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Ceftaroline
Systematic (IUPAC) name
(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
Identifiers
CAS number 400827-46-5
ATC code none
PubChem 16007393
Chemical data
Formula C 24H25N8O10PS4  
Mol. mass 744.736661 [g/mol]
SMILES eMolecules & PubChem
Synonyms PPI 0903, TAK-599
Pharmacokinetic data
Bioavailability  ?
Metabolism  ?
Half life 2.13-2.89 hours
Excretion 46.4% Kidney, renal
Therapeutic considerations
Pregnancy cat.  ?
Legal status
Routes Intravenous, Intramuscular

Ceftaroline (INN) (pronounced /sɛf tar ɒ liːn/) is a fifth-generation cephalosporin antibiotic. It is notable for its activity against Methicillin-resistant Staphylococcus aureus (MRSA) and Gram positive bacteria. It retains the activity of later generation cephalosporins having broad spectrum activity against Gram negative bacteria. It is currently being investigated for community-acquired pneumonia[1] and complicated skin and skin structure infection.[2][3][4]

Ceftaroline is being developed by Forest Laboratories, under a license from Takeda.[4] In vitro studies show that it has a similar spectrum to ceftobiprole, the only other fifth-generation cephalosporin to date, although no head to head clinical trials have been conducted. Currently, ceftaroline and ceftobiprole are on an unnamed subclass of cephalosporins by the Clinical and Laboratory Standards Institute (CLSI).

Contents

Mechanism of action

Beta-lactam antibiotics inhibit bacterial peptidoglycan synthesis by binding the penicillin binding proteins (PBPs) in the bacterial cell wall. Inhibition of PBPs leads to irregularities in cell wall structures, such as elongation, lesions, loss of selective permeability, and eventual cell death and lysis. In particular, ceftaroline can effectively bind to and inhibit PBP-2a, the type of PBP produced by MRSA and not well inhibited by other antibiotics currently in clinical use.[5][6]

Clinical use

Ceftaroline is a novel cephalosporin that has activity against MRSA with phase III clinical trials for complicated skin and skin structure infections with reported non-inferior efficacy against MRSA compared to vancomycin and aztreonam[2][3] Recently, ceftaroline has completed phase III clinical trials for community-acquired pneumonia comparing it against ceftriaxone with non-inferior results and similar adverse reaction profile.[1] However there are only published results for Phase II clinical trials in treatment of complicated skin and skin structure infections.[7] The manufacturer plans to file a New Drug Application (NDA) to the Food and Drug Administration by the end of this year for both community-acquired pneumonia and complicated skin and skin structure infections. [8]

Chemistry

Ceftaroline, also known as ceftaroline fosamil acetate, is a prodrug that is converted to active metabolite and inactive metabolite ceftaroline-M1. Initial in vitro and in vivo animal studies referred to Ceftaroline as TAK-599 and PPI-0903.[9][10]

Characteristic of cephalosporins, ceftaroline has a bicyclic ring with four member β-lactam ring fused to a six member cephem ring. Ceftaroline is thought to have activity against MRSA with its 1,3 thiazole ring.[11]

Synonyms

References

  1. ^ a b P, Eckberg; Friedland HD, et al.. "FOCUS 1 and 2: Randomized, Double-blinded, Multicenter Phase 3 Trials of the Efficacy and Safety of Ceftaroline (CPT) vs. Ceftriaxone (CRO) in Community-acquired pneumonia (CAP).". 2009 Interscience Conference on Antimicrobial Agents and Chemotherapy / Infectious Disease Society of America Conference.  
  2. ^ a b R, Corey; Wilcox M, Talbot GH, et al.. "CANVAS-1: Randomized, Double-blinded, Phase 3 Study (P903-06) of the Efficacy and Safety of Ceftaroline vs. Vancomycin plus Aztreonam in Complicated Skin and Skin Structure Infections (cSSSI).". 2008 Interscience Conference on Antimicrobial Agents and Chemotherapy / Infectious Disease Society of America Conference.  
  3. ^ a b Kanafani ZA, Corey GR (February 2009). "Ceftaroline: a cephalosporin with expanded Gram-positive activity". Future Microbiology 4: 25–33. doi:10.2217/17460913.4.1.25. PMID 19207097. http://www.futuremedicine.com/doi/abs/10.2217/17460913.4.1.25?url_ver=Z39.88-2003&rfr_id=ori:rid:crossref.org&rfr_dat=cr_pub%3dncbi.nlm.nih.gov.  
  4. ^ a b Parish D, Scheinfeld N (February 2008). "Ceftaroline fosamil, a cephalosporin derivative for the potential treatment of MRSA infection". Current Opinion in Investigational Drugs (London, England : 2000) 9 (2): 201–9. PMID 18246523.  
  5. ^ Villegas-Estrada A, Lee M, Hesek D, Vakulenko SB, Mobashery S (July 2008). "Co-opting the cell wall in fighting methicillin-resistant Staphylococcus aureus: potent inhibition of PBP 2a by two anti-MRSA beta-lactam antibiotics". Journal of the American Chemical Society 130 (29): 9212–3. doi:10.1021/ja8029448. PMID 18582062. PMC 2747592. http://dx.doi.org/10.1021/ja8029448.  
  6. ^ Zhanel GG, Sniezek G, Schweizer F, Zelenitsky S, Lagacé-Wiens PR, Rubinstein E, Gin AS, Hoban DJ, Karlowsky JA (2009). "Ceftaroline: a novel broad-spectrum cephalosporin with activity against meticillin-resistant Staphylococcus aureus". Drugs 69 (7): 809–31. doi:10.2165/00003495-200969070-00003. PMID 19441869.  
  7. ^ Talbot GH, Thye D, Das A, Ge Y (October 2007). "Phase 2 study of ceftaroline versus standard therapy in treatment of complicated skin and skin structure infections". Antimicrobial Agents and Chemotherapy 51 (10): 3612–6. doi:10.1128/AAC.00590-07. PMID 17682094. PMC 2043268. http://aac.asm.org/cgi/pmidlookup?view=long&pmid=17682094.  
  8. ^ BUSINESS WIRE (2009-09-12). "Forest Laboratories Presents Analysis of Two Positive Pivotal Phase III Studies of Ceftaroline for the Treatment of Community-Acquired Pneumonia (CAP) at ICAAC". Press release. http://www.businesswire.com/news/home/20090912005009/en. Retrieved 2009-10-19.  
  9. ^ a b Y, Ge; Floren L, Redman R, et. al.. "The pharmacokinetics and safety of ceftaroline (PPI-0903) in healthy subjects receiving multiple-dose intravenous infusions.". 2006 Interscience Conference on Antimicrobial Agents and Chemotherapy / Infectious Disease Society of America Conference.  
  10. ^ Yukihiro I, Junko B (2008). "Stability and Stabilization Studies of TAK-599 (Ceftaroline Fosamil) a Novel N-Phosphono Type Prodrug of Anti-methicillin Resistant Staphylococcus aureus Cephalosporin T-91825". Chem Pharm Bull 56 (10): 1406-11. doi:10.1248/cpb.56.1406. PMID 18827379. http://www.jstage.jst.go.jp/article/cpb/56/10/1406/_pdf.  
  11. ^ a b Ishikawa t, Nobuyuki M, et al. (2003). "TAK-599, a novel N-phosphono type prodrug of anti-MRSA cephalosporin T-91825: Synthesis, physicochemical and pharmacological properties". Bioorg Med Chem 11 (11): 2427-2437. PMID 12735989.  
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