Ceftaroline fosamil

Ceftaroline fosamil

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	EU EMA: Zinforo US FDA: Ceftaroline
Pregnancy category	AU: B1 US: B (No risk in non-human studies)
Routes of administration	Intravenous
Legal status	AU: S4 (Prescription only) US: ℞-only
Pharmacokinetic data
Protein binding	20%
Biological half-life	2.5 hours
Excretion	Urine (88%), faeces (6%)
Identifiers
CAS Number	400827-46-5
ATC code	J01DI02
PubChem	CID 16007393 CID 9852981
ChemSpider	8028692
UNII	7P6FQA5D21
ChEBI	CHEBI:70718
ChEMBL	CHEMBL501122
Synonyms	PPI 0903, TAK-599
Chemical data
Formula	C24H25N8O10PS4
Molar mass	744.736661 g/mol
SMILES 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 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 Key:ZCCUWMICIWSJIX-NQJJCJBVSA-N
(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

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

• Known serious hypersensitivity to ceftaroline or other members of the cephalosporin class
• Anaphylaxis and anaphylactoid reactions^[11]

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]

• Diarrhea
• Nausea
• Rash

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

1. Kollef MH (December 2009). "New antimicrobial agents for methicillin-resistant Staphylococcus aureus". Crit Care Resusc 11 (4): 282–6. PMID 20001879.
2. 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.
3. 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.
4. 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.
5. 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.
6. "Forest Announces FDA Approval of Teflaro(TM) (ceftaroline fosamil) for the Treatment of Community-Acquired Bacterial Pneumonia and Acute Bacterial Skin and Skin Structure Infection" (Press release). Forest Laboratories. 2010-10-29. Retrieved October 30, 2010.
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. PMC 2043268. PMID 17682094.
8. "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). BUSINESS WIRE. 2009-09-12. Retrieved 2009-10-19.
9. "New Drug Approvals". 2010-10-29. Retrieved 2010-11-08.
10. "FDA approves Teflaro for treatment of bacterial infections". 30 Oct 2010.
11. "Teflaro". 2010-10-29. Retrieved 2010-11-08.
12. 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.
13. 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.
14. 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.