title: Prospective surveillance of antiviral resistance in hospitalized infants less than 12 months of age with A(H3N2) influenza infection and treated with oseltamivir.
abstract: BACKGROUND
  Infants exhibit elevated influenza virus loads and prolonged viral shedding, which may increase the risk for resistance development, especially in cases of suboptimal exposure to antiviral therapy.
  
  
  METHODS
  We performed a prospective surveillance of hospitalized infants undergoing oseltamivir therapy during the 2008-2009 and 2011-2012 influenza seasons at two paediatric hospitals in Germany. A total of 37 infants less than 1 year of age with laboratory confirmed influenza A(H3N2) infection received oseltamivir as per physician's order for 5 days (2008-2009 season: 2 mg/kg twice daily; 2011-2012 season: 2.0 mg/kg; 2.5 mg/kg and 3.0 mg/kg twice daily for infants <1 month; 2-3 months and 4-12 months, respectively). Virus load, the susceptibility to neuraminidase inhibitors (NAIs), and the presence of molecular markers of resistance to NAIs was assessed for influenza viruses recovered from respiratory samples collected at baseline and during follow-up visits.
  
  
  RESULTS
  Overall, 73% of the infants continued to shed viral RNA detectable by reverse transcription (RT)-PCR after dose number 10 of oseltamivir; 12 infants shed viruses, 2 of them (both 9 months of age) shed resistant viruses. Resistance was characterized by ≥1,000-fold increase of 50% inhibitory concentration (IC50) for oseltamivir, up to 50-fold for zanamivir and elevated Km values when compared to susceptible A(H3N2) strains. Sanger sequencing revealed the selection of the NA-R292K substitution in both instances (after dose number 10 on day 6).
  
  
  CONCLUSIONS
  Our data suggest that it may be relevant to monitor antiviral resistance systematically in all infants, considering that the European Medicines Agency has recently extended the licensure for oseltamivir to include full-term infants.
authors.affiliation: Charité University Medical Center, Department of Pediatrics, Berlin, Germany.|Vienna Vaccine Safety Initiative, Berlin, Germany.
authors.forename: Barbara
authors.initials: B
authors.lastname: Rath
authors.affiliation: Charité University Medical Center, Department of Pediatrics, Berlin, Germany.
authors.forename: Xi
authors.initials: X
authors.lastname: Chen
authors.affiliation: Klinikum Worms, Department of Pediatrics and Adolescent Medicine, Worms, Germany.
authors.forename: Vera
authors.initials: V
authors.lastname: Spies
authors.affiliation: Charité University Medical Center, Department of Pediatrics, Berlin, Germany.
authors.forename: Susann
authors.initials: S
authors.lastname: Muehlhans
authors.affiliation: Charité University Medical Center, Department of Pediatrics, Berlin, Germany.
authors.forename: Patrick
authors.initials: P
authors.lastname: Obermeier
authors.affiliation: Charité University Medical Center, Department of Pediatrics, Berlin, Germany.
authors.forename: Franziska
authors.initials: F
authors.lastname: Tief
authors.affiliation: Charité University Medical Center, Department of Pediatrics, Berlin, Germany.
authors.forename: Lea
authors.initials: L
authors.lastname: Seeber
authors.affiliation: Charité University Medical Center, Department of Pediatrics, Berlin, Germany.
authors.forename: Katharina
authors.initials: K
authors.lastname: Karsch
authors.affiliation: Robert Koch Institute, Division of Influenza Viruses and Other Respiratory Viruses, National Reference Centre for Influenza, Berlin, Germany.
authors.forename: Jeanette
authors.initials: J
authors.lastname: Milde
authors.affiliation: Klinikum Worms, Department of Pediatrics and Adolescent Medicine, Worms, Germany.
authors.forename: Heino
authors.initials: H
authors.lastname: Skopnik
authors.affiliation: Robert Koch Institute, Division of Influenza Viruses and Other Respiratory Viruses, National Reference Centre for Influenza, Berlin, Germany.
authors.forename: Brunhilde
authors.initials: B
authors.lastname: Schweiger
authors.affiliation: Robert Koch Institute, Division of Influenza Viruses and Other Respiratory Viruses, National Reference Centre for Influenza, Berlin, Germany.
authors.forename: Susanne C
authors.initials: SC
authors.lastname: Duwe
mesh_terms: D000998:Antiviral Agents / Q000627:therapeutic use; D024882:Drug Resistance, Viral; D004791:Enzyme Inhibitors / Q000627:therapeutic use; D005260:Female; D006760:Hospitalization; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D053122:Influenza A Virus, H3N2 Subtype / Q000187:drug effects* / Q000235:genetics; D007251:Influenza, Human / Q000175:diagnosis / Q000188:drug therapy* / Q000453:epidemiology / Q000821:virology*; D008297:Male; D008826:Microbial Sensitivity Tests; D009439:Neuraminidase / Q000037:antagonists & inhibitors; D053139:Oseltamivir / Q000494:pharmacology* / Q000627:therapeutic use*; D062486:Public Health Surveillance; D012367:RNA, Viral; D019562:Viral Load
chemical_list: D000998:Antiviral Agents; D004791:Enzyme Inhibitors; D012367:RNA, Viral; D053139:Oseltamivir; D009439:Neuraminidase