title: Efficacy of Clarithromycin-Naproxen-Oseltamivir Combination in the Treatment of Patients Hospitalized for Influenza A(H3N2) Infection: An Open-label Randomized, Controlled, Phase IIb/III Trial.
abstract: Influenza causes excessive hospitalizations and deaths. The study assessed the efficacy and safety of a clarithromycin-naproxen-oseltamivir combination for treatment of serious influenza.
  
  
  
  From February to April 2015, we conducted a prospective open-label, randomized, controlled trial. Adult patients hospitalized for A(H3N2) influenza were randomly assigned to a 2-day combination of clarithromycin 500 mg, naproxen 200 mg, and oseltamivir 75 mg twice daily, followed by 3 days of oseltamivir or to oseltamivir 75 mg twice daily without placebo for 5 days as a control method (1:1). The primary end point was 30-day mortality. The secondary end points were 90-day mortality, serial nasopharyngeal aspirate (NPA) virus titer, percentage of neuraminidase-inhibitor-resistant A(H3N2) virus (NIRV) quasispecies, pneumonia severity index (PSI), and duration of hospital stay.
  
  
  
  Among the 217 patients with influenza A(H3N2) enrolled, 107 were randomly assigned to the combination treatment. The median age was 80 years, and 53.5% were men. Adverse events were uncommon. Ten patients died during the 30-day follow-up. The combination treatment was associated with lower 30-day mortality (P = .01), less frequent high dependency unit admission (P = .009), and shorter hospital stay (P < .0001). The virus titer and PSI (days 1-3; P < .01) and the NPA specimens with NIRV quasispecies ≥ 5% (days 1-2; P < .01) were significantly lower in the combination treatment group. Multivariate analysis showed that combination treatment was the only independent factor associated with lower 30-day mortality (OR, 0.06; 95% CI, 0.004-0.94; P = .04).
  
  
  
  Combination treatment reduced both 30- and 90-day mortality and length of hospital stay. Further study of the antiviral and immunomodulatory effects of this combination treatment of severe influenza is warranted.
  
  
  
  BioMed Central; No.: ISRCTN11273879 DOI 10.1186/ISRCTN11273879; URL: www.isrctn.com/ISRCTN11273879.
authors.affiliation: Carol Yu Centre for Infection and Division of Infectious Diseases, State Key Laboratory of Emerging Infectious Diseases, Department of Microbiology, the University of Hong Kong, Queen Mary Hospital, Hong Kong Special Administrative Region, China; Department of Medicine, the University of Hong Kong, Queen Mary Hospital, Hong Kong Special Administrative Region, China.
authors.forename: Ivan F N
authors.initials: IFN
authors.lastname: Hung
authors.affiliation: Carol Yu Centre for Infection and Division of Infectious Diseases, State Key Laboratory of Emerging Infectious Diseases, Department of Microbiology, the University of Hong Kong, Queen Mary Hospital, Hong Kong Special Administrative Region, China.
authors.forename: Kelvin K W
authors.initials: KKW
authors.lastname: To
authors.affiliation: Carol Yu Centre for Infection and Division of Infectious Diseases, State Key Laboratory of Emerging Infectious Diseases, Department of Microbiology, the University of Hong Kong, Queen Mary Hospital, Hong Kong Special Administrative Region, China.
authors.forename: Jasper F W
authors.initials: JFW
authors.lastname: Chan
authors.affiliation: Carol Yu Centre for Infection and Division of Infectious Diseases, State Key Laboratory of Emerging Infectious Diseases, Department of Microbiology, the University of Hong Kong, Queen Mary Hospital, Hong Kong Special Administrative Region, China.
authors.forename: Vincent C C
authors.initials: VCC
authors.lastname: Cheng
authors.affiliation: Department of Medicine, the University of Hong Kong, Queen Mary Hospital, Hong Kong Special Administrative Region, China.
authors.forename: Kevin S H
authors.initials: KSH
authors.lastname: Liu
authors.affiliation: Department of Medicine, the University of Hong Kong, Queen Mary Hospital, Hong Kong Special Administrative Region, China.
authors.forename: Anthony
authors.initials: A
authors.lastname: Tam
authors.affiliation: Department of Medicine, the University of Hong Kong, Queen Mary Hospital, Hong Kong Special Administrative Region, China.
authors.forename: Tuen-Ching
authors.initials: TC
authors.lastname: Chan
authors.affiliation: Carol Yu Centre for Infection and Division of Infectious Diseases, State Key Laboratory of Emerging Infectious Diseases, Department of Microbiology, the University of Hong Kong, Queen Mary Hospital, Hong Kong Special Administrative Region, China.
authors.forename: Anna Jinxia
authors.initials: AJ
authors.lastname: Zhang
authors.affiliation: Carol Yu Centre for Infection and Division of Infectious Diseases, State Key Laboratory of Emerging Infectious Diseases, Department of Microbiology, the University of Hong Kong, Queen Mary Hospital, Hong Kong Special Administrative Region, China.
authors.forename: Patrick
authors.initials: P
authors.lastname: Li
authors.affiliation: Carol Yu Centre for Infection and Division of Infectious Diseases, State Key Laboratory of Emerging Infectious Diseases, Department of Microbiology, the University of Hong Kong, Queen Mary Hospital, Hong Kong Special Administrative Region, China.
authors.forename: Tin-Lun
authors.initials: TL
authors.lastname: Wong
authors.affiliation: Department of Medicine, the University of Hong Kong, Queen Mary Hospital, Hong Kong Special Administrative Region, China.
authors.forename: Ricky
authors.initials: R
authors.lastname: Zhang
authors.affiliation: Department of Medicine, the University of Hong Kong, Queen Mary Hospital, Hong Kong Special Administrative Region, China.
authors.forename: Michael K S
authors.initials: MKS
authors.lastname: Cheung
authors.affiliation: LKS Faculty of Medicine, the University of Hong Kong, Queen Mary Hospital, Hong Kong Special Administrative Region, China.
authors.forename: William
authors.initials: W
authors.lastname: Leung
authors.affiliation: Carol Yu Centre for Infection and Division of Infectious Diseases, State Key Laboratory of Emerging Infectious Diseases, Department of Microbiology, the University of Hong Kong, Queen Mary Hospital, Hong Kong Special Administrative Region, China.
authors.forename: Johnson Y N
authors.initials: JYN
authors.lastname: Lau
authors.affiliation: Carol Yu Centre for Infection and Division of Infectious Diseases, State Key Laboratory of Emerging Infectious Diseases, Department of Microbiology, the University of Hong Kong, Queen Mary Hospital, Hong Kong Special Administrative Region, China.
authors.forename: Manson
authors.initials: M
authors.lastname: Fok
authors.affiliation: Carol Yu Centre for Infection and Division of Infectious Diseases, State Key Laboratory of Emerging Infectious Diseases, Department of Microbiology, the University of Hong Kong, Queen Mary Hospital, Hong Kong Special Administrative Region, China; Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, Zhejiang University, Hangzhou, China.
authors.forename: Honglin
authors.initials: H
authors.lastname: Chen
authors.affiliation: Carol Yu Centre for Infection and Division of Infectious Diseases, State Key Laboratory of Emerging Infectious Diseases, Department of Microbiology, the University of Hong Kong, Queen Mary Hospital, Hong Kong Special Administrative Region, China.
authors.forename: Kwok-Hung
authors.initials: KH
authors.lastname: Chan
authors.affiliation: Carol Yu Centre for Infection and Division of Infectious Diseases, State Key Laboratory of Emerging Infectious Diseases, Department of Microbiology, the University of Hong Kong, Queen Mary Hospital, Hong Kong Special Administrative Region, China; Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, Zhejiang University, Hangzhou, China. Electronic address: kyyuen@hku.hk.
authors.forename: Kwok-Yung
authors.initials: KY
authors.lastname: Yuen
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D000900:Anti-Bacterial Agents / Q000627:therapeutic use*; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000627:therapeutic use*; D000998:Antiviral Agents / Q000627:therapeutic use*; D017291:Clarithromycin / Q000627:therapeutic use*; D024882:Drug Resistance, Viral; D004359:Drug Therapy, Combination; D005260:Female; D006760:Hospitalization; D006801:Humans; D053122:Influenza A Virus, H3N2 Subtype; D007251:Influenza, Human / Q000188:drug therapy* / Q000276:immunology; D007902:Length of Stay; D008297:Male; D009026:Mortality; D009288:Naproxen / Q000627:therapeutic use*; D009305:Nasopharynx / Q000821:virology; D053139:Oseltamivir / Q000627:therapeutic use*; D012720:Severity of Illness Index; D016896:Treatment Outcome; D019562:Viral Load
chemical_list: D000900:Anti-Bacterial Agents; D000894:Anti-Inflammatory Agents, Non-Steroidal; D000998:Antiviral Agents; D053139:Oseltamivir; D009288:Naproxen; D017291:Clarithromycin
keywords: A(H3N2); clarithromycin; hospitalized; naproxen; oseltamivir