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

Ceftobiprole (Ro 63-9141) has MIC90 values of 0.25, 2, and 2 mcg/mL, respectively, making it effective against major Gram-positive bacteria such as Enterococcus faecalis, methicillin-resistant Staphylococcus aureus, and Streptococcus pneumoniae (PRSP). The antibiotic cefbiproro, which has a minimum inhibitory concentration (MIC) of 2 μg/ml, also showed strong in vitro action against a number of clinical isolates of methicillin-resistant Staphylococcus aureus (CA-MRSA), Staphylococcus aureus (VISA), and Staphylococcus aureus (VRSA) [1]. With MICs ranging from 0.12 to 4 mg/L (just one resistant strain exhibited a MIC of 4 mg/L), cefbiproro exhibits strong levels of activity against Staphylococcus aureus. Furthermore, ceftobiprole has a MIC50 and MIC90 of 0.5 mg/L against methicillin-susceptible Staphylococcus aureus (MSSA) strains, which is two times higher than that of MRSA strains (1 mg/L). Moreover, cefbiproro had a slightly higher MIC50 and MIC90 of 0.5 mg/L and 1 mg/L for Panton-Valentine leukocidin (PVL) + MRSA compared to PVL-MRSA (MIC50 and MIC90 of 1 mg/L) [2].

Ceftobiprole medocaril is an antibacterial indicated for the treatment of adult patients with _Staphylococcus aureus_ bloodstream infections (bacteremia) (SAB), including those with right-sided infective endocarditis. It is additionally indicated in adult patients with acute bacterial skin and skin structure infections (ABSSSI). It is indicated in adult and pediatric patients ≥3 months of age for the treatment of community-acquired bacterial pneumonia (CABP). In Canada, it is indicated for the treatment of both community- and hospital-acquired pneumonia (excluding ventilator-associated pneumonia).
In a neutropenic murine thigh infection model, therapeutic efficacy is correlated with the time that the unbound plasma concentration of ceftobiprole exceeds the minimum inhibitory concentration (MIC) of _S. aureus_, _S. pneumoniae_, and _Enterobacterales spp._ It is not active against Gram-negative bacteria producing extended-spectrum beta-lactamases (ESBLs) from the TEM, SHV, or CTX-M families, serine carbapenemases (such as KPC), class B metallo-beta-lactamases, class C (AmpC cephalosporinases) if expressed at high levels, and Ambler class D beta-lactamases including carbapenemases. Ceftobiprole is not indicated for use in patients with ventilator-associated bacterial pneumonia (VABP) - in clinical trials, a statistically significant increase in mortality was seen in patients with VABP treated with ceftobiprole medocaril as compared to comparator-treated patients.

Absorption
Because cefbiprole medocaril is administered intravenously, its bioavailability is 100%. After multiple doses, the mean Cmax and AUC0-8h were 33.0 µg/mL and 102 µgh/mL, respectively.
Elimination Route
The active drug [cefbiprole] is primarily excreted unchanged via the kidneys. Approximately 89% of the administered dose is excreted in the urine as active cefbiprole (83%), open-ring metabolites (5%), and cefbiprole (<1%). Due to significant renal excretion, dose reduction may be necessary in patients with renal insufficiency receiving cefbiprole treatment.
Volume of Distribution
The steady-state volume of distribution of the active drug [Ceftobiprole] is 15.5–18.0 L, which is similar to the extracellular fluid volume of the human body.
Clearance
The mean clearance of the active drug [Ceftobiprole] after multiple doses was 4.98 L/h.
Protein Binding
The active drug [Ceftobiprole] has very low binding to plasma proteins (16%).
Metabolism/Metabolites
The conversion of the prodrug Ceftobiprole methyl ester to the active drug Ceftobiprole is rapid and mediated by nonspecific plasma esterases. Ceftobiprole itself is metabolized into a microbially inactive open-ring metabolite, which accounts for approximately 4% of the parent drug exposure in subjects with normal renal function.
Biological Half-Life
The half-life of the active drug [Ceftobiprole] after multiple doses is approximately 3.3 hours.

For adult patients with Staphylococcal bacteremia (SAB), the most common side effects of Zevtera include anemia, nausea, hypokalemia, vomiting, diarrhea, elevated liver function markers (liver enzymes and bilirubin), elevated serum creatinine, hypertension, leukopenia, fever, abdominal pain, fungal infection, headache, and dyspnea. For adult patients with acute bacterial skin and skin structure infection (ABSSSI), the most common side effects of Zevtera include nausea, diarrhea, headache, injection site reaction, elevated liver enzymes, rash, vomiting, and taste disturbance. For adult patients with community-acquired bacterial pneumonia (CABP), the most common side effects of Zevtera include nausea, elevated liver enzymes, vomiting, diarrhea, headache, rash, insomnia, abdominal pain, phlebitis, hypertension, and dizziness. For pediatric patients with community-acquired bacterial pneumonia (CABP), the most common side effects of Zevtera include vomiting, headache, elevated liver enzymes, diarrhea, infusion site reaction, phlebitis, and fever.
Zevtera should not be used if the patient has a known history of severe allergy to Ceftobiprole or any component of Zevtera, or to other members of the cephalosporin class of antibiotics.
Zevtera comes with several warnings and precautions, such as increased mortality in patients with ventilator-associated bacterial pneumonia (unapproved use), allergic reactions, seizures and other central nervous system reactions, and Clostridium difficile-associated diarrhea.
https://www.fda.gov/news-events/press-announcements/fda-approves-new-antibiotic-three-different-uses

[1]. Ceftobiprole, a Broad-Spectrum Cephalosporin With Activity against Methicillin-Resistant Staphylococcus aureus (MRSA). P T. 2008 Nov;33(11):631-41.
[2]. In vitro activity of ceftobiprole on 440 Staphylococcus aureus strains isolated from bronchopulmonary infections. Med Mal Infect. 2017 Mar;47(2):152-157.
[3]. 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.

Ceftobiprole is a fifth-generation cephalosporin antibiotic. Its molecular structure contains (E)-[(3'R)-2-oxo[1,3'-bipyrrolidine]-3-methylene]methyl and [(2Z)-2-(5-amino-1,2,4-thiadiazol-3-yl)-2-(hydroxyimino)acetyl]amino side chains at positions 3 and 7, respectively. It is used to treat hospital-acquired pneumonia (HAP, excluding ventilator-associated pneumonia, VAP) and community-acquired pneumonia (CAP). It is an antibacterial drug belonging to the cephalosporin and thiadiazole classes. Ceftobiprole is a cephalosporin antibiotic effective against methicillin-resistant Staphylococcus aureus (MRSA). It was discovered by Basel Pharmaceuticals and is currently being developed by Johnson & Johnson's research and development division. Ceftobiprole is the first cephalosporin to demonstrate clinical efficacy in patients with methicillin-resistant Staphylococcus aureus (MRSA) infections. If approved by regulatory agencies, it is expected to become one of the effective treatments for complicated skin infections and pneumonia. Ceftobiprole is a broad-spectrum fifth-generation pyrrolidone cephalosporin with antibacterial activity. Ceftobiprole binds to and inactivates penicillin-binding proteins (PBPs) located on the inner membrane of bacterial cell walls. PBPs are enzymes involved in the final stages of bacterial cell wall assembly and the remodeling of the cell wall during bacterial growth and division. Inactivation of PBPs interferes with the cross-linking of peptidoglycan chains, which is crucial for maintaining the strength and rigidity of the bacterial cell wall. This leads to weakening of the bacterial cell wall and cell lysis. Drug Indications: For the treatment of severe bacterial infections in hospitalized patients.

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Mechanism of Action
Cephalexin antibiotics, such as Ceftobiprole, have bactericidal activity, and their mechanism of action is the same as that of other β-lactam antibiotics (such as penicillins). Cephalosporins disrupt the synthesis of the peptidoglycan layer in bacterial cell walls. The peptidoglycan layer is crucial for the structural integrity of the cell wall, especially in Gram-positive bacteria. The final transpeptidation step in peptidoglycan synthesis is promoted by a transpeptidase called penicillin-binding protein (PBP). PBP binds to the D-Ala-D-Ala terminus of the peptidoglycan precursor (cell wall peptide), causing the peptidoglycan to cross-link. β-lactam antibiotics mimic this site, competitively inhibiting the cross-linking of peptidoglycan with PBP.

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Pharmacodynamics
Ceftobiprole is a cephalosporin antibiotic effective against methicillin-resistant Staphylococcus aureus (MRSA).

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Ceftobiprole levodopa is a cephalosporin that can be used as a prodrug.
Ceftobiprole medocaril is a prodrug of Ceftobiprole, a fifth-generation semi-synthetic cephalosporin antibiotic. Ceftobiprole is a broad-spectrum antibiotic active against both Gram-positive and Gram-negative bacteria, including methicillin-resistant Staphylococcus aureus (MRSA). In February 2010, the European Medicines Agency's Committee for Medicinal Products for Human Use (CHMP) issued a negative opinion on Ceftobiprole sodium (ceftobiprole medocaril), recommending its rejection for marketing authorization in the European Union, primarily due to issues with the quality of data from pivotal clinical studies. The drug was first approved in Canada in October 2017 for the treatment of certain bacterial pneumonia patients, and subsequently approved in the United States in April 2024 for the treatment of skin and soft tissue infections and bacteremia. Ceftobiprole sodium is the sodium salt form of Ceftobiprole sodium, a water-soluble prodrug of Ceftobiprole. Ceftobiprole is a pyrrolidone cephalosporin antibiotic with bactericidal activity. Ceftobiprole binds to and inactivates penicillin-binding protein (PBP), an enzyme involved in the final stages of cell wall assembly and remodeling during bacterial growth and division. This drug exhibits broad-spectrum antibacterial activity against both Gram-negative and Gram-positive bacteria, including methicillin-resistant Staphylococcus aureus (MRSA), vancomycin-intermediate Staphylococcus aureus (VISA), and vancomycin-resistant Staphylococcus aureus (VRSA). Ceftobiprole is not readily hydrolyzed by class A and C β-lactamases. A randomized, controlled, double-blind, multinational, multicenter trial evaluated the efficacy of Zevtera in treating Staphylococcus aureus bacteremia (SAB). In this trial, researchers randomized 390 participants to either the Zevtera group (192 participants) or the daptomycin plus optional aztreonam group (control group) (198 participants). The primary efficacy endpoint was overall success rate at the post-treatment assessment visit (defined as survival, symptom improvement, clearance of Staphylococcus aureus bacteremia, no new Staphylococcus aureus bacteremia complications, and no use of other potentially effective antibiotics), performed 70 days after randomization for antibiotics. The overall success rate was 69.8% in participants treated with Zevtera and 68.7% in participants treated with the control drug. The efficacy of Zevtera in treating acute bacterial skin and skin structure infections (ABSSSI) was evaluated in a randomized, controlled, double-blind, multicenter trial. In this trial, researchers randomized 679 participants to receive either Zevtera (335 participants) or vancomycin plus aztreonam [control drug] (344 participants). The primary efficacy endpoint was early clinical response within 48–72 hours of treatment initiation. Early clinical efficacy was defined as a reduction of at least 20% in primary skin lesions, survival for at least 72 hours, and no need for additional antibiotic treatment or unplanned surgery. In subjects treated with Zevtera, 91.3% achieved early clinical efficacy within the specified time, compared to 88.1% in subjects receiving the control drug. A randomized, controlled, double-blind, multinational, multicenter trial evaluated the efficacy of Zevtera in treating community-acquired bacterial pneumonia (CABP) in adults. In this trial, 638 adult patients hospitalized for CABP requiring at least 3 days of intravenous antibiotic treatment were randomized to either the Zevtera group (314 subjects) or ceftriaxone plus linezolid (control drug) (324 subjects). The primary efficacy endpoint was clinical cure rate at the cure assessment visit, conducted 7–14 days after the end of treatment. In subjects treated with Zevtera, 76.4% achieved clinical cure, compared to 79.3% in those treated with the control drug. Another analysis considered an earlier clinical success timepoint of day 3, with a success rate of 71% in the Zevtera group and 71.1% in the control drug group. Given the similar course of community-acquired bacterial pneumonia (CABP) in adults and children, Zevtera was approved today for use in children aged 3 months to 18 years with CABP. This approval is based on evidence from Zevtera’s CABP trial in adults and a trial that included 138 children aged 3 months to 18 years with pneumonia. https://www.fda.gov/news-events/press-announcements/fda-approves-new-antibiotic-three-different-uses

C20H22N8O6S2

534.56900

534.11

C, 44.94; H, 4.15; N, 20.96; O, 17.96; S, 12.00

209467-52-7

252188-71-9 (medocaril);209467-52-7; 376653-43-9;

135413542

Light yellow to yellow solid powder

2.0±0.1 g/cm3

1.942

-2.69

5

13

6

36

1100

3

O=C(C(N12)=C(/C=C3C(N([C@H]4CNCC4)CC/3)=O)CS[C@]2([H])[C@H](NC(/C(C5=NSC(N)=N5)=N\O)=O)C1=O)O

VOAZJEPQLGBXGO-SDAWRPRTSA-N

InChI=1S/C20H22N8O6S2/c21-20-24-14(26-36-20)11(25-34)15(29)23-12-17(31)28-13(19(32)33)9(7-35-18(12)28)5-8-2-4-27(16(8)30)10-1-3-22-6-10/h5,10,12,18,22,34H,1-4,6-7H2,(H,23,29)(H,32,33)(H2,21,24,26)/b8-5+,25-11-/t10-,12-,18-/m1/s1

(6R,7R)-7-((Z)-2-(5-amino-1,2,4-thiadiazol-3-yl)-2-(hydroxyimino)acetamido)-8-oxo-3-((E)-((R)-2-oxo-[1,3'-bipyrrolidin]-3-ylidene)methyl)-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid

Ro 63-9141; Ro-63-9141; Ro63-9141; BAL 9141;Ceftobiprole medocaril; Ceftobiprole medocaril sodium; BAL5788; Ro 65-5788; (6R,7R)-7-[[(2Z)-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; AC1OCFF8; Zeftera; UNII-5T97333YZK; BAL-9141; BAL9141.

2934.99.9001

Powder      -20°C    3 years

                     4°C     2 years

In solvent   -80°C    6 months

                  -20°C    1 month

Note: This product is not stable in solution, please use freshly prepared working solution for optimal results.

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

DMSO : ~4.95 mg/mL (~9.26 mM)

Solubility in Formulation 1: ≥ 0.5 mg/mL (0.94 mM) (saturation unknown) in 10% DMSO + 40% PEG300 + 5% Tween80 + 45% Saline (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 5.0 mg/mL clear DMSO stock solution to 400 μL PEG300 and mix evenly; then add 50 μL Tween-80 to the above solution and mix evenly; then add 450 μL normal saline to adjust the volume to 1 mL.
Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH₂ O to obtain a clear solution.

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Solubility in Formulation 2: ≥ 0.5 mg/mL (0.94 mM) (saturation unknown) in 10% DMSO + 90% (20% SBE-β-CD in Saline) (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 5.0 mg/mL clear DMSO stock solution to 900 μL of 20% SBE-β-CD physiological saline solution and mix evenly.
Preparation of 20% SBE-β-CD in Saline (4°C，1 week): Dissolve 2 g SBE-β-CD in 10 mL saline to obtain a clear solution.

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Solubility in Formulation 3: ≥ 0.5 mg/mL (0.94 mM) (saturation unknown) in 10% DMSO + 90% Corn Oil (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 5.0 mg/mL clear DMSO stock solution to 900 μL of corn oil and mix evenly.

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 (Please use freshly prepared in vivo formulations for optimal results.)