Pharmacokinetics,toxicity and clinical efficacy of linezolid in Japanese pediatric patients

ObjectivesThe aims of the present study were (a) to evaluate the pharmacokinetics of linezolid, and (b) to assess the toxicity and clinical efficacy of linezolid in Japanese pediatric patients.Patients and methodsRoutine clinical data including serum linezolid total and unbound concentrations were collected from 15 pediatric patients (0–13 years old). Pharmacokinetics of linezolid was assumed to follow one-compartment with the first-order absorption model. The relationship between risk for thrombocytopenia and linezolid concentrations, and the variations in C-reactive protein (CRP) concentrations and body temperatures were evaluated as clinical efficacy assessment.ResultsBody weight (WT) and maturation of body function were significant covariates for pharmacokinetics of linezolid in pediatric patients. The elimination half-life of linezolid in a pediatric patient with a WT of 9.9 kg and age of 24 months (median of this study) was 3.0 h. Thrombocytopenia was detected in three patients (21.4%), and the minimum concentrations (C_min) in these patients were significantly higher than those in patients without thrombocytopenia (P < 0.05). The CRP concentrations decreased more than 50% in all pediatric patients after the treatment with linezolid, however body temperatures at the end of treatment were higher than 37.5 °C in 6 patients (42.9%).ConclusionsAlthough dose adjustment based on body size was performed for pediatric patients, thrombocytopenia was detected in 21.4% of pediatric patients, and higher C_min was associated with the risk of thrombocytopenia. These results encourage the implementation of individual dose adjustment based on linezolid serum concentrations for safe and appropriate treatment with linezolid.     

Relationship between cytopenia and gestational age in infants and neonates treated with linezolid therapy

BackgroundLinezolid has been the common antimicrobial treatment for Gram-positive infection even in neonates and infants. Major adverse events associated with linezolid treatment is cytopenia. However, there were few reports about the relationship between cytopenia and gestational age. Primary objective of this study was to compare the relationship between cytopenia in infants and neonates treated with linezolid therapy and gestational age.MethodsIn total, 44 patients were divided into two groups depend on their gestational age [<180 days; low gestational age group (20 patients); >180 days group; high gestational age group (24 patients)]. All patients treated with linezolid from April 2014 to March 2018 at NICU or GCU of Aichi Medical University Hospital. Investigation items were as follows; sex, age, weight, duration of treatment, Apgar score, laboratory data, rate of patients with blood transfusion, concomitant medications, hematologic abnormalities during linezolid treatment.ResultsThe incidence of overall cytopenia in low gestational age group was significantly higher than high gestational age group (65.0 % vs. 25.0 %; p < 0.05). Of note, the incidence of thrombocytopenia in low gestational age group showed significantly higher than high gestational age group (45.0% vs. 8.3%, p < 0.05). Then, the proportion of patients occurred thrombocytopenia who received linezolid 10 mg/kg every 8 h were higher than 10 mg/kg every 12 h in both groups.ConclusionIn cases linezolid is administered three times a day should be more carefully of thrombocytopenia in patients with gestational days less than 180 days.     

Efficacy and safety of linezolid for Gram-positive orthopedic infections: a prospective case series

Linezolid is an attractive alternative for orthopedic infections because of oral bioavailability and activity against methicillin-resistant staphylococci and vancomycin-resistant enterococci. To determine efficacy and safety, we prospectively monitored 51 consecutive adults who were not vancomycin candidates and who received linezolid for 53 Gram-positive orthopedic infections, usually chronic osteomyelitis (n = 25) or prosthetic joint infection (n = 23). Pathogens were usually Staphylococcus aureus (n = 27) or coagulase-negative staphylococci (n = 19); 38 were methicillin resistant. After remission, 17 infections required long-term suppression, usually because of retained hardware. Clinical and microbiologic failure occurred in only one patient. The most common adverse events were thrombocytopenia (n = 5) and anemia (n = 5), necessitating treatment discontinuation in 3 patients. One patient developed reversible optic and irreversible peripheral neuropathy after 24 months of linezolid. Linezolid, with surgery, may be a reasonable alternative for Gram-positive orthopedic infections. We recommend weekly hematologic monitoring, and, if therapy lasts >2 months, periodic ophthalmologic monitoring.     

利奈唑胺治疗14例神经外科术后耐甲氧西林葡萄球菌颅内感染临床分析

目的 初步评价利奈唑胺治疗神经外科术后患者耐甲氧西林葡萄球菌(MRS)颅内感染的临床疗效及安全性.方法 回顾性总结2009年3月至2011年11月本院神经重症监护病房(NICU)及亚低温治疗中心使用利奈唑胺治疗14例MRS颅内感染患者的资料.于治疗前及治疗7d、14d取血及脑脊液(CSF)培养,进行实验室、病原学和细菌学检查,评估利奈唑胺的临床疗效及不良反应.结果 给予MRS颅内感染患者静脉滴注利奈唑胺治疗14 d后,患者临床症状和CSF化验指标显著好转;CSF葡萄糖(mmol/L)由1.00(0.65)升至3.15(1.60),CSF蛋白定量(mg/L)由2238.50(2072.50)降至606.50(217.30),CSF白细胞数(×106/L)由920.00(1587.50)降至30.00(40.00),CSF中性粒细胞比例＞0.20者由14例减少至1例;血清中降钙素原(PCT)水平(μg/L)明显降低并恢复正常[由0.65(1.16)降至0.08(0.09),均P＜0.01].临床总有效率为85.7％(12/14),CSF细菌清除率达100％.给予利奈唑胺期间,患者未发生明显不良反应.结论 利奈唑胺能够有效控制MRS颅内感染和缓解炎症反应,疗效明确,具有良好的安全性.     

莫西沙星治疗儿童重症肺炎支原体肺炎的安全性和有效性分析

目的:评价儿童应用莫西沙星治疗重症肺炎支原体肺炎的安全性与有效性。方法:回顾性分析2017年1月至2020年4月,北京儿童医院重症医学科应用莫西沙星治疗重症肺炎支原体肺炎的患儿。收集临床资料,判定临床疗效,分析用药安全性,总结肺炎支原体对大环内酯类抗生素耐药基因突变情况。结果:39例重症肺炎支原体肺炎患儿应用莫西沙星治...     

The first case of teeth discoloration induced by linezolid in children in China Mainland

Linezolid is an oxazolidinone antimicrobial agent often used to treat multidrug-resistant Gram-positive bacterial infections. The common adverse reactions of linezolid are diarrhea, nausea, headache and bone marrow suppression, and so on. Here, we report the first case of teeth discoloration induced by linezolid linked with extrinsic discoloration in China Mainland. This case report highlights a rare adverse reactions of a commonly used antibiotic.     

Clinical experience with linezolid in infants and children

The worldwide spread of multidrug-resistant organisms has required the development of new antimicrobials. Linezolid, the first oxazolidinone, has a broad spectrum of activity against Gram-positive bacteria, including resistant strains. Although approved by the Food and Drug Administration in 2002, the clinical experience with linezolid in the paediatric population is still limited, also given the fact that in most European countries the paediatric use of linezolid is off-label. In this paper we summarize the actual evidence on both licensed and off-label clinical uses of linezolid in children, including efficacy, safety and tolerability issues. Taking into account the potential bias in comparing heterogeneous clinical trials and reports, the available literature data suggest that linezolid is a safe and effective agent for the treatment of serious Gram-positive bacterial infections in neonates and children. At present, linezolid is reserved for those children who are intolerant to or fail conventional agents. A linezolid-containing regimen can be a valuable option for treating multidrug-resistant and extensively drug-resistant tuberculosis in children as well as disseminated non-tuberculous mycobacterial infections. Given the rare occurrence of serious side effects, careful monitoring of haematological parameters, possible drug interactions and neurological manifestations is recommended in linezolid-treated children, especially in case of prolonged treatments. Appropriate linezolid dosage and hospital infection control measures are essential to avoid the spread of linezolid resistance. Further studies are needed to establish novel paediatric indications for linezolid use and to assess the tolerability of long-term treatments.     

Comparative study on safety of linezolid and vancomycin in the treatment of infants and neonates for Gram-positive bacterial infections

Background

Vancomycin has been the common antimicrobial treatment for Gram-positive infection even in neonates and infants, while it is difficult to adjust blood concentration. Linezolid is also effective for Gram-positive infection, and is not necessary to monitor drug blood concentration. Primary objective of this study was to compare the safety of linezolid and vancomycin in infants and neonates for resistant Gram-positive infections.

脑脊液与血清利奈唑胺浓度监测指导颅内感染临床治疗的价值

目的监测神经外科手术后颅内感染患者应用利奈唑胺抗感染治疗时脑脊液利奈唑胺药物浓度及血脑屏障通透率,指导利奈唑胺临床应用。 方法选取2019年6月至2019年11月入住青岛大学附属医院神经外科监护室的颅脑术后感染患者6例,静脉应用利奈唑胺抗感染治疗。连续监测患者脑脊液及血液利奈唑胺浓度、脑脊液常规、脑脊液生化及一般生命体征,分析利奈唑胺血脑屏障通透率。 结果利奈唑胺给药前0.5 h的血清和脑脊液药物谷浓度分别为（4.65±2.72）μg/ml和（3.78±1.53）μg/ml。在开始用药后2 h,血清中利奈唑胺的最大平均浓度为（12.53±3.79）μg/ml,而脑脊液中最大平均浓度为（5.55±2.00）μg/ml。脑脊液利奈唑胺曲线下面积/血清曲线下面积约为45%。所有患者应用利奈唑胺抗感染治疗后,颅内感染均得到治愈。 结论利奈唑胺具有满意的血脑屏障通透率,临床治疗效果良好。静脉应用利奈唑胺脑脊液浓度个体间差异大,推荐临床监测脑脊液浓度指导应用。     

利奈唑胺治疗广泛耐药结核病的临床疗效观察

目的观察利奈唑胺（Lzd）治疗广泛耐药结核病（XDR-TB）的临床疗效和安全性。方法2009年4～8月起采用含Lzd为主的化疗方案治疗8例XDR—TB患者。根据患者用药史及药敏试验结果采用个体化化疗方案,Lzd用法：治疗开始时应用600mg,静脉滴注,2次／d,应用时间为1—6周;之后减为600mg,静脉滴注,1次／d。结果Lzd应用疗程最长为11个月,最短为2个月,平均约6个月15d。3例发热患者体温均于用药第2天恢复正常,8例患者咳嗽、咳痰均有明显改善,胸闷、气促等症状也有改善。治疗6个月时,空洞闭合6例,2例空洞未闭合。所有患者痰抗酸染色涂片均阴转,转阴性时间为7—210d,平均67d。所有患者痰培养均阴转,转阴性时间为7—210d,平均73d。3例患者在治疗2～4周时出现恶心、呕吐等胃肠道反应,减量后症状消失。末梢神经炎2例,视力下降2例,均在治疗6个月时出现,停药后改善。3例出现血液系统不良反应。1例表现为白细胞减少,1例中度贫血,1例在治疗2周时出现重度贫血停用Lzd,并给予输血2周后恢复正常,后将Lzd改为600mg,1次／d,未再出现贫血。结论Lzd治疗XDR—TB可明显改善患者的临床症状,促进病灶吸收和空洞闭合,加速痰菌阴转,提高XDR—TB患者的生活质量,不良反应较轻且能耐受。     

In vitro activity between linezolid and other antimicrobial agents against Mycobacterium abscessus complex

Linezolid (LZD) serves as an effective option in the treatment of Mycobacterium abscessus complex (MABC) infection. Unfortunately, the combined activities of LZD with other antimicrobial agents against MABC have not been evaluated systemically. In this study, we randomly selected 32 Mycobacterium abscessus and 32 Mycobacterium massiliense isolates for the determination of in vitro synergistic effect between LZD and other antimicrobial agents, including amikacin (AMK), moxifloxacin (MOX), cefoxitin (CFX) and tigecycline (TGC). Out of 64 MABC isolates tested, only one (1.6%, 1/64) and two (3.2%, 2/64) exhibited resistance to AMK and LZD, respectively. Statistical analysis revealed that the percentage of TGC-resistant isolates was significantly lower among M. massiliense (9.4%, 3/32) than that among M. abscessus (25.0%, 8/32, P < 0.001). In addition, LZD and AMK showed synergy for 29 MABC isolates (45.3%), whereas no antagonism was noted for this combination. The second mostly frequent synergistic effect was found in LZD plus TGC combination, and 26.6% (17/64) of the strains tested exhibited synergy. In contrast, LZD-CFX and LZD-MOX combinations appeared antagonistic for half of the isolates (48.4%, 31/64 for CFX and 51.6%, 33/64), and almost no synergistic effect was reported in any of the strains for these two combinations. In conclusion, our data reveal that LZD and AMK show the most potent activity against MABC. The frequent synergism is observed in LZD-AMK and LZD-TGC combinations, while LZD rarely exhibits in vitro synergy with MOX and CFX when tested against MABC.     

Safety and efficacy of ketorolac in children after cardiac surgery

Objective  To evaluate the nephrotoxic and opioid-sparing effects of ketorolac in children after cardiac surgery. Design  A retrospective cohort study. Setting  A Cardiac Critical Care Unit in a university-affiliated children’s hospital. Subjects  Children less than 18 years of age who underwent low-risk cardiac surgery from July 2002 to December 2005. Results  Among 248 children studied, 108 received ketorolac and 140 did not. The ketorolac group was older, included a larger proportion of atrial septum defect repairs and a smaller proportion of ventricular septum defect repairs compared to the control group. The median change in serum creatinine did not differ between the ketorolac group and the control group (% change [IQR]); 12% [1–25] increase versus 12% [−3 to 31] increase, P = 0.86. On postoperative day 0 or 1, the ketorolac group received less opioids than control group. There was no difference in duration of mechanical ventilation or in length of stay between groups. Conclusion  Ketorolac started in the first 12 h after a low-risk cardiac surgery in children is not associated with a measurable difference in renal function. The data suggest that ketorolac may be effective in reducing the exposure to opioids. Further studies are required to define subsets of children after cardiac surgery who could safely benefit from ketorolac therapy to reduce pain.     

Evaluation of the relationship between linezolid exposure and hyponatremia

IntroductionAims of this study were (a) to assess the development ratio of hyponatremia during treatment with linezolid and (b) to evaluate the relationship between the risk of hyponatremia and linezolid exposure and patient background.MethodClinical data including linezolid serum concentrations and serum sodium values were collected at Toyama University Hospital and Kyorin University Hospital. Data from 89 patients were used for the analysis, and a nadir serum sodium level ≤130 mmol/L during the treatment with linezolid was defined as hyponatremia. Mann-Whitney's U test was used to evaluate the effects of the area under the time-concentration curve (AUC) of linezolid at the nadir sodium level, clinical characteristics (e.g. laboratory data), and baseline serum sodium levels on the development of hyponatremia.ResultsThe hyponatremia was occurred in 21 of 89 patients (23.6%). Data are compared for baseline and nadir serum sodium levels of patients with and without hyponatremia. In both groups, nadir serum sodium levels were significantly different from those of the baseline values (P < 0.05). The values of AUC_0-12, accumulated AUC, baseline serum sodium levels and age were significantly different between patients with and without hyponatremia (P < 0.05).ConclusionsLinezolid exposure, age, and baseline sodium levels were detected as the risk factors for linezolid-related hyponatremia. Our findings suggest that regular monitoring of serum sodium levels is desirable during treatment with linezolid, especially for the elderly and patients with low serum sodium levels before the start of linezolid administration.     

Safety and efficacy of fentanyl administered by patient controlled analgesia in children with cancer pain

Background Pain is the most common discomfort experienced by children with cancer and occurs in almost 89% of patients in an advanced stage of the disease. It is most often not adequately treated because of inexperience and unfounded fears of analgesic treatment. In adults, patient controlled analgesia (PCA) is widely administered, while in children with moderate to severe cancer pain its use is still under evaluation for safety and efficacy. Goals of work To evaluate the efficacy and safety of fentanyl administered by PCA in children with cancer pain. Materials and methods Eighteen children (range 6 to 15 years) with moderate to severe pain were enrolled and treated with fentanyl by PCA plus background infusion (BI) (BI of 1 μg/kg/h with booster doses of 1 μg/kg by intravenous route). To evaluate efficacy and safety of the analgesic treatment, different subjective and objective parameters were monitored at 4-h intervals. In addition, patients’ satisfaction was assessed by a questionnaire at the end of the treatment. Main results All children experienced a good degree of analgesia and did not require any other analgesic drug during the treatment. Both subjective and objective parameters improved after starting pain-relieving treatment and no major side effects occurred. The questionnaire administered to the children showed a high grade of satisfaction. Conclusions PCA plus BI with fentanyl administered by intravenous route is a safe and efficacious method for analgesia in children with moderate to severe cancer pain. Our policy of fentanyl-treatment did not show any major side effects.     

Evaluation of the safety and efficacy of liposomal amphotericin B (L-AMB) in children

A multicenter, uncontrolled clinical study has been conducted to evaluate the safety, efficacy, and pharmacokinetics of liposomal amphotericin B (L-AMB) in children. In this article, the safety and efficacy of L-AMB are discussed. Subjects were diagnosed with invasive fungal infection (definitely diagnosed cases), possible fungal infection (clinically diagnosed cases), and febrile neutropenia with suspected fungal infection (febrile neutropenia cases). Of the 39 subjects treated with L-AMB, 18 received a definite (11) or clinical (7) diagnosis of invasive fungal infection. In these subjects, excluding one unevaluable subject, L-AMB was effective in nine out of 17 subjects(52.9%). Of 12 febrile neutropenia cases, improvement in clinical symptoms, etc., was observed for six but these were excluded from the efficacy analysis because they concomitantly used medications that may have affected efficacy. The causative fungus was identified in four out of 39 subjects and confirmed to be eliminated by treatment with L-AMB in one subject. Adverse events possibly related to L-AMB (adverse drug reactions) were reported in 36 out of 39 subjects (92.3%). The most commonad verse drug reaction was decreased potassium in 20 out of 39 subjects (51.3%), but all these subjects recovered with appropriate treatment, for example potassium supplementation.In a Japanese Phase II clinical study of adult patients, the incidence of adverse drug reactions was 95.3%(82/86 subjects) and the efficacy was 63.6% (42/66). Taken together, these data indicate that the safety and efficacy of L-AMB are almost the same in pediatric and adult patients.     

咔哒唑胺与利奈唑胺对艰难梭菌的敏感性实验

目的 比较咔哒唑胺与利奈唑胺对不同基因和毒素型别的艰难梭菌的抑菌效果,以及咔哒唑胺对艰难梭菌芽孢形成的影响。方法 采用咔哒唑胺与利奈唑胺对10株不同基因型别的艰难梭菌、1株产气荚膜梭菌和1株脆弱拟杆菌进行药物敏感性实验,获得各菌株测试药物对应的最低抑菌浓度（MIC）值。选取其中1株艰难梭菌ATCC BAA-1803,核糖体027型高毒株,试验咔哒唑胺对菌株芽孢形成的影响,从而对药物进行评价。结果 艰难梭菌咔哒唑胺MIC为0.25 g/ml（0.03~0.25 g/ml）,利奈唑胺MIC为4.0 g/ml（0.5~16.0 g/ml）,艰难梭菌咔哒唑胺MIC值低于利奈唑胺16倍。2种抗生素对不同基因型别与毒素型别的艰难梭菌均具有良好抑菌效果,同时对产气荚膜梭菌也具有抑菌效果。咔哒唑胺对脆弱拟杆菌不产生抑菌效果,利奈唑胺对其有抑菌效果。咔哒唑胺能抑制艰难梭菌芽孢形成。结论 临床常见的不同基因型和毒素型别的艰难梭菌对咔哒唑胺敏感,咔哒唑胺可用于治疗艰难梭菌感染。     

Linezolid-resistant Staphylococcus aureus isolated from 2006 through 2008 at six hospitals in Japan

Limited use of linezolid for treating methicillin-resistant Staphylococcus aureus (MRSA) infection was approved in Japan in 2006. We report here the status of linezolid-resistant MRSAs in Japan. Eleven linezolid-resistant clinical isolates from 11 patients at six hospitals were collected from 2006 through 2008. The minimal inhibitory concentration (MIC) of linezolid in these strains varied from 8 to 64 μg/ml. All strains had at least one G2576T mutation in the chromosomal gene(s) encoding domain V of the 23S ribosomal RNA (rRNA). Chromosomal DNA encoding five copies of the domain V region was analyzed by polymerase chain reaction (PCR). Strains with the linezolid MICs of 64, 32, 16, and 8 μg/ml had the G2576T mutation(s) in four, three (or four), two, and one copy of the 23S rRNA genes, respectively. These results suggest that the level of linezolid resistance seems to be roughly correlated with the number of mutations in the genes encoding 23S rRNA. DNA samples from all 11 strains were subjected to pulsed-field gel electrophoresis and were classified into seven independent clones having >92% identity. Among the 11 patients, five had been treated with linezolid and the remainder, in two hospitals, had no history of prior linezolid use. The results suggested possible nosocomial infections by linezolid-resistant MRSA.     

Disseminated Nocardia farcinica infection in a patient with myasthenia gravis successfully treated by linezolid: a case report and literature review

Nocardiosis is increasingly being diagnosed because of a growing population of immunocompromised hosts and improvements in the detection of Nocardia species in clinical laboratories. Historically, sulphonamides have been the first-line therapy for the treatment of nocardiosis, but sulphonamides tend to have a high rate of drug allergy in clinical settings. In this report, we described a disseminated Nocardia farcinica infection that occurred in a patient with myasthenia gravis who suffered from multiple drug allergies and was successfully treated using linezolid. We undertook a review of the literature of previously reported cases of nocardiosis treated with linezolid. To date, only 15 cases of nocardiosis treated with linezolid have been published. All cases exhibited long-term tolerance of linezolid, and 14 of 15 cases showed either an improvement in or complete clearance of the infection. According to the literature review, linezolid is an attractive alternative to trimethoprim-sulfamethoxazole for the treatment of disseminated nocardiosis, despite limited clinical evidence to support this claim.     

利奈唑胺对革兰阳性球菌的体外抗菌活性研究

目的检测利奈唑胺对临床分离的金黄色葡萄球菌、表皮葡萄球菌、溶血葡萄球菌、粪肠球菌、屎肠球菌等革兰阳性球菌的体外抗菌活性,为临床合理使用抗生素提供依据。方法采用VITEK-32全自动微生物分析仪和ATB自动微生物分析仪鉴定和药敏系统对临床分离的常见革兰阳性球菌267株进行鉴定和药敏试验．根据其药敏结果比较8种抗菌药物对葡萄球菌、肠球菌的抗菌活性。结果在临床分离的267株菌中金黄色葡萄球闺111株,MRSA74株（占66．7％）,凝同酶阴性葡萄球菌96株（表皮葡萄球菌57株、溶血葡萄球菌39株）,MRCNS有80株（占86．0％）,粪肠球菌45株、屎肠球菌13株。利奈唑胺对207株葡萄球菌、58株肠球菌体外抗菌活性分别为100％,93．1％,与万古霉素相当,明显高于其他常用的抗生素（如红霉素、头孢唑林、环丙沙星等）。其对金黄色葡萄球菌、凝固酶阴性葡萄球菌、肠球菌的MIC50和MIC90分别为1．1mg／L;1.1mg／L：2.4mg／L。结论耐甲氧西林葡萄球菌发生率高,多重耐药严重,利奈唑胺对葡萄球菌的抗菌活性与万古霉素相当．对肠球菌也有较强的抗菌活性。葡萄球菌、肠球菌对左氧氟沙星、四环素、红霉素均产生了不同程度的耐药性。