title: Premedication with Clarithromycin Is Effective against Secondary Bacterial Pneumonia during Influenza Virus Infection in a Pulmonary Emphysema Mouse Model.
abstract: Secondary bacterial pneumonia (SBP) during influenza increases the severity of chronic obstructive pulmonary disease (COPD) and its associated mortality. Macrolide antibiotics, including clarithromycin (CAM), are potential treatments for a variety of chronic respiratory diseases owing to their pharmacological activities, in addition to antimicrobial action. We examined the efficacy of CAM for the treatment of SBP after influenza infection in COPD. Specifically, we evaluated the effect of CAM in elastase-induced emphysema mice that were inoculated with influenza virus (strain A/PR8/34) and subsequently infected with macrolide-resistant Streptococcus pneumoniae CAM was administered to the emphysema mice 4 days prior to influenza virus inoculation. Premedication with CAM improved pathologic responses and bacterial load 2 days after S. pneumoniae inoculation. Survival rates were higher in emphysema mice than control mice. While CAM premedication did not affect viral titers or exert antibacterial activity against S. pneumoniae in the lungs, it enhanced host defense and reduced inflammation, as evidenced by the significant reductions in total cell and neutrophil counts and interferon (IFN)-γ levels in bronchoalveolar lavage fluid and lung homogenates. These results suggest that CAM protects against SBP during influenza in elastase-induced emphysema mice by reducing IFN-γ production, thus enhancing immunity to SBP, and by decreasing neutrophil infiltration into the lung to prevent injury. Accordingly, CAM may be an effective strategy to prevent secondary bacterial pneumonia in COPD patients in areas in which vaccines are inaccessible or limited.
authors.affiliation: Department of Infectious Diseases, Unit of Molecular Microbiology and Immunology (T.H., K.I.), Department of Cardiopulmonary Rehabilitation Sciences (Y.I.), Department of Respiratory Medicine (N.S., H.M.), and Department of Laboratory Medicine (K.K, K.Y.), Nagasaki University Graduate School of Biomedical Sciences, Nagasaki, Japan; Second Department of Internal Medicine, Nagasaki University School of Medicine, Nagasaki, Japan (T.H., A.H., T.M., S.N., T.K., N.S., H.M., S.K.).
authors.forename: Tatsuhiko
authors.initials: T
authors.lastname: Harada
authors.affiliation: Department of Infectious Diseases, Unit of Molecular Microbiology and Immunology (T.H., K.I.), Department of Cardiopulmonary Rehabilitation Sciences (Y.I.), Department of Respiratory Medicine (N.S., H.M.), and Department of Laboratory Medicine (K.K, K.Y.), Nagasaki University Graduate School of Biomedical Sciences, Nagasaki, Japan; Second Department of Internal Medicine, Nagasaki University School of Medicine, Nagasaki, Japan (T.H., A.H., T.M., S.N., T.K., N.S., H.M., S.K.) yuji-i@nagasaki-u.ac.jp.
authors.forename: Yuji
authors.initials: Y
authors.lastname: Ishimatsu
authors.affiliation: Department of Infectious Diseases, Unit of Molecular Microbiology and Immunology (T.H., K.I.), Department of Cardiopulmonary Rehabilitation Sciences (Y.I.), Department of Respiratory Medicine (N.S., H.M.), and Department of Laboratory Medicine (K.K, K.Y.), Nagasaki University Graduate School of Biomedical Sciences, Nagasaki, Japan; Second Department of Internal Medicine, Nagasaki University School of Medicine, Nagasaki, Japan (T.H., A.H., T.M., S.N., T.K., N.S., H.M., S.K.).
authors.forename: Atsuko
authors.initials: A
authors.lastname: Hara
authors.affiliation: Department of Infectious Diseases, Unit of Molecular Microbiology and Immunology (T.H., K.I.), Department of Cardiopulmonary Rehabilitation Sciences (Y.I.), Department of Respiratory Medicine (N.S., H.M.), and Department of Laboratory Medicine (K.K, K.Y.), Nagasaki University Graduate School of Biomedical Sciences, Nagasaki, Japan; Second Department of Internal Medicine, Nagasaki University School of Medicine, Nagasaki, Japan (T.H., A.H., T.M., S.N., T.K., N.S., H.M., S.K.).
authors.forename: Towako
authors.initials: T
authors.lastname: Morita
authors.affiliation: Department of Infectious Diseases, Unit of Molecular Microbiology and Immunology (T.H., K.I.), Department of Cardiopulmonary Rehabilitation Sciences (Y.I.), Department of Respiratory Medicine (N.S., H.M.), and Department of Laboratory Medicine (K.K, K.Y.), Nagasaki University Graduate School of Biomedical Sciences, Nagasaki, Japan; Second Department of Internal Medicine, Nagasaki University School of Medicine, Nagasaki, Japan (T.H., A.H., T.M., S.N., T.K., N.S., H.M., S.K.).
authors.forename: Shota
authors.initials: S
authors.lastname: Nakashima
authors.affiliation: Department of Infectious Diseases, Unit of Molecular Microbiology and Immunology (T.H., K.I.), Department of Cardiopulmonary Rehabilitation Sciences (Y.I.), Department of Respiratory Medicine (N.S., H.M.), and Department of Laboratory Medicine (K.K, K.Y.), Nagasaki University Graduate School of Biomedical Sciences, Nagasaki, Japan; Second Department of Internal Medicine, Nagasaki University School of Medicine, Nagasaki, Japan (T.H., A.H., T.M., S.N., T.K., N.S., H.M., S.K.).
authors.forename: Tomoyuki
authors.initials: T
authors.lastname: Kakugawa
authors.affiliation: Department of Infectious Diseases, Unit of Molecular Microbiology and Immunology (T.H., K.I.), Department of Cardiopulmonary Rehabilitation Sciences (Y.I.), Department of Respiratory Medicine (N.S., H.M.), and Department of Laboratory Medicine (K.K, K.Y.), Nagasaki University Graduate School of Biomedical Sciences, Nagasaki, Japan; Second Department of Internal Medicine, Nagasaki University School of Medicine, Nagasaki, Japan (T.H., A.H., T.M., S.N., T.K., N.S., H.M., S.K.).
authors.forename: Noriho
authors.initials: N
authors.lastname: Sakamoto
authors.affiliation: Department of Infectious Diseases, Unit of Molecular Microbiology and Immunology (T.H., K.I.), Department of Cardiopulmonary Rehabilitation Sciences (Y.I.), Department of Respiratory Medicine (N.S., H.M.), and Department of Laboratory Medicine (K.K, K.Y.), Nagasaki University Graduate School of Biomedical Sciences, Nagasaki, Japan; Second Department of Internal Medicine, Nagasaki University School of Medicine, Nagasaki, Japan (T.H., A.H., T.M., S.N., T.K., N.S., H.M., S.K.).
authors.forename: Kosuke
authors.initials: K
authors.lastname: Kosai
authors.affiliation: Department of Infectious Diseases, Unit of Molecular Microbiology and Immunology (T.H., K.I.), Department of Cardiopulmonary Rehabilitation Sciences (Y.I.), Department of Respiratory Medicine (N.S., H.M.), and Department of Laboratory Medicine (K.K, K.Y.), Nagasaki University Graduate School of Biomedical Sciences, Nagasaki, Japan; Second Department of Internal Medicine, Nagasaki University School of Medicine, Nagasaki, Japan (T.H., A.H., T.M., S.N., T.K., N.S., H.M., S.K.).
authors.forename: Koichi
authors.initials: K
authors.lastname: Izumikawa
authors.affiliation: Department of Infectious Diseases, Unit of Molecular Microbiology and Immunology (T.H., K.I.), Department of Cardiopulmonary Rehabilitation Sciences (Y.I.), Department of Respiratory Medicine (N.S., H.M.), and Department of Laboratory Medicine (K.K, K.Y.), Nagasaki University Graduate School of Biomedical Sciences, Nagasaki, Japan; Second Department of Internal Medicine, Nagasaki University School of Medicine, Nagasaki, Japan (T.H., A.H., T.M., S.N., T.K., N.S., H.M., S.K.).
authors.forename: Katsunori
authors.initials: K
authors.lastname: Yanagihara
authors.affiliation: Department of Infectious Diseases, Unit of Molecular Microbiology and Immunology (T.H., K.I.), Department of Cardiopulmonary Rehabilitation Sciences (Y.I.), Department of Respiratory Medicine (N.S., H.M.), and Department of Laboratory Medicine (K.K, K.Y.), Nagasaki University Graduate School of Biomedical Sciences, Nagasaki, Japan; Second Department of Internal Medicine, Nagasaki University School of Medicine, Nagasaki, Japan (T.H., A.H., T.M., S.N., T.K., N.S., H.M., S.K.).
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Mukae
authors.affiliation: Department of Infectious Diseases, Unit of Molecular Microbiology and Immunology (T.H., K.I.), Department of Cardiopulmonary Rehabilitation Sciences (Y.I.), Department of Respiratory Medicine (N.S., H.M.), and Department of Laboratory Medicine (K.K, K.Y.), Nagasaki University Graduate School of Biomedical Sciences, Nagasaki, Japan; Second Department of Internal Medicine, Nagasaki University School of Medicine, Nagasaki, Japan (T.H., A.H., T.M., S.N., T.K., N.S., H.M., S.K.).
authors.forename: Shigeru
authors.initials: S
authors.lastname: Kohno
mesh_terms: D000818:Animals; D058491:Bacterial Load / Q000187:drug effects; D002452:Cell Count; D018925:Chemokines / Q000378:metabolism; D017291:Clarithromycin / Q000494:pharmacology* / Q000627:therapeutic use; D060085:Coinfection / Q000150:complications / Q000188:drug therapy; D004195:Disease Models, Animal; D053118:Influenza A Virus, H1N1 Subtype / Q000502:physiology; D008168:Lung / Q000187:drug effects / Q000378:metabolism / Q000382:microbiology / Q000821:virology; D051379:Mice; D009504:Neutrophils / Q000166:cytology / Q000187:drug effects; D009976:Orthomyxoviridae Infections / Q000150:complications*; D018410:Pneumonia, Bacterial / Q000150:complications* / Q000188:drug therapy* / Q000276:immunology / Q000378:metabolism; D011656:Pulmonary Emphysema / Q000150:complications*; D013296:Streptococcus pneumoniae / Q000187:drug effects / Q000502:physiology; D016019:Survival Analysis; D019562:Viral Load / Q000187:drug effects
chemical_list: D018925:Chemokines; D017291:Clarithromycin