Penicillin-binding proteins (PBPs); bacterial cell wall synthesis.

头孢比普酯钠是头孢比普酯的钠盐形式，头孢比普酯本身是头孢比普的一种水溶性前体药物。头孢比普是一种吡咯烷酮类头孢菌素抗生素，具有杀菌活性。它通过与青霉素结合蛋白（PBPs）结合并使其失活来发挥作用，这些酶参与细菌细胞壁组装的终末阶段以及在细菌生长和分裂过程中的细胞壁重塑。该药物对革兰阴性菌和革兰阳性菌均表现出广谱活性，包括耐甲氧西林金黄色葡萄球菌（MRSA）、万古霉素中度敏感金黄色葡萄球菌（VISA）和耐万古霉素金黄色葡萄球菌（VRSA）。此外，头孢比普对A类和C类β-内酰胺酶的水解作用不敏感。
头孢比普已在体外实验中表现出对革兰阳性菌和革兰阴性菌的活性。
作为头孢比普酯的活性成分，头孢比普通过抑制细菌细胞壁合成发挥杀菌作用。其作用机制主要是通过与关键的青霉素结合蛋白（PBPs）结合，抑制其转肽酶活性，从而干扰细菌细胞壁肽聚糖层的合成。头孢比普在体外对革兰阳性菌和革兰阴性菌均显示出活性。在包括耐甲氧西林金黄色葡萄球菌（MRSA）在内的革兰阳性菌中，头孢比普能够与PBP2a结合。此外，它还能与肺炎链球菌（青霉素中度敏感）的PBP2b、肺炎链球菌（青霉素耐药）的PBP2x以及粪肠球菌的PBP5结合。

Ceftobiprole medocaril（BAL5788；sc；3 × q12h；BAL9141 等效物的每日总剂量，2.1、4.2 或 8.4 mg/kg）感染瑞士雌性白化小鼠（体重 20 至 22 g）的 Penr Cros Ctxs 菌株 P-15986导致 10 天累积生存率范围为 57% 至 100%[1]。当剂量从 40 mg/kg 增加至 160 mg/kg 时，头孢比普罗 medocaril（10、40、160 mg/kg；单剂量；皮下注射）的 T1/2 范围为 20 至 31 分钟。在中性粒细胞减少大腿感染的小鼠中，对于增加的单剂量，Cmax/剂量值从1.08下降到0.90，而AUC/剂量值范围从0.585到1.33[2]。
头孢比普酯是一种抗菌药物，适用于治疗成人患者的金黄色葡萄球菌血流感染（菌血症）（SAB），包括合并右侧感染性心内膜炎的患者。该药物还适用于治疗成人患者的急性细菌性皮肤及皮肤结构感染（ABSSSI），以及年龄≥3个月的成人和儿童患者的社区获得性细菌性肺炎（CABP）。在加拿大，该药的适应症还包括社区获得性和医院获得性肺炎（不包括呼吸机相关性肺炎）的治疗。

在一项中性粒细胞减少小鼠大腿感染模型中，头孢比普酯的治疗效果与药物游离血浆浓度超过金黄色葡萄球菌、肺炎链球菌和肠杆菌目细菌最低抑菌浓度（MIC）的时间相关。该药物对产生TEM、SHV或CTX-M家族超广谱β-内酰胺酶（ESBLs）的革兰阴性菌无效，对产丝氨酸碳青霉烯酶（如KPC）、B类金属β-内酰胺酶、高水平表达的C类（AmpC头孢菌素酶）以及Ambler D类β-内酰胺酶（包括碳青霉烯酶）的细菌亦无活性。头孢比普酯不适用于呼吸机相关性细菌肺炎（VABP）患者——临床试验显示，与对照治疗组相比，使用头孢比普酯治疗的VABP患者死亡率存在统计学意义上的显著升高。

Absorption
Because ceftobiprole medocaril is administered intravenously, its bioavailability is 100%. The mean Cmax and AUC0-8h after multiple-dose administration are 33.0 µg/mL and 102 µg*h/mL, respectively.

Route of Elimination
Active [ceftobiprole] is eliminated primarily unchanged by renal excretion. Approximately 89% of the administered dose is recovered in the urine as active ceftobiprole (83%), the open-ring metabolite (5%) and ceftobiprole medocaril (<1%). Due to the significant degree of renal elimination, patients with renal impairment who are undergoing treatment with ceftobiprole may require lower doses.

Volume of Distribution
The steady-state volume of distribution of active [ceftobiprole] is 15.5-18.0 L, which approximates extracellular fluid volume in humans.

Clearance
The mean clearance of active [ceftobiprole] following multiple-dose administration is 4.98 L/h.

Protein Binding
Active [ceftobiprole] is minimally (16%) bound to plasma proteins.

Metabolism / Metabolites
Conversion of prodrug ceftobiprole medocaril to the active moiety ceftobiprole occurs rapidly and is mediated by non-specific plasma esterases. Ceftobiprole itself is minimally metabolized to a microbiologically inactive open-ring metabolite, which accounts for approximately 4% of the parent exposure in subject with a normal renal function.

Biological Half-Life
The half-life of active [ceftobiprole] following multiple-dose administration is approximately 3.3 hours.

For adults with SAB, the most common side effects of Zevtera included anemia, nausea, low levels of potassium in the blood (hypokalemia), vomiting, diarrhea, increased levels of certain liver tests (hepatic enzymes and bilirubin), increased blood creatinine, high blood pressure, low white blood cell count (leukopenia), fever, abdominal pain, fungal infection, headache and shortness of breath (dyspnea).
For adults with ABSSSI, the most common side effects of Zevtera included nausea, diarrhea, headache, injection site reaction, increased levels of hepatic enzymes, rash, vomiting and altered taste (dysgeusia).
For adults with CABP, the most common side effects of Zevtera included nausea, increased levels of hepatic enzymes, vomiting, diarrhea, headache, rash, insomnia, abdominal pain, vein inflammation (phlebitis), high blood pressure and dizziness. For pediatric patients with CABP, the most common side effects of Zevtera included vomiting, headache, increased levels of hepatic enzymes, diarrhea, infusion site reaction, vein inflammation (phlebitis) and fever.
Patients should not use Zevtera if they have a known history of severe hypersensitivity to ceftobiprole or any of the components of Zevtera, or other members of the cephalosporin antibacterial class.
Zevtera comes with certain warnings and precautions such as increased mortality in ventilator-associated bacterial pneumonia patients (an unapproved use), hypersensitivity reactions, seizures and other central nervous system reactions and Clostridioides difficile-associated diarrhea.
https://www.fda.gov/news-events/press-announcements/fda-approves-new-antibiotic-three-different-uses

[1]. Efficacy of BAL5788, a prodrug of cephalosporin BAL9141, in a mouse model of acute pneumococcal pneumonia. Antimicrob Agents Chemother. 2004 Apr;48(4):1105-11.
[2]. In vivo pharmacodynamics of ceftobiprole against multiple bacterial pathogens in murine thigh and lung infection models. Antimicrob Agents Chemother. 2008 Oct;52(10):3492-6.

Ceftobiprole medocaril is a [ceftobiprole] prodrug.
Ceftobiprole Medocaril Sodium is a water-soluble prodrug of ceftobiprole, a pyrrolidinone cephalosporin antibiotic, with bactericidal activity. Ceftobiprole binds to and inactivates penicillin-binding proteins (PBPs), enzymes involved in the terminal stages of bacterial cell wall assembly and cell wall reshaping during bacterial growth and division. This agent exhibits a broad spectrum of activity against gram-negative and gram-positive pathogens including methicillin-resistant S. aureus (MRSA), vancomycin-intermediate S. aureus (VISA) and vancomycin-resistant S. aureus (VRSA). Ceftobiprole is refractory to hydrolysis by class A and class C lactamases.

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Drug Indication
Treatment of pneumonia
Treatment of complicated skin and soft-tissue infections

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Ceftobiprole is a fifth-generation cephalosporin antibiotic having (E)-[(3'R)-2-oxo[1,3'-bipyrrolidin]-3-ylidene]methyl and [(2Z)-2-(5-amino-1,2,4-thiadiazol-3-yl)-2-(hydroxyimino)acetyl]amino side groups located at positions 3 and 7 respectively; developed for the treatment of hospital-acquired pneumonia (HAP, excluding ventilator-associated pneumonia, VAP) and community-acquired pneumonia (CAP). It has a role as an antimicrobial agent. It is a cephalosporin and a member of thiadiazoles.
Ceftobiprole is a cephalosporin antibiotic with activity against methicillin-resistant Staphylococcus aureus. It was discovered by Basilea Pharmaceutica and is being developed by Johnson & Johnson Pharmaceutical Research and Development. Ceftobiprole is the first cephalosporin to demonstrate clinical efficacy in patients with infections due to methicillin-resistant staphylococci and, if approved by regulatory authorities, is expected to be a useful addition to the armamentarium of agents for the treatment of complicated skin infections and pneumonia.
Ceftobiprole is a broad-spectrum, fifth-generation, pyrrolidinone cephalosporin with antibacterial activity. Ceftobiprole binds to and inactivates penicillin-binding proteins (PBPs) located on the inner membrane of the bacterial cell wall. PBPs are enzymes involved in the terminal stages of assembling the bacterial cell wall and in reshaping the cell wall during growth and division. Inactivation of PBPs interferes with the cross-linkage of peptidoglycan chains necessary for bacterial cell wall strength and rigidity. This results in the weakening of the bacterial cell wall and causes cell lysis.

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Drug Indication
For the treatment of serious bacterial infections in hospitalised patients.

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Mechanism of Action
Cephalosporins, such as ceftobiprole, are bactericidal and have the same mode of action as other beta-lactam antibiotics (such as penicillins). Cephalosporins disrupt the synthesis of the peptidoglycan layer of bacterial cell walls. The peptidoglycan layer is important for cell wall structural integrity, especially in Gram-positive organisms. The final transpeptidation step in the synthesis of the peptidoglycan is facilitated by transpeptidases known as penicillin binding proteins (PBPs). PBPs bind to the D-Ala-D-Ala at the end of muropeptides (peptidoglycan precursors) to crosslink the peptidoglycan. Beta-lactam antibiotics mimic this site and competitively inhibit PBP crosslinking of peptidoglycan.

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Pharmacodynamics
Ceftobiprole, a cephalosporin antibiotic, is active against methicillin-resistant Staphylococcus aureus.

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Ceftobiprole medocaril is a cephalosporin. It has a role as a prodrug.
Ceftobiprole medocaril is a prodrug of [ceftobiprole], a fifth-generation semisynthetic cephalosporin antibacterial. Ceftobiprole is a broad-spectrum agent with demonstrated activity against both Gram-positive and Gram-negative bacteria, including antibiotic-resistant strains of Staphylcoccus aureus (methicillin-resistant Staphylococcus aureus; MRSA). The EMA's Committee for Medicinal Products for Human Use (CHMP) adopted a negative opinion of ceftobiprole medocaril in February 2010, recommending the refusal of its marketing authorization in the European Union primarily due to data quality issues in pivotal clinical studies. It received its first approval in Canada in October 2017 for use in certain patients with bacterial pneumonia, and was subsequently approved in the United States with additional indications for skin and skin structure infections and bacteremia in April 2024.
Ceftobiprole Medocaril Sodium is the sodim salt form of ceftobiprole medocaril, a water-soluble prodrug of ceftobiprole, a pyrrolidinone cephalosporin antibiotic, with bactericidal activity. Ceftobiprole binds to and inactivates penicillin-binding proteins (PBPs), enzymes involved in the terminal stages of bacterial cell wall assembly and cell wall reshaping during bacterial growth and division. This agent exhibits a broad spectrum of activity against gram-negative and gram-positive pathogens including methicillin-resistant S. aureus (MRSA), vancomycin-intermediate S. aureus (VISA) and vancomycin-resistant S. aureus (VRSA). Ceftobiprole is refractory to hydrolysis by class A and class C lactamases.

Zevtera’s efficacy in treating SAB was evaluated in a randomized, controlled, double-blind, multinational, multicenter trial. In the trial, researchers randomly assigned 390 subjects to receive Zevtera (192 subjects) or daptomycin plus optional aztreonam [the comparator] (198 subjects). The primary measure of efficacy for this trial was the overall success (defined as survival, symptom improvement, S. aureus bacteremia bloodstream clearance, no new S. aureus bacteremia complications and no use of other potentially effective antibiotics) at the post-treatment evaluation visit, which occurred 70 days after being randomly assigned an antibiotic. A total of 69.8% of subjects who received Zevtera achieved overall success compared to 68.7% of subjects who received the comparator.
Zevtera’s efficacy in treating ABSSSI was evaluated in a randomized, controlled, double-blind, multinational trial. In the trial, researchers randomly assigned 679 subjects to receive either Zevtera (335 subjects) or vancomycin plus aztreonam [the comparator] (344 subjects). The primary measure of efficacy was early clinical response 48-72 hours after start of treatment. Early clinical response required a reduction of the primary skin lesion by at least 20%, survival for at least 72 hours and the absence of additional antibacterial treatment or unplanned surgery. Of the subjects who received Zevtera, 91.3% achieved an early clinical response within the necessary timeframe compared to 88.1% of subjects who received the comparator.
Zevtera’s efficacy in treating adult patients with CABP was evaluated in a randomized, controlled, double-blind, multinational, multicenter trial. In the trial, researchers randomly assigned 638 adults hospitalized with CABP and requiring IV antibacterial treatment for at least 3 days to receive either Zevtera (314 subjects) or ceftriaxone with optional linezolid [the comparator] (324 subjects). The primary measurement of efficacy were clinical cure rates at test-of-cure visit, which occurred 7-14 days after end-of-treatment. Of the subjects who received Zevtera, 76.4% achieved clinical cure compared to 79.3% of subjects who received the comparator. An additional analysis considered an earlier timepoint of clinical success at Day 3, which was 71% in patients receiving Zevtera and 71.1% in patients receiving the comparator.
Given the similar course of CABP in adults and pediatric patients, today’s approval of Zevtera in pediatric patients three months to less than 18 years with CABP was supported by evidence from the CABP trial of Zevtera in adults and a trial in 138 pediatric subjects three months to less than 18 years of age with pneumonia.
https://www.fda.gov/news-events/press-announcements/fda-approves-new-antibiotic-three-different-uses

C26H26N8O11S2

690.66

690.116

376653-43-9

Ceftobiprole medocaril sodium;252188-71-9; 209467-52-7 (ceftobiprole); 376653-43-9 (free acid)

135456161

Typically exists as solid at room temperature

2.0±0.1 g/cm3

1.865

-1.28

310

4

17

9

47

1560

3

S1CC(/C=C2/C(N(CC/2)[C@H]2CN(C(=O)OCC3=C(C)OC(=O)O3)CC2)=O)=C(C(=O)O)N2C([C@H]([C@@H]12)NC(/C(/C1=NSC(N)=N1)=N\O)=O)=O

HFTSMHTWUFCYMJ-FDNJTQOMSA-N

InChI=1S/C26H26N8O11S2/c1-10-14(45-26(41)44-10)8-43-25(40)32-4-3-13(7-32)33-5-2-11(20(33)36)6-12-9-46-22-16(21(37)34(22)17(12)23(38)39)28-19(35)15(30-42)18-29-24(27)47-31-18/h6,13,16,22,42H,2-5,7-9H2,1H3,(H,28,35)(H,38,39)(H2,27,29,31)/b11-6+,30-15+/t13-,16-,22-/m1/s1

(6R,7R)-7-[[(2E)-2-(5-amino-1,2,4-thiadiazol-3-yl)-2-hydroxyiminoacetyl]amino]-3-[(E)-[1-[(3R)-1-[(5-methyl-2-oxo-1,3-dioxol-4-yl)methoxycarbonyl]pyrrolidin-3-yl]-2-oxopyrrolidin-3-ylidene]methyl]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid

Ceftobiprole; 209467-52-7; ceftobiprol; ceftobiprolum; BAL9141-000;

2934.99.9001

Powder      -20°C    3 years

                     4°C     2 years

In solvent   -80°C    6 months

                  -20°C    1 month

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

注意: 如下所列的是一些常用的体内动物实验溶解配方，主要用于溶解难溶或不溶于水的产品（水溶度<1 mg/mL）。 建议您先取少量样品进行尝试，如该配方可行，再根据实验需求增加样品量。

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注射用配方1: DMSO : Tween 80： Saline = 10 : 5 : 85 (如： 100 μL DMSO → 50 μL Tween 80 → 850 μL Saline)
*生理盐水/Saline的制备：将0.9g氯化钠/NaCl溶解在100 mL ddH ₂ O中，得到澄清溶液。
注射用配方 2: DMSO : PEG300 ：Tween 80 : Saline = 10 : 40 : 5 : 45 (如： 100 μL DMSO → 400 μL PEG300 → 50 μL Tween 80 → 450 μL Saline)
注射用配方 3: DMSO : Corn oil = 10 : 90 (如： 100 μL DMSO → 900 μL Corn oil)
示例: 以注射用配方 3 (DMSO : Corn oil = 10 : 90) 为例说明, 如果要配制 1 mL 2.5 mg/mL的工作液, 您可以取 100 μL 25 mg/mL 澄清的 DMSO 储备液，加到 900 μL Corn oil/玉米油中, 混合均匀。

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注射用配方 4: DMSO : 20% SBE-β-CD in Saline = 10 : 90 [如：100 μL DMSO → 900 μL (20% SBE-β-CD in Saline)]
*20% SBE-β-CD in Saline的制备（4°C，储存1周）：将2g SBE-β-CD (磺丁基-β-环糊精) 溶解于10mL生理盐水中，得到澄清溶液。
注射用配方 5: 2-Hydroxypropyl-β-cyclodextrin : Saline = 50 : 50 (如： 500 μL 2-Hydroxypropyl-β-cyclodextrin (羟丙基环胡精)→ 500 μL Saline)
注射用配方 6: DMSO : PEG300 : Castor oil : Saline = 5 : 10 : 20 : 65 (如： 50 μL DMSO → 100 μL PEG300 → 200 μL Castor oil → 650 μL Saline)
注射用配方 7: Ethanol : Cremophor : Saline = 10： 10 : 80 (如： 100 μL Ethanol → 100 μL Cremophor → 800 μL Saline)
注射用配方 8: 溶解于Cremophor/Ethanol (50 : 50), 然后用生理盐水稀释。
注射用配方 9: EtOH : Corn oil = 10 : 90 (如： 100 μL EtOH → 900 μL Corn oil)
注射用配方 10: EtOH : PEG300：Tween 80 : Saline = 10 : 40 : 5 : 45 (如： 100 μL EtOH → 400 μL PEG300 → 50 μL Tween 80 → 450 μL Saline)

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口服配方 1: 悬浮于0.5% CMC Na (羧甲基纤维素钠)
口服配方 2: 悬浮于0.5% Carboxymethyl cellulose (羧甲基纤维素)
示例: 以口服配方 1 (悬浮于 0.5% CMC Na)为例说明, 如果要配制 100 mL 2.5 mg/mL 的工作液, 您可以先取0.5g CMC Na并将其溶解于100mL ddH2O中，得到0.5%CMC-Na澄清溶液；然后将250 mg待测化合物加到100 mL前述 0.5%CMC Na溶液中，得到悬浮液。

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口服配方 3: 溶解于 PEG400 (聚乙二醇400)
口服配方 4: 悬浮于0.2% Carboxymethyl cellulose (羧甲基纤维素)
口服配方 5: 溶解于0.25% Tween 80 and 0.5% Carboxymethyl cellulose (羧甲基纤维素)
口服配方 6: 做成粉末与食物混合

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注意: 以上为较为常见方法，仅供参考， InvivoChem并未独立验证这些配方的准确性。具体溶剂的选择首先应参照文献已报道溶解方法、配方或剂型，对于某些尚未有文献报道溶解方法的化合物，需通过前期实验来确定（建议先取少量样品进行尝试），包括产品的溶解情况、梯度设置、动物的耐受性等。

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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;
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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。