from the first reported infected patient in may 2009 through january 2010 , a total of 740,835 patients in south korea were reported as having pandemic ( h1n1 ) 2009 virus infection .
a total of 225 patients ( 0.03% ) died of disease related to pandemic ( h1n1 ) 2009 . during this period ,
physicians in local clinics and tertiary hospitals sent specimens from 67 patients who were suspected of having drug - resistant pandemic ( h1n1 ) 2009 to the korea centers for disease control ; 11 patients ( 16% ) had drug - resistant virus ( figure ) .
after confirmation of drug resistance , epidemic intelligence service officers obtained clinical and epidemiologic data by medical record review and interviews with household contacts and attending physicians for all patients .
clinical course and outcome of 11 patients with oseltamivir - resistant pandemic ( h1n1 ) 2009 , south korea .
symptom aggravation was defined as influenza - related symptoms that worsened regardless of new infiltrations seen by chest radiography .
symptom improvement was defined as influenza - related symptoms ( nasal stiffness , sore throat , cough , myalgia , fatigue , headache , and fever ) that were absent or mild .
ed , emergency department . to investigate whether virus contained genetic markers associated with resistance to antiviral drugs , a conventional genotyping assay ( sequencing ) was performed , and neuraminidase ( na ) and matrix 2 genes were sequenced .
all 11 patients had virus with a histidine - to - tyrosine mutation at residue 275 of the na protein ( h275y ) ; 1 patient also had virus with an i117 m mutation ( figure ) .
detailed molecular epidemiologic data and genetic characteristics of the isolates are described elsewhere ( 2 ) . of the 11 patients ,
6 were < 59 months of age and 5 had underlying immunosuppressive conditions ; only 1 patient was immunocompetent and > 59 months of age ( table ) . three patients from whom samples before and after treatment with oseltamivir were available showed evidence of having acquired the h275y mutation during oseltamivir therapy .
none of the 11 patients received oseltamivir chemoprophylaxis . * specimens were obtained from oropharyngeal ( n = 7 ) and nasopharyngeal ( n = 2 ) swabs , nasopharyngeal washings ( n = 1 ) , and brochoalveolar lavage fluid ( n = 1 ) . 
patients who had underlying diseases such as hiv infection , malignancy , liver cirrhosis , or chronic renal failure , or patients receiving immunosuppressive treatment . 
 carbapenem - resistant pseudomonas aeruginosa ( patient 3 ) , carbapenem - resistant acinetobacter 
 baumanii ( patient 4 ) , and penicillin - susceptible streptococcus pneumonia ( patient 10 ) .  of the 3 patients , 1 was infected with carbapenem - resistant p. aeruginosa ( patient 3 ) and 1 was infected with carbapenem - resistant a. baumanii ( patient 4 ) .
we also tested 100 persons who had contact with the 11 patients for possible transmission of drug resistance .
eight of 100 were confirmed as having been infected with pandemic ( h1n1 ) 2009 virus before the 11 patients were infected .
influenza - like illnesses developed in the 11 patients a median of 2 days ( range 17 days ) after the 8 contact persons were confirmed as having pandemic ( h1n1 ) 2009 .
five of the 8 contact patients were children ; none had an immunosuppressive condition or were given oseltamivir chemoprophylaxis before illness ; and 7 of 8 were < 59 months of age .
oseltamivir - resistance tests were not performed for these 8 patients because they all received oseltamivir therapy and their clinical symptoms resolved .
therefore , the possibility of transmitted resistance from contact patients was not demonstrated in this study .
all 11 patients were initially given the usual dose of oseltamivir ( 75 mg 2/day in adults ) .
after detection of oseltamivir resistance , treatment regimens were as follows : 3 patients were given high - dose oseltamivir ( 150 mg 2/day in adults ) , 3 patients were given combination therapy ( oseltamivir and amantadine ; oseltamivir and peramivir ; and oseltamivir , amantadine , and ribavirin , respectively ) ; 3 patients were given zanamivir nasally ; and 2 patients continued to receive oseltamivir .
seven of the 11 patients had complications during treatment : 6 had viral or secondary bacterial pneumonia and 1 had acute respiratory distress syndrome ( table ) .
patient 3 died 15 days after confirmation of infection with pandemic ( h1n1 ) 2009 virus and 10 days after the emergence of oseltamivir - resistant virus .
patient 4 died 15 days after confirmation of infection and 4 days after emergence of oseltamivir - resistant virus .
patient 8 , who was infected with virus that had h275y and i117 m mutations , died 18 days after confirmation of infection and 4 days after the emergence of oseltamivir - resistant virus .
our nationwide surveillance of drug - resistant pandemic ( h1n1 ) 2009 in south korea indicated that most patients were children ( < 59 months of age ) or immunocompromised .
all isolates had the h275y mutation in the na protein , and 1 isolate also had the i117 m mutation in the same protein .
our finding that oseltamivir resistance developed in immunocompromised patients is consistent with those of recent case reports that described development of oseltamivir resistance in immunosuppressed patients receiving this drug ( 3,4 ) .
a recent study in australia reported that 4 of 32 adult oncology and hematology patients were infected with oseltamivir - resistant virus with the h275y mutation ( 5 ) . in 3 of our patients ( patients 3 , 5 , and 11 ) drug - resistant
thus , we suggest that physicians be alert to emergence of oseltamivir - resistant pandemic ( h1n1 ) 2009 , particularly if there is treatment failure with oseltamivir or prolonged viral shedding is evident . more than half of our patients were < 59 months of age , indicating that a younger age may be a risk factor for infection with drug - resistant pandemic ( h1n1 ) 2009 .
clinical trials have reported oseltamivir resistance in < 5.5% of children with seasonal influenza ( 6 ) .
explanations for the higher rate of drug resistance in children than in adults are that children have a more protracted course of influenza , longer viral shedding times , and higher viral titers ( 7 ) .
another explanation might be that we can not rule out suboptimal dosing of oseltmaivir in children , although world health organization dose standards were used ( 8) and all pharmacies were given instructions on emergency compounding of oseltmaivir .
availability of pretreatment and posttreatment samples indicated that resistance to oseltamivir developed during treatment in > 3 patients .
one case report ( 9 ) , 1 report of a cluster of cases in vietnam ( 10 ) , and 1 outbreak in a hematologic ward ( 11 ) documented patient - to - patient transmission of oseltamivir - resistant virus .
one of our patients was infected with virus that had a novel na mutation ( i117 m ) .
a previous study indicated that the i117v mutation in avian influenza virus ( h5n1 ) was associated with low - level oseltamivir resistance ( 12 ) .
the i117 m mutation of na may contribute to oseltamivir resistance , but it is not clear whether isolates with these 2 na mutations have higher levels of resistance or virulence than the h275y na mutant .
we found few patients with drug - resistant pandemic ( h1n1 ) 2009 in south korea .
however , our study was based on the nationwide surveillance system for drug resistance among patients with suspected oseltamivir treatment failures , which is different from other surveillance systems , in which all isolated viruses are tested .
thus , we can not report the prevalence of drug - resistant pandemic ( h1n1 ) 2009 and risk factors for drug - resistant virus infection in south korea .
further studies are needed to monitor oseltamivir resistance , especially in immunosuppressed or pediatric patients when treatment failure with oseltamivir or prolonged viral shedding occur .
 eleven patients with drug - resistant pandemic ( h1n1 ) 2009 were identified in south korea during may 2009january 2010 . 
 virus isolates from all patients had the h275y mutation in the neuraminidase gene . 
 one isolate had the i117 m mutation . 
 of the 11 patients , 6 were < 59 months of age , and 5 had underlying immunosuppressive conditions . 