Sequential emergence of colistin and rifampicin resistance in an OXA-72- producing outbreak strain of Acinetobacter baumannii

Objectives

This study reported a hospital outbreak due to an extensively drug-resistant (XDR) OXA-72-producing strain of Acinetobacter baumannii (A. baumannii).

Indirect activation of pregnane X receptor in the induction of hepatic CYP3A11 by high-dose rifampicin in mice

Rifampicin (RIF), a typical ligand of human pregnane X receptor (PXR), powerfully induces the expression of cytochrome P450 3A4 (CYP3A4) in humans. Although it is thought that RIF is not a ligand of rodent PXR, treatment with high-dose RIF (e.g. more than 20?mg/kg) increases the expression of CYP3A in the mouse liver. In this study, we investigated whether the induction of CYP3A by high-dose RIF in the mouse liver is mediated via indirect activation of mouse PXR (mPXR). The results showed that high-dose RIF increased the expression of CYP3A11 and other PXR-target genes in the liver of wild-type mice but not PXR-knockout mice. However, the results of reporter gene and ligand-dependent assembly assays showed that RIF does not activate mPXR in a ligand-dependent manner. In addition, high-dose RIF stimulated nuclear accumulation of mPXR in the mouse liver, and geldanamycin and okadaic acid attenuated the induction of Cyp3a11 and other PXR-target genes in primary hepatocytes, suggesting that high-dose RIF triggers nuclear translocation of mPXR. In conclusion, the present study suggests that high-dose RIF stimulates nuclear translocation of mPXR in the liver of mice by indirect activation, resulting in the transactivation of Cyp3a11 and other PXR-target genes.     

利福霉素钠与利福平治疗肺结核安全性评价

目的 比较利福霉素钠和利福平在治疗肺结核中的安全性.方法 792例肺结核患者分为利福霉素钠组(393例)和利福平组(399例),治疗2个月后评价其安全性.结果 利福霉素钠不良反应发生率(12.47％),较利福平(18.29％)低,严重不良反应发生率:利福霉素钠为1.78％,利福平为5.76％,差异有统计学意义;主要表现为肝损伤、过敏反应、肾功能损伤、血细胞减少和消化道不适.结论 利福霉素钠的不良反应发生率和严重程度小于利福平,若患者不能耐受利福平,可考虑利福霉素钠作为替代治疗.     

利福霉素钠和利福平在治疗肺结核中的安全性比较

目的分析利福霉素钠和利福平在治疗肺结核中的安全性。方法选取2018年8月至2019年9月本院收治的50例肺结核患者为研究对象,采用随机分组法分为两组,每组25例。对照组采取利福平治疗,观察组采取利福霉素钠治疗。比较两组临床效果及不良反应发生率。结果观察组治疗总有效率为96.00%,明显高于对照组的60.00%(P<0.05);观察组不良反应发生率为4.00%,明显低于对照组的40.00%(P<0.05);治疗3、6、12、18、24个月,观察组痰菌转阴率均高于对照组,差异均有统计学意义(P<0.05)。结论利福霉素钠和利福平均可改善肺结核患者病情,但利福霉素钠临床效果更佳,不良反应发生率更低,痰菌转阴率更高,可作为临床治疗首要考虑方案。     

复合三联抗结核药聚乳酸-羟基乙酸缓释微球的制备及体外释药特性

目的 :制备复合异烟肼(H)、利福平(R)、吡嗪酰胺(Z)的聚乳酸-羟基乙酸(HRZ/PLGA)缓释微球,观察其理化性质和体外缓释特性。方法:以PLGA(450mg)为载体,避光条件下称取H(40mg)、R(60mg)、Z(125mg),采用复乳-溶剂挥发法制备HRZ/PLGA缓释微球,应用扫描电镜观察微球的形态特征;应用高效液相色谱法(HPLC)测定其载药量、包封率;采用溶出法、HPLC于3h、6h、12h、1d、2d、3d、6d、9d、12d、15d、20d、25d、30d、40d、50d测定H、R、Z三种药物的浓度,观察其是否均大于10倍最低抑菌浓度(MIC),计算其日均释药率、累计释药率。结果:HRZ/PLGA微球在电镜下观察呈圆球形,平均粒径为10.3±4.7μm;H、R、Z三种药物的载药量分别为(18.02±0.36)%、(22.46±0.24)%、(21.68±0.37)%,包封率分别为(54.79±1.13)%、(72.35±0.39)%、(67.21±0.68)%;体外缓释试验显示微球缓释前12d左右,三种药物的累计缓释度均超过了50%,日均释药率分别为5.05%、4.89%、6.86%;第12天后三药的缓释基本趋于稳定,日均释药率分别为0.17%、0.26%、0.16%;三种药物缓释到50d时均大于10倍MIC。结论:HRZ/PLGA微球具有优良的载药及药物缓释效果,是一种理想的复合抗结核药物缓释系统。     

抗结核药缓释涂层在兔脊柱结核模型体内的抗结核性能及组织相容性观察

目的:观察抗结核药异烟肼(H)、利福平(R)、吡嗪酰胺(Z)缓释涂层在兔脊柱结核模型体内的抗结核性能及组织相容性。方法:选取健康新西兰兔构建L4/5脊柱结核模型,将建模成功的60只模型兔随机分为A、B、C三组,每组20只,其中A组(实验组)病灶清除术后植入包裹HRZ缓释涂层的自体髂骨;B组(对照组)病灶清除术后植入包裹空白涂层的自体髂骨;C组(空白对照组)病灶清除术后单纯植入自体髂骨。术后观察实验兔一般状况及伤口情况;造模前1d、病灶清除术前及术后1d、3d、7d、14d、28d、56d、84d、112d进行血沉(ESR)、C反应蛋白(CRP)检测;术前以及术后14d、28d、56d进行肝肾功能检测;术后28d时A组随机处死5只兔,取心脏、肝脏、脊髓、脾脏及肾脏组织制作病理切片观察;术后56d行脊柱X线片检查后,每组随机处死5只兔在植骨部位局部取材进行骨-材料界面组织病理学观察。结果:术后B组1只兔切口感染,C组1只兔死亡、1只兔截瘫,其余兔术后一般状况良好。三组造模前和手术前的ESR和CRP均无统计学差异(P0.05);三组手术前的ESR和CRP均较造模前显著性升高(P0.01)。三组术后1d时ESR和CRP均较术前显著性升高,3d时CRP达到峰值,7d时ESR达到高峰,此后逐渐下降;A组至术后56d时CRP降至造模前水平,84d时ESR降至造模前水平;B、C组至112d时CRP和ESR均仍显著性高于造模前水平(P0.05)。A组术后7d、56d、84d及112d的ESR和CRP均低于同时间点B、C组(P0.05),B组与C组同时间点无显著性差异(P0.05)。三组间术前和术后14d、28d、56d的肝、肾功能指标比较均无统计学差异(P0.05);三组术后14d、28d、56d的肝、肾功能指标与术前比较均无统计学差异(P0.05)。术后28d时A组心脏、肝脏、脾脏、脊髓及肾脏组织未见器质性改变及组织损伤征象。术后56d时A组植骨融合情况优于B组及C组(P0.05),骨-材料界面组织病理切片骨小梁面积显著性高于B组及C组(P0.01)。结论:HRZ缓释涂层在兔体内具有优良的抗结核性能和组织相容性。     

Relative Bioavailability of Rifampicin in Four Chinese Fixed-dose Combinations Compared with Rifampicin in Free Combinations

Background:

Decreases in the bioavailability of rifampicin (RFP) can lead to the development of drug resistance and treatment failure. Therefore, we investigated the relative bioavailability of RFP from one four-drug fixed-dose combination (FDC; formulation A) and three two-drug FDCs (formulations B, C, and D) used in China, compared with RFP in free combinations of these drugs (reference), in healthy volunteers.

Methods:

Eighteen and twenty healthy Chinese male volunteers participated in two open-label, randomized two-period crossover (formulations A and C) or one three-period crossover (formulations B and D) study, respectively. The washout period between treatments was 7 days. Bioequivalence was assessed based on 90% confidence intervals, according to two one-sided t-tests. All analyses were done with DAS 3.1.5 (Mathematical Pharmacology Professional Committee of China, Shanghai, China).

Results:

Mean pharmacokinetic parameter values of RFP obtained for formulations A, B, C, and D products were 11.42 ± 3.41 μg/ml, 7.86 ± 5.78 μg/ml, 13.05 ± 6.80 μg/ml, and 16.18 ± 3.87 μg/ml, respectively, for peak plasma concentration (C_max), 91.43 ± 30.82 μg·h⁻¹ ·ml⁻¹, 55.49 ± 37.58 μg·h⁻¹ ·ml⁻¹, 96.50 ± 47.24 μg·h⁻¹ ·ml⁻¹, 101.47 ± 33.07 μg·h⁻¹ ·ml⁻¹, respectively, for area under the concentration-time curve (AUC_{0−24 h}).

Conclusions:

Although the concentrations of RFP for formulations A, C, and D were within the reported acceptable therapeutic range, only formulation A was bioequivalent to the reference product. The three two-drug FDCs (formulations B, C and D) displayed inferior RFP bioavailability compared with the reference (Chinese Clinical Trials registration number: ChiCTR-TTRCC-12002451).     

Design and Study of Rifampicin Oral Controlled Release Formulations

Oral controlled release formulations of rifampicin have been developed by using hydroxypropyl methylcellulose polymer at different ratios. From in vitro release data, we found that the release was extended with an increase of polymer proportion from 20% to 40%. However, increase in polymer beyond 40% resulted in no significant change in the release rate. There was a distinct difference in the release rate and release character due to variation in the compression force. The release kinetics were analyzed using Ritger and Peppas exponential equation. Stability studies at ambient storage conditions for 1 year showed that formulations were stable.     

利福平致急性肾功能衰竭伴急性溶血性贫血及肝功能异常1例文献分析

目的为临床及时发现、诊断、治疗利福平所致急性肾功能衰竭提供参考。方法对我院利福平致急性肾功能衰竭1例及国内已经报道的临床资料进行综合分析。结果综合我院1例利福平致急性肾功能衰竭及文献报道共44例患者的一般资料、给药方法、发生时间、处理及结果,其中32例既往有使用利福平史,在服药后15分钟至50天发病,积极治疗后可缓解。结论在使用利福平的过程中应密切监测肾功能,及时发现利福平所致的急性肾功能衰竭。