Synercid, Compassionate Use Antibiotic


New drugs on the way, but will resistance reappear? Prudent use of new antibiotics will be crucial

What agents are in the pipeline for treating patients with antibiotic-resistant infections? One investigational agent, Synercid, is available on a compassionate-use basis for patients with vancomycin-resistant enterococcal (VRE) and staphylococcal infections, such as methicillin-resistant S. aureus (MRSA), although it is far from a panacea for the problem. Its manufacturer, Rhone-Poulenc Rorer in Collegeville, PA, claims Synercid would be effective against vancomycin-resistant S. aureus (VRSA) if it occurs, but that claim is only based on theory.

Sharon Cerwinka, MS, compassionate-use program director for the company, says Synercid is a new class of antibiotic called “streptogramins.” The generic name for Synercid is quinupristin/dalfopristin. It works on the bacterial ribosome to prevent protein syntheses.

Since Syncercid became available for compassionate use early last year, Cerwinka estimates about 400 patients have received it, and 500 have been turned down.

“For compassionate use, either the bug has to be resistant, or the patient has to be intolerant or allergic to other agents,” Cerwinka says. “A third indication is if there has been a very clear treatment failure with another antibiotic.”

Clinical trials have been conducted on more than 1,000 patients in the US, Europe, and South Africa – including those who have received it on a compassionate basis – but data are not yet available. Cerwinka says early phase I trials did find a very slight increased risk of liver toxicity of less than 1%. Unlike other antibiotics, Syncercid is metabolized through the liver rather than the kidneys.

Cerwinka says that if VRSA occurs, and if the drug is approved by the US Food and Drug Administration, Synercid will be “very appropriate” therapy to treat the infection. Nevertheless, its efficacy against VRSA is purely theoretical because the VRSA organism doesn’t exist yet, and no testing of it has been performed at Rhone-Poulenc or by any other drug company that she knows of. But it has been tested successfully with other resistant organisms, such as MRSA.

“One of our hopes is that Synercid will be another antibiotic out there so physicians won’t have to use vancomycin all the time to treat MRSA,” she says. “It will relieve some of that natural pressure to use vancomycin.”

Robert Gaynes, MD, chief of surveillance activity for the hospital infections program at the federal Centers for Disease Control and Prevention in Atlanta, says he has heard anecdotal reports that Synercid is effective in only about 60 to 70% of patients with VRE, even when laboratory data indicate the organism is susceptible.

“That may be due to the fact that the patients who are getting VRE are so sick,” Gaynes says. “It’s hard to tell what those patients die of.”

Cerwinka admits that Synercid trials do indicate that some patients do die despite treatment with the drug, but like Gaynes, she says that many of those patients have cancer, trauma, or other complications that contribute to their mortality.

New drugs probably no panacea

Nevertheless, Gaynes says that Synercid is not the sole answer to antibiotic resistance.

“It is probably not going to be the panacea,” he says. “It’s a static drug. The strategy of finding a new drug will ultimately fail, because what happens when you get resistance to Synercid?”

Cerwinka says that although it is possible that VRE and other organisms could become resistant to Synercid, it does contain a combination of 2 antibiotics, which will make it more difficult for resistance to occur.

“We have to use better judgment in how we use it,” she says. “But one of the positive things about Synercid is that it’s a two-component antibiotic. Essentially, the organisms will have to become resistant to both of the components to make it truly inactive.”

Cerwinka estimates that Synercid will be up for review by the Rockville, MD-based FDA sometime within the next 2 years. Thus, if it’s approved, Synercid could be on the market by 1997.

When Synercid becomes available, every effort should be made to limit use of the drug to the most severe cases, urges Dennis Maki, MD, chief of infectious diseases at the University of Wisconsin Hospital and Clinics in Madison. For example, Synercid is one of the few antimicrobials with efficacy against strains of enterococci that are resistant to both vancomycin and ampicillin, Maki says, adding that it also will be one of the first agents called upon if VRSA appears.

“If Synercid starts becoming used as an all-purpose, third-generation cephalosporin-like drug or is used as heavily as most of the broad-spectrum antibiotics are used in hospitals, we will very quickly see resistance, and its usefulness will erode,” Maki warns. “I would much rather see that there literally be a mandate that the drug be used only for culture-proven resistant infections – MRSA, VRE, or rare cases of staph that are resistant to vancomycin.

Promising compound under study

Meanwhile, Eli Lilly and Co. in Indianapolis is developing another antibiotic that is demonstrating efficacy against VRE, MRSA, and penicillin resistant Streptococcus pneumoniae in initial trials. The compound – currently called LY333328 – is a semisynthetic glycopeptide that is proving active against nearly all gram-positive bacteria tested in the laboratory. Though human trials will not begin until next year, in vitro and animal studies indicate the compound has greater activity against bacteria than such natural glycopeptide antibiotics as vancomycin and teicoplanin, Lilly officials report.

“We believe that it is going to be a major compound against VRE,” says Jennifer Stotka, MD, medical director of infectious disease research. “…It is much more active against S. aureus, including MRSA, than vancomycin.

One potential advantage the compound may have over other antibiotics is that it appears not only to stop bacterial reproduction but also to kill existing bacteria, the company claims. Researchers, however, are encountering some minor toxicity and formulation issues as development continues, including the histamine release and flushing known as “red man syndrome,” Stotka says. This syndrome occurs with other antibiotics such as vancomycin, especially if they are infused too quickly. Patients become very hot and their faces and upper bodies become flushed and red.

“We are in preclinical development, so we are still working on formulation,” she says. “As with any new compound there are formulation hurdles to overcome, and we are working on those currently.”

Lilly also reports the promising finding that the compound is showing little or no ability to select or induce antibiotic resistance in vitro among exposed bacteria.

“The bugs are smart – eventually resistance is likely to develop,” Stotka concedes. “If this drug is used wisely, maybe we can avoid the problems that we know occur with the overuse – the misuse – of antibiotics.”

While promising, such new compounds must be proved in human trials before they will elicit much enthusiasm from clinicians, says Fred C. Tenover, PhD, chief of the CDC nosocomial pathogens laboratory branch.

“I can’t speak to this particular drug, but we have learned in the medical community that until we see the human trials, we don’t get very excited about drugs,” he says. “Some of them – although very potent against bacteria – have incredible side effects. They never make it to market because they are just too toxic. That may be 50% of the compounds that come out.”

Even when the hurdles to market are cleared, the likelihood that new antibiotics will develop resistance down the line is very real.

“When ciprofloxacin came out as an oral agent in the 1980’s, the drug companies were touting it as a wonderful approach to treating MRSA in the outpatient arena,” Gaynes says. “But now, ciprofoxacin is basically useless against MRSA, and that happened very quickly. So no matter how great a new antibiotic may look in the laboratory, it may go right down the toilet quickly if it’s not used judiciously.”

Editor’s note: For more information on Synercid, contact Sharon Cerwinka at: Rhone-Poulenc Rorer, 500 Arcola Rd., MS CM6, Collegeville, PA 19426-0107 Telephone: 610-454-5404 or 610-454-3071