ICPs warn use new drug wisely or lose it quickly

Linezolid debut interlaces hopes and warnings

Extending a wary welcome to a much-needed new class of antibiotics, infection control professionals warn that the recent approval of linezolid for drug-resistant infections will be of little avail if hospitals don’t tighten their grip on clinical formularies. Nosocomial infections with methicillin-resistant Staphylococcus aureus (MRSA) and vancomycin-resistant enterococci (VRE) are among the approved uses of the new drug, which is being distributed under the brand name Zyvox by Pharmacia and Upjohn in Kalamazoo, MI.

"This drug is effective against the two bugs that we worry about the most at the moment," says William Schaffner, MD, chairman of the department of preventive medicine at Vanderbilt Uni-versity Medical School in Nashville. "It should not be used in other [non-indicated] circumstances." Indeed, linezolid could be a key weapon against rising vancomycin resistance if the medical community doesn’t undermine its efficacy with injudicious use, he warns. "I would try to use vancomycin first and keep this one back for the ultimate reserve," he says. "This should be the last brigade of cavalry that comes over the hill. Hold this in reserve until we have to use it, until we are faced with vancomycin resistance."

With IV and oral formulations, linezolid comes from the first new class of antibiotics — the oxazolidinone class — to be approved in 35 years. The approval was supported by controlled clinical trials that enrolled more than 4,000 patients. As previously reported, linezolid uses a novel mechanism: blocking bacterial protein synthesis from starting rather than sabotaging it once it has begun. (See Hospital Infection Control, November 1999, p. 153.) The Food and Drug Administration approval states that the drug is indicated for adults in the treatment of nosocomial pneumonia, community-acquired pneumonia, complicated and uncomplicated skin and skin structure infections, and VRE infections caused by indicated bacteria. The indications also include approval for use in complicated skin infections and nosocomial pneumonia caused by MRSA.

Linezolid could become a key weapon in preventing bloodstream infections, which have a 30% mortality rate and infect between 175,000 and 350,000 patients a year, says Richard Wenzel, MD, professor and chairman of the department of internal medicine at Virginia Commonwealth Univer-sity in Richmond. "It’s great to have another drug, particularly for antibiotic-resistant organisms that are causing life-threatening infections," he says. "This new drug has some advantages, in that you can take it by pill as well as having it administered intravenously."

Oral administration means that a central catheter may not be required for drug delivery, eliminating patient discomfort and the risk of clotting and infection, he says. "Also, by having a pill, you are able to switch the patient over quickly and you might have shorter lengths of stay," he says. "It should be used only for life-threatening hospital infections. Hopefully, it won’t be used in the community. The usual time between the introduction of a drug and finding some resistance, even if it is low-level, is usually within the first three years. So there is certainly some crude relationship between use and finding resistance. The organisms are very adaptable."

Wenzel says the major use in his hospital will likely be "hospital-acquired enterococcus that has a good chance or is known to be resistant to vancomycin." For MRSA, vancomycin could continue to be used unless there was an IV access problem or renal toxicity due to the drug. Linezolid would then be a good alternative, he says. "What this really does is add options that we didn’t have, that can be tailored to specific clinical situations, whether they are due to patient problems or organism resistance," he says.

A paradoxical question

But the usual fanfare and media coverage accompanying the drug’s approval raised a paradoxical question to Schaffner: Do business pressures to market and sell a new antimicrobial ultimately contribute to its overuse and waning efficacy? "I am concerned because the company has invested a very substantial sum of money in bringing this novel agent to market, and my congratulations to them," says Schaffner, adding in jest, "Now, I would love for them not to have a marketing division."

Noting that there already are the first signs of resistance to linezolid in clinical trials, Schaffner frets that an invaluable "niche" antibiotic will be lost in the coming years if it is used injudiciously. "There is no such thing as panacea-mycin,’" he says. "I really think in order for this drug to remain effective over the long term — a decade, 15 years — it has to be held in reserve and released only on specific indications. It should not be used prophylactically. It should not be used as empiric therapy unless in a particular institution, under restricted circumstances: An infectious disease physician, hospital epidemiologist, or infection control committee approves it use. But this is the paradox: That won’t help the management of the company or its stockholders. They will wonder why they are not selling this hand over fist."

The balancing act between business and medical interests has long been an issue in the pharmaceutical realm, adds Robert Moellering, MD, professor of medicine at Harvard Medical School in Cambridge, MA, who conducted laboratory trials with linezolid. "This is always a conflict," he tells HIC. "Pharmaceuticals are in the business to make money. They are not nonprofit organizations. Part of their excuse for making money is so they can plow it back into research to find new drugs. Part of it is that they have stockholders they are beholden to. There is always a balancing act — I’m sure even within the pharmaceutical industry — to sell as much as you can but not to destroy the drug by overuse and the creation of resistance. That is a very tough balance."

ICPs should stress appropriate use

The key to preserving the drug’s efficacy will be the physicians who prescribe it, he adds, noting that it is clinicians — not pharmaceutical companies — that have the ultimate responsibility for an antibiotic’s use. "That is the real challenge," he says. "It should be used for those situations where it really has advantages over other currently available antibiotics — and that includes [for] organisms that are resistant to everything else. It includes infections in patients who are allergic to other drugs and therefore can’t tolerate them."

Indeed, laboratory and clinical studies suggest continued use of linezolid in situations where the drug is ineffective sparks the first emergence of resistant bacteria, he says. "There have been a few cases of the emergence of resistance, mostly in VRE," he says. "We know from the studies in the laboratory that it is possible to make resistant mutants. We know the mechanism by which some of these have become resistant."

Clinical resistance emerged in VRE infections in patients with implanted or artificial devices, which can provide safe harbors for bacteria, he says. "These artificial devices serve as sheltering places for the bacteria and make it much more difficult for the antibiotic to eradicate them," Moellering says. "It’s definitely a possibility that this will occur. The longer you expose bacteria to the drug in a setting where the bug can’t be killed, the more likely you are to see the emergence of resistance. For the most part in the clinical studies, the emergence of resistance has not been a huge problem. That is not a reason for complacency, however, because we have seen that with other drugs."

ICPs can play a role in averting that complacency by educating medical staff and critical committees about the availability and indicated uses of the drug, adds Ona Baker Montgomery, RN, MSHA, CIC, infection control coordinator at the Department of Veterans Affairs Medical Center in Amarillo, TX. "Infection control professionals should be involved in evaluating new classes of antibiotics like this that have substantial potential for benefit in limited infectious disease treatment, but also substantial potential for misuse," she says. "They should be interfacing with their pharmacy and therapeutics committee through the infection control committee to encourage judicious use and possibly some restrictions."