Article: Daptomycin

Daptomycin is a lipopeptide antibiotic. It is active only against Gram-positive organisms. It is a true antibiotic in that it is a naturally occurring compound which is found in the soil saprotroph, Streptomyces roseosporus; the compound was initially called LY146032 and was first discovered by Eli Lilly in the 1980's (Counter 1984) as part of their drug development programme. The rights to LY146032 were bought by Cubist Pharmaceuticals in 1997, who brought it to the US market in Nov 2003 as Cubicin®.

Pharmacology

Daptomycin is only active against Gram-positive bacteria. The precise mechanism of action is currently (13 Nov 2005) unknown. It is known that daptomycin requires calcium ions in order to work, it binds to bacterial cell membranes and causes rapid depolarization; loss of membrane potential leads to inhibition of protein, RNA, and DNA synthesis, which results in cell death. The bacteriocidal acitivity of daptomycin is concentration dependent. Because of its novel mechanism of activity, daptomycin may be active against organisms resistant to methicillin, vancomycin, and linezolid.

It has proven in vitro activity against Enterococci (including glycopeptide-resistant Enterococci (GRE)), Staphylococci (including methicillin-resistant Staphylococcus aureus), Streptococci and Corynebacteria.

Daptomycin cannot be used to treat pulmonary infections because it is inactivated by surfactant.

There is in vitro evidence of synergy with β-lactam antibiotics. The is no evidence of antagonism so far. Daptomycin is unaffected by concurrent administration of probenecid.

Indications

Daptomycin is licensed in the US for skin and skin structure infections caused by gram-positive infections, Staphylococcus aureus bacteraemia and right-sided Staph. aureus endocarditis. It is currently (14 Nov 2005) not available outside of the US.

In Phase III clinical trials, daptomycin performed poorly in patients with left-sided endocarditis. There are no studies using daptomycin to treat patients with prothetic valve endocarditis or meningitis. Daptomycin is inactivated by surfactant and cannot be used to treat pulmonary infections.

Dosage

In skin and soft tissue infections, 4 mg/kg daptomycin is given intravenously once daily. For Staph. aureus bacteraemia or right-sided endocarditis, the licensed dose is 6mg/kg given intravenously once daily. Daptomycin has a half-life of 8 hours.

Daptomycin is supplied as a sterile preservative-free pale yellow to light brown lyophilized 500mg cake that must be reconstituted with 0.9% saline prior to use.

The dose of daptomycin must be reduced in renal impairment. The is no information available on dosing in children (aged less than 18 years).

Adverse reactions

Daptomycin can cause an increase in blood creatine kinase (CK) levels. There are reports of myopathy and rhabdomyolysis occuring in patients simultaneously taking statins but whether this is due entirely to the statin or whether daptomycin potentiates this effect is unknown. The manufacturer advise that statins should be discontinued while the patient is being treated with daptomycin.

There are no studies examining the effects of daptomycin in pregnancy or in breast milk.