Low Incidence of Rimantadine Resistance in Field Isolates of Influenza A Viruses
Identifieur interne : 001288 ( Istex/Corpus ); précédent : 001287; suivant : 001289Low Incidence of Rimantadine Resistance in Field Isolates of Influenza A Viruses
Auteurs : Thedi Ziegler ; Mark L. Hemphill ; Marja-Liisa Ziegler ; Gilda Perez-Oronoz ; Alexander I. Klimov ; Alan W. Hampson ; Helen L. Regnery ; Nancy J. CoxSource :
- The Journal of Infectious Diseases [ 0022-1899 ] ; 1999.
Abstract
The spread of drug-resistant influenza viruses type A to close contacts in families, schools, and nursing homes has been well documented. To investigate whether drug-resistant influenza viruses circulate in the general population, 2017 isolates collected in 43 countries and territories during a 4-year period were tested for drug susceptibility in a bioassay. Drug resistance was confirmed by detection of specific mutations on the M2 gene that have been shown to confer resistance to amantadine or rimantadine. Sixteen viruses (0.8%) were found to be drug-resistant. Only 2 of these resistant viruses were isolated from individuals who received amantadine or rimantadine treatment at the time the specimens were collected. For 12 individuals use of amantadine or rimantadine could be excluded, and from the remaining 2 patients information about medication was unavailable. These results indicate that the circulation of drug-resistant influenza viruses is a rare event, but surveillance for drug resistance should be continued.
Url:
DOI: 10.1086/314994
Links to Exploration step
ISTEX:15E93149EEF33A88BE1EC9E3D90430C168223F3DLe document en format XML
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Box 5000, FIN-90401 Oulu, Finland (thedi.ziegler@oulu.fi).</mods:affiliation></affiliation></author><author><name sortKey="Perez Oronoz, Gilda" sort="Perez Oronoz, Gilda" uniqKey="Perez Oronoz G" first="Gilda" last="Perez-Oronoz">Gilda Perez-Oronoz</name><affiliation><mods:affiliation>Influenza Branch, Division of Viral and Rickettsial Diseases, National Center for Infectious Diseases, Centers for Disease Control and Prevention, Atlanta, Georgia</mods:affiliation></affiliation></author><author><name sortKey="Klimov, Alexander I" sort="Klimov, Alexander I" uniqKey="Klimov A" first="Alexander I." last="Klimov">Alexander I. Klimov</name><affiliation><mods:affiliation>Influenza Branch, Division of Viral and Rickettsial Diseases, National Center for Infectious Diseases, Centers for Disease Control and Prevention, Atlanta, Georgia</mods:affiliation></affiliation></author><author><name sortKey="Hampson, Alan W" sort="Hampson, Alan W" uniqKey="Hampson A" first="Alan W." last="Hampson">Alan W. 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Cox</name><affiliation><mods:affiliation>Influenza Branch, Division of Viral and Rickettsial Diseases, National Center for Infectious Diseases, Centers for Disease Control and Prevention, Atlanta, Georgia</mods:affiliation></affiliation></author></analytic><monogr></monogr><series><title level="j" type="main">The Journal of Infectious Diseases</title><title level="j" type="abbrev">The Journal of Infectious Diseases</title><idno type="ISSN">0022-1899</idno><idno type="eISSN">1537-6613</idno><imprint><publisher>The University of Chicago Press</publisher><date when="1999-10">1999</date><biblScope unit="vol">180</biblScope><biblScope unit="issue">4</biblScope><biblScope unit="page" from="935">935</biblScope><biblScope unit="page" to="939">939</biblScope></imprint><idno type="ISSN">0022-1899</idno></series></biblStruct></sourceDesc><seriesStmt><idno type="ISSN">0022-1899</idno></seriesStmt></fileDesc><profileDesc><textClass></textClass></profileDesc></teiHeader><front><div type="abstract">The spread of drug-resistant influenza viruses type A to close contacts in families, schools, and nursing homes has been well documented. To investigate whether drug-resistant influenza viruses circulate in the general population, 2017 isolates collected in 43 countries and territories during a 4-year period were tested for drug susceptibility in a bioassay. Drug resistance was confirmed by detection of specific mutations on the M2 gene that have been shown to confer resistance to amantadine or rimantadine. Sixteen viruses (0.8%) were found to be drug-resistant. Only 2 of these resistant viruses were isolated from individuals who received amantadine or rimantadine treatment at the time the specimens were collected. For 12 individuals use of amantadine or rimantadine could be excluded, and from the remaining 2 patients information about medication was unavailable. These results indicate that the circulation of drug-resistant influenza viruses is a rare event, but surveillance for drug resistance should be continued.</div></front></TEI><istex><corpusName>oup</corpusName><keywords><teeft><json:string>rimantadine</json:string><json:string>amantadine</json:string><json:string>resistant virus</json:string><json:string>serrasn</json:string><json:string>october</json:string><json:string>virus infection</json:string><json:string>nursing home</json:string><json:string>drug resistance</json:string><json:string>antimicrob agent chemother</json:string><json:string>resistant</json:string><json:string>virus</json:string><json:string>disease control</json:string><json:string>geographic origin</json:string><json:string>virus dilution</json:string><json:string>in part</json:string><json:string>medical microbiology</json:string><json:string>virus replication</json:string><json:string>transmembrane domain</json:string><json:string>other country</json:string><json:string>semiclosed institution</json:string><json:string>virus type</json:string><json:string>infectious disease</json:string><json:string>drug susceptibility</json:string><json:string>bovine serum albumin</json:string><json:string>rare event</json:string><json:string>ambient temperature</json:string><json:string>nucleoprotein synthesis</json:string><json:string>amino acid change</json:string><json:string>channel activity</json:string><json:string>additional virus</json:string><json:string>amantadine rimantadine</json:string><json:string>drugresistant virus</json:string><json:string>other person</json:string><json:string>other individual</json:string><json:string>apparent transmission</json:string><json:string>up respiratory tract infection</json:string><json:string>other resistant virus</json:string><json:string>hong kong</json:string><json:string>control virus</json:string><json:string>virus resistant</json:string><json:string>arch intern</json:string><json:string>channel protein</json:string><json:string>mdck cell</json:string></teeft></keywords><author><json:item><name>Thedi Ziegler</name><affiliations><json:string>Influenza Branch, Division of Viral and Rickettsial Diseases, National Center for Infectious Diseases, Centers for Disease Control and Prevention, Atlanta, Georgia</json:string></affiliations></json:item><json:item><name>Mark L. 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Department of Pediatrics, University of Turku, Finland (M.-L.Z.).</p></note></author><author xml:id="author-0001"><persName><surname>Hemphill</surname><forename type="first">Mark L.</forename></persName><affiliation><orgName>Influenza Branch</orgName><orgName type="department">Division of Viral and Rickettsial Diseases</orgName><orgName type="institution">National Center for Infectious Diseases</orgName><orgName type="institution">Centers for Disease Control and Prevention</orgName><address><addrLine>Atlanta, Georgia</addrLine></address></affiliation></author><author xml:id="author-0002" role="corresp"><persName><surname>Ziegler</surname><forename type="first">Marja-Liisa</forename></persName><affiliation><orgName>Influenza Branch</orgName><orgName type="department">Division of Viral and Rickettsial Diseases</orgName><orgName type="institution">National Center for Infectious Diseases</orgName><orgName type="institution">Centers for Disease Control and Prevention</orgName><address><addrLine>Atlanta, Georgia</addrLine></address></affiliation><note place="foot" n="FN1"><ref>a</ref><p>Present affiliations: Department of Medical Microbiology, University of Oulu, Finland (T.Z.); Department of Pediatrics, University of Turku, Finland (M.-L.Z.).</p></note><email>thedi.ziegler@oulu.fi</email></author><author xml:id="author-0003"><persName><surname>Perez-Oronoz</surname><forename type="first">Gilda</forename></persName><affiliation><orgName>Influenza Branch</orgName><orgName type="department">Division of Viral and Rickettsial Diseases</orgName><orgName type="institution">National Center for Infectious Diseases</orgName><orgName type="institution">Centers for Disease Control and Prevention</orgName><address><addrLine>Atlanta, Georgia</addrLine></address></affiliation></author><author xml:id="author-0004"><persName><surname>Klimov</surname><forename type="first">Alexander I.</forename></persName><affiliation><orgName>Influenza Branch</orgName><orgName type="department">Division of Viral and Rickettsial Diseases</orgName><orgName type="institution">National Center for Infectious Diseases</orgName><orgName type="institution">Centers for Disease Control and Prevention</orgName><address><addrLine>Atlanta, Georgia</addrLine></address></affiliation></author><author xml:id="author-0005"><persName><surname>Hampson</surname><forename type="first">Alan W.</forename></persName><affiliation><orgName type="institution">WHO Influenza Center</orgName><orgName>CSL Ltd</orgName><address><addrLine>Parkville, Victoria</addrLine><country key="AU" xml:lang="en">AUSTRALIA</country></address></affiliation></author><author xml:id="author-0006"><persName><surname>Regnery</surname><forename type="first">Helen L.</forename></persName><affiliation><orgName>Influenza Branch</orgName><orgName type="department">Division of Viral and Rickettsial Diseases</orgName><orgName type="institution">National Center for Infectious Diseases</orgName><orgName type="institution">Centers for Disease Control and Prevention</orgName><address><addrLine>Atlanta, Georgia</addrLine></address></affiliation></author><author xml:id="author-0007"><persName><surname>Cox</surname><forename type="first">Nancy J.</forename></persName><affiliation><orgName>Influenza Branch</orgName><orgName type="department">Division of Viral and Rickettsial Diseases</orgName><orgName type="institution">National Center for Infectious Diseases</orgName><orgName type="institution">Centers for Disease Control and Prevention</orgName><address><addrLine>Atlanta, Georgia</addrLine></address></affiliation></author><idno type="istex">15E93149EEF33A88BE1EC9E3D90430C168223F3D</idno><idno type="ark">ark:/67375/HXZ-QD35M1F1-F</idno><idno type="DOI">10.1086/314994</idno></analytic><monogr><title level="j" type="main">The Journal of Infectious Diseases</title><title level="j" type="abbrev">The Journal of Infectious Diseases</title><idno type="hwp">jinfdis</idno><idno type="publisher-id">jid</idno><idno type="pISSN">0022-1899</idno><idno type="eISSN">1537-6613</idno><imprint><publisher>The University of Chicago Press</publisher><date when="1999-10">1999</date><biblScope unit="vol">180</biblScope><biblScope unit="issue">4</biblScope><biblScope unit="page" from="935">935</biblScope><biblScope unit="page" to="939">939</biblScope></imprint></monogr></biblStruct></sourceDesc></fileDesc><encodingDesc><schemaRef type="ODD" url="https://xml-schema.delivery.istex.fr/tei-istex.odd"></schemaRef><appInfo><application ident="pub2tei" version="1.0.10" when="2019-12-09"><label>pub2TEI-ISTEX</label><desc>A set of style sheets for converting XML documents encoded in various scientific publisher formats into a common TEI format.
<ref target="http://www.tei-c.org/">We use TEI</ref></desc></application></appInfo></encodingDesc><profileDesc><abstract><p>The spread of drug-resistant influenza viruses type A to close contacts in families, schools, and nursing homes has been well documented. To investigate whether drug-resistant influenza viruses circulate in the general population, 2017 isolates collected in 43 countries and territories during a 4-year period were tested for drug susceptibility in a bioassay. Drug resistance was confirmed by detection of specific mutations on the M2 gene that have been shown to confer resistance to amantadine or rimantadine. Sixteen viruses (0.8%) were found to be drug-resistant. Only 2 of these resistant viruses were isolated from individuals who received amantadine or rimantadine treatment at the time the specimens were collected. For 12 individuals use of amantadine or rimantadine could be excluded, and from the remaining 2 patients information about medication was unavailable. These results indicate that the circulation of drug-resistant influenza viruses is a rare event, but surveillance for drug resistance should be continued.</p></abstract><textClass ana="subject"><keywords scheme="heading"><term>Major Articles</term></keywords></textClass><langUsage><language ident="EN"></language></langUsage></profileDesc><revisionDesc><change when="2019-12-09" who="#istex" xml:id="pub2tei">formatting</change></revisionDesc></teiHeader></istex:fulltextTEI><json:item><extension>txt</extension><original>false</original><mimetype>text/plain</mimetype><uri>https://api.istex.fr/ark:/67375/HXZ-QD35M1F1-F/fulltext.txt</uri></json:item></fulltext><metadata><istex:metadataXml wicri:clean="corpus oup, element #text not found" wicri:toSee="no header"><istex:xmlDeclaration>version="1.0"</istex:xmlDeclaration><istex:docType PUBLIC="-//NLM//DTD Journal Publishing DTD v2.3 20070202//EN" URI="journalpublishing.dtd" name="istex:docType"></istex:docType><istex:document><article article-type="research-article">
<front>
<journal-meta>
<journal-id journal-id-type="hwp">jinfdis</journal-id>
<journal-id journal-id-type="publisher-id">jid</journal-id>
<journal-title>The Journal of Infectious Diseases</journal-title>
<abbrev-journal-title>The Journal of Infectious Diseases</abbrev-journal-title>
<issn pub-type="ppub">0022-1899</issn>
<issn pub-type="epub">1537-6613</issn>
<publisher>
<publisher-name>The University of Chicago Press</publisher-name>
</publisher>
</journal-meta>
<article-meta>
<article-id pub-id-type="doi">10.1086/314994</article-id>
<article-categories>
<subj-group subj-group-type="heading">
<subject>Major Articles</subject>
</subj-group>
</article-categories>
<title-group>
<article-title>Low Incidence of Rimantadine Resistance in Field Isolates of Influenza A Viruses</article-title>
</title-group>
<contrib-group>
<contrib contrib-type="author">
<name><surname>Ziegler</surname><given-names>Thedi</given-names></name><xref ref-type="aff" rid="AFF1"><sup>1</sup></xref><xref rid="FN1" ref-type="author-notes"><sup>a</sup></xref>
</contrib>
<contrib contrib-type="author">
<name><surname>Hemphill</surname><given-names>Mark L.</given-names></name><xref ref-type="aff" rid="AFF1"><sup>1</sup></xref>
</contrib>
<contrib contrib-type="author" corresp="yes">
<name><surname>Ziegler</surname><given-names>Marja-Liisa</given-names></name><xref ref-type="aff" rid="AFF1"><sup>1</sup></xref><xref rid="FN1" ref-type="author-notes"><sup>a</sup></xref><xref rid="cor1" ref-type="corresp"></xref>
</contrib>
<contrib contrib-type="author">
<name><surname>Perez-Oronoz</surname><given-names>Gilda</given-names></name><xref ref-type="aff" rid="AFF1"><sup>1</sup></xref>
</contrib>
<contrib contrib-type="author">
<name><surname>Klimov</surname><given-names>Alexander I.</given-names></name><xref ref-type="aff" rid="AFF1"><sup>1</sup></xref>
</contrib>
<contrib contrib-type="author">
<name><surname>Hampson</surname><given-names>Alan W.</given-names></name><xref ref-type="aff" rid="AFF2"><sup>2</sup></xref>
</contrib>
<contrib contrib-type="author">
<name><surname>Regnery</surname><given-names>Helen L.</given-names></name><xref ref-type="aff" rid="AFF1"><sup>1</sup></xref>
</contrib>
<contrib contrib-type="author">
<name><surname>Cox</surname><given-names>Nancy J.</given-names></name><xref ref-type="aff" rid="AFF1"><sup>1</sup></xref>
</contrib>
<aff id="AFF1"><sup>1</sup><institution>Influenza Branch, Division of Viral and Rickettsial Diseases, National Center for Infectious Diseases, Centers for Disease Control and Prevention</institution>, <addr-line>Atlanta, Georgia</addr-line></aff>
<aff id="AFF2"><sup>2</sup><institution>WHO Influenza Center, CSL Ltd.</institution>, <addr-line>Parkville, Victoria</addr-line>, <country>Australia</country></aff>
</contrib-group>
<author-notes>
<corresp id="cor1">Reprints or correspondence: Dr. Thedi Ziegler, Dept. of Medical Microbiology, University of Oulu, P.O. Box 5000, FIN-90401 Oulu, Finland (<email>thedi.ziegler@oulu.fi</email>).</corresp>
<fn id="FN1" fn-type="current-aff">
<label>a</label>
<p>Present affiliations: Department of Medical Microbiology, University of Oulu, Finland (T.Z.); Department of Pediatrics, University of Turku, Finland (M.-L.Z.).</p>
</fn>
</author-notes>
<pub-date pub-type="ppub">
<month>10</month>
<year>1999</year>
</pub-date>
<volume>180</volume>
<issue>4</issue>
<fpage>935</fpage>
<lpage>939</lpage>
<history>
<date date-type="received">
<day>8</day>
<month>1</month>
<year>1999</year>
</date>
<date date-type="rev-recd">
<day>9</day>
<month>6</month>
<year>1999</year>
</date>
</history>
<copyright-statement>© 1999 by the Infectious Diseases Society of America</copyright-statement>
<copyright-year>1999</copyright-year>
<abstract>
<p>The spread of drug-resistant influenza viruses type A to close contacts in families, schools, and nursing homes has been well documented. To investigate whether drug-resistant influenza viruses circulate in the general population, 2017 isolates collected in 43 countries and territories during a 4-year period were tested for drug susceptibility in a bioassay. Drug resistance was confirmed by detection of specific mutations on the M2 gene that have been shown to confer resistance to amantadine or rimantadine. Sixteen viruses (0.8%) were found to be drug-resistant. Only 2 of these resistant viruses were isolated from individuals who received amantadine or rimantadine treatment at the time the specimens were collected. For 12 individuals use of amantadine or rimantadine could be excluded, and from the remaining 2 patients information about medication was unavailable. These results indicate that the circulation of drug-resistant influenza viruses is a rare event, but surveillance for drug resistance should be continued.</p>
</abstract>
</article-meta>
</front>
<body>
<p>The usefulness of amantadine and rimantadine in the prevention and treatment of infections caused by type A influenza viruses has been well established in numerous clinical studies [<xref ref-type="bibr" rid="R1">1</xref>–<xref ref-type="bibr" rid="R7">7</xref>]. If taken during the entire duration of an outbreak, these drugs are 70%–90% effective in preventing influenza. Amantadine or rimantadine therapy initiated within the first 2 days after onset of disease can reduce the duration of symptoms and shorten the time of recovery [<xref ref-type="bibr" rid="R5">5</xref>, <xref ref-type="bibr" rid="R7">7</xref>].</p>
<p>Individuals who receive amantadine or rimantadine for the treatment of influenza virus infection may excrete viruses resistant to these drugs [<xref ref-type="bibr" rid="R8">8</xref>–<xref ref-type="bibr" rid="R13">13</xref>]. Up to 30% of treated patients with H3N2 subtype infection shed resistant virus in one study [<xref ref-type="bibr" rid="R8">8</xref>]. These resistant strains can apparently be transmitted to close contacts and cause typical influenza [<xref ref-type="bibr" rid="R8">8</xref>].</p>
<p>To our current understanding, amantadine and rimantadine inhibit the uncoating process of influenza virus after it has entered the host cell by endocytosis [<xref ref-type="bibr" rid="R14">14</xref>–<xref ref-type="bibr" rid="R18">18</xref>]. Acidification of the endosomal environment leads to a flow of protons to the inner part of the virion through ion channels formed by homotetramers of the M2 protein, a transmembrane protein. A decrease of pH in the inner part of the virus causes the dissociation of the M protein, the major structural protein of the virus, and the ribonucleoprotein complex is released into the cytoplasm of the infected cell to initiate virus replication. Amantadine and rimantadine block the proton flow through the M2 ion channel and thus prevent the release of viral RNA into the cytoplasm of the infected cells. In human influenza viruses, single amino acid changes at 4 sites on the 27 amino acids spanning the transmembrane domain of the M2 protein can confer drug resistance [<xref ref-type="bibr" rid="R18">18</xref>].</p>
<p>One might expect the circulation of drug-resistant viruses in countries where amantadine or rimantadine or both have been in use for several years, such as some eastern European countries, as well as France, the United Kingdom, and the United States. In Russia and other countries of the former Soviet Union, rimantadine has been in wide use for more than 2 decades [<xref ref-type="bibr" rid="R19">19</xref>]. In France, rimantadine was licensed in 1987 [<xref ref-type="bibr" rid="R20">20</xref>]. However, only limited information is available about the possible circulation of drug-resistant influenza viruses in the community outside affected families and closed or semiclosed institutions, such as dormitories or nursing homes. Since the licensing of rimantadine in the United States in 1993, drug-susceptibility testing has been done as a standard procedure in the characterization of influenza virus type A isolates submitted to the World Health Organization (WHO) Collaborating Center for Influenza at the Centers for Disease Control and Prevention (CDC) in Atlanta, Georgia. We present surveillance data collected during the 2-year periods preceding and following the approval of rimantadine in the United States. These data will serve as baseline information for continued worldwide surveillance of influenza strains.</p>
<sec sec-type="materials|methods">
<title>Materials and Methods</title>
<p>A total of 2017 viruses submitted to the WHO Collaborating Center for Influenza, CDC, from October 1991 through September 1995 were included in this study. The sample includes all viruses submitted to CDC by WHO National Influenza Laboratories outside the United States. Viruses from the Unites States represented all geographic areas. Viruses received at CDC had been isolated in primary monkey kidney cells, Madin-Darby canine kidney cells (MDCK), or embryonated hens' eggs. Cell-derived isolates were propagated in MDCK cells, and egg isolates were propagated in eggs after arrival at CDC. The geographic origin of the viruses is shown in <xref ref-type="fig" rid="T1">table 1</xref>.</p>
<p>Drug susceptibility was determined by a bioassay that monitors virus nucleoprotein synthesis in infected MDCK cell cultures in the presence or absence of rimantadine at a concentration of 1 <italic>μ</italic>/mL [<xref ref-type="bibr" rid="R18">18</xref>, <xref ref-type="bibr" rid="R21">21</xref>]. Ninety-six-well cell culture plates (Costar, Cambridge, MA) were seeded with MDCK cells (ATCC CCL34; American Type Culture Collection, Manassas, VA). Approximately 2 × 10<sup>4</sup> cells in 100 <italic>μ</italic>L of Dulbecco's modified Eagle medium supplemented with 1% fetal bovine serum, 0.2% bovine serum albumin, 25 m<italic>M</italic> HEPES, penicillin, and streptomycin were added to each well, and the plates were incubated at 36°C in a humidified 5% CO<sub>2</sub> atmosphere overnight. The next morning, without prior removal of growth medium, viruses were added in 3 half-logarithmic dilutions, starting at 1 : 1000 for egg-grown isolates and 1 : 330 for cell culture-grown viruses. Fifty microliters of virus dilution was added to each of 4 wells. An additional 50 <italic>μ</italic>L of medium containing 0.2% bovine serum albumin, antibiotics, and 8 <italic>μ</italic>g of l-tosylamide-2-phenylethyl chloromethyl ketone-trypsin was added to 2 wells of each virus dilution. To the other 2 wells, 50 <italic>μ</italic>L the same medium containing 4 <italic>μ</italic>g of rimantadine was pipetted. The viruses A/Singapore/l/57(sensitive) (H2N2) and A/Turkey/Oregon/71 (resistant) (H7N3) were included as controls in each test [<xref ref-type="bibr" rid="R18">18</xref>, <xref ref-type="bibr" rid="R21">21</xref>]. The plates were wrapped in plastic film and centrifuged at 700 <italic>g</italic> at ambient temperature for 45 min. The wrap was then removed, and the plates were incubated at 36°C for 6 h. Thereafter, medium was aspirated, the cells were washed twice with PBS fixed with 80% acetone in PBS at ambient temperature for 10 min, and again washed twice with PBS. EIA for the quantification of nucleoprotein synthesis was done in the wells, and a ⩾50% inhibition of nucleoprotein synthesis at ⩾1 virus dilutions in the presence of rimantadine was regarded as a sensitive pattern. Drug resistance was verified by partial nucleotide sequence analysis of the M2 gene [<xref ref-type="bibr" rid="R11">11</xref>] or by polymerase chain reaction restriction analysis [<xref ref-type="bibr" rid="R22">22</xref>].</p>
</sec>
<sec sec-type="results">
<title>Results</title>
<p>Sixteen (0.8%) of the 2017 viruses were resistant to rimantadine and possessed a drug-resistant genotype as verified by the detection of relevant mutations in the transmembrane domain of the M2 gene (<xref ref-type="fig" rid="T2">table 2</xref>). Fifteen of the viruses had an amino acid change at residue 31 (serine to asparagine) and 1 at residue 30 (alanine to threonine). Over 80% of all viruses analyzed, including all 16 resistant viruses, were of the H3N2 subtype. Five resistant viruses were found during the first year of observation, 2 during the second, 8 during the third, and 1 during the fourth year. Eight drug-resistant viruses were from the United States, and 8 were from 4 other countries or territories. Five resistant viruses originated from Australia collected during the first year of surveillance. None of the Australian isolates already submitted to CDC for the 3 subsequent years of surveillance (1992, 1993, and 1994) was found to be resistant. However, detection of this cluster of resistant viruses prompted us to solicit and investigate 104 additional viruses that were available in the strain collection of the WHO Collaborating Centre for Influenza Reference and Research in Parkville, Victoria. These additional viruses were collected from 1989 through 1993. Four of these viruses were resistant; 3 of those were isolated during 1992 and 1 during 1993 (data not shown). Altogether, 198 viruses from Australia were analyzed, and 9 (4.5%) of them were drug resistant.</p>
<p>Two patients (isolates 94017156 and 94016508, <xref ref-type="fig" rid="T2">table 2</xref>) were receiving amantadine and/or rimantadine at the time the drug-resistant viruses were isolated. Two other persons with resistant isolates (isolates 93012047 and 93011761, <xref ref-type="fig" rid="T2">table 2</xref>) lived or worked at institutions where other individuals were receiving amantadine or rimantadine at the time the drug-resistant isolate was collected. Two individuals with viruses resistant to the 2 drugs (isolates 94017935 and 95021738, <xref ref-type="fig" rid="T2">table 2</xref>) were living on bases of the US Armed Forces where amantadine has been in use.</p>
</sec>
<sec sec-type="discussion">
<title>Discussion</title>
<p>The results of this study indicate that the isolation of drug-resistant influenza viruses is a rare event. Less than 1% of the viruses analyzed were resistant. In an earlier study [<xref ref-type="bibr" rid="R23">23</xref>], 5 (2%) of 246 isolates collected over a period of 10 years from patients in Huntington, West Virginia, were resistant to amantadine and rimantadine. All 5 resistant viruses were obtained from 3 members of the same family who had received rimantadine for treatment or prevention of influenza virus infection. In another study, none of the 105 viruses collected during 2 consecutive epidemic seasons in France were resistant to rimantadine [<xref ref-type="bibr" rid="R20">20</xref>].</p>
<p>In several studies, the apparent transmission of drug-resistant viruses to close, susceptible contacts in families and other semi-closed settings has been described [<xref ref-type="bibr" rid="R8">8</xref>, <xref ref-type="bibr" rid="R10">10</xref>]. Recently, it was reported that a drug-resistant virus was isolated from a nursing home resident who had neither received amantadine nor rimantadine or had any documented contacts with individuals taking either drug [<xref ref-type="bibr" rid="R11">11</xref>]. Amantadine prophylaxis and therapy was initiated at this nursing home 1 day after the specimen that harbored the resistant virus had been collected.</p>
<p>In this study, only 2 of the 16 patients whose isolates were resistant are known to have received amantadine and/or rimantadine for the treatment of influenza virus infections. Transmission of drug-resistant viruses to close contacts in semiclosed institutions is the most likely explanation for 2 other rimantadine-resistant isolates. One of these 2 individuals was a resident of a nursing home where amantadine has been used for some inhabitants during the influenza epidemic (isolate 93012047, <xref ref-type="fig" rid="T2">table 2</xref>). The other person, an X-ray technician, worked at a hospital where amantadine and rimantadine were used (isolate 93011761, <xref ref-type="fig" rid="T2">table 2</xref>). Two more resistant viruses were obtained from individuals who lived on 2 different bases of the US Armed Forces. One of these persons did not take amantadine or rimantadine; for the other individual, information about the use of antiviral drugs is not available. However, amantadine has been used at both bases. For 9 of the 10 remaining individuals, the use of amantadine or rimantadine can be excluded, and for 1 patient no information could be obtained.</p>
<p>None of the 156 isolates from countries in Europe where amantadine and rimantadine have been in use were found to be resistant. In the United States, amantadine was approved in 1976, and rimantadine was licensed in 1993. All 3 resistant US isolates for which no association with drug use could be established were isolated during the influenza season immediately after the approval of rimantadine in the United States. One of these isolates was from a 33-year-old man with an upper respiratory tract infection (isolate 94016797, <xref ref-type="fig" rid="T2">table 2</xref>). The two other resistant viruses were obtained from a 12-month-old child hospitalized for upper respiratory tract infection and febrile seizures (isolate 94016414, <xref ref-type="fig" rid="T2">table 2</xref>) and from a 6-year-old with fever and respiratory infection (isolate 94016568, <xref ref-type="fig" rid="T2">table 2</xref>).</p>
<p>The relatively young age of most patients from whom resistant viruses have been isolated is surprising, but this reflects in part the age structure of patients whose isolates have been received at CDC. The age of the patient could be identified for 4515 isolates submitted during the 4-year study period. As many as 79% of these patients were age <40 years at the time the specimen was collected.</p>
<p>In our study, none of the 193 isolates from China, Hong Kong, and Singapore were found to be resistant. However, 1 resistant virus was isolated from a 1-year-old child in Taiwan. No further information about this patient was available. The other resistant virus from east and southeast Asia was associated with possible amantadine use at a military base of the US Armed Forces in Guam. Use of amantadine in China and Hong Kong in recent years makes surveillance in Asia for resistance increasingly important, because many epidemic strains have been detected first in Asian countries [<xref ref-type="bibr" rid="R24">24</xref>].</p>
<p>All 5 resistant viruses isolated during the first year of our study were obtained from unrelated individual cases in Australia. The overall percentage of resistant viruses obtained from Australia (9 of 198 isolates collected over 6 years) was unexpected, because there is little use of amantadine or rimantadine for prophylaxis or treatment of influenza virus infections in Australia. All 9 resistant viruses had the amino acid change from serine to asparagine at position 31. To examine the possibility of laboratory contamination, we aligned the M2 nucleotide sequences of these 9 viruses with those of the control viruses and of the resistant reference strain A/Puerto Rico/8/34. There was sufficient nucleotide heterogeneity to conclude that these were 9 individual viruses, clearly distinguishable from each other and from any of the control viruses (data not shown). It cannot be excluded that the persons from whom these resistant viruses were isolated had contact with patients who used amantadine for neurologic indications. It is also possible that these viruses are naturally resistant viruses that circulated for a limited period. With the high mutation frequency of influenza virus genes, it seems probable that naturally resistant viruses could emerge and circulate in a population. It is not known whether viruses with the sensitive phenotype have a selective advantage over viruses with a resistant phenotype. However, it has been shown that resistant viruses could be transmitted through 6 successive generations of exposed chickens [<xref ref-type="bibr" rid="R25">25</xref>].</p>
<p>In conclusion, our data indicate that the isolation of amantadine- or rimantadine-resistant influenza viruses occurs infrequently. Our sample does not show any trend for an increased frequency of circulation of drug-resistant viruses over time. There appears to be no need, based on these data, to change existing recommendations for the use of amantadine and rimantadine [<xref ref-type="bibr" rid="R26">26</xref>, <xref ref-type="bibr" rid="R27">27</xref>]. The current surveillance program will be continued, and if appropriate, screening may be included for resistance to the neuraminidase inhibitors, a new class of anti-influenza drugs [<xref ref-type="bibr" rid="R28">28</xref>, <xref ref-type="bibr" rid="R29">29</xref>].</p>
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<title>Figures and Tables</title>
<fig id="T1" position="float">
<label>Table 1</label>
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<p>Geographic origin and year of isolation of the 2017 viruses tested for rimantadine susceptibility.</p>
</caption>
<graphic mimetype="image" xlink:href="180-4-935-tbl001.tif"></graphic>
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<p>Sixteen rimantadine-resistant influenza A isolates.</p>
</caption>
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<fn-group>
<fn fn-type="presented-at">
<p>Presented in part: 7th International Conference on Antiviral Research, Charleston, South Carolina, February–March 1994 (late-breaker abstract); 13th Annual Meeting of the American Society for Virology, Madison, Wisconsin, July 1994 (abstract W18-5).</p>
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</article></istex:document></istex:metadataXml><mods version="3.6"><titleInfo><title>Low Incidence of Rimantadine Resistance in Field Isolates of Influenza A Viruses</title></titleInfo><titleInfo type="alternative" contentType="CDATA"><title>Low Incidence of Rimantadine Resistance in Field Isolates of Influenza A Viruses</title></titleInfo><name type="personal"><namePart type="given">Thedi</namePart><namePart type="family">Ziegler</namePart><affiliation>Influenza Branch, Division of Viral and Rickettsial Diseases, National Center for Infectious Diseases, Centers for Disease Control and Prevention, Atlanta, Georgia</affiliation><description>a Present affiliations: Department of Medical Microbiology, University of Oulu, Finland (T.Z.); Department of Pediatrics, University of Turku, Finland (M.-L.Z.).</description><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Mark L.</namePart><namePart type="family">Hemphill</namePart><affiliation>Influenza Branch, Division of Viral and Rickettsial Diseases, National Center for Infectious Diseases, Centers for Disease Control and Prevention, Atlanta, Georgia</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal" displayLabel="corresp"><namePart type="given">Marja-Liisa</namePart><namePart type="family">Ziegler</namePart><affiliation>Influenza Branch, Division of Viral and Rickettsial Diseases, National Center for Infectious Diseases, Centers for Disease Control and Prevention, Atlanta, Georgia</affiliation><affiliation>E-mail: thedi.ziegler@oulu.fi</affiliation><affiliation>Reprints or correspondence: Dr. Thedi Ziegler, Dept. of Medical Microbiology, University of Oulu, P.O. Box 5000, FIN-90401 Oulu, Finland (thedi.ziegler@oulu.fi).</affiliation><description>a Present affiliations: Department of Medical Microbiology, University of Oulu, Finland (T.Z.); Department of Pediatrics, University of Turku, Finland (M.-L.Z.).</description><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Gilda</namePart><namePart type="family">Perez-Oronoz</namePart><affiliation>Influenza Branch, Division of Viral and Rickettsial Diseases, National Center for Infectious Diseases, Centers for Disease Control and Prevention, Atlanta, Georgia</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Alexander I.</namePart><namePart type="family">Klimov</namePart><affiliation>Influenza Branch, Division of Viral and Rickettsial Diseases, National Center for Infectious Diseases, Centers for Disease Control and Prevention, Atlanta, Georgia</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Alan W.</namePart><namePart type="family">Hampson</namePart><affiliation>WHO Influenza Center, CSL Ltd., Parkville, Victoria, Australia</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Helen L.</namePart><namePart type="family">Regnery</namePart><affiliation>Influenza Branch, Division of Viral and Rickettsial Diseases, National Center for Infectious Diseases, Centers for Disease Control and Prevention, Atlanta, Georgia</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Nancy J.</namePart><namePart type="family">Cox</namePart><affiliation>Influenza Branch, Division of Viral and Rickettsial Diseases, National Center for Infectious Diseases, Centers for Disease Control and Prevention, Atlanta, Georgia</affiliation><role><roleTerm type="text">author</roleTerm></role></name><typeOfResource>text</typeOfResource><genre type="research-article" displayLabel="research-article" authority="ISTEX" authorityURI="https://content-type.data.istex.fr" valueURI="https://content-type.data.istex.fr/ark:/67375/XTP-1JC4F85T-7">research-article</genre><originInfo><publisher>The University of Chicago Press</publisher><dateIssued encoding="w3cdtf">1999-10</dateIssued><copyrightDate encoding="w3cdtf">1999</copyrightDate></originInfo><abstract>The spread of drug-resistant influenza viruses type A to close contacts in families, schools, and nursing homes has been well documented. To investigate whether drug-resistant influenza viruses circulate in the general population, 2017 isolates collected in 43 countries and territories during a 4-year period were tested for drug susceptibility in a bioassay. Drug resistance was confirmed by detection of specific mutations on the M2 gene that have been shown to confer resistance to amantadine or rimantadine. Sixteen viruses (0.8%) were found to be drug-resistant. Only 2 of these resistant viruses were isolated from individuals who received amantadine or rimantadine treatment at the time the specimens were collected. For 12 individuals use of amantadine or rimantadine could be excluded, and from the remaining 2 patients information about medication was unavailable. These results indicate that the circulation of drug-resistant influenza viruses is a rare event, but surveillance for drug resistance should be continued.</abstract><note type="footnotes">Present affiliations: Department of Medical Microbiology, University of Oulu, Finland (T.Z.); Department of Pediatrics, University of Turku, Finland (M.-L.Z.).</note><relatedItem type="host"><titleInfo><title>The Journal of Infectious Diseases</title></titleInfo><titleInfo type="abbreviated"><title>The Journal of Infectious Diseases</title></titleInfo><genre type="journal" authority="ISTEX" authorityURI="https://publication-type.data.istex.fr" valueURI="https://publication-type.data.istex.fr/ark:/67375/JMC-0GLKJH51-B">journal</genre><identifier type="ISSN">0022-1899</identifier><identifier type="eISSN">1537-6613</identifier><identifier type="PublisherID">jid</identifier><identifier type="PublisherID-hwp">jinfdis</identifier><part><date>1999</date><detail type="volume"><caption>vol.</caption><number>180</number></detail><detail type="issue"><caption>no.</caption><number>4</number></detail><extent unit="pages"><start>935</start><end>939</end></extent></part></relatedItem><relatedItem type="references" displayLabel="R1"><titleInfo><title>A controlled trial of amantadine and rimantadine in the prophylaxis of influenza A infections</title></titleInfo><name type="personal"><namePart type="given">R</namePart><namePart type="family">Dolin</namePart></name><name type="personal"><namePart type="given">RC</namePart><namePart type="family">Reichman</namePart></name><name type="personal"><namePart type="given">HP</namePart><namePart type="family">Madore</namePart></name><name type="personal"><namePart type="given">R</namePart><namePart type="family">Maynard</namePart></name><name type="personal"><namePart type="given">PN</namePart><namePart type="family">Linton</namePart></name><name type="personal"><namePart type="given">J</namePart><namePart type="family">Webber-Jones</namePart></name><genre>journal</genre><note>DolinR ReichmanRC MadoreHP MaynardR LintonPN Webber-JonesJ A controlled trial of amantadine and rimantadine in the prophylaxis of influenza A infections N Engl J Med 1982 307 580 4</note><relatedItem type="host"><titleInfo><title>N Engl J Med</title></titleInfo><part><date>1982</date><detail type="volume"><caption>vol.</caption><number>307</number></detail><extent unit="pages"><start>580</start><end>4</end><list>580-4</list></extent></part></relatedItem></relatedItem><relatedItem type="references" displayLabel="R2"><titleInfo><title>Protective efficacy of low-dose amantadine in adults challenged with wild-type influenza A virus</title></titleInfo><name type="personal"><namePart type="given">SD</namePart><namePart type="family">Sears</namePart></name><name type="personal"><namePart type="given">ML</namePart><namePart type="family">Clements</namePart></name><genre>journal</genre><note>SearsSD ClementsML Protective 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