 2008, there were 699,506 nonobstetric discharges in 15- to 20-year-olds, of which 39,619 (5.6%) had an AUD diagnosis with or without an injury diagnosis. The overall annual incidence of AUD hospitalization was 18.3 per 10,000 boys and 12.3 per 10,000 girls. Native American boys in the Midwest had the highest incidence (101 per 10,000), and Asian/Pacific Islander girls in the South had the lowest (2 per 10,000). The estimated total charges for these hospitalizations were $755 million in 2008. CONCLUSIONS: Hospitalization care for underage drinking is common, especially in certain race and in certain geographic regions and is associated with a substantial health care expenditure.

Putative association of DNA methyltransferase 1 (DNMT1) polymorphisms with clearance of HBV infection.

DNA methyltransferase (DNMT) 1 is the key enzyme responsible for DNA methylation, which often occurs in CpG islands located near the regulatory regions of genes and affects transcription of specific genes. In this study, we examined the possible association of DNMT1 polymorphisms with HBV clearance and the risk of hepatocellular carcinoma (HCC). Seven common polymorphic sites were selected by considering their allele frequencies, haplotype-tagging status and LDs for genotyping in larger-scale subjects (n = 1,100). Statistical analysis demonstrated that two intron polymorphisms of DNMT1, +34542G > C and +38565G > T, showed significant association with HBV clearance in a co-dominant model (OR = 1.30, P(corr) = 0.03) and co- dominant/recessive model (OR = 1.34-1.74, P(corr) = 0.01-0.03), respectively. These results suggest that two intron polymorphisms of DNMT1,+34542G > C and +38565G > T, might affect HBV clearance.

Fluoroquinolone resistance in pediatric bloodstream infections because of Escherichia coli and Klebsiella species.

In pediatric bloodstream infections with fluoroquinolone (FQ)-resistant Escherichia coli and Klebsielia species, we noted an association between FQ resistance and extended-spectrum beta-lactamase (ESBL) production (OR, 12; 95% CI: 2.28-83.8). A case control study revealed no significant risk factors (including prior antibiotic use) for FQ resistance among ESBL E coli and Klebsiella species (ESBL-EK).

Burkholderia glumae infection in an infant with chronic granulomatous disease.

An 8-month-old boy developed a necrotic lung mass from which Burkholderia glumae was recovered, leading to the diagnosis of chronic granulomatous disease (CGD). While other Burkholderia species have been identified as important pathogens in persons with CGD, B. glumae has not been previously reported to cause human infection.

Disruption of tight junctions during traversal of the respiratory epithelium by Burkholderia cenocepacia.

Burkholderia cenocepacia is an opportunistic bacterial species capable of causing life-threatening respiratory tract infection in persons with cystic fibrosis (CF). Unlike most other pathogens in CF, which typically remain confined to the endobronchial spaces, B. cenocepacia can traverse airway epithelium to cause bacteremia and sepsis. The mechanisms by which this occurs, however, are unknown. We examined the transmigration of B. cenocepacia through polarized respiratory epithelium. Representatives of three "epidemic" lineages common among CF patients in North America were able to traverse polarized 16HBE14o- cells in vitro. Transmigration of bacteria was associated with significant perturbations in epithelial permeability, as measured by a loss of transepithelial electrical resistance and increased flux of bovine serum albumin across the cell layer. Terminal deoxynucleotidyltransferase-mediated dUTP-biotin nick end labeling and trypan blue exclusion assays, as well as lactate dehydrogenase levels, did not indicate excessive cytotoxicity or cell death in infected cell layers. Rather, confocal fluorescence microscopy demonstrated the loss of occludin from tight junctions. In contrast, zonula occludens 1 was well preserved along intercellular borders. Western blot analysis showed a shift in the major occludin isoforms from high- to low-phosphorylation states during infection. These observations suggest that B. cenocepacia traverses polarized respiratory epithelium by the dephosphorylation and dissociation of occludin from the tight-junction complex.