CDC: Resistance makes 2 older flu drugs ineffective

Jan 14, 2006 (CIDRAP News) – The dominant strain of influenza virus in the United States has unexpectedly turned highly resistant to the two older antiviral flu drugs in use, prompting federal health officials today to advise physicians to stop using them for the rest of this season.

The Centers for Disease Control and Prevention (CDC) announced that clinicians should stop prescribing amantadine and rimantadine, known as adamantanes, and substitute one of the two neuraminidase inhibitors—oseltamivir (Tamiflu) and zanamivir (Relenza). Oseltamivir and zanamivir are newer and more costly than amantadine and rimantadine, and many countries are stockpiling oseltamivir for possible use if the H5N1 avian flu virus evolves into a pandemic strain of flu.

The CDC tested 120 influenza A(H3N2) virus isolates from around the nation and found that 109 of them, or 91%, were resistant to amantadine and rimantadine. That compares with 11% last year and only 1.9% the year before, the agency said.

"What this means is that clinicians should not use amantadine or rimantadine to treat influenza because the drugs will not be effective," CDC Director Dr. Julie Gerberding said at an unusual Saturday press teleconference today.

"We don't think this is going to affect a large number of patients, because not many patients typically are treated with these drugs," Gerberding said.

She explained that oseltamivir and zanamivir have increasingly been replacing amantadine and rimantadine, though she couldn't give any figures. The newer drugs are effective against both A and B types of flu, whereas the older drugs work only for type A, and the newer drugs also may have fewer side effects, she said.

Gerberding said the supply of oseltamivir for treating seasonal flu should be adequate even though the limited production capacity of Roche, the manufacturer, has hampered countries' efforts to stockpile it in case of a pandemic.

"We understand there's a bottleneck of production that’s limiting our ability to build a stockpile, but . . . we've not experienced any shortages for treating patients," she said. "The amount of Tamiflu in our stockpile far exceeds the amount of antivirals that have ever been used to treat influenza."

Gerberding said the CDC expects that oseltamivir and zanamivir will remain effective for treating flu "for the foreseeable future." All H3 and H1 viruses tested have been susceptible to them, the agency said.

Patients who are currently being treated with amantadine or rimantadine should be switched to one of the newer drugs immediately, she said.

Using a new, high-throughput test for viral resistance, CDC scientists first noted the high frequency of resistance yesterday, Gerberding. But they wanted to confirm the findings further before making an announcement.

"We just didn't feel it was responsible to wait 3 more days to get through the [holiday] weekend," she said in explaining the decision to announce the news today.

"We don't know what accounts for this unexpected increase in resistance," Gerberding said. She said it could result from a spontaneous mutation or it could relate to overuse of amantadine and rimantadine in countries where the drugs don't require a prescription.

Resistance to the drugs has been increasing globally in recent years, she said, adding, "There is certainly a trend in the direction of increasing resistance, but I don't think we were expecting it to be so dramatic so soon this year."

A CDC advisory for clinicians says that a single point mutation at any of five amino acid positions on the flu virus's M2 protein can confer resistance to both amantadine and rimantadine. The mutation does not decrease the virus's transmissibility.

Gerberding said there is no evidence that the increased resistance makes H3N2 viruses more virulent.

She stressed that the resistance finding pertains only to "good old, garden-variety seasonal flu" and is unrelated to avian flu or a potential flu pandemic.

However, the CDC has been monitoring H5N1 avian flu viruses as they have become available, she said. "Some are susceptible to these drugs and some are resistant to these drugs," she said. "I think the lesson here is that flu constantly evolves and you're always one mutation away from increased resistance."

Countries have not stockpiled amantadine or rimantadine for use in a flu pandemic, because many of the H5N1 virus samples from Asia have been resistant to them. However, in recent months some H5N1 strains have been reported to be susceptible to the two drugs.

Seasonal flu activity is beginning to increase around the country, with 18 states reporting either widespread or regional activity, the CDC said in a news release today.

"This year over 80 million doses of vaccine have been distributed but remaining supplies vary from state to state so individuals may have to check with more than one provider to receive vaccine," the agency said. "Also, CDC will have available 3.5 million doses from its stockpile to sell through manufacturers as soon as possible. In addition there are doses of vaccine presently available for sale by manufacturers and distributors."

See also:

CDC information on antiviral drugs for influenza
http://www.cdc.gov/flu/professionals/treatment/

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