The first known outbreak of Staphylococcus aureus resistant to linezolid and methicillin should be a wake-up call to U.S. clinicians, who frequently rely on linezolid when other antibiotics fail. Linezolid was used widely in the Madrid hospital where the resistance developed, and although the facility was able to reduce its reliance on the potent drug, physicians need to take heed of their experience and limit their use of antibiotics, experts said.
“It's a call to all physicians to be very circumspect as to how we use antibiotics, or we are going to lose them,” said Robert P. Gaynes, MD, an associate professor of infectious disease at Emory University School of Medicine and the Atlanta Veterans Affairs Medical Center. “We don't want to have to deal with a post-antibiotic era.”
No one is more aware of that threat than Miguel Sánchez García, MD, PhD, the first author of the report on the outbreak. (JAMA 2010;303:2260.) He and his colleagues at the 1,000-bed tertiary care Hospital Clínico San Carlos and Universidad Complutense de Madrid suspected they faced an outbreak when physicians diagnosed a second case of LRSA, as they dubbed the dual-resistant strain of bacteria.
“Linezolid is extensively used in our and all other hospitals in Spain and abroad because it an efficacious and relatively safe treatment option for MRSA [methicillin-resistant Staphylococcus aureus],” Dr. Sánchez García said. “The development of linezolid-resistance in MRSA is therefore bad news for everyone.”
Dr. Sánchez García and his colleagues described the outbreak as involving 12 patients between April 13 and June 26, 2008. The infection caused ventilator-associated pneumonia in six patients and bacteremia in three. Six patients died, five in the intensive care unit. One of the deaths was attributed to the LRSA infection.
The hospital responded to the outbreak rapidly, reducing 202 defined daily doses of linezolid in April 2008 to 25 doses in July 2008. No new cases of the resistant infection have been identified since April 2008.
Dr. Sánchez García said the outbreak demonstrates the need to change the way the drug is prescribed. “Empirical use, when you still do not have microbiological information, and directed therapy with linezolid should be restricted,” he said. Studies of the organism isolated in the Madrid hospital showed that the resistant-form of S. aureus was susceptible to sulfamethoxazole-trimethoprim, glycopeptides, tigecycline, and daptomycin.
This particular form of resistant organism was associated with the cfr gene, which is located on a plasmid that can be transferred between strains of the same or different species of bacteria, he said. “This ‘transferability’ is the worrisome aspect of cfr-mediated linezolid-resistance. The cfr gene causes an alteration of the linezolid target on the ribosome after it has been produced ‘post-transcriptionally.’”
Dr. Gaynes said the molecular evolution of the strains and resistance mechanism occurred in a short period of time, which he called “a disturbing element.” Physicians should be aware that resistance can occur quickly, he said. Linezolid was first approved for use in 2000, and was the first available antibiotic of its class, oxazolidinone. It is available as a tablet and intravenously. Given over a short period of time, it is relatively safe. Long-term use has been associated with bone marrow suppression, low platelet counts, and peripheral neuropathy.
Studies show these side effects with longtime use are fairly common, and physicians should be aware that they can occur, he said. The dearth of new antibiotics in the pipeline coupled with resistant strains of bacteria was one reason that the U.S. Food and Drug Administration approved linezolid, but Dr. Gaynes said it needs to be used with caution. “That is not to say that it might not be useful. But using it in a cavalier way is going to result in adverse effects for the patient or cause resistance,” he said.
David Talan, MD, a professor of medicine in residence at the University of California Los Angeles School of Medicine and the chairman of emergency medicine at Olive View-UCLA Medical Center, said the report shows that organisms, from the use of antibiotics, “can develop resistance to new agents, but in this case, it doesn't seem to be frequent.” Emergency physicians undoubtedly will see patients who have linezolid-resistant bacterial infections in future, he said, adding that it appears the resistant organism is susceptible to vancomycin and sulfamethoxazole-trimethoprim. “This is not the superbug,” he said.
One advantage of linezolid, said Dr. Talan, an expert in infectious disease in the emergency setting, is that it does not have to be given intravenously, as is the case with vancomycin and other drugs. That's a real benefit for patients because staying in the hospital can expose them to other resistant organisms. “If linezolid helps them get out of the hospital where they might be exposed to these organisms, then that is a good effect. It is an alternative to keeping patients in a hospital setting,” he said.
Dr. Sánchez García agreed that it was important that linezolid is the only available oral therapy for MRSA. “However, if a patient is meant to be admitted, I definitely would suggest considering other options, like glycopeptides, daptomycin, tigecycline, etc.” Asked if LRSA could evolve into a community-acquired infection, he noted that most first cases occurred in outpatients with skin diseases who had been receiving oral linezolid for months.
Dr. Gaynes, in an editorial accompanying the JAMA study noted that antibiotics as a drug class “are virtually unique because once an antibiotic is released for wide scale use, its efficacy diminishes.” (JAMA 2010;303:2293.) That pattern has been seen with penicillin, gentamicin, ciprofloxacin, and other important antibiotics. “The observation has been repeatedly made, yet clinicians do not seem to be learning from the mistakes that continue to occur with each new antibiotic. … No one doubts the importance of infection-control practices in limiting outbreaks with antibiotic-resistant organisms, but optimizing antibiotic use remains essential for successful control of such outbreaks,” he wrote.
“Antibiotic stewardship” will require more than suggestion, he noted. “No longer can clinicians' unrestricted use of antibiotics and ignoring suggestions from those who attempt to improve or alter antibiotic use be tolerated.” Stewardship programs must become part of quality improvement strategies in hospitals with established universal benchmarks for antibiotic use, he said.
“The problem with resistance in antibiotics in general is that we don't have a pipeline of a lot of new drugs coming,” he said. “That means we have to make good use of what we have available now.”
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