Daptomycin

(Cubicin, Cubist Pharmaceuticals)

 

Summary: Daptomycin is a newly-approved antibacterial agent, the first lipopeptide agent to be released onto the market.  Its spectrum of activity is limited to Gram-positive organisms, including a number of highly resistant species (MRSA, VISA, VRSA, VRE).  It appears to be more rapidly bactericidal than vancomycin.  Daptomycin has been approved for the treatment of complicated skin and soft tissue infections. Trials assessing daptomycinís efficacy in treating complicated urinary tract infections and endocarditis/bacteremia are ongoing. Its approved dosing regimen is 4mg/kg IV once daily. Dose adjustment is necessary in renal dysfunction.  Daptomycinís primary toxicity is reversible dose-related myalgias and weakness.

 

History and Development: 

Daptomycin is a nautral product derived from Streptomyces roseosporus.  The drug was originally developed by Lilly in the early 1980s but was abandoned after early clinical trials.  Cubist Pharmaceuticals licensed daptomycin in 1997 and began new clinical trials with the agent in 1999.

 

Structure and Mechanism of Action

Daptomycinís structure consists of a 13-member amino acid peptide linked to a 10-carbon lipophilic tail. 

This structure results in a novel mechanism of action, the disruption of the bacterial membrane through the formation of transmembrane channels.  These channels cause leakage of intracellular ions leading to depolarizing the cellular membrane and inhibition of macromolecular synthesis.

 

Pharmacodynamics: 

Daptomycin has rapid bactericidal activity.  In vitro time-kill studies have demonstrated faster killing of S. aureus (including MRSA) and Enterococci (including VRE) compared to vancomycin.

Daptomycin displays concentration-dependent killing, with efficacy predicted best by Cmax/MIC and AUC/MIC ratios.  The drug possesses a significant post-antbiotic effect, with growth inhibition occurring up to 6 hours after drug exposure.

Bacteria in the stationary growth phase, as occurs in endocarditis or foreign body infections, may be better inhibited by daptomycin compared to vancomycin or nafcillin.

 

Spectrum of Activity:

Daptomycin is unable to permeate the outer membrane of Gram-negative bacteria, thus its spectrum is limited to Gram-positive organisms only.

Daptomycin has activity against Staphylococci (including MRSA, VISA, and VRSA), Enterococci (both E. faecalis and E.faecium, including VRE), and Streptococci (including DRSP), as well as most other aerobic and anaerobic Gram-positive bacteria. (See Table 1)

Table 1: Daptomycin Activity in Vitro

Organism

MSSA

MRSA

VISA

VRSA

MRSE

E. faecalis

E. faecium (VRE)

PRSP

MIC90 (mcg/ml)

0.25-0.5

0.5-1

0.5-1

1

0.5-1

1-2

2-4

0.25-1

Organism

Viridans Strep

C. perfringens

Peptostreptococcus

C. jeikeium

Leuconostoc

Lactobacillus

MIC90 (mcg/ml)

1

1

0.06-1

0.25

0.25

16

                         

MSSA=methicillin-susceptible Staphylococcus aureus MRSA=methicillin-resistant Staphylococcus aureus VISA=vancomycin-intermediate Staphylococcus aureus VRSA=vancomycin-resistant Staphylococcus aureus MRSE=methicillin-resistant Staphylococcus epidermidis VRE=vancomycin-resistant Enterococcus PRSP=penicillin-resistant Streptococcus pneumoniae

Breakpoints for daptomycin have not been fully defined.  Staphylococci and Streptococci with MICs of £ 1 mcg/ml, and Enterococci with MICs £ 4 mcg/ml would be expected to be susceptible.  Current FDA-approved breakpoints apply only to Staph aureus (MSSA and MRSA), Strep pyogenes and agalactidae, and Enterococcus faecalis.

 

Resistance:

Resistance to daptomycin has been encountered both in vitro and in vivo after exposure to daptomycin, but appears to be exceedingly rare at present.  The mechanism(s) of resistance are not fully defined but likely relate to alterations of the cellular membrane.  Cross-resistance with other antibiotic classes has not been observed.

Multiple passages of Staphylococci and Enterococci in subinhibitory drug concentrations resulted in MIC increases in a stepwise fashion.  No single pattern of genetic change was noted, and it is likely that multiple genetic steps are required for the generation of a mutant.

Two isolates with resistance to daptomycin were encountered in clinical trials (one S. aureus and one E. faecalis), out of more than 1000 courses of therapy (rate <0.2%).

 

 

 

Pharmacokinetics:

AbsorptionAvailable only as an intravenous formulation.

DistributionHighly protein bound ( 90%).  Penetration into restricted compartments such as the CNS has not been characterized.

MetabolismNot an inhibitor or inducer of hepatic oxidative enzymes (e.g. CYP 3A4).  Inactive metabolites represent a small percentage of total drug administered.
Excretion:  Renal excretion is the primary mode of elimination, with approximately 60% of the dose excreted unchanged in the urine.  Dose adjustment is required for patients with a creatinine clearance less than 30 ml/min (Table 2)

Table 2. Daptomycin dosage

Renal function

Daptomycin Dosage

Creatinine clearance 30 ml/min

4mg/kg IV q24h

Creatinine clearance <30 ml/min

4mg/kg IV q48h

Intermittent hemodialysis

4mg/kg IV q48h

Peritoneal dialysis

4mg/kg IV q48h

Continuous renal replacement

No data

 

Drug Interactions:

No significant drug interactions with daptomycin have been noted in early clinical trials.  As noted, daptomycin is not an inhibitor or inducer of the CYP450 enzymes.

As there may be overlapping musculoskeletal toxicity between the HMG-CoA reductase inhibitors (ďstatinsĒ) and daptomycin, caution is advised when these drugs are used concomitantly.

No studies have shown in vitro antagonism between daptomycin and other antimicrobials.  Some studies suggest synergy when daptomycin is combined with aminoglycosides or rifampin against Enterococci, and with oxacillin and aminoglycosides against Staphylococci.

 

Toxicity:

The primary toxicities associated with daptomycin use are myopathies, manifested as muscle pain or weakness and associated with elevations in creatine phosphokinase.  The incidence of this toxicity was less than 5% in clinical trials.  Administration of daptomycin as a single daily dosage, as opposed to divided doses as had been previously studied, appears to reduce this toxicity.

Nerve conduction deficits appeared in a small number (<1%) of patients in daptomycin clinical trials, manifested as paresthesias or reversible paralysis (e.g. Bellís palsy).  Patients receiving daptomycin should be monitored for development of this toxicity.

Daptomycin is classified as a Category B agent in pregnancy based on animal studies.  There is no human data on its use during pregnancy.  It is not known if daptomycin is excreted in breast milk.  Daptomycin has not been studied in pediatric patients.

 

Clinical Trials:

Daptomycinís approval was based on the result of two randomized, multicenter, investigator-blinded trials comparing daptomycin to either vancomycin or a pencillinase-resistant penicillin (PRSP) in the treatment of complicated skin and skin structure infections (cSSSI).  These studies combined enrolled 558 patients with cSSSI known or suspected to be due to Gram-positive organisms.  Patients could not be bacteremic prior to trial entry nor have known or suspected infections at other sites, neutropenia, HIV with CD4<200, elevated plasma CPK, or creatinine clearance <30ml/min.  The investigator assigned patients to either the vancomycin or PRSP arm of the study based on their risk of having MRSA.  Patients within each arm were then randomized to receive vancomycin/PRSP or daptomycin for 7-14 days, with the option to switch to oral therapy after 4 days.  Clinical and microbiological outcomes were similar between daptomycin and comparator.

A study comparing daptomycin to ceftriaxone in the treatment of community-acquired pneumonia was performed in North and South America, Europe, Australia, and New Zealand.  There were strong regional differences in trial results, with some areas unable to demonstrate the noninferiority of daptomycin.  The results of this trial have not been published. Daptomycin is not approved for the management of pneumonia and the company does not plan to pursue this indication.  Due to the results of these trials and concerns regarding daptomycinís penetration into lung tissue, daptomycin may not be a good choice in the management of respiratory tract infections.

Clinical trials are ongoing examining daptomycinís efficacy in the treatment of complicated urinary tract infections, bacteremia, and endocarditis.  Trials in endocarditis and bacteremia are utilizing a higher dose (6 mg/kg IV q24h) than the currently approved dose.

 

 

Cost:

UCSF acquisition cost: 500mg = $129.05/vial   Typical cost for 70kg pt: $129.05/day (single-use vials)

Cost of comparable agents

                Vancomycin 1g IV q12h = $11/day

                Linezolid 600mg IV q12h = $128/day         Linezolid 600mg po BID = $96/day

                Synercid (quinupristin/dalfopristin) 7.5mg IV q8h (70kg patient) = $275/day

 

Place in Therapy:

Daptomycin represents another addition to the Gram-positive armamentarium, with favorable pharmacokinetics, a novel mechanism of action, rapid bactericidal activity, and an acceptable safety profile.  However, defining its place in therapy is made difficult by the lack of clinical data in conditions such as nosocomial pneumonia, bacteremia, osteomyelitis, and endocarditis.   Until further data are available, daptomycin should be restricted to treatment of serious infections where standard therapy is not possible due to organism resistance and/or patient intolerance.  The drug should be added to the list of agents not to be dispensed without approval of the Infectious Diseases service or Infectious Diseases Pharmacy.

 

References:

Cubicin (Daptomycin) product monograph.  Cubist Pharmaceuticals. 2003.

Tedesco KL and Rybak MJ.  Daptomycin.  Pharmacotherapy 2004;24:41-57.

Tally FP and DeBruin MF.  Development of daptomycin for Gram-positive infections.  J. Antimicrob. Chemother. 2000;46:523-526.

Safdar N, Andes D, Craig WA.  In vivo pharmacodynamic activity of daptomycin. Antimicrob. Ag. Chemother. 2004;48:63-68.

Sakoulas G, Eliopoulos GM, Alder J, et al.  Efficacy of daptomycin in experimental endocarditis due to methicillin-resistant Staphylococcus aureus. Antimicrob. Ag. Chemother. 2003;47:1714-1718.

Vaudaux P, Francois P, Bisognano C, et al.  Comparative efficacy of daptomycin and vancomycin in the therapy of experimental foreign body infection due to Staphylococcus aureus.  J. Antimicrob. Chemother. 2003;52:89-95.