Ceftaroline fosamil

Identification

Name
Ceftaroline fosamil
Accession Number
DB06590
Type
Small Molecule
Groups
Approved, Investigational
Description

Ceftaroline fosamil is a cephalosporin antibacterial indicated for the treatment of the following infections caused by designated susceptible bacteria: Acute bacterial skin and skin structure infections. Community-acquired bacterial pneumonia.

Structure
Thumb
Synonyms
  • (6R,7R)-7-[(2Z)-2-ethoxyimino-2-[5-(phosphonoamino)-1,2,4-thiadiazol-3-yl]acetyl]amino]-3-[4-(1-methylpyridin-1-ium-4-yl)-1,3-thiazol-2-yl]sulfanyl]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylate
  • Ceftarolina fosamilo
  • Ceftaroline
  • Ceftaroline fosamil
  • Ceftarolinum fosamilum
External IDs
PPI 0903 / PPI-0903 / TAK-599
Product Ingredients
IngredientUNIICASInChI Key
Ceftaroline fosamil acetateEZ9W6O5S09400827-46-5UGHHNQFYEVOFIV-VRDMTWHKSA-N
Ceftaroline fosamil acetate monohydrateP9VXV1408Y400827-55-6KRWPPVCZNGQQHZ-IINIBMQSSA-N
Prescription Products
NameDosageStrengthRouteLabellerMarketing StartMarketing End
TeflaroPowder, for solution600 mg/20mLIntravenousAllergan2010-10-29Not applicableUs
TeflaroPowder, for solution400 mg/20mLIntravenousAllergan2010-10-29Not applicableUs
ZinforoInjection, powder, for solution600 mgIntravenousPfizer Ireland Pharmaceuticals2012-08-23Not applicableEu
International/Other Brands
Zinforo (AstraZeneca)
Categories
UNII
7P6FQA5D21
CAS number
229016-73-3
Weight
Average: 684.67
Monoisotopic: 684.010281362
Chemical Formula
C22H21N8O8PS4
InChI Key
ZCCUWMICIWSJIX-NQJJCJBVSA-N
InChI
InChI=1S/C22H21N8O8PS4/c1-3-38-26-13(16-25-21(43-28-16)27-39(35,36)37)17(31)24-14-18(32)30-15(20(33)34)12(9-40-19(14)30)42-22-23-11(8-41-22)10-4-6-29(2)7-5-10/h4-8,14,19H,3,9H2,1-2H3,(H4-,24,25,27,28,31,33,34,35,36,37)/b26-13-/t14-,19-/m1/s1
IUPAC Name
4-(2-{[(6R,7R)-2-carboxylato-7-[(2Z)-2-(ethoxyimino)-2-[5-(phosphonoamino)-1,2,4-thiadiazol-3-yl]acetamido]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-en-3-yl]sulfanyl}-1,3-thiazol-4-yl)-1-methylpyridin-1-ium
SMILES
[H][C@]12SCC(SC3=NC(=CS3)C3=CC=[N+](C)C=C3)=C(N1C(=O)[C@H]2NC(=O)C(=N/OCC)\C1=NSC(NP(O)(O)=O)=N1)C([O-])=O

Pharmacology

Indication

Ceftaroline fosamil is indicated for the treatment of patients with the following infections caused by susceptible isolates of the designated microorganisms.

Associated Conditions
Pharmacodynamics

The time that unbound plasma concentration of ceftaroline exceeds the minimum inhibitory concentration (MIC) of the infecting organism has been shown to best correlate with efficacy in a neutropenic murine thigh infection model with S. aureus and S. pneumoniae.

No significant effect on QTc (corrected QT interval) interval was detected at peak plasma concentration or at any other time.

Mechanism of action

Ceftaroline fosamil is an antibacterial drug.

Absorption
Not Available
Volume of distribution

Median 20.3 L (18.3-21.6 L).

Protein binding

approximately 20%.

Metabolism

Ceftaroline fosamil is converted into bioactive ceftaroline in plasma by a phosphatase enzyme. Hydrolysis of the beta-lactam ring of ceftaroline occurs to form the microbiologically inactive, open-ring metabolite ceftaroline M-1.

Route of elimination

primarily eliminated by the kidneys (6% in feces within 48 hours).

Half life

1.60 hours (600 mg dose).

Clearance
Not Available
Toxicity

LD50/LC50: Draize test, rabbit, eye: 100 mg/24H Moderate; Oral, mouse: LD50 = 300 mg/kg; Oral, rabbit: LD50 = 3200 mg/kg; Oral, rat: LD50 = 980 mg/kg.

Affected organisms
  • Gram-negative Bacteria
  • Gram-positive Bacteria
  • Streptococcus pneumoniae
  • Staphylococcus aureus
Pathways
Not Available
Pharmacogenomic Effects/ADRs
Not Available

Interactions

Drug Interactions
DrugInteraction
(R)-warfarinThe risk or severity of bleeding can be increased when Ceftaroline fosamil is combined with (R)-warfarin.
(S)-WarfarinThe risk or severity of bleeding can be increased when Ceftaroline fosamil is combined with (S)-Warfarin.
4-hydroxycoumarinThe risk or severity of bleeding can be increased when Ceftaroline fosamil is combined with 4-hydroxycoumarin.
AbacavirCeftaroline fosamil may decrease the excretion rate of Abacavir which could result in a higher serum level.
AcarboseCeftaroline fosamil may decrease the excretion rate of Acarbose which could result in a higher serum level.
AceclofenacCeftaroline fosamil may decrease the excretion rate of Aceclofenac which could result in a higher serum level.
AcemetacinThe risk or severity of nephrotoxicity can be increased when Ceftaroline fosamil is combined with Acemetacin.
AcenocoumarolThe risk or severity of bleeding can be increased when Ceftaroline fosamil is combined with Acenocoumarol.
AcetaminophenCeftaroline fosamil may decrease the excretion rate of Acetaminophen which could result in a higher serum level.
Acetylsalicylic acidThe risk or severity of nephrotoxicity can be increased when Acetylsalicylic acid is combined with Ceftaroline fosamil.
Food Interactions
Not Available

References

Synthesis Reference

http://www.google.com/patents/US20110071114

General References
  1. Steed ME, Rybak MJ: Ceftaroline: a new cephalosporin with activity against resistant gram-positive pathogens. Pharmacotherapy. 2010 Apr;30(4):375-89. doi: 10.1592/phco.30.4.375. [PubMed:20334458]
  2. Kollef MH: New antimicrobial agents for methicillin-resistant Staphylococcus aureus. Crit Care Resusc. 2009 Dec;11(4):282-6. [PubMed:20001879]
  3. Kanafani ZA, Corey GR: Ceftaroline: a cephalosporin with expanded Gram-positive activity. Future Microbiol. 2009 Feb;4(1):25-33. doi: 10.2217/17460913.4.1.25. [PubMed:19207097]
  4. Parish D, Scheinfeld N: Ceftaroline fosamil, a cephalosporin derivative for the potential treatment of MRSA infection. Curr Opin Investig Drugs. 2008 Feb;9(2):201-9. [PubMed:18246523]
  5. MacGowan AP, Noel AR, Tomaselli S, Bowker KE: Pharmacodynamics of ceftaroline against Staphylococcus aureus studied in an in vitro pharmacokinetic model of infection. Antimicrob Agents Chemother. 2013 Jun;57(6):2451-6. doi: 10.1128/AAC.01386-12. Epub 2013 Mar 4. [PubMed:23459495]
External Links
KEGG Drug
D08884
PubChem Compound
9852981
PubChem Substance
175427075
ChemSpider
8028692
ChEBI
70718
ChEMBL
CHEMBL501122
RxList
RxList Drug Page
Drugs.com
Drugs.com Drug Page
PDRhealth
PDRhealth Drug Page
Wikipedia
Ceftaroline_fosamil
ATC Codes
J01DI02 — Ceftaroline fosamil
FDA label
Download (210 KB)
MSDS
Download (568 KB)

Clinical Trials

Clinical Trials
PhaseStatusPurposeConditionsCount
1CompletedNot AvailableInfection NOS1
1CompletedBasic ScienceHealthy Male Volunteers1
1CompletedBasic ScienceHealthy Volunteers2
1CompletedBasic ScienceKidney Diseases1
1CompletedHealth Services ResearchDrug Safety1
1RecruitingTreatmentCerebrospinal Fluid Shunts / Ventriculoperitoneal Shunt1
1RecruitingTreatmentMeningitis / Ventriculitis1
1RecruitingTreatmentPneumonia1
1, 2RecruitingTreatmentBone Infection / Hematogenously Acquired Staphylococcus Aureus Osteomyelitis / Osteomyelitis1
2CompletedTreatmentBacterial Infections1
2CompletedTreatmentUrinary Tract Infections (UTIs)1
2TerminatedTreatmentInfected Spacers / Prosthetic Joint Infections of Hip / Prosthetic Joint Infections of Knee1
2TerminatedTreatmentLate-onset Sepsis1
2, 3CompletedTreatmentCommunity Acquired Pneumonia (CAP) / Infection NOS1
2, 3CompletedTreatmentInfections, Pediatrics1
3CompletedTreatmentBacterial Infections2
3CompletedTreatmentCommunity-Acquired Bacterial Pneumonia (CABP) / Lung Infection of Individual Not Recently Hospitalized1
3CompletedTreatmentComplicated Skin and Soft Tissue Infection1
3CompletedTreatmentPneumonia, Bacterial2
3TerminatedTreatmentComplicated Skin and Soft Tissue Infection1
4CompletedNot AvailableInfection NOS1
4CompletedTreatmentBacteremia1
4CompletedTreatmentCommunity-acquired / Pneumonia, Bacterial1
4CompletedTreatmentInfection NOS1
4CompletedTreatmentInfection NOS / Pneumonia1
4CompletedTreatmentMethicillin-resistant Staphylococcus Aureus (MRSA) Bacteremia / Staphylococcus Aureus Bacteraemia1
4CompletedTreatmentSkin Diseases, Infectious / Staphylococcal Skin Infections1
4Not Yet RecruitingTreatmentFractures, Open1
4RecruitingPreventionSurgical Site Infections1
4RecruitingTreatmentCommunity Acquired Pneumonia (CAP)1
4TerminatedPreventionAcute acute bacterial skin and skin structure infections / Bacteremia / Endocarditis / Health Care Associated Pneumonia / Osteomyelitis/Septic Arthritis1
4WithdrawnTreatmentCommunity-Acquired Bacterial Pneumonia (CABP)1
4WithdrawnTreatmentJoint Infections / Osteomyelitis1

Pharmacoeconomics

Manufacturers
Not Available
Packagers
Not Available
Dosage forms
FormRouteStrength
Powder, for solutionIntravenous400 mg/20mL
Powder, for solutionIntravenous600 mg/20mL
Injection, powder, for solutionIntravenous600 mg
Prices
Not Available
Patents
Patent NumberPediatric ExtensionApprovedExpires (estimated)
US8247400No2012-08-212031-02-10Us
US6417175No2002-07-092022-04-11Us
US7419973No2008-09-022021-12-15Us
US6906055No2005-06-142021-12-15Us
US9629861No2017-04-252030-09-21Us

Properties

State
Solid
Experimental Properties
PropertyValueSource
water solubility>100 mg/ml# Steed ME, Rybak MJ: Ceftaroline: a new cephalosporin with activity against resistant gram-positive pathogens. Pharmacotherapy. 2010 Apr;30(4):375-89. "Pubmed":http://www.ncbi.nlm.nih.gov/pubmed/20334458
Predicted Properties
PropertyValueSource
Water Solubility0.0245 mg/mLALOGPS
logP-0.79ALOGPS
logP-3.7ChemAxon
logS-4.5ALOGPS
pKa (Strongest Acidic)1.8ChemAxon
pKa (Strongest Basic)0.39ChemAxon
Physiological Charge-1ChemAxon
Hydrogen Acceptor Count13ChemAxon
Hydrogen Donor Count4ChemAxon
Polar Surface Area223.24 Å2ChemAxon
Rotatable Bond Count11ChemAxon
Refractivity171.63 m3·mol-1ChemAxon
Polarizability63.9 Å3ChemAxon
Number of Rings5ChemAxon
Bioavailability0ChemAxon
Rule of FiveNoChemAxon
Ghose FilterNoChemAxon
Veber's RuleNoChemAxon
MDDR-like RuleYesChemAxon
Predicted ADMET features
PropertyValueProbability
Human Intestinal Absorption-0.9668
Blood Brain Barrier-0.9688
Caco-2 permeable-0.6428
P-glycoprotein substrateSubstrate0.7512
P-glycoprotein inhibitor INon-inhibitor0.8295
P-glycoprotein inhibitor IIInhibitor0.556
Renal organic cation transporterNon-inhibitor0.8255
CYP450 2C9 substrateNon-substrate0.589
CYP450 2D6 substrateNon-substrate0.8067
CYP450 3A4 substrateNon-substrate0.5087
CYP450 1A2 substrateNon-inhibitor0.6682
CYP450 2C9 inhibitorNon-inhibitor0.6399
CYP450 2D6 inhibitorNon-inhibitor0.8544
CYP450 2C19 inhibitorNon-inhibitor0.6139
CYP450 3A4 inhibitorInhibitor0.5
CYP450 inhibitory promiscuityLow CYP Inhibitory Promiscuity0.6434
Ames testNon AMES toxic0.6505
CarcinogenicityNon-carcinogens0.7956
BiodegradationNot ready biodegradable0.9875
Rat acute toxicity2.5251 LD50, mol/kg Not applicable
hERG inhibition (predictor I)Weak inhibitor0.9887
hERG inhibition (predictor II)Non-inhibitor0.7316
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/MSNot Available
Predicted MS/MS Spectrum - 20V, Positive (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 40V, Positive (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 10V, Negative (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 20V, Negative (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 40V, Negative (Annotated)Predicted LC-MS/MSNot Available

Taxonomy

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 / Aryl thioethers / 2,4-disubstituted thiazoles / N-methylpyridinium compounds / Vinylogous thioesters / 1,3-thiazines / Pyridinium derivatives / Organic phosphoramides / Thiadiazoles / Tertiary carboxylic acid amides
show 18 more
Substituents
Cephalosporin / N-acyl-alpha amino acid or derivatives / Alpha-amino acid or derivatives / Aryl thioether / 2,4-disubstituted 1,3-thiazole / N-methylpyridinium / Meta-thiazine / Organic phosphoric acid derivative / Pyridine / Vinylogous thioester
show 32 more
Molecular Framework
Aromatic heteropolycyclic compounds
External Descriptors
cephalosporin, iminium betaine, 1,3-thiazole, oxime O-ether, thiadiazoles, organic phosphoramidate (CHEBI:70718)

Drug created on March 19, 2008 10:38 / Updated on November 21, 2018 10:22