Viral resistance: Deja vu?

When sulfa drugs and penicillin became available, they were hailed for their miraculous ability to fight infection and save lives. Understandably, they were used liberally; and it did not take long for microbes to adapt. All clinicians are familiar with antibiotic resistance and its many problems. Most of us try to avoid indiscriminate prescribing of antibiotics. In addition, we avoid unnecessary use of the most recent and sophisticated antibiotics. This is not only because of their formidable costs, but even more because we know that the more they are used, the sooner we are likely to be confronted by resistant strains of pathogens. However, there are some questions as to whether we have learned the lessons of resistance well enough to apply the principles to nonantibiotic medications.

Just as antibiotics revolutionized medical care by providing us weapons to use against bacteria, antiviral agents have offered us some tools to use against viruses. Reaction to publicity about a possible influenza pandemic has been softened somewhat by the advent of effective antiviral agents. In particular, seasonal and pandemic influenza can be treated with neuraminidase inhibitors. Oseltamivir (Tamiflu, Roche Laboratories) has attracted the attention not only of the medical community, but also of the general public. Many of us have had patients request prescriptions for Tamiflu. Many physicians comply with this request, particularly since it has been shown that efficacy is best when the drug is taken as soon as possible following onset of symptoms. (1) Requests for Tamiflu are common not only among otolaryngologists, but also among physicians in general. (2) However, as pointed out by Moscona, having a supply of Tamiflu in every medicine cabinet is potentially dangerous. (2) If people use Tamiflu indiscriminately every time they start to feel symptoms of a cold, it will not be long before the drug's value is impaired substantially. Resistant strains have been identified already, including those found in subjects who have died of influenza A while taking the medication, and resistance was absent in survivors. (3) The development of resistance to oseltamivir was predicted in 1998 on the basis of its chemical structure. (4) Zanamivir (Relenza, GlaxoSmithKline) does not have a similar chemical structure, and so far resistance to Relenza has not been reported except in immunocompromised patients. At present, Relenza is available only as an inhaled medication, and its use has been more limited than that of Tamiflu. Nevertheless, even though its chemical structure may be more favorable than that of Tamiflu with regard to resistance, if Relenza is used widely and indiscriminately, the development of resistance would not be surprising.

The pattern with which this story is evolving is familiar. Physicians were delighted when adamantanes became available as antiviral agents. However, their use was followed by the development of resistant influenza viruses. Introduction of the neuraminidase inhibitors was met with enthusiasm because they are less likely than the adamantanes to select resistant influenza viruses; but the world of viral organisms remains remarkably resilient, and fatal viral neuraminidase resistance has been documented already. If use increases as people worry more about influenza and Avian flu, the problem will worsen.

Otolaryngologists spend a considerable amount of time and energy treating patients with infection. We know all too well that some infections (bacterial and viral) can be lethal even in this era of modern medicine. It is incumbent upon us to do everything in our power to preserve the efficacy of the lifesaving agents in our armamentarium. We should remain familiar with the information about antiviral agents, including their proper uses, shortcomings, and propensity to facilitate the development of resistant organisms. Most importantly, we should use these medications conservatively, and in accordance with the best scientific guidelines, so that effective antiviral medication is still available to help us save lives when we really need it.

References

(1.) Moscona A. Neuraminidase inhibitors for influenza. N Engl J Med 2005;353:1363-73.

(2.) Moscona A. Oseltamivir resistance--Disabling our influenza defenses. N Engl J Med 2005;353:2633-36.

(3.) de Jong MD, Tran TT, Truong HK, et al. Oseltamivir resistance during treatment of influenza A (H5N1) infection. N Engl J Med 2005;353:2667-72.

(4.) Varghese JN, Smith PW, Sollis SL, et al. Drug design against a shifting target: A structural basis for resistance to inhibitors in a variant of influenza virus neuraminidase. Structure 1998;6:735-46.

ROBERT THAYER SATALOFF, MD, DMA 

Editor-in-Chief

EAR, NOSE & THROAT JOURNAL