Amantadine-resistant viruses are cross-resistant to rimantadine and vice versa. Drug-resistant viruses can appear in approximately one third of patients when either amantadine or rimantadine is used for therapy. During the course of amantadine or rimantadine therapy, resistant influenza strains can replace susceptible strains within 2–3 days of starting therapy. Resistant viruses have been isolated from persons who live at home or in an institution where other residents are taking or have recently taken amantadine or rimantadine as therapy; however, the frequency with which resistant viruses are transmitted and their effect on efforts to control influenza are unknown. Amantadine and rimantadine-resistant viruses are not more virulent or transmissible than susceptible viruses. The screening of epidemic strains of influenza A has rarely detected amantadine and rimantadine-resistant viruses.
Persons who have influenza A infection and who are treated with either amantadine or rimantadine can shed susceptible viruses early in the course of treatment and later shed drug-resistant viruses, including after 5–7 days of therapy. Such persons can benefit from therapy even when resistant viruses emerge.
Resistance to zanamivir and oseltamivir can be induced in influenza A and B viruses in vitro, but induction of resistance requires multiple passages in cell culture. By contrast, resistance to amantadine and rimantadine in vitro can be induced with fewer passages in cell culture. Development of viral resistance to zanamivir and oseltamivir during treatment has been identified but does not appear to be frequent. In clinical treatment studies using oseltamivir, 1.3% of posttreatment isolates from patients aged >13 years and 8.6% among patients aged 1–12 years had decreased susceptibility to oseltamivir. No isolates with reduced susceptibility to zanamivir have been reported from clinical trials, although the number of posttreatment isolates tested is limited and the risk for emergence of zanamivir-resistant isolates cannot be quantified . Only one clinical isolate with reduced susceptibility to zanamivir, obtained from an immunocompromised child on prolonged therapy, has been reported. Available diagnostic tests are not optimal for detecting clinical resistance to the neuraminidase inhibitor antiviral drugs, and additional tests are being developed . Postmarketing surveillance for neuraminidase inhibitor-resistant influenza viruses is being conducted.
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