达托霉素
2024年达托霉素市场发展现状
达托霉素市场发展现状引言达托霉素是一种广谱的抗生素，常用于治疗多种细菌引起的感染，如呼吸道感染、皮肤和软组织感染等。
它属于大环内酯类药物，具有良好的抗菌活性和渗透性，在临床上应用广泛。
本文旨在探讨达托霉素市场发展现状，并对未来的市场趋势进行分析。
市场规模与增长趋势近年来，达托霉素市场呈现出稳步增长的态势。
根据市场研究数据显示，2019年全球达托霉素市场规模达到X亿美元，预计到2025年将增长至Y亿美元。
市场规模的快速增长主要受以下几个因素的影响：1.高效抗菌谱：达托霉素对多种细菌具有较强的抗菌活性，包括耐药菌株。
如MRSA（金黄色葡萄球菌耐甲氧西林菌株）等细菌引起的感染，达托霉素表现出较高的疗效，这为其市场需求提供了坚实基础。
2.药物疗效的改进：随着科学技术的进步和药物研发的不断推进，达托霉素的疗效逐渐得到了提高。
新的配方和剂型的引入，也为患者提供了更为便捷和有效的治疗选择。
3.全球老龄化人口增加：随着全球老龄化程度的加深，慢性疾病的发病率上升，导致感染性疾病的发生率也相应增加。
而达托霉素在老年人中的应用较为广泛，因此市场需求呈现出明显增长势头。
市场竞争格局目前，达托霉素市场的竞争格局较为激烈。
除了原研企业的产品，也出现了多个仿制药企业投放到市场。
主要的市场竞争因素包括价格、产品质量、市场渠道和品牌影响力等。
1.原研企业的优势：原研企业在药物研发和生产上具有较高的技术实力和经验，他们可以依靠自身的强大研发平台，维持与竞争对手的差异化竞争。
2.仿制药的崛起：仿制药在价格上具有明显优势，这使得一些患者和医疗机构倾向于选择仿制药。
一些仿制药企业通过降低成本，在市场竞争中占据一定的份额。
3.品牌影响力：在医药市场中，知名原研企业具有较高的品牌影响力，这使得一些患者和医生更加信任其产品的疗效和质量。
因此，品牌建设和品牌推广对于企业在市场竞争中具有重要作用。
市场发展机遇与挑战虽然达托霉素市场面临一些机遇，但也存在一些挑战需要应对。
注射用达托霉素Daptomycin-详细说明书与重点
注射用达托霉素Daptomycin英文名：Daptomycin for Injection汉语拼音：Zhu She Yong Da Tuo Mei Su【成份】本品主要成份为达托霉素。
【性状】本品为淡黄色至浅棕色的冻干粉或块状物。
【适应症】金黄色葡萄球菌(包括甲氧西林敏感和甲氧西林耐药)导致的伴发右侧感染性心内膜炎的血流感染（菌血症）。
如果确定或怀疑的病原体包括革兰阴性菌或厌氧菌，则临床上可采用联合抗菌治疗。
在患有由金黄色葡萄球菌引起的左侧感染性心内膜炎的患者中，尚未证实克必信的有效性。
在金黄色葡萄球菌血流感染的患者中进行的克必信临床试验，包含来自左侧感染性心内膜炎患者的资料；在这些患者中，疗效不佳（见临床研究）。
在人工瓣膜心内膜炎或脑膜炎患者中，尚未对克必信进行评价。
若患者患有持续性或复发性金黄色葡萄球菌感染，或临床疗效欠佳，应该重复进行血培养。
如果金黄色葡萄球菌的血培养为阳性，则应采用标准操作规程进行该菌株的MIC药敏试验，并且应进行诊断性评估，以排除罕见的感染病灶存在（见注意事项）。
本药不适用于治疗肺炎。
应获得适当的标本进行微生物学检查，以便分离和鉴定引起感染的病原体，并测定其对达托霉素的敏感性。
当等待试验结果时，可以采用经验性治疗。
根据微生物学检查结果，应对抗菌治疗进行调整。
为了延缓耐药性的发展，并维持本药和其它抗菌药的疗效，克必信应仅用来治疗被确定或强烈怀疑由敏感菌引起的感染。
在获得培养和药敏结果后，应考虑选择或调整抗菌治疗。
缺乏这些资料的情况下，当地的流行病学和敏感性趋势有助于经验性治疗的抗菌药物选择。
【规格】0.5g【用法用量】金黄色葡萄球菌(包括甲氧西林敏感和甲氧西林耐药)导致的伴发右侧感染性心内膜炎的血流感染（菌血症）：将6mg/kg本药溶解在0.9%氯化钠注射液中，以30分钟的时程滴注，每24小时1次，至少2-6周。
疗程应根据主管医生的实际诊断而定。
使用本药超过28天的安全数据很有限。
达托霉素的作用与功效
达托霉素的作用与功效达托霉素是一种广谱抗生素，常用于治疗呼吸道和泌尿道感染等疾病。
它的作用机制是通过抑制细菌蛋白质合成来杀死细菌或抑制它们的生长。
达托霉素被广泛用于临床治疗，并被认为是安全有效的药物之一。
以下是达托霉素的作用和功效的详细介绍。
1. 抗菌谱广泛：达托霉素对多种细菌具有优良的抗菌活性。
它对革兰氏阳性菌和阴性菌都有杀灭作用，包括耐药菌株。
因此，达托霉素被广泛应用于治疗和预防细菌感染。
2. 高渗透性：达托霉素在体内的分布均匀，可以迅速进入各种组织和体液。
它可以通过细胞膜进入细菌细胞，并在细菌内部积累。
达托霉素对细菌的渗透性能够使其在细菌感染时迅速达到治疗浓度，发挥有效的杀菌作用。
3. 持久的杀菌活性：达托霉素的半衰期较长，使其具有持续的治疗效果。
通过一天一次的给药，可以保持达到有效治疗浓度达12-24小时，从而实现对细菌的持续杀菌作用。
4. 广泛用于呼吸道感染：达托霉素在治疗呼吸道感染方面表现出色。
它可以用于治疗细菌性鼻窦炎、扁桃体炎、中耳炎、支气管炎和肺炎等上呼吸道和下呼吸道感染。
达托霉素能迅速进入呼吸道组织并在肺组织中积累，从而实现有效的杀菌作用。
5. 治疗泌尿道感染：达托霉素也被广泛应用于治疗泌尿道感染。
它可以用于治疗尿路感染、肾盂肾炎和前列腺炎等疾病。
达托霉素进入泌尿道组织后能够在尿液中高浓度存在，从而对泌尿道感染的细菌起到杀菌作用。
6. 高效克服耐药性：达托霉素对耐药细菌株表现出高度的活性。
它不仅对传统的对青霉素、头孢菌素和万古霉素产生耐药性的细菌表现出杀菌作用，而且对耐甲氧西林金黄色葡萄球菌（MRSA）和产大肠杆菌（ESBL）的细菌产生的耐药性也表现出优良的杀菌效果。
7. 老年和儿童患者的良好耐受性：与其他一些广谱抗生素相比，达托霉素在老年和儿童患者中的耐受性良好。
它对胃肠道的刺激作用较轻，不会引起严重的胃肠道反应，这对老年和儿童患者来说非常重要。
总之，达托霉素是一种广谱抗生素，具有广谱的抗菌活性，可用于呼吸道和泌尿道感染的治疗。
达托霉素
达托霉素
达托霉素是由Lilly（礼来）公司最初研究,在2012年湖北威德利化学科技有限公司通过高新技术仿制环脂肽类抗生素--达托霉素（Daptomycin）,达托霉素是继万古霉素之后第二代糖肽类抗生素药，湖北威德利化学科技有限公司通过链霉菌发酵液中提取得到，具有不同的化学结构，而且其作用与其他抗生素不同，是万古霉素有效的替代者。
基本信息：
[产品名称]：达托霉素
[中文同义名]：达妥霉素
[英文名]：Daptomycin
[CAS No]：103060-53-3
[分子量]：1620.67
[分子式]：C72H101N17O26
[质量标准]：企业出口标准
[包装规格]：100克/袋，1KG/铝听。
[质量标准]：含量≥93.0%
产品优势：我司研发达托霉素的外观是黄.色或者淡黄.色精细无定形粉末，在达托霉素HPLC 和达托霉素IR以及达托霉素UV均符合国外药典注册标准规定，达托霉素比旋度是+17°到+28°，达托霉素酸碱度PH呈偏酸性，在3到5之间，我司的达托霉素原料产品质量高于国外注册标准，如炽灼残渣国外标准规定是≤4%，而我司可以达到≤2%以下。
含量更是高于规定的93%以上，达到98%以上。
更详细的其他指标信息可以向我司销售经理索要详细质检报告。
储存建议：湖北威德利化学科技有限公司建议达托霉素于密闭容器储存，温度在-20℃到5℃之间，如需运输，请保持温度为2℃到8℃。
达托霉素临床综述
达托霉素临床试验综述1.临床试验与文献总结1.1 临床试验总结本申报品种为原料药，属注册分类3（其注射剂属化药注册分类6），根据我国相关法律法规可以免临床。
1.2 临床试验文献总结1.2.1 生物药剂学研究总结本品种的制剂为静脉注射剂，生物利用度为100。
尚未见生物等效性试验资料。
，2，3，41.2.2 临床药理学研究总结1人体药代动力学（PK）研究、药效学（PD）研究：达托霉素获FDA 批准按照4mg/kg 的剂量使用，可在体内表现出线性良好的药代动力学曲线，血药浓度-时间曲线严格遵循两室模型的一级消除动力学，最大血药浓度为57g/ml，曲线下面积AUC 为494g×h/ml，消除半衰期t 为8～9h，表观分布容积为0.09L/kg，血清蛋白结合率约92，抗生素后效应为3～6h。
该药主要通过肾脏消除，三分之二的药物以原药形式排泄，没有发现结构性和毒性代谢。
此外，达托霉素在体内不能透过血脑屏障。
健康志愿者日注射本品1～8mg/kg，药动学数据提示呈线性代谢，首次注射4、6 和8mg/kg 剂量后最大血药浓度分别为55、86 和116 g/mL，蛋白结合率为90～94，平均半衰期t1/2为7.74±0.63小时。
24 小时尿中原型药物排泄为59.7±10.2，注射4mg/kg 本品后的1 和2 小时，皮肤炎性疱液中的药物浓度分别是49.4 和14.5 g/mL。
达托霉素是从一株发酵的链霉菌属玫瑰色孢子中提取出来的具有独特环结构的脂肽类抗生素。
它由一个十碳烷侧链与一个环状β氨基酸肽链N-末端的色氨酸连接而成。
达托霉素具有在体外抗所有革兰阳性菌的作用。
这些菌包括耐药菌，如耐万古霉素的肠球菌（VRE）、耐甲氧西林的金葡菌（MRSA）、甲氧西林敏感金葡菌（MSSA）、糖肽类敏感的金葡菌（GISA）、凝固酶阴性的葡萄球菌（CNS）和耐青霉素的肺炎链球菌（PRSP），对于这些耐药菌可选择的抗生素很少。
达托霉素
Generic Name】Daptomycin Injection,Powder,Lyophilized,for Solution[FDA]【Brand Name】Cubicin【Active Ingredients】达托霉素【Description】CUBICIN contains daptomycin, a cyclic lipopeptide antibacterial agent derived from the fermentation of Streptomyces roseosporus. The chemical name isN-decanoyl-L-tryptophyl-D-asparaginyl-L-aspartyl-L-threonylglycyl-L-ornithyl-L-aspartyl-D-alanyl-L-aspartylglycyl-D-seryl-threo-3-methyl-L-glutamyl-3-anthrani loyl-L-alanine ε1-lactone. The chemical structure is:The empirical formula is C72H101N17O26; the molecular weight is 1620.67. CUBICIN issupplied as a sterile, preservative-free, pale yellow to light brown, lyophilized cake containing approximately 900 mg/g of daptomycin for intravenous (IV) use following reconstitution with 0.9% sodium chloride injection. The only inactive ingredient is sodium hydroxide, which is used in minimal quantities for pH adjustment. Freshly reconstituted solutions of CUBICIN range in color from pale yellow to light brown.【Clinical Pharmacology】PharmacokineticsThe mean (SD) pharmacokinetic parameters of daptomycin at steady-state following IV administration of 4 to 12 mg/kg q24h to healthy young adults are summarized in Table 1.Daptomycin pharmacokinetics were generally linear and time-independent at doses of 4 to 12 mg/kg q24h. Steady-state trough concentrations were achieved by the third daily dose. The mean (SD) steady-state trough concentrations attained following administration of 4, 6, 8, 10, and 12 mg/kg q24h were 5.9 (1.6), 6.7 (1.6), 10.3 (5.5), 12.9 (2.9), and 13.7 (5.2) µg/mL, respectively.Table 1. Mean (SD) CUBICIN Pharmacokinetic Parameters in HealthyVolunteers at Steady-StatePharmacokinetic Parameters*Dose†AUC0-24t1/2V ss CL T C max(mg/kg) (µg*h/mL)(h) (L/kg) (mL/h/kg) (µg/mL)4 (N=6) 494 (75) 8.1(1.0) 0.096(0.009)8.3 (1.3) 57.8 (3.0)6 (N=6) 632 (78) 7.9(1.0) 0.101(0.007)9.1 (1.5) 93.9 (6.0)8 (N=6) 858 (213) 8.3(2.2) 0.101(0.013)9.0 (3.0) 123.3(16.0)10 (N=9) 1039 (178) 7.9(0.6) 0.098(0.017)8.8 (2.2) 141.1(24.0)12 (N=9) 1277 (253) 7.7(1.1) 0.097(0.018)9.0 (2.8) 183.7(25.0)*AUC0-24, area under the concentration-time curve from 0 to 24 hours; t½, terminalelimination half-life; Vss , volume of distribution at steady-state; CLT, plasmaclearance; Cmax, maximum plasma concentration.†Doses of CUBICIN in excess of 6 mg/kg have not been approved.DistributionDaptomycin is reversibly bound to human plasma proteins, primarily to serum albumin, in a concentration-independent manner. The overall mean binding ranged from 90 to 93%.In clinical studies, mean serum protein binding in subjects with CLCR≥30 mL/min was comparable to that observed in healthy subjects with normal renalfunction. However, there was a trend toward decreasing serum protein binding amongsubjects with CLCR<30 mL/min (87.6%), including those receiving hemodialysis (85.9%) and continuous ambulatory peritoneal dialysis (CAPD) (83.5%). The protein binding of daptomycin in subjects with hepatic impairment (Child-Pugh B) was similar to that in healthy adult subjects.The volume of distribution at steady-state (Vss) of daptomycin in healthy adult subjects was approximately 0.10 L/kg and was independent of dose.MetabolismIn vitro studies with human hepatocytes indicate that daptomycin does not inhibit or induce the activities of the following human cytochrome P450 isoforms: 1A2, 2A6, 2C9, 2C19, 2D6, 2E1, and 3A4. In in vitro studies, daptomycin was not metabolized by human liver microsomes. It is unlikely that daptomycin will inhibit or induce the metabolism of drugs metabolized by the P450 system.In 5 healthy young adults after infusion of radiolabeled 14C-daptomycin, the plasma total radioactivity was similar to the concentration determined by microbiological assay. In a separate study, no metabolites were observed in plasma on Day 1 following administration of CUBICIN at 6 mg/kg to subjects. Inactive metaboliteshave been detected in urine, as determined by the difference in total radioactive concentrations and microbiologically active concentrations. Minor amounts of three oxidative metabolites and one unidentified compound were detected in urine. The site of metabolism has not been identified.ExcretionDaptomycin is excreted primarily by the kidney. In a mass balance study of 5 healthy subjects using radiolabeled daptomycin, approximately 78% of the administered dose was recovered from urine based on total radioactivity (approximately 52% of the dose based on microbiologically active concentrations) and 5.7% of the dose was recovered from feces (collected for up to 9 days) based on total radioactivity.Because renal excretion is the primary route of elimination, dosage adjustment is necessary in patients with severe renal insufficiency (CLCR<30 mL/min) (see DOSAGE AND ADMINISTRATION).Special PopulationsRenal InsufficiencyPopulation derived pharmacokinetic parameters were determined for infected patients (complicated skin and skin structure infections and S. aureus bacteremia) and noninfected subjects with varying degrees of renal function (Table 2). Plasmaclearance (CLT ), elimination half-life (t1/2), and volume of distribution (Vss) weresimilar in patients with complicated skin and skin structure infections compared with those with S. aureus bacteremia. Following the administration of CUBICIN 4 mg/kg q24h, the mean CLTwas 9%, 22%, and 46% lower among subjects and patients withmild (CLCR 50–80 mL/min), moderate (CLCR30–<50 mL/min), and severe (CLCR<30 mL/min)renal impairment, respectively, than in those with normal renal function (CLCR>80mL/min). The mean steady-state systemic exposure (AUC), t1/2, and Vssincreased withdecreasing renal function, although the mean AUC was not markedly different for patients with CLCR30–80 mL/min compared with those with normal renal function. Themean AUC for patients with CLCR<30 mL/min and for patients on hemodialysis (dosed post-dialysis) was approximately 2 and 3 times higher, respectively, than for patients with normal renal function. Following the administration of CUBICIN 4mg/kg q24h, the mean Cmax ranged from 60 to 70 µg/mL in patients with CLCR≥30 mL/min,while the mean Cmax for patients with CLCR<30 mL/min ranged from 41 to 58 µg/mL. Themean Cmaxranged from 80 to 114 µg/mL in patients with mild-to-moderate renal impairment and was similar to that of patients with normal renal function after the administration of CUBICIN 6 mg/kg q24h. In patients with renal insufficiency, both renal function and creatine phosphokinase (CPK) should be monitored more frequently. CUBICIN should be administered following the completion of hemodialysis on hemodialysis days (see DOSAGE AND ADMINISTRATION for recommendeddosage regimens).Table 2. Mean (SD) Daptomycin Population Pharmacokinetic Parameters Following Infusion of 4 mg/kg or 6 mg/kg to Infected Patients and Noninfected Subjects with Varying Degrees of Renal FunctionRenal Functiont1/2*V ss*CL T*AUC0-∞*AUC ss†C min,ss†(h) (L/kg) (mL/h/kg) (µg*h/mL)(µg*h/mL)(µg*h/mL)4 mg/kg 4 mg/kg 4 mg/kg 4 mg/kg 6 mg/kg 6 mg/kgNote: CL CR, creatinine clearance estimated using the Cockcroft-Gault equation with actual body weight; AUC0-∞, area under theconcentration-time curve extrapolated to infinity; AUC ss, area under the concentration-time curve calculated over the 24-hour dosing interval at steady-state; C min,ss, trough concentration at steady-state; NA, not applicable.Normal 9.39(4.74) 0.13(0.05)10.9 (4.0) 417 (155) 545 (296) 6.9 (3.5)(CL CR >80mL/min)N=165 N=165 N=165 N=165 N=62 N= 61Mild Renal Impairment 10.75(8.36)0.12(0.05)9.9 (4.0) 466 (177) 637 (215) 12.4 (5.6)(CL CR 50−80mL/min)N=64 N=64 N=64 N=64 N=29 N=29Moderate Renal Impairment 14.70(10.50)0.15(0.06)8.5 (3.4) 560 (258) 868 (349) 19.0 (9.0)(CL CR 30−<50mL/min)N=24 N=24 N=24 N=24 N=15 N=14Severe Renal Impairment 27.83(14.85)0.20(0.15)5.9 (3.9) 925 (467) 1050, 892 24.4, 21.4(CL CR <30mL/min)N=8 N=8 N=8 N=8 N=2 N=2Hemodialysis 29.81(6.13) 0.15(0.04)3.7 (1.9) 1244 (374) NA NAN=21 N=21 N=21 N=21*Parameters obtained following a single dose from patients with complicated skin and skin structure infections and healthy subjects.†Parameters obtained at steady-state from patients with S. aureus bacteremia. Hepatic InsufficiencyThe pharmacokinetics of daptomycin were evaluated in 10 subjects with moderatehepatic impairment (Child-Pugh Class B) and compared with healthy volunteers (N=9) matched for gender, age, and weight. The pharmacokinetics of daptomycin were not altered in subjects with moderate hepatic impairment. No dosage adjustment is warranted when administering CUBICIN to patients with mild-to-moderate hepatic impairment. The pharmacokinetics of daptomycin in patients with severe hepatic insufficiency have not been evaluated.GenderNo clinically significant gender-related differences in daptomycin pharmacokinetics have been observed. No dosage adjustment is warranted based on gender when administering CUBICIN.GeriatricThe pharmacokinetics of daptomycin were evaluated in 12 healthy elderly subjects (≥75 years of age) and 11 healthy young controls (18 to 30 years of age). Following administration of a single 4 mg/kg IV dose, the mean total clearance of daptomycinincreased approximately 58% in was reduced approximately 35% and the mean AUC0-∞elderly subjects compared with young healthy subjects. There were no differences . No dosage adjustment is warranted for elderly patients with normal renal in Cmaxfunction.ObesityThe pharmacokinetics of daptomycin were evaluated in 6 moderately obese (Body Mass Index [BMI] 25 to 39.9 kg/m2) and 6 extremely obese (BMI ≥40 kg/m2) subjects and controls matched for age, sex, and renal function. Following administration of a single 4 mg/kg IV dose based on total body weight, the plasma clearance of daptomycin normalized to total body weight was approximately 15% lower in moderately obese subjects and 23% lower in extremely obese subjects compared with nonobeseof daptomycin increased approximately 30% in moderately obese controls. The AUC0-∞and 31% in extremely obese subjects compared with nonobese controls. The differences were most likely due to differences in the renal clearance of daptomycin. No dosage adjustment of CUBICIN is warranted in obese subjects.PediatricThe pharmacokinetics of daptomycin in pediatric populations (<18 years of age) have not been established.Drug-Drug InteractionsDrug-drug interaction studies were performed with CUBICIN and other drugs that arelikely to be either coadministered or associated with overlapping toxicity. AztreonamIn a study in which 15 healthy adult subjects received a single dose of CUBICIN 6mg/kg IV, aztreonam 1 g IV, and both in combination, the Cmax and AUC0-∞of daptomycinwere not significantly altered by aztreonam; the Cmax and AUC0-∞of aztreonam alsowere not significantly altered by daptomycin. No dosage adjustment of either antibiotic is warranted when coadministered.TobramycinIn a study in which 6 healthy adult males received a single dose of CUBICIN 2 mg/kgIV, tobramycin 1 mg/kg IV, and both in combination, the mean Cmax and AUC0-∞ofdaptomycin increased 12.7% and 8.7%, respectively, when administered withtobramycin. The mean Cmax and AUC0-∞of tobramycin decreased 10.7% and 6.6%,respectively, when administered with CUBICIN. These differences were not statistically significant. The interaction between daptomycin and tobramycin with a clinical dose of CUBICIN is unknown. Caution is warranted when CUBICIN is coadministered with tobramycin.WarfarinIn 16 healthy subjects, concomitant administration of CUBICIN 6 mg/kg q24h for 5 days followed by a single oral dose of warfarin (25 mg) had no significant effect on the pharmacokinetics of either drug and did not significantly alter the INR (International Normalized Ratio) (see PRECAUTIONS, Drug Interactions).SimvastatinIn 20 healthy subjects on a stable daily dose of simvastatin 40 mg, administration of CUBICIN 4 mg/kg IV q24h for 14 days (N=10) was not associated with a higher incidence of adverse events than in subjects receiving placebo once daily (N=10) (see PRECAUTIONS, Drug Interactions).ProbenecidConcomitant administration of probenecid (500 mg 4 times daily) and a single doseof CUBICIN 4 mg/kg IV did not significantly alter the Cmax and AUC0-∞of daptomycin. Nodosage adjustment of CUBICIN is warranted when CUBICIN is coadministered with probenecid.MICROBIOLOGYDaptomycin is an antibacterial agent of a new class of antibiotics, the cyclic lipopeptides. Daptomycin is a natural product that has clinical utility in the treatment of infections caused by aerobic Gram-positive bacteria. The in vitro spectrum of activity of daptomycin encompasses most clinically relevantGram-positive pathogenic bacteria. Daptomycin retains potency againstantibiotic-resistant Gram-positive bacteria, including isolates resistant to methicillin, vancomycin, and linezolid.Daptomycin exhibits rapid, concentration-dependent bactericidal activity against Gram-positive organisms in vitro. This has been demonstrated both by time-kill curves and by MBC/MIC ratios (minimum bactericidal concentration/minimum inhibitory concentration) using broth dilution methodology. Daptomycin maintained bactericidal activity in vitro against stationary phase S. aureus in simulated endocardial vegetations. The clinical significance of this is not known.Mechanism of ActionThe mechanism of action of daptomycin is distinct from that of any other antibiotic. Daptomycin binds to bacterial membranes and causes a rapid depolarization of membrane potential. This loss of membrane potential causes inhibition of protein, DNA, and RNA synthesis, which results in bacterial cell death.Mechanism of ResistanceAt this time, no mechanism of resistance to daptomycin has beenidentified. Currently, there are no known transferable elements that confer resistance to daptomycin.Cross-ResistanceCross-resistance has not been observed with any other antibiotic class.Interactions with Other AntibioticsIn vitro studies have investigated daptomycin interactions with other antibiotics. Antagonism, as determined by kill curve studies, has not been observed. In vitro synergistic interactions of daptomycin with aminoglycosides, β-lactam antibiotics, and rifampin have been shown against some isolates of staphylococci (including some methicillin-resistant isolates) and enterococci (including some vancomycin-resistant isolates).Complicated Skin and Skin Structure Infection (cSSSI) StudiesThe emergence of daptomycin non-susceptible isolates occurred in 2 infected patients across the set of Phase 2 and pivotal Phase 3 clinical trials. In one case, a non-susceptible S. aureus was isolated from a patient in a Phase 2 study who received CUBICIN at less than the protocol-specified dose for the initial 5 days of therapy. In the second case, a non-susceptible Enterococcus faecalis was isolated from a patient with an infected chronic decubitus ulcer enrolled in a salvage trial.S. aureus Bacteremia/Endocarditis and Other Post-Approval StudiesIn subsequent clinical trials, non-susceptible isolates were recovered. S. aureus was isolated from a patient in a compassionate-use study and from 7 patients in the S. aureus bacteremia/endocarditis study (see PRECAUTIONS). An E. faecium was isolated from a patient in a VRE study.Daptomycin has been shown to be active against most isolates of the following microorganisms both in vitro and in clinical infections, as described in the INDICATIONS AND USAGE section.Aerobic and facultative Gram-positive microorganisms:Enterococcus faecalis (vancomycin-susceptible isolates only)Staphylococcus aureus (including methicillin-resistant isolates)Streptococcus agalactiaeStreptococcus dysgalactiae subsp. equisimilisStreptococcus pyogenesThe following in vitro data are available, but their clinical significance is unknown. Greater than 90% of the following microorganisms demonstrate an in vitro MIC less than or equal to the susceptible breakpoint for daptomycin versus the bacterial genus. The efficacy of daptomycin in treating clinical infections due to these microorganisms has not been established in adequate and well-controlled clinical trials.Aerobic and facultative Gram-positive microorganisms:Corynebacterium jeikeiumEnterococcus faecalis (vancomycin-resistant isolates)Enterococcus faecium (including vancomycin-resistant isolates)Staphylococcus epidermidis (including methicillin-resistant isolates) Staphylococcus haemolyticusSusceptibility Testing MethodsSusceptibility testing by dilution methods requires the use of daptomycin susceptibility powder. The testing of daptomycin also requires the presence of physiological levels of free calcium ions (50 mg/L of calcium, using calcium chloride) in Mueller-Hinton broth medium.Dilution TechniqueQuantitative methods are used to determine antimicrobial MICs. These MICs provide estimates of the susceptibility of bacteria to antimicrobial compounds. The MICs should be determined using a standardized procedure1, 2 based on a broth dilution method or equivalent using standardized inoculum and concentrations of daptomycin. The use of the agar dilution method is not recommended with daptomycin2. The MICs should be interpreted according to the criteria in Table 3.A report of “Susceptible” indicates that the pathogen is likely to be inhibited if the antimicrobial compound in the blood reaches the concentrations usually achievable.Table 3. Susceptibility Interpretive Criteria forDaptomycinPathogenBroth Dilution MIC* (µg/mL)S I RNote: S, Susceptible; I, Intermediate; R, Resistant.Staphylococcus aureus≤1(†) (†)(methicillin-susceptible andmethicillin-resistant)Streptococcus pyogenes, Streptococcusagalactiae,≤1(†) (†)and Streptococcus dysgalactiaesubsp. equisimilisEnterococcus faecalis≤4(†) (†)(vancomycin-susceptible only)*The MIC interpretive criteria for S. aureus and E. faecalis are applicable only to tests performed by broth dilution using Mueller-Hinton broth adjusted to a calcium content of 50 mg/L; the MIC interpretive criteria for Streptococcus spp. other than S. pneumoniae are applicable only to tests performed by broth dilution using Mueller-Hinton broth adjusted to a calcium content of 50 mg/L, supplemented with 2 to 5% lysed horse blood, inoculated with a direct colony suspension and incubated in ambient air at 35ºC for 20 to 24 hours.†The current absence of data on daptomycin-resistant isolates precludes defining any categories other than “Susceptible.” Isolates yielding test results suggestive of a “Non-Susceptible” category should be retested, and if the result is confirmed, the isolate should be submitted to a reference laboratory for further testing.Diffusion TechniqueQuantitative methods that require measurement of zone diameters have not been shown to provide reproducible estimates of the susceptibility of bacteria to daptomycin. The use of the disk diffusion method is not recommended with daptomycin2, 3.Quality ControlStandardized susceptibility test procedures require the use of quality control microorganisms to control the technical aspects of the procedures. Standard daptomycin powder should provide the range of values noted in Table 4. Quality control microorganisms are specific strains of organisms with intrinsic biological properties relating to resistance mechanisms and their genetic expression within bacteria; the specific strains used for microbiological quality control are not clinically significant.Table 4. Acceptable Quality ControlRanges for Daptomycin to Be Used inValidation of Susceptibility TestResultsQuality Control StrainBroth DilutionMIC Range*(μg/mL) Enterococcusfaecalis ATCC292121−4Staphylococcusaureus ATCC 292130.25−1Streptococcuspneumoniae ATCC49619†0.06−0.5*The quality control ranges for S. aureus and E. faecalis are applicable only to tests performed by broth dilution using Mueller-Hinton broth adjusted to a calcium content of 50 mg/L; the quality control ranges for S. pneumoniae are applicable only to tests performed by broth dilution using Mueller-Hinton broth adjusted to a calcium content of 50 mg/L, supplemented with 2 to 5% lysed horse blood, inoculated witha direct colony suspension and incubated in ambient air at 35ºC for 20 to 24 hours.†This organism may be used for validation of susceptibility test results when testing Streptococcus spp. other than S. pneumoniae.【Animal Pharmacology】In animals, daptomycin administration has been associated with effects on skeletal muscle with no changes in cardiac or smooth muscle. Skeletal muscle effects were characterized by degenerative/regenerative changes and variable elevations in CPK. No fibrosis or rhabdomyolysis was evident in repeat-dose studies up to the highest doses tested in rats (150 mg/kg/day) and dogs (100 mg/kg/day). The degree of skeletal myopathy showed no increase when treatment was extended from 1 month to up to 6 months. Severity was dose-dependent. All muscle effects, including microscopic changes, were fully reversible within 30 days following cessation of dosing.In adult animals, effects on peripheral nerve (characterized by axonal degeneration and frequently accompanied by significant losses of patellar reflex, gag reflex, and pain perception) were observed at doses higher than those associated with skeletal myopathy. Deficits in the dogs’ patellar reflexes were seen within 2 weeks of the start of treatment at 40 mg/kg (9 times the human Cat the 6 mg/kgmaxq24h dose), with some clinical improvement noted within 2 weeks of the cessation of dosing. However, at 75 mg/kg/day for 1 month, 7/8 dogs failed to regain full patellar reflex responses within the duration of a 3-month recovery period. In a separate study in dogs receiving doses of 75 and 100 mg/kg/day for 2 weeks, minimal residual histological changes were noted at 6 months after cessation of dosing. However, recovery of peripheral nerve function was evident.Tissue distribution studies in rats have shown that daptomycin is retained in the kidney but appears to only minimally penetrate across the blood-brain barrier following single and multiple doses.【Clinical Studies】Complicated Skin and Skin Structure InfectionsAdult patients with clinically documented cSSSI (Table 10) were enrolled in two randomized, multinational, multicenter, investigator-blinded studies comparing CUBICIN (4 mg/kg IV q24h) with either vancomycin (1 g IV q12h) or ananti-staphylococcal semi-synthetic penicillin (i.e., nafcillin, oxacillin, cloxacillin, or flucloxacillin; 4 to 12 g IV per day). Patients known to have) bacteremia at baseline were excluded. Patients with creatinine clearance (CLCR between 30 and 70 mL/min were to receive a lower dose of CUBICIN as specified in the protocol; however, the majority of patients in this subpopulation did not have the dose of CUBICIN adjusted. Patients could switch to oral therapy after a minimum of 4 days of IV treatment if clinical improvement was demonstrated.One study was conducted primarily in the United States and South Africa (study 9801), and the second (study 9901) was conducted at non-US sites only. Both studies were similar in design but differed in patient characteristics, including history of diabetes and peripheral vascular disease. There were a total of 534 patients treated with CUBICIN and 558 treated with comparator in the two studies. The majority (89.7%) of patients received IV medication exclusively.The efficacy endpoints in both studies were the clinical success rates in the intent-to-treat (ITT) population and in the clinically evaluable (CE) population. In study 9801, clinical success rates in the ITT population were 62.5% (165/264) in patients treated with CUBICIN and 60.9% (162/266) in patients treated with comparator drugs. Clinical success rates in the CE population were 76.0% (158/208) in patients treated with CUBICIN and 76.7% (158/206) in patients treated with comparator drugs. In study 9901, clinical success rates in the ITT population were 80.4% (217/270) in patients treated with CUBICIN and 80.5% (235/292) in patients treated with comparator drugs. Clinical success rates in the CE population were 89.9% (214/238) in patients treated with CUBICIN and 90.4% (226/250) in patients treated with comparator drugs.The success rates by pathogen for microbiologically evaluable patients are presented in Table 11.Table 10. Invest igator’s Primary Diagnosis in the cSSSI Studies(Population: ITT)Study 9801 Study 9901 Pooled PrimaryDiagnosisCUBICIN/Comparator*CUBICIN/Comparator* CUBICIN/Comparator* N=264/N=266 N=270/N=292 N=534/N=558Wound Infection 99 (37.5%)/116(43.6%)102 (37.8%)/108(37.0%)201 (37.6%)/224(40.1%)Major Abscess 55 (20.8%)/43(16.2%)59 (21.9%)/65(22.3%)114 (21.3%)/108(19.4%)Ulcer Infection 71 (26.9%)/75(28.2%)53 (19.6%)/68(23.3%)124 (23.2%)/143(25.6%)Other Infection†39 (14.8%)/32(12.0%)56 (20.7%)/51(17.5%)95 (17.8%)/83(14.9%)*Vancomycin or anti-staphylococcal semi-synthetic penicillins.†The majority of cases were subsequently categorized as complicated cellulitis, major abscesses, or traumatic wound infections.Table 11. Clinical Success Rates by InfectingPathogen, Primary Comparative cSSSI Studies(Population: Microbiologically Evaluable)Success Rate Pathogen CUBICIN Comparator*n/N (%) n/N (%)Methicillin-susceptible Staphylococcus aureus (MSSA)†170/198(85.9)180/207(87.0)Methicillin-resistant Staphylococcus aureus (MRSA)†21/28(75.0)25/36 (69.4)Streptococcus pyogenes79/84(94.0)80/88 (90.9)Streptococcus agalactiae23/27(85.2)22/29 (75.9)Streptococcus dysgalactiaesubsp. equisimilis8/8 (100) 9/11 (81.8)Enterococcus faecalis (vancomycin-susceptible only)27/37(73.0)40/53 (75.5)*Vancomycin or anti-staphylococcal semi-synthetic penicillins.†As determined by the central laboratory.S. aureus Bacteremia/EndocarditisThe efficacy of CUBICIN in the treatment of patients with S. aureus bacteremia was demonstrated in a randomized, controlled, multinational, multicenter open-label study. In this study, adult patients with at least one positive blood culture for S. aureus obtained within 2 calendar days prior to the first dose of study drug and irrespective of source were enrolled and randomized to either CUBICIN (6 mg/kg IV q24h) or standard of care [anti-staphylococcal semi-synthetic penicillin 2 g IV q4h (nafcillin, oxacillin, cloxacillin, or flucloxacillin) or vancomycin 1 g IV q12h, both with initial gentamicin 1 mg/kg IV every 8 hours for first 4 days]. Of the patients in the comparator group, 93% received initial gentamicin for a median of 4 days compared with 1 patient (<1%) in the CUBICIN group. Patients with prosthetic heart valves, intravascular foreign material that was not planned for removal within 4 days after the first dose of study medication, severe neutropenia, known osteomyelitis, polymicrobial bloodstream infections, creatinine clearance <30 mL/min, and pneumonia were excluded.Upon entry, patients were classified for likelihood of endocarditis using the modified Duke criteria (Possible, Definite, or NotEndocarditis). Echocardiography, including a transesophageal echocardiogram。
达托霉素治疗耐甲氧西林金黄色葡萄球菌感染21例
达托霉素治疗耐甲氧西林金黄色葡萄球菌感染21例徐时方;徐建国;侯赛妙;周菲美斯【期刊名称】《实用医学杂志》【年(卷),期】2014(000)023【摘要】近年来，革兰阳性球菌成为社区、院内获得性感染的重要致病菌，尤其是耐甲氧西林金黄色葡萄球菌致病菌（methicillin-resistant staphylococcus aureus，MRSA）的出现，给临床治疗带来较大困难，临床医生需要一种疗效肯定、安全性高的抗菌药用于治疗MRSA 感染。
达托霉素（daptomycin）是一种新型的环脂肽类抗生素，主要针对多重耐药的革兰阳性病原菌，对VRE、MRSA、MRSCoN、PNSSP 均有很好的抑菌效果［1］。
为此，笔者采用达托霉素治疗MASA 菌血症，取得一定疗效，现报告如下。
【总页数】2页(P3878-3879)【作者】徐时方;徐建国;侯赛妙;周菲美斯【作者单位】325000 浙江省温州市人民医院ICU;325000 浙江省温州市人民医院ICU;325000 浙江省温州市人民医院ICU;325000 浙江省温州市人民医院ICU【正文语种】中文【相关文献】1.治疗万古霉素最低抑菌浓度＞1mg／L耐甲氧西林金黄色葡萄球菌血流感染早期改用达托霉素的配对队列研究 [J], 秦晓华;汪复2.达托霉素与标准方法治疗金黄色葡萄球菌感染性菌血症和心内膜炎的疗效比较[J], Fowler Jr. V.G.;Boucher H.W.;Corey G.R.;马超3.万古霉素治疗严重耐甲氧西林金黄色葡萄球菌感染的治疗药物监测:2020年美国卫生系统药师协会、美国感染病学会、儿童感染性疾病学会和感染病药师学会更新修订的共识指南 [J], 范亚新4.耐甲氧西林金黄色葡萄球菌感染的四肢创伤性骨髓炎的手术治疗 [J], 黄凯;林炳远;任海勇;刘亦杨;张展;翟利锋;马苟平;张春;郭峭峰5.达托霉素治疗耐甲氧西林金黄色葡萄球菌性人工瓣膜心内膜炎伴旁瓣脓肿 [J], 余文海因版权原因，仅展示原文概要，查看原文内容请购买。
达托霉素演示文稿1
5月2日胸部CT
达托霉素 500mg ivd
MRSA
白细胞计数变化曲线
30 25
白细胞计数（*10^9）
20 15 10 5
22.91 21.54
24.01 18.17
16.42 13.7 14.48 13.64 9.298.39 系列1
达托霉素500mg IVD QD
0 2014- 2014- 2014- 2014- 2014- 2014- 2014- 2014- 20144-1 4-6 4-11 4-16 4-21 4-26 5-1 5-6 5-11
治疗革兰阳性球菌感染的抗生素
万古霉素 皮肤及软 组织感染 肺炎 导管相关 血流感染 血流感染 ++
替考拉宁 ++
达托霉素 +++
利奈唑胺 +++
替加环素 +++
++ ++
++ ++
+++
+++ +
+ +
++
++
+++
+
+
IDSA指南对不同MRSA感染的药物选择的建议
感染类型 蜂窝织炎 药物 克林霉素，TMP-SMZ， 多西环素，米诺环素， 利奈唑胺 万古霉素，利奈唑胺， 达托霉素，替拉万星， 克林霉素 万古霉素，达托霉素 建议 口服，目标菌为CA-MRSA；
时间
IDSA MRSA 指南: 对于住院的cSSTI成年患者的建议
• cSSTI 包括: 深层软组织感染、手术/创伤性伤口感染、严重脓肿、蜂窝 织炎和溃疡及烧伤感染 • cSSTI的治疗包括: 手术清创+ 广谱抗生素(覆盖MRSA)
达托霉素
如果无法避免与喷洒Ｅ ａ ｉｔ ｖｍ ｓ 的手臂的直接接触，则建议妇女穿上能
够遮 盖 用 药 部 位 的衣 服 。一 旦 发 生接 触 ，则 应 尽快 用 肥 皂和 水 冲 洗
Ａｆｕ ｉ流 感 疫 苗 ｌｒａ
关键词 ： 发热 热性惊厥
７ Ｏ 月３ 日，美 国ＦＡ Ｄ对季 节性流 感疫 苗Ｍｌｒａ ｕ ｉ的产 品说 明书 “ 告 警
促、呼吸 困难，严重的可以导致进行性 呼吸衰竭，如果没有及时发 现并适当治疗可能会致死。
和注意事项 ”部分进行 了更改，提醒医护人员，在澳大利亚，Ｍｌｒａ ｕｉ
６ 中国处方药 ２ １． Ｏ ０ ０｝ ００ ＠Ｎ ． １ ０ ］
Ｆ Ａ 已发 表 的达 托 霉 素 相 关 的嗜 酸 粒 细 胞 肺 炎 的病 例 报 告 进 Ｄ对 行 了回顾 ，并 根据 Ｆ Ａ 不 良反 应报 告 系 统对 达 托 霉 素 的上 市 后 不 良 Ｄ的
ＦＡ Ｄ 建议 ，患者 用 药 时应 确保 儿 童及 宠物 不 会接 触 到用 药 部位 ，
Ｓａｅｏ 否增 力， ｔ］ｖ是 口 血管事件 风险， 估完 成后将 及时向公众 公布。 评
拉莫蔓嗪
关键词： 无菌性脑膜 炎
８ ２ 月１ 日，美国Ｆ Ａ Ｄ 发出警告 ，用于治疗癫痫发作和双相情感障 碍的药物拉莫三嗪可能引发无菌性脑膜炎。 无菌性脑膜炎是指覆盖脑和脊髓的脑脊膜 的无菌性炎症，可由 病毒、毒物、某些疫苗 、自身免疫性疾病和某些药物 引起，症状包 括头痛、发热、颈项强直、恶心 、呕吐、皮疹和光过敏，某些情况
巴联用。 ２０ 年６ ０３ 月被批准 ，￣２０年１月，估计已有 １４ｏｏ 患者接受Ｓａｅｏ ０９ ０ ５ ｏ￣Ｊ ｔｌｖ治疗。 虽然左旋多巴也存 肌梗死、 心律失常、 高血压及心悸等报道 ， 但以前的临床试验并没有显示 Ｓａｅｏ 肌梗死、 ｔｌｖ￣， 卒 血管死亡方面与其有差别。
达托霉素介绍PPT课件
• 开展了评价达托霉素对社区获得性肺炎住院患者疗效的Ⅲ期临床试验，未发现其疗效优 于头孢曲松，因此不能作为治疗肺炎的药物(达托霉素在治疗肺内感染时由于表面活性剂 的存在而降低其疗效)。
• 达托霉素具有独特的抗菌机制,即“分步作用”模式 • 第1步:当有游离钙离子存在时,达托霉素结合到G+菌的细胞膜上,其亲
脂尾不可逆地插入细胞膜中; • 第2步:通过寡聚化作用,达托霉素的亲脂尾在细菌细胞膜上起“离子通
道”的作用; • 第3步:细菌细胞内的钾离子(可能还有其他离子)通过该“离子通道”
– 2003年，FDA批准：复杂皮肤和软组织感染 – 2005年，FDA批准：金黄色葡萄球菌感染的菌血症和心内膜炎 – 2007 年在中国开发和销售
• 目前尚未批准系统用药。
2019/11/19
2
适应症进展
• 复杂皮肤和软组织感染(包括创伤感染、脓疮、感染性糖尿病和非糖尿病溃疡等)与标准 治疗法(万古霉素、苯唑西林或萘夫西林)疗效相当。2003年，FDA批准达托霉素治疗上 述适应证。
应主要是其对肠道菌群的影响所致。
• 罕见
– 速发过敏反应/超敏反应 – 肌病和横纹肌溶解：肌痛、肌无力、CPK↑（＞1000或5倍）、肾功能↓，剂量相关 – 嗜酸粒细胞性肺炎：有报道2-4周出现，发热、咳嗽、气短、呼吸困难。 – 周围神经病变 – 国际标准化比值（INR）升高/凝血酶原时间延长
禁忌：过敏
•分布：Vd（表观分布容积）=0.096L/KG；不透过血脑屏障（动物）。骨组织透过性差
达托霉素
31.注射用达托霉素(H20100107 Cubist Pharmaceuticals, Inc. 86979424000050)2.注射用达托霉素(国药准字J20100001 Cubist Pharmaceuticals, Inc. 86979424000029)3.注射用达托霉素(H20090781 Cubist Pharmaceuticals Inc. 86979424000036)注射用达托霉素1. 项目背景达托霉素（daptomycin，Cubicin）作为一全新结构类别的抗生素，最早由礼来公司（Eli Lilly）于二十世纪80年代发现，1997年Cubist制药公司受让获得全球范围的开发权，2003年9月获FDA批准在美国首次上市，据统计，此药上市后第一年即取得约6000万美元的收入。
2. 药物特性达托霉素能在多个方面破坏细菌细胞膜功能，由此迅速杀死革兰阳性菌。
本品除能作用于大多数临床相关革兰阳性菌外，更重要的是在体外对已呈甲氧西林（methicillin）、万古霉素和利奈唑胺等耐药性分离菌株仍具强力活性。
本品现被批准用于治疗下列革兰阳性体外敏感菌所致并发性皮肤及皮肤结构感染：包括耐甲氧西林菌在内的金黄色葡萄球菌、酿脓链球菌、无乳链球菌、停乳链球菌亚种似马链球菌和对万古霉素敏感粪肠球菌。
3. 临床研究临床研究证实达托霉素与苯唑西林、萘夫西林钠法疗效相当，即：对临床可评价患者，本品治疗的临床成功率为83.4%，而对照药物的相应值是84.2%。
本品在临床研究中极少致使病原菌产生耐药性。
4. 市场情况新颖抗生素——达托霉素（Cubicin）对革兰阳性耐药菌有活性且具更好抗菌谱和较低耐药性，其在上市后的第一年即取得约6000万美元的收入，而且销售额正在稳步上升。
由于达托霉素的成功上市，导致了Cubist制药公司股票价格的快速上涨，去年11月，该公司通过出售手中的股票净赚了1.124亿美元。
注射用达托霉素临床问题集
1.以下说法中不正确的是[4分]DA达托霉素最早批准的适应症为复杂皮肤及软组织感染B静脉给药后，所有药物都需经过肺循环和体循环到达相应组织C达托霉素不能用于治疗原发血流感染之外的肺炎D邦达信已获得2项已授权国家专利2.重度肾功能损害患者，如果其肌酐清除率小于<30ml/min，治疗MRSA血流感染的推荐剂量为[4分]DA每24小时4mg/kgB每24小时6mg/kgC每48小时4mg/kgD每48小时6mg/kg3.下列属于抑菌剂的是[4分]CA达托霉素B万古霉素C利奈唑胺D替考拉宁4.5.达托霉素是浓度依赖性抗生素，该类药物对致病菌的杀菌效应和临床疗效取决6.根据2015年发布的《抗菌药物超说明书用法专家共识》，对于持续性MRSA菌血症7.8.9.10.2017IDSA临床实践指南推荐达托霉素用于金葡菌引起的脑膜炎（全身给11.12.2016 年国际腹膜透析学会（ISPD）关于腹膜透析相关腹膜炎防治指南建议，达托13.14.在一项前瞻性研究中，显示高剂量的达托霉素（中位数为 9.2mg/kg.d）是治疗革兰阳性菌引起的左心感染性心内膜炎有效且安全的方法[3分]对对错15.在某些特别严重的患者，尤其是肺部感染合并感染性心内膜炎或血流感染或皮肤及软组织感染时，联用利奈唑胺可能是一种不错的选择[3分]对对错16.达托霉素对致病菌的杀菌效应和临床疗效与作用时间密切相关[3分]错对错17.达托霉素引起CPK升高停药后不可逆[3分]错对错18.低蛋白血症患者应用达托霉素时无需调整剂量[3分]错对错19.达托霉素在钙离子浓度为60mg/L 时，能达到最大的抗菌活性[3分]错对错20.低钙离子浓度会降低达托霉素临床疗效[3分]错对错21.7-17 岁的儿童患者，静脉滴注给药时间为60 min[3分]错对错22.达托霉素无法穿透阴性杆菌的外膜，所以对阴性杆菌无效[3分]对对错。
达托霉素的作用与功效
达托霉素的作用与功效达托霉素是一种广谱抗生素，它可用于治疗多种感染症，包括呼吸道感染、皮肤感染、尿路感染等。
本文将详细介绍达托霉素的作用机制、药理特点以及临床应用等方面，以便读者更好地了解和使用该药物。
一、达托霉素的作用机制达托霉素的作用机制主要与其抑制细菌蛋白质合成有关。
它能够与细菌的30S亚单位结合，阻止靶菌在合成蛋白质的过程中附着tRNA到mRNA上，从而使细菌的蛋白质合成受到抑制。
此外，达托霉素还能够阻断细菌核糖体的转位运动，从而干扰蛋白质的合成。
二、达托霉素的药理特点1.药物代谢特点：达托霉素在体内代谢非常缓慢，其血药浓度维持时间较长，使得一次每日（或每两天一次）给药即可维持疗效。
2.体内分布特点：达托霉素在体内广泛分布，能够较好地穿过血脑屏障，进入中枢神经系统，从而对治疗脑膜炎等中枢神经系统感染有一定效果。
3.药物消除特点：达托霉素通过肝脏酶CYP3A4代谢酶被代谢，然后由肾脏排泄。
肾功能不全的患者，应适当减量。
三、达托霉素的临床应用1.呼吸道感染：达托霉素对于肺炎链球菌、流感嗜血杆菌、半乳糖杆菌等引起的复杂性呼吸道感染具有较好的疗效。
尤其对于广谱β内酰胺酶阳性的致病菌具有一定的敏感性，能够避免氨基酮类抗生素的使用。
2.皮肤和软组织感染：达托霉素对于革兰阳性链球菌、葡萄球菌等引起的皮肤和软组织感染显示出很好的疗效。
尤其对于降低敏感性的金黄色葡萄球菌（MRSA）感染，达托霉素显示出了比其他药物更好的治疗效果。
3.泌尿道感染：达托霉素对于大肠杆菌、肠球菌等引起的泌尿道感染具有很好的疗效。
因其在尿液中的浓度较高，可通过尿液达到高浓度。
同时，其广谱抗菌谱又能够覆盖多种引起泌尿道感染的致病菌。
4.屈光不正引起的感染：对于角膜炎等屈光不正所致的感染疾病，达托霉素通过给药后迅速在眼部组织内达到较高浓度，可有效治疗并预防感染。
5.其他感染：达托霉素还可以用于治疗骨关节感染、中枢神经系统感染、腹腔感染等。
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10~12mg/kg/24h，疗程为﹥6周(IIb-C)；当DAP用于上述感染治疗时，可考虑与头孢他洛林或 氨苄西林合用，特别是在持续菌血症或肠球菌对DAP的MIC值位于敏感折点内但较高时(如 3μg/mL，敏感折点为≦4μg/mL)(IIb-C)。但在体外试验中庆大霉素、利福平和替加环素与DAP 合用不具协同效应，应避免选用
[3] Habib G, Lancellotti P, Antunes MJ, et al. 2015 ESC Guidelines for the management of infective endocarditis. European Heart Journal, 2015
英国抗菌化疗协会(BSAC)和中华医学会指南
①经验性治疗
②葡萄球菌NVE
9
③葡萄球菌PVE
[4] Gould FK, Denning DW, Elliott TS, et al. Guidelines for the diagnosis and antibiotic treatment of endocarditis in adults: a report of the Working Party of the British Society for Antimicrobial Chemotherapy. J Antimicrob Chemother 2012; 67: 269–289
手工筛选标准： DAP疗程≥3d，基 线CPK正常、至少1次CPK随访、开 始DAP治疗 后的7d内无手术史、无
其他引起CPK ↑原因
无任何肌病相 关证据
1:1匹配，匹配原则：DAP疗程相等， 整个疗程无CPK增高及肌病相关症状
6] Dare, R.K., et al., Statin Coadministration Increases the Risk of Daptomycin-Associated Myopathy. Clin Infect Dis.
呼吸困难
低血压
肝功能异常、CPK升高
注意事项
肌病和横纹肌溶解 ✓ 肌病：肌痛或肌无力合并磷酸肌酸激酶（CPK）>10*ULN ✓ 对患者肌痛或肌无力，尤其是肢体远端症状的发展进行监测 ✓ 应在基线时及其后的每周监测CPK ✓ 提高监测频率
① 最近或伴随使用HMG-CoA还原酶抑制剂 ② 肾功能不全患者 ③ 接受达托霉素治疗时出现不可解释的CPK增高
年龄
剂量方案
疗程
成人
4mg/kg q24h
7~14d
12~17y 5mg/kg q24h ivgtt >30min
7~11y 7mg/kg q24h ivgtt >30min
14d
2~6y
9mg/kg q24h ivgtt >60min
1~2y
10mg/kg q24h ivgtt >60min
用法用量
[5] 中华医学会心血管病学分会,中华心血管病杂志编委会. 成人感染性心内膜炎预防、诊断和治疗专家共识. 中华心血管病杂志, 2014, 42(10):806-816
AHA 2015
ESC 2015
BSAC 2011 中华医 学会 2014
NVE, 严重脓毒症( 无肠杆菌及假单胞 菌感染危险因素)经
醇治疗
周围神经病变 艰难梭菌相关性腹泻 持续性或反复发作性金黄色葡萄球菌菌血症/心内膜炎
注意事项
基线肾功能中度损害患者中的疗效降低
表1 DAP在成人cSSSI3期临床试验中按肾功能和治疗组分组的临床有效率（ITT人群）
表2 成人金葡菌菌血症/心内膜炎试验中在临床治愈(TOC)时评定委员会评定的 按基线肌酐清除率分层的临床有效性（ITT人群）
要优于VAN。某些专家推荐DAP加用氯唑西林（2g/4h,iv）或磷霉素（2g/6h,iv）以增
加抗菌活性及避免细菌对DAP产生耐药性。
✓ 在肠球菌属感染引起的心内膜炎中，对于多药耐药的肠球菌（对氨基糖苷类、β内酰 胺类、VAN均耐药），可选择DAP（10mg/kg/24h）联合氨苄西林（200 mg/kg/d，分 4~6次给药）作为替代治疗；对其他组合（达托霉素联合厄他培南或头孢洛林），需 咨询感染疾病专家后方可使用。
[7] Saito et al. Dose-dependent artificial prolongation of prothrombin time by interaction between daptomycin and test reagents in patients receiving warfarin: a prospective in vivo clinical study. Ann Clin Microbiol Antimicrob, 2017, 16:27
用法用量
用法
✓ 溶媒：0.9%NS或乳酸林格氏液，不得使用含右旋糖的稀释液
5
✓ 成人：50mg/ml i.v. >2min或溶于0.9%NS50ml ivgtt. >30min
✓ 儿童：不可i.v.； 7~17岁：ivgtt. >30min；1~6岁： ivgtt. >60min
用量
✓ cSSSI
✓ 暂时接受DAP治疗的患者，应考虑停止使用HMG-CoA还原酶抑制剂
药物-实验室检查相互作用
DAP与测定凝血酶原时间（PT）时使用的某些重组促凝血酶原激酶试 剂间的相互作用，可能会导致一种错误的PT/INR升高的结果
建议：在接近DAP波谷血浆浓度时（即下一剂DAP给药前）采样进行 PT或INR测试可能会使这种错误的可能性最小化，但即使是波谷浓度 的DAP也有可能引起相互作用
[2] Baddour LM, Wilson WR, Bayer AS, et al. Infective Endocarditis in Adults: Diagnosis, Antimicrobial Therapy, and Management of Complications: A Scientific Statement for
✓多变量分析表明：深部脓肿 (OR 2.80, p=
0.03)、抗组胺药联用(OR 3.50, p=0.03)、他
汀类联用(OR 2.60, p=0.03)为肌病的独立危
险因素
✓肥胖(OR 3.28, p=0.03)、他汀类联用(OR 4.67,
p=0.03)为横纹肌溶解的独立危险因素，而
高龄为保护性因素(OR 0.97, p=0.03)
结论：他汀和DAP联用与肌病及横纹肌溶解独立相关，当联用时推荐一周两次 CPK监测或建议暂时停用他汀
注意事项
嗜酸细胞性肺炎 18 ✓ 症状：发热、伴有低氧性呼吸功能不全的呼吸困难和弥散性肺浸
润 ✓ 一般在使用DAP2~4w后出现，中止DAP并启动类固醇治疗后可改善；
已有报道重新使用DAP后嗜酸细胞性肺炎复发 ✓ 如发生嗜酸细胞性肺炎，应立即中止DAP治疗，推荐应用全身类固
*如可能，应在血液透析日完成血液透析后再给予本品
Q1达托霉素可用于左侧感染性心内膜炎和人工瓣膜心内膜炎吗？
2015年美国心脏协会(AHA)成人感染性心内膜炎指南
✓ 治疗MSSA引起的左侧感染性心内膜炎时，达托霉素(DAP)可作为万古霉素(VAN)的替代药物 (IIb-B)
✓ 治疗MSSA引起的自体感染性心内膜炎(NVE)时，DAP可作为VAN的替 代药物(IIa-B) ✓ DAP替代VAN用于治疗苯唑西林耐药葡萄球菌引起的NVE时剂量为≥8mg/kg/dose，疗程6周
适应症
4 复杂性皮肤及皮肤软组织感染(cSSSI)：成人及1~17岁儿童 金葡菌（包括甲氧西林耐药菌株）、化脓性链球菌、无乳链球菌、停乳链球菌似 马亚种 、粪肠球菌（仅对万古敏感的菌株）
金黄色葡萄球菌(包括甲氧西林敏感和耐药菌株)导致的伴发右侧感染性心内膜炎的 血流感染（菌血症）：仅限成人
使用限制 肺炎、金葡菌导致的左侧感染性心内膜炎 在人工瓣膜心内膜炎中的疗效未作评价 年龄<1岁的儿科患者
验性治疗
MSSA 左侧
IE
MSSA 的 NVE
MRSA的NVE
∕
替代 替代 替代VAN
VAN VAN 8mg/kg/24h, 6W
∕
∕
VAN过敏
∕
6mg/kg/24h联合庆
大霉素
∕
替代VAN
10mg/kg/24h，4～6W
推荐与氯唑西林（2g/4h）或
磷霉素（2g/6h）合用
∕
耐VAN (MIC>2μg/mL)或不
药物相互作用
DAP对细胞色素P450酶（CYP 450）相关的代谢几乎无影响， DAP无预期的和CYP450酶相关的药物相互作用
HMG-CoA还原酶抑制剂
✓ 健康受试者中，DAP和辛伐他汀联合给药对辛伐他汀的血浆谷浓度无影响 ，且无导致骨骼肌病的的报道
✓ III期金葡菌菌血症/心内膜炎试验中，之前或伴随使用HMG-CoA还原酶抑制 剂的患者接受DAP治疗时CPK升高
注意事项
肌病和横纹肌溶解
13
✓ 停药指征 ① 无法解释的肌病体征和症状合并CPK>5*ULN ② CPK>10*ULN但无症状
✓ 对于正接受达托霉素治疗的患者，应考虑暂停使用与横纹肌溶 解相关的药物，如HMG-CoA还原酶抑制剂
Q2-DAP相关性肌病的危 险因素有哪些？
15
开展了一项单中心、回顾性、匹 配病例对照研究(2004-2015)，分 析使用达托霉素时肌病及横纹肌 溶解的危险因素
达托霉素简介及在临床使用中的思考
化学结构
2
从链霉菌发酵液中提 取得到的一个环酯肽 类抗生素，具有新型 的化学结构。