Impact of Weight on Treatment Efficacy and Safety in Complicated Skin and Skin Structure Infections and Nosocomial Pneumonia Caused by Methicillin-Resistant Staphylococcus aureus

Background

There are few data on dose optimization and clinical outcomes of antimicrobial agents based on patients’ weight, despite the rising prevalence of obesity. Because there are physiologic, pharmacologic, and dosing differences related to weight, it is important to evaluate the impact of weight on antimicrobial agents to optimize clinical outcomes.

Objectives

This study compared effects of weight on efficacy and safety in patients treated with linezolid or vancomycin for complicated skin and skin structure infections (cSSSIs) and nosocomial pneumonia (NP) caused by methicillin-resistant Staphylococcus aureus (MRSA).

Methods

We analyzed data from 2 clinical trials of patients randomized to receive a fixed dose of linezolid or weight-based dosing of vancomycin for the treatment of cSSSIs or NP caused by MRSA. For each study, patients were stratified into quartiles (Q1–4 [lowest to highest weight, respectively]). Clinical success, microbiologic success, and adverse events (AEs) were evaluated.

Results

The analysis included 632 patients with cSSSIs (linezolid, n = 316; vancomycin, n = 316) and 447 patients with NP (linezolid, n = 224; vancomycin, n = 223). Among patients with cSSSIs, clinical success rates at the study end with fixed-dose linezolid were similar across all weight quartiles and similar to weight-based dosing of vancomycin for Q1–3. Among Q4 (the highest weight quartile [97–295 kg]), clinical success with vancomycin was significantly lower compared with linezolid (69.5% vs 86.2%; P = 0.03). Among patients with NP, no significant differences in success rates between fixed-dose linezolid and weight-based dosing of vancomycin were observed across all quartiles. Frequencies of AEs were consistent across the quartiles for both indications and by treatment.

Conclusions

Except for Q4 within the vancomycin-treated patients for MRSA cSSSI, the efficacy of fixed-dosed linezolid and weight-based dosing of vancomycin was maintained across all weight quartiles and MRSA infection types. The AEs were consistent with the known safety profiles of each drug regardless of weight quartile. ClinicalTrials.gov identifiers: NCT00087490 and NCT00084266.     

Assessment of absolute oral bioavailability of linezolid tablets in Chinese healthy male volunteers

AIM： Linezolid is a member of oxazolidinones, which is a novel class of antibiotics. The study is to determine the absolute bioavailability of linezolid tablets in Chinese healthy male volunteers. METHODS： A randomized, open cross-over study was conducted in 22 healthy male volunteers, a single oral dose of 600 mg linezolid tablets or Ⅳ infusion of 600 mg linezolid were given to subjects, respectively. Blood sampies were obtained at different time points and sent to American AvTech laboratories. Plasma concentrations of linezolid were determined by high-performance liquid chromatography （HPLC）, pharmacokinetic parameters and absolute bioavailability were calculated. RESULTS： After oral and IV infusion administration of 600 mg linezolid, the elimination half-life （ t1/2 ） was （4.3 ± 1.0） h and （4.4±0.9） h, respectively. The area under plasma concentration-time curve （AUC0-∞ ） of linezolid were （87 ± 20） μg·mL^-1·h and （96 ± 21） μg·mL^-1·h, respectively. The absolute oral bioavailability was 93 % ± 23 % following single oral dose of 600 mg linezolid tablets. Analyses of two one-sided t tests and 90% confidence interval showed that linezolid tablet and Ⅳ formulation are equivalent with respect to AUC.[第一段]     

The occurrence of antimicrobial substances in toilet,sink and shower drainpipes of clinical units: A neglected source of antibiotic residues

Antibiotics represent one of the most important drug groups used in the management of bacterial infections in humans and animals. Due to the increasing problem of antibiotic resistance, assurance of the antibacterial effectiveness of these substances has moved into the focus of public health. The reduction in antibiotic residues in wastewater and the environment may play a decisive role in the development of increasing rates of antibiotic resistance. The present study examines the wastewater of 31 patient rooms of various German clinics for possible residues of antibiotics, as well as the wastewater of five private households as a reference.To the best of our knowledge, this study shows for the first time that in hospitals with high antibiotic consumption rates, residues of these drugs can be regularly detected in toilets, sink siphons and shower drains at concentrations ranging from 0.02?μg·L^?1 to a maximum of 79?mg·L^?1. After complete flushing of the wastewater siphons, antibiotics are no longer detectable, but after temporal stagnation, the concentration of the active substances in the water phases of respective siphons increases again, suggesting that antibiotics persist through the washing process in biofilms. This study demonstrates that clinical wastewater systems offer further possibilities for the optimization of antibiotic resistance surveillance.     

多中心耐利奈唑胺凝固酶阴性葡萄球菌耐药机制及同源性分析

目的:了解江苏地区利奈唑胺耐药凝固酶阴性葡萄球菌耐药机制及菌株流行性。方法:收集2017—2018年江苏省3家三级医院临床和环境分离利奈唑胺耐药凝固酶阴性葡萄球菌共38株(头状葡萄球菌32株、人葡萄球菌4株、表皮葡萄球菌1株和缓慢葡萄球菌1株),采用微量肉汤稀释法检测常规药物的敏感性,并采用E-test试验检测菌株对利奈唑胺的最低抑菌浓度(MIC);采用PCR扩增和测序技术检测cfr、optrA、23S rRNA第V功能区基因;采用脉冲场凝胶电泳(PFGE)对分离菌株进行同源性分析。结果:38株凝固酶阴性葡萄球菌对利奈唑胺、青霉素和苯唑西林均耐药,对万古霉素均敏感;对克林霉素、左氧氟沙星和环丙沙星的耐药率大于95%;38株菌株中检出cfr基因31株;23S rRNAⅤ功能区检出G2576T突变35株,其中2株人葡萄球菌同时检出C2319T突变,另检出C2319T突变人葡萄球菌和表皮葡萄球菌各1株;所有菌株均未检出optrA基因;32株头状葡萄球菌PFGE具有高度的相似性,均为同一个克隆株;4株人葡萄球菌为同一克隆株。结论:江苏地区流行的耐利奈唑胺凝固酶阴性葡萄球菌主要是由cfr基因和23S rRNAⅤ功能区基因突变造成,并存在头状葡萄球菌和人葡萄球菌的克隆播散。     

利奈唑胺体外诱导粪肠球菌V区突变及耐药相关性研究

目的 观察利奈唑胺是否能在体外诱导肠球菌产生高水平耐药,同时探索其耐药机制与23S rRNA的V区突变的关系,以及突变的基因拷贝数是否与耐药程度(MIC值)相关.方法 5株耐药机制未明的利奈唑胺低水平耐药粪肠球菌(MIC:4～ 16 μg/mL)持续给予利奈唑胺进行体外诱导,观察其耐药水平变化;采用PCR技术扩增诱导菌和ATCC 29212的23S rRNA的V区片段以及编码核糖体蛋白L3、L4基因片段,分析有无V区和L3、I4突变及V区突变拷贝数.结果 通过利奈唑胺持续诱导,5株耐药菌的MIC值较原菌株获得8～32倍增加,最高MIC值超过256 mg/L;其中有3株菌23S rRNA的V583区发生G2576T突变,其余2株菌未发现V区突变;所有诱导菌未发现L3、L4核糖体蛋白氨基酸改变.结论 利奈唑胺在体外可诱导粪肠球菌MIC值迅速增加,其V区G2576T突变与高水平耐药密切相关,且突变拷贝数量与MIC值增高呈正相关.     

脑脊液中利奈唑胺质量浓度测定方法的建立及临床应用

目的建立人脑脊液中利奈唑胺质量浓度测定方法并开展临床检测。方法使用高效液相色谱仪(HPLC),采用外标法。色谱条件为:色谱柱:Agilent 5TC-C18(2),250mm×4.6mm;流动相:甲醇-水(40∶60);流速:1.0mL·min~(-1);柱温:25℃;紫外检测波长:250nm。结果利奈唑胺质量浓度在0.31~40 mg·L~(-1)范围内线性关系良好(r=0.999 6),定量下限为0.31mg·L~(-1),方法回收率、提取回收率均大于85%,高、中、低3个质量浓度日内、日间精密度的RSD值均小于5%。药物干扰试验中美罗培南、头孢曲松及头孢他啶对利奈唑胺的测定无影响。对8例患者开展27例次脑脊液利奈唑胺质量浓度测定,平均质量浓度为2.67±1.11mg·L~(-1)。结论建立的利奈唑胺脑脊液质量浓度测定方法简单、方便、灵敏、准确,可用于临床检测;利奈唑胺在脑脊液中的质量浓度个体差异较大。     

Linezolid-induced dyserythropoiesis: chloramphenicol toxicity revisited

Abstract
We report here two cases of dyserythropoietic anaemia associated with long-term linezolid use that share striking similarities to chloramphenicol-associated myelotoxicity. (Intern Med J 2005; 35: 626–628)     

Undifferentiated Nasopharyngeal Carcinoma in Children: a report of four cases

Abstract

Nasopharyngeal carcinoma in early stages in children is a highly curable neoplasm. The major cause of treatment failure is the development of distant metastases, predominantly in advanced stages. This paper reports about four young patients with undifferentiated nasopharyngeal carcinoma treated with preradiation chemotherapy, locoregional radiotherapy and maintenance chemotherapy up to a total period of two years. Treating these four children, we noticed that preradiation chemotherapy caused satisfactory regression of the primary tumor. Three patients are still without signs of disease after 28 to 88 months and one died due to tumor progression. Further studies have to confirm our observations and support research in designing the optimal combination of effective chemotherapeutic agents and radiotherapy.     

Weight-adjusted versus fixed dose of linezolid for Chinese healthy volunteers of higher and lower body weight: a Phase I pharmacokinetic and pharmacodynamic study

Objectives: The objective was to evaluate the pharmacokinetic and pharmacodynamic properties of a single intravenous fixed dose compared with a weight-adjusted dose of linezolid.

Methods: A Phase I, comparative clinical trial was conducted involving 20 healthy male Chinese volunteers, assigned into low weight (LW) (50 kg < weight ≤ 55 kg) and high weight (HW) (≥ 80 kg) groups. All subjects were administrated single dose of linezolid (600 mg/30 min) and, after 72 h washout period, another single-dose (10 mg/kg/30 min). Plasma linezolid concentrations were measured by liquid chromatography-tandem mass spectrometry. A Monte Carlo simulation was used to evaluate the probability of pharmacodynamic target attainment (PTA).

Results: With 600 mg dose, plasma concentrations in LW group were much higher than that in HW group. A persistent serum inhibitory activity was observed in LW group; the inhibitory activity was lower in HW group. The PTA in HW group was lower than in LW group. For 10 mg/kg dose, both HW and LW groups had similar plasma concentrations. The HW and LW groups had similar serum inhibitory effects. The PTA in HW and LW groups also showed no difference.

Conclusions: Our findings suggest that a weight-adjusted, 10 mg/kg regimen of linezolid may be more appropriate than fixed dosing for patients of different body weight.