Chemical Properties
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Definition
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.
Description
Daptomycin is the first entry of a new class of cyclic lipopeptide antibiotics that disrupts
multiple aspects of bacterial membrane function including disruption of membrane
potential and amino acid transport, inhibition of lipoteichoic acid synthesis and inhibition
of peptidoglycan synthesis. It is indicated for the treatment of complicated skin and skinstructure
infections (cSSSI) caused by a range of Gram-positive bacteria. This is distinct
from previous classes of antibiotics that inhibit bacterial cell wall biosynthesis, bacterial
DNA replication, and folate coenzyme biosynthesis. Due to this unique mechanism,
cross-resistance has not been noted with any other class of antibiotics. It is produced by
the fermentation of Streptomyces roseporus. The fatty acid side chain is a key
determinant of acute toxicity, with the ten-carbon chain least acutely toxic to mice.
Daptomycin has shown efficacy in a variety of animal models versus several Grampositive
infectious agents including methicillin-susceptible S aureus, vancomycinresistant
E faecalis, spyogenes and S pneumoniae. It retains in vitro activity against
methicillin, vancomycin and linezolid-resistant strains including Staphylococcus aureus
(MRSA and VRSA), which is the leading cause of hospital-acquired infections
(nosocomial infections (Nis)). The MIC values against Gram-positive pathogens are
relatively low, ranging from 0.06 to 2.0 mg/mL. In two clinical studies treating patients
(ca. 1090 for both arms of both studies) with complicated skin and soft tissue infections
(cSSTIs) in which gram-positive pathogens were suspected and parenteral antibiotics
were required, daptomycin provided similar clinical success rates as compared to
standard therapy with vancomycin or semisynthetic penicillins such as cloxacillin,
oxacillin, or flucloxacillin. The daptomycin treated group showed more rapid
improvement as noted by scoring on day three or four and also had a shorter duration
of treatment versus the standard therapy group (7 vs 8 days). It is dosed once daily
(4 mg/kg/day) by intravenous infusion and has a half-life of 8.1 h. It is primarily cleared
renally and thus requires dosing adjustments for those with severe renal insufficiency
(CLCR ,30 mL/min). Clinical safety of daptomycin is similar to other antibiotics.
Brand name
Cubicin (Cubist).
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.
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.
Side effects
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.
Metabolism
In-vitro studies indicate that daptomycin is not
metabolised by, and does not affect, the cytochrome P450
isoenzyme system. Little or no metabolism is thought
to take place although 4 minor metabolites have been
detected in the urine
Daptomycin is excreted mainly via renal filtration with
about 78% and 6% of a dose recovered in the urine and
faeces, respectively
References
1) Jung?et al. (2004),?Structural transitions as determinants of the action of the calcium-dependent antibiotic daptomycin; Chem. Biol.,?11?949
2) Steenbergen?et al. (2005),?Daptomycin: a lipopeptide antibiotic for the treatment of serious Gram-positive infections; J. Antimicrob. Chemother.,?55?283
