Genetic Adaptation and Acquisition of Macrolide Resistance in Haemophilus spp. during Persistent Respiratory Tract Colonization in Chronic Obstructive Pulmonary Disease (COPD) Patients Receiving Long-Term Azithromycin Treatment
Patients with chronic obstructive pulmonary disease (COPD) benefit from the immunomodulatory effect of azithromycin, but long-term administration may alter colonizing bacteria. Our goal was to identify changes in Haemophilus influenzae and Haemophilus parainfluenzae during azithromycin treatment. Fifteen patients were followed while receiving prolonged azithromycin treatment (Hospital Universitari de Bellvitge, Spain). Four patients (P02, P08, P11, and P13) were persistently colonized by H. influenzae for at least 3 months and two (P04 and P11) by H. parainfluenzae. Isolates from these patients (53 H. influenzae and 18 H. parainfluenzae) were included to identify, by whole-genome sequencing, antimicrobial resistance changes and genetic variation accumulated during persistent colonization. All persistent lineages isolated before treatment were azithromycin-susceptible but developed resistance within the first months, apart from those belonging to P02, who discontinued the treatment. H. influenzae isolates from P08-ST107 acquired mutations in 23S rRNA, and those from P11-ST2480 and P13-ST165 had changes in L4 and L22. In H. parainfluenzae, P04 persistent isolates acquired changes in rlmC, and P11 carried genes encoding MefE/MsrD efflux pumps in an integrative conjugative element, which was also identified in H. influenzae P11-ST147. Other genetic variation occurred in genes associated with cell wall and inorganic ion metabolism. Persistent H. influenzae strains all showed changes in licA and hgpB genes. Other genes (lex1, lic3A, hgpC, and fadL) had variation in multiple lineages. Furthermore, persistent strains showed loss, acquisition, or genetic changes in prophage-associated regions. Long-term azithromycin therapy results in macrolide resistance, as well as genetic changes that likely favor bacterial adaptation during persistent respiratory colonization. IMPORTANCE The immunomodulatory properties of azithromycin reduce the frequency of exacerbations and improve the quality of life of COPD patients. However, long-term administration may alter the respiratory microbiota, such as Haemophilus influenzae, an opportunistic respiratory colonizing bacteria that play an important role in exacerbations. This study contributes to a better understanding of COPD progression by characterizing the clinical evolution of H. influenzae in a cohort of patients with prolonged azithromycin treatment. The emergence of macrolide resistance during the first months, combined with the role of Haemophilus parainfluenzae as a reservoir and source of resistance dissemination, is a cause for concern that may lead to therapeutic failure. Furthermore, genetic variations in cell wall and inorganic ion metabolism coding genes likely favor bacterial adaptation to host selective pressures. Therefore, the bacterial pathoadaptive evolution in these severe COPD patients raise our awareness of the possible spread of macrolide resistance and selection of host-adapted clones.
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American Society for Microbiology
2023
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Subjects: | Haemophilus influenzae, Haemophilus parainfluenzae, Persistence, Macrolide resistance, Azithromycin, Adaptation, |
Online Access: | http://hdl.handle.net/10261/335990 |
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Haemophilus influenzae Haemophilus parainfluenzae Persistence Macrolide resistance Azithromycin Adaptation Haemophilus influenzae Haemophilus parainfluenzae Persistence Macrolide resistance Azithromycin Adaptation |
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Haemophilus influenzae Haemophilus parainfluenzae Persistence Macrolide resistance Azithromycin Adaptation Haemophilus influenzae Haemophilus parainfluenzae Persistence Macrolide resistance Azithromycin Adaptation Carrera-Salinas, Anna González-Díaz, Aida Ehrlich, Rachel L. Berbel, Dàmaris Tubau, Fe Pomares, Xavier Garmendia, Juncal Domínguez, M. Ángeles Ardanuy, Carmen Huertas, Daniel Marín, Alicia Montón, Conchita Mell, Joshua Chang Santos, Salud Martí, Sara Genetic Adaptation and Acquisition of Macrolide Resistance in Haemophilus spp. during Persistent Respiratory Tract Colonization in Chronic Obstructive Pulmonary Disease (COPD) Patients Receiving Long-Term Azithromycin Treatment |
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Patients with chronic obstructive pulmonary disease (COPD) benefit from the immunomodulatory effect of azithromycin, but long-term administration may alter colonizing bacteria. Our goal was to identify changes in Haemophilus influenzae and Haemophilus parainfluenzae during azithromycin treatment. Fifteen patients were followed while receiving prolonged azithromycin treatment (Hospital Universitari de Bellvitge, Spain). Four patients (P02, P08, P11, and P13) were persistently colonized by H. influenzae for at least 3 months and two (P04 and P11) by H. parainfluenzae. Isolates from these patients (53 H. influenzae and 18 H. parainfluenzae) were included to identify, by whole-genome sequencing, antimicrobial resistance changes and genetic variation accumulated during persistent colonization. All persistent lineages isolated before treatment were azithromycin-susceptible but developed resistance within the first months, apart from those belonging to P02, who discontinued the treatment. H. influenzae isolates from P08-ST107 acquired mutations in 23S rRNA, and those from P11-ST2480 and P13-ST165 had changes in L4 and L22. In H. parainfluenzae, P04 persistent isolates acquired changes in rlmC, and P11 carried genes encoding MefE/MsrD efflux pumps in an integrative conjugative element, which was also identified in H. influenzae P11-ST147. Other genetic variation occurred in genes associated with cell wall and inorganic ion metabolism. Persistent H. influenzae strains all showed changes in licA and hgpB genes. Other genes (lex1, lic3A, hgpC, and fadL) had variation in multiple lineages. Furthermore, persistent strains showed loss, acquisition, or genetic changes in prophage-associated regions. Long-term azithromycin therapy results in macrolide resistance, as well as genetic changes that likely favor bacterial adaptation during persistent respiratory colonization. IMPORTANCE The immunomodulatory properties of azithromycin reduce the frequency of exacerbations and improve the quality of life of COPD patients. However, long-term administration may alter the respiratory microbiota, such as Haemophilus influenzae, an opportunistic respiratory colonizing bacteria that play an important role in exacerbations. This study contributes to a better understanding of COPD progression by characterizing the clinical evolution of H. influenzae in a cohort of patients with prolonged azithromycin treatment. The emergence of macrolide resistance during the first months, combined with the role of Haemophilus parainfluenzae as a reservoir and source of resistance dissemination, is a cause for concern that may lead to therapeutic failure. Furthermore, genetic variations in cell wall and inorganic ion metabolism coding genes likely favor bacterial adaptation to host selective pressures. Therefore, the bacterial pathoadaptive evolution in these severe COPD patients raise our awareness of the possible spread of macrolide resistance and selection of host-adapted clones. |
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Fundación Respira |
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Fundación Respira Carrera-Salinas, Anna González-Díaz, Aida Ehrlich, Rachel L. Berbel, Dàmaris Tubau, Fe Pomares, Xavier Garmendia, Juncal Domínguez, M. Ángeles Ardanuy, Carmen Huertas, Daniel Marín, Alicia Montón, Conchita Mell, Joshua Chang Santos, Salud Martí, Sara |
format |
artículo |
topic_facet |
Haemophilus influenzae Haemophilus parainfluenzae Persistence Macrolide resistance Azithromycin Adaptation |
author |
Carrera-Salinas, Anna González-Díaz, Aida Ehrlich, Rachel L. Berbel, Dàmaris Tubau, Fe Pomares, Xavier Garmendia, Juncal Domínguez, M. Ángeles Ardanuy, Carmen Huertas, Daniel Marín, Alicia Montón, Conchita Mell, Joshua Chang Santos, Salud Martí, Sara |
author_sort |
Carrera-Salinas, Anna |
title |
Genetic Adaptation and Acquisition of Macrolide Resistance in Haemophilus spp. during Persistent Respiratory Tract Colonization in Chronic Obstructive Pulmonary Disease (COPD) Patients Receiving Long-Term Azithromycin Treatment |
title_short |
Genetic Adaptation and Acquisition of Macrolide Resistance in Haemophilus spp. during Persistent Respiratory Tract Colonization in Chronic Obstructive Pulmonary Disease (COPD) Patients Receiving Long-Term Azithromycin Treatment |
title_full |
Genetic Adaptation and Acquisition of Macrolide Resistance in Haemophilus spp. during Persistent Respiratory Tract Colonization in Chronic Obstructive Pulmonary Disease (COPD) Patients Receiving Long-Term Azithromycin Treatment |
title_fullStr |
Genetic Adaptation and Acquisition of Macrolide Resistance in Haemophilus spp. during Persistent Respiratory Tract Colonization in Chronic Obstructive Pulmonary Disease (COPD) Patients Receiving Long-Term Azithromycin Treatment |
title_full_unstemmed |
Genetic Adaptation and Acquisition of Macrolide Resistance in Haemophilus spp. during Persistent Respiratory Tract Colonization in Chronic Obstructive Pulmonary Disease (COPD) Patients Receiving Long-Term Azithromycin Treatment |
title_sort |
genetic adaptation and acquisition of macrolide resistance in haemophilus spp. during persistent respiratory tract colonization in chronic obstructive pulmonary disease (copd) patients receiving long-term azithromycin treatment |
publisher |
American Society for Microbiology |
publishDate |
2023 |
url |
http://hdl.handle.net/10261/335990 |
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dig-idab-es-10261-3359902023-09-28T10:52:02Z Genetic Adaptation and Acquisition of Macrolide Resistance in Haemophilus spp. during Persistent Respiratory Tract Colonization in Chronic Obstructive Pulmonary Disease (COPD) Patients Receiving Long-Term Azithromycin Treatment Carrera-Salinas, Anna González-Díaz, Aida Ehrlich, Rachel L. Berbel, Dàmaris Tubau, Fe Pomares, Xavier Garmendia, Juncal Domínguez, M. Ángeles Ardanuy, Carmen Huertas, Daniel Marín, Alicia Montón, Conchita Mell, Joshua Chang Santos, Salud Martí, Sara Fundación Respira Ministerio de Sanidad (España) Fundació Catalana de Pneumologia Ministerio de Ciencia, Innovación y Universidades (España) Agencia Estatal de Investigación (España) Centro de Investigación Biomédica en Red Enfermedades Respiratorias (España) Instituto de Salud Carlos III European Commission Generalitat de Catalunya Ministerio de Educación, Cultura y Deporte (España) Haemophilus influenzae Haemophilus parainfluenzae Persistence Macrolide resistance Azithromycin Adaptation Patients with chronic obstructive pulmonary disease (COPD) benefit from the immunomodulatory effect of azithromycin, but long-term administration may alter colonizing bacteria. Our goal was to identify changes in Haemophilus influenzae and Haemophilus parainfluenzae during azithromycin treatment. Fifteen patients were followed while receiving prolonged azithromycin treatment (Hospital Universitari de Bellvitge, Spain). Four patients (P02, P08, P11, and P13) were persistently colonized by H. influenzae for at least 3 months and two (P04 and P11) by H. parainfluenzae. Isolates from these patients (53 H. influenzae and 18 H. parainfluenzae) were included to identify, by whole-genome sequencing, antimicrobial resistance changes and genetic variation accumulated during persistent colonization. All persistent lineages isolated before treatment were azithromycin-susceptible but developed resistance within the first months, apart from those belonging to P02, who discontinued the treatment. H. influenzae isolates from P08-ST107 acquired mutations in 23S rRNA, and those from P11-ST2480 and P13-ST165 had changes in L4 and L22. In H. parainfluenzae, P04 persistent isolates acquired changes in rlmC, and P11 carried genes encoding MefE/MsrD efflux pumps in an integrative conjugative element, which was also identified in H. influenzae P11-ST147. Other genetic variation occurred in genes associated with cell wall and inorganic ion metabolism. Persistent H. influenzae strains all showed changes in licA and hgpB genes. Other genes (lex1, lic3A, hgpC, and fadL) had variation in multiple lineages. Furthermore, persistent strains showed loss, acquisition, or genetic changes in prophage-associated regions. Long-term azithromycin therapy results in macrolide resistance, as well as genetic changes that likely favor bacterial adaptation during persistent respiratory colonization. IMPORTANCE The immunomodulatory properties of azithromycin reduce the frequency of exacerbations and improve the quality of life of COPD patients. However, long-term administration may alter the respiratory microbiota, such as Haemophilus influenzae, an opportunistic respiratory colonizing bacteria that play an important role in exacerbations. This study contributes to a better understanding of COPD progression by characterizing the clinical evolution of H. influenzae in a cohort of patients with prolonged azithromycin treatment. The emergence of macrolide resistance during the first months, combined with the role of Haemophilus parainfluenzae as a reservoir and source of resistance dissemination, is a cause for concern that may lead to therapeutic failure. Furthermore, genetic variations in cell wall and inorganic ion metabolism coding genes likely favor bacterial adaptation to host selective pressures. Therefore, the bacterial pathoadaptive evolution in these severe COPD patients raise our awareness of the possible spread of macrolide resistance and selection of host-adapted clones. This study was funded by the Fundación Española del Pulmón SEPAR (88/2016 to D.H. and 1116/2020 to S.M.); Fondo de Investigaciones Sanitarias (PI16/00977 to S.M.); Fundació Catalana de Pneumologia, FUCAP (Beca Albert Agustí 2017 to D.H.); Ministerio de Ciencia, Innovación y Universidades (MICIU; RTI2018-096369-B-I00 to J.G.); and Centro de Investigación Biomédica en Red de Enfermedades Respiratorias (CIBERES; CB06/06/0037 and CB06/06/1102), an initiative of the Instituto de Salud Carlos III (ISCIII). The European Regional Development Fund/European Social Fund (ERDF/ESF; “Investing in your future”) also provided financial support, and CERCA Program/Generalitat de Catalunya provided institutional support. Bioinformatic analysis was supported by an Amazon Web Services (AWS) research grant (to S.M.). S.S. received financial support by Menarini. A.C.-S. was supported by Formación de Profesorado Universitario from the Ministerio de Educación of Spain (FPU16/02202), and S.M. was supported byMiguel Servet contract (CP19/00096) (ISCIII). We declare that there is no conflict of interest regarding the publication of this article. 2023-09-28T10:50:04Z 2023-09-28T10:50:04Z 2023 2023-09-28T10:50:04Z artículo doi: 10.1128/spectrum.03860-22 e-issn: 2165-0497 Microbiology Spectrum 11(1): (2023) http://hdl.handle.net/10261/335990 #PLACEHOLDER_PARENT_METADATA_VALUE# #PLACEHOLDER_PARENT_METADATA_VALUE# info:eu-repo/grantAgreement/AEI/Plan Estatal de Investigación Científica y Técnica y de Innovación 2017-2020/RTI2018-096369-B-I00/ES/ANALISIS MULTIMODAL DE LA INTERACION HUESPED-PATOGENO EN EL SISTEMA RESPIRATORIO PARA DESARROLLO DE HERRAMIENTAS INNOVADORAS FRENTE A LA INFECCION POR HAEMOPHILUS INFLUENZAE/ info:eu-repo/grantAgreement/MECD//FPU16%2F02202/ES/FPU16%2F02202/ Publisher's version The underlying dataset has been published as supplementary material of the article in the publisher platform at 10.1128/spectrum.03860-22 http://dx.doi.org/10.1128/spectrum.03860-22 Sí open application/pdf American Society for Microbiology |