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Daptomycin is a member of the A 21978 complex of high molecular weight cyclic lipopeptides with potent antibiotic activity, notably against MRSA, VISA and VRSA bacterial strains. Originally isolated from Streptomyces roseosprous by Eli Lily in the 1980s, daptomycin was selected and developed by Cubist Pharmaceticals for human use. Daptomycin exhibits Ca-dependent depolarisation of the bacterial membrane resulting in loss of membrane potential leading to inhibition of DNA, RNA and protein synthesis which results in cell death.

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ChEBI: A polypeptide comprising N-decanoyltryptophan, asparagine, aspartic acid, threonine, glycine, ornithine, aspartic acid, D-alanine, aspartic acid, glycine, D-serine, threo-3-methylglutamic ac d and 3-anthraniloylalanine (also known as kynurinine) coupled in sequence and lactonised by condensation of the carboxylic acid group of the 3-anthraniloylalanine with the alcohol group of the threonine residue.

Pharmaceutical Applications

A semisynthetic lipopeptide derived from a fermentation product of Streptomyces roseosporus.
Daptomycin is a cyclic peptide with a lipophilic tail and thus resembles the polymyxins structurally. Its useful activity is restricted to Gram-positive cocci, notably Staph. aureus and its chief attraction is that it retains activity against multiresistant strains. Its activity in vitro is greatly potentiated by the presence of calcium (but not magnesium) ions and in these conditions it is more potently bactericidal than the glycopeptides.

Pharmacokinetics

Oral absorption: Poor
C_max 4 mg/kg intravenous infusion :55 mg/L end infusion
Plasma half-life: 8–9 h
Volume of distribution:c.0.1 L/kg
Plasma protein binding: 92–95%
Oral absorption is poor and it is administered intravenously. It is eliminated predominantly by the kidneys, about half the dose being excreted unchanged within 24 h. The plasma halflife increases in patients with impaired renal function so that the dosage interval should be extended. Around 10% of an administered dose is removed by peritoneal and hemodialysis.

Clinical Use

Daptomycin is a fermentation product having a cyclic lipopeptide structure. It is primarily active against Gram-positive infections, especially those involved in skin/skin structure infections. It is given IV but must be administered over a period of 30 minutes or more. It binds to cell membranes and causes depolarization, which interrupts protein, DNA, and RNA synthesis. Daptomycin is bactericidal. Although resistance can be achieved in vitro, resistance has been slow to emerge in the clinic. Patients should be monitored for muscle pain or weakness, because some incidence of elevated serum creatinine phosphokinase is associated with its use. A small number of clinical trial patients also developed conditions related to decreases in nerve conduction (e.g., paresthesias and Bell's palsy). Daptomycin is eliminated primarily by the kidney, so dose adjustment may be necessary in cases of renal insufficiency.

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It is generally well-tolerated, but gastrointestinal side effects, headache and various other adverse reactions occur with varying frequency. Less commonly, but more seriously, myalgia, muscle weakness and myositis may occur requiring regular monitoring of creatine kinase during treatment. Rhabdomyolysis has been reported, but is very rare.

Drug interactions

In vitro experiments using human hepatocytes demonstrated that daptomycin has no effects on hepatic CYP450-mediated drug metabolism and, therefore, suggest that daptomycin is unlikely to show potential for pharmacokinetic interactions with concomitantly administered drugs that are metabolized by CYP450 isoforms. Drug interaction single- and multiple-dose studies were performed in healthy subjects. No clinically relevant interactions were found when daptomycin 2–6 mg/kg was administered with aztreonam, tobramycin, warfarin, simvastatin, and probenecid. Although no specific drug interactions have been detected when daptomycin is co-administered with HMG-CoA reductase inhibitors (e.g. simvastatin), a number of patients who developed creatine phosphokinase (CPK) increases in a study of daptomycin efficacy in S. aureus bacteremia/endocarditis were receiving concomitant HMGCoA reductase inhibitors. Thus, monitoring of CPK levels is probably warranted in patients with risk factors and timely cessation of potential agents if myopathy is noted.

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