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

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.
Ceftobiprole has demonstrated _in vitro_ activity against Gram-positive and Gram-negative bacteria.
[Ceftobiprole], the active moiety of ceftobiprole medocaril, exhibits its bactericidal activity by inhibition of bacterial cell wall synthesis. This activity is mediated through binding to essential penicillin-binding proteins (PBPs) and inhibiting their transpeptidase activity, which is essential for the synthesis of the peptidoglycan layer of the bacterial cell wall. Ceftobiprole has demonstrated _in vitro_ activity against both Gram-positive and Gram-negative bacteria. In Gram-positive bacteria, including methicillin-resistant _Staphylococcus aureus_ (MRSA), Ceftobiprole binds to PBP2a. Ceftobiprole also binds to PBP2b in _Streptococcus pneumoniae_ (penicillin-intermediate), PBP2x in _S. pneumoniae_ (penicillin resistant), and to PBP5 in _Enterococcus faecalis_.

Ceftobiprole medocaril (BAL5788; sc; 3 × q12h; total daily dosages of BAL9141 equivalents, 2.1, 4.2, or 8.4 mg/kg) infected Penr Cros Ctxs strain P-15986 in female Swiss albino mice (body weight, 20 to 22 g) resulted in ten-day cumulative survival rates ranging from 57 to 100%[1]. When the dose increased from 40 mg/kg to 160 mg/kg, ceftobiprole medocaril (10, 40, 160 mg/kg; single dose; sc) had T1/2s ranging from 20 to 31 minutes. In neutropenic thigh-infected mice, the Cmax/dose values fall from 1.08 to 0.90, while the AUC/dose values range from 0.585 to 1.33 for the increasing single doses[2].

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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 [cefepime] 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 [cefepime] after multiple doses was 4.98 L/h.
Protein Binding
The active drug [cefepime] has very low binding to plasma proteins (16%).
Metabolism/Metabolites
The conversion of the prodrug cefepime methyl ester to the active drug cefepime is rapid and mediated by nonspecific plasma esterases. Cefepime 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 [cefepime] 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 cefepime 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]. 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 prodrug of cefbipro. Cefbipro is a water-soluble prodrug of cefbipro, a pyrrolidone cephalosporin antibiotic with bactericidal activity. Cefbipro binds to and inactivates penicillin-binding protein (PBP). PBP is an enzyme involved in the final stages of cell wall assembly and remodeling during bacterial growth and division. This drug has 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). Cefbipro is not readily hydrolyzed by class A and C β-lactamases.

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Drug Indications
Treatment of Pneumonia
Treatment of Complicated Skin and Soft Tissue Infections
Cefepirox is a fifth-generation cephalosporin antibiotic with (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. It is a cephalosporin, belonging to the thiadiazole class of drugs.
Cefepirox is a cephalosporin antibiotic active against methicillin-resistant Staphylococcus aureus (MRSA). It was discovered by Basel Pharmaceuticals and is currently being developed by the research and development division of Johnson & Johnson. Cefepime is the first cephalosporin to demonstrate clinical efficacy in patients with MRSA infection. If approved by regulatory agencies, it is expected to become an effective treatment for complicated skin infections and pneumonia. Cefepime is a broad-spectrum, fifth-generation pyrrolidone cephalosporin with antibacterial activity. Cefepime binds to and inactivates penicillin-binding proteins (PBPs) located on the inner membrane of bacterial cell walls. Penicillin-binding proteins (PBPs) are enzymes involved in the final stages of bacterial cell wall assembly and cell wall remodeling during growth and division. Inactivation of PBPs interferes with the cross-linking of peptidoglycan chains, which is crucial for maintaining the strength and rigidity of bacterial cell walls. This leads to weakened bacterial cell walls, ultimately resulting in cell lysis. Indications: For the treatment of severe bacterial infections in hospitalized patients. Mechanism of Action: Cephalosporins, such as cefepime, have bactericidal activity, and their mechanism of action is the same as other β-lactam antibiotics, such as penicillins. Cephalosporins disrupt the synthesis of the peptidoglycan layer in bacterial cell walls. This peptidoglycan layer is crucial for maintaining the structural integrity of the cell wall, especially in Gram-positive bacteria. The final step in peptidoglycan synthesis, the transpeptidase reaction, is catalyzed 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 PBP with peptidoglycan.

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

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Cefepime levodopa is a cephalosporin. It is 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 medocaril, recommending its rejection for marketing authorization in the European Union, primarily due to issues with the quality of data from key clinical studies. Cefepime sodium 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 skin structure infections and bacteremia. Cefepime sodium is the sodium salt form of cefepime, a water-soluble prodrug of which is a pyrrolidone cephalosporin antibiotic with bactericidal activity. Cefepime binds to and inactivates penicillin-binding proteins (PBPs), enzymes 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). Cefepime 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

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

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)

Note: Listed below are some common formulations that may be used to formulate products with low water solubility (e.g. < 1 mg/mL), you may test these formulations using a minute amount of products to avoid loss of samples.

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Injection Formulation 1: DMSO : Tween 80： Saline = 10 : 5 : 85 (i.e. 100 μL DMSO stock solution → 50 μL Tween 80 → 850 μL Saline)
*Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH ₂ O to obtain a clear solution.
Injection Formulation 2: DMSO : PEG300 ：Tween 80 : Saline = 10 : 40 : 5 : 45 (i.e. 100 μL DMSO → 400 μLPEG300 → 50 μL Tween 80 → 450 μL Saline)
Injection Formulation 3: DMSO : Corn oil = 10 : 90 (i.e. 100 μL DMSO → 900 μL Corn oil)
Example: Take the Injection Formulation 3 (DMSO : Corn oil = 10 : 90) as an example, if 1 mL of 2.5 mg/mL working solution is to be prepared, you can take 100 μL 25 mg/mL DMSO stock solution and add to 900 μL corn oil, mix well to obtain a clear or suspension solution (2.5 mg/mL, ready for use in animals).

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Injection Formulation 4: DMSO : 20% SBE-β-CD in saline = 10 : 90 [i.e. 100 μL DMSO → 900 μL (20% SBE-β-CD in saline)]
*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.
Injection Formulation 5: 2-Hydroxypropyl-β-cyclodextrin : Saline = 50 : 50 (i.e. 500 μL 2-Hydroxypropyl-β-cyclodextrin → 500 μL Saline)
Injection Formulation 6: DMSO : PEG300 : castor oil : Saline = 5 : 10 : 20 : 65 (i.e. 50 μL DMSO → 100 μLPEG300 → 200 μL castor oil → 650 μL Saline)
Injection Formulation 7: Ethanol : Cremophor : Saline = 10： 10 : 80 (i.e. 100 μL Ethanol → 100 μL Cremophor → 800 μL Saline)
Injection Formulation 8: Dissolve in Cremophor/Ethanol (50 : 50), then diluted by Saline
Injection Formulation 9: EtOH : Corn oil = 10 : 90 (i.e. 100 μL EtOH → 900 μL Corn oil)
Injection Formulation 10: EtOH : PEG300：Tween 80 : Saline = 10 : 40 : 5 : 45 (i.e. 100 μL EtOH → 400 μLPEG300 → 50 μL Tween 80 → 450 μL Saline)

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Oral Formulation 1: Suspend in 0.5% CMC Na (carboxymethylcellulose sodium)
Oral Formulation 2: Suspend in 0.5% Carboxymethyl cellulose
Example: Take the Oral Formulation 1 (Suspend in 0.5% CMC Na) as an example, if 100 mL of 2.5 mg/mL working solution is to be prepared, you can first prepare 0.5% CMC Na solution by measuring 0.5 g CMC Na and dissolve it in 100 mL ddH2O to obtain a clear solution; then add 250 mg of the product to 100 mL 0.5% CMC Na solution, to make the suspension solution (2.5 mg/mL, ready for use in animals).

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Oral Formulation 3: Dissolved in PEG400
Oral Formulation 4: Suspend in 0.2% Carboxymethyl cellulose
Oral Formulation 5: Dissolve in 0.25% Tween 80 and 0.5% Carboxymethyl cellulose
Oral Formulation 6: Mixing with food powders

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Note: Please be aware that the above formulations are for reference only. InvivoChem strongly recommends customers to read literature methods/protocols carefully before determining which formulation you should use for in vivo studies, as different compounds have different solubility properties and have to be formulated differently.

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