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2010 New Drug Approvals - Pt. XVI - Ceftaroline Fosamil (Teflaro)



ATC code (partial): J01DI

On October 29th, FDA has approved Ceftaroline Fosamil under the trade name Teflaro. Ceftaroline Fosamil (previously known by the research code TAK-599, the parent drug, Ceftaroline is also known as T-91,825) is an antibiotic indicated for the treatment of adults with acute bacterial skin and skin structure infections (ABSSSI) caused by susceptible Gram-positive and Gram-negative microorganisms, such as Staphylococcus aureus (including methicillin-susceptible and -resistant isolates), Streptococcus pyogenes, Streptococcus agalactiae, Escherichia coli, Klebsiella pneumoniae, and Klebsiella oxytoca, and also for the treatment of community-acquired bacterial pneumonia (CABP) caused by susceptible Gram-positive and Gram-negative bacteria, such as Streptococcus pneumoniae (including cases with concurrent bacteremia), Staphylococcus aureus (methicillin-susceptible isolates only), Haemophilus influenzae, Klebsiella pneumoniae, Klebsiella oxytoca, and Escherichia coli.

Ceftaroline Fosamil is a semisynthetic antibacterial of the cephalosporin class of beta-lactams, which are originally identified in 1948 from the Cephalosporum/Acremonium. Ceftaroline Fosamil is the phosphamide prodrug of the bioactive Ceftaroline. Like other drugs in the same class, the bactericidal action of Ceftaroline is mediated through covalent binding to essential penicillin-binding proteins (PBPs) in the bacteria wall. In particular, ceftaroline is bactericidal against S. aureus, including methicillin-resistant S. aureus (MRSA), due to its affinity for PBP2a (Uniprot: Q53707, ChEMBL: 19669), the type of PBP produced by MRSA and not well inhibited by other antibiotics such as methicillin (ChEMBL: 116716), oxacillin (ChEMBL: 156432), penicillin, and amoxicillin (ChEMBL: 657723). Ceftaroline is also active against S. pneumoniae due to its affinity for PBP2x (Uniprot: P14677, ChEMBL: 102467).

Ceftaroline Fosamil is a large 'small-molecule' semisynthetic prodrug (Molecular Weight of 685.7 g.mol-1 for Ceftaroline Fosamil itself and 762.7 g.mol-1 for the monoacetate salt), slightly lipophilic and soluble in water. Following injection, Ceftaroline Fosamil has a volume of distribution of 20.3L, a low plasma protein binding (ppb) of 20%, an elimination half-life of 1.6hr and a plasma clearance of 9.58 L/hr. Ceftaroline Fosamil is primarily eliminated by the kidneys (88% of the dose is recovered in urine) and mainly as the active metabolite ceftaroline (64% as ceftaroline and 2% as an inactive metabolite). Ceftaroline is not an inhibitor or substrate of the major cytochrome P450 isoenzymes. The recommended dosage of Ceftaroline Fosamil is 600mg every 12 hours by intravenous infusion administrated over an hour.

The full prescribing information can be found here. Like other cephalosporins, Ceftaroline Fosamil structure (6R,7R)-7-{(2Z)-2-(ethoxyimino)-2-[5-(phosphonoamino)-1,2,4thiadiazol-3-yl]acetamido}-3-{[4-(1-methylpyridin-1-ium-4-yl)-1,3-thiazol-2-yl]sulfanyl}-8-oxo-5-thia-1azabicyclo[4.2.0]oct-2-ene-2-carboxylate contains a cyclic amide (the beta-lactam ring) fused with a six member ring (the cephem ring). Another notable feature of Ceftaroline Fosamil is the thiazolylthio group, which is thought to be crucial for the activity against MRSA.

NAME="Ceftaroline Fosamil"
TRADEMARK_NAME="Teflaro"
ATC_code= NA
SMILES="CCO\N=C(/C(=O)N[C@H]1[C@H]2SCC(=C(N2C1=O)C(=O)O)Sc3nc(cs3)c4cc[n+](C)cc4)\c5nsc(NP(=O)(O)O)n5"
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)/p+1/b26-13-/t14-,19-/m1/s1"
ChemDraw=Ceftaroline_Fosamil.cdx

The license holder is Forest Pharmaceuticals, Inc. and the product website is www.teflaro.com.

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