Daptomycin

Daptomycin is a lipopeptide antibiotic used in the treatment of systemic and life-threatening infections caused by Gram-positive organisms. It is a naturally occurring compound found in the soil saprotroph Streptomyces roseosporus. Its distinct mechanism of action makes it useful in treating infections caused by multiple drug-resistant bacteria. It is marketed in the United States under the trade name Cubicin by Cubist Pharmaceuticals. Daptomycin is a lipopeptide antibiotic used in the treatment of systemic and life-threatening infections caused by Gram-positive organisms. It is a naturally occurring compound found in the soil saprotroph Streptomyces roseosporus. Its distinct mechanism of action makes it useful in treating infections caused by multiple drug-resistant bacteria. It is marketed in the United States under the trade name Cubicin by Cubist Pharmaceuticals. Daptomycin, originally designated as 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-positive organisms. 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 for use in people older than 18 years, began marketing the drug under the trade name Cubicin. Cubicin is marketed in the EU and in several other countries by Novartis following its purchase of Chiron Corporation, the previous licensee. Daptomycin has a distinct mechanism of action, disrupting multiple aspects of bacterial cell membrane function. It inserts into the cell membrane in a phosphatidylglycerol-dependent fashion, where it then aggregates. The aggregation of daptomycin alters the curvature of the membrane, which creates holes that leak ions. This causes rapid depolarization, resulting in a loss of membrane potential leading to inhibition of protein, DNA, and RNA synthesis, which results in bacterial cell death. It has been proposed that the formation of spherical micelles by Daptomycin may affect the mode of action. Daptomycin is bactericidal against Gram-positive bacteria only. It has proven in vitro activity against enterococci (including glycopeptide-resistant enterococci (GRE)), staphylococci (including methicillin-resistant Staphylococcus aureus), streptococci, corynebacteria and stationary-phase Borrelia burgdorferi persisters. Daptomycin resistance is still uncommon, but has been increasingly reported in GRE, starting in Korea in 2005, in Europe in 2010, in Taiwan 2011, and in the USA, where nine cases have been reported from 2007 to 2011. Daptomycin resistance emerged in five of the six cases while they were treated. The mechanism of resistance is unknown. A 4 million year-old strain of Paenibacillus isolated from soil samples in Lechuguilla Cave was found to be naturally resistant to daptomycin. Daptomycin is approved for use in adults in the United States for skin and skin structure infections caused by Gram-positive infections, S. aureus bacteraemia, and right-sided S. aureus endocarditis. It binds avidly to pulmonary surfactant, so cannot be used in the treatment of pneumonia. There seems to be a difference in working daptomycin on hematogenous pneumonia. Daptomycin has been shown to be non-inferior to standard therapies (nafcillin, oxacillin, flucloxacillin or vancomycin) in the treatment of bacteraemia and right-sided endocarditis caused by S. aureus. A study in Detroit, Michigan compared 53 patients treated for suspected MRSA skin or soft tissue infection with daptomycin against vancomycin, showing faster recovery (4 versus 7 days) with daptomycin.