利奈唑胺和万古霉素治疗重症医学科院内耐甲氧西林金黄色葡萄球菌肺炎疗效及安全性研究

目的比较利奈唑胺与万古霉素对ICU患者耐甲氧西林金黄色葡萄球菌(MRSA)肺部感染的疗效及安全性。方法对2008年5月至2010年11月温州市中医院收治的72例肺部MRSA感染的患者,分别给予利奈唑胺(0.6 g/次,每日2次)和万古霉素(1.0 g/次,每日2次)治疗,观察并比较两种方法的临床疗效、细菌学疗效及不良反应。结果万古霉素与利奈唑胺治疗MRSA的治愈率分别为25.7%和18.9%,临床总有效率分别为65.7%和51.4%,细菌清除率分别为71.4%和48.6%,不良反应总发生率为8.5%和5.4%,两组间MRSA治愈率、总有效率和不良反应总发生率比较差异无统计学意义(P>0.05),细菌清除率比较差异有统计学意义(P<0.05)。结论对于ICU患者肺部MRSA感染,利奈唑胺与万古霉素敏感率均很高,总体疗效相似,且安全性及耐受性较好,利奈唑胺痰菌清除率略高于后者。     

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。     

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。     

Effect of antibiotics, alone and in combination, on Panton–Valentine leukocidin production by a Staphylococcus aureus reference strain

The capacity of Staphylococcus aureus strain LUG855 to release Panton–Valentine leukocidin (PVL) in the presence of sub-inhibitory concentrations of anti-staphylococcal drugs was examined. Oxacillin enhanced PVL release 2.5-fold, while clindamycin, linezolid, fusidic acid and rifampicin were inhibitory, and vancomycin, pristinamycin, tetracycline, ofloxacin and co-trimoxazole had no effect. In combination with oxacillin, sub-inhibitory concentrations of clindamycin or rifampicin inhibited PVL induction significantly, linezolid was less inhibitory, and fusidic acid did not inhibit PVL induction by oxacillin. These data support the use of oxacillin in combination with clindamycin, rifampicin or linezolid for the treatment of PVL-positive S. aureus infections.     

Structural basis for cross-resistance to ribosomal PTC antibiotics

Clinically relevant antibiotics that target the ribosomal peptidyl transferase center (PTC), a highly conserved ribosomal region, exert their inhibitory action by exploiting the flexibility of PTC nucleotides, which trigger modulations of the shape of the antibiotic binding pocket. Resistance to these antibiotics was observed clinically and in vitro. Based on the crystal structures of the large ribosomal subunit from eubacterium suitable to represent pathogens in complex with these antibiotics, it was found that all nucleotides mediating resistance to PTC antibiotics cluster on one side of the PTC. Over half of the nucleotides affecting resistance reside in regions of lower sequence conservation, and are too distal to make Van der Waals interactions with the bound drugs. Alterations of the identity of these nucleotides may not lethally affect ribosome function, but can hamper antibiotic binding through changes in the conformation and flexibility of specific PTC nucleotides. Comparative analysis revealed properties likely to lead to cross-resistance and enabled their parameterization. As the same nucleotides are frequently involved in resistance to more than a single family of antibiotics, the common pattern explains medically observed cross-resistance to PTC antibiotics and suggests the potential for a wider clinical threat.     

Linezolid therapy for infective endocarditis

Linezolid is not yet recognised as a standard therapy for infective endocarditis. This report describes nine patients with endocarditis treated with linezolid and 33 similar cases from the medical literature. The majority of cases involved multiresistant strains, and the reasons for administering linezolid were refractory disease (60%), intolerance (28%), sequential therapy (12%) and a resistant pathogen (1%). Linezolid was administered for a mean of 37 days, with a successful outcome in 79% of cases. Reversible adverse effects were described in ten cases. The mean follow-up period was 8.5 months. Further data from randomised controlled clinical trials are needed to determine the efficacy and safety of linezolid for treating endocarditis.     

利奈唑胺治疗耐甲氧西林金黄色葡萄球菌重症肺炎15例

目的 观察利奈唑胺治疗耐甲氧西林金葡菌(MRSA)重症肺部炎疗效.方法 选取我院ICU MRSA重症肺炎患者15例,给予利奈唑胺治疗,检测治疗前后血白细胞、乳酸、IL-1β、IL-6、TNF-α水平.结果 临床有效率达73.3%,治疗前后血白细胞计数、乳酸及各炎性因子水平呈明显下降趋势,差异有统计学意义,P<0.01.结论 利奈唑胺对MRSA重度肺部感染有较好的疗效.     

Linezolid absolute bioavailability and the effect of food on oral bioavailability.

Linezolid is a novel oxazolidinone antibiotic that has a spectrum of activity encompassing a variety of Gram-positive bacteria. The objectives of this study were twofold: (1) to compare the absorption of linezolid tablets given immediately following a high-fat meal with the absorption of tablets administered while fasting, and (2) to assess the bioavailability of a 375-mg oral dose given while fasting relative to a 375-mg dose of linezolid sterile solution given intravenously. Venous blood samples were taken over the 48 h following the single dose administration of both the oral and intravenous (IV) treatment. Samples were subsequently frozen for the determination of linezolid concentrations by HPLC. The only statistically significant difference between the fasted and the fed treatment was in peak plasma concentration, with the mean C(max) for fasted subjects being 23% greater than that for subjects after consumption of a high-fat meal. Comparable AUC(0-infinity) values were measured under both conditions, indicating that the overall extent of absorption is the same. Therefore, the difference in C(max), while statistically significant, should not affect the therapeutic efficacy of linezolid when it is administered with food. There were no statistically significant differences in AUC(0-infinity), CL or half-life between the fasted oral treatment and the intravenous treatment. As expected, C(max) was statistically different between the two treatments. However, the mean absolute bioavailability (F) of the tablet, using the IV sterile solution as the reference treatment, was 103% (+/-20%).     

Linezolid alone and in combination with rifampicin prevents experimental vascular graft infection due to methicillin-resistant Staphylococcus aureus and Staphylococcus epidermidis

BACKGROUND: In this report we describe the in vivo antibacterial activity of linezolid in an experimental graft infection model in rats and compare it with teicoplanin. The objective of this study was also to determine the effects of the interaction of linezolid when it was combined with rifampicin and test this effect against strains of methicillin-resistant Staphylococcus aureus and Staphylococcus epidermidis. MATERIALS AND METHODS: Graft infections were established in the subcutaneous tissue of 130 Wistar rats by implantation of Dacron grafts followed by a topical inoculation with 2 x 10(7) CFU of clinical isolates of MRSA and MRSE. The study included a control group and six groups for each of the staphylococcal strains: an inoculated group that did not receive any antibiotic prophylaxis, two inoculated groups that received intraperitoneal prophylaxis with teicoplanin or linezolid alone, an inoculated group that received rifampicin-soaked grafts, and two inoculated groups that received a combination prophylaxis consisting of intraperitoneal teicoplanin or linezolid and rifampicin-soaked grafts. RESULTS: There was a reduction in the quantitative bacterial graft cultures in all prophylaxis groups when compared with inoculated control groups. There was not a statistically significant difference between linezolid and teicoplanin prophylaxis groups. The best results were obtained by a combination of rifampicin-soaked grafts with linezolid or teicoplanin. CONCLUSIONS: We found no evidence to suggest that linezolid differs from teicoplanin regarding effectiveness in the prevention of prosthetic vascular graft infection. Linezolid plus rifampicin and teicoplanin plus rifampicin are demonstrated to be valuable prophylactic regimens.     

利奈唑胺和万古霉素对革兰阳性菌所致脓毒血症治疗作用的Meta分析

目的:评估利奈唑胺与万古霉素治疗革兰阳性菌所致脓毒血症的有效性和安全性。方法:从Pubmed、CNKI、万方数据库获得关于利奈唑胺与万古霉素治疗革兰阳性菌所致脓毒血症的随机对照试验(RCTs)的文献。评估2种药物对脓毒血症的临床治愈率、微生物学清除率、对金黄色葡萄球菌和耐甲氧西林金黄色葡萄球菌清除率及不良反应发生率。结果:共纳入的8个随机对照试验,包括3 668个革兰阳性球菌脓毒血症感染患者。Meta分析结果显示,在临床可评估患者中,与万古霉素比较,利奈唑胺在临床治愈率(OR=1.18,95% CI(0.82-1.71),P=0.37)、微生物学总治愈率(OR=1.26,95%CI(0.97-1.65),P=0.09)、对金黄色葡萄球菌细菌(MRSA)清除率(OR=1.24,95%CI(0.72-2.11),P=0.44)和对耐甲氧西林金黄色葡萄球菌细菌清除率(OR=1.58,95%CI(0.99-2.54),P=0.06)及不良反应发生率(OR=0.96,95%CI(0.80-1.14),P=0.63)与万古霉素相当。结论:在治疗革兰阳性球菌(例如金黄色葡萄球菌和耐甲氧西林金黄色葡萄球菌)导致的脓毒血症中,利奈唑胺与万古霉素的治疗效果相当。但还需要更严格设计的、大样本的随机双盲对照试验来进一步验证和支持。