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Background:    A lipopeptide is a molecule consisting of a lipid connected to a peptide. Bacteria express these molecules. They are bound by TLR 1, and other, Toll-like receptors.
Certain lipopeptides are used as antibiotics. Examples: Surfactin, Daptomycin, Echinocandins (e.g., caspofungin)    
Daptomycin (Cubicin ®) -- Infectious Disease -ALL Agents (INDEX)

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 Daptomycin (Cubicin ®): top of page

Cyclic Lipopeptide.   Daptomycin

Daptomycin belongs to the cyclic lipopeptide class of antibacterials. Daptomycin has clinical utility in the treatment of infections caused by aerobic, Gram-positive bacteria. The in vitro spectrum of activity of daptomycin encompasses most clinically relevant Gram-positive pathogenic bacteria.

Daptomycin exhibits rapid, concentration-dependent bactericidal activity against Gram-positive bacteria in vitro. This has been demonstrated both by time-kill curves and by MBC/MIC (minimum bactericidal concentration/minimum inhibitory concentration) ratios using broth dilution methodology. Daptomycin maintained bactericidal activity in vitro against stationary phase S. aureus in simulated endocardial vegetations. The clinical significance of this is not known.

Mechanism of Action
The mechanism of action of daptomycin is distinct from that of any other antibacterial. Daptomycin binds to bacterial cell membranes and causes a rapid depolarization of membrane potential. This loss of membrane potential causes inhibition of DNA, RNA, and protein synthesis, which results in bacterial cell death.

Mechanism of Resistance
The mechanism(s) of daptomycin resistance is not fully understood. Currently, there are no known transferable elements that confer resistance to daptomycin.

Complicated Skin and Skin Structure Infection (cSSSI) Trials
The emergence of daptomycin non-susceptible isolates occurred in 2 infected patients across the set of Phase 2 and pivotal Phase 3 clinical trials of cSSSI. In one case, a non-susceptible S. aureus was isolated from a patient in a Phase 2 trial who received CUBICIN at less than the protocol-specified dose for the initial 5 days of therapy. In the second case, a non-susceptible Enterococcus faecalis was isolated from a patient with an infected chronic decubitus ulcer who was enrolled in a salvage trial.

S. aureus Bacteremia/Endocarditis and Other Post-Approval Trials
In subsequent clinical trials, non-susceptible isolates were recovered. S. aureus was isolated from a patient in a compassionate-use trial and from 7 patients in the S. aureus bacteremia/endocarditis trial [see Clinical Trials (14.2)]. An E. faecium was isolated from a patient in a vancomycin-resistant enterococci trial.

Interactions with Other Antibacterials
In vitro studies have investigated daptomycin interactions with other antibacterials. Antagonism, as determined by kill curve studies, has not been observed. In vitro synergistic interactions of daptomycin with aminoglycosides, ß-lactam antibacterials, and rifampin have been shown against some isolates of staphylococci (including some methicillin-resistant isolates) and enterococci (including some vancomycin-resistant isolates).

Activity In Vitro and In Vivo

Daptomycin has been shown to be active against most isolates of the following Gram-positive bacteria both in vitro and in clinical infections, as described in Indications and Usage.

Gram-Positive Bacteria
Enterococcus faecalis (vancomycin-susceptible isolates only)
Staphylococcus aureus (including methicillin-resistant isolates)
Streptococcus agalactiae
Streptococcus dysgalactiae subsp. equisimilis
Streptococcus pyogenes

The following in vitro data are available, but their clinical significance is unknown. At least 90% of the following Gram-positive bacteria exhibit an in vitro minimum inhibitory concentration (MIC) less than or equal to the susceptible breakpoint for daptomycin versus the bacterial genus. However, the efficacy of CUBICIN in treating clinical infections due to these bacteria has not been established in adequate and well-controlled clinical trials.

Gram-Positive Bacteria
Corynebacterium jeikeium
Enterococcus faecalis (vancomycin-resistant isolates)
Enterococcus faecium (including vancomycin-resistant isolates)
Staphylococcus epidermidis (including methicillin-resistant isolates)
Staphylococcus haemolyticus

CUBICIN is indicated for the treatment of the infections listed below.

Complicated Skin and Skin Structure Infections
Complicated skin and skin structure infections (cSSSI) caused by susceptible isolates of the following Gram-positive bacteria: Staphylococcus aureus (including methicillin-resistant isolates), Streptococcus pyogenes, Streptococcus agalactiae, Streptococcus dysgalactiae subsp. equisimilis, and Enterococcus faecalis (vancomycin-susceptible isolates only).

Staphylococcus aureus Bloodstream Infections (Bacteremia), Including Those with Right-Sided Infective Endocarditis, Caused by Methicillin-Susceptible and Methicillin-Resistant Isolates

Limitations of Use
CUBICIN is not indicated for the treatment of pneumonia.

CUBICIN is not indicated for the treatment of left-sided infective endocarditis due to S. aureus. The clinical trial of CUBICIN in patients with S. aureus bloodstream infections included limited data from patients with left-sided infective endocarditis; outcomes in these patients were poor [see Clinical Trials (14.2)]. CUBICIN has not been studied in patients with prosthetic valve endocarditis.

Appropriate specimens for microbiological examination should be obtained in order to isolate and identify the causative pathogens and to determine their susceptibility to daptomycin.

To reduce the development of drug-resistant bacteria and maintain the effectiveness of CUBICIN and other antibacterial drugs, CUBICIN should be used only to treat infections that are proven or strongly suspected to be caused by susceptible bacteria.

When culture and susceptibility information is available, it should be considered in selecting or modifying antibacterial therapy. In the absence of such data, local epidemiology and susceptibility patterns may contribute to the empiric selection of therapy. Empiric therapy may be initiated while awaiting test results.


Daptomycin High Daily Dosing:

Doses up to 10 mg/kg may be used for complicated bacteremia.
Source: Bope ET, Kellerman D. Conn's Current Therapy 2014: Expert Consult: Online. Elsevier Health Sciences, Nov 14, 2013.
"Some experts recommend 8-10 mg/kg once daily for complicated bactermia or infective endocarditis."
Source:  Lexi-Comp, Inc. (Lexi-Drugs). Lexi-Comp, Inc.; April 30, 2014.
A total of 44 pts were identified, representing 0.8% of CORE® patients; 59% were female, 27% were > 65 yrs old, 32% were critically ill, and 20% had an initial CrCL <30 mL/min with 11% of pts on dialysis. Of these 44 pts, 38 (86%) were evaluable for efficacy. DAP median (min, max) dose was 10 mg/kg (10, 14.75; 34% > 10 mg/kg). The median (min, max) DAP duration of therapy was 15 days (1, 78). In evaluable pts, the clinical success rate was 81.8% (31/38). The most common diagnoses were skin infections (32%) and bacteremia (26%), with S. aureus (37%; 93% MRSA) and Enterococcus spp. (26%; 60% VRE) the most common pathogens. Median (min, max) time to clinical response was 3.5 days (1, 26) in successfully treated pts (n=22). In the safety population, 6 (14%) of the 44 pts experienced 1 or more non-drug related serious adverse events (SAEs). Three pts (7%) reported 4 possibly related adverse events (AEs), which included elevated creatine phosphokinase (n=3) and myopathy (n=1). DAP was discontinued due to AEs in 4 pts (9%).

DAP was rarely administered at doses ≥ 10 mg/kg. Usage patterns, outcomes and AEs were consistent with prior analyses from this registry. Although not studied in randomized controlled trials, high dose DAP may be a reasonable alternative in pts with serious Gram positive infections.
Kristine C. Willett, PharmD1, Dina Besece, PharmD2, Alicia Desilets, PharmD1, Patrick McDaneld, PharmD2,3, Jessica Moreno, PharmD2,3, MinJung Yoon, MPH2 and Kenneth C. Lamp, PharmD2, (1)Massachusetts College of Pharmacy and Health Sciences, Manchester, NH, (2)Cubist Pharmaceuticals, Lexington, MA, (3)Massachusetts College of Pharmacy and Health Sciences, Worcester, MA

Source: IDWeek (2012): Safety and Clinical Outcomes of Daptomycin at Doses of ≥10 mg/kg.  Session: Poster Abstract Session: Antimicrobial Chemotherapy. Friday, October 19, 2012.

Administration Duration

CUBICIN should be administered intravenously either by injection over a two (2) minute period or by infusion over a thirty (30) minute period.

Complicated Skin and Skin Structure Infections
CUBICIN 4 mg/kg should be administered intravenously in 0.9% sodium chloride injection once every 24 hours for 7 to 14 days.

Staphylococcus aureus Bloodstream Infections (Bacteremia), Including Those with Right-Sided Infective Endocarditis, Caused by Methicillin-Susceptible and Methicillin-Resistant Isolates
CUBICIN 6 mg/kg should be administered intravenously in 0.9% sodium chloride injection once every 24 hours for 2 to 6 weeks. There are limited safety data for the use of CUBICIN for more than 28 days of therapy. In the Phase 3 trial, there were a total of 14 patients who were treated with CUBICIN for more than 28 days.

Renal Dosing:   Crcl <30 mL/min: 4-6 mg/kg every 48 hours depending on indication.
Hemodialysis (administer after hemodialysis) and/or CAPD: 4-6 mg/kg every 48 hours.

The recommended dosage regimen for patients with creatinine clearance (CLCR) <30 mL/min, including patients on hemodialysis or continuous ambulatory peritoneal dialysis (CAPD), is 4 mg/kg (cSSSI) or 6 mg/kg (S. aureus bloodstream infections) once every 48 hours (Table 1). When possible, CUBICIN should be administered following the completion of hemodialysis on hemodialysis days.

Table 1. Recommended Dosage of CUBICIN in Adult Patients

Creatinine Clearance
Dosage Regimen
cSSSI S. aureus Bloodstream Infections
≥30 mL/min 4 mg/kg once every 24 hours 6 mg/kg once every 24 hours
<30 mL/min, including hemodialysis and CAPD 4 mg/kg once every 48 hours* 6 mg/kg once every 48 hours*

*When possible, administer CUBICIN following the completion of hemodialysis on hemodialysis days.

Preparation of CUBICIN for Administration
CUBICIN is supplied in single-use vials, each containing 500 mg daptomycin as a sterile, lyophilized powder. The contents of a CUBICIN vial should be reconstituted, using aseptic technique, to 50 mg/mL as follows:
Note: To minimize foaming, AVOID vigorous agitation or shaking of the vial during or after reconstitution.
1] Remove the polypropylene flip-off cap from the CUBICIN vial to expose the central portion of the rubber stopper.

2] Slowly transfer 10 mL of 0.9% sodium chloride injection through the center of the rubber stopper into the CUBICIN vial, pointing the transfer needle toward the wall of the vial.

3] Ensure that all of the CUBICIN powder is wetted by gently rotating the vial.

4] Allow the wetted product to stand undisturbed for 10 minutes.

5] Gently rotate or swirl the vial contents for a few minutes, as needed, to obtain a completely reconstituted solution.

For intravenous (IV) injection over a period of 2 minutes, administer the appropriate volume of the reconstituted CUBICIN (concentration of 50 mg/mL).

For IV infusion over a period of 30 minutes, the appropriate volume of the reconstituted CUBICIN (concentration of 50 mg/mL) should be further diluted, using aseptic technique, into a 50 mL IV infusion bag containing 0.9% sodium chloride injection.

Parenteral drug products should be inspected visually for particulate matter prior to administration.

No preservative or bacteriostatic agent is present in this product. Aseptic technique must be used in the preparation of final IV solution. Stability studies have shown that the reconstituted solution is stable in the vial for 12 hours at room temperature and up to 48 hours if stored under refrigeration at 2 to 8°C (36 to 46°F).

The diluted solution is stable in the infusion bag for 12 hours at room temperature and 48 hours if stored under refrigeration. The combined storage time (reconstituted solution in vial and diluted solution in infusion bag) should not exceed 12 hours at room temperature or 48 hours under refrigeration.
CUBICIN vials are for single use only.

Compatible Intravenous Solutions
CUBICIN is compatible with 0.9% sodium chloride injection and lactated Ringer's injection.

Supplied:  250 mg, 500 mg  (Injection - powder for reconstitution)


National Institutes of Health, U.S. National Library of Medicine, DailyMed Database.
Provides access to the latest drug monographs submitted to the Food and Drug Administration (FDA). Please review the latest applicable package insert for additional information and possible updates.  A local search option of this data can be found here.

Lipopeptides (e.g. daptomycin)