Linezolid for infective endocarditis: A structured approach based on a national database experience

Current data on the frequency and efficacy of linezolid (LNZ) in infective endocarditis (IE) are based on small retrospective series. We used a national database to evaluate the effectiveness of LNZ in IE.This is a retrospective study of IE patients in the Spanish GAMES database who received LNZ. We defined 3 levels of therapeutic impact: LNZ < 7 days, LNZ high-impact (≥ 7 days, > 50% of the total treatment, and > 50% of the LNZ doses prescribed in the first weeks of treatment), and LNZ ≥ 7 days not fulfilling the high-impact criteria (LNZ-NHI). Effectiveness of LNZ was assessed using propensity score matching and multivariate analysis of high-impact cases in comparison to patients not treated with LNZ from the GAMES database matched for age-adjusted comorbidity Charlson index, heart failure, renal failure, prosthetic and intracardiac IE device, left-sided IE, and Staphylococcus aureus. Primary outcomes were in-hospital mortality and one-year mortality. Secondary outcomes included IE complications and relapses.From 3467 patients included in the GAMES database, 295 (8.5%) received LNZ. After excluding 3 patients, 292 were grouped as follows for the analyses: 99 (33.9%) patients in LNZ < 7 days, 11 (3.7%) in LNZ high-impact, and 178 (61%) in LNZ-NHI. In-hospital mortality was 51.5%, 54.4%, and 19.1% respectively. In the propensity analysis, LNZ high-impact group presented with respect to matched controls not treated with LNZ higher in-hospital mortality (54.5% vs 18.2%, P = .04). The multivariate analysis showed an independent relationship of LNZ use with in-hospital mortality (odds ratio 9.06, 95% confidence interval 1.15--71.08, P = .03).Treatment with LNZ is relatively frequent, but most cases do not fulfill our high-impact criteria. Our data suggest that the use of LNZ as definitive treatment in IE may be associated with higher in-hospital mortality.     

长疗程高剂量利奈唑胺致可逆性血小板减少1例

<正>利奈唑胺(linezolid)化学名称为:(S)-N [[3-[3-氟-4-(4-吗啉基)苯基1]-2-氧代-5-恶唑烷基]甲基]-乙酰胺,为第1个人工合成的应用于临床的新型嗯唑烷酮类抗菌药,通过与细菌50S亚基附近界面的30S亚基结合,抑制mRNA     

利奈唑胺、去甲万古霉素等抗菌药物对耐甲氧西林金黄色葡萄球菌的抗菌活性

目的:研究北京市三家医院耐甲氧西林金黄色葡萄球菌(MRSA)耐药现状,评价利奈唑胺、去甲万古霉素等药物的抗菌活性。方法:收集解放军总医院、北京医院、北京协和医院三家医院分离的非重复MRSA111株,头孢西丁纸片法确认MRSA,采用琼脂稀释法测定抗菌药物的最低抑菌浓度(MIC)。结果:111株MRSA,对β-内酰胺类的耐药率为100%,对红霉素的耐药率为92.8%,对氨基糖苷类(奈替米星、庆大霉素)的耐药率为99.1%,对氟喹酮类(加替沙星、莫西沙星、左氧氟沙星)的耐药率为91.9%~99.1%,对氯霉素的耐药率为3.6%,对去甲万古霉素、利奈唑胺全部敏感,对去甲万古霉素MIC50和MIC90分别为0.5和1μg/mL,对利奈唑胺的MIC50和MIC90均为2μg/mL。结论:北京三家医院分离的MRSA对本研究的大多数抗菌药物均耐药,去甲万古霉素和利奈唑胺对于MRSA有很高的抗菌活性。     

Successful treatment with linezolid of meningitis complicated with subdural empyema in a 6-month-old boy

Recent findings have focused on the possible role of linezolid as a suitable candidate for the treatment of central nervous system infections. The linezolid treatment for meningitis was sporadically reported in adults but there was no report in children. Here, we present a 6-month-old boy with meningitis and subdural empyema which was unresponsive to more conventional agents but successfully treated with linezolid therapy. A previously healthy 6-month-old boy was referred to our clinic for deteriorating general condition with fever, vomiting and seizures. He had fever and tense-bulging anterior fontanelle. Based on his first cerebrospinal fluid (CSF) results, empirical antibiotic therapy for bacterial meningitis consisting of vancomycin and ceftriaxone was started. However, CSF culture yielded no micro-organisms but blood culture showed coagulase-negative Staphylococci. On the 7th day, he still had high fever and the erythrocyte sedimentation rate (ESR) and serum CRP levels had risen by 105 mm/h and 36.2 mg/dl, respectively. On 10th day, computerized cranial tomography showed bilateral frontoparietal subdural empyema. Purulent material was evacuated by burr hole, and gram stains of the material showed polymorphonuclear leukocytes and no microorganisms. Clinical and CSF findings of our case were, unresponsiveness to vancomycin, ceftriaxone and consecutive meropenem treatment while we still observed subdural empyema during these treatments. For this reason we started linezolid 10 mg/kg twice daily. Clinical signs improved dramatically, with both completely normal neurological findings and normalization of CSF and radiological findings. To the of our best knowledge, linezolid treatment of meningitis in children has not been reported previously. Clinical and CSF findings of our case were improved completely with linezolid treatment. Also, control cranial computerized tomography showed the total recovery of subdural empyema. Here we present the youngest case with meningitis which was successfully treated with linezolid treatment.     

Emergence of methicillin‐resistant coagulase‐negative staphylococci resistant to linezolid with rRNA gene C2190T and G2603T mutations

The aim of this article were to determinate the mechanism of linezolid resistance in coagulase‐negative methicillin‐resistant staphylococci from hospitals in the northeast of Brazil. We identified the isolates using VITEK^® 2 and MALDI‐TOF. Susceptibility to antibiotics was measured by the disk‐diffusion method and by Etest^®. Extraction of the whole genome DNA was performed, followed by screening of all the strains for the presence of mecA and cfr genes. The domain V region of 23S rRNA gene was sequenced and then aligned with a linezolid‐susceptible reference strain. Pulsed‐field gel electrophoresis (PFGE) macro‐restriction analysis was performed. Three linezolid‐resistant Staphylococcus hominis and two linezolid‐resistant Staphylococcus epidermidis strains were analyzed. The isolates showed two point mutations in the V region of the 23S rRNA gene (C2190T and G2603T). We did not detect the cfr gene in any isolate by PCR. The S. hominis showed the same pulsotype, while the S. epidermidis did not present any genetic relation to each other. In conclusion, this study revealed three S. hominis and two S. epidermidis strains with resistance to linezolid due to a double mutation (C2190T and G2603T) in the domain V of the 23S rRNA gene. For the first time, the mutation of C2190T in S. epidermidis is described. This study also revealed the clonal spread of a S. hominis pulsotype between three public hospitals in the city of Natal, Brazil. These findings highlight the importance of continued vigilance of linezolid resistance in staphylococci.     

Predicting and preventing antimicrobial resistance utilizing pharmacodynamics: Part I gram positive bacteria

Introduction: Antimicrobial resistance is a potentially inevitable consequence of widespread use of antibiotics in the healthcare system. An enhanced understanding of pharmacodynamic (PD) targets that prevent antimicrobial resistance development will improve currently availably therapies and help to guide future drug development strategies. Current in vitro methods to predict bacterial resistance to antimicrobials consist of serial dilution experiments, determination of the mutant prevention concentration (MPC), mutant selection window (MSW), and human simulated pharmacodynamics studies. Clinical trial data and real -world surveillance studies can help validate or disprove in vitro modeling.

Areas covered: This review will discuss methods of predicting development of resistance and how the use of pharmacodynamics can reduce or eliminate the emergence of resistance among Staphylococcus aureus, Streptococcus pneumoniae, and Enterococcus species.

Expert opinion: Pharmacodynamic targets can be used successfully to guide antimicrobial therapy to prevent resistance development. Currently, PD targets do not take into consideration horizontal resistance gene transfer and various factors may lead to different PD targets based on sites of infection. Further research is necessary to guide future drug development strategies and optimize new drug therapies.     

利奈唑胺耐药粪肠球菌的耐药机制与感染危险因素调查

目的研究利奈唑胺耐药粪肠球菌(linezolid-resistant Enterococcus faecalis,LRE)的耐药机制并分析其感染的临床特征及危险因素。方法收集2014-2018年从住院患者无菌体液标本中分离的LRE(MIC≥8 mg/L),利用PCR及测序技术检测菌株中的optrA、cfr、poxtA基因,23S rRNA V区突变以及由rplC和rplD编码的核糖体蛋白L3、L4的突变。回顾性收集LRE感染患者的临床和实验室资料,通过病例对照研究对LRE感染的危险因素进行分析。结果5年内共检出85株LRE,耐药机制主要包括获得optrA基因(98.8%),核糖体蛋白L4突变(36.5%)、L3突变(4.7%)。共纳入85例LRE感染病例组和85例利奈唑胺敏感粪肠球菌(linezolid-susceptible Enterococcus faecalis,LSE)感染对照组。多因素分析表明,从外院转入(OR:2.8,95%CI:1.3~6.1,P=0.007)、高龄(≥60岁)(OR:2.3,95%CI:1.1~5.0,P=0.034)、恶性肿瘤(OR:5.5,95%CI:2.5~12.5,P<0.001)、气管插管(OR:3.8,95%CI:1.7~8.3,P=0.001)、先前碳青霉烯类(OR:0.1,95%CI:0~0.5,P=0.003)和氟喹诺酮类(OR:4.3,95%CI:1.4~13.7,P=0.013)的使用为LRE感染的危险因素。结论携带optrA基因是LRE的主要耐药机制,外院转入、高龄、恶性肿瘤、气管插管、先前碳青霉烯类和氟喹诺酮类抗菌药物的使用是LRE感染的独立危险因素。     

利奈唑胺治疗神经外科术后颅内感染疗效分析

目的评价利奈唑胺治疗神经外科术后颅内感染的临床疗效及安全性,为术后颅内感染的治疗提供参考。方法通过病历查询系统收集2011年1月-2012年12月北京天坛医院51例术后颅内感染后使用利奈唑胺治疗的患者病历资料,根据利奈唑胺治疗前后患者症状、体温、脑脊液细菌培养结果及脑脊液白细胞数、蛋白质、葡萄糖变化等指标,参照颅内感染的判定标准,评价患者使用利奈唑胺治疗颅内感染的有效性及安全性。结果51例神经外科术后发生颅内感染的患者在使用利奈唑胺治疗后,感染痊愈30例,显效12例,进步5例,无效4例,总有效率92.16%。有效的47例患者中,利奈唑胺的平均治疗时间为12.5 d（2～27 d）。其中11例脑脊液培养出革兰阳性菌者经利奈唑胺治疗后,脑脊液细菌培养均转为阴性。 结论利奈唑胺可有效控制万古霉素等治疗无效的葡萄球菌属、肠球菌属等革兰阳性菌引起的术后颅内感染。     

Nafamostat mesilate inhibits linezolid metabolism via its antioxidant effects

Patients who undergo renal replacement therapy often exhibit a high plasma linezolid concentration. Linezolid is metabolized via oxidation. Nafamostat mesilate has antioxidant effects and is frequently used as an anticoagulant during renal replacement therapy. We aimed to investigate the effect of nafamostat mesilate on plasma linezolid concentration. We examined whether the co‐administration of linezolid and nafamostat had any effect on plasma linezolid concentration. Mice were randomly allocated to two groups (n = 18/group): linezolid (100 mg kg^?1, subcutaneous injection) + nafamostat (30 mg kg^?1, intraperitoneal injection) and linezolid + saline. At 5 hours, the linezolid concentration was significantly higher in the linezolid + nafamostat co‐administration group than that in the linezolid + saline group (20.6 ± 9.8 vs 3.6 ± 1.2 μg/mL, respectively P < .001). The antioxidant effects of nafamostat may inhibit linezolid metabolism, resulting in the adverse event of high linezolid concentration if both are administered concurrently during renal replacement therapy.