UPLC-MS/MS法测定动物源性食品中万古霉素、去甲万古霉素残留量的不确定度评估

对UPLC-MS/MS法测定动物源性食品中万古霉素、去甲万古霉素残留量的不确定度进行了评估,建立数学模型,找出影响测量不确定度的各种因素,对各种不确定度分量进行评估和计算合成。结果表明,重复试验、标准溶液配制过程、回收率、标准曲线拟合是不确定度的主要来源。

组合链霉素和利福平抗性突变去甲基万古霉素高产菌株的选育

在去甲基万古霉素生产菌株东方拟无枝酸菌的菌种选育中,利用核糖体工程育种方法,筛选得到的新菌株在发酵水平以及改善气丝及孢子生长贫瘠方面均有较大提高。首轮采用链霉素抗性筛选,得到突变株3-30,斜面外观丰满程度明显好于原对照株,发酵效价提高11.9%;第二轮组合链霉素和利福平抗性结合高能电子诱变育种,进一步巩固了育种成效,得到一系列代谢特点呈多样性的菌株,其中04-102发酵水平较原出发菌株提高45.8%,代谢速度加快,传代稳定性亦得到显著改善。

骨水泥载万古霉素超声低频脉冲型治疗的起始时间对药动药效产生的影响分析

目的:研究低频脉冲超声治疗的起始时间对载万古霉素骨水泥的药物动力学、药效释放以及抗菌活性的影响。方法:选择50只健康大鼠,在大鼠髋关节均植入载万古霉素的骨水泥以及标准金黄色葡萄球菌(ATCC13565,中国生物鉴定研究所),随后将50只大鼠随机分成观察组、对照组,观察组在植入后12 h进行低频超声治疗,对照组在植入后30 min进行低频超声治疗,两组均治疗12 h后取4只大鼠测定髋关节内的渗血量,其余大鼠测定髋关节内的药物浓度,计算药物动力及药效参数,在植入48 h后计数髋关节腔内的活菌量并进行组间比较。结果:观察组、对照组均在植入3 h后达到药物浓度高峰,对照组3 h后药物浓度呈明显的下降态势,并在14 h后下降到MIC以下,观察组在3 h后也呈下降态势,但在12 h采用低频超声治疗后,药物浓度再次上升,并一直持续在MIC以上至第34小时;观察组Cmax/MIC(5.58±1.86)明显低于对照组的(14.81±2.41),差异具有统计学意义(P<0.05);观察组T>mic(35.08±5.98)h明显高于对照组的(13.49±1.49)h,差异具有统计学意义(P<0.05);对照组菌落数、渗血量明显高于观察组(P<0.05)。结论:与植入后立即进行超声治疗相比,在第12小时进行治疗能够有效提高血液的T>mic,提高载万古霉素骨水泥的抗菌作用。

稳可信治疗重症监护病房阳性球菌的临床研究

目的比较红霉素和万古霉素治疗阳性球菌的疗效和不良反应。方法对60例应用红霉素治疗和60例应用万古霉素治疗阳性球菌患者的效果及不良反应分析。结果红霉素和万古霉素治疗阳性球菌的疗效比较,红霉素为36.5%;万古霉素为89.5%;两组的治愈率比较有显著差异,有统计学意义(P<0.01)。结论万古霉素是治疗革兰阳性球菌的有效药物。

Molecular Epidemiology of Oxacillin-resistant Staphylococcus aureus and in vitro Activity of Glycopeptides against Staphylococcus species

The purpose of this subject was to investigate molecular epidemiology of oxacillin-resistant Staphylococcus aureus (MRSA) isolated from hospitalized patients, and to survey the in vitro activity of teicoplanin, vancomycin and other 9 antibiotics against Staphylococcus species . MRSA were detected by oxacillin-NaCl-containing screen agar. The homology of nosocomial MRSA from ICU and RCU was determined by pulse-field gel electrophoresis. Agar diffusion, E test and agar dilution were used to compare the in vitro activity of teicoplanin and vancomycin against Staphylococcus spp from 2001 to 2003 at Peking Union Medical College Hospital. WHONET-5.3 software was used to analyze the antimicrobial susceptibility data. From 2001 to 2003, the prevalences of MRSA were 56.5%, 65.3%, 64.7%, respectively. PFGE found most of MRSA from ICU and RCU were closely related. All of S.aureus and S.epidimidis isolates were susceptible to teicoplanin and vancomycin from 2001 to 2003. However, 1 isolate of S.haemolyticus was resistant and 9 isolates intermediate to teicoplanin. The minimal inhibitory concentration of teicoplanin did not correlate well with zone diameter, when inoculum increased by 100 folds, the zone diameters of teicoplanin decreased more greatly than those of vancomycin. In 2002, severe outbreaks caused by MRSA strains had been found in ICU and RCU wards. Teicoplanin and vancomycin had good activity against clinical isolates of Staphylococci spp . Teicoplanin was less active than vancomycin against S.haemolyticus . Most of S.haemolyticus isolates were intermediate to teicoplanin. Antimicrobial susceptibility testing of teicoplanin was influenced by the diffusion speed in the agar and inoculum size.

Using sensitive surface plasmon resonance to detect binding of peptide molecules and immobilized vancomycin

To perform the mechanism study of special association for vancomycin and D-Ala-D-Ala-containing peptides on the interface of solution and self-assemble monolayer, the binding between vancomycin and pentapeptide （Lys-Lys-Gly-D-Ala-D-Ala） was investigated by flow injection surface plasmon resonance （FI-SPR） and flow injection quartz crystal microbalance （FI-QCM）. To facilitate the formation of a compact vancomycin adsorbates layer with a uniform surface orientation, vancomycin molecules were attached onto a preformed alkanethiol self-assembled monolayer. By optimizing the conditions for the binding between Lys-Lys-Gly-D-Ala-D-Ala and vancomycin on the assembled chip, the detecting limit of Lys-Lys-Gly-D-Ala-D-Ala was greatly improved （reaching 0.5 ×10^- 6 mol/L or 7.5 × 10^-12 mol）. The equilibrium constant of the association of Lys-Lys-Gly-D-Ala-D-Ala with vancomycin was also obtained （KAds=5.0×10^4 L/tool）.

Ototoxicity of vancomycin in guinea pigs

Objective: To study the effect of vancomycin (V) with multiple intravenous injections on the inner ear of albino guinea pigs. Methods: Three groups of animals were injected with vancomycin hydrochloride (54, 108, 216 mg/kg respectively once a day for 14 d). Two groups were treated with gentamycin (GM) (80 mg·kg -1 ·d -1 ) and saline respectively as control groups. Auditory brainstem responses (ABR) and the duration of post-rotatory nystagmus (PRN) were measured before and after administration. Surface preparation and scanning electron microscopy (SEM) of the cochlea were performed for histological examination. Results: In V 54, 108 mg/kg group, similar to saline control, there was 0-1.1 dB of threshold shift. In V 216 mg/kg group, average hearing loss was 1.0-5.7 dB immediately after administration and 1.3-3.8 dB after 14 d, which was significantly lower than those in GM control group. As the saline control, no significant difference was found in PRN in all V groups before and after treatment; while in the GM group, PRN decreased significantly after treatment. Morphological evaluation demonstrated that in all V and saline animals there was no obvious missing of outer and inner hair cells and SEM showed normal surface morphology. In the GM group, there was 10%-30% of outer and inner hair cells lost in the basal turn. Conclusion: The ototoxicity of vancomycin is absent or minimal after multiple introvenous administration within this dose range.

Comparative Evaluation of Pharmacist-Managed Vancomycin Dosing in a Community Hospital Following Implementation of a System-Wide Vancomycin Dosing Guideline

Purpose： Evaluate the implementation of a large hospital system vancomycin dosing guideline in a community hospital with pharmacist vancomycin management. Design： Single center, retrospective and prospective quality assessment study. Methods： Pharmacist-managed vancomycin therapy was evaluated pre and post-implementation of a new dosing guideline in a study population of 586 from one community hospital. Results： Of the study population, 274 patients evaluated pre-implementation were compared to 312 patients post-implementation of the large hospital-system guideline （46.8% and 53.2%, respectively）. There was no significant difference in demographics between both patient populations. Days of vancomycin therapy was shorter in the post-implementation group （4.32 ＋ 2.241） versus the pre-implementation group [（4.81 ±2.764）, p = 0.018]. Days to goal trough was longer in the post-implementation group （3.51 ±1.622） compared to the pre-implementation group [（3.09 ±2.046）, p = 0.054]. A post-hoe regression analysis was conducted, showing that age, days of vancomycin therapy and goal trough are predictors for 77% of cases within the post-implementation group. Conclusion： The implementation of a new vancomycin dosing guideline significantly impacted days of vancomycin therapy and days to goal trough in patients on vancomycin managed by pharmacists. Our results encourage completion of future studies utilizing the regression analysis data, which may impact the future care of patient on vancomycin managed by pharmacists.

Tricuspid Valve Endocarditis in a Patient with Congenital Heart Disease

The present study reports a case of a young patient who presented for 3 months dyspnea, edema of lower limbs, fever and important weight loss. She evolved with acute fever, hematemesis and focal seizures. An echocardiogram was performed demonstrating file presence of interventricular, interatrial, and extensive echogenic imaging and of poorly defined borders throughout the septal cusp of the tricuspid valve, suggestive of vegetation, chest tomography that observed several foci of pulmonary abscess and blood culture evidencing the presence of Staphylococcus aureus. She was treated with Vancomycin, Meropenem and Amphotericin, along with clinical support. She underwent surgery to exchange the tricuspid valve for a biological prosthesis, evolving with clinical improvement and receiving discharge from hospital.

Efficacy and safety of fidaxomicin versus vancomycin for Clostridium difficile infection: systematic review and meta-analysis

To compare the efficacy and safety of fidaxomicin and vancomycin for the treatment of patients with Clostridium difficile infection （CD1）, randomized controlled trials （RCTs） of fidaxomicin versus vancomycin for the treatment of CDI published in Pubmed, Embase, Web of Science and the Cochrane library were searched. Two reviewers independently extracted the data. The primary outcome was the rates of clinical cure. The secondary endpoints were the rates of CDI recurrence in the 4 weeks period after the end of therapy and rates of global cure, adverse events. Meta-analysis was performed using the Mantle-Haenszel fixed effect method （FEM）. Odds ratios （ORs） with 95% confidence intervals （95% CIs） were reported. The results indicated that two large randomized controlled trials were included in the meta-analysis. Clinical cure with fidaxomicin was similar to with vancomycin both in the modified intention to treat （OR = 1.17, 95% CI 0.82-1.66, P = 0.40） and in the per-protocol population （OR = 1.24, 95% CI 0.80-1.92, P = 0.34）. There were no significant differences in the rates of clinical cure between fidaxomicin and vancomycin in the subgroups analyzed by age, patients＇ status, and previous CDI, infection with B 1 strain, severity baseline, and exposure to concomitant antibiotics. Recurrence of CDI was significantly less common among fidaxomicin-treated patients compared with vancomycin-treated patients both in the modified intention-to-treat population （OR = 0.47, 95% CI 0.34-0.65, P〈0.00001） and in the per-protocol population （OR = 0.45, 95% CI 0.31-0.62, P〈0.0001）. Treatment with fidaxomicin compared with vancomycin was associated with significantly higher rates of global cure both in the modifed intention-to-treat population （OR = 1.75, 95% CI 1.35-2.27, P〈0.0001） and in the per-protocol population （OR = 1.86, 95% CI 1.40-2.47, P〈0.0001）. Our recta-analysis suggests that fidaxomicin is not superior to vancomycin in rates of clinical cure, while fidaxomicin significantly decreases the rates of CDI recurrence and significantly improves the rates of global cure compared with vancomycin. Thus, fidaxomicin is a promising candidate for treatment of the CDI, especially in decreasing the rates of CDI recurrence and improving the rates of global cure.

Analysis for the vancomycin plasma concentration data in infants by clinical pharmacists

In the present study, clinical pharmacists monitored the blood concentration of vancomycin in children in the Infant Ward from 2013 to 2014, and the drug dose was adjusted according to its plasma concentration. Moreover, we analyzed the plasma concentration of vancomycin in infants in the hospital from 2013 to 2014. Simultaneously, we also discussed the necessity of regular therapeutic drug monitoring of vancomycin in infants, and the important role of clinical pharmacists was further explored. The results showed that it was necessary to routinely monitor the therapeutic drug in infants. Clinical pharmacists performed medication monitoring, which improved the effectiveness of vancomycin and prevented its adverse effects. In addition, it is a new treatment model for the participation of clinical pharmacists in the clinical treatment.

A prospective cohort study on the relationship between vancomycin steady-state trough concentration and efficacy and safety in Chinese adults

Clinical guidelines recommend a steady-state vancomycin(VCM)trough concentration(SVTC)of 10–15 mg/L for regular infections and 15–20 mg/L for severe infections.However,clinical trials have shown that increasing SVTC is not beneficial for efficacy,and instead it leads to nephrotoxicity.To verify whether increasing the SVTC results in improved clinical outcomes with sustainable adverse effects,we prospectively determined its correlation with clinical efficacy and safety.The participants included patients hospitalized with Gram-positive bacterial infections from March 2017 through October 2018.The patients were classified into group I(SVTC<10 mg/L),II(10≤SVTC≤20 mg/L),or III(SVTC>20 mg/L).Clinical,microbiological,and laboratory data were collected.Clinical outcomes between group I and II were matched after propensity score matching(PSM).A total of 331 patients were included in this study.Clinical failure occurred in 59(29%)of 204 patients on day 14,with no significant difference between groups I and II(P=0.535).Infection recurred at 28 d in 62(30%)of 204 patients,and no significant difference in infection recurrence was observed between both the groups(log-rank,P=0.674).Except for a significant increase in the incidence of acute kidney injury in group II,no significant difference was observed between two groups for any clinical results.The incidence of adverse events in groups I and II was significantly lower than that in group III(P<0.001).SVTC had an applicable cut-off point at 14.55 mg/L.SVTC was not correlated with VCM clinical efficacy,while it was a good indicator of nephrotoxicity.

Polydopamine-assisted functionalization of heparin and vancomycin onto microarc-oxidized 3D printed porous Ti6Al4V for improved hemocompatibility,osteogenic and anti-infection potencies

Enhanced antiinfection activities, improved hemocompatibility and osteo-compatibility, and reinforced osseointegration are among the most important considerations in designing multifunctional orthopedic biomaterials.Hereby, anti-infective and osteogenic multifunctional 3 D printed porous Ti6 Al4 V implant with excellent hemocompatibility was successfully designed and fabricated. In brief, osteogenic micro-arc oxidation（MAO） coatings with micro/nanoscale porous topography were generated in situ on3 D printed Ti6 Al4 V scaffolds, on which heparin and vancomycin were easily immobilized. The surface microstructure,morphology, and chemical compositions were characterized employing scanning electron microscopy（SEM）, X-ray photoelectron spectroscopy（XPS） and Fourier transform infrared spectroscopy（FTIR）. High loading capacity and sustained vancomycin release profiles were revealed using high performance liquid chromatography（HPLC）. Favorable antibacterial and antibiofilm performances against pathogenic Staphylococcus aureus（S. aureus） were validated in vitro through microbial viability assays, Live/Dead bacterial staining, and crystal violet staining. Human mesenchymal stem cells（h MSCs） were seeded on the scaffolds and their proliferation and viability were assessed using Cell Counting Kit and Live/Dead cell viability kit. Further, osteoblastic differentiation abilities were evaluated using alkaline phosphatase（ALP） activity as a hall marker. Additionally, the improved hemocompatibility of the heparinized scaffolds was confirmed by activated partial thromboplastin time（APTT）, prothrombin time（PT） and thrombin time（TT）. Overall, our results show that the surface-modified 3 D printed porous Ti6 Al4 V possesses balanced antibacterial and osteogenic functions while exhibiting extra anticlotting effects, boding well for future application in customized functional reconstruction of intricate bone defects.

Rapid eradication of antibiotic-resistant bacteria and biofilms by MXene and near-infrared light through photothermal ablation

With the development and rising of antimicrobial resistance,rapid and effective killings of bacteria are urgently needed,especially for antibiotic-resistant bacteria and bacterial biofilms that are usually hard to be treated with conventional antibiotics.Here,a rapid and broad-spectrum antibacterial strategy is demonstrated through photothermal ablation with MXene and light.Ti3C2 MXenes,when combined with 808 nm light,show significant antibacterial effects in just 20 min.The antibacterial strategy is effective to 15 bacterial species tested,including methicillin-resistant Staphylococcus aureus(MRSA)and vancomycin-resistant Enterococci(VRE).In addition,the rapid antibacterial strategy works for MRSA biofilms,by damaging the structures as well as killing bacteria in biofilms.Furthermore,the investigation of the antibacterial mechanisms shows that Ti3C2 with light kills bacteria mainly physically through inserting/contact and photothermal effect.This work broadens the potential applications of MXene and provides a way to eradicate bacteria and biofilms physically,without the likelihood of resistance development.

Population pharmacokinetics of vancomycin in Chinese elderly patients and its application for dose individualisation

In the present study, we aimed to develop a population pharmacokinetics(PPK) model of vancomycin(VCM) and propose the individualised dosage regimen for Chinese elderly patients. The data were collected prospectively from Chinese elderly patients receiving VCM therapy. Steady-state trough concentrations of VCM were determined using an enzyme-multiplied immunoassay. Patients’ sex, age, body weight, concomitant medications, infection type, and laboratory findings were recorded. The PPK model was developed using nonlinear mixed-effects model software. Moreover, we used Monte Carlo simulations to develop an initial dosage regimen targeting various VCM through concentration ranges based on the final model. We found that VCM clearance(CL) was significantly influenced by post-craniotomy meningitis(PCM) and glomerular filtration rate in elderly patients. Additionally, a new dosage regimen was proposed to individualise VCM regimen for PCM and non-PCM elderly patients. A PPK model was established to estimate the individual VCM CL for elderly patients, which could be applied for individualising doses in the target population.

Selective inactivation of Gram-positive bacteria in vitro and in vivo through metabolic labelling

Bacterial infections are grave threats to human health,particularly those caused by the most common Grampositive bacteria.The massive administration of broad-spectrum antibiotics to treat various bacterial infections has led to the evolution and spread of drug resistance.As a universal antimicrobial technique unapt to induce drug resistance,photothermal therapy(PTT)is attracting extensive attention in recent years.However,its unspecific killing capability and side effects towards adjacent mammalian cells severely impede the practical applications.Herein,we proposed a metabolic engineering strategy to selectively inactivate Gram-positive bacteria by PTT.A bioorthogonal photothermal agent was prepared by the conjugation of IR-780 iodide and dibenzocyclooctyne(IR780-DBCO).Upon pre-metabolizing with 3-azido-D-alanine,Gram-positive bacteria rather than Gramnegative ones,such as Staphylococcus aureus and vancomycinresistant Enterococcus faecalis(VRE),could be specifically tied up by the explosive IR780-DBCO via copper-free click chemistry.Thereafter,they spontaneously detonated under 15 min near-infrared light irradiation and inactivated nearly 100% Gram-positive bacteria in vitro.Moreover,superbug VRE-induced infection was significantly inhibited by this approach in a mouse skin wound model.This metabolic labelling-based photothermal ablation strategy specific to Gram-positive microbes would stimulate the development of precise antibacterial candidates for preclinical applications.

Analysis of anti-infection therapeutic schedule analysis for neonatal Streptococcus agalactiae meningitis and discussion on the indications for drug withdrawal

The clinical manifestations of neonatal GBS meningitis are as follows:non-specificity,long hospital stay,easy to cause neurological complications,and sequelae.Clinical pharmacist participated in the anti-infective treatment of a neonatal Streptococcus agalactiae meningitis whose cerebrospinal fluid was still abnormal when the drug was stopped.According to the PK/PD characteristics of antibacterial drugs,the permeability of the blood-brain barrier,and the adjustment of the antibiotic dose,the reasons for the decrease in the number of cerebrospinal fluid cells after vancomycin treatment were analyzed.Clinical pharmacists also analyzed the efficacy of linezolid in the treatment of neonatal bacterial meningitis,and discussed the indications for stopping medication when the cerebrospinal fluid is abnormal,so as to improve the safety and effectiveness of antibiotics in the treatment of neonatal bacterial meningitis.