HEALTH-SYSTEM EDITION

P & T PORTFOLIO

Generic name

Daptomycin

Proprietary name/manufacturer

Cubicin/Cubist

FDA-approved indication

Daptomycin is approved for treating complicated skin and skin structure infections caused by susceptible strains of the gram-positive microorganisms Staphylococcus aureus (including methicillin-resistant strains), Streptococcus pyogenes, S. agalactiae, S. dysgalactiae subsp. equisimilis, and Enterococcus faecalis (vancomycin-susceptible strains only). Combination therapy may be clinically indicated if the documented or presumed pathogens include gram-negative or anaerobic organisms.

Pharmacology

Daptomycin is a cyclic lipopeptide bactericidal antibiotic with activity limited to gram-positive pathogens. Its antibacterial effects are mediated by disruption of multiple aspects of bacterial plasma membrane function, including peptidoglycan synthesis, lipoteichoic acid synthesis, and bacterial membrane potential. A loss of membrane potential leads to inhibition of protein, DNA, and RNA synthesis, which results in bacterial cell death. This mechanism of action is distinct from other antibiotics.

Efficacy

The approval of daptomycin was based upon results from two comparator clinical trials involving more than 1,000 adult patients with complicated skin and skin structure infections. In these studies, patients were randomized to receive daptomycin, vancomycin, or a semi-synthetic penicillin (nafcillin, oxacillin, cloxacillin, or flucloxacillin). Study results demonstrated that daptomycin was at least as effective as standard treatments. In the first study, clinical success rates in the intent-to-treat population and the clinically evaluable population for daptomycin were 62.5% and 76%, respectively, with comparator drug clinical success rates of 60.9% and 76.7%, respectively. In the second study, clinical success rates for daptomycin were 80.4% and 89.9%, compared with rates of 80.5% and 90.4% for the comparator agents.

Precautions

*Monitor creatine phosphokinase (CPK) weekly. Also monitor for the development of muscle pain or weakness, particularly of the distal extremities. Discontinue daptomycin in patients with unexplained signs and symptoms of myopathy in conjunction with CPK elevation > 1000 U/liter (about five times the upper limit of normal) or in patients without reported symptoms who have marked elevations in CPK (M 10 x ULN).

*Consider temporary discontinuation of agents associated with rhabdomyolysis (HMG-CoA reductase inhibitors) in patients receiving daptomycin.

*Possible peripheral and cranial neuropathy was observed in a small number of subjects.

Pharmacokinetics

Adverse effects

The most common adverse effects seen with daptomycin, occurring in 3%-6% of patients, were constipation, nausea, injection-site reactions, headache, diarrhea, insomnia, rash, and vomiting.

Conclusion/comments

Daptomycin, a once-daily parenteral antibacterial agent, has demonstrated efficacy for the treatment of complicated skin and skin structure infections caused by susceptible strains of gram-positive organisms. It is the first approved cyclic lipopeptide antibiotic and has a mechanism of action distinct from other anti-infectives. In view of this, daptomycin may retain potency against antibiotic-resistant gram-positive bacteria, including isolates resistant to methicillin, vancomycin, or linezolid. Comparative data with linezolid and quinupristin/dalfopristin are lacking. The postantibiotic effect of daptomycin and its concentration-dependent bactericidal activity favor once-daily dosing. Daptomycin may be a beneficial alternative in patients who are intolerant to, have a slow response to, or have failed on vancomycin. Muscle toxicity and daptomycin use in renally impaired patients will be areas of postmarketing focus for the manufacturer. Daptomycin is also being studied for the treatment of infective endocarditis bacteremia and as an oral formulation.

Published November 2003. Content based on medical literature and product information available at that time.

 

P&T Portfolio: Cubicin. Drug Topics Nov. 17, 2003;147:HSE26.