Development of daptomycin for Gram-positive infections

Abstract

Gram-positive bacteria are an important cause of serious infections, particularly those originating in hospitals, and are becoming increasingly resistant to many antibiotics hitherto regarded as standard therapy for these infections.1 Daptomycin is an investigational antibiotic that kills most clinically significant Gram-positive bacteria.2–4 These include resistant pathogens for which there are very few therapeutic alternatives, such as vancomycin-resistant enterococci (VRE), methicillin-resistant Staphylococcus aureus (MRSA), glycopeptide intermediately susceptible S. aureus (GISA), coagulase-negative staphylococci (CNS) and penicillin-resistant Streptococcus pneumoniae (PRSP). The cyclic lipopeptide daptomycin (Figure 1) is a fermentation product of Streptomyces roseosporus. It was discovered in the early 1980s, at Eli Lilly and Company (Lilly), and was developed as LY 146032 for intravenous treatment of serious Gram-positive infections. Nineteen Phase 1 and two Phase 2 clinical studies involving more than 370 subjects were conducted in the 1980s and early 1990s. The results in skin and soft tissue infections and bacteraemia were encouraging, and clinical results with endocarditis suggested the potential for efficacy at higher doses.3,4 However, Lilly was not satisfied with the overall clinical results observed with the twice-daily dosing regimen utilized in these studies. In 1997, Cubist Pharmaceuticals Inc. (Cubist) licensed worldwide rights from Lilly with the intention of developing daptomycin for the treatment of serious Gram-positive infections in hospitalized patients. Clinical trials conducted by Cubist commenced in the USA and Europe in 1999. Daptomycin has a unique mechanism of action, killing Gram-positive bacteria by disrupting multiple aspects of bacterial plasma membrane function without penetrating into the cytoplasm.5–7 The drug exhibits rapid, concentration-dependent bactericidal activity in vitro against Gram-positive organisms, including enterococci (Figure 2).8–13 It acts against most clinically significant Gram-positive bacteria but not against Gram-negative bacteria. Daptomycin's antibacterial activity against antibiotic-resistant strains such as MRSA, VRE and PRSP is comparable to that against antibiotic-susceptible strains of these species. The MIC of daptomycin for antibiotic-susceptible strains is typically four-fold lower than that of vancomycin. Daptomycin produces a post-antibiotic effect (PAE) and regrowth times in vitro that are prolonged and concentration dependent.8,14 PAEs lasting from 1 to 6 h were observed against Enterococcus faecalis and S. aureus after exposure to daptomycin concentrations ranging from 0.25 to 16 mg/L (from one- to eight-fold the MIC). Spontaneous acquisition of resistance to daptomycin is rare.15,16 Resistant organisms have been isolated by serial passage in liquid media containing incremental subinhibitory concentrations of daptomycin. Resistant isolates of S. aureus have also been isolated following chemical mutagenesis with N-methyl-N′-nitro-N-nitrosoguanidine.16 The results of in vitro interaction studies suggest that daptomycin will not adversely affect the activity of other antimicrobials. Against 70 clinical isolates, interactions with 25 antimicrobials were additive or indifferent; antagonism was not observed.4 Synergic interactions occurred between daptomycin and gentamicin against staphylococci and enterococci. Daptomycin has been shown to be effective in a number of in vivo animal models of bacterial infection of the soft tissues, bloodstream, kidneys, heart, lungs and bone, including those caused by Gram-positive strains resistant to standard therapies (e.g. MRSA and VRE).4,15,17–27 Pharmacodynamic studies in mice have suggested that daptomycin's bactericidal activity is concentration dependent.28–30 In laboratory animals, daptomycin has been associated with adverse effects that involve skeletal muscle, kidneys, the gastrointestinal tract and the nervous system.4 Skeletal muscle is the tissue most sensitive to the adverse effects of daptomycin. Mild myopathy was easily predicted and monitored by measuring serum creatine phosphokinase (CPK) concentrations and was reversible upon cessation of therapy. Axonal degeneration of peripheral nerves occurred at dose levels approximately four-fold higher than for myopathy. Renal and gastrointestinal toxicities were noted only in rats. Skeletal muscle adverse effects were dependent on dosing frequency as well as dose level. Dog studies showed that skeletal muscle adverse effects were greater with fractionated compared with once-daily administration of the same total daily dose.31 Thus, once-daily dosing may increase the therapeutic-toxicity ratio by increasing efficacy and decreasing skeletal muscle adverse effects, as demonstrated in pharmacokinetic/pharmacodynamic models. With once-daily administration, daptomycin exhibits linear pharmacokinetics and minimal accumulation with doses up to 6 mg/kg