title: Relationship between azithromycin susceptibility and administration efficacy for nontypeable Haemophilus influenzae respiratory infection.
abstract: Nontypeable Haemophilus influenzae (NTHI) is an opportunistic pathogen that is an important cause of acute exacerbations of chronic obstructive pulmonary disease (AECOPD). COPD is an inflammatory disease of the airways, and exacerbations are acute inflammatory events superimposed on this background of chronic inflammation. Azithromycin (AZM) is a macrolide antibiotic with antibacterial and anti-inflammatory properties and a clinically proven potential for AECOPD prevention and management. Relationships between AZM efficacy and resistance by NTHI and between bactericidal and immunomodulatory effects on NTHI respiratory infection have not been addressed. In this study, we employed two pathogenic NTHI strains with different AZM susceptibilities (NTHI 375 [AZM susceptible] and NTHI 353 [AZM resistant]) to evaluate the prophylactic and therapeutic effects of AZM on the NTHI-host interplay. At the cellular level, AZM was bactericidal toward intracellular NTHI inside alveolar and bronchial epithelia and alveolar macrophages, and it enhanced NTHI phagocytosis by the latter cell type. These effects correlated with the strain MIC of AZM and the antibiotic dose. Additionally, the effect of AZM on NTHI infection was assessed in a mouse model of pulmonary infection. AZM showed both preventive and therapeutic efficacies by lowering NTHI 375 bacterial counts in lungs and bronchoalveolar lavage fluid (BALF) and by reducing histopathological inflammatory lesions in the upper and lower airways of mice. Conversely, AZM did not reduce bacterial loads in animals infected with NTHI 353, in which case a milder anti-inflammatory effect was also observed. Together, the results of this work link the bactericidal and anti-inflammatory effects of AZM and frame the efficacy of this antibiotic against NTHI respiratory infection.
authors.affiliation: Instituto de Agrobiotecnología, CSIC-Universidad Pública Navarra-Gobierno Navarra, Mutilva, Spain Centro de Investigación Biomédica en Red de Enfermedades Respiratorias (CIBERES), Madrid, Spain.
authors.forename: Begoña
authors.initials: B
authors.lastname: Euba
authors.affiliation: Instituto de Agrobiotecnología, CSIC-Universidad Pública Navarra-Gobierno Navarra, Mutilva, Spain.
authors.forename: Javier
authors.initials: J
authors.lastname: Moleres
authors.affiliation: Instituto de Agrobiotecnología, CSIC-Universidad Pública Navarra-Gobierno Navarra, Mutilva, Spain.
authors.forename: Cristina
authors.initials: C
authors.lastname: Viadas
authors.affiliation: Facultad de Veterinaria, Universidad de Zaragoza, Zaragoza, Spain.
authors.forename: Montserrat
authors.initials: M
authors.lastname: Barberán
authors.affiliation: Instituto de Agrobiotecnología, CSIC-Universidad Pública Navarra-Gobierno Navarra, Mutilva, Spain.
authors.forename: Lucía
authors.initials: L
authors.lastname: Caballero
authors.affiliation: Instituto de Agrobiotecnología, CSIC-Universidad Pública Navarra-Gobierno Navarra, Mutilva, Spain.
authors.forename: María-Jesús
authors.initials: MJ
authors.lastname: Grilló
authors.affiliation: Centre for Infection and Immunity, Queen's University Belfast, Belfast, United Kingdom.
authors.forename: José Antonio
authors.initials: JA
authors.lastname: Bengoechea
authors.affiliation: Pulmonary Department, Clínica Universidad de Navarra, Pamplona, Spain.
authors.forename: Juan Pablo
authors.initials: JP
authors.lastname: de-Torres
authors.affiliation: Centro de Investigación Biomédica en Red de Enfermedades Respiratorias (CIBERES), Madrid, Spain Microbiology Department, Hospital Universitari Bellvitge, IDIBELL, University of Barcelona, Barcelona, Spain.
authors.forename: Josefina
authors.initials: J
authors.lastname: Liñares
authors.affiliation: Microbiology Department, Clínica Universidad de Navarra, Pamplona, Spain.
authors.forename: José
authors.initials: J
authors.lastname: Leiva
authors.affiliation: Instituto de Agrobiotecnología, CSIC-Universidad Pública Navarra-Gobierno Navarra, Mutilva, Spain Centro de Investigación Biomédica en Red de Enfermedades Respiratorias (CIBERES), Madrid, Spain juncal.garmendia@unavarra.es.
authors.forename: Junkal
authors.initials: J
authors.lastname: Garmendia
mesh_terms: D000818:Animals; D017963:Azithromycin / Q000627:therapeutic use*; D002460:Cell Line; D004847:Epithelial Cells / Q000821:virology; D005260:Female; D006192:Haemophilus Infections / Q000188:drug therapy*; D006193:Haemophilus influenzae / Q000187:drug effects* / Q000472:pathogenicity*; D006801:Humans; D016676:Macrophages, Alveolar / Q000821:virology; D051379:Mice; D012141:Respiratory Tract Infections / Q000188:drug therapy*
chemical_list: D017963:Azithromycin