New dosing brings daptomycin to approval

Once-daily dosing decreses toxicity

Pharmacists now have another antibiotic to use in the treatment of complicated skin and skin structure infections.

The U.S. Food and Drug Administration (FDA) recently approved daptomycin for injection (Cubicin) to treat the infections. It is specifically indicated for the treatment of complicated skin and skin structure infections caused by susceptible strains of the following gram-positive microorganisms: S. aureus (including methicillin-resistant strains), S. pyogenes, S. agalactiae, S. dysgalactiae subspecies equisimilis, and E. faecalis (vancomycin-susceptible strains only). The drug is not indicated for the treatment of pneumonia.

Daptomycin is the first approved product in a class of antibiotics called cyclic lipopeptide antibacterial agents. The drug is an important, welcomed alternative because it is cidal, not static like antibiotics such as linezolid (Zyvox) and quinupristin/dalfopristin (Synercid), says David N. Gilbert, MD, director of medication education at Providence Portland (OR) Medical Center and professor of medicine at Oregon Health and Science University in Portland. He also is the immediate past president of the Infectious Diseases Society of America in Alexandria, VA.

New dosing minimizes toxicity

Although the FDA newly approved daptomycin, the drug has been in the pipeline since the 1980s. Eli Lilly initially researched daptomycin as a multiple daily-dose drug in several clinical trials, but halted development of it in the early 1990s because of potential toxicities in the form of myopathy.

Cubist Pharmaceuticals then took an interest in daptomycin. The company licensed the product and found that once-daily dosing of the drug decreased the risk of myopathy. The product was once again taken into clinical trials.

The FDA approved daptomycin based on a review of clinical studies involving more than 1,400 adults that demonstrated the drug’s safety and efficacy. The clinical studies demonstrated daptomycin was equivalent to standard therapy (such as vancomycin or semisynthetic penicillins such as oxacillin or nafcillin) in the treatment of complicated skin and skin structure infections.

Most adverse events reported in the clinical studies of daptomycin were mild to moderate in intensity. The most common adverse events included gastrointestinal disorders, injection site reactions, fever, headache, insomnia, dizziness, and rash.

Blood tests showing muscle injury were found rarely in patients in clinical trials. Most of these patients had no symptoms, and the blood tests returned to normal after therapy.

"It is important that pharmacists realize that we may not see the problems with toxicity in the newer clinical settings that perhaps were seen when [daptomycin] was being dosed several times a day," says Linda Garrelts-McLean, PharmD, CDE, director of program development for Jones Pharmacy in Spokane, WA.

Cubist recommends that patients receiving daptomycin be monitored for the development of muscle pain or weakness. Blood tests measuring creatine phosphokinase levels (CPK) also should be monitored weekly in patients receiving the treatment. Those who develop unexplained elevations in CPK while taking daptomycin should be monitored more frequently.

"I think the toxicities can be managed by doing the lab work and monitoring to make sure it is a safe medication as well as efficacious for our patients," Garrelts-McLean says.

The product packaging says daptomycin 4 mg/kg should be administered over a 30-minute period by intravenous infusion in 0.9% sodium chloride injection once every 24 hours for seven to 14 days. Doses of daptomycin higher than 4 mg/kg/day have not been studied in Phase III controlled clinical trials. In Phase 1 and II clinical studies, CPK elevations appeared to be more frequent when daptomycin was dosed more frequently than once daily.

Because the kidney primarily eliminates daptomycin, a dosage modification is recommended for patients with creatinine clearance of less than 30 mL/min, including patients receiving hemodialysis or continuous ambulatory peritoneal dialysis. This modification is 4 mg/kg once every 48 hours. Whenever possible, daptomycin should be administered following hemo-dialysis on hemodialysis days.

Pharmacists can expect to have daptomycin available early this month. The drug will be supplied in single-use vials containing either 250 mg or 500 mg daptomycin as a sterile, lyophilized powder. The contents of a daptomycin 250 mg vial should be reconstituted with 5 mL of 0.9% sodium chloride injection. The contents of a daptomycin 500 mg vial should be reconstituted with 10 mL of 0.9% sodium chloride injection. Reconstituted daptomycin should be further diluted with 0.9% sodium chloride injection to be administered by intravenous infusion over a period of 30 minutes.

Potential still not known

Daptomycin should be helpful in the treatment of complicated skin and skin structure infections, Gilbert says. "We currently are suffering an epidemic of methicillin-resistant soft-tissue infections acquired in the community, not in the hospitals, in otherwise healthy people."

He particularly looks forward, however, to data showing the results of the drug being used in patients with vancomycin-resistant enterococci.

"The full story on the drug is not yet available because the studies are still in progress," Gilbert explains. "We are hopeful that those studies will confirm the efficacy of the drug for the staph infections not only in the skin but more serious invasive MRSA infections."

He says he expects daptomycin off-label use to be common prior to FDA approval of additional indications.