Many newer drugs—parenteral and oral—have been proposed to replace vancomycin for treating Gram-positive infections, particularly methicillin-resistant Staphylococcus aureus. “One reason to use newer drugs is that you don’t have to monitor them,” says Dr. Ronald Jones, president and CEO of JMI Labs in North Liberty, Iowa. “That’s one possible advantage of daptomycin or linezolid, which is the dominant alternative now. If you don’t have to monitor, treatment cost is lower even if drug unit cost is higher.”
However, says Dr. Paul G. Ambrose, director of the Institute for Clinical Pharmacodynamics, while linezolid, daptomycin, and quinupristin/dalfopristin (Synercid) are all approved for Gram-positive organisms, “there is little evidence that they are more effective than vancomycin for MRSA.” In addition, each of the proposed alternatives has its own problem: Synercid is difficult to administer and has to be given over long periods; linezolid decreases platelet count and suppresses bone marrow; and resistance to daptomycin has emerged during therapy. Also, daptomycin can’t be used in pulmonary infections. Dr. Jones adds, “Synercid has been largely abandoned because of severe myalgias.”
“A boatload” of newer parenteral drugs against MRSA is in development, Dr. Ambrose says. Second-generation glycopeptides include telavancin, oritavancin, and dalbavancin. A potential advantage is infrequent dosing. Oritavancin was rejected for concerns about the age of the clinical study data (nearly a decade old) in its initial application. Parenteral cephalosporins include ceftobiprole and ceftaroline. “Ceftobiprole didn’t do very well in pneumonia; it doesn’t have good tissue penetration,” Dr. Ambrose says. Good in vitro activity was demonstrated for TR-700, a second-generation oxazolidinone-like linezolid.
An oral agent, NXL-103, which, like Synercid, is composed of two streptogramin antibiotics (linopristin/flopristin), is supposed to cover all community-acquired MRSA. It will soon go into phase three clinical trials.
For now, Dr. Jones says, “There are some older oral agents that we can still use with some confidence for mild to moderate MRSA infections that present in outpatients.” For instance, in 2008 less than five percent of community-acquired MRSA strains were resistant to doxycycline or trimethoprim/sulfamethoxazole.
—William Check, PhD