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Amantadine and Rimantadine Resistance Very High

February 3, 2006

Amantadine and rimantadine are anti-viral drugs in the "adamantane" class, commonly used to treat and prevent influenza A. Viral resistance to adamantanes is now alarmingly high, according to a report published on February 2 in the in the Journal of the American Medical Association (JAMA) online.

Researchers Rick A Bright, PhD, and colleagues from the Centers for Disease Control and Prevention (CDC) in Atlanta analyzed influenza samples from people in 26 US states, the study found that 92% of them were resistant to amantadine.

They concluded that amantadine should not be used to treat or prevent influenza A for the remainder of the 2005-2006 flu season and recommended ongoing surveillance of influenza viruses for drug-resistance.

"Our results highlight the importance of continued surveillance for the emergence and transmission of influenza viruses resistant to antiviral drugs. They serve as a warning to the medical community of the speed at which resistant influenza viruses can become predominant circulating strains and spread throughout a continent," Dr Bright and colleagues wrote.

Influenza A viruses are a major cause of illness and death in the US and infect about 10-15% of the population annually, according to Dr Bright and colleagues. While vaccination is the primary preventative strategy against influenza infection, antiviral drug therapy-including use of amantadine and rimantadine-has been effective in treating patients with the flu, particularly in nursing homes and long-term care facilities. However, resistance to these drugs is rapidly growing around the world.

Clinical Trial

The researchers analyzed 209 influenza isolates collected from patients in 26 states during the period October 1 through December 31, 2005 and tested these samples for drug resistance, as part of ongoing surveillance. Isolates came from World Health Organization collaborating laboratories and National Respiratory and Enteric Virus Surveillance System laboratories.

The study's objective was to investigate the frequency of adamantane-resistant influenza A viruses circulating in the US during the early 2005-2006 influenza season.

Using gene-sequencing assays, the researchers identified viruses that contained mutations (within the M2 gene) known to confer resistance to both amantadine and rimantadine. Of the 209 samples, 193 (92.3%) contained an amino acid change correlated with adamantane resistance. The drug-resistant viruses came from a variety of states across the US.

"Of the 209 A (H3N2) viruses screened, we found an alarmingly high adamantane resistance rate of 92 percent," the researchers wrote. "These viruses were isolated from patients residing in 26 states, representing all regions of the United States. This rate was much higher than the rate found among viruses collected within the United States during previous influenza seasons."

Accompanying Editorial

David M Weinstock, MD and Gianna Zuccotti, MD, MPH, from Memorial Sloan-Kettering Cancer Center, New York, wrote in the same issue of JAMA, "the global burden of influenza infection is staggering. In a typical year, approximately 20 percent of the world's population is infected and more than a half million individuals die of influenza-associated complications.

The report by Bright and colleagues is a clarion call for action from the medical community. Physicians and other health care professionals must
(1) educate patients and communities;
(2) organize an international response through governmental and nongovernmental organizations;
(3) advocate against the release of over-the-counter antiviral drugs, either directly by major drug companies or through licensing agreements with generic manufacturers; and
(4) recognize the powerful influences that affect prescribing practices before assigning culpability to those who have inappropriately used adamantanes."

They concluded, "The response must be global and immediate. If successful, there is some evidence that the prevalence of resistance not only might stabilize, but actually decrease."

Adamantane Resistance Among Influenza A Viruses Isolated Early During the 2005-2006 Influenza Season in the United States. Rick A Bright, PhD et al, Journal of the American Medical Association, volume 295, published online February 2, 2006.
Adamantane Resistance in Influenza A, David M Weinstock, MD and Gianna Zuccotti, MD, MPH, Journal of the American Medical Association, volume 295, published online February 2, 2006.

Posted: February 2006