利奈唑胺与万古霉素对耐甲氧西林金黄色葡萄球菌血流感染的有效性和安全性比较

目的比较万古霉素和利奈唑胺治疗耐甲氧西林金黄色葡萄球菌(MRSA)血流感染的效果及安全性。方法纳入MRSA血流感染患者14例,随机分为万古霉素组(n=8)和利奈唑胺组(n=6)。观察两种药物治疗后的临床效果及药物不良反应。结果两组28d病死率(16.7%和12.5%,P>0.05)、细菌清除率(83.3%和87.5%,P>0.05)、血管活性药物使用时间(3±1和4±1d,P>0.05)比较无统计学差异;万古霉素组退热时间短于利奈唑胺组(4.5±0.6和5.4±0.9d,P<0.05),细菌清除时间短于利奈唑胺组(4.0±0.8和4.4±0.9d,P<0.05),但ICU住院时间长于利奈唑胺组(19.8±2.5和16.4±2.7d,P<0.05)。两组治疗后白细胞、中性粒细胞比值与治疗前相比,自第3天开始下降,第5天出现明显下降(P<0.05),但组间比较无统计学差异(P>0.05);降钙素原(PCT)、C反应蛋白(CRP)结果与上述变化相似,在治疗第5天开始与治疗前出现明显差异(P<0.05);万古霉素组内生肌酐清除率(CrCl)在第3天下降,于第5天达到峰值,与治疗前相比有统计学差异(P<0.05),第1...     

Capnocytophaga spp. Brain Abscess in an Immunocompetent Host: Problems in Antimicrobial Chemotherapy and Literature Review

Abstract

The fourth case report of a brain abscess due to the fastidious Gram-negative organism Capnocytophaga spp. is described and discussed on the grounds of clinical, microbiological, and therapeutic evidence. A probable origin from a cat bite and/or an underlying severe mandibulary granuloma is suspected. Due to lack of clinical and neuroradiological response to neurosurgery and a combination of imipenem-amikacin-clindamycin-fluconazole, second-line empiric linezolid treatment proved rapidly successful, in the absence of further microbial isolations. In vitro antimicrobial susceptibility testing is often unpredictable for Capnocytophaga spp., and agents usually active on Gram-positive organisms may also be effective, both in vitro and in vivo. Due to its favorable brain penetration and its dual mode of administration, linezolid may be an alternative option for patients with multiple risk factors, brain abscess of suspected polymicrobial origin, and lack of response to empiric or culture-driven therapeutic attempts.     

Economic Evaluation of Linezolid Versus Teicoplanin for the Treatment of Infections Caused by Gram-Positive Microorganisms in Spain

Abstract

The aim of this study was to perform a comparative cost-effectiveness analysis of linezolid vs teicoplanin (i.v., switching to oral/i.m. respectively) in Spain. A decision tree model was used with the results of a randomized, comparative, controlled clinical trial with linezolid vs teicoplanin in the treatment of infections caused by Gram-positive microorganisms, with a timeline of 31 days. The efficacy endpoint was the percentage of patients with clinical healing or improvement in their infection. Direct medical costs were included using Spanish 2005 prices. Average cost per patient, average cost-effectiveness ratio and several sensitivity analyses were carried out. In the intent-to-treat (ITT) analysis linezolid obtained a higher percentage of therapeutic success than teicoplanin (95.5% vs 87.6% respectively, p = 0.005), both with similar tolerability. The average cost per treated patient was €8,064.76 for linezolid vs €8,727.36 for teicoplanin, with an incremental cost of €622.59 (?7,6%). Linezolid yielded a lower average cost-effectiveness ratio, €8,444.78 (8,195.90 – 8,709.25) than teicoplanin, €9,962.74 (9,465.68 – 10,502.23), with a slight reduction in average cost per successfully treated patient of 15.2% (€1,517.96). The results were robust to the sensitivity analysis. In conclusion, linezolid is a more cost-effective option than teicoplanin in the treatment of infections caused by Gram-positive microorganisms, since it offers superior clinical benefits with a lower use of associated resources.     

Mechanism of action of the oxazolidinone antibacterial agents

Oxazolidinones represent a new class of synthetic antibacterial agents active against multiply-resistant Gram-positive pathogens, including methicillin-resistant Staphylococcus aureus (MRSA), penicillin-resistant streptococci and vancomycin-resistant enterococci. Eperezolid and linezolid are two novel analogues, which have respectively completed Phase I and Phase II clinical testing. The lack of cross-resistance between oxazolidinones and other antibiotics supports a novel mechanism of action. Oxazolidinones are protein synthesis inhibitors which target an early step involving the binding of N-formylmethionyl-tRNA to the ribosome. Binding studies demonstrate that these agents interact with the 50S subunit, but not the 30S subunit of the ribosome. Crosslinking experiments provide evidence for an interaction with both the 16S rRNA of the small subunit and the 23S rRNA of the large subunit. Development of resistance in the laboratory is slow, resulting in two independently isolated point mutations at G2447U and G2576U of the 23S rRNA. This review discusses the results of published studies involving oxazolidinone mechanism of action.     

住院患者使用利奈唑胺致贫血的相关危险因素

目的：探讨住院患者使用利奈唑胺（LZD）治疗期间发生贫血不良反应的相关危险因素。方法：采用回顾性研究,收集2012年5月至2017年5月温州医科大学附属第一医院接受LZD治疗且监测血药浓度的161例住院患者的临床资料,采用logistic回归分析LZD诱发贫血不良反应的相关危险因素。结果：31例（占19.2%）患者被评估为LZD相关性贫血,LZD治疗期间,中重度肾功能不全患者[GFR＜60 mL·（min·1.73 m2）-1]（OR=3.47,95%CI：1.49～8.13,P=0.004）以及药物谷浓度≥7 mg·L-1（OR=2.87,95%CI：1.11～6.93,P=0.024）者发生相关性贫血风险更高。结论：LZD相关性贫血与肾功能及体内药物浓度密切相关。     

(S)-5-乙酰胺甲基-3-[(3-氯-4-取代胺甲基)苯基]-2-噁唑烷酮的合成及抗菌活性

3-氯-4-甲基苯胺经氯甲酸苄酯酰化、与（R）-正丁酸缩水甘油酯环合、甲磺酰化、叠氮化、叠氮还原成胺、氨基乙酰化、苄位溴化得（固-5-乙酰胺甲基-3-[（3-氯-4-溴甲基）苯基]-2-噁唑烷酮（Ⅷ），后者与胺类化合物进行取代反应生成（D-5-乙酰胺甲基-3-[（3-氯-4-取代胺甲基）苯基]-2-噁唑烷酮。35个新化合物的结构经^1HNMR、元素分析或MS确证，并测定了它们的体外抗菌活性，发现化合物113对金葡菌和表葡菌的活性与吗啉噁酮相当。11和113对肠球菌的活性优于诺氟沙星。     

(S)-5-乙酰胺甲基-3-［(4-取代胺甲基)苯基］-2-噁唑烷酮衍生物的合成及抗菌活性

目的研究噁唑烷酮类衍生物的合成及抗菌活性。方法以4-甲基-3-卤代苯胺为原料，经氯甲酸苄酯酰化、与(R)-丁酸缩水甘油酯环合、甲磺酰化、叠氮化、叠氮还原成胺、胺基乙酰化、苄位溴化得到中间体取代溴苄VIIIa和VIIIb。VIIIa和VIIIb与胺类化合物包括脂肪胺、芳香胺发生取代反应生成IXa和IXb；测定目标化合物的体外抗菌活性。结果设计、合成了51个新化合物，其结构经¹H NMR、元素分析或MS确证。并测定了它们的比旋光度等理化常数。化合物VIIb，IXa1，IXa2，IXa7，IXb1，IXb3，IXb10，IXb16和IXb23对G⁺菌有一定的活性，但不如对照品吗啉噁酮和诺氟沙星。结论在吗啉噁酮结构中苯环4位和吗啉基之间插入亚甲基，不能提高化合物的抗菌活性。     

全基因测序分析耐甲氧西林金黄色葡萄球菌利奈唑胺耐药相关变异位点

目的通过全基因组测序研究利奈唑胺(LZD)敏感株和诱导耐药耐甲氧西林金黄色葡萄球菌(MRSA)之间基因变异位点差异,了解LZD耐药基因变异位点。方法采用不同浓度梯度的LZD对遗传背景清晰的MRSA-MS4母株进行诱导,获得LZD耐药菌株MRSA-MS4-LZD100,测定最低抑菌浓度(MIC),采用普通聚合酶链反应(PCR)扩增MRSA-MS4-LZD100 23S rRNA V区及核糖体蛋白L3/L4基因,测序后与野生株比较,获得相应的突变位点;采用Illumina HiSeq 2000测序技术对样品DNA进行paired-end(PE)测序,构建Illumina PE文库,利用生物信息学完成该菌株的全基因组测序。结果经过32代诱导,获得MRSA-MS4-LZD100菌株,其LZD MIC为96μg/mL。PCR测序分析提示其V区多拷贝基因均存在G2447T突变,L3蛋白存在Gly113Val突变;全基因组包含2 744 315 bp碱基对,注释后共有2 509个基因,11个tRNA编码基因,以及2个完整的rRNA基因编码操纵子,获得PubMed全基因序列号(JXMJ00000000);共找出101个SNP和6个Small indel突变,发生于外显子的SNP占16个,SNP后导致氨基酸序列改变的蛋白质包括IstB ATP结合区域包含蛋白、凝集因子A及转座子IS1272等,而发生于外显子的Small indel占3个,Small indel突变后导致氨基酸序列改变的蛋白质包括假设蛋白、30S核糖体蛋白S1、凝集因子A。结论经LZD诱导获得LZD耐药MRSA-MS4-LZD100菌株,测序分析提示该菌株存在除23S rRNA V区及L3蛋白基因以外的突变位点,为进一步研究隐性LZD耐药机制指明了方向。