Ceftaroline fosamil

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Ceftaroline fosamil
300px
Space-filling model of the ceftaroline fosamil molecule as a zwitterion
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
Clinical data
Trade names Teflaro, Zinforo
Licence data EMA:Link, US FDA:link
Pregnancy
category
  • AU: B1
  • US: B (No risk in non-human studies)
Legal status
Routes of
administration		 Intravenous
Pharmacokinetic data
Protein binding 20%
Biological half-life 2.5 hours
Excretion Urine (88%), faeces (6%)
Identifiers
CAS Number 400827-46-5 YesY
ATC code J01DI02 (WHO)
PubChem CID: 16007393
ChemSpider 8028692 N
UNII 7P6FQA5D21 N
ChEBI CHEBI:70718 N
ChEMBL CHEMBL501122 N
Synonyms PPI 0903, TAK-599
Chemical data
Formula C24H25N8O10PS4
Molecular mass 744.736661 g/mol
  • O=C4N3/C(=C(/Sc2nc(c1cc[n+](cc1)C)cs2)CS[C@@H]3[C@@H]4NC(=O)C(=N\OCC)/c5nc(sn5)NP(=O)(O)O)C([O-])=O
  • 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 N
  • Key:ZCCUWMICIWSJIX-NQJJCJBVSA-N N
 NYesY (what is this?)  (verify)

Ceftaroline fosamil (INN) /sɛfˈtæroʊliːn/, brand name Teflaro in the US and Zinforo in Europe, is an advanced-generation[1] cephalosporin antibiotic. It is active 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[2] and complicated skin and skin structure infection.[3][4][5]

Ceftaroline is being developed by Forest Laboratories, under a license from Takeda.[5] Ceftaroline has received approval from the U.S. Food and Drug Administration for the treatment of community-acquired bacterial pneumonia and acute bacterial skin infections on October 29, 2010.[6] In vitro studies show 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. Ceftaroline and ceftobiprole are on an unnamed subclass of cephalosporins by the Clinical and Laboratory Standards Institute (CLSI).

Clinical use

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Main article: Cephalosporin

Ceftaroline is a novel cephalosporin with 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.[3][4] In 2009, ceftaroline had completed phase-III clinical trials for community-acquired pneumonia comparing it against ceftriaxone with non-inferior results and similar adverse reaction profile.[2] However, only results for phase-II clinical trials in treatment of complicated skin and skin structure infections have been published.[7] Sept 2009 : Phase III trials results reported.[8] On September 8, 2010, the FDA Advisory Committee recommended approval for the treatment of community acquired bacterial pneumonia and complicated skin and skin structure infections.[9] In Oct 2010, the FDA approval was gained for community-acquired bacterial pneumonia and acute bacterial skin and skin structure infections, including MRSA.[10]

Safety

The clinical studies indicated ceftaroline was well tolerated. The overall rate of adverse events was comparable between the two treatment groups (The CANVAS I and CANVAS II trials evaluated ceftaroline monotherapy versus vancomycin plus aztreonam in adult patients with complicated skin and skin structure infections caused by Gram-positive and Gram-negative bacteria.). The overall discontinuation rate for ceftaroline-treated patients was 2.7% compared to a rate of 3.7% for the comparator group-treated patients. The most common adverse reactions occurring in > 2% of patients receiving ceftaroline in the pooled phase-III clinical trials were diarrhea, nausea, and rash.:[11]

Contraindications

Warnings and precautions

The warnings and precautions associated with ceftaroline include:[11]

Hypersensitivity reactions

Serious hypersensitivity (anaphylactic) reactions and serious skin reactions have been reported with beta-lactam antibiotics, including ceftaroline. Exercise caution in patients with known hypersensitivity to beta-lactam antibiotics including ceftaroline. Before therapy with ceftaroline is instituted, careful inquiry about previous hypersensitivity reactions to other cephalosporins, penicillins, or carbapenems should be made. If this product is to be given to penicillin- or other beta-lactam-allergic patients, caution should be exercised because cross sensitivity among beta-lactam antibacterial agents has been clearly established. If an allergic reaction to ceftaroline occurs, the drug should be discontinued. Serious acute hypersensitivity reactions require emergency treatment with epinephrine and other emergency measures, that may include airway management, oxygen, intravenous fluids, antihistamines, corticosteroids, and vasopressors as clinically indicated.

Clostridium difficile-associated diarrhea

Clostridium difficile-associated diarrhea (CDAD) has been reported for nearly all antibacterial agents including ceftaroline, and may range in severity from mild diarrhea to fatal colitis. Careful medical history is necessary because CDAD has been reported to occur more than two months after the administration of antibacterial agents. If CDAD is suspected or confirmed, antibacterials not directed against C. difficile should be discontinued, if possible.

Development of drug-resistant bacteria

Prescribing ceftaroline in the absence of a proven or strongly suspected bacterial infection is unlikely to provide benefit to the patient and increases the risk of the development of drug-resistant bacteria.

Direct Coombs test seroconversion

In the pooled phase-III CABP trials, 51/520 (9.8%) of patients treated with ceftaroline compared to 24/534 (4.5%) of patients treated with ceftriaxone seroconverted from a negative to a positive direct Coombs' test result. No clinical adverse reactions representing hemolytic anemia were reported in any treatment group. If anemia develops during or after treatment with ceftaroline, drug-induced hemolytic anemia should be considered. If drug-induced hemolytic anemia is suspected, discontinuation of ceftaroline should be considered and supportive care should be administered to the patient if clinically indicated.

Interactions

No clinical drug-drug interaction studies have been conducted with ceftaroline fosamil. In vitro studies in human liver microsomes indicated that neither ceftaroline fosamil nor ceftaroline inhibits the major cytochrome P450 isoenzymes. Therefore, neither ceftaroline fosamil nor ceftaroline is expected to inhibit or induce the clearance of drugs that are metabolized by these metabolic pathways in a clinically relevant manner.

Use in specific populations

For pregnant or nursing mothers, ceftaroline fosamil should be used only if the potential benefit outweighs the potential risk to the fetus or child. Safety and effectiveness in pediatric patients has not been studied.

Because elderly patients 65 years of age or older are more likely to have decreased renal function and ceftaroline is excreted primarily by the kidney, care should be taken in dose selection in this age group as in younger patients with impaired renal function. Dosage adjustment is required in patients with moderately (30 to ‰¤ 50 mL/min) or severely (< 30 mL/min) impaired renal function.

The pharmacokinetics of ceftaroline in patients with hepatic impairment have not been established.

Side effects

No adverse reactions occurred in greater than 5% of patients receiving ceftaroline. The most common adverse reactions occurring in > 2% of patients receiving ceftaroline in the pooled phase-III clinical trials were:[11]

Chemistry

Ceftaroline fosamil is used in form of the acetate. It is a prodrug that is converted to active metabolite ceftaroline and inactive metabolite ceftaroline-M1. Initial in vitro and in vivo animal studies referred to ceftaroline fosamil acetate as PPI-0903.[12][13]

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.[14]

References

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