Daptomycin (Cubicin®)

Brand Name: Cubicin®¹

Generic Name: Daptomycin¹

Manufacturer: Cubist Pharmaceuticals¹

Drug Class: cyclic lipopeptide antibiotic^1,2

Uses: Daptomycin is indicated for the treatment of complicated skin and skin structure infections caused by susceptible strains of gram-positive organisms. Daptomycin is not active against gram-negative bacteria.^{1, 2}

Daptomycin exhibits concentration-dependent bactericidal activity against the following organisms:^{1, 2}

• Staphylococcus aureus (including methicillin-resistant strains)
• Streptococcus pyogenes
• Streptococcus agalactia
• Streptococcus dysgalactiae subspecies equisimillis
• Enterococcus faecalis (vancomycin-susceptible strains only)

Daptomcyin is NOT indicated for the treatment of pneumonia.^{1, 2}

Mechanism of Action: Daptomycin is the first agent in a new class of drugs, the cyclic lipopeptides. Daptomycin works by binding bacterial cell membranes and causing depolarization of membrane potential. As a result, protein, DNA, and RNA synthesis is inhibited. This leads to cell death. Daptomycin is not able to penetrate the membrane of gram-negative organisms; therefore it is only active against gram-positive bacteria.¹

Pharmacokinetics:

Metabolism: Daptomycin does not appear to inhibit or induce cytochrome P-450 isoforms 1A2, 2A6, 2C9, 2C19, 2D6, 2E1, and 3A4. It is unknown whether daptomycin undergoes hepatic metabolism.^{1, 3}

Excretion: The primary route of excretion of daptomycin is via the kidney.¹

Efficacy: Currently, there are no published trials evaluating the safety and efficacy of daptomycin. The following studies were evaluated based on the executive summary obtained from the manufacturer. These trials will be published in June 2004.

Pivotal Phase 3 Trials of Cubicin^TM (daptomycin for injection) in the Treatment of Complicated Skin and Skin Structure Infections⁴

Two randomized, controlled, investigator-blinded trials were conducted at multiple sites in 5 countries in patients with complicated skin and skin structure infections (cSSSI). Subjects were randomized to receive either daptomycin 4 mg/kg I.V. for 7 to 14 days or an agent from the comparator group (vancomycin, oxacillin, nafcillin, cloxacillin, flucloxacillin).

The modified intent-to-treat population (MITT) included a total of 421 patients from Study 1 and 468 patients from Study 2 who had received at least one dose of study medication and had an infecting Gram-positive organism isolated at baseline.  The clinically evaluable group included 445 patients from Study 1 and 507 patients from Study 2 who met clinical criteria for study infection, received the correct study drug for the appropriate duration and intensity, had necessary clinical evaluations performed and did not receive potentially confounding non-study antibiotics. The primary efficacy endpoint was the difference in success rate (comparator-daptomycin).

The success rates in the MITT population of the 2 studies combined were 75.8% for the daptomycin group and 76.2% for the comparator group. The 95% confidence interval for the difference in success rate was (–5.7, 5.0). In the clinically evaluable group, patients receiving daptomycin had a 82.1% success rate while patients receiving a comparator drug had a 82.9% success rate. The 95% confidence interval for the difference in success rate was (-3.8,5.2). 

The study appears to have been blinded only to the investigators. This increases the likelihood that the treatment groups were made known to the investigators at any point during the study. ¹ The results were evaluated using an exclusion-of-subjects method and may not accurately reflect the usefulness of the drug in clinical practice.  Subjects who dropped out were not accounted for in the executive summary. The investigators concluded that daptomycin was not inferior to the comparator agents in the treatment of skin and skin structure infections.

Adverse Effects: The following adverse events occurred in > 2% of daptomcyin patients in Phase III studies:^{1, 5}

Warnings/Precautions:

Skeletal muscle: Elevations in serum creatinine phosphokinase (CPK) occurred in 15/534 (2.8%) of daptomycin-treated patients compared to 10/558 (1.8%) of comparator-group patients. Daptomcyin use should be discontinued in any patient with unexplained signs and symptoms of myopathy and CPK elevation > 1000 U/L. CPK levels should be monitored twice weekly in patients receiving daptomycin.^{1, 3}

Drug Interactions:  

HMG CoA reductase inhibitors: Concomitant HMG CoA reductase inhibitor and daptomycin therapy may increase the risk of myopathy.^{1, 3}

Warfarin: Although no drug interactions have been noted in healthy subjects receiving both warfarin and daptomycin, anticoagulant activity should be monitored for the first several days after initiating daptomycin therapy.¹

Dosing/Administration:^{1, 3}

Usual Dose: The usual intravenous dose for complicated skin and skin structure infections is 4 mg/kg every 24 hours for 7 to 14 days.

Geriatric Dosage: No dosage adjustment is required for patients > 75 years of age with normal renal function.

Pediatric Dosage: The safety and efficacy of daptomycin in patients less than 18 years of age has not been determined.

Obesity: No dosage adjustment is required in obese patients.

Renal Impairment: In patients with an estimated creatinine clearance of less than 30 ml/min, the dose should be adjusted to 4 mg/kg every 48 hours.

Hemodialysis: In patients receiving hemodialysis and daptomycin the dose of daptomycin is 4 mg/kg every 48 hours, after dialysis on dialysis days.

Peritoneal Dialysis: In patients receiving peritoneal dialysis and daptomcyin the dose of daptomycin is 4 mg/kg every 48 hours.

Hepatic Impairment: In patients with moderate hepatic impairment, the dose does not need to be adjusted. Daptomycin has not been studied in patients with severe hepatic impairment.

Conclusion: Daptomycin appears to be a safe and effective addition to the armamentarium of agents for gram-positive skin and skin structure infections. However its relatively high cost and the availability of other effective agents may preclude its use in many patients. Furthermore, daptomycin is not effective in treatment of pneumonia^{1, 2} and has not yet been proven to be efficacious in the treatment of bacteremia or endocarditis, although a study is currently underway to evaluate the use of daptomycin for these indications.² These factors, combined with the paucity of published clinical trials concerning its use, reserve daptomycin for patients who cannot tolerate or are resistant to treatment with other agents.

Recommended References:

1.       Cubicin® product information. www.cubicin.com. [Accessed 5/21/2004]

2.       Carpenter CF and Chambers HF. Daptomycin: another novel agent for treating infections due to drug-resistant gram-positive pathogens. Clinical Infectious Disease 2004;38:994-1000.

3.       Daptomycin (Drug Evaluation). In: Hutchison TA & Shahan DR (Eds): DRUGDEX System. MICROMEDEX, Greenwood Villiage, Colorado (Edition Expires 6/04).

4.       Arbeit RD, Maki D, Tally FP et al. Executive Summary: Pivotal Phase 3 Clinical Trials of Cubicin^TM (daptomycin for injection) in the Treatment of Complicated Skin and Skin Structure Infections. Obtained from Cubist Pharmaceuticals, Inc. (5/27/04). To be published in: Clinical Infectious Disease 2004;38.

5.       Wickersham RM, Novak KK, Harmon LD, McCarron SM, Schweain SL, editors. Drug Facts & Comparisons. St. Louis: Wolters Kluwer Company; 1312.

Christina Hoban, PharmD