Ceftobiprole

Identification

Summary

Ceftobiprole is a broad spectrum 5th-generation cephalosporin antibacterial indicated for certain kinds of pneumonia, bacteremia, and skin and skin structure infections, including those caused by MRSA.

Generic Name
Ceftobiprole
DrugBank Accession Number
DB04918
Background

Ceftobiprole is a fifth-generation semisynthetic cephalosporin antibacterial which is available commercially as the prodrug ceftobiprole medocaril. 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.8 It received its first approval in Canada in October 2017 for use in certain patients with bacterial pneumonia,6 and was subsequently approved in the United States with additional indications for skin and skin structure infections and bacteremia in April 2024.7,9

Type
Small Molecule
Groups
Approved, Investigational
Structure
Weight
Average: 534.57
Monoisotopic: 534.110372808
Chemical Formula
C20H22N8O6S2
Synonyms
  • Ceftobiprol
  • Ceftobiprole
External IDs
  • BAL-9141
  • BAL-9141-000
  • BAL-9141000
  • BAL9141-000
  • RO 63-9141
  • RO-63-9141
  • RO-639141

Pharmacology

Indication

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.7 It is additionally indicated in adult patients with acute bacterial skin and skin structure infections (ABSSSI).7 It is indicated in adult and pediatric patients ≥3 months of age for the treatment of community-acquired bacterial pneumonia (CABP).7

In Canada, it is additionally indicated for the treatment of hospital-acquired pneumonia (excluding ventilator-associated pneumonia).6

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Contraindications & Blackbox Warnings
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Pharmacodynamics

Ceftobiprole has demonstrated in vitro activity against Gram-positive and Gram-negative bacteria. 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.7

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.7

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.7

Mechanism of action

Ceftobiprole, the active moiety of ceftobiprole medocaril, exhibits its bactericidal activity by inhibition of bacterial cell wall synthesis.7 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.7

Ceftobiprole has demonstrated in vitro activity against both Gram-positive and Gram-negative bacteria.7 In Gram-positive bacteria, including methicillin-resistant Staphylococcus aureus (MRSA), Ceftobiprole binds to PBP2a.6 Ceftobiprole also binds to PBP2b in Streptococcus pneumoniae (penicillin-intermediate), PBP2x in S. pneumoniae (penicillin resistant), and to PBP5 in Enterococcus faecalis.6

TargetActionsOrganism
AMecA
inhibitor
Staphylococcus aureus
APenicillin-binding protein 2x
inhibitor
Streptococcus pneumoniae serotype 4 (strain ATCC BAA-334 / TIGR4)
UPeptidoglycan synthase FtsINot AvailableEscherichia coli (strain K12)
APenicillin-binding protein 2B
inhibitor
Streptococcus pneumoniae (strain ATCC BAA-255 / R6)
APenicillin-binding protein 2X
inhibitor
Streptococcus pneumoniae (strain ATCC BAA-255 / R6)
Absorption

Because ceftobiprole medocaril is administered intravenously, its bioavailability is 100%.6 The mean Cmax and AUC0-8h of ceftobiprole after multiple-dose administration are 33.0 µg/mL and 102 µg*h/mL, respectively.6

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.7,6

Protein binding

Active ceftobiprole is minimally (16%) bound to plasma proteins.7,6

Metabolism

Conversion of prodrug ceftobiprole medocaril to the active moiety ceftobiprole occurs rapidly and is mediated by non-specific plasma esterases.6 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.6

Route of elimination

Active ceftobiprole is eliminated primarily unchanged by renal excretion.6 Approximately 89% of the administered dose is recovered in the urine as active ceftobiprole (83%), the open-ring metabolite (5%) and ceftobiprole medocaril (<1%).6

Half-life

The half-life of active ceftobiprole following multiple-dose administration is approximately 3.3 hours.7,6

Clearance

The mean clearance of active ceftobiprole following multiple-dose administration is 4.98 L/h.7,6

Adverse Effects
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Toxicity

There are no data regarding overdosage with ceftobiprole medocaril. In cases of suspected overdose, discontinue therapy and institute general symptomatic and supportive treatment. Ceftobiprole can be removed from the circulation via hemodialysis, however no information is available on the use of hemodialysis to treat ceftobiprole overdose.7

Pathways
Not Available
Pharmacogenomic Effects/ADRs
Not Available

Interactions

Drug Interactions
This information should not be interpreted without the help of a healthcare provider. If you believe you are experiencing an interaction, contact a healthcare provider immediately. The absence of an interaction does not necessarily mean no interactions exist.
DrugInteraction
AbacavirCeftobiprole may decrease the excretion rate of Abacavir which could result in a higher serum level.
AbciximabThe therapeutic efficacy of Abciximab can be decreased when used in combination with Ceftobiprole.
AceclofenacThe risk or severity of nephrotoxicity can be increased when Ceftobiprole is combined with Aceclofenac.
AcemetacinThe risk or severity of nephrotoxicity can be increased when Ceftobiprole is combined with Acemetacin.
AcenocoumarolThe risk or severity of bleeding can be increased when Ceftobiprole is combined with Acenocoumarol.
Food Interactions
No interactions found.

Categories

Drug Categories
Chemical TaxonomyProvided by Classyfire
Description
This compound belongs to the class of organic compounds known as cephalosporins. These are compounds containing a 1,2-thiazine fused to a 2-azetidinone to for a oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid moiety or a derivative thereof.
Kingdom
Organic compounds
Super Class
Organoheterocyclic compounds
Class
Lactams
Sub Class
Beta lactams
Direct Parent
Cephalosporins
Alternative Parents
N-acyl-alpha amino acids and derivatives / 1,3-thiazines / Pyrrolidine-2-ones / N-alkylpyrrolidines / Thiadiazoles / Tertiary carboxylic acid amides / Heteroaromatic compounds / Ketoximes / Secondary carboxylic acid amides / Amino acids
show 12 more
Substituents
2-pyrrolidone / Alpha-amino acid or derivatives / Amine / Amino acid / Amino acid or derivatives / Aromatic heteropolycyclic compound / Azacycle / Azetidine / Azole / Carbonyl group
show 28 more
Molecular Framework
Aromatic heteropolycyclic compounds
External Descriptors
Not Available
Affected organisms
  • Streptococcus pyogenes
  • Streptococcus pneumoniae
  • Haemophilus influenzae
  • Escherichia coli
  • Staphylococcus aureus
  • Klebsiella pneumoniae
  • Haemophilus parainfluenzae

Chemical Identifiers

UNII
5T97333YZK
CAS number
209467-52-7
InChI Key
VOAZJEPQLGBXGO-SDAWRPRTSA-N
InChI
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
IUPAC Name
(6R,7R)-7-[(2Z)-2-(5-amino-1,2,4-thiadiazol-3-yl)-2-(N-hydroxyimino)acetamido]-8-oxo-3-{[(3E,3'R)-2-oxo-[1,3'-bipyrrolidin]-3-ylidene]methyl}-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid
SMILES
[H][C@@]1(NC(=O)C(=N/O)\C2=NSC(N)=N2)C(=O)N2C(C(O)=O)=C(CS[C@]12[H])\C=C1/CCN(C1=O)[C@]1([H])CCNC1

References

General References
  1. Davies TA, Page MG, Shang W, Andrew T, Kania M, Bush K: Binding of ceftobiprole and comparators to the penicillin-binding proteins of Escherichia coli, Pseudomonas aeruginosa, Staphylococcus aureus, and Streptococcus pneumoniae. Antimicrob Agents Chemother. 2007 Jul;51(7):2621-4. Epub 2007 Apr 30. [Article]
  2. Noel GJ: Clinical profile of ceftobiprole, a novel beta-lactam antibiotic. Clin Microbiol Infect. 2007 Jun;13 Suppl 2:25-9. [Article]
  3. Yun HC, Ellis MW, Jorgensen JH: Activity of ceftobiprole against community-associated methicillin-resistant Staphylococcus aureus isolates recently recovered from US military trainees. Diagn Microbiol Infect Dis. 2007 Dec;59(4):463-6. Epub 2007 Oct 29. [Article]
  4. Lin G, Appelbaum PC: Activity of ceftobiprole compared with those of other agents against Staphylococcus aureus strains with different resistotypes by time-kill analysis. Diagn Microbiol Infect Dis. 2008 Feb;60(2):233-5. Epub 2007 Nov 7. [Article]
  5. Noel GJ, Strauss RS, Amsler K, Heep M, Pypstra R, Solomkin JS: Results of a double-blind, randomized trial of ceftobiprole treatment of complicated skin and skin structure infections caused by gram-positive bacteria. Antimicrob Agents Chemother. 2008 Jan;52(1):37-44. Epub 2007 Oct 22. [Article]
  6. Health Canada Product Monograph: Zevtera (ceftobiprole medocaril sodium) for intravenous injection [Link]
  7. FDA Approved Drug Products: Zevtera (ceftobiprole medocaril sodium) injection for intravenous use [Link]
  8. EMA Refusal Assessment Report: Zeftera [Link]
  9. FDA Press Announcement: FDA Approves New Antibiotic for Three Different Uses [Link]
KEGG Drug
D08885
PubChem Compound
12993649
PubChem Substance
175426903
ChemSpider
23350302
ChEBI
140407
ChEMBL
CHEMBL520642
ZINC
ZINC000004424091
Wikipedia
Ceftobiprole

Clinical Trials

Clinical Trials

Pharmacoeconomics

Manufacturers
Not Available
Packagers
Not Available
Dosage Forms
Not Available
Prices
Not Available
Patents
Not Available

Properties

State
Solid
Experimental Properties
Not Available
Predicted Properties
PropertyValueSource
Water Solubility0.159 mg/mLALOGPS
logP-1.3ALOGPS
logP-4.7Chemaxon
logS-3.5ALOGPS
pKa (Strongest Acidic)2.89Chemaxon
pKa (Strongest Basic)10.4Chemaxon
Physiological Charge-1Chemaxon
Hydrogen Acceptor Count11Chemaxon
Hydrogen Donor Count5Chemaxon
Polar Surface Area203.44 Å2Chemaxon
Rotatable Bond Count6Chemaxon
Refractivity131.04 m3·mol-1Chemaxon
Polarizability51.22 Å3Chemaxon
Number of Rings5Chemaxon
Bioavailability0Chemaxon
Rule of FiveNoChemaxon
Ghose FilterNoChemaxon
Veber's RuleNoChemaxon
MDDR-like RuleYesChemaxon
Predicted ADMET Features
PropertyValueProbability
Human Intestinal Absorption+0.9848
Blood Brain Barrier-0.9231
Caco-2 permeable-0.6329
P-glycoprotein substrateSubstrate0.821
P-glycoprotein inhibitor INon-inhibitor0.8638
P-glycoprotein inhibitor IINon-inhibitor0.9971
Renal organic cation transporterNon-inhibitor0.9155
CYP450 2C9 substrateNon-substrate0.8546
CYP450 2D6 substrateNon-substrate0.7979
CYP450 3A4 substrateNon-substrate0.5567
CYP450 1A2 substrateNon-inhibitor0.686
CYP450 2C9 inhibitorNon-inhibitor0.7322
CYP450 2D6 inhibitorNon-inhibitor0.8646
CYP450 2C19 inhibitorNon-inhibitor0.6778
CYP450 3A4 inhibitorNon-inhibitor0.8981
CYP450 inhibitory promiscuityLow CYP Inhibitory Promiscuity0.9212
Ames testNon AMES toxic0.5598
CarcinogenicityNon-carcinogens0.8598
BiodegradationReady biodegradable0.7278
Rat acute toxicity2.4586 LD50, mol/kg Not applicable
hERG inhibition (predictor I)Weak inhibitor0.7721
hERG inhibition (predictor II)Non-inhibitor0.7278
ADMET data is predicted using admetSAR, a free tool for evaluating chemical ADMET properties. (23092397)

Spectra

Mass Spec (NIST)
Not Available
Spectra
SpectrumSpectrum TypeSplash Key
Predicted MS/MS Spectrum - 10V, Positive (Annotated)Predicted LC-MS/MSsplash10-000i-0010090000-509740d33b7136d8e458
Predicted MS/MS Spectrum - 10V, Negative (Annotated)Predicted LC-MS/MSsplash10-004i-0390000000-9ae7b6adc00f2b1dcb51
Predicted MS/MS Spectrum - 20V, Positive (Annotated)Predicted LC-MS/MSsplash10-0g4u-0964460000-5bf6f192b20774db1b36
Predicted MS/MS Spectrum - 20V, Negative (Annotated)Predicted LC-MS/MSsplash10-00di-4926130000-c6588976646ab88569cb
Predicted MS/MS Spectrum - 40V, Negative (Annotated)Predicted LC-MS/MSsplash10-00fr-1900100000-93f21addd5b8886fe6f1
Predicted MS/MS Spectrum - 40V, Positive (Annotated)Predicted LC-MS/MSsplash10-0r03-2501890000-dd503c852af583137d47
Chromatographic Properties
Collision Cross Sections (CCS)
AdductCCS Value (Å2)Source typeSource
[M-H]-244.0475815
predicted
DarkChem Lite v0.1.0
[M-H]-219.90514
predicted
DeepCCS 1.0 (2019)
[M+H]+245.3068815
predicted
DarkChem Lite v0.1.0
[M+H]+222.11086
predicted
DeepCCS 1.0 (2019)
[M+Na]+245.1662815
predicted
DarkChem Lite v0.1.0
[M+Na]+228.02339
predicted
DeepCCS 1.0 (2019)

Targets

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insights and accelerate drug research.
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Kind
Protein
Organism
Staphylococcus aureus
Pharmacological action
Yes
Actions
Inhibitor
General Function
Transferase activity, transferring glycosyl groups
Specific Function
Not Available
Gene Name
mecA
Uniprot ID
Q7DHH4
Uniprot Name
MecA
Molecular Weight
76102.075 Da
References
  1. Davies TA, Page MG, Shang W, Andrew T, Kania M, Bush K: Binding of ceftobiprole and comparators to the penicillin-binding proteins of Escherichia coli, Pseudomonas aeruginosa, Staphylococcus aureus, and Streptococcus pneumoniae. Antimicrob Agents Chemother. 2007 Jul;51(7):2621-4. Epub 2007 Apr 30. [Article]
  2. FDA Approved Drug Products: Zevtera (ceftobiprole medocaril sodium) injection for intravenous use [Link]
  3. Health Canada Product Monograph: Zevtera (ceftobiprole medocaril sodium) for intravenous injection [Link]
Kind
Protein
Organism
Streptococcus pneumoniae serotype 4 (strain ATCC BAA-334 / TIGR4)
Pharmacological action
Yes
Actions
Inhibitor
General Function
Penicillin binding
Specific Function
Penicillin-binding proteins (PBPs) function in the late steps of murein biosynthesis. Beta-lactams inactivate the PBPs by acylating an essential serine residue in the active site of these proteins.
Gene Name
pbpX
Uniprot ID
P14677
Uniprot Name
Penicillin-binding protein 2x
Molecular Weight
82312.475 Da
References
  1. Davies TA, Page MG, Shang W, Andrew T, Kania M, Bush K: Binding of ceftobiprole and comparators to the penicillin-binding proteins of Escherichia coli, Pseudomonas aeruginosa, Staphylococcus aureus, and Streptococcus pneumoniae. Antimicrob Agents Chemother. 2007 Jul;51(7):2621-4. Epub 2007 Apr 30. [Article]
Kind
Protein
Organism
Escherichia coli (strain K12)
Pharmacological action
Unknown
General Function
Peptidoglycan glycosyltransferase activity
Specific Function
Essential cell division protein that is required for the synthesis of peptidoglycan at the division septum (PubMed:1103132, PubMed:9614966). Catalyzes the synthesis of cross-linked peptidoglycan fr...
Gene Name
ftsI
Uniprot ID
P0AD68
Uniprot Name
Peptidoglycan synthase FtsI
Molecular Weight
63876.925 Da
References
  1. Davies TA, Page MG, Shang W, Andrew T, Kania M, Bush K: Binding of ceftobiprole and comparators to the penicillin-binding proteins of Escherichia coli, Pseudomonas aeruginosa, Staphylococcus aureus, and Streptococcus pneumoniae. Antimicrob Agents Chemother. 2007 Jul;51(7):2621-4. Epub 2007 Apr 30. [Article]
Kind
Protein
Organism
Streptococcus pneumoniae (strain ATCC BAA-255 / R6)
Pharmacological action
Yes
Actions
Inhibitor
General Function
Not Available
Specific Function
Penicillin binding
Gene Name
penA
Uniprot ID
P0A3M6
Uniprot Name
Penicillin-binding protein 2B
Molecular Weight
73872.305 Da
References
  1. Davies TA, Page MG, Shang W, Andrew T, Kania M, Bush K: Binding of ceftobiprole and comparators to the penicillin-binding proteins of Escherichia coli, Pseudomonas aeruginosa, Staphylococcus aureus, and Streptococcus pneumoniae. Antimicrob Agents Chemother. 2007 Jul;51(7):2621-4. Epub 2007 Apr 30. [Article]
  2. Health Canada Product Monograph: Zevtera (ceftobiprole medocaril sodium) for intravenous injection [Link]
  3. FDA Approved Drug Products: Zevtera (ceftobiprole medocaril sodium) injection for intravenous use [Link]
Kind
Protein
Organism
Streptococcus pneumoniae (strain ATCC BAA-255 / R6)
Pharmacological action
Yes
Actions
Inhibitor
Curator comments
Per prescribing information: "Ceftobiprole has a high affinity for ... PBP2x and PBP2b in penicillin-resistant Streptococcus pneumoniae."
General Function
Penicillin binding
Specific Function
Penicillin-binding proteins (PBPs) function in the late steps of murein biosynthesis. Beta-lactams inactivate the PBPs by acylating an essential serine residue in the active site of these proteins.
Gene Name
pbpX
Uniprot ID
P59676
Uniprot Name
Penicillin-binding protein 2X
Molecular Weight
82342.565 Da
References
  1. FDA Approved Drug Products: Zevtera (ceftobiprole medocaril sodium) injection for intravenous use [Link]
  2. Health Canada Product Monograph: Zevtera (ceftobiprole medocaril sodium) for intravenous injection [Link]

Transporters

Kind
Protein
Organism
Humans
Pharmacological action
No
Actions
Inhibitor
General Function
Sodium-independent organic anion transmembrane transporter activity
Specific Function
Mediates the Na(+)-independent uptake of organic anions such as pravastatin, taurocholate, methotrexate, dehydroepiandrosterone sulfate, 17-beta-glucuronosyl estradiol, estrone sulfate, prostagland...
Gene Name
SLCO1B1
Uniprot ID
Q9Y6L6
Uniprot Name
Solute carrier organic anion transporter family member 1B1
Molecular Weight
76447.99 Da
References
  1. FDA Approved Drug Products: Zevtera (ceftobiprole medocaril sodium) injection for intravenous use [Link]
Kind
Protein
Organism
Humans
Pharmacological action
No
Actions
Inhibitor
General Function
Sodium-independent organic anion transmembrane transporter activity
Specific Function
Mediates the Na(+)-independent uptake of organic anions such as 17-beta-glucuronosyl estradiol, taurocholate, triiodothyronine (T3), leukotriene C4, dehydroepiandrosterone sulfate (DHEAS), methotre...
Gene Name
SLCO1B3
Uniprot ID
Q9NPD5
Uniprot Name
Solute carrier organic anion transporter family member 1B3
Molecular Weight
77402.175 Da
References
  1. FDA Approved Drug Products: Zevtera (ceftobiprole medocaril sodium) injection for intravenous use [Link]
Kind
Protein
Organism
Humans
Pharmacological action
No
Actions
Inhibitor
General Function
Organic anion transmembrane transporter activity
Specific Function
Mediates hepatobiliary excretion of numerous organic anions. May function as a cellular cisplatin transporter.
Gene Name
ABCC2
Uniprot ID
Q92887
Uniprot Name
Canalicular multispecific organic anion transporter 1
Molecular Weight
174205.64 Da
References
  1. FDA Approved Drug Products: Zevtera (ceftobiprole medocaril sodium) injection for intravenous use [Link]
Kind
Protein
Organism
Humans
Pharmacological action
No
Actions
Inhibitor
General Function
Transporter activity
Specific Function
Involved in the ATP-dependent secretion of bile salts into the canaliculus of hepatocytes.
Gene Name
ABCB11
Uniprot ID
O95342
Uniprot Name
Bile salt export pump
Molecular Weight
146405.83 Da
References
  1. FDA Approved Drug Products: Zevtera (ceftobiprole medocaril sodium) injection for intravenous use [Link]

Drug created at October 21, 2007 22:23 / Updated at May 29, 2024 19:09