Cargando…

Dual β-lactam combination therapy for multi-drug resistant Pseudomonas aeruginosa infection: enhanced efficacy in vivo and comparison with monotherapies of penicillin-binding protein inhibition

The aim of the study was to determine the efficacy of dual β-lactam combination treatments derived from eight approved drugs against Galleria mellonella larvae infected with MDR strains of P. aeruginosa. Carbapenem-resistant P. aeruginosa NCTC 13437 and an unrelated clinical isolate were used to inf...

Descripción completa

Detalles Bibliográficos
Autores principales: Siriyong, Thanyaluck, Murray, Rachael M., Bidgood, Lucy E., Young, Simon A., Wright, Florence, Parcell, Benjamin J., Voravuthikunchai, Supayang Piyawan, Coote, Peter J.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group UK 2019
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6591303/
https://www.ncbi.nlm.nih.gov/pubmed/31235728
http://dx.doi.org/10.1038/s41598-019-45550-z
_version_ 1783429703119405056
author Siriyong, Thanyaluck
Murray, Rachael M.
Bidgood, Lucy E.
Young, Simon A.
Wright, Florence
Parcell, Benjamin J.
Voravuthikunchai, Supayang Piyawan
Coote, Peter J.
author_facet Siriyong, Thanyaluck
Murray, Rachael M.
Bidgood, Lucy E.
Young, Simon A.
Wright, Florence
Parcell, Benjamin J.
Voravuthikunchai, Supayang Piyawan
Coote, Peter J.
author_sort Siriyong, Thanyaluck
collection PubMed
description The aim of the study was to determine the efficacy of dual β-lactam combination treatments derived from eight approved drugs against Galleria mellonella larvae infected with MDR strains of P. aeruginosa. Carbapenem-resistant P. aeruginosa NCTC 13437 and an unrelated clinical isolate were used to infect G. mellonella larvae and the efficacy of twenty-eight dual β-lactam combination therapies were compared to their constituent monotherapies. For the most potent combinations identified, penicillin-binding protein (PBP) inhibition profiles were measured and compared with each constituent antibiotic. Five of the dual β-lactam combinations resulted in greater than 70% survival of infected G. mellonella. Two combinations showed potent, enhanced efficacy versus both strains − ceftazidime + meropenem and aztreonam + meropenem. Comparison of PBP inhibition profiles revealed that the enhanced efficacy of these two dual β-lactam combinations could not be explained by more potent inhibition of PBPs or inhibition of a broader range of PBPs. A possible contribution to the enhanced efficacy of the combinations could be stimulation of innate immunity via increased haemocyte numbers compared to their constituent monotherapies. Combinations of β-lactam antibiotics show promise in overcoming MDR P. aeruginosa and are worthy of additional study and development.
format Online
Article
Text
id pubmed-6591303
institution National Center for Biotechnology Information
language English
publishDate 2019
publisher Nature Publishing Group UK
record_format MEDLINE/PubMed
spelling pubmed-65913032019-07-02 Dual β-lactam combination therapy for multi-drug resistant Pseudomonas aeruginosa infection: enhanced efficacy in vivo and comparison with monotherapies of penicillin-binding protein inhibition Siriyong, Thanyaluck Murray, Rachael M. Bidgood, Lucy E. Young, Simon A. Wright, Florence Parcell, Benjamin J. Voravuthikunchai, Supayang Piyawan Coote, Peter J. Sci Rep Article The aim of the study was to determine the efficacy of dual β-lactam combination treatments derived from eight approved drugs against Galleria mellonella larvae infected with MDR strains of P. aeruginosa. Carbapenem-resistant P. aeruginosa NCTC 13437 and an unrelated clinical isolate were used to infect G. mellonella larvae and the efficacy of twenty-eight dual β-lactam combination therapies were compared to their constituent monotherapies. For the most potent combinations identified, penicillin-binding protein (PBP) inhibition profiles were measured and compared with each constituent antibiotic. Five of the dual β-lactam combinations resulted in greater than 70% survival of infected G. mellonella. Two combinations showed potent, enhanced efficacy versus both strains − ceftazidime + meropenem and aztreonam + meropenem. Comparison of PBP inhibition profiles revealed that the enhanced efficacy of these two dual β-lactam combinations could not be explained by more potent inhibition of PBPs or inhibition of a broader range of PBPs. A possible contribution to the enhanced efficacy of the combinations could be stimulation of innate immunity via increased haemocyte numbers compared to their constituent monotherapies. Combinations of β-lactam antibiotics show promise in overcoming MDR P. aeruginosa and are worthy of additional study and development. Nature Publishing Group UK 2019-06-24 /pmc/articles/PMC6591303/ /pubmed/31235728 http://dx.doi.org/10.1038/s41598-019-45550-z Text en © The Author(s) 2019 Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.
spellingShingle Article
Siriyong, Thanyaluck
Murray, Rachael M.
Bidgood, Lucy E.
Young, Simon A.
Wright, Florence
Parcell, Benjamin J.
Voravuthikunchai, Supayang Piyawan
Coote, Peter J.
Dual β-lactam combination therapy for multi-drug resistant Pseudomonas aeruginosa infection: enhanced efficacy in vivo and comparison with monotherapies of penicillin-binding protein inhibition
title Dual β-lactam combination therapy for multi-drug resistant Pseudomonas aeruginosa infection: enhanced efficacy in vivo and comparison with monotherapies of penicillin-binding protein inhibition
title_full Dual β-lactam combination therapy for multi-drug resistant Pseudomonas aeruginosa infection: enhanced efficacy in vivo and comparison with monotherapies of penicillin-binding protein inhibition
title_fullStr Dual β-lactam combination therapy for multi-drug resistant Pseudomonas aeruginosa infection: enhanced efficacy in vivo and comparison with monotherapies of penicillin-binding protein inhibition
title_full_unstemmed Dual β-lactam combination therapy for multi-drug resistant Pseudomonas aeruginosa infection: enhanced efficacy in vivo and comparison with monotherapies of penicillin-binding protein inhibition
title_short Dual β-lactam combination therapy for multi-drug resistant Pseudomonas aeruginosa infection: enhanced efficacy in vivo and comparison with monotherapies of penicillin-binding protein inhibition
title_sort dual β-lactam combination therapy for multi-drug resistant pseudomonas aeruginosa infection: enhanced efficacy in vivo and comparison with monotherapies of penicillin-binding protein inhibition
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6591303/
https://www.ncbi.nlm.nih.gov/pubmed/31235728
http://dx.doi.org/10.1038/s41598-019-45550-z
work_keys_str_mv AT siriyongthanyaluck dualblactamcombinationtherapyformultidrugresistantpseudomonasaeruginosainfectionenhancedefficacyinvivoandcomparisonwithmonotherapiesofpenicillinbindingproteininhibition
AT murrayrachaelm dualblactamcombinationtherapyformultidrugresistantpseudomonasaeruginosainfectionenhancedefficacyinvivoandcomparisonwithmonotherapiesofpenicillinbindingproteininhibition
AT bidgoodlucye dualblactamcombinationtherapyformultidrugresistantpseudomonasaeruginosainfectionenhancedefficacyinvivoandcomparisonwithmonotherapiesofpenicillinbindingproteininhibition
AT youngsimona dualblactamcombinationtherapyformultidrugresistantpseudomonasaeruginosainfectionenhancedefficacyinvivoandcomparisonwithmonotherapiesofpenicillinbindingproteininhibition
AT wrightflorence dualblactamcombinationtherapyformultidrugresistantpseudomonasaeruginosainfectionenhancedefficacyinvivoandcomparisonwithmonotherapiesofpenicillinbindingproteininhibition
AT parcellbenjaminj dualblactamcombinationtherapyformultidrugresistantpseudomonasaeruginosainfectionenhancedefficacyinvivoandcomparisonwithmonotherapiesofpenicillinbindingproteininhibition
AT voravuthikunchaisupayangpiyawan dualblactamcombinationtherapyformultidrugresistantpseudomonasaeruginosainfectionenhancedefficacyinvivoandcomparisonwithmonotherapiesofpenicillinbindingproteininhibition
AT cootepeterj dualblactamcombinationtherapyformultidrugresistantpseudomonasaeruginosainfectionenhancedefficacyinvivoandcomparisonwithmonotherapiesofpenicillinbindingproteininhibition