Emergence and Possible Transmission of Amantadine-resistant Viruses during Nursing Home Outbreaks of Influenza A (H3N2)

Abstract

Outbreaks of influenza A (H3N2, A/Shanghai/11/87-like) occurred in two partially (60% and 79%) vaccinated nursing home populations in January 1988. A retrospective cohort study using chart review was designed to assess the effectiveness of influenza vaccination and amantadine prophylaxis (100 mg per day) in controlling the outbreaks and to determine the amantadine susceptibility of influenza viruses isolated from case-patients. The point estimate of vaccine efficacy in preventing influenza-like illness was -33% (95% confidence interval -115% to 18%). However, 9% of vaccinated case-patients died within 14 days after onset of influenza-like illness compared with 26% of unvaccinated case-patients (relative risk = 0.4, 95% confidence interval 0.1-1.0). There was no significant difference in illness severity among case-patients who became ill before amantadine prophylaxis was started (n = 84) compared with those who became ill while taking amantadine (n = 34). Four virus isolates obtained before amantadine prophylaxis was started demonstrated 52-68% inhibition by 1 microgram/ml of amantadine; by comparison, six isolates (resistant viruses) obtained from residents who became ill while taking amantadine demonstrated 1-18% inhibition. The resistant viruses had four different RNA sequences in the gene coding for the M2 protein transmembrane region. Three resistant viruses with identical RNA sequences were isolated from residents living in contiguous rooms who had onset of signs and symptoms during a 6-day interval. Further studies are needed to determine how frequently and under what circumstances resistant viruses occur when antiviral agents are used to control institutional influenza A outbreaks. Strategies for antiviral agent administration that limit the emergence and transmission of resistant virus strains may be needed.

Incidence of Amantadine‐Resistant Influenza A Viruses in Sentinel Surveillance Sites and Nursing Homes in Niigata, Japan

“…Up to approximately one-third of the patients shed resistant viruses when amantadine or rimantadine is used for therapy (7,10,12). Transmission of drug-resistant viruses to close, sensitive contacts in families and other semi-closed settings has been described (5,6,9,12,14,(20)(21)(22). Thus, the results indicate that resistant viruses can occur quickly and be transmitted when used in an outbreak situation at nursing homes when amantadine is administered either for neurological indications or influenza treatment, as reported previously (9).…”

Detection of Amantadine-Resistant Influenza A Virus Strains in Nursing Homes by PCR-Restriction Fragment Length Polymorphism Analysis with Nasopharyngeal Swabs

“…In recent years, many investigators have revealed the appearance of amantadine-resistant viruses in nursing homes or household settings where prophylactic or therapeutic use of the drug occurs (8,12,14). Up to approximately one-third of patients may shed resistant viruses when amantadine or rimantadine is used for therapy (7,8).…”

“…It is well-established that single nucleotide changes leading to corresponding amino acid substitutions of one of four critical sites-amino acids 26, 27, 30, and 31-in the transmembrane region of the M2 protein confer resistance (6,11,13,16). In the clinical field, we can detect actual resistant viruses by several methods, such as enzyme-linked immunosorbent assay (1,9,12,14,18), plaque reduction (7), TCID 50 /0.2-ml titration (15), sequencing analysis (1, 9, 12-15), or PCR-RFLP methods (6,13).…”

Emerging pathogens: Dynamics, mutation and drug resistance

“…3b do not correlate with published experiences in using this strategy of mass chemoprophylaxis (with or without treatment of ill persons). Termination of the outbreak is usually found and the number of clinical prophylaxis failures is usually very low, even in studies reporting the emergence of resistant variants [2,3,5]. In such circumstances, clinical influenza has developed in 4 -10% of patients receiving prophylaxis and proven prophylaxis failures due to resistant virus has occuired in 2 -3% of prophylaxis recipients.…”