The compound LY 146032 was discovered by researchers at Eli Lilly and Company in the late 1980s.
LY 146032 showed promise in Phase I/II clinical trials for treatment of infection caused by Gram-positiveorganisms. Lilly ceased development because high dose therapy was associated with adverse effects on skeletal muscle, including myalgia and potential myositis. The rights to LY 146032 were acquired by Cubist Pharmaceuticals in 1997, which following U.S. Food and Drug Administration (FDA) approval in September 2003 began marketing the drug under the trade name CUBICIN . Cubicin is marketed in the EU and several other countries by Novartis following its purchase of Chiron Corporation, previous licensee.[2][3]
[edit]Mechanism of action
Daptomycin has a distinct mechanism of action, disrupting multiple aspects of bacterial cell membranefunction. It appears to bind to the membrane and cause rapid depolarization, resulting in a loss of membrane potential leading to inhibition of protein, DNA and RNA synthesis, which results in bacterial cell death.
[edit]Microbiology
Daptomycin is active against Gram-positive bacteria only. It has proven in vitro activity against enterococci(including glycopeptide-resistant Enterococci (GRE)), staphylococci (including methicillin-resistantStaphylococcus aureus), streptococci and corynebacteria.
[edit]Clinical use
[edit]Indications
Daptomycin is approved in the United States for skin and skin structure infections caused by Gram-positiveinfections, Staphylococcus aureus bacteraemia and right-sided S. aureus endocarditis. It binds avidly topulmonary surfactant, and therefore cannot be used in the treatment of pneumonia.[4] There seems to be a difference in working daptomycin on hematogenous pneumonia.[5]
[edit]Efficacy
Daptomycin has been shown to be not inferior to standard therapies (nafcillin, oxacillin, flucloxacillin or vancomycin) in the treatment of bacteraemia and right-sided endocarditis caused by Staphylococcus aureus.[6] A study in Detroit, Michigancompared 53 patients treated suspected MRSA skin or soft tissue infection with daptomycin against vancomycin, has been shown to result in faster recovery from skin and soft tissue infections (4 days versus 7 days).[7] The main problems with this study were that vancomycin controls were historical (which means that the improved outcomes observed in the daptomycin treated patients could be due to improvements in practice over time that were unrelated to daptomycin use), and the target drug levels were low (lower limit 5 mg/dl, compared to the 10 mg/dl or 15 mg/dl currently recommended).
In Phase III clinical trials, limited data showed that daptomycin was associated with poor outcomes in patients with left-sided endocarditis[citation needed]. It is inactivated by pulmonary surfactants and is not indicated for the treatment of pneumonia. Daptomycin has not been studied in patients with prosthetic valveendocarditis or meningitis.[8]