Evaluating biapenem dosage regimens in intensive care unit patients with Pseudomonas aeruginosa infections: a pharmacokinetic/pharmacodynamic analysis using Monte Carlo simulation

This study was conducted to identify optimal dosage regimens and estimate pharmacokinetic/pharmacodynamic (PK/PD) characteristics of short-infusion (SI) versus extended-infusion (EI) biapenem against Pseudomonas aeruginosa infections in Chinese intensive care unit (ICU) patients. A total of 85 strains of P. aeruginosa were collected, and the minimum inhibitory concentration (MIC) of biapenem was measured by the serial two-fold agar dilution method. We designed four frequently used clinical regimens: biapenem 300?mg I.V. q12h, q8h, and q6h, and 600?mg q12h. The Monte Carlo Simulation (MCS) was performed using previously published pharmacokinetic data to calculate the probability of target attainment (PTA) and the cumulative fraction of response (CFR) of these regimens as an SI (0.5?h) and an EI (1?h, 2?h, 3?h, and 4?h).For a target of 40%fT_>MIC (serum drug concentration remains above the MIC for a dosing period), none of the regimens achieved any CFRs>90% for P. aeruginosa, multidrug–resistant P. aeruginosa (MDR-PA) and even non–MDR-PA. The traditional biapenem SI regimens most commonly seen in clinical practice were insufficient in treating both MDR and non-MDR P. aeruginosa in ICU patients. However, biapenem 600?mg q12h over 2–4?h EI regimens could achieve CFR>90% with 20%fT_>MIC. Clinical trials should aim to validate the potentially greater PK/PD index with higher, more frequent doses and longer extended infusions.     

临床耐碳青霉烯类肺炎克雷伯菌分子流行病学特征研究

目的 分析近5年耐碳青霉烯类肺炎克雷伯菌的耐药特性及其携带碳青霉烯酶基因等分子流行病学特征,为有效控制院内感染提供依据。方法 收集2012年1月-2016年12月苏州大学附属第二医院临床标本中分离的耐碳青霉烯类肺炎克雷伯菌,用最低抑菌浓度(minimal inhibitory concentration, MIC)法、KB法分析菌株对抗菌药物的敏感性,用改良碳青霉烯灭活试验检测产碳青霉烯酶表型,并通过聚合酶链反应(polymerase chain reaction, PCR)筛选blaKPC、blaNDM、blaIMP、blaVIM和blaOXA48碳青霉烯酶基因,通过脉冲场凝胶电泳(pulsed-field gel electrophoresis, PFGE)和多位点序列分型(multiple locus sequence typing, MLST)检测细菌的同源性和相关遗传性。统计分析相关患者临床资料。结果 共分离到82株耐碳青霉烯类肺炎克雷伯菌,主要来源于呼吸道43株(52.44%),中段尿12株(14.63%),血液10株(12.20%),无菌体液8株(9.76%),分泌物8株(9.76%),导管1株(1.22%),对头孢菌素类和β-内酰胺类抗菌药物表现为高度耐药(85.4%~100%),碳青霉烯灭活试验阳性率为84.1%。PCR检测到71株细菌携带碳青霉烯酶基因,包括KPC阳性56株(78.87%)、NDM阳性10株(14.08%)、IMP阳性4株(5.64%)、VIM阳性1株(1.41%)。感染患者主要集中在重症监护室(ICU)病区(41株,50.00%)和神经外科(14株,17.07%)。2016年检出的32株中有23株(71.9%)PFGE呈高度同源性,且MLST分型均为ST11,其余7株为ST64型(21.9%),2株为ST23型(6.2%)。结论 本院肺炎克雷伯菌主要分布于ICU,以呼吸道标本检出率最高,对碳青霉烯类耐受主要由于产KPC酶,需进一步加强临床耐药细菌的监测,为临床合理使用抗菌药物和严格执行消毒隔离措施提供参考依据。     

氨基糖苷类对禽肠道细菌的耐药判定标准研究进展

禽消化道细菌病是危害养禽业的主要问题之一,沙门菌病、大肠埃希菌病等家禽肠道细菌病的流行日趋复杂,越来越难以控制,且不断出现新的流行与致病特点,不仅会造成严重肠道疾病而且会产生死亡。氨基糖苷类抗生素是高效、广谱抗生素,在临床上广泛应用,但是养殖业用药的不合理导致细菌的氨基糖苷耐药性日趋严重,这在很大程度上降低了其临床应用的潜力。而耐药监测需要判定标准,目前我国并没有相关标准,主要参考美国临床和实验室标准化协会(CLSI)和欧盟抗菌药物敏感性试验委员会(EUCAST)中的折点。当前CLSI和欧盟EUCAST标准中氨基糖苷类抗生素对禽消化道细菌病折点的制定并不完全,所以要全面建立符合我国国情的流行病学临界值和药效学临界值,为折点的制定工作提供科学数据,以监测耐药性的产生,分析耐药现状和发展规律,更科学地指导临床用药和新药开发。     

Childhood polybrominated diphenyl ether (PBDE) exposure and executive function in children in the HOME Study

Prenatal exposure to polybrominated diphenyl ethers (PBDEs) have been reported to impair executive function in children, but little is known whether childhood PBDE exposures play a role. Using the Health Outcomes and Measures of the Environment (HOME) Study, a prospective birth cohort in the greater Cincinnati area, we investigated the association between repeated measures of PBDEs during childhood and executive function at 8 years in 208 children and whether effect modification by child sex was present. We used child serum collected at 1, 2, 3, 5, and 8 years to measure PBDEs. The Behavior Rating Inventory of Executive Function was completed by parents to assess executive function at 8 years. We used multiple informant models to examine childhood PBDEs during several exposure windows. Null associations were observed between early childhood PBDEs and executive function. However, we observed significant adverse associations between a 10-fold increase in concurrent concentrations of BDE-28 (β = 4.6, 95% CI 0.5, 8.7) and BDE-153 (β = 4.8, 95% CI 0.8, 8.8) with behavioral regulation. In addition, PBDEs at 8 years were significantly associated with poorer emotional and impulse control. No associations were noted between childhood PBDEs and metacognition or global executive function. However, child sex significantly modified the associations, with significantly poorer executive function among males with higher concurrent BDE-153, and null associations in females. Our study findings suggest that concurrent PBDE exposures during childhood may be associated with poorer executive function, specifically behavior regulation. Males may also be more sensitive to adverse associations of concurrent PBDEs on executive function.     

Enzymatic synthesis of glucuronidated metabolites of two neurological active agents using plant glucuronosyltransferases

Abstract

Glucuronidation is an important and popular metabolic reaction in vivo of drugs. The further evaluation of biological activity and toxicity of glucuronides is necessary in the course of the drug research and development. However, the synthesis of glucuronides is limited by the lack of efficient approach. Herein, we have developed a new glucuronide synthesis method using plant uridine diphosphate-dependent glucuronosyltransferases (UGTs), UGT88D4, UGT88D7, and EpGT8, enabling the convenient preparation for corresponding O-glucuronide metabolites (1a, 2a, 3a, and 3b) in milligram scale of two neurological active agents, IMM-H004 (1) and FLZ (2). Their structures were characterized by spectroscopic data analyses.     

Oligo-peptide I-C-F-6 inhibits hepatic stellate cell activation and ameliorates CCl4-induced liver fibrosis by suppressing NF-κB signaling and Wnt/β-catenin signaling

Oligo-peptide I-C-F-6 is a Carapax trionycis extract component that has an effect on hepatic fibrosis, however, its mechanism of action is still unclear. This study investigated whether oligo-peptide I-C-F-6 could inhibit liver fibrosis by suppressing NF-κB and Wnt/β-catenin signaling, which are important in liver fibrosis. HSC-T6 cells were treated with oligo-peptide I-C-F-6, and rats were divided randomly into five groups: control (saline), CCl₄, CCl₄ plus oligo-peptide I-C-F-6 (0.12 and 0.24 mg/kg), and CCl₄ plus colchicine (0.11 mg/kg). Here, we demonstrated that oligo-peptide I-C-F-6 ameliorated liver injury, inflammation, and hepatic fibrogenesis induced by CCl₄. Oligo-peptide I-C-F-6 also inhibited the activation of hepatic stellate cells (HSCs) in vivo and in vitro, as evaluated by the expression of transforming growth factor-β1 (TGF-β1) and α-smooth muscle actin (α-SMA), which is a specific marker of HSC activation. Moreover, oligo-peptide I-C-F-6 significantly reduced the expression and distribution of β-catenin, P-AKT, phospho (P)-GSK-3β, nuclear factor κB (NF-κB) P65, phospho-P65, and IκB kinase α/β (IKK-α/β) levels; additionally, IκB-α level was elevated both in vivo and in vitro. Together, these results indicate that oligo-peptide I-C-F-6 has hepatoprotective and anti-fibrotic effects in animal models of liver fibrosis, the mechanism of which may be related to modulating NF-κB and Wnt/β-catenin signaling.     

矽肺并发慢性阻塞性肺疾病稳定期患者呼吸功能锻炼的护理干预

目的观察呼吸功能锻炼的护理干预措施对矽肺并发慢性阻塞性肺疾病(COPD)稳定期患者的临床治疗疗效。方法随机抽取2017年8月至2018年4月泰山医学院附属莱钢医院职业病科住院60例矽肺并发COPD稳定期患者并分为两组。对照组:30例,给予常规治疗加呼吸功能锻炼;观察组:30例,在对照组治疗的基础上给予护理干预措施。2个月后,比较干预前后两组患者的肺功能、血气分析、6 min步行距离。结果干预后观察组第1秒用力呼气容积(FEV1.0)、用力肺活量(FVC)、氧分压(PaO2)及6 min步行距离较对照组明显升高,差异有统计学意义(P<0.05),两组FEV1.0/FVC、二氧化碳分压(PaCO2)的差异无统计学意义(P>0.05)。 结论护理干预措施能有效改善矽肺并发COPD稳定期患者的FEV1.0、FVC、PaO2及6 min步行距离。     

Morphological measurement of biologic width in Chinese people

This study evaluated the biologic width in a Chinese population. Ten autopsy specimens of human jaws from 5 male Han Chinese cadavers were collected. Block sections of the jaws were dissected at autopsy. Six-mum-thick, mesio-distal and bucco-lingual sections were cut and stained with hematoxylin and eosin. The widths of the junctional epithelium and connective tissue were measured with a micrometer microscope at the middle of the mesial, distal, buccal, and lingual sites. Differences in biologic width among the 4 measured sites as well as between anterior and posterior teeth were compared. The mean biologic width was 2.17 mm. The width of the junctional epithelium was 1.07 mm, and that of the connective tissue 1.10 mm. The biologic width varied among the 4 sites and the width of the posterior teeth was greater than that of the anterior teeth.