• Hiroshi Kakeya, Masafumi Seki, Koichi Izumikawa, Kosuke Kosai, Yoshitomo Morinaga, Shintaro Kurihara, Shigeki Nakamura, Yoshifumi Imamura, Taiga Miyazaki, Misuzu Tsukamoto, Katsunori Yanagihara, Takayoshi Tashiro, and Shigeru Kohno.
• 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.
• Plos One. 2014 Jan 1; 9 (3): e91293.

BackgroundMacrolides 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.MethodsPatients 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).ResultsWe 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).ConclusionTo 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.Name Of RegistryUniversity hospital Medical Information Network (UMIN).Trial Registration NoUMIN000005371.

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