Synercid offers new hope for VRE, but not a panacea

FDA panel gives its endorsement

A Food and Drug Administration advisory committee has recommended approval of a new antibiotic, quinupristin/dalfopristin (Synercid), for patients with severe gram-positive bacterial infections, including patients infected with some resistant strains. Although the drug is not a panacea for the current epidemic of antibiotic resistance in many U.S. hospitals, experts familiar with quinupristin/dalfopristin (Q/D) say it does offer hope for patients with certain types of infections that can't be treated with other antimicrobials.

The FDA's Anti-Infective Drugs Advisory Com mittee in Rockville, MD, recently recommended that the intravenous drug be approved. Once an advisory committee recommends a drug for approval, it may take several months before the drug receives full FDA approval and can be marketed.

The advisory committee recommended Q/D for the following indications and gram-positive pathogens:

· infections due to vancomycin-resistant Enterococcus faecium;

· complicated skin and skin-structure infections;

· nosocomial pneumonia.

"Synercid is a significant addition to the arsenal of anti-infective weapons," says Robert Moellering, MD, professor of medicine at Harvard University and a lead investigator for clinical trials of the drug. "Synercid will help doctors fight the rising tide of gram-positive bacterial resistance to currently available treatments."

A new class of antibiotics

Q/D is an injectable streptogramin, which is the first new class of antibiotics to be reviewed by the FDA in more than 10 years. It is composed of the two compounds quinupristin and dalfopristin, which work "synergistically at up to 16 times the power of either agent alone to kill susceptible bacteria through a two-pronged attack on protein synthesis in bacterial cells," says Doug Arbesfeld, spokesman for Rhone-Poulenc Rorer, Collegeville, PA, the company that makes the drug. Without the ability to manufacture new proteins, the bacterial cells die, he explains.

That's not to say Q/D doesn't pose some problems during actual use. During investigational studies of the drug, superinfection occurred in some patients. Peter Linden, MD, associate professor of anesthesiology and medicine and co-director of the liver transplant intensive care unit at the University of Pittsburgh Medical Center, was an investigator of Q/D trials through the emergency-use program of the drug for patients with vancomycin-resistant E. faecium. In a poster presented at the 36th Interscience Conference on Antimicrobial Agents and Chemotherapy in New Orleans in 1996, Linden reported on 68 patients who received Q/D from three to 44 days (for an average of 14.9 days) for serious vancomycin-resistant E. faecium.

Follow-up cultures indicated that 15 patients developed a superinfection with the more treatable E. faecalis species, indicating that E. faecalis is resistant to Q/D. Patients who were most likely to develop a superinfection were those who had E. faecalis at one or more body sites before starting Q/D. Mortality was lower in the 15 patients with superinfection (53%) compared with 53 patients (74%) without superinfection.

"On therapy, usually for VRE infection, one sees the emergence in 5% to 10% of cases of E. faecalis, which have been uniformly susceptible to both vancomycin and ampicillin at our center and most other centers," Linden explains. "So in fact, those infections [with E. faecalis] have been fairly treatable. If you look at the outcomes of patients with superinfections, they actually fared better than patients who didn't [have superinfections], because we were selecting for a population who survived to the point of even having a superinfection. So clinically, it hasn't been a major problem, and there haven't been any resistant Staphylococcus aureus strains develop on therapy."

Is drug effective against MRSA?

As for methicillin-resistant S. aureus (MRSA), Linden says Q/D appears to be "comparable" to vancomycin for treating nosocomial pneumonia and for skin and skin-structure infections. It will be particularly important for use in patients with MRSA who develop vancomycin allergy or whose infection doesn't respond to vancomycin. He says it is still unclear, though, how much bactericidal vs. bacteriostatic effect Q/D has on MRSA infections that may require bactericidal therapy, such as endocarditis, meningitis, or osteomyelitis.

"Right now, there are only a fairly limited number of cases of endocarditis that are due to MRSA that have been treated with Synercid," he adds.

Central IV line usually required

There is concern that Q/D may become overused in the same way that other antimicrobials such as vancomycin currently are, he adds. Linden predicts hospital formularies will restrict its use to appropriate indications only. Another factor that will restrict its use is cost, Linden predicts, although Rhone-Poulenc Rorer declined to reveal the cost of the drug. In addition, Q/D can only be given intravenously, and it has a "high rate" of phlebitis when given in peripheral intravenous lines, so patients almost always require a central IV line to receive it.

"So there are some natural impediments toward people using it empirically, before we even get to the resistance issue," Linden says.

He adds that empirical use of Q/D may be warranted in patients with a blood culture result indicating an enterococcal infection is present, but the strain hasn't been identified as vancomycin-resistant yet.

"If you have a very sick patient and you're in an institution that has a high rate of VRE infection, in that setting you might use [Q/D] empirically," Linden says. "It might turn out to be E. faecalis that's ampicillin-susceptible, but you may not know that for two or three days."

To prevent overuse of Q/D, some hospitals may want to consider "cycling" it with vanco mycin, "meaning this would be the preferential staph and enterococcal agent for a time, and then vancomycin would be preferred.

"This is a protocol situation where all patients with a certain indication and type of organism would be treated preferentially with one type of antimicrobial rather than another for a period of months," Linden says. "That way, alternating different agents may have a favorable ecologic effect on bacterial resistance rather than overusing only one drug for the same frequent indication."

He adds that it may not be feasible for hospitals to implement antimicrobial cycling because it is costly, and because Q/D is difficult to give peripherally.

"I don't know if [physicians] are going to be willing to put in central lines just to keep cycling," Linden says.

What about using Q/D for treating the first strains of vancomycin intermediate-resistant S. aureus infections (VISA)? Fred Tenover, PhD, chief of the nosocomial pathogens laboratory branch at the Centers for Disease Control and Prevention in Atlanta, says Q/D has been shown to be effective against VISA in vitro. He says other drugs such as trimethoprim/sulfamethoxazole also appear to be effective against VISA in vitro, so Q/D wouldn't necessarily need to be the first-line agent used for such an infection, should it occur.

Most importantly, Tenover says Q/D is meant to be used for distinctive indications.

"I think this is a drug that people see as having a specific niche as opposed to a broad-spectrum antibiotic," he notes. "It's not what you'd give [a patient] for a community-acquired bloodstream infection or community-acquired urinary tract infection. It doesn't have any of those indications. It was given a very unique set of indications, primarily for resistant organisms."