利奈唑胺的合成

对利奈唑胺合成工艺进行优化。以吗啉和3,4-二氟硝基苯为原料,经取代、还原反应得到中间体5;( R) -环氧氯丙烷、邻苯二甲酰亚胺钾盐发生取代反应合成中间体9;最后中间体5和9经取代、环化、水解合成目标产物利奈唑胺,总收率36.5%（以3,4-二氟硝基苯计）。     

Linezolid‐induced pure red cell aplasia in a patient with Staphylococcus epidermidis infection after allogeneic stem cell transplantation

Linezolid (LZD) is the first oxazolidinone antibiotic that is effective against drug‐resistant gram‐positive organisms. Hematological toxicities such as thrombocytopenia, anemia, and leukocytopenia are common in LZD therapy. However, LZD‐induced pure red cell aplasia (PRCA) is very rare. A 56‐year‐old man with myelodysplastic syndrome underwent allogeneic bone marrow transplantation from a human leukocyte antigen‐matched and ABO blood type‐matched unrelated male donor. He had bacteremia caused by Staphylococcus epidermidis after engraftment of neutrophils and red blood cells. We first administered vancomycin, but then changed to intravenous LZD because of kidney damage. Two weeks after LZD therapy, the patient's hemoglobin and reticulocyte levels were 6.8 g/dL and 0.3%, respectively. Bone marrow examination revealed red blood cell aplasia (myeloid/erythroid ratio was 402). The patient showed rapid recovery of normal erythropoiesis within 2 weeks of LZD cessation. It is important to be aware of the hematological effects associated with LZD in the setting of stem cell transplantation,particularly for those with pre‐existing myelosuppression, renal insufficiency, and those receiving concomitant drugs that produce bone marrow suppression. We advocate that a reticulocyte count be performed periodically for detecting bone marrow suppression, including PRCA, during LZD therapy.     

Implant stability in the treatment of MRSA bone implant infections with linezolid versus vancomycin in a rabbit model

The increasing prevalence of methicillin‐resistant Staphylococcus aureus (MRSA) infections represents a significant healthcare burden. Vancomycin and linezolid exhibit potent clinical and microbiological activity in MRSA infections. Our purpose was to investigate the efficacy of linezolid versus vancomycin in experimental implant infections and the influence on implant stability in a rabbit model. Thirty‐six female New Zealand White rabbits received surgical insertion of titanium implants into their distal femurs and were randomly assigned to six groups (A: infected, no treatment; B: infected, vancomycin; C: infected, linezolid; D: no infection, no treatment; E/F: no infection, vancomycin or linezolid, respectively). Antibiotics were administered, and plasma levels determined. Bone‐implant specimens were tested for mechanical stability of fixation. Quantitative histomorphometry of bone and soft tissue was performed using computerized image analysis. Plasma levels of linezolid and vancomycin were within the respective therapeutic ranges. Microbiological analysis of specimens from infected rabbits showed MRSA tissue colonization in all untreated animals, in two of six vancomycin‐treated animals, and in none of the linezolid‐treated animals. Antibiotic treatment improved mechanical stability significantly (p = 0.004) with both vancomycin and linezolid. Mechanical testing correlated with histomorphometry results. A significant negative correlation was found between displacement of the implant and the percentage of calcified tissue around the implant, and a significant positive correlation was found between displacement of the implant and the amount of noncalcified tissue. Our data indicate that both treatment regimens improved implant stability. © 2011 Orthopaedic Research Society Published by Wiley Periodicals, Inc. J Orthop Res 30:190–195, 2012     

Systematic review and meta-analysis of the efficacy and safety of therapy with linezolid containing regimens in the treatment of multidrug-resistant and extensively drug-resistant tuberculosis

Background

Linezolid containing regimens have been proposed as potentially valuable alternatives for the treatment of patients with multidrug-resistant tuberculosis (MDR-TB) or extensively drug-resistant TB (XDR-TB).

Methods

A systematic review and meta-analysis was conducted to assess the efficacy, safety and tolerability of linezolid for drug-resistant TB (DR-TB) treatment. We searched the Cochrane Controlled Trial Registry, PubMed, Embase, Science Citation Index Expanded (SCI) and China National Knowledge Infrastructure (CNKI), database up to May 2014 to identify studies providing data of the use of linezolid for the treatment of DR-TB.

Results

The search yielded 15 studies (367 patients) including one randomized controlled trial (RCT), covering 239 patients who could be evaluated for effectiveness; 83% [95% confidence interval (CI), 75-90%; I²=62.8%] had a favorable outcome, defined as either cure or treatment completion. The pooled rate of culture conversion was 89% (95% CI, 83-95%; I²=49.6%). Between the group receiving daily linezolid doses of ≤600 or >600 mg, the mortality was considerably lower in patients treated with less than 600 mg/day (P value <0.001). Of 367 patients for whom data on safety was available, peripheral neuropathy (31%, 95% CI, 19-42%; I²=81.7%) and anemia (25%, 95% CI, 15-34%; I²=76.6%) were the main adverse effects. Patients receiving less than 600 mg/day were more likely to experience nervous system adverse events (P value <0.01).

Conclusions

The available evidence suggests that linezolid could be considered as a promising option as treatment of MDR/XDR TB. Randomized trials are warranted to define the dose and frequency of administration.     

Detection of the classical G2576U mutation in linezolid resistant Staphylococcus aureus along with isolation of linezolid resistant Enterococcus faecium from a patient on short-term linezolid therapy: First report from India

Purpose: Linezolid is an effective drug against methicillin-resistant Staphylococcus aureus (MRSA) and vancomycin-resistant enterococci (VRE). We describe the emergence of linezolid resistance in MRSA and VRE from India. Material and Methods: One MRSA and two VRE strains were isolated from a patient on linezolid therapy of one week duration. All three isolates were resistant to linezolid with minimal inhibitory concentrations (MIC) ≥4 mg/L. The 746-bp region flanking the possible G2576U mutation on the corresponding DNA from the 23S rRNA was amplified by polymerase chain reaction (PCR) and amplicons were sequenced for all the three isolates. Conjugation experiments using the linezolid resistant MRSA (LRMRSA) and linezolid resistant VRE (LRVRE) isolates as donors and wild strains of corresponding genera as recipients were performed. Results: The MRSA isolate had the classical G2576U mutation. High quality value scores in the sequencing software validated the mutation. Conjugation studies did not indicate presence of transferable resistance for linezolid. Sequencing did not indicate presence of any mutation in the two LRVRE isolates. Conclusions: This is the first report from India citing resistance in Staphylococcus and Enterococcus against Linezolid.     

Combined treatment with ceftriaxone and linezolid of pneumococcal meningitis: a case series including penicillin-resistant strains

This study evaluated the role of linezolid in the treatment of patients suffering from pneumococcal meningitis. Treatment included ceftriaxone (4000 mg every 24 h), linezolid (600 mg every 12 h) and dexamethasone (8 mg every 6 h). Linezolid was withdrawn if a penicillin-susceptible isolate of Streptococcus pneumoniae was identified. Of 16 patients studied, seven were infected with penicillin-non-susceptible isolates of S. pneumoniae, two died, and three reported sequelae. No toxicity was reported. It was concluded that linezolid can be used for the treatment of pneumococcal meningitis, as an alternative to vancomycin or rifampicin, in regimens including a third-generation cephalosporin.     

Linezolid: pharmacokinetic characteristics and clinical studies

Linezolid is an oxazolidinone indicated in the treatment of nosocomial and community-acquired pneumonia, complicated and uncomplicated skin and skin structure infections and vancomycin-resistant Enterococcus infections. The drug is also approved for use in complicated skin infections and nosocomial pneumonia caused by methicillin-resistant Staphylococcus aureus , concurrent bacteremia associated with vancomycin-resistant Enterococcus faecium and concurrent bacteremia associated with community-acquired pneumonia caused by penicillin-susceptible Streptococcus pneumoniae .     

Clinical experience with linezolid for the treatment of central nervous system infections

Linezolid, an oxazolidinone, exhibits bacteriostatic activity against virtually all Gram-positive bacteria and even covers atypical organisms like mycobacteria and Nocardia. However, little is known about its effectiveness for central nervous system (CNS) infections. We report on our good experience with linezolid for the treatment of CNS infections in 10 patients, amongst whom three were caused by mycobacteria. While six of our patients clinically improved during linezolid therapy even after failure of various antibiotics, it was unsuccessful in one case. Side-effects were only mild gastrointestinal problems in one patient after long term-treatment, which however led to the cessation of therapy. Linezolid appears to be a safe alternative to vancomycin for therapy-resistant CNS infections because of its good CSF penetration and few side-effects.     

25例利奈唑胺致黑舌或黑毛舌不良反应文献分析

目的分析利奈唑胺致黑舌或黑毛舌不良反应的发生情况及临床特点,为合理用药提供参考。方法检索Cochrane图书馆、Pub Med、中国知网数据库、万方期刊论文数据库、维普期刊数据库,对2000年1月—2021年1月收载的利奈唑胺致黑舌或黑毛舌不良反应报道文献进行分析。分别对患者性别、年龄、用药原因、用法用量、黑舌或黑毛舌发生时间、临床表现、处理措施、临床转归时间等方面进行分析。结果检索到20篇共25例关于利奈唑胺致黑舌或黑毛舌不良反应的文献报道,其中男性17例,女性8例;最小年龄5岁,最大年龄83岁,各年龄段均有黑舌或黑毛舌不良反应发生,以≤15岁和50岁年龄段患者居多;19例(76%)患者在用药后1～2周出现黑舌或黑毛舌不良反应;在停用利奈唑胺并保持良好的口腔卫生习惯后,黑舌或黑毛舌不良反应症状好转或消失。结论利奈唑胺致黑舌或黑毛舌不良反应为罕见的良性自限性不良反应,发病机制尚不明确,临床医师和药师应加强利奈唑胺的用药监测并做好解释,以消除患者恐慌心理。