利奈唑胺的合成新方法

目的 研究抗菌药利奈唑胺的合成新方法。方法 以 3,4-二氟硝基苯为起始原料合成 3-氟-4-吗啉苯基异氰酸酯,在无溶剂条件下与(R)-环氧氯丙烷经 MgI2 或 MgBr2 催化环合得到(R)-3-氟-4-吗啉苯基噁唑烷酮,然后经叠氮基取代、还原、乙酰化得到利奈唑胺。结果与结论 利奈唑胺及关键中间体的结构经1H-NMR、MS谱确证,目标化合物的总收率为35%。该合成路线具有原料易得、步骤简短、收率高、操作简便的特点。     

利奈唑胺在不同疾病患者中药动学变化的临床意义

利奈唑胺是第一个用于临床的新型噁唑烷酮类抗菌药,在体内外对葡萄球菌、链球菌、肠球菌等多重耐药革兰阳性细菌有强大的抗菌作用,可作为治疗革兰阳性菌感染的糖肽类多重耐药的替换药物。现对其在囊性纤维化患者、肾功能不全患者、中性粒细胞减少的癌症患者、血液滤过患者等不同疾病患者中的药动学特点进行综述,以期为其在国内的临床合理应用提供参考。     

Synthesis and antibacterial activity of substituted oxotriazolylphenyl oxazolidinones

A series of 3-(4'-(2'-alkyl-3'-oxy-1',2',4'-triazolyl)-phenyl)-5-substituted oxazolidinones was designed and synthesized for in vitro antibacterial activity testing against fourteen Gram-negative and six Gram-positive standard organisms. The minimum inhibitory concentration (MIC) was determined by agar dilution at concentrations of 0.10, 0.20, 0.39, 0.78, 1.56, 3.13, 6.25 microg/mL. Different alkyl groups at the 2'-position played an important role in the activity against Gram-positive organisms. (S)-3-(4'-(2'-ethyl-3'-oxy-1',2',4'-triazolyl)-phenyl)-5-acetamidomethyloxazolidinone was active against Staphylococcus epidermidis, Streptococcus pneumoniae, Streptococcus enteridis and Streptococcus nonhemolyticus, whereas 2'-methyl, 2'-propyl and 2'-n-butyl counterparts did not show activity at 6.25 microg/mL. Modification of the 5-substitutent of oxazolidinones also affected the activity against Gram-positive organisms. (S)-3-(4'-(2'-ethyl-3'-oxy-1',2',4'-triazolyl)-phenyl)-5-acetamidomethyloxazolidinones was approximately two fold more potent than 5-chloroacetamido, 5-dichloroacetamido and 5-trifluoroacetamido counterparts against Streptococcus enteridis. None of these compounds showed growth inhibition against fourteen Gram-negative organisms at 6.25 microg/mL.     

Treatment of Post-Traumatic Hand Staphylococcus aureus Osteomyelitis with Oral Linezolid

Abstract

The Authors report on the use of linezolid for the treatment of three patients with osteomyelitis. All three patients had post-traumatic multisensitive hand bone methicillin-susceptible Staphylococcus aureus osteomyelitis, which did not respond to antimicrobial regimens including drugs in vitro active against the isolated strains. Clinical cure and microbiologic eradication was obtained with oral linezolid in all three patients. Linezolid was well tolerated. Mild thrombocytopenia was observed in one patient at the end of the third week of treatment and it was promptly resolved after the discontinuation of linezolid. Linezolid minimum inhibitory concentrations (MICs) consisted of 2 mg/l for all three S. aureus isolates while the bactericidal activity in vitro was not present up to the linezolid concentration of 32 mg/l. In spite of a lack of in vitro bactericidal activity, linezolid was effective in curing the patients and eradicating the infection. Trough and peak plasma concentrations of linezolid were above the MICs of the isolates. These values ranged from 3.93 to 14.95 mg/l at trough and 5.03 to 25.91 mg/l at peak. The oral bioavailability, pharmacokinetic profile and antibacterial spectrum of linezolid make this oxazolidonone antimicrobial an attractive drug for the treatment of chronic osteomyelitis. Prolonged administration requires careful surveillance for side effects, until these complications are better understood.     

A toxicogenomic approach for identifying biomarkers for myelosuppressive anemia in rats

Myelosuppressive anemia is a serious side effect associated with several drugs. Thus, there is an increasing demand for sensitive biomarkers for the early detection of myelosuppressive anemia during toxicological studies. We applied a toxicogenomic approach to identify useful biomarker genes reflecting myelosuppressive anemia in the rat liver. Expression of the hemoglobin beta chain complex (Hbb), aminolevulinic acid synthase 2 (Alas2), and cell division cycle 25 homolog B (Cdc25b) genes changed as a result of anemia induced by the myelosuppressive agents linezolid, cisplatin, and carboplatin, suggesting that these genes may be suitable biomarkers. Moreover, evaluation of perfused and unperfused livers indicated that changes in the expression of these genes originate in circulating reticulocytes in the liver. Erythroid differentiation-associated changes in expression of the Hbb, Alas2, and Cdc25b genes were confirmed in vitro using Friend leukemia cells. In conclusion, our current research provides novel evidence that gene expression in circulating reticulocytes contained in the liver changes dramatically under myelosuppressive conditions. While further large-scale validation studies are needed, our results indicate that the genes we identified might be useful biomarkers for the sensitive detection of myelosuppressive anemia in rats.     

利奈唑胺致全血细胞减少

1例68岁女性患者,因感染性心内膜炎口服利奈唑胺0.6 g,2次/d,半个月后感觉疲乏、倦怠,血常规检查示白细胞4.18×109/L,红细胞3.23×1012/L,血红蛋白76 g/L,血小板40×109/L,遂停药。11 d后血象恢复正常,再次口服利奈唑胺0.6 g,2次/d,用药14 d复查血常规,白细胞3.50×109/L,红细胞2.51×1012/L,血红蛋白71 g/L,血小板36×109/L,遂再次停药。停药后患者连续5 d发热(体温最高时38.5℃),伴咳嗽、咯黄痰及鼻塞,遂入院。入院后未给予抗感染药物,先后3次输注浓缩红细胞(每次400 ml)。血常规示:白细胞5.90×109/L,红细胞3.33×1012/L,血红蛋白95 g/L,血小板158×109/L,故在入院第21天给予利奈唑胺0.6 g静脉注射,2次/d。入院第36天复查血常规,白细胞2.30×109/L,红细胞2.21×1012/L,血红蛋白61 g/L,血小板29×109/L,遂再次停用利奈唑胺。先后3次输注悬浮红细胞(每次400 ml),皮下注射重组人粒细胞集落刺激因子150μg,1次/d,共4 d。应患者要求准予出院。     

耐异质性利奈唑胺金黄色葡萄球菌筛选及耐药机制分析

目的建立耐异质性利奈唑胺葡萄球菌筛选方法,并对其耐药机制进行初步分析。方法常规方法检测葡萄球菌属临床分离株对万古霉素、替考拉宁、头孢西丁、利奈唑胺耐药性,采用菌谱分析法筛选耐异质性利奈唑胺葡萄球菌,琼脂稀释法和E-test法检测利奈唑胺MIC值,PCR方法检测其耐药cfr基因。结果未检出利奈唑胺中介或耐药菌株;耐异质性利奈唑胺金黄色葡萄球菌的检出率为1.04%;琼脂稀释法和E-test法检测异质性耐药菌株MIC结果一致;未检出利奈唑胺耐药cfr基因。结论利奈唑胺对葡萄球菌属在体外具有较强抗菌活性,该研究未检出利奈唑胺中介或耐药葡萄球菌属,其耐药机制和临床意义有待进一步研究。     

Antimicrobial treatment concepts for orthopaedic device-related infection

Successful management of orthopaedic device-related infections requires combined surgical and antimicrobial therapy. Because of the heterogeneity of clinical situations, controlled trials are lacking. Although rational concepts for surgical treatment have been published, many aspects of antimicrobial therapy are still not well documented. In this review, some of these knowledge gaps are discussed, and rational arguments for initial parenteral treatment are presented. In addition, the interpretation of data regarding bone penetration is discussed. Whereas rifampin is now a standard combination partner in the treatment of staphylococcal infections, its role against other microorganisms is still unclear. Finally, in view of the increasing prevalence of methicillin-resistant staphylococci and their decreasing susceptibility to vancomycin, data are provided on linezolid and daptomycin, which can potentially be used in bone and joint infections.