Glycopeptide

达巴万星是一种静脉注射的半合成脂糖肽，旨在治疗对抗生素具有抗药性的微生物引起的疾病。达拉帕万星对革兰氏阳性菌（如 S.MRSA、VISA 和 VRE 金黄色葡萄球菌的非 VanA 菌株）具有强大的体外杀菌作用。旨在治疗主要由 β-溶血性链球菌和 MRSA 引起的困难皮肤和皮肤结构感染 (cSSSI)，事实证明它比现有的糖肽治疗药物更有效[1][2]。

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Dalbavancin对炭疽杆菌菌株的敏感性。[1]
Dalbavancin显示出强大的体外活性。30株炭疽杆菌的MIC范围为≤0.03至0.5μg/ml（图1），MIC50为0.06μg/ml，MIC90为0.25μg/ml。相比之下，万古霉素MIC范围为1至4μg/ml。对于三次MIC测定，单个菌株的MIC变化不超过一次稀释

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进行抗菌药物敏感性试验（AST）以评估抗菌药物对各种细菌的体外活性。AST结果以最低抑菌浓度（MIC）表示，用于抗菌药物开发和耐药性开发监测的研究，以及抗菌治疗指导的临床环境Dalbavancin是一种半合成脂糖肽抗菌剂，于2014年5月获得美国食品和药物管理局（FDA）批准，用于治疗由革兰氏阳性菌引起的急性细菌性皮肤和皮肤结构感染。与目前的抗葡萄球菌疗法相比，Dalbavancin的优势在于其半衰期长，可以每周给药一次Dalbavancin对金黄色葡萄球菌（包括对甲氧西林敏感的金黄色葡萄菌[MSSA]和对甲氧青霉素耐药的金黄色葡菌[MRSA]）、凝固酶阴性葡萄球菌、肺炎链球菌、心绞痛链球菌群、β-溶血性链球菌和万古霉素敏感肠球菌具有活性。与其他最近的脂糖肽药物类似，CLSI和ISO肉汤敏感性测试方法的优化包括在制备储备溶液时使用二甲基亚砜（DMSO）作为溶剂，以及使用聚山梨酯80（P80）来减轻药物对塑料的粘附。在临床研究之前和Dalbavancin的初步开发期间，没有使用P-80进行药敏研究，MIC结果往往高出2-4倍，琼脂稀释药敏法也获得了同样高的MIC结果。Dalbavancin于2005年首次被纳入CLSI肉汤微量稀释方法表，并于2006年进行了修订，以澄清DMSO和P-80的使用。此处所示的肉汤微量稀释（BMD）程序是Dalbavancin特有的，符合CLSI和ISO方法，并逐步详细说明，重点是为清晰起见添加的关键步骤[6]。

使用Dalbavancin（15–240 mg/kg；腹腔注射；每 36 或 72 小时一次；持续 14 天；雌性 BALB/c 小鼠）治疗可在所有剂量方案中产生 80%–100% 的存活率 [1]。 炭疽杆菌是炭疽的病原体，当它被人类吸入或摄入时，会产生致命的疾病。Dalbavancin是一种新型的半合成脂糖肽，对革兰氏阳性细菌的活性比万古霉素强，在人体内的半衰期支持每周给药一次。Dalbavancin显示出对炭疽杆菌的强效体外活性（MIC范围<=0.03至0.5mg/l；MIC（50）和MIC（90）分别为0.06和0.25mg/l），这使我们在小鼠吸入性炭疽模型中测试了其疗效。单次腹腔注射5mg/kg和20mg/kg体重的Dalbavancin后，小鼠血浆中Dalbavancin的峰值浓度分别为15mg/kg和71mg/kg。在20mg/kg的剂量下，给药后6天内可以检测到Dalbavancin的活性（终末半衰期为53小时），这表明两次给药之间的长间隔是可行的。这些小鼠接受了50至100倍于Ames炭疽杆菌菌株中位致死剂量的挑战，这种接种物可以在4天内杀死未经治疗的动物。Dalbavancin的疗效为80%至100%，这取决于42天时的存活率，即在攻击后24小时开始治疗，每36小时（q36h）采用15至120mg/kg的方案，每72小时（q72h）采用30至240mg/kg的方案。同时测试了已知可以保护100%动物的环丙沙星方案。延迟达伐他汀治疗（攻击后36或48小时开始），每36小时60毫克/千克或每72小时120毫克/千克，仍能提供70%至100%的存活率。低MIC和体内长期有效性表明，Dalbavancin可能具有作为替代治疗或预防炭疽杆菌感染的潜力。[1]

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Dalbavancin在小鼠吸入性炭疽模型中的疗效。（i） 暴露后预防模型。[1]
从攻击后24小时开始，每36小时（≥15mg/kg）或每72小时（≥30mg/kg）腹腔注射Dalbavancin14天，可提供显著的保护作用（p<0.001）。尽管所有对照组小鼠在攻击后4天内死亡，但用Dalbavancin治疗的小鼠中有80%至100%在所有剂量方案下存活（图3）。没有迹象表明Dalbavancin的使用方案存在剂量反应关系。相比之下，如前所述，服用30mg/kg环丙沙星，每天两次，持续14天，可获得100%的存活率。 （ii）暴露后治疗模式。[1]
在攻击后36至42小时，吸入性炭疽引起的临床症状和死亡在小鼠模型中变得明显。包括环丙沙星和多西环素在内的治疗药物的疗效在之后服用时会显著降低。从攻击后36或48小时开始，腹腔注射60 mg/kg q36h或120 mg/kg q72h的Dalbavancin延迟治疗可提供70%至100%的保护（图4）。相比之下，从攻击后48小时开始，每天两次以30mg/kg的剂量腹腔注射环丙沙星，持续14天，保护了100%的小鼠。因此，即使治疗延迟到攻击后36或48小时，间歇性Dalbavancin治疗也能提供显著的保护（与对照组的结果相比，P<0.001），其疗效至少与每天两次的环丙沙星相当（P>0.05）。本研究中使用环丙沙星治疗获得的存活率与之前研究中获得的生存率的差异很可能是由于气溶胶系统固有的实验内部和实验之间的最终孢子挑战剂量的变化。由于这种变化，48小时开始治疗前的死亡人数在治疗开始时组间动物数量不同。

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根据治疗期间大腿负荷的增加，即2.30±0.14 log10 CFU/大腿，金黄色葡萄球菌分离株在未经治疗的对照小鼠中的体内毒力相似。感染后两小时，通过腹膜内途径给药Dalbavancin，每12小时给药一次7倍剂量的Dalbavancin（2.5、5、10、20、40、80和160mg/kg），持续6天的治疗期。在治疗开始和研究结束时对未治疗的对照组进行采样。从动物身上取出大腿，并立即进行CFU测定。这些研究的结果通过使用S形剂量效应模型进行分析（32）。与每个终点剂量相关的PK/PD指数的大小用以下方程式计算：log10 D=log10[E/（Emax−E）]/（N+log10 ED50），其中E是静态剂量（D）的对照生长，E是1-log杀伤的对照生长-1 log单位，E是2-log杀伤的控制生长-2 log单位。
分别对7个和6个分离株实现了1-log杀灭和2-log杀灭的结果（图2A和表2）。使用游离药物浓度，还考虑了与PK/PD相关的驱动因素AUC/MIC相关的Dalbavancin体内暴露反应数据。计算药物累积并将其纳入AUC估计值。使用S形Emax模型，七个应变数据集的数据拟合很强（R2=0.86），如图2B所示。表2中还显示了与三个治疗终点中的每一个相关的AUC/MIC数值。观察到净停滞，Dalbavancin游离药物AUC（fAUC）/MIC值接近25。在中性粒细胞减少的小鼠中，fAUC/MIC值接近50和100分别与生物体负荷的1-log和2-log减少相关。[5]

对Dalbavancin的敏感性。[1]
根据临床和实验室标准研究所（CLSI）的方法，在阳离子调节的Mueller Hinton肉汤（CAMHB）中，通过肉汤微量稀释法测定MIC，一式三份（11，12）。最终抗生素浓度为0.03至64μg/ml。在35°C下孵育18至24小时后，通过目视和分光光度法（600 nm）测定MIC。对质量控制菌株金黄色葡萄球菌ATCC 29213进行了平行检测

Protocol [6]
注：参考CLSI文件M7-A10和M100-S25和/或ISO/FDIS 20776-1，了解抗菌药物敏感性参考肉汤微量稀释方法的全部细节。参考方法允许在某些特定于接种物制备和MIC面板生产的程序中进行选择，以实现相同的最终结果。这里详细介绍的方法涉及一种抗菌剂Dalbavancin，其中一些步骤代表了参考程序可能采用的几种方法之一。应采取适当的安全预防措施（符合生物安全2级）。用于本视频出版物的MIC面板格式如表1所示。

1.储存Dalbavancin粉末[6]
收到诊断级Dalbavancin粉末后，在-20℃的干燥环境中储存在非除霜冰箱中。使用前，粉末应在打开前平衡至室温。

2.准备MIC面板稀释液[6]
在无菌玻璃或塑料管中，在纯DMSO中制备不高于1600µg/ml的Dalbavancin储备溶液，并在制备当天使用，或在-20至-60℃或以下储存，以备将来在非解冻冰箱中使用。在称量粉末时，考虑随粉末一起收到的文件中提供的Dalbavancin的效力（例如，800µg/ml的储备制剂见方程式1）。
按照表2中第1列（“源浓度”）所示的方案，用无菌玻璃或塑料管中的纯DMSO稀释储备稀释液。使用一支移液管测量稀释剂，另一支移管将初始Dalbavancin原液加入第一根试管中。对于每个后续的Dalbavancin库存浓度，使用一个新的移液管。
用纯DMSO制备100倍MIC面板最终浓度稀释液（中等浓度）。如表2第2-4列所示，将适当体积的源和DMSO混合以达到所需的中间浓度（使用的体积将取决于要制造的MIC面板的数量）。
制备0.004%P80：将0.1 ml P80加入4.9 ml dH2O中，制备2%P80的新鲜工作储备溶液。通过0.22微米的过滤器进行消毒，并在制备当天使用溶液。通过将2%P80稀释至1:500（例如，0.3 ml 2%P80至149.7 ml CAMHB）来制备0.004%P80稀释剂。
在阳离子调节的Mueller Hinton肉汤（CAMHB）中进一步稀释步骤2.2中制备的中间浓度1:100，该肉汤补充了0.004%（v/v）的聚山梨酯-80（P-80）P-80和/或LHB（用于链球菌），以两倍于最终浓度的方式添加，因为添加接种物（步骤4.3）将导致1:2的稀释。见表2中的第6和第7列。

3.准备MIC面板[6]
将步骤2.3中制备的每种Dalbavancin溶液50µl分配到MIC面板的适当孔中，并仅在一个孔（生长控制孔）中加入培养基。此步骤可使用带有无菌尖端的多通道移液管。
立即使用面板或用塑料薄膜密封，放入塑料袋中，并立即放入≤-20℃（最好≤-60℃）的非除霜冰箱中，直至需要。如果使用冷冻面板，在继续进行面板接种之前，拆下密封件，将单个面板放在实验室工作台上15-30分钟（直到孔内容物解冻）。

4.接种MIC面板，进行纯化并设置菌落计数[6]
从18-24小时血琼脂或其他非选择性琼脂平板中选择几个分离良好的菌落。用无菌环或拭子触摸每个菌落的顶部，转移到1-5ml CAMHB或生理盐水中，直到浊度等于0.5 McFarland标准。通过与0.5 McFarland或光度计进行目视比较来评估浊度。
在制备后15-30分钟内，将接种物在CAMHB中稀释1:100（100µl加入10 ml CAMHB中）。除肺炎链球菌外，对于大多数针对Dalbavancin进行测试的细菌，这种稀释液将提供5 x 105 CFU/ml的最终孔浓度（可接受的范围为2-8 x 105 CFU/ml）。对于肺炎链球菌，基于浊度与0.5 McFarland的比较，细菌浓度通常要低得多，因此，将接种物稀释1:25（400µl至10 ml CAMHB+10%+LHB）。
在接种物制备后15分钟内，将50µl最终接种物转移到步骤3中制备的MIC面板的每个孔（无菌对照孔除外）。使用无菌尖端的多通道移液管可用于此步骤。
通过使用无菌环将1-10µl等分试样从阳性生长对照孔转移并铺展到非选择性琼脂（例如，含有5%羊血的胰蛋白酶大豆琼脂）中，进行纯度检查。
用单通道移液管和无菌尖端从生长对照孔中取出10µl，并转移到10ml生理盐水（1:1000稀释液）中，以设置菌落计数。用单通道移液管和无菌尖端将100µl混合并转移到合适的非选择性琼脂培养基（例如，含有5%羊血的胰蛋白酶大豆琼脂）中，并用无菌环铺展在整个琼脂表面，在不同方向重复两次，以确保接种物均匀分布（1:10稀释）。

5.培养MIC板、菌落计数板和纯度板[6]
在孵育之前，用塑料带或紧密贴合的塑料盖将每个MIC面板或不超过4个面板的堆叠密封在塑料袋中。或者，将空的MIC面板放在不超过4个MIC面板的堆叠顶部，将湿纸巾放入塑料容器中，将MIC面板放入塑料容器，并用盖子牢牢关闭容器。
在接种后30分钟内，将MIC面板在35°C±2°C的环境空气培养箱中培养16-20小时（葡萄球菌和肠球菌）和20-24小时（链球菌）。在相同条件下孵育菌落计数和纯度板，但在5%CO2培养箱中孵育链球菌除外。

6.读取MIC和菌落计数板；检查纯度板[6]
将MIC读取为肉眼检测到的完全抑制孔中细菌生长的最低浓度。
在菌落计数板上计数菌落。将每个菌落乘以稀释因子（1:10000）（例如，50个菌落相当于5 x 105 CFU/ml）。可接受的范围为20-80个菌落（2-8 x 105 CFU/ml），用作近似指南。
检查纯度板。如果所有菌落都与步骤4.1中使用的菌落相似，则可以认为接种物是纯的。如果存在任何其他菌落，则MIC面板中可能存在污染物，应重复测试。

Animal/Disease Models: Female balb/c (Bagg ALBino) mouse: (6-8 weeks) challenged with Ames strain of B. anthracis[1]
Doses: 15 mg/kg, 30 mg/kg, 60 mg/kg, 120 mg/kg, 240 mg/kg
Route of Administration: intraperitoneal (ip)injection; every 36 h or 72 h; for 14 days
Experimental Results: The efficacy was 80 to 100%, as determined by the rate of survival at 42 days, when treatment was initiated 24 h postchallenge with regimens of 15 to 120 mg/kg every 36 h or 30 to 240 mg/kg every 72 h.

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Pharmacokinetics.[1]
Female ICR mice weighing 23 to 27 g were utilized. Single Dalbavancin doses of 5 and 20 mg/kg of body weight were administered i.p. or i.v. (via the tail vein) in 5% glucose solution. Blood samples were collected by cardiac puncture, while the mice were under halothane anesthesia, at 0.08, 0.25, 0.5, 1, 2, 4, 8, 12, 24, 48, 72, 96, and 144 h after dosing. Three animals per route, dose, and time point were utilized. The blood was collected in heparinized tubes, which were centrifuged to prepare the plasma. The plasma samples were stored at −20°C until analysis. Dalbavancin concentrations were determined by a microbiological agar diffusion assay that measures the total drug concentration, as described previously. The values of the PK parameters were determined by noncompartmental analysis. Efficacy studies.[1]
Female BALB/c mice (age, 6 to 8 weeks) were challenged by aerosol with between 50 and 100 times the established 50% lethal dose (3.4 × 104 CFU) of a spore preparation of the Ames strain of B. anthracis. In the postexposure prophylaxis model, antibiotic treatment (administered in 0.2 ml i.p.) was initiated 24 h after challenge. Treatment groups (10 mice per group) received Dalbavancin once every 36 h (q36h) at doses ranging from 15 to 120 mg/kg or every 72 h (q72h) at doses ranging from 30 to 240 mg/kg for 14 days. A regimen of ciprofloxacin known to protect 100% of animals (30 mg/kg twice daily for 14 days) was tested in parallel. In the postexposure treatment experiments, the administration of Dalbavancin at 60 mg/kg q36h or 120 mg/kg q72h was initiated at later times (36 or 48 h) after challenge, when symptoms of infection could have appeared. Control mice received phosphate-buffered saline (PBS). The mice were monitored for survival for 42 days, at which time the surviving animals were killed and their organs were harvested to determine the tissue bacterial burden. For animals that died or that were moribund at earlier times, their organs were harvested at those times. Lungs, spleens, and the mediastinum region (lymph nodes) were aseptically removed, weighed, and homogenized in 1 ml of sterile water. Homogenates were serially diluted 10-fold in water, and 100-μl aliquots were plated on sheep blood agar. To determine the numbers of CFU of the anthrax spores, homogenates were heat shocked for 15 min at 65°C to kill vegetative cells, serially diluted, and plated as described above.

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The current studies were designed to define the pharmacodynamic (PD) target for Dalbavancin against S. aureus strains with dalbavancin MICs at or above the current FDA breakpoint (≥0.12 μg/ml), some of which were vancomycin-intermediate S. aureus (VISA) strains. The results from these studies provide a pharmacodynamic rationale in support of the current clinical dosing regimens. Furthermore, the data provide a starting point for the development of revised susceptibility breakpoints for this new compound. Seven strains of Staphylococcus aureus (including four vancomycin-intermediate S. aureus [VISA] strains) were studied (Table 1). The Dalbavancin and vancomycin MIC values were determined in triplicate using CLSI reference broth microdilution methods, in the presence of polysorbate 80. The Dalbavancin MIC range for the S. aureus isolates was 0.12 to 0.50 μg/ml. The neutropenic murine thigh infection model was used for all studies. Mice were inoculated with 107 CFU/ml of each strain. Single-dose plasma pharmacokinetic studies were performed with thigh-infected mice given intraperitoneal doses (0.2 ml/dose) of dalbavancin (2.5, 10, 40, 80, or 160 mg/kg). Dalbavancin plasma concentrations were measured with a liquid chromatography-tandem mass spectrometry (LC-MS/MS) assay (Fig. 1); the lower limit of quantification for the assay was 0.05 μg/ml. Sample analysis precision (coefficient of variation [CV]) ranged from 5% to 6.4%, and accuracy (bias) ranged from −3.5% to −10.0%. Peak levels were observed by 2 to 6 h. Dalbavancin exhibited relatively linear pharmacokinetics, based on the dose-area under the concentration-time curve (AUC) relationship. The half-life was long and varied from 4.1 to 9.31 h. A protein binding value of 98.4%, based on prior studies in this model, was used. [5]

Absorption, Distribution and Excretion
In healthy subjects, dalbavancin AUC0-24h and Cmax both increased proportionally to dose following single intravenous (IV) dalbavancin doses ranging from 140 mg to 1500 mg, indicating linear pharmacokinetics. No apparent accumulation of dalbavancin was observed following multiple IV infusions administered once weekly for up to eight weeks, with 1000 mg on Day 1 followed by up to seven weekly 500 mg doses, in healthy adults with normal renal function.
Following administration of a single 1000 mg dose in healthy subjects, an average of 33% of the administered dalbavancin dose was excreted in urine as unchanged dalbavancin and approximately 12% of the administered dose was excreted in urine as the metabolite hydroxy-dalbavancin through 42 days post-dose. Approximately 20% of the administered dose was excreted in feces through 70 days post-dose.
Clearance and volume of distribution at steady state are comparable between healthy subjects and patients with infections. The volume of distribution at steady state was similar to the volume of extracellular fluid.
0.0513 L/h.

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Metabolism / Metabolites
Dalbavancin is not a substrate, inhibitor, or inducer of CYP450 isoenzymes. Subsequently, metabolites have not been observed in significant amounts in human plasma. The metabolites hydroxy-dalbavancin and mannosyl aglycone have been detected in urine (< 25% of administered dose). The metabolic pathways responsible for producing these metabolites have not been identified; however, due to the relatively minor contribution of metabolism to the overall elimination of dalbavancin, drug-drug interactions via inhibition or induction of metabolism of dalbavancin are not anticipated. Hydroxy-dalbavancin and mannosyl aglycone show significantly less antibacterial activity compared to dalbavancin.

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Biological Half-Life
Terminal half life is 346 hours.

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Dalbavancin PKs in mouse plasma.[1]
The concentrations of dalbavancin (bound and unbound) in plasma at different sampling times after i.p. administration are shown in Fig. 2, and the values of the PK and the pharmacodynamic (PD) parameters for the 5- and 20-mg/kg doses are presented in Table 1. The peak plasma concentrations (Cmax) of dalbavancin, attained 2 h after i.p. administration, were 15.2 and 71.3 μg/ml with the 5-mg/kg and 20-mg/kg doses, respectively. The terminal half-life achieved with the 20-mg/kg dose was 53 h. At the dose of 20 mg/kg i.p., dalbavancin was detectable (≥0.4 μg/ml) in plasma for 6 days after administration. From 2 h on, the levels in plasma closely followed the kinetics obtained with i.v. administration of the same doses (Fig. 2). However, the areas under the concentration-time curves (AUCs; calculated to infinity) were somewhat lower after i.p. administration (176 and 848 mg·h/liter with the 5- and 20-mg/kg doses, respectively) than after i.v. administration (200 and 1,071 mg·h/liter, respectively; data not shown). As observed in other studies with animals and humans (6, 16, 27, 33, 34), the PKs of dalbavancin in mice were dose proportional, on the basis of comparisons of the AUCs achieved with doses of 5 and 20 mg/kg.

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After a single infusion of dalbavancin, the maximal plasma concentration (C max) and area under the plasma concentration-time curve (AUC) increased in a proportional manner from 500 mg to 1000 mg (C max: 157 μg/ml and 299 μg/ml; AUClast: 10,850 μg·h/ml and 22,679 μg·h/ml, on the 500-mg and 1000-mg regimens, respectively) with low inter-subject variability. The mean terminal phase half-life (t 1/2) was 204 and 193 h after the 500-mg and 1000-mg dose, respectively. Clearance and volume of distribution were similar for the two dose concentrations. Treatment-emergent adverse events reported were considered to be of mild intensity. There were no relevant changes in laboratory values or vital signs over time in subjects in either treatment group. Conclusions: Overall, dalbavancin 500 mg and dalbavancin 1000 mg, administered as a single 30-min infusion, was well tolerated in this population and resulted in plasma exposures similar to those in non-Asians.[3]

Effects During Pregnancy and Lactation
◉ Summary of Use during Lactation
Dalbavancin is 93% plasma protein bound and is poorly absorbed orally, so it is not likely to reach the bloodstream of the infant or cause any adverse effects in breastfed infants. If dalbavancin is required by the mother, it is not a reason to discontinue breastfeeding. Monitor the infant for possible effects on the gastrointestinal tract, such as diarrhea, vomiting, and candidiasis (e.g., thrush, diaper rash).
◉ Effects in Breastfed Infants
Relevant published information was not found as of the revision date.
◉ Effects on Lactation and Breastmilk
Relevant published information was not found as of the revision date.

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Protein Binding
Dalbavancin is reversibly bound to human plasma proteins, primarily to albumin. The plasma protein binding of dalbavancin is 93% and is not altered as a function of drug concentration, renal insufficiency, or hepatic insufficiency.

[1]Antimicrob Agents Chemother. 2010 Mar;54(3):991-6.;

[2]Ther Clin Risk Manag. 2008 Feb;4(1):31-40.

[3]Clin Drug Investig. 2015 Dec;35(12):785-93.

[4]J Antimicrob Chemother. 2016 Jan;71(1):276-8.

[5]Antimicrob Agents Chemother. 2015 Dec;59(12):7833-6.

[6]J Vis Exp. 2015 Sep 9:(103):53028.

Pharmacodynamics
The antibacterial activity of dalbavancin appears to best correlate with the ratio of area under the concentration-time curve to minimal inhibitory concentration (AUC/MIC) for Staphylococcus aureus based on animal models of infection. An exposure-response analysis of a single study in patients with complicated skin and skin structure infections supports the two-dose regimen for which dalbavancin injection is administered. Subsequently, the recommended dosage regimen of dalbavancin in patients with normal renal function is 1500 mg, administered either as a single dose, or 1000 mg followed one week later by 500 mg [FDA Label, F2356. Dalbavancin should be administered over 30 minutes by intravenous infusion. Furthermore, inn a randomized, positive- and placebo-controlled, thorough QT/QTc study, 200 healthy subjects received either dalbavancin 1000 mg intravenous (IV), dalbavancin 1500 mg IV, oral moxifloxacin 400 mg, or placebo. Neither dalbavancin 1000 mg nor dalbavancin 1500 mg had any clinically relevant adverse effect on cardiac repolarization.

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Dalbavancin is a semisynthetic glycopeptide used for the treatment of acute bacterial skin and skin structure infections caused or suspected to be caused by susceptible isolates of designated Gram-positive microorganisms including MRSA. It has a role as an antibacterial drug and an antimicrobial agent. It is a carbohydrate acid derivative, a monosaccharide derivative, a glycopeptide and a semisynthetic derivative.
Dalbavancin is a second-generation lipoglycopeptide antibiotic that was designed to improve on the natural glycopeptides currently available, such as vancomycin and teicoplanin. Modifications from these older glycoprotein classes facilitated a similar mechanism of action for dalbavancin but with increased activity and once-weekly dosing. Its use is indicated for the treatment of acute bacterial skin and skin structure infections (ABSSSI) caused by the following gram-positive microorganisms: Staphylococcus aureus (including methicillin-susceptible and methicillin-resistant strains), S. pyogenes, S. agalactiae, S. dysgalactiae, the S. anginosus group (including S. anginosus, S. intermedius, and S. constellatus), and Enterococcus faecalis (vancomycin susceptible strains). Dalbavancin acts by interfering with bacterial cell wall synthesis by binding to the D-alanyl-D-alanine terminus of nascent cell wall peptidoglycan and preventing cross-linking.

Dalbavancin is a second-generation, semi-synthetic lipoglycopeptide antibiotic, with bactericidal activity against a variety of gram-positive bacteria. Upon administration, dalbavancin binds, at a site different from that of penicillins and cephalosporins, tightly to the D-alanyl-D-alanine portion of peptidoglycan chains, thereby preventing peptidoglycan elongation and interfering with bacterial cell wall synthesis. This leads to activation of bacterial autolysins and induces cell wall lysis.
DALBAVANCIN is a Unknown drug with a maximum clinical trial phase of IV (across all indications) that was first approved in 2014 and has 3 approved and 7 investigational indications.

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Drug Indication
Dalbavancin for injection is indicated for the treatment of adult patients with acute bacterial skin and skin structure infections (ABSSSI), caused by susceptible isolates of the following gram-positive microorganisms: Staphylococcus aureus (including methicillin-susceptible and methicillin-resistant strains), Streptococcus pyogenes, Streptococcus agalactiae, Streptococcus dysgalactiae, Streptococcus anginosus group (including Streptococcus anginosus, Streptococcus intermedius, Streptococcus constellatus) and Enterococcus faecalis (vancomycin susceptible strains). Dalbavancin is not active against gram-negative bacteria; therefore, combination therapy may be clinically indicated if the ABSSSI is polymicrobial and includes a suspected or documented gram-negative pathogen. To reduce the development of drug-resistant bacteria and maintain the effectiveness of dalbavancin and other antibacterial drugs, dalbavancin should be used only to treat infections that are proven or strongly suspected to be caused by susceptible bacteria. When culture and susceptibility information are available, they should be considered in selecting or modifying antibacterial therapy. In the absence of such data, local epidemiology and susceptibility patterns may contribute to the empiric selection of therapy.

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Bacillus anthracis, the causative agent of anthrax, can produce fatal disease when it is inhaled or ingested by humans. Dalbavancin, a novel, semisynthetic lipoglycopeptide, has potent activity, greater than that of vancomycin, against Gram-positive bacteria and a half-life in humans that supports once-weekly dosing. Dalbavancin demonstrated potent in vitro activity against B. anthracis (MIC range, < or =0.03 to 0.5 mg/liter; MIC(50) and MIC(90), 0.06 and 0.25 mg/liter, respectively), which led us to test its efficacy in a murine inhalation anthrax model. The peak concentrations of dalbavancin in mouse plasma after the administration of single intraperitoneal doses of 5 and 20 mg/kg of body weight were 15 and 71 mg/kg, respectively. At 20 mg/kg, the dalbavancin activity was detectable for 6 days after administration (terminal half-life, 53 h), indicating that long intervals between doses were feasible. The mice were challenged with 50 to 100 times the median lethal dose of the Ames strain of B. anthracis, an inoculum that kills untreated animals within 4 days. The efficacy of dalbavancin was 80 to 100%, as determined by the rate of survival at 42 days, when treatment was initiated 24 h postchallenge with regimens of 15 to 120 mg/kg every 36 h (q36h) or 30 to 240 mg/kg every 72 h (q72h). A regimen of ciprofloxacin known to protect 100% of animals was tested in parallel. Delayed dalbavancin treatment (beginning 36 or 48 h postchallenge) with 60 mg/kg q36h or 120 mg/kg q72h still provided 70 to 100% survival. The low MICs and long duration of efficacy in vivo suggest that dalbavancin may have potential as an alternat[1]

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Increasing rates of antimicrobial resistance among strains of Streptococcus, Staphylococcus, and Enterococcus spp. have been widely documented. At least 50% of nosocomial Staphylococcus aureus infections in intensive care units in the US and UK are due methicillin-resistant S. aureus (MRSA). Drug resistance is not confined to hospitals, and community-acquired MRSA (CA-MRSA) strains are now common causes of complicated skin and soft-tissue infections (cSSTIs) in many regions. Dalbavancin is a novel parenterally administered semisynthetic lipoglycopeptide similar to the naturally produced glycopeptides vancomycin and teicoplanin. Dalbavancin features a multifaceted mechanism of action that inhibits bacterial cell wall formation by two different mechanisms that enhances its activity against a wide range of gram-positive bacteria including staphylococci, streptococci, enterococci, and some anaerobes. Additionally, dalbavancin possesses unique pharmacokinetic properties, the most significant of which is a long terminal half-life that allows for once weekly dosing. This attribute may prove to yield clinical and cost benefit. Overall, clinical trials indicate that dalbavancin is a safe, well-tolerated, and effective antimicrobial agent. In the largest investigation evaluating dalbavancin for the treatment of cSSTIs, it appeared to be as effective as linezolid. Dalbavancin, which is expected to receive FDA approval in 2008, appears to be a promising new antimicrobial agent for the treatment of cSSTIs. [2]

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Dalbavancin is a novel lipoglycopeptide with activity against Staphylococcus aureus, including glycopeptide-resistant isolates. The in vivo investigation reported here tested the effects of this antibiotic against seven S. aureus isolates with higher MICs, including several vancomycin-intermediate strains. Results of 1-log kill and 2-log kill were achieved against seven and six of the isolates, respectively. The mean free-drug area under the concentration-time curve (fAUC)/MIC values for net stasis, 1-log kill, and 2-log kill were 27.1, 53.3, and 111.1, respectively. [5]

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Animal models alone will of necessity provide the fundamental efficacy data needed for the development of therapeutics active against biological threat agents, such as B. anthracis. The mouse anthrax inhalation model is the first step in meeting the FDA's “animal rule” (46). The results obtained with dalbavancin in this model warrant further study with mice and strongly indicate a need to progress to studies with the nonhuman primate model of B. anthracis infection.[1]

C88H101CL3N10O28

1853.15

1850.585

C, 57.04; H, 5.49; Cl, 5.74; N, 7.56; O, 24.17

2227366-51-8

Dalbavancin;171500-79-1

Typically exists as White to light yellow solid at room temperature

573 Ų

22

30

22

129

3740

18

CC(C)CCCCCCCCC(=O)N[C@@H]1[C@H]([C@@H]([C@H](O[C@H]1OC2=C3C=C4C=C2OC5=C(C=C(C=C5)[C@H]([C@H]6C(=O)N[C@@H](C7=C(C(=CC(=C7)O)O[C@@H]8[C@H]([C@H]([C@@H]([C@H](O8)CO)O)O)O)C9=C(C=CC(=C9)[C@H](C(=O)N6)NC(=O)[C@@H]4NC(=O)[C@@H]1C2=C(C(=CC(=C2)OC2=C(C=CC(=C2)[C@H](C(=O)N[C@H](CC2=CC=C(O3)C=C2)C(=O)N1)NC)O)O)Cl)O)C(=O)NCCCN(C)C)O)Cl)C(=O)O)O)O.Cl

PEXPCJWLNBNBNT-AXKGEONOSA-N

InChI=1S/C88H100Cl2N10O28.ClH/c1-38(2)13-10-8-6-7-9-11-14-61(106)94-70-73(109)75(111)78(86(120)121)128-87(70)127-77-58-31-43-32-59(77)124-55-24-19-42(29-50(55)89)71(107)69-85(119)98-67(80(114)92-25-12-26-100(4)5)48-33-44(102)34-57(125-88-76(112)74(110)72(108)60(37-101)126-88)62(48)47-28-40(17-22-52(47)103)65(82(116)99-69)95-83(117)66(43)96-84(118)68-49-35-46(36-54(105)63(49)90)123-56-30-41(18-23-53(56)104)64(91-3)81(115)93-51(79(113)97-68)27-39-15-20-45(122-58)21-16-39;/h15-24,28-36,38,51,60,64-76,78,87-88,91,101-105,107-112H,6-14,25-27,37H2,1-5H3,(H,92,114)(H,93,115)(H,94,106)(H,95,117)(H,96,118)(H,97,113)(H,98,119)(H,99,116)(H,120,121);1H/t51-,60-,64-,65-,66-,67+,68+,69+,70-,71-,72-,73-,74+,75+,76+,78+,87-,88+;/m1./s1

(2S,3S,4R,5R,6S)-6-[[(1S,2R,19R,22R,34S,37R,40R,52S)-5,32-dichloro-52-[3-(dimethylamino)propylcarbamoyl]-2,26,31,44,49-pentahydroxy-22-(methylamino)-21,35,38,54,56,59-hexaoxo-47-[(2R,3S,4S,5S,6R)-3,4,5-trihydroxy-6-(hydroxymethyl)oxan-2-yl]oxy-7,13,28-trioxa-20,36,39,53,55,58-hexazaundecacyclo[38.14.2.23,6.214,17.219,34.18,12.123,27.129,33.141,45.010,37.046,51]hexahexaconta-3,5,8,10,12(64),14(63),15,17(62),23(61),24,26,29(60),30,32,41(57),42,44,46(51),47,49,65-henicosaen-64-yl]oxy]-3,4-dihydroxy-5-(10-methylundecanoylamino)oxane-2-carboxylic acid;hydrochloride

Dalbavancin (hydrochloride); CHEMBL3301650; Dalbavancin hydrochloride (5:8);

2934.99.9001

Powder      -20°C    3 years

                     4°C     2 years

In solvent   -80°C    6 months

                  -20°C    1 month

注意： 请将本产品存放在密封且受保护的环境中，避免吸湿/受潮。

Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)

DMSO : 250 mg/mL (134.91 mM)
H2O : 50 mg/mL (26.98 mM)

配方 1 中的溶解度: ≥ 2.08 mg/mL (1.12 mM) (饱和度未知) in 10% DMSO + 40% PEG300 + 5% Tween80 + 45% Saline (这些助溶剂从左到右依次添加，逐一添加), 澄清溶液。
例如，若需制备1 mL的工作液，可将100 μL 20.8 mg/mL澄清DMSO储备液加入400 μL PEG300中，混匀；然后向上述溶液中加入50 μL Tween-80，混匀；加入450 μL生理盐水定容至1 mL。
*生理盐水的制备：将 0.9 g 氯化钠溶解在 100 mL ddH₂O中，得到澄清溶液。

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配方 2 中的溶解度: ≥ 2.08 mg/mL (1.12 mM) (饱和度未知) in 10% DMSO + 90% (20% SBE-β-CD in Saline) (这些助溶剂从左到右依次添加，逐一添加), 澄清溶液。
例如，若需制备1 mL的工作液，可将 100 μL 20.8 mg/mL澄清DMSO储备液加入900 μL 20% SBE-β-CD生理盐水溶液中，混匀。
*20% SBE-β-CD 生理盐水溶液的制备（4°C，1 周）：将 2 g SBE-β-CD 溶解于 10 mL 生理盐水中，得到澄清溶液。

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配方 3 中的溶解度: ≥ 2.08 mg/mL (1.12 mM) (饱和度未知) in 10% DMSO + 90% Corn Oil (这些助溶剂从左到右依次添加，逐一添加), 澄清溶液。
例如，若需制备1 mL的工作液，可将 100 μL 20.8 mg/mL 澄清 DMSO 储备液加入到 900 μL 玉米油中并混合均匀。

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请根据您的实验动物和给药方式选择适当的溶解配方/方案：
1、请先配制澄清的储备液(如：用DMSO配置50 或 100 mg/mL母液(储备液));
2、取适量母液，按从左到右的顺序依次添加助溶剂，澄清后再加入下一助溶剂。以 下列配方为例说明 (注意此配方只用于说明，并不一定代表此产品 的实际溶解配方):
10% DMSO → 40% PEG300 → 5% Tween-80 → 45% ddH2O (或 saline);
假设最终工作液的体积为 1 mL, 浓度为5 mg/mL: 取 100 μL 50 mg/mL 的澄清 DMSO 储备液加到 400 μL PEG300 中，混合均匀/澄清；向上述体系中加入50 μL Tween-80，混合均匀/澄清；然后继续加入450 μL ddH2O (或 saline)定容至 1 mL；
3、溶剂前显示的百分比是指该溶剂在最终溶液/工作液中的体积所占比例;
4、 如产品在配制过程中出现沉淀/析出，可通过加热(≤50℃)或超声的方式助溶;
5、为保证最佳实验结果，工作液请现配现用！
6、如不确定怎么将母液配置成体内动物实验的工作液，请查看说明书或联系我们;
7、 以上所有助溶剂都可在 Invivochem.cn网站购买。