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。     

Staphylococcus coagulasa negativos resistentes al linezolid: características fenotípicas,genotípicas y sensibilidad a combinaciones de antibióticos

Objective

We recovered 22 coagulase-negative staphylococci isolates in our hospital to study their identity, susceptibility, epidemiological profile, linezolid resistance mechanisms, and the possibilities of different antibiotic combinations.

Methods

Isolate identification was performed using mass spectrometry (Vitek-MS, bioMérieux). Susceptibility testing was carried out with the Vitek-2 system and the broth microdilution method according to CLSI guidelines. Pulsed-field gel electrophoresis (PFGE) was performed to analyze the genetic relationship between isolates. Linezolid resistance mechanisms were evaluated by PCR/sequencing: presence of cfr gene, point mutations in domain V of 23S ribosomal RNA and additional ribosomal mutations (in the rplC, rplD and rplV genes).The in vitro activity of linezolid was investigated alone and in combination with another three antibiotics acting on different cellular targets, using E-test strips.

Results

Twenty isolates were identified as Staphylococcus epidermidis, and 2 as Staphylococcus hominis. PFGE showed that isolates belonged to diverse clones, 21 of them presented mutations in the domain V region of 23S rRNA and the cfr gene was found in 54.5%.Prior administration of linezolid was documented in most of cases.Linezolid in combination with gentamicin showed a synergistic activity in 45.5% of isolates.

Conclusions

Staphylococcus epidermidis was the most prevalent linezolid-resistant coagulase-negative staphylococci. All isolates showed increased MIC values compared to other anti-staphylococcal drugs and several linezolid resistance mechanisms. Our data suggest that linezolid plus gentamicin could be a synergistic combination against linezolid-resistant coagulase-negative staphylococci.     

Vancomycin‐resistant enterococcal meningitis in an autologous stem cell transplant recipient cured with linezolid

Enterococci are an unusual cause of meningitis, with most cases reported in the literature preceded by neurosurgical procedures. Spread to the meninges from an enterococcal bloodstream infection is even more rare, with few cases reported in the literature. We report the first documented case, to our knowledge, of successful treatment of vancomycin‐resistant enterococcal (VRE) meningitis with linezolid therapy in an immunosuppressed hematopoietic stem cell transplant recipient. Our case highlights the success of monotherapy with linezolid for VRE meningitis. A literature review is provided, which reveals that there is little evidenced‐based data on the optimal therapy for VRE meningitis.     

An updated approach to healthcare-associated meningitis

Among hospital-associated infections, healthcare-associated central nervous system infections are quite important because of high morbidity and mortality rates. The causative agents of healthcare-associated meningitis differ according to the status of immune systems and underlying diseases. The most frequent agents are Gram-negative bacilli (Pseudomonas spp., Acinetobacter spp., Escherichia coli and Klebsiella pneumoniae) and Gram-positive cocci (Staphylococcus aureus and coagulase-negative staphylococci). There are currently several problems in the treatment strategies of healthcare-associated meningitis due to a globally increasing resistance problem. Strategies targeting multidrug-resistant pathogens are especially limited. This review focuses on healthcare-associated meningitis and the current treatment strategies with a particular focus on methicillin-resistant Staphylococcus aureus (MRSA) meningitis.     

Resistant pathogen-associated skin and skin-structure infections: antibiotic options

Complicated skin and skin-structure infections (cSSSIs) are among the most common infections treated in the hospital setting. They are a significant clinical problem, partially owing to increasing resistance of infecting bacteria to current antibiotic therapies (nosocomial and community-acquired methicillin-resistant Staphylococcus aureus, extended spectrum β-lactamase-producing-Enterobacteriaceae, and multidrug-resistant [MDR] Pseudomonas aeruginosa, among others). The optimal choice of antibacterial therapy among the few available options for infections caused by MDR pathogens is fundamental to maximize clinical effectiveness and minimize the likelihood of further resistance development. Few antimicrobial agents are currently available to treat MDR bacteria in cSSSIs. In this context, the use of new antibiotic agents (i.e., linezolid, daptomycin and tigecycline) and the optimization of the pharmacodynamic targets of classic antibiotics (i.e., carbapenems) is one potential solution to these problems, and some of these agents are highlighted in this article. The purpose of this article is to provide clinicians with an evidence-based review of MDR pathogens causing cSSSIs, the implications of resistance to currently used drug therapy, and to identify new therapeutic options for resistant pathogens causing cSSSIs.     

Linezolid for the treatment of drug-resistant infections

Multidrug-resistant pathogens have become increasingly common in contemporary healthcare. Specific to Gram-positive pathogens, methicillin-resistant Staphylococcus aureus (MRSA) is of particular concern, as it has been associated with increased hospital length of stay, higher healthcare expenditures and poorer outcomes. To date, linezolid is the first and only oxazolidinone approved by the US FDA for the treatment of infections caused by Gram-positive pathogens, including MRSA. This article will serve as a comprehensive review of linezolid, including an overview of the current market and its in vitro activity, with an in-depth review of its pharmacokinetic and pharmacodynamic profile. Emphasis will be placed on clinical data for the drug, both on- and off-label. The article will conclude with a brief overview of linezolid’s pharmacoeconomic implications and safety profile, followed by a commentary and 5-year prospective analysis remarking on the future of the antimicrobial field as it relates to MRSA.     

Recent advances in oxazolidinone antibacterial agent research

The oxazolidinone class of antibacterial agents, as exemplified by linezolid (Zyvox^®, Pharmacia Corp.), represents the first completely new class of antibacterial agents to achieve regulatory approval in over 30 years. Due to their potent activity against multi-drug resistant Gram-positive bacteria, discovery research in this area has flourished, with many pharmaceutical companies worldwide beginning research programmes. With the expanded research efforts, new understanding of the oxazolidinone structure–activity relationship has led to an increased spectrum of activity to include the fastidious Gram-negative pathogens Haemophilus influenzae and Moraxella catarrhalis. In addition, a deeper understanding of the toxicology, mechanism of action, and mechanism of resistance has emerged.     

肾功能不全对利奈唑胺代谢物浓度及血小板减少的影响分析

目的:探讨肾功能对利奈唑胺谷浓度及代谢物PNU-142300浓度的影响,评估利奈唑胺谷浓度及PNU-142300浓度对血小板减少(linezolid induced-thrombocytopenia,LIT)的影响及预警价值。方法:收集2019年11月至2022年1月在南京医科大学附属苏州医院住院期间使用利奈唑胺的患者,分为肾功能不全组与肾功能正常组,比较2组利奈唑胺谷浓度和PNU-142300浓度的差异,分析不同利奈唑胺谷浓度下LIT的发生风险。绘制受试者工作特征(receiver operation characteristic,ROC)曲线,评估利奈唑胺谷浓度及PNU-142300浓度对LIT的预警价值。结果:共收集92例患者,肾功能不全组40例,肾功能正常组52例。肾功能不全组利奈唑胺谷浓度及PNU-142300浓度更高(P＜0.01;P＜0.01),两者与肾功能均存在一定的负相关(Spearman's r=-0.371,P＜0.01;Spearman's r=-0.451,P＜0.01)。共19例患者发生LIT,肾功能不全组12例(30.00%),肾功能正常组7例(13.46%),差异无统计学意义(P=0.052)。利奈唑胺谷浓度≥7mg·L^-1相比于＜7mg·L^-1发生LIT的风险增加(Log-Rank P=0.010);肾功能不全者LIT风险增加(Log-Rank P=0.036)。LIT组利奈唑胺谷浓度和PNU-142300浓度更高(P＜0.01)。利奈唑胺谷浓度和PNU-142300浓度折点分别为12.10mg·L^-1、4.63mg·L^-1。结论:肾功能不全者利奈唑胺谷浓度及PNU-142300浓度更高。利奈唑胺谷浓度＞12.10mg·L^-1、PNU-142300浓度＞4.63mg·L^-1时LIT发生风险增加。