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bGram-positive bacteria naturally produce extracellular vesicles. However, little is known regarding the functions of Gram-positive bacterial extracellular vesicles, especially in the bacterial community. Here, we investigated the role of Staphylococcus aureus extracellular vesicles in interbacterial communication to cope with antibiotic stress. We found that S. aureus liberated BlaZ, a ␤-lactamase protein, via extracellular vesicles. These extracellular vesicles enabled other ampicillin-susceptible Gram-negative and Gram-positive bacteria to survive in the presence of ampicillin. However, S. aureus extracellular vesicles did not mediate the survival of tetracycline-, chloramphenicol-, or kanamycin-susceptible bacteria. Moreover, S. aureus extracellular vesicles did not contain the blaZ gene. In addition, the heat-treated S. aureus extracellular vesicles did not mediate the survival of ampicillinsusceptible bacteria. The ␤-lactamase activities of S. aureus soluble and extracellular vesicle-associated BlaZ were similar, but only the extracellular vesicle-associated BlaZ was resistant to protease digestion, which suggests that the enzymatic activity of BlaZ in extracellular vesicles is largely protected by the vesicle structure. Our observations provide evidence of the important role of S. aureus extracellular vesicles in antibiotic resistance, which allows the polymicrobial community to continue to evolve and prosper against antibiotics.

The release of extracellular vesicles, also known as outer membrane vesicles, membrane vesicles, exosomes, and microvesicles, is an evolutionarily conserved phenomenon from bacteria to eukaryotes. It has been reported that Mycobacterium tuberculosis releases extracellular vesicles harboring immunologically active molecules, and these extracellular vesicles have been suggested to be applicable in vaccine development and biomarker discovery. However, the comprehensive proteomic analysis has not been performed for M. tuberculosis extracellular vesicles. In this study, we identified a total of 287 vesicular proteins by four LC-MS/MS analyses with high confidence. In addition, we identified several vesicular proteins associated with the virulence of M. tuberculosis. This comprehensive proteome profile will help elucidate the pathogenic mechanism of M. tuberculosis. The data have been deposited to the ProteomeXchange with identifier PXD001160 (http://proteomecentral.proteomexchange.org/dataset/PXD001160).

Current in vitro cell culture models do not reflect human physiology, and various efforts have been made to enhance existing models. Reconstitution of three-dimensional (3D) tissue structure has been one of the strategies, since 3D tissue structure provides essential cellular environmental cues for cell functions. Previously, we developed a novel hydrogel microfabrication technique for constructing an accurate 3D replica of human intestinal villi epithelium. In this study, genetic and physiological properties of the 3D villi model were examined to gain a better insight into the barrier function of gut epithelium and its interaction with microbes. Gene expression study of Caco-2 on the 3D villi scaffold revealed that expression of MUC17, which is one of the transmembrane mucins, was highly enhanced in the 3D villi model, compared to a monolayer culture. Cells on the scaffold were almost immune to bacterial infection, while MUC17 knockdown in Caco-2 cells restored bacterial infectivity. The 3D villi model also exhibited changes in the barrier function compared to the 2D model, manifested by changes in transepithelial electrical resistance (TEER) and permeability of FITC-dextran. Knockdown of MUC17 resulted in reduction of tight junction protein expression and further increase in permeability, suggesting an important role of MUC17 in the barrier function against pathogens and xenobiotics. Our study suggests that mimicking the 3D tissue architecture of the small intestine induces physiological changes in human intestinal cells.

BackgroundGenetic polymorphisms of cytochrome P450 enzymes, especially CYP2C19 influence voriconazole pharmacokinetics. However, the impact of CYP2C19 genetic polymorphisms on the therapeutic efficacy and toxicity of voriconazole therapy are not well established.Materials and MethodsIn this prospective observational study, we analyzed all consecutive adult patients with hematologic diseases who were treated for invasive aspergillosis (IA) with voriconazole between January 2011 and June 2012. CYP2C19 genotype and routine therapeutic drug monitoring of voriconazole were performed. The target range for voriconazole trough levels was 1-5.5 mg/L.ResultsA total of 104 consecutive patients were enrolled, including 39 homozygous extensive metabolizers (EMs, 38%), 50 heterozygous extensive metabolizers (HEMs, 48%), and 15 poor metabolizers (PMs, 14%). The initial voriconazole trough levels were 1.8, 2.7, and 3.2 mg/L in EMs, HEMs, and PMs, respectively (P = 0.068). Out-of-range initial trough levels were most frequently observed in EMs (46%) followed by HEMs (26%) and PMs (0%) (P = 0.001). The frequency of initial trough levels < 1 mg/L but not > 5.5 mg/L differed significantly among the 3 groups (P = 0.005). However, treatment response, all-cause and IA-attributable mortality, and the occurrence of voriconazole-related adverse events did not differ significantly among the 3 groups (P = 0.399, P = 0.412, P = 0.317, and P = 0.518, respectively).ConclusionsWhile none of the initial voriconazole trough levels in PMs was outside the target range, subtherapeutic initial trough levels were frequent in EMs. Although there was no significant relationship between CYP2C19 genotype and either the clinical outcomes of IA or toxicity of voriconazole, further large-scale multicenter studies using clinical data from homogeneous populations are required.

This study shows that therapeutic drug monitoring is indicated in patients with a voriconazole-related SAE and that dose adjustment is required if the trough concentration of voriconazole exceeds 5.83 mg/l.

These results suggest that the TSO exercise can be recommended for preventing or correcting HV deformity at an early stage.

To define the risk factors and clinical outcomes of community-onset bacteremia caused by extended-spectrum β-lactamase (ESBL)-producing Escherichia coli (ESBLEC), we analyzed 50 consecutive cases of community-onset bacteremia caused by ESBLEC at a secondary hospital in South Korea from 2005 to 2010. Risk factors were assessed by conducting a case-double control study in which cases were compared with (1) control patients with community-onset bacteremia due to non-ESBLEC, and (2) those with community-onset bacteremia not caused by E. coli. Clinical outcome was assessed among patients with community-onset E. coli bacteremia. Community-onset bacteremia due to ESBLEC accounted for 6.7% of all community-onset E. coli bacteremia. In addition, an increasing proportion of ESBLEC among patients without any healthcare risk factors was observed. Comparison with both control groups revealed that the recent use of antibiotics (odds ratio [OR], 4.3; 95% confidence interval [CI], 1.5-12.3) was an independent risk factor for ESBL acquisition. Factors influencing the 30-day mortality were a high Acute Physiology and Chronic Health Evaluation (APACHE) II score (OR, 1.5; 95% CI, 1.1-2.0) and severe sepsis or septic shock (OR, 26.6; 95% CI, 1.5-470.7) and malignancy (OR, 11.9; 95% CI, 1.1-134.8). Increased mortality was not statistically associated either with ESBL production or with inappropriate empirical therapy. ESBLEC has emerged as a significant cause of community-onset bacteremia in this hospital, suggesting that ESBLEC are widely disseminated in the South Korean community.