Full text of DOI:10.1093/jac/46.4.523

Journal of Antimicrobial Chemotherapy (2000) 46, 523–526
JAC
Leading article
Development of daptomycin for Gram-positive infections
Francis P. Tally* and Michael F. DeBruin
Cubist Pharmaceuticals, Inc., 24 Emily Street, Cambridge, MA 02139, USA
Gram-positive bacteria are an important cause of serious antibacterial activity against antibiotic-resistant strains such
infections, particularly those originating in hospitals, and as MRSA, VRE and PRSP is comparable to that against
are becoming increasingly resistant to many antibiotics antibiotic-susceptible strains of these species. The MIC of
hitherto regarded as standard therapy for these infections.1 daptomycin for antibiotic-susceptible strains is typically
Daptomycin is an investigational antibiotic that kills most four-fold lower than that of vancomycin.
clinically significant Gram-positive bacteria.2–4 These
Daptomycin produces a post-antibiotic effect (PAE) and
include resistant pathogens for which there are very few regrowth times in vitro that are prolonged and concentra-
therapeutic alternatives, such as vancomycin-resistant tion dependent.8,14 PAEs lasting from 1 to 6 h were observed
enterococci (VRE), methicillin-resistant Staphylococcus against Enterococcus faecalis and S. aureus after exposure
aureus (MRSA), glycopeptide intermediately susceptible to daptomycin concentrations ranging from 0.25 to 16 mg/L
S. aureus (GISA), coagulase-negative staphylococci (CNS) (from one- to eight-fold the MIC).
and penicillin-resistant Streptococcus pneumoniae (PRSP).
Spontaneous acquisition of resistance to daptomycin is
The cyclic lipopeptide daptomycin (Figure 1) is a fer- rare.15,16 Resistant organisms have been isolated by serial
mentation product of Streptomyces roseosporus. It was passage in liquid media containing incremental sub-
discovered in the early 1980s, at Eli Lilly and Company inhibitory concentrations of daptomycin. Resistant isolates
(Lilly), and was developed as LY 146032 for intravenous of S. aureus have also been isolated following chemical
treatment of serious Gram-positive infections. Nineteen mutagenesis with N-methyl-Nꢀ-nitro-N-nitrosoguanidine.16
Phase 1 and two Phase 2 clinical studies involving more
The results of in vitro interaction studies suggest that
than 370 subjects were conducted in the 1980s and early daptomycin will not adversely affect the activity of other
1990s. The results in skin and soft tissue infections and antimicrobials. Against 70 clinical isolates, interactions
bacteraemia were encouraging, and clinical results with with 25 antimicrobials were additive or indifferent; antagon-
endocarditis suggested the potential for efficacy at higher ism was not observed.4 Synergic interactions occurred
doses.3,4 However, Lilly was not satisfied with the overall between daptomycin and gentamicin against staphylococci
clinical results observed with the twice-daily dosing regi- and enterococci.
men utilized in these studies. In 1997, Cubist Pharmaceuti-
Daptomycin has been shown to be effective in a number
cals Inc. (Cubist) licensed worldwide rights from Lilly with of in vivo animal models of bacterial infection of the
the intention of developing daptomycin for the treatment soft tissues, bloodstream, kidneys, heart, lungs and bone,
of serious Gram-positive infections in hospitalized patients. including those caused by Gram-positive strains resistant
Clinical trials conducted by Cubist commenced in the USA to standard therapies (e.g. MRSA and VRE).4,15,17–27
and Europe in 1999.
Pharmacodynamic studies in mice have suggested that
Daptomycin has a unique mechanism of action, killing daptomycin’s bactericidal activity is concentration depen-
Gram-positive bacteria by disrupting multiple aspects of dent.28–30
bacterial plasma membrane function without penetrating
In laboratory animals, daptomycin has been associated
into the cytoplasm.5–7 The drug exhibits rapid, concentra- with adverse effects that involve skeletal muscle, kidneys,
tion-dependent bactericidal activity in vitro against Gram- the gastrointestinal tract and the nervous system.4 Skeletal
positive organisms, including enterococci (Figure 2).8–13 It muscle is the tissue most sensitive to the adverse effects
acts against most clinically significant Gram-positive bac- of daptomycin. Mild myopathy was easily predicted and
teria but not against Gram-negative bacteria. Daptomycin’s monitored by measuring serum creatine phosphokinase
*Corresponding author. Tel: ꢁ1-617-576-1999; Fax: ꢁ1-617-576-0232; E-mail: ftally@cubist.com
523
© 2000 The British Society for Antimicrobial Chemotherapy

Leading article
(CPK) concentrations and was reversible upon cessation of ent on dosing frequency as well as dose level. Dog studies
therapy. Axonal degeneration of peripheral nerves occurred showed that skeletal muscle adverse effects were greater
at dose levels approximately four-fold higher than for with fractionated compared with once-daily administration
myopathy. Renal and gastrointestinal toxicities were noted of the same total daily dose.31 Thus, once-daily dosing
only in rats. Skeletal muscle adverse effects were depend- 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 in healthy volunteers.4 Plasma clear-
ance is low, resulting in part from high protein binding
(87–94%).32 Excretion of the drug occurs primarily via the
kidney, with approximately 80% of the total dose, of which
two-thirds is intact drug, recovered in the urine. There is
low potential for interference with hepatically metabolized
drugs,4 although daptomycin may displace other protein-
bound drugs.
The efficacy of daptomycin in a range of animal models
suggests that it may be clinically useful in treating a wide
variety of Gram-positive bacterial infections. Two multi-
centre, randomized Phase 2 trials evaluated the clinical
efficacy of daptomycin compared with conventional therapy
(ꢀ-lactam agents or vancomycin) in a total of 285 patients.3,4
Daptomycin demonstrated activity against a variety of
causative organisms, including S. aureus. Efficacy against
skin and soft tissue infections was comparable to that of
conventional therapy. Clinical cure or improvement
occurred in 29 of 30 (96.6%) evaluable patients treated
with daptomycin, 2 mg/kg once daily, compared with 37 of
39 (94.9%) treated with conventional therapy. The number
of evaluable patients was low for several reasons, including
the fact that many of those enrolled did not have a bac-
teriologically confirmed infection and there was a high
number of heroin addicts, who did not complete follow up,
Figure 1. Amino acid structure and location of decanoic acid
side chain of daptomycin.
Figure 2. In vitro kill rates with daptomycin and vancomycin for (a) Staphylococcus aureus and (b) Enterococcus faecalis.
Daptomycin MIC ꢂ 1 mg/L; vancomycin MIC ꢂ 4 mg/L. (Adapted with permission from Hanberger, H., Nilsson, L. E., Maller, R. &
Isaksson, B. (1991). Antimicrobial Agents and Chemotherapy 35, 1710–6. Reprinted with permission. © American Society for
Microbiology.)
524

Leading article
among those recruited. A favourable bacteriological out- tion will be studied in Phase 3 comparative, randomized
come (i.e. pathogen eliminated) occurred with daptomycin trials. Further studies may include the evaluation of dapto-
and conventional therapy in 96.1% and 93.9% of evaluable mycin for the treatment of endocarditis.
patients, respectively.
A broad spectrum of antibacterial activity, rapid, con-
When daptomycin was administered to patients with centration-dependent bactericidal activity, low frequency
bacteraemia as a 6 mg/kg loading dose followed by 3 mg/kg of resistance, linear pharmacokinetics and a once-daily
every 12 h for up to 34 days, it produced a favourable clini- dosing regimen are factors that suggest that daptomycin
cal outcome and bacteriological cure in 17 of 19 (89.5%) may be a useful antibiotic for the treatment of Gram-
evaluable patients. The number of conventionally treated positive infections. The drug’s potential efficacy against
patients was too small for meaningful comparison.
resistant pathogens adds to its appeal and the results of
Intravenous daptomycin given to healthy male subjects clinical trials will provide more data on its safety and
in Phase 1 studies was well tolerated at single doses of up to efficacy against infections caused by such strains.
6 mg/kg and multiple doses of up to 3 mg/kg every 12 h.4 In
the Phase 2 trials, adverse events and rates of discontinua-
tion due to such events were comparable between patients
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