title: Efficacy of β-Lactam-plus-Macrolide Combination Therapy in a Mouse Model of Lethal Pneumococcal Pneumonia.
abstract: Community-acquired pneumonia is a common disease with considerable morbidity and mortality, for which Streptococcus pneumoniae is accepted as a leading cause. Although β-lactam-plus-macrolide combination therapy for this disease is recommended in several guidelines, the clinical efficacy of this strategy against pneumococcal pneumonia remains controversial. In this study, we examined the effects of β-lactam-plus-macrolide combination therapy on lethal mouse pneumococcal pneumonia and explored the mechanisms of action in vitro and in vivo We investigated survival, lung bacterial burden, and cellular host responses in bronchoalveolar lavage fluids obtained from mice infected with pneumonia and treated with ceftriaxone, azithromycin, or both in combination. Although in vitro synergy was not observed, significant survival benefits were demonstrated with combination treatment. Lung neutrophil influx was significantly lower in the ceftriaxone-plus-azithromycin-treated group than in the ceftriaxone-treated group, whereas no differences in the lung bacterial burden were observed on day 3 between the ceftriaxone-plus-azithromycin-treated group and the ceftriaxone-treated group. Notably, the analysis of cell surface markers in the ceftriaxone-plus-azithromycin combination group exhibited upregulation of presumed immune checkpoint ligand CD86 and major histocompatibility complex class II in neutrophils and CD11b-positive CD11c-positive (CD11b(+) CD11c(+)) macrophages and dendritic cells, as well as downregulation of immune checkpoint receptors cytotoxic-T lymphocyte-associated antigen 4 and programmed death 1 in T helper and T regulatory cells. Our data demonstrate that the survival benefits of ceftriaxone-plus-azithromycin therapy occur through modulation of immune checkpoints in mouse pneumococcal pneumonia. In addition, immune checkpoint molecules may be a novel target class for future macrolide research.
authors.affiliation: Department of Microbiology and Infectious Diseases, Toho University School of Medicine, Ota-ku, Tokyo, Japan Department of Respiratory Medicine and Infectious Diseases, Oita University Faculty of Medicine, Yufu, Oita, Japan.
authors.forename: Daisuke
authors.initials: D
authors.lastname: Yoshioka
authors.affiliation: Department of Microbiology and Infectious Diseases, Toho University School of Medicine, Ota-ku, Tokyo, Japan.
authors.forename: Chiaki
authors.initials: C
authors.lastname: Kajiwara
authors.affiliation: Department of Microbiology and Infectious Diseases, Toho University School of Medicine, Ota-ku, Tokyo, Japan.
authors.forename: Yoshikazu
authors.initials: Y
authors.lastname: Ishii
authors.affiliation: Department of Respiratory Medicine and Infectious Diseases, Oita University Faculty of Medicine, Yufu, Oita, Japan.
authors.forename: Kenji
authors.initials: K
authors.lastname: Umeki
authors.affiliation: Department of Respiratory Medicine and Infectious Diseases, Oita University Faculty of Medicine, Yufu, Oita, Japan.
authors.forename: Kazufumi
authors.initials: K
authors.lastname: Hiramatsu
authors.affiliation: Department of Respiratory Medicine and Infectious Diseases, Oita University Faculty of Medicine, Yufu, Oita, Japan.
authors.forename: Jun-Ichi
authors.initials: J
authors.lastname: Kadota
authors.affiliation: Department of Microbiology and Infectious Diseases, Toho University School of Medicine, Ota-ku, Tokyo, Japan kazu@med.toho-u.ac.jp.
authors.forename: Kazuhiro
authors.initials: K
authors.lastname: Tateda
mesh_terms: D000818:Animals; D000900:Anti-Bacterial Agents / Q000494:pharmacology*; D017963:Azithromycin / Q000494:pharmacology*; D051940:B7-2 Antigen / Q000235:genetics / Q000276:immunology; D058491:Bacterial Load / Q000187:drug effects; D039481:CD11b Antigen / Q000235:genetics / Q000276:immunology; D039521:CD11c Antigen / Q000235:genetics / Q000276:immunology; D002443:Ceftriaxone / Q000494:pharmacology*; D017714:Community-Acquired Infections; D003713:Dendritic Cells / Q000187:drug effects / Q000276:immunology / Q000473:pathology; D004195:Disease Models, Animal; D004359:Drug Therapy, Combination; D005260:Female; D015870:Gene Expression; D000949:Histocompatibility Antigens Class II / Q000235:genetics / Q000276:immunology; D006801:Humans; D016676:Macrophages, Alveolar / Q000187:drug effects / Q000276:immunology / Q000473:pathology; D051379:Mice; D008808:Mice, Inbred CBA; D009504:Neutrophils / Q000187:drug effects / Q000276:immunology / Q000473:pathology; D011018:Pneumonia, Pneumococcal / Q000188:drug therapy* / Q000382:microbiology / Q000401:mortality / Q000473:pathology; D061026:Programmed Cell Death 1 Receptor / Q000235:genetics / Q000276:immunology; D013296:Streptococcus pneumoniae / Q000187:drug effects* / Q000254:growth & development / Q000472:pathogenicity; D016019:Survival Analysis; D013602:T-Lymphocytes, Cytotoxic / Q000187:drug effects / Q000276:immunology / Q000473:pathology; D006377:T-Lymphocytes, Helper-Inducer / Q000187:drug effects / Q000276:immunology / Q000473:pathology
chemical_list: D000900:Anti-Bacterial Agents; D051940:B7-2 Antigen; D039481:CD11b Antigen; D039521:CD11c Antigen; C497965:Cd86 protein, mouse; D000949:Histocompatibility Antigens Class II; C491383:Pdcd1 protein, mouse; D061026:Programmed Cell Death 1 Receptor; D002443:Ceftriaxone; D017963:Azithromycin