following the first report of 2009 pandemic influenza a ( h1n1 ; hereafter referred to h1n1 2009 ) in april 2009 , the infection became a pandemic .
the drugs of choice for the treatment and prophylaxis of h1n1 2009 are neuraminidase inhibitors including oseltamivir ( tamiflu [ roche ] ) and zanamivir ( relenza [ glaxosmithkline ] ) . however , increasing use of oseltamivir has led to the emergence of the oseltamivir - resistant h1n1 2009 virus , which harbors an h274/275y or i223v neuraminidase mutation . as of 9 february 2011 , 370 cases of oseltamivir - resistant h1n1 2009 infection had been reported to the world health organization.1 it has been suggested that oseltamivir - resistant seasonal influenza or h1n1 2009 harboring the h274/275y mutation is less virulent than are strains that are oseltamivir - sensitive.2 - 4 for this reason , fatal infections by these resistant viruses are rarely reported,5 - 7 although fatalities have occurred in severely immunocompromised patients with hematologic disorders or cancer with prolonged viral shedding despite oseltamivir therapy . some adult cases of oseltamivir - resistant h1n1 2009 have also been reported in korea ; however , these were not fatal despite the presence of prolonged viral shedding.8,9 here , we report a rapidly fatal case of oseltamivir - resistant h1n1 2009 in an adult patient in korea .
a 60-year - old male korean visited chonnam national university hospital because of chest pain and shortness of breath for 7 days . the patient had hypertension and
the patient had end - stage renal disease and had been receiving hemodialysis for 2 years .
the patient also had dilated cardiomyopathy ; his cardiac ejection fraction was 36% with global hypokinesia , and the end - diastolic and end - systolic diameters of the left ventricle were 65 mm and 54 mm , respectively , on echocardiography .
the patient began empiric therapy with oseltamivir ( 75 mg twice per day ) within 24 h of the development of symptoms , which was prescribed at a local clinic .
other examination findings were a blood pressure of 120/80 mmhg , pulse rate of 63 beats / min , respiratory rate of 20/min , and body temperature of 36. crackle was present in both lower lung fields on chest auscultation .
the initial laboratory examination revealed a white blood cell count of 15,400/mm , a hemoglobin level of 10.1 g / dl , and a platelet count of 141,000/mm .
his c - reactive protein level was 8.6 mg / dl . on initial arterial blood analysis , the values of ph , pao2 , paco2 , and bicarbonate ions were 7.365 , 49.0 mmhg , 33.3 mmhg , and 18.6 mmol / l , respectively .
cardiomegaly and pulmonary infiltration in the right lower , right middle , and left lower lobes were observed on chest radiography and computed tomography ( fig .
the acute physiology and chronic health evaluation ( apache ) ii score and pneumonia severity index of the patient upon presentation were 26 and 151 , respectively .
after blood and sputum sampling for respiratory virus analysis , reverse - transcriptase polymerase chain reaction ( rt - pcr ) and bacterial culture , empirical intravenous antibiotic therapy with ceftriaxone and clindamycin was initiated . on the second day of hospitalization ,
sputum rt - pcr for h1n1 2009 was performed on hospital days one and three . on the fourth day of hospitalization , sputum rt - pcr for h1n1 2009 from a specimen acquired on hospital day
the apache ii score and pneumonia severity index of the patient were aggravated to 37 and 191 , respectively .
the patient was isolated and began to receive a double dose of oseltamivir therapy ( 150 mg twice per day ) .
the initial antibiotics were changed to ceftriaxone and levofloxacin . despite administration of oseltamivir and antibiotics , mechanical ventilation , inotropics , and continuous renal replacement therapy , the patient 's pneumonia worsened and led to multi - organ failure .
the patient died on the sixth day of hospitalization , despite 3 days of antiviral therapy and 6 days of antibacterial therapy .
sequence analysis performed at the korea centers for disease control and prevention revealed an h275y neuraminidase gene mutation , as described elsewhere.10
we have presented the case of a 60-year - old korean male patient who was infected with oseltamivir - resistant h1n1 2009 , which proved lethal .
oseltamivir - resistant h1n1 2009 was first reported in september 2009 , and the number of cases has been steadily increasing , including in south korea.1,10 although the incidence of oseltamivir - resistant h1n1 2009 infections is increasing , fatal cases have been reported only rarely . in south korea ,
the present case shows some differences in clinical characteristics compared to previously reported fatal cases .
first , unlike our case , most fatal cases of oseltamivir - resistant virus infection have occurred in patients with severe immunosuppression associated with hematologic disorders or cancer.5 - 7 second , the clinical course of oseltamivir - resistant virus infection is usually insidious despite inappropriate antiviral therapy , because the virulence of oseltamivir - resistant influenza virus is thought to be lower than that of oseltamivir - sensitive viruses.8,9 animal studies have suggested that oseltamivir - resistant h1n1 2009 , as well as seasonal influenza , is less virulent and less transmissible than oseltamivir - sensitive viruses . in the present case , however , although the infection was caused by oseltamivir - resistant virus , pneumonia progressed rapidly and led to death .
this suggests that some clone of oseltamivir - resistant h1n1 2009 is sufficiently virulent to cause rapidly fatal pneumonia .
third , most cases of oseltamivir - resistant virus infections have occurred in patients who had undergone prolonged oseltamivir therapy.5 - 9 the present patient was treated short - term with oseltamivir before acquisition of oseltamivir resistance .
this highlights that oseltamivir resistance after short - term drug exposure is also possible , and that the use of zanamivir should be considered in patients with clinical deterioration , despite oseltamivir therapy .
 it has been suggested that oseltamivir - resistant influenza viruses harboring the h274/275y mutation are less virulent than are those that are oseltamivir - sensitive , and fatality attributed to infection with an oseltamivir - resistant virus is very rare . 
 here we report the first fatal adult case of oseltamivir - resistant 2009 pandemic influenza a ( h1n1 ) in korea . a 60-year - old korean male who had hypertension , diabetes mellitus , chronic kidney disease , and dilated cardiomyopathy visited chonnam national university hospital because of a 7-day history of chest pain and dyspnea . 
 the patient was at another clinic and had been medicated with oseltamivir ( 75 mg twice daily ) beginning 7 days before admission . 
 empirical antibiotics were started on the first day of hospitalization . 
 reverse - transcriptase polymerase chain reaction for 2009 pandemic influenza a ( h1n1 ) was reported to be positive , and a double dose of oseltamivir ( 150 mg twice per day ) was started on day four of hospitalization . however , the pneumonia worsened and the patient died , despite 3 days of high - dose antiviral therapy and 6 days of antibacterial therapy . 
 an h275y mutation was detected in the neuraminidase gene sequence . 
 this case shows that oseltamivir resistance after short - term drug exposure is possible and can be fatal , emphasizing that early use of zanamivir should be considered in suspicious cases . 
INTRODUCTION
CASE REPORT
DISCUSSION