Oct 27, 2008 – WASHINGTON, DC (CIDRAP News) – Health officials worldwide are becoming increasingly concerned about influenza viruses' resistance to antiviral drugs, which can shut down a flu infection or mitigate symptoms. Flu antivirals are vital for reducing severe illness and death in average flu seasons and could be essential bulwarks against an influenza pandemic if one began.
There are currently only four antiviral drugs for flu, grouped into two classes, the adamantanes (amantadine and rimantadine) and the neuraminidase inhibitors (oseltamivir, or Tamiflu, and zanamivir, or Relenza). Flu scientists have known since 2005 that seasonal flu viruses have become widely resistant to the adamantanes, with at least 90% of H3N2 strains and at least 15% of H1N1 strains impervious to the drugs. That leaves only oseltamivir and the less widely used zanamivir as treatment options and has made oseltamivir the most commonly used influenza antiviral in the world.
But speaking at a major infectious-disease meeting here Sunday, Dr. Nila Dharan of the Centers for Disease Control and Prevention (CDC) disclosed that 12.6% (142 of 1,124) of H1N1 isolates sent to the CDC from around the United States during the 2007-08 season were resistant to oseltamivir, versus less than 1% before 2007.
And in a troubling addition, the CDC found that none of the patients who gave the isolates had taken oseltamivir, casting doubt on the widely held belief that oseltamivir resistance, when it occurs, is not transmissible. 1. (Dharan NJ, Gubareva L, Klimov A, et al. Oseltamivir-resistant influenza A [H1N1] in the United States, 2007-2008 [Abstract V-918])
The finding was announced on the second day of the 48th Interscience Conference on Antimicrobial Agents and Chemotherapy, a 15,000-person gathering known as ICAAC, which this year is being held in conjunction with the 46th annual meeting of the Infectious Diseases Society of America. It comes on the heels of an Oct 14 World Health Organization (WHO) announcement that during the southern hemisphere flu season this past summer, oseltamivir-resistant viruses were found in South Africa, Australia, Argentina, Chile, Kenya, New Caledonia, New Zealand, and Uruguay.
Last January, toward the end of the 2007-08 northern hemisphere flu season, the WHO reported that surveillance networks had found oseltamivir-resistant viruses in 9 out of 18 European countries surveyed, though the sample sizes were small.
Worrisomely, the mutation that confers resistance also appears in areas where seasonal flu co-exists with avian influenza H5N1. "In the last year or so we have seen a massive increase in seasonal flu resistance to oseltamivir," Dr. Jeremy Farrar of the Oxford University Clinical Research Unit at Vietnam’s Hospital for Tropical Diseases said today at the conference. "In Ho Chi Minh City at the moment, 60% of seasonal flu isolates are drug-resistant."
Farrar was part of the treatment team for two Vietnamese H5N1 patients who were found to have the mutated virus in 2005 during treatment with oseltamivir and who died of the infection.
"There is a lot of concern about emerging resistance to oseltamivir," Dr. Trish Perl, director of hospital epidemiology and infection control at the Johns Hopkins Hospital in Baltimore, said at the meeting yesterday during a separate presentation on hospitals' pandemic preparations.
If a flu pandemic begins, she said, "We may not have the luxury of immunoprophylaxis. We may have to rely on basic infection control."
Protecting newborns from flu
In other news from the meeting, a study presented yesterday by Dr. Emmanuel Walter Jr. of Duke Children's Hospital suggested that newborn infants, who are too young to be safely vaccinated against flu, could be protected from the disease by vaccinating their mothers, fathers and siblings before mother and baby leave the hospital. Vaccinating the family members creates a cocoon of immunity around newborns, who are at much higher risk than older children for potentially life-threatening flu complications.
The study was carried out at Durham (North Carolina) Regional Hospital. Researchers distributed educational information, set up a vaccination clinic, and compared the number of flu shots given to new mothers and family members over 5 months with the number given at Duke, where no program was in place. The number of flu shots given rose 16% at Durham, and 40 percent of mothers agreed to be vaccinated. (Walter EB Jr, Swamy G, Allred N, et al. Influenza immunization of household contacts of newborns in the hospital setting [Abstract G1-1209])
High-dose flu shots for elderly
At the other end of the age spectrum, researchers funded by vaccine-maker Sanofi Pasteur reported that poor response to flu shots by the elderly could be improved by giving those over age 65 a much larger dose of the vaccine.
Dr. Ann Falsey of the University of Rochester School of Medicine and Dentistry and colleagues from St. Louis University and the St. Louis VA Medical Center gave a vaccine with four times the normal amount of hemagglutinin, a flu-virus protein, to 2,575 volunteers over age 65, and gave the normal vaccine to an additional 1,262 volunteers. Four weeks after the shot, the high-dose volunteers showed twice the level of flu antibodies seen in the standard-dose volunteers. (Falsey AR, Capellan J, Yau E, et al. Improved immunogenicity after high dose compared to standard influenza vaccine in seronegative adults aged [at least] 65 Years [Abstract G-1191])
Testing nondrug flu defenses
In another study focused on prevention, University of Michigan researchers led by assistant professor of epidemiology Allison Aiello found that wearing standard surgical masks and regularly using an alcohol-based hand sanitizer can cut flu transmission in the community by up to 50%. Participants were randomly assigned to a control group or to using a mask or mask plus hand sanitizer for 6 weeks in the 2006-07 flu season. Only those who used both the mask and the gel reported a drop in their rate of flu-like symptoms such as fever, chills, and body aches.
The researchers cautioned, though, that the results may not be robust because the 2006-07 season was relatively mild. They are currently computing results from the same intervention conducted in the 2007-08 season, which was more severe.
The study is the first prospective investigation to report that nonpharmaceutical interventions—a broad category that includes home quarantine and isolation, social distancing, and school closings—can play a role in reducing flu transmission. That could be an important finding in an influenza pandemic, when pharmaceutical measures such as vaccine and antivirals are expected to be in short supply. (Aiello AE, Murray G, Coulborn R, et al. Mask use reduces seasonal influenza-like illness in the community setting [Abstract V-924])
C difficile peak follows flu peak
And in an example of unintended consequences, Dr. Philip Polgreen of the University of Iowa reported a newly recognized statistical association between influenza outbreaks and the incidence of Clostridium difficile–associated disease, a severe diarrheal illness that can be drug-resistant and that occurs after antibiotics wipe out the normal bacterial inhabitants of the gut.
Using 8 years' worth of hospital discharge data, Polgreen plotted the monthly incidence of C difficile outbreaks in the United States and found that the disease routinely peaks within 2 months after the height of flu season. He theorizes that the outbreaks are the after-effect of antibiotics prescribed during flu season. The antibiotics may have been appropriately prescribed for secondary bacterial illnesses as well as inappropriately for viral symptoms that the drugs would not affect, he said. (Polgreen PM, Bohnett LC, Cavanaugh JE. A time series analysis of C. difficile and its seasonal association with influenza [Abstract K-502])
Nicoll A, Ciancio B, Kramarz P. Observed oseltamivir resistance in seasonal influenza viruses in Europe: interpretation and potential implications. Eurourveillance 2008 Jan 31;13(5) [Full text]
Deyde VM, Xu X, Bright RA, et al. Surveillance of resistance to adamantanes among influenza A(H3N2) and A(H1N1) viruses isolated worldwide. J Infect Dis 2007 Jul 15;196(2):249 [Abstract]
de Jong MD, Tran TT, Truong HK, et al. Oseltamivir resistance during treatment of influenza A (H5N1) infection. N Engl J Med 2005 Dec 22;353(25):2667-72 [Full text]
Aug 25 CIDRAP News story "H1N1 viruses growing more resistant to Tamiflu"