DURHAM, N.C. -- Duke University Medical Center researchers have demonstrated in an international clinical trial the effectiveness and safety of a new drug for treating bloodstream and heart infections caused by Staphylococcus aureus bacteria, a major cause of sickness and death worldwide.
Based on the trial, the Food and Drug Administration already has approved the drug -- daptomycin -- for treating heart infections and bacteremia, also known as bloodstream infection or blood poisoning, caused by S. aureus, according to Vance G. Fowler Jr., M.D., an associate professor of infectious diseases who participated in the study.
"This is the first new drug the FDA has approved in two decades for treating these types of potentially life-threatening infections," Fowler said. "This advance adds a new weapon to our dwindling arsenal of antibiotics against these difficult-to-treat infections."
Daptomycin had been approved by the FDA in 2003 for treating skin infections caused by S. aureus. But until now, Fowler said, no one knew definitively whether the drug would be effective against the more serious bloodstream and heart infections.
The researchers published their findings in the August 17, 2006, issue of the New England Journal of Medicine. Cubist Pharmaceuticals, which manufactures daptomycin, funded the study.
S. aureus bacteria are common in the environment. People whose immune systems have been weakened by disease or certain medical treatments, including surgery or receiving intravenous catheters, are at greater risk of infection. For patients in hospitals, S. aureus is a leading cause of bloodstream infection and infection at surgical sites, among other problems.
S. aureus now causes up to 2 million infections and 90,000 deaths per year worldwide, most of them in health-care settings, Fowler said.
Treating S. aureus infections is difficult because many strains have developed resistance to all penicillin-related antibiotics, according to the researchers. For these highly resistant strains -- called methicillin-resistant S. aureus, or MRSA -- the drug vancomycin has been the only consistently reliable treatment alternative. Recently, however, MRSA strains with resistance to vancomycin have appeared.
"The rising prevalence of S. aureus infections and the organism's increasing resistance to drugs make these bacteria a growing threat to medical care throughout the world," said Ralph Corey, M.D., a professor of infectious diseases who participated in the study.
In the study, the research team tested daptomycin's ability to combat two specific types of infection caused by S. aureus, including MRSA strains. The first type was bacteremia, or bloodstream infection. The second was infective endocarditis, which is an infection of the inside lining of the heart. Endocarditis due to S. aureus is a particularly severe form of the infection. It can involve either the tricuspid, mitral, or aortic valves and often occurs in patients with pre-existing heart disease.
The randomized, controlled trial enrolled 246 patients with bacteremia, with or without endocarditis, from 44 centers in four countries. Patients were randomly assigned to one of two treatment groups. One group received six milligrams of daptomycin per kilogram of body weight, administered intravenously once daily. The other group received standard antibiotic therapy, which consisted of an initial four-day course of the antibiotic gentamicin plus a full course of either an antistaphylococcal penicillin or vancomycin, depending on bacterial susceptibilities.
The researchers evaluated patients during antibiotic treatment until discharge. In addition, because up to 10 percent of S. aureus infections can reoccur after antibiotics are stopped, all patients were evaluated again six weeks after treatment ended.
The results showed daptomycin was as effective as standard therapy, Fowler said. Daptomycin was more successful at eliminating drug-resistant S. aureus, at 44.4 percent success versus 31.8 percent. However, the standard therapy slightly outperformed daptomycin for S. aureus without drug resistance, at 48.6 percent success versus 44.6 percent. Neither of these differences was statistically significant, Fowler said. Both types of treatment took roughly the same amount of time -- eight or nine days -- to clear an MRSA infection.
"Having another drug in our armamentarium against S. aureus not only will give physicians a new treatment option, but also may help slow the current troubling spread of drug resistance among these bacteria," Fowler said.
The study also was designed to assess daptomycin's safety, because the doses given to study participants were higher than dosages approved for skin infections (four milligrams per kilogram of body weight). Previous studies performed before FDA approval of daptomycin had suggested that higher doses might cause significant side effects in humans.
Daptomycin proved to be easier on the kidneys than standard therapy, Fowler said. The researchers suggest this probably is due to the use of gentamicin in the study group, given that drug's potent renal toxicity. Patients receiving daptomycin experienced fewer adverse events that caused kidney impairment (6.7 percent versus 18.1 percent). Daptomycin also affected kidney performance less than standard therapy, as measured by the organ's ability to filter creatinine protein from the bloodstream.
Fowler has served as a consultant for Cubist, as well as for the pharmaceutical companies Inhibitex and Merck, which manufacture other agents used to treat or prevent S. aureus infections. He also has received grant support from Inhibitex, Merck and two other pharmaceutical companies, Nabi and Theravance, and lecture fees from Cubist, Nabi and Pfizer, another pharmaceutical company.
Corey has served as a consultant for Cubist and has received grant support from Theravance, Merck, and Inhibitex.
Other researchers involved in the study were Helen W. Boucher, Elias Abrutyn, Adolf W. Karchmer, Mark E. Rupp, Donald P. Levine, Henry F. Chambers, Francis P. Tally, Gloria A. Vigliani, Christopher H. Cabell, Arthur Stanley Link, Ignace DeMeyer, Scott G. Filler, Marcus Zervos, Paul Cook, Jeffrey Parsonnet, Jack M. Bernstein, Connie Savor Price, Graeme N. Forrest, Gerd Fätkenheuer, Marcelo Gareca, Susan J. Rehm, Hans Reinhardt Brodt, Alan Tice, and Sara E. Cosgrove.
Journal
New England Journal of Medicine