Efficacy and tolerance of rifampicin–linezolid compared with rifampicin–cotrimoxazole combinations in prolonged oral therapy for bone and joint infections

Both linezolid and cotrimoxazole are antibiotics that are well suited for oral therapy of bone and joint infections (BJI) caused by otherwise resistant Gram-positive cocci (GPC) (resistance to fluoroquinolones, maccolides, betalactamines). However, in this context, no data are currently available regarding the safety and tolerance of these antibiotics in combination with rifampicin. The objective of this study was to compare the efficacy and safety of a combination of rifampicin and linezolid (RLC) with those of a combination of rifampicin and cotrimoxazole (RCC) in the treatment of BJI. Between February 2002 and December 2006, 56 adult patients (RLC, n  = 28; RCC, n  = 28), including 36 with infected orthopaedic devices (RLC, n  = 18; RCC, n  = 18) and 20 with chronic osteomyelitis (RLC, n  = 10; RCC, n  = 10), were found to be eligible for inclusion in this study. Patients who discontinued antibiotic therapy within 4 weeks of commencing treatment were considered to represent cases of treatment failure and were excluded. Rates of occurrence of adverse effects were similar in the two groups, at 42.9% in the RLC group and 46.4% in the RCC group (p = 1.00), and led to treatment discontinuation in four (14.3%) RLC and six (21.4%) RCC patients. Cure rates were found to be similar in the two groups (RLC, 89.3%, RCC, 78.6%; p = 0.47). Prolonged oral RLC and RCC therapy were found to be equally effective in treating patients with BJI caused by resistant GPC, including patients with infected orthopaedic devices. However, the lower cost of cotrimoxazole compared with linezolid renders RCC an attractive treatment alternative to RLC. Further larger clinical studies are warranted to confirm these preliminary results.     

利奈唑胺致血小板减少3例

3例男性患者,年龄46～91岁,给予利奈唑胺600mg,2次/d静脉滴注治疗感染。给药前血小板计数正常,治疗3～17d后均出现血小板减少。血小板计数分别为95×109/L、74×109/L、86×109/L。停用利奈唑胺,改用亚胺培南-西司他丁钠、万古霉素、美洛培南,其他治疗不变,2～9d后血小板计数恢复正常。     

利奈唑胺致乳酸酸中毒及其防治

利奈唑胺为恶唑烷酮类抗生素,主要用于耐万古霉素的肠球菌和耐甲氧西林金黄色葡萄球菌感染的治疗。患者应用利奈唑胺后1～16周可发生血乳酸水平升高,甚至导致乳酸酸中毒。临床表现为恶心、呕吐、腹泻、心动过速,甚至意识模糊。利奈唑胺诱导乳酸酸中毒的机制可能与抑制线粒体蛋白质合成有关。防治措施如下：应用利奈唑胺时应监测血乳酸水平;一旦乳酸水平超过正常值应立即停药;严重乳酸酸中毒患者应予对症治疗;利奈唑胺应避免与5-羟色胺再摄取抑制剂合用。     

Pediatric Obesity: Pharmacokinetic Alterations and Effects on Antimicrobial Dosing

Limited data exist for appropriate drug dosing in obese children. This comprehensive review summarizes pharmacokinetic (PK) alterations that occur with age and obesity, and these effects on antimicrobial dosing. A thorough comparison of different measures of body weight and specific antimicrobial agents including cefazolin, cefepime, ceftazidime, daptomycin, doripenem, gentamicin, linezolid, meropenem, piperacillin‐tazobactam, tobramycin, vancomycin, and voriconazole is presented. PubMed (1966–July 2015) and Cochrane Library searches were performed using these key terms: children, pharmacokinetic, obesity, overweight, body mass index, ideal body weight, lean body weight, body composition, and specific antimicrobial drugs. PK studies in obese children and, if necessary, data from adult studies were summarized. Knowledge of PK alterations stemming from physiologic changes that occur with age from the neonate to adolescent, as well as those that result from increased body fat, become an essential first step toward optimizing drug dosing in obese children. Excessive amounts of adipose tissue contribute significantly to body size, total body water content, and organ size and function that may modify drug distribution and clearance. PK studies that evaluated antimicrobial dosing primarily used total (or actual) body weight (TBW) for loading doses and TBW or adjusted body weight for maintenance doses, depending on the drugs’ properties and dosing units. PK studies in obese children are imperative to elucidate drug distribution, clearance, and, consequently, the dose required for effective therapy in these children. Future studies should evaluate the effects of both age and obesity on drug dosing because the incidence of obesity is increasing in pediatric patients.     

Linezolid Versus Vancomycin in the Empiric Treatment of Nosocomial Pneumonia: A Cost-Utility Analysis Incorporating Results from the ZEPHyR Trial

ObjectiveTo examine the cost-effectiveness of vancomycin versus linezolid in the empiric treatment of nosocomial pneumonias incorporating results from a recent prospective, double-blind, multicenter, controlled trial in adults with suspected methicillin-resistant Staphylococcus aureus (MRSA) nosocomial pneumonia.MethodsA decision-analytic model examining the cost-effectiveness of linezolid versus vancomycin for the empiric treatment of nosocomial pneumonia was created. Publicly available cost, efficacy, and utility data populated relevant model variables. A probabilistic sensitivity analysis varied parameters in 10,000 Monte-Carlo simulations, and univariate sensitivity analyses assessed the impact of model uncertainties and the robustness of our conclusions.ResultsResults indicated that the cost per quality-adjusted life-year (QALY) increased 6% ($22,594 vs. $23,860) by using linezolid versus vancomycin for nosocomial pneumonia. The incremental cost per QALY gained by using linezolid over vancomycin was $6,089, and the incremental cost per life saved was $68,615 with the use of linezolid. Vancomycin dominated linezolid in the subset of patients with documented MRSA. The incremental cost per QALY gained using linezolid if no mortality benefit exists between agents or a 60-day time horizon was analyzed was $19,608,688 and $443,662, respectively.ConclusionsLinezolid may be a cost-effective alternative to vancomycin in the empiric treatment of patients with suspected MRSA nosocomial pneumonia; however, results of our model were highly variable on a number of important variables and assumptions including mortality differences and time frame analyzed.     

利奈唑胺骨水泥在关节置换术后感染治疗中应用的系列探索研究之一——利奈唑胺骨水泥的物理、力学性能研究

目的：探讨利奈唑胺骨水泥物理和力学性能改变,以指导利奈唑胺骨水泥在治疗人工关节置换术后感染中的临床应用。方法根据在40 g骨水泥中加入不同剂量的利奈唑胺,将样本共分成8个组,每组测定5个样本,8组分别是：Ⅰ组为对照组,不加抗生素,第Ⅱ到第Ⅷ组加入抗生素的量分别为1.2、2.4、3.6、4.8、6.0、7.2及8.4g。分别测定各组面团期时间、压缩强度、弯曲模量和弯曲强度。结果各组面团时间在2′50″～3′40″之间。随着抗生素剂量的增加,面团时间也随之增加。各组的压缩强度、弯曲模量和弯曲强度均优于ISO 5833标准,且有统计学差异（ P＜0.05）,Ⅱ组的压缩强度、弯曲模量和弯曲强度与对照组没有统计学差异,但高于其他各组,与其他各组间有统计学差异。而第Ⅷ组的压缩强度、弯曲模量和弯曲强度均低于其他各组,且有统计学差异。结论面团时间随着利奈唑胺剂量的增加而增加。如果利奈唑胺骨水泥用于预防性使用,则每40 g骨水泥中最多可以加入1.2g利奈唑胺,否则会影响骨水泥的强度。如果利奈唑胺骨水泥用于制作占位器,在每40 g骨水泥中最多不要加入超过7.2 g的利奈唑胺,不至于太影响骨水泥占位器的强度,但是加入的最佳剂量是多少,本系列实验的另一部分会有详细交代。     

利奈唑胺体外诱导粪肠球菌耐药株23S rRNA V区基因突变位点分析

目的阐明体外诱导利奈唑胺耐药粪肠球菌的核糖体23SrRNA V区基因位点变异特征。方法收集1株血流感染的粪肠球菌和1株粪肠球菌质控菌ATCC29212（编号分别为F3和F4菌株,均为利奈唑胺敏感株）,通过体外浓度倍增法诱导利奈唑胺耐药;挑取单克隆,经E-test条测定MIC值,获得各菌株的耐药浓度梯度;提取耐药菌株基因组DNA,PCR扩增23SrRNA V区基因,扩增产物经测序后与野生株比较,获得V区的突变位点。结果经体外多步法诱导利奈唑胺耐药的不同MIC值粪肠球菌共13株。PCR测序分析2株母株均无变异位点,23SrRNA V区的突变位点主要是G2576U,此外还有T2504A、G2505A、C2610A、C2424U。结论体外多步法可诱导粪肠球菌利奈唑胺耐药,耐药机制与23SrRNA V区位点突变密切相关,突变位点随着MIC值的增高而增多。     

Antimicrobial susceptibility testing of Mycobacteroides (Mycobacterium) abscessus complex,Mycolicibacterium (Mycobacterium) fortuitum,and Mycobacteroides (Mycobacterium) chelonae

The drug susceptibility of rapidly growing mycobacteria (RGM) varies among isolates. Treatment strategies similarly differ depending on the isolate, and for some, no clear strategy has been identified. This complicates clinical management of RGM. Following Clinical and Laboratory Standards Institute standard M24-A2, we assessed the susceptibility of 140 RGM isolates to 14 different antimicrobial drugs by measuring their minimal inhibitory concentrations (MICs). We also investigated the correlation of clarithromycin (CAM) MICs with the erm(41) and rrl gene mutations in the Mycobacteroides (Mycobacterium) abscessus complex, the rrl mutation in Mycobacteroides (Mycobacterium) chelonae, and the erm(39) mutation in Mycolicibacterium (Mycobacterium) fortuitum to determine the contribution of these mutations to CAM susceptibility. The five species and subspecies examined included 48 M. abscessus subsp. abscessus isolates (34.3%), 35 (25.0%) being M. abscessus subsp. massiliense, and two (1.4%) being M. abscessus subsp. bolletii. The M. abscessus complex accounted for 85 isolates (60.7%) in total, whereas 43 isolates (30.7%) were M. fortuitum, and 12 (8.6%) were M. chelonae. Our results demonstrated species-specific susceptibility to antimicrobials. In most cases, susceptibility to CAM could be predicted based on genetic pattern, but since one isolate did not fit that pattern, MIC values needed to be measured. Some isolates also exhibited rates of resistance to other drugs that differed from those previously reported in other locations, indicating that accurate identification of the bacterial isolate and use of the correct method for determining MIC are both important for the diagnosis of RGM.     

利奈唑胺联合抗结核药物治疗结核性脑膜炎疗效和安全性的Meta分析

目的 系统评价利奈唑胺联合抗结核药物治疗结核性脑膜炎的临床疗效和安全性。方法 检索PubMed、CochraneLibrary、EMbase、Web of science、中国生物医学数据库（CBM）、中国学术期刊全文数据库（CNKI）、万方数据库、维普数据库等国内外数据库,搜索发表于2020年7月13日前的关于利奈唑胺联合抗结核药物治疗结核性脑膜炎的临床随机对照试验（RCT）。由2位研究者提取文献资料及进行方法学质量评价,利用Revman 5.2和STATA 10.0软件进行Meta分析。结果 共纳入17篇RCTs,包含1 196例患者。Meta分析结果显示：利奈唑胺联合抗结核药治疗结核性脑膜炎的有效率高于对照组（OR=3.53,95% CI=2.09~5.95,P<0.05）;联合治疗4周后,试验组脑脊液压力（SMD=-50.79,95% CI=-53.86~47.72,P<0.05）指标和格拉斯哥昏迷指数评分（SMD=1.22,95% CI=0.97~1.48,P<0.05）优于对照组;在不良反应方面,4周内利奈唑胺联合抗结核药治疗组的不良反应发生率与对照组近似（RR=1.12,95% CI=0.90~1.38,P=0.32）。结论 当前证据表明利奈唑胺联合抗结核药物治疗结核性脑膜炎有较好的临床疗效,不良反应发生率与对照组相近,且可防可控,故该药用于治疗结核性脑膜炎值得临床推广应用。