β-lactam; bacterial cell wall synthesis

Ceftaroline (TAK-599) is a novel N-phosphono prodrug of anti-methicillin-resistant Staphylococcus aureus (MRSA) cephalosporin 2a (T-91825) that has high affinity for penicillin-binding protein (PBP) 2' (IC(50); 0.90 microg/mL) and shows potent in vitro anti-MRSA activity (MIC against MRSA N133; 1.56 microg/mL), comparable to that of vancomycin (1.56 microg/mL). [1]

Ceftaroline fosamil acetate (sc), with an ED50 of 1.60-2.37 mg/kg, protects mice against experimental systemic infection induced by Staphylococcus aureus N133[1]. In rats and monkeys, ceftarolin fostil acetate hydrate (10 mg/kg; subcutaneous injection) rapidly leaves the blood and is successfully converted to T-91825 [1]. With ED50s of 1.60–2.37 mg/kg, ceftaroline fosamil (s.c.) protects mice from experimental systemic infection caused by S. aureus N133[1].
In the blood of rats and monkeys, ceftaroline fosamil (10 mg/kg; s.c.) vanishes quickly and smoothly transforms into T-91825[1].

High-performance liquid chromatography was used to determine the concentrations of linezolid (lower detection limit, 0.1 mg/liter; coefficient of variation, <10%). Assays with vancomycin were performed by an immunoenzymatic method with a COBAS MIRA unit and EMIT reagents (detection threshold, 2.5 mg/liter; coefficient of variation, 4.1 to 6.9%). Active ceftaroline concentrations were determined by a microbiologic assay with Bacillus subtilis as the test organism and antibiotic medium 2 as the diffusion medium (lower detection limit, 0.25 mg/liter; intraday and interday variations, <10%). [2]

Using the neutropenic lung infection model, 17 clinical S. aureus isolates (2 MSSA, 15 MRSA) are investigated. For a duration of 24 hours, groups of six mice are treated with Ceftaroline fosamil starting three hours after inoculation. Doses of ceftaroline fosamil are injected subcutaneously in increments of 0.2 mL. Normal saline is given to control animals in the same amounts, ways, and intervals as the treatment plans[1].

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For ceftaroline, blood samples were taken from six healthy rabbits after administration of a ceftaroline acetate bolus of 10 and 30 mg/kg of body weight in order to determine the spontaneous drug kinetics. The simulation was intended to provide apparent values of pharmacokinetic parameters close to those observed in healthy volunteers after a 1-h infusion of a 600-mg dose (ca. 10 mg/kg) of ceftaroline acetate: mean half-life (t1/2), 1.57 to 2.63 h; peak concentration (Cmax), 18.96 to 21.02 mg/liter; and area under the curve (AUC), 56.08 mg·h/liter. A total dose of 58 mg/kg needed to be infused into the rabbit over a 12-h period in order to simulate the kinetics in human serum after the administration of a 10-mg/kg dose (i.e., 600 mg twice daily).
For each MRSA strain, the animals were randomly assigned to either no treatment (controls), ceftaroline regimen mimicking the human dose of 10 mg/kg every 12 h (q12h) (600 mg q12h), a linezolid regimen mimicking the human dose of 10 mg/kg q12h (600 mg q12h), and vancomycin administered by a constant intravenous infusion in order to reach a steady-state 20× MIC in serum.
Experimental endocarditis was induced with an inoculum of 108 CFU of S. aureus. Treatment was started 24 h after inoculation for a 4-day regimen. Aortic valve vegetations were excised, weighed, and then homogenized in 0.5 ml of saline buffer and used for quantitative cultures on agar for 24 h at 37°C. Dilutions at 10−1, 10−2, and 10−4 were prepared to eliminate potential carryover effects. To evaluate whether ceftaroline treatment could induce the selection of variants resistant in vivo, undiluted vegetation homogenates were spread on agar plates containing the active form of ceftaroline at a concentration corresponding to fourfold the MIC. Bacterial counts were determined after 48 h of incubation at 37°C.[2]

Absorption, Distribution and Excretion
primarily eliminated by the kidneys (6% in feces within 48 hours).
Median 20.3 L (18.3-21.6 L).

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Metabolism / Metabolites
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.

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Biological Half-Life
1.60 hours (600 mg dose).

Protein Binding
approximately 20%.

[1]. TAK-599, a novel N-phosphono type prodrug of anti-MRSA cephalosporin T-91825: synthesis, physicochemical and pharmacological properties. Bioorg Med Chem. 2003 May 29;11(11):2427-37.

[2]. Ceftaroline fosamil: a novel broad-spectrum cephalosporin with expanded anti-Gram-positive activity. J Antimicrob Chemother. 2010 Nov;65 Suppl 4:iv9-16.

[3]. Ceftaroline fosamil, a cephalosporin derivative for the potential treatment of MRSA infection. Curr Opin Investig Drugs. 2008 Feb;9(2):201-9.

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.

C22H22N8O8PS4+.C2H3O2-.H2O

762.752

762.041

400827-55-6

Ceftaroline fosamil;400827-46-5; 229016-73-3; 400827-55-6

16007393

Typically exists as solid at room temperature

1.884

6

20

10

48

1240

2

O.C([O-])(=O)C.C(C1=C(SC2=NC(C3=CC=[N+](C)C=C3)=CS2)CS[C@H]2N1C(=O)[C@H]2NC(=O)/C(=N\OCC)/C1N=C(NP(O)(O)=O)SN=1)(O)=O

KRWPPVCZNGQQHZ-IINIBMQSSA-N

InChI=1S/C22H21N8O8PS4.C2H4O2.H2O/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;1-2(3)4;/h4-8,14,19H,3,9H2,1-2H3,(H4-,24,25,27,28,31,33,34,35,36,37);1H3,(H,3,4);1H2/b26-13-;;/t14-,19-;;/m1../s1

acetic acid;(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;hydrate

Ceftaroline fosamil hydrate; TAK-599 hydrate; TAK599 hydrate; PPI0903 hydrate; PPI-0903 hydrate

2934.99.9001

Powder      -20°C    3 years

                     4°C     2 years

In solvent   -80°C    6 months

                  -20°C    1 month

Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)

May dissolve in DMSO (in most cases), if not, try other solvents such as H2O, Ethanol, or DMF with a minute amount of products to avoid loss of samples

Note: Listed below are some common formulations that may be used to formulate products with low water solubility (e.g. < 1 mg/mL), you may test these formulations using a minute amount of products to avoid loss of samples.

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Injection Formulation 1: DMSO : Tween 80： Saline = 10 : 5 : 85 (i.e. 100 μL DMSO stock solution → 50 μL Tween 80 → 850 μL Saline)
*Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH ₂ O to obtain a clear solution.
Injection Formulation 2: DMSO : PEG300 ：Tween 80 : Saline = 10 : 40 : 5 : 45 (i.e. 100 μL DMSO → 400 μLPEG300 → 50 μL Tween 80 → 450 μL Saline)
Injection Formulation 3: DMSO : Corn oil = 10 : 90 (i.e. 100 μL DMSO → 900 μL Corn oil)
Example: Take the Injection Formulation 3 (DMSO : Corn oil = 10 : 90) as an example, if 1 mL of 2.5 mg/mL working solution is to be prepared, you can take 100 μL 25 mg/mL DMSO stock solution and add to 900 μL corn oil, mix well to obtain a clear or suspension solution (2.5 mg/mL, ready for use in animals).

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Injection Formulation 4: DMSO : 20% SBE-β-CD in saline = 10 : 90 [i.e. 100 μL DMSO → 900 μL (20% SBE-β-CD in saline)]
*Preparation of 20% SBE-β-CD in Saline (4°C，1 week): Dissolve 2 g SBE-β-CD in 10 mL saline to obtain a clear solution.
Injection Formulation 5: 2-Hydroxypropyl-β-cyclodextrin : Saline = 50 : 50 (i.e. 500 μL 2-Hydroxypropyl-β-cyclodextrin → 500 μL Saline)
Injection Formulation 6: DMSO : PEG300 : castor oil : Saline = 5 : 10 : 20 : 65 (i.e. 50 μL DMSO → 100 μLPEG300 → 200 μL castor oil → 650 μL Saline)
Injection Formulation 7: Ethanol : Cremophor : Saline = 10： 10 : 80 (i.e. 100 μL Ethanol → 100 μL Cremophor → 800 μL Saline)
Injection Formulation 8: Dissolve in Cremophor/Ethanol (50 : 50), then diluted by Saline
Injection Formulation 9: EtOH : Corn oil = 10 : 90 (i.e. 100 μL EtOH → 900 μL Corn oil)
Injection Formulation 10: EtOH : PEG300：Tween 80 : Saline = 10 : 40 : 5 : 45 (i.e. 100 μL EtOH → 400 μLPEG300 → 50 μL Tween 80 → 450 μL Saline)

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Oral Formulation 1: Suspend in 0.5% CMC Na (carboxymethylcellulose sodium)
Oral Formulation 2: Suspend in 0.5% Carboxymethyl cellulose
Example: Take the Oral Formulation 1 (Suspend in 0.5% CMC Na) as an example, if 100 mL of 2.5 mg/mL working solution is to be prepared, you can first prepare 0.5% CMC Na solution by measuring 0.5 g CMC Na and dissolve it in 100 mL ddH2O to obtain a clear solution; then add 250 mg of the product to 100 mL 0.5% CMC Na solution, to make the suspension solution (2.5 mg/mL, ready for use in animals).

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Oral Formulation 3: Dissolved in PEG400
Oral Formulation 4: Suspend in 0.2% Carboxymethyl cellulose
Oral Formulation 5: Dissolve in 0.25% Tween 80 and 0.5% Carboxymethyl cellulose
Oral Formulation 6: Mixing with food powders

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Note: Please be aware that the above formulations are for reference only. InvivoChem strongly recommends customers to read literature methods/protocols carefully before determining which formulation you should use for in vivo studies, as different compounds have different solubility properties and have to be formulated differently.

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 (Please use freshly prepared in vivo formulations for optimal results.)