48-[3-[(4S)-4-amino-5-hydroxy-4,6-dimethyloxan-2-yl]oxy-4,5-dihydroxy-6-(hydroxymethyl)oxan-2-yl]oxy-22-(2-amino-2-oxoethyl)-5,15-dichloro-2,18,32,35,37-pentahydroxy-19-[[4-methyl-2-(methylamino)pentanoyl]amino]-20,23,26,42,44-pentaoxo-7,13-dioxa-21,24,27,41,43-pentazaoctacyclo[26.14.2.23,6.214,17.18,12.129,33.010,25.034,39]pentaconta-3,5,8(48),9,11,14,16,29(45),30,32,34(39),35,37,46,49-pentadecaene-40-carboxylic acid | 1404-90-6

• 物质功能分类: 原料药 - 抗生素类药物 - 多肽类药
• 分子结构分类: 有机化合物 - 有机酸及其衍生物 - 羧酸及其衍生物
• 英文名称: 48-[3-[(4S)-4-amino-5-hydroxy-4,6-dimethyloxan-2-yl]oxy-4,5-dihydroxy-6-(hydroxymethyl)oxan-2-yl]oxy-22-(2-amino-2-oxoethyl)-5,15-dichloro-2,18,32,35,37-pentahydroxy-19-[[4-methyl-2-(methylamino)pentanoyl]amino]-20,23,26,42,44-pentaoxo-7,13-dioxa-21,24,27,41,43-pentazaoctacyclo[26.14.2.23,6.214,17.18,12.129,33.010,25.034,39]pentaconta-3,5,8(48),9,11,14,16,29(45),30,32,34(39),35,37,46,49-pentadecaene-40-carboxylic acid
• CAS: 1404-90-6
• 化学式: C₆₆H₇₅Cl₂N₉O₂₄
• 分子量: 1449.2
• InChiKey: MYPYJXKWCTUITO-BSRCFTEOSA-N

物化性质

• 熔点：
  >274°C (dec.)
• 密度：
  1.2882 (rough estimate)
• 溶解度：
  二甲基亚砜（微溶）
• 稳定性/保质期：
  When reconstituted with sterile water for injection, vancomycin hydrochloride injection is stable for 2 weeks at room temperature; the manufacturers state that reconstituted injections may be stored for 96 hours at 2 - 8 °C without substantial loss of potency. When reconstituted as directed in 0.9% sodium chloride injection or 5% dextrose injection, solutions prepared from ADD-Vantage vials of the drug are stable for 24 hours at room temperature. Vancomycin solutions containing 5 mg/mL in 0.9% sodium chloride injection or 5% dextrose injection are reportedly stable for at least 17 days when stored at 24 °C in glass or PVC containers and for at least 63 days when stored at 5 °C or -10 °C in glass containers. Following reconstitution with sterile water for injection as directed, vancomycin solutions that have been further diluted to a concentration of 5 mg/mL in 5 - 30% dextrose injection are stable when stored in plastic syringes for 24 hours at 4 eg C and then subsequently for 2 hours at room temperature.
• 分解：
  When heated to decomposition, it emits toxic fumes of /nitric oxide/ and /chlorine/.
• 解离常数：
  pka1 = 2.6; pKa2 = 7.2; pKa3 = 8.6; pKa4 = 9.6; pKa5 = 10.5; pKa6 = 11.7

计算性质

• 辛醇/水分配系数(LogP)：
  -2.6
• 重原子数：
  101
• 可旋转键数：
  13
• 环数：
  12.0
• sp3杂化的碳原子比例：
  0.42
• 拓扑面积：
  531
• 氢给体数：
  19
• 氢受体数：
  26

ADMET

毒理性

• 肝毒性

静脉注射万古霉素与1%至5%的患者中血清转氨酶水平的轻微、短暂和无症状升高有关，但与此相比，类似或略低的异常率通常与比较药物有关。在罕见的情况下，血清酶升高更为明显，并可能伴有轻度症状，尽管通常没有黄疸。近年来，万古霉素与过敏反应有关，包括史蒂文斯-约翰逊综合征、中毒性表皮坏死松解症和药物反应、嗜酸性粒细胞增多和全身症状（DRESS）的独特综合征。这些形式的过敏通常在开始静脉注射（iv）万古霉素治疗后的几天到3到4周内出现。发热和严重的皮肤皮疹通常主导临床表现，但系统性症状可以包括肾脏、呼吸或心脏衰竭，中性粒细胞减少，血小板减少和肝脏损伤。与万古霉素相关的DRESS综合征的病例通常伴有血清酶升高（案例1），但显著升高、症状和黄疸并不常见。万古霉素诱导的DRESS综合征的通常系统性特征是肾脏而非肝脏损伤，但过敏反应的特征通常比器官特异性损伤更明显。然而，在罕见的情况下，肝脏损伤可能很严重（案例2），并可能导致肝衰竭和死亡。接受静脉注射万古霉素的患者通常有多种合并症，包括败血症，并接受多种抗生素，这使得将过敏反应和肝脏损伤归因于万古霉素变得困难。其他更知名的DRESS综合征的原因包括别嘌醇、磺胺类药物和芳香抗惊厥药。这些DRESS综合征的其他原因更可能与临床上明显的甚至致命的肝脏损伤有关。 万古霉素还与几种急性输注反应有关，最值得注意的是过敏性休克和万古霉素潮红反应，以前被称为“红人综合症”。万古霉素潮红反应通常发生在初次输注万古霉素的前15到20分钟，尤其是在快速输注和高剂量（1000毫克在不到60分钟内输注）时。这种反应的特点是潮红、红斑和通常发生在面部、颈部和上半身的瘙痒，有时伴有胸痛和背痛以及不同程度的低血压。罕见地，潮红反应与口服万古霉素治疗有关，特别是在有活动性结肠炎和肾功能障碍的老年患者中。症状的原因可能是万古霉素或金黄色葡萄球菌毒素的直接作用导致肥大细胞的急性脱颗粒。这种反应的介质是组胺和其他活性胺或肥大细胞颗粒中的成分。万古霉素潮红反应的人血浆组胺水平通常升高，但血浆组胺水平的变化与症状的严重程度的相关性较差。然而，可以通过预先使用抗组胺药来预防或减轻万古霉素潮红反应的症状。也许更好的方法是使用较慢的输注速度和较低的万古霉素剂量。肝脏损伤不是万古霉素潮红反应的特征，但在持续或严重低血压的情况下可能会继发出现。 可能性评分：B（很可能是导致临床上明显肝脏损伤的原因，通常与DRESS综合征有关）。

Intravenous vancomycin is associated with minor, transient and asymptomatic elevations in serum aminotransferase levels in 1% to 5% of patients, but similar or minimally lower rates of abnormalities are usually reported with comparative agents. In rare instances, the serum enzyme elevations are more marked and may be associated with mild symptoms, although usually without jaundice. In recent years, vancomycin has been linked to hypersensitivity reactions, including Stevens-Johnson syndrome, toxic epidermal necrolysis and the distinctive syndrome of drug reaction, eosinophilia and systemic symptoms (DRESS). These forms of hypersensitivity generally arise within a few days to 3 to 4 weeks after initiation of intravenous (iv) vancomycin therapy. Fever and severe skin rash generally dominate the clinical presentation, but systemic symptoms can include renal, respiratory or heart failure, neutropenia, thrombocytopenia, and liver injury. Cases of DRESS syndrome associated with vancomycin are often accompanied by serum enzyme elevations (Case 1), but marked elevations, symptoms and jaundice are uncommon. The usual systemic features of vancomycin induced DRESS syndrome are renal rather than liver injury but features of hypersensitivity are usually more prominent than organ-specific injury. Nevertheless, in rare instances the liver injury can be severe (Case 2) and result in hepatic failure and death. Patients who receive intravenous vancomycin often have multiple comorbidities including sepsis and receive multiple antibiotics which make the attribution of the hypersensitivity reactions and liver injury with vancomycin difficult. Other more well-known causes of DRESS syndrome include allopurinol, sulfonamides, and the aromatic anticonvulsants. These other causes of DRESS syndrome are more likely to be associated with clinically apparent and even fatal liver injury. Vancomycin is also associated with several forms of acute infusion reactions, most notably anaphylaxis and the vancomycin flushing reaction, previously known as “red man syndrome”. Vancomycin flushing reactions occur typically during the first 15 to 20 minutes of an initial infusion of vancomycin, most commonly when given rapidly and in relative high doses (1000 mg given over less than 60 minutes). The reaction is characterized by flushing, erythema, and itching usually of the face, neck and upper torso, sometimes accompanied by chest and back pain and variable degrees of hypotension. Rarely, flushing reactions have been associated with oral vancomycin therapy, particularly in elderly patients with active colitis and renal dysfunction. The cause of the symptoms is probably the acute degranulation of mast cells by the direct effect of vancomycin or S. Aureus toxins. The mediator of the reaction is histamine and other active amines or components in mast cell granules. Plasma histamine levels are usually elevated in persons with vancomycin flushing reactions, but the correlation of changes in plasma histamine levels and severity of symptoms is poor. Nevertheless, the symptoms of the vancomycin flushing reaction can be prevented or ameliorated by pretreatment with antihistamines. Perhaps a better approach is the use of slower infusion rates and lower doses of vancomycin. Liver injury is not a feature of vancomycin flushing reactions but can arise secondarily in cases with prolonged or severe hypotension. Likelihood score: B (highly likely cause of clinically apparent liver injury usually in association with DRESS syndrome).

来源:LiverTox

毒理性

• 肝毒性

在获得许可前的对照试验中，使用Dalbavancin、Oritavancin或Telavancin治疗期间，血清ALT升高是常见的，发生在多达25%的患者中。然而，血清转氨酶升高超过正常上限三倍的情况并不常见，接受Dalbavancin、Oritavancin或Telavancin治疗的患者中，这种情况的发生率为0.8%至6%。此外，这些肝脏测试异常的发生率与对照臂并没有太大差异。在糖肽类抗生素治疗期间ALT升高通常是短暂的、无症状的，严重程度仅为轻至中度，很少导致剂量调整或提前终止治疗。在这些药物的注册试验中没有报告出现黄疸的临床明显肝损伤。自从这些药物获得批准并更广泛使用以来，没有公开发表的报告将肝损伤归因于糖肽类抗生素，尽管有报道过敏反应，有时可能与轻至中度的肝损伤有关。尽管如此，这三种药物相对较新，使用并不广泛，且使用时间相对较短，没有与严重肝损伤案例相关联。

In prelicensure controlled trials, serum ALT elevations during therapy with dalbvancin, oritavancin or telavancin were common, occurring in up to 25% of patients. Serum aminotransferase elevations above three times the upper limit of normal, however, were uncommon, occurring in 0.8% to 6% of patients receiving dalbavancin, oritavancin or telavancin. Furthermore, these rates of liver test abnormalities were not very different from those in comparator arms. The ALT elevations during glycopeptide antibiotic therapy were in general transient, asymptomatic and only mild-to-moderate in severity, rarely leading to dose modifications or early discontinuations. There were no reports of clinically apparent liver injury with jaundice in the registration trials of these agents. Since their approval and more wide scale use, there have been no published reports of liver injury attributed to glycopeptide antibiotics, although hypersensitivity reactions have been reported which can sometimes be associated with a mild-to-moderate degree of liver injury. Regardless, these three agents are relatively new, have not been widely used and when used, are given for a relatively short period of time and none have been linked to serious cases of liver injury.

来源:LiverTox

毒理性

• 相互作用

万古霉素与麻醉剂的联合使用已与过敏样反应和输注反应（例如，低血压、潮红、红斑、荨麻疹、瘙痒）的频率增加有关。在接受万古霉素和麻醉剂的同时治疗的儿科患者中，出现了红斑和组胺样潮红。如果在诱导麻醉前将万古霉素作为1小时的静脉输注给药，可能会最小化输注相关的不良反应的风险。

Concomitant use of vancomycin and anesthetic agents has been associated with anaphylactoid reactions and an increased frequency of infusion reactions (e.g., hypotension, flushing, erythema, urticaria, pruritus). Erythema and histamine-like flushing has occurred in pediatric patients receiving vancomycin and anesthetic agents concomitantly. The risk of infusion-related adverse effects may be minimized if vancomycin is given as a 1-hour IV infusion prior to induction of anesthesia.

来源:Hazardous Substances Data Bank (HSDB)

毒理性

• 相互作用

在体外，万古霉素和氨基糖苷类抗生素对许多金黄色葡萄球菌、非肠球菌D群链球菌（牛链球菌）、肠球菌（粪肠球菌）和绿色链球菌的抗菌作用具有协同作用。然而，万古霉素和氨基糖苷类抗生素的联合使用与耳毒性和/或肾毒性的风险增加有关。

In vitro, the antibacterial effects of vancomycin and aminoglycosides are synergistic against many strains of Staphylococcus aureus, nonenterococcal group D streptococci (Streptococcus bovis), enterococci (Enterococcus faecalis), and viridans streptococci. However, concomitant use of vancomycin and aminoglycosides is associated with an increased risk of ototoxicity and/or nephrotoxicity.

来源:Hazardous Substances Data Bank (HSDB)

毒理性

• 相互作用

由于可能存在累加毒性，其他耳毒性和/或肾毒性药物（例如，氨基糖苷类、两性霉素B、杆菌肽、顺铂、粘菌素、多粘菌素B）与万古霉素的联合或序贯系统性或局部使用需要仔细连续监测肾脏和听觉功能。在接受万古霉素治疗的病人中应谨慎使用这些药物。

Because of the possibility of additive toxicities, the concurrent or sequential systemic or topical use of other ototoxic and/or nephrotoxic drugs (e.g., aminoglycosides, amphotericin B, bacitracin, cisplatin, colistin, polymyxin B) and vancomycin requires careful serial monitoring of renal and auditory function. These drugs should be used with caution in patients receiving vancomycin therapy.

来源:Hazardous Substances Data Bank (HSDB)

吸收、分配和排泄

盐酸万古霉素在大多数患者中从胃肠道几乎不被吸收，必须通过非胃肠道给药来治疗全身性感染。口服生物利用度通常小于5%；然而，有限的数据表明，在某些患有结肠炎和/或肾功能不全的患者中，通过肠道或口服给予万古霉素后可能会产生具有临床意义的血清药物浓度。

Vancomycin hydrochloride is not appreciably absorbed from the GI tract in most patients and must be given parenterally for the treatment of systemic infections. Oral bioavailability usually is less than 5%; however, limited data suggest that clinically important serum concentrations of the drug may result following enteral or oral administration of vancomycin in some patients with colitis and/or in those with renal impairment.

来源:Hazardous Substances Data Bank (HSDB)

吸收、分配和排泄

在肾功能正常的成年人中，接受多次1克剂量的万古霉素（15 mg/kg）通过静脉输液1小时，输液完成后立即的平均血浆浓度约为63微克/毫升，而2小时和11小时后的平均血浆浓度分别约为23和8微克/毫升。当多次给予500毫克剂量的药物通过静脉输液30分钟时，输液后立即的平均血浆浓度约为49微克/毫升，输液后6小时的平均血浆浓度约为10微克/毫升。

In adults with normal renal function who received multiple 1 g doses of vancomycin (15 mg/kg) given by IV infusion over 1 hour, mean plasma concentrations immediately after completion of the infusion are approximately 63 ug/mL and mean plasma concentrations 2 and 11 hours later are approximately 23 or 8 ug/mL, respectively. When multiple 500-mg doses are given by IV infusion over 30 minutes, mean plasma concentrations are about 49 ug/mL immediately following the infusion and about 10 ug/mL 6 hours after infusion.

来源:Hazardous Substances Data Bank (HSDB)

吸收、分配和排泄

静脉注射后，万古霉素会分布到乳汁中。口服万古霉素的系统吸收非常低，目前尚不清楚药物在口服给药后是否会分布到人乳中。

Vancomycin is distributed into milk following IV administration. Systemic absorption of oral vancomycin is very low and it is not known whether the drug distributes into human milk following oral administration.

来源:Hazardous Substances Data Bank (HSDB)

吸收、分配和排泄

万古霉素容易通过胎盘，并分布到脐带血中。

Vancomycin readily crosses the placenta and is distributed into cord blood.

来源:Hazardous Substances Data Bank (HSDB)

吸收、分配和排泄

万古霉素在大约10到100微克/毫升的血清浓度下，通过超滤法测量，大约有55%与血清蛋白结合。静脉注射盐酸万古霉素后，抑制性浓度存在于胸膜、心包、腹水和关节液中；在尿液中；在腹膜透析液中；以及心耳组织中。盐酸万古霉素不易通过正常的脑膜扩散到脊髓液中；但是，当脑膜发炎时，它能够进入脊髓液。

Vancomycin is approximately 55% serum protein bound as measured by ultrafiltration at vancomycin serum concentrations of 10 to 100 mcg/mL. After IV administration of vancomycin hydrochloride, inhibitory concentrations are present in pleural, pericardial, ascitic, and synovial fluids; in urine; in peritoneal dialysis fluid; and in atrial appendage tissue. Vancomycin hydrochloride does not readily diffuse across normal meninges into the spinal fluid; but, when the meninges are inflamed, penetration into the spinal fluid occurs.

来源:Hazardous Substances Data Bank (HSDB)

安全信息

• 海关编码：
  3004209090

制备方法与用途

万古霉素简介

万古霉素是一种糖肽类抗生素，通过以高亲和力结合到敏感细菌细胞壁前体肽聚末端的丙氨酰丙氨酸来阻断构成细菌细胞壁的高分子肽聚糖合成，导致细胞壁缺损而杀灭细菌。它主要用于革兰阳性菌严重感染，特别是对其他抗菌药耐药或疗效不佳的耐甲氧西林金黄色葡萄球菌、表皮葡萄球菌、肠球菌等所致的严重感染。

适应症

万古霉素限用于以下情况：

• 耐甲氧苯青霉素（MRSA）的金黄色葡萄球菌引起的系统性感染；
• 难辨梭状芽孢杆菌引发的肠道感染和系统感染；
• 对青霉素类或头孢菌素类抗生素过敏，或经上述抗生素治疗无效的严重葡萄球菌感染患者；
• 青霉素过敏者的心内膜炎（包括肠球菌心内膜炎、棒状杆菌属心内膜炎）及青霉素不过敏和过敏的血液透析患者因葡萄球菌引起的动静脉分流感染。

分离提纯

一种万古霉素菌株及其发酵产万古霉素的方法如下：

1. 将万古霉素生产菌株在液体培养基中进行种子培养，其组成包括酵母粉3～6g/L、麦芽提取物3～5g/L、蛋白胨10～15g/L、葡萄糖15～20g/L，pH为6.8；在28～30℃下以40/250mL的装液量和150～220rpm的速度摇床培养24～48小时。
2. 液体发酵培养基组成包括糊精100～150g/L、土豆蛋白15～25g/L、黄豆粉15～25g/L、磷酸氢二钾0.1～0.5g/L、消沫剂1～3g/L、氯化钠1.2～1.6g/L，pH为6.8～7.2。在相同条件下培养90～130小时后，获得含净抗生素活性洗脱液。
3. 将步骤1中的溶液沉淀，并搅拌晶体浆料，调节pH值至完全沉淀形成晶体沉淀物。
4. 溶解步骤3中得到的晶体沉淀物为水溶液并通过阴离子交换树脂转化为万古霉素。

生物活性

Vancomycin是一种用于治疗各种细菌感染的大分子糖肽化合物（分子量1450 Da），结构独特，不同于现有任何抗生素。它通过抑制革兰阳性菌细胞壁合成第二阶段发挥作用，对多种革兰阳性菌如金黄色葡萄球菌、表皮葡萄球菌、肺炎链球菌、牛链球菌等具有活性。

体外研究

Vancomycin是一种大分子糖肽化合物，分子量为1450 Da。它结构独特且与现有任何抗生素无关。这种药物通过抑制革兰阳性菌的细胞壁合成第二阶段发挥作用，对抗多种革兰阳性菌有效。

体内研究

万古霉素静脉给药时应至少持续1小时以减少输液相关不良反应。在正常肌酐清除率的情况下，万古霉素具有30至60分钟的α分布相和6至12小时的β消除半衰期，分布容积为0.4～1 L/kg。其与蛋白质的结合率为10%至50%。

研究显示，万古霉素能改善感染小鼠的临床、腹泻及组织病理学评分，并提高生存率。影响万古霉素整体活性的因素包括组织分布、菌落大小以及蛋白结合效应等。