title: Efficacy of combination therapy with oseltamivir phosphate and azithromycin for influenza: a multicenter, open-label, randomized study.
abstract: BACKGROUND
  Macrolides have antibiotic and immunomodulatory activities, which may have a favorable effect on the clinical outcome of patients with infections, including influenza. This study aimed to evaluate the effects of combination therapy with an anti-influenza agent, oseltamivir, and a single-dose formulation of azithromycin (AZM), which has been used for influenza-related secondary pneumonia, on influenza patients. The primary endpoint was a change in the expression levels of inflammatory cytokines. Secondary endpoints were the time required for resolution of influenza-related symptoms, incidence of complications, and adverse reactions.
  
  
  METHODS
  Patients with seasonal influenza were enrolled in this multicenter, open-label, randomized study. Patients were stratified according to the presence of a high risk factor and were randomized to receive combination therapy with oseltamivir plus an extended-release formulation of AZM (combo-group) or oseltamivir monotherapy (mono-group).
  
  
  RESULTS
  We enrolled 107 patients and randomized them into the mono-group (56 patients) or the combo-group (51 patients). All patients were diagnosed with influenza A infection, and none of the patients had comorbid pneumonia. Statistically significant differences were not observed in the expression levels of inflammatory cytokines and chemokines between the 2 groups. The maximum temperature in the combo-group was lower than that in the mono-group on day 3 through day 5 (p = 0.048), particularly on day 4 (p = 0.037).
  
  
  CONCLUSIONS
  To our knowledge, this is the first prospective, randomized, clinical trial of oseltamivir and AZM combination therapy for influenza. Although the difference in inflammatory cytokine expression level was not statistically significant, combination therapy showed an early resolution of some symptoms.
  University hospital Medical Information Network (UMIN).
  
  
  BACKGROUND
  UMIN000005371.
authors.affiliation: Department of Infection Control Science, Graduate School of Medicine, Osaka City University, Osaka, Japan; Department of Molecular Microbiology and Immunology, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki, Japan.
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Kakeya
authors.affiliation: Divison of Infection and Control and Prevention, Osaka University Hospital, Osaka, Japan.
authors.forename: Masafumi
authors.initials: M
authors.lastname: Seki
authors.affiliation: Department of Molecular Microbiology and Immunology, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki, Japan; Nagasaki University Infection Control and Education Center, Nagasaki University Hospital, Nagasaki, Japan.
authors.forename: Koichi
authors.initials: K
authors.lastname: Izumikawa
authors.affiliation: Nagasaki University Infection Control and Education Center, Nagasaki University Hospital, Nagasaki, Japan.
authors.forename: Kosuke
authors.initials: K
authors.lastname: Kosai
authors.affiliation: Department of Laboratory Medicine, Nagasaki University Hospital, Nagasaki, Japan.
authors.forename: Yoshitomo
authors.initials: Y
authors.lastname: Morinaga
authors.affiliation: Nagasaki University Infection Control and Education Center, Nagasaki University Hospital, Nagasaki, Japan.
authors.forename: Shintaro
authors.initials: S
authors.lastname: Kurihara
authors.affiliation: Department of Molecular Microbiology and Immunology, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki, Japan.
authors.forename: Shigeki
authors.initials: S
authors.lastname: Nakamura
authors.affiliation: Department of Molecular Microbiology and Immunology, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki, Japan.
authors.forename: Yoshifumi
authors.initials: Y
authors.lastname: Imamura
authors.affiliation: Department of Molecular Microbiology and Immunology, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki, Japan.
authors.forename: Taiga
authors.initials: T
authors.lastname: Miyazaki
authors.affiliation: Nagasaki University Infection Control and Education Center, Nagasaki University Hospital, Nagasaki, Japan.
authors.forename: Misuzu
authors.initials: M
authors.lastname: Tsukamoto
authors.affiliation: Department of Laboratory Medicine, Nagasaki University Hospital, Nagasaki, Japan.
authors.forename: Katsunori
authors.initials: K
authors.lastname: Yanagihara
authors.affiliation: Department of Health Sciences, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki, Japan.
authors.forename: Takayoshi
authors.initials: T
authors.lastname: Tashiro
authors.affiliation: Department of Molecular Microbiology and Immunology, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki, Japan.
authors.forename: Shigeru
authors.initials: S
authors.lastname: Kohno
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000998:Antiviral Agents / Q000009:adverse effects / Q000627:therapeutic use*; D017963:Azithromycin / Q000009:adverse effects / Q000627:therapeutic use*; D016207:Cytokines / Q000378:metabolism; D004359:Drug Therapy, Combination; D005260:Female; D006801:Humans; D018836:Inflammation Mediators / Q000378:metabolism; D007251:Influenza, Human / Q000175:diagnosis / Q000188:drug therapy*; D008297:Male; D008875:Middle Aged; D053139:Oseltamivir / Q000627:therapeutic use*; D016896:Treatment Outcome; D055815:Young Adult
chemical_list: D000998:Antiviral Agents; D016207:Cytokines; D018836:Inflammation Mediators; D053139:Oseltamivir; D017963:Azithromycin