Pharmacodynamics of ceftazidime plus tobramycin combination dosage regimens against hypermutable Pseudomonas aeruginosa isolates at simulated epithelial lining fluid concentrations in a dynamic in vitro infection model

Objectives: Hypermutable Pseudomonas aeruginosa strains are a major challenge in cystic fibrosis. We investigated bacterial killing and resistance emergence for approved ceftazidime and tobramycin regimens, alone and in combination. Methods: Pseudomonas aeruginosa PAO Delta mutS and six hypermutable...

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Autores: Tait, Jessica R, Bilal, Hajira, Kim, Tae Hwan, Oh, Abigail, Peleg, Anton Y, Boyce, John D, Oliver, Antonio, Bergen, Phillip J, Nation, Roger L, Landersdorfer, Cornelia B
Tipo de recurso: artículo
Fecha de publicación:2021
País:España
Institución:Instituto de Salud Carlos III (ISCIII)
Repositorio:Repisalud
Idioma:inglés
OAI Identifier:oai:repisalud.isciii.es:20.500.12105/23181
Acceso en línea:https://hdl.handle.net/20.500.12105/23181
Access Level:acceso abierto
Palabra clave:Pharmacokinetics
Pharmacodynamics
Optimised dosing
Antibiotic combination
Dynamic in vitro infection model
Mathematical modelling
Ceftazidima
Pruebas de Sensibilidad Microbiana
Humanos
Pseudomonas aeruginosa
Antibacterianos
Tobramicina
Tobramycin
Anti-Bacterial Agents
Microbial Sensitivity Tests
Ceftazidime
Humans
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spelling Pharmacodynamics of ceftazidime plus tobramycin combination dosage regimens against hypermutable Pseudomonas aeruginosa isolates at simulated epithelial lining fluid concentrations in a dynamic in vitro infection modelTait, Jessica RBilal, HajiraKim, Tae HwanOh, AbigailPeleg, Anton YBoyce, John DOliver, AntonioBergen, Phillip JNation, Roger LLandersdorfer, Cornelia BPharmacokineticsPharmacodynamicsOptimised dosingAntibiotic combinationDynamic in vitro infection modelMathematical modellingCeftazidimaPruebas de Sensibilidad MicrobianaHumanosPseudomonas aeruginosaAntibacterianosTobramicinaTobramycinAnti-Bacterial AgentsMicrobial Sensitivity TestsCeftazidimeHumansPseudomonas aeruginosaObjectives: Hypermutable Pseudomonas aeruginosa strains are a major challenge in cystic fibrosis. We investigated bacterial killing and resistance emergence for approved ceftazidime and tobramycin regimens, alone and in combination. Methods: Pseudomonas aeruginosa PAO Delta mutS and six hypermutable clinical isolates were examined using 48-h static concentration time-kill (SCTK) studies (inoculum similar to 10(7.5) CFU/mL); four strains were also studied in a dynamic in vitro model (IVM) (inoculum similar to 10(8) CFU/mL). The IVM simulated concentration-time profiles in epithelial lining fluid following intravenous administration of ceftazidime (3 g/day and 9 g/day continuous infusion), tobramycin (5 mg/kg and 10 mg/kg via 30-min infusion 24-hourly; half-life 3.5 h), and their combinations. Time courses of total and less-susceptible populations were determined. Results: Ceftazidime plus tobramycin demonstrated synergistic killing in SCTK studies for all strains, although to a lesser extent for ceftazidime-resistant strains. In the IVM, ceftazidime and tobramycin monotherapies provided <= 5.4 and <= 3.4 log(10) initial killing, respectively; however, re-growth with resistance occurred by 72 h. Against strains susceptible to one or both antibiotics, high-dose combination regimens provided >6 log(10) initial killing, which was generally synergistic from 8-24 h, and marked suppression of re-growth and resistance at 72 h. The time course of bacterial density in the IVM was well described by mechanism-based models, enabling Monte Carlo simulations (MCSs) to predict likely effectiveness of the combination in patients. Conclusion: Results of the IVM and MCS suggested antibacterial effect depends both on the strain's susceptibility and hypermutability. Further investigation of the combination against hypermutable P. aeruginosa strains is warranted. (C) 2021 The Authors. Published by Elsevier Ltd on behalf of International Society for Antimicrobial Chemotherapy.Elsevier20242024-09-1820212021-09-0120212021-09-01research articlehttp://purl.org/coar/resource_type/c_2df8fbb1info:eu-repo/semantics/articlehttps://hdl.handle.net/20.500.12105/23181reponame:Repisaludinstname:Instituto de Salud Carlos III (ISCIII)Inglésengopen accesshttp://purl.org/coar/access_right/c_abf2Attribution-NonCommercial-NoDerivatives 4.0 Internationalhttp://creativecommons.org/licenses/by-nc-nd/4.0/info:eu-repo/semantics/openAccessoai:repisalud.isciii.es:20.500.12105/231812026-06-12T12:43:37Z
dc.title.none.fl_str_mv Pharmacodynamics of ceftazidime plus tobramycin combination dosage regimens against hypermutable Pseudomonas aeruginosa isolates at simulated epithelial lining fluid concentrations in a dynamic in vitro infection model
title Pharmacodynamics of ceftazidime plus tobramycin combination dosage regimens against hypermutable Pseudomonas aeruginosa isolates at simulated epithelial lining fluid concentrations in a dynamic in vitro infection model
spellingShingle Pharmacodynamics of ceftazidime plus tobramycin combination dosage regimens against hypermutable Pseudomonas aeruginosa isolates at simulated epithelial lining fluid concentrations in a dynamic in vitro infection model
Tait, Jessica R
Pharmacokinetics
Pharmacodynamics
Optimised dosing
Antibiotic combination
Dynamic in vitro infection model
Mathematical modelling
Ceftazidima
Pruebas de Sensibilidad Microbiana
Humanos
Pseudomonas aeruginosa
Antibacterianos
Tobramicina
Tobramycin
Anti-Bacterial Agents
Microbial Sensitivity Tests
Ceftazidime
Humans
Pseudomonas aeruginosa
title_short Pharmacodynamics of ceftazidime plus tobramycin combination dosage regimens against hypermutable Pseudomonas aeruginosa isolates at simulated epithelial lining fluid concentrations in a dynamic in vitro infection model
title_full Pharmacodynamics of ceftazidime plus tobramycin combination dosage regimens against hypermutable Pseudomonas aeruginosa isolates at simulated epithelial lining fluid concentrations in a dynamic in vitro infection model
title_fullStr Pharmacodynamics of ceftazidime plus tobramycin combination dosage regimens against hypermutable Pseudomonas aeruginosa isolates at simulated epithelial lining fluid concentrations in a dynamic in vitro infection model
title_full_unstemmed Pharmacodynamics of ceftazidime plus tobramycin combination dosage regimens against hypermutable Pseudomonas aeruginosa isolates at simulated epithelial lining fluid concentrations in a dynamic in vitro infection model
title_sort Pharmacodynamics of ceftazidime plus tobramycin combination dosage regimens against hypermutable Pseudomonas aeruginosa isolates at simulated epithelial lining fluid concentrations in a dynamic in vitro infection model
dc.creator.none.fl_str_mv Tait, Jessica R
Bilal, Hajira
Kim, Tae Hwan
Oh, Abigail
Peleg, Anton Y
Boyce, John D
Oliver, Antonio
Bergen, Phillip J
Nation, Roger L
Landersdorfer, Cornelia B
author Tait, Jessica R
author_facet Tait, Jessica R
Bilal, Hajira
Kim, Tae Hwan
Oh, Abigail
Peleg, Anton Y
Boyce, John D
Oliver, Antonio
Bergen, Phillip J
Nation, Roger L
Landersdorfer, Cornelia B
author_role author
author2 Bilal, Hajira
Kim, Tae Hwan
Oh, Abigail
Peleg, Anton Y
Boyce, John D
Oliver, Antonio
Bergen, Phillip J
Nation, Roger L
Landersdorfer, Cornelia B
author2_role author
author
author
author
author
author
author
author
author
dc.contributor.none.fl_str_mv
dc.subject.none.fl_str_mv Pharmacokinetics
Pharmacodynamics
Optimised dosing
Antibiotic combination
Dynamic in vitro infection model
Mathematical modelling
Ceftazidima
Pruebas de Sensibilidad Microbiana
Humanos
Pseudomonas aeruginosa
Antibacterianos
Tobramicina
Tobramycin
Anti-Bacterial Agents
Microbial Sensitivity Tests
Ceftazidime
Humans
Pseudomonas aeruginosa
topic Pharmacokinetics
Pharmacodynamics
Optimised dosing
Antibiotic combination
Dynamic in vitro infection model
Mathematical modelling
Ceftazidima
Pruebas de Sensibilidad Microbiana
Humanos
Pseudomonas aeruginosa
Antibacterianos
Tobramicina
Tobramycin
Anti-Bacterial Agents
Microbial Sensitivity Tests
Ceftazidime
Humans
Pseudomonas aeruginosa
description Objectives: Hypermutable Pseudomonas aeruginosa strains are a major challenge in cystic fibrosis. We investigated bacterial killing and resistance emergence for approved ceftazidime and tobramycin regimens, alone and in combination. Methods: Pseudomonas aeruginosa PAO Delta mutS and six hypermutable clinical isolates were examined using 48-h static concentration time-kill (SCTK) studies (inoculum similar to 10(7.5) CFU/mL); four strains were also studied in a dynamic in vitro model (IVM) (inoculum similar to 10(8) CFU/mL). The IVM simulated concentration-time profiles in epithelial lining fluid following intravenous administration of ceftazidime (3 g/day and 9 g/day continuous infusion), tobramycin (5 mg/kg and 10 mg/kg via 30-min infusion 24-hourly; half-life 3.5 h), and their combinations. Time courses of total and less-susceptible populations were determined. Results: Ceftazidime plus tobramycin demonstrated synergistic killing in SCTK studies for all strains, although to a lesser extent for ceftazidime-resistant strains. In the IVM, ceftazidime and tobramycin monotherapies provided <= 5.4 and <= 3.4 log(10) initial killing, respectively; however, re-growth with resistance occurred by 72 h. Against strains susceptible to one or both antibiotics, high-dose combination regimens provided >6 log(10) initial killing, which was generally synergistic from 8-24 h, and marked suppression of re-growth and resistance at 72 h. The time course of bacterial density in the IVM was well described by mechanism-based models, enabling Monte Carlo simulations (MCSs) to predict likely effectiveness of the combination in patients. Conclusion: Results of the IVM and MCS suggested antibacterial effect depends both on the strain's susceptibility and hypermutability. Further investigation of the combination against hypermutable P. aeruginosa strains is warranted. (C) 2021 The Authors. Published by Elsevier Ltd on behalf of International Society for Antimicrobial Chemotherapy.
publishDate 2021
dc.date.none.fl_str_mv 2021
2021-09-01
2021
2021-09-01
2024
2024-09-18
dc.type.none.fl_str_mv research article
http://purl.org/coar/resource_type/c_2df8fbb1
dc.type.openaire.fl_str_mv info:eu-repo/semantics/article
format article
dc.identifier.none.fl_str_mv https://hdl.handle.net/20.500.12105/23181
url https://hdl.handle.net/20.500.12105/23181
dc.language.none.fl_str_mv Inglés
eng
language_invalid_str_mv Inglés
language eng
dc.rights.none.fl_str_mv open access
http://purl.org/coar/access_right/c_abf2
Attribution-NonCommercial-NoDerivatives 4.0 International
http://creativecommons.org/licenses/by-nc-nd/4.0/
dc.rights.openaire.fl_str_mv info:eu-repo/semantics/openAccess
rights_invalid_str_mv open access
http://purl.org/coar/access_right/c_abf2
Attribution-NonCommercial-NoDerivatives 4.0 International
http://creativecommons.org/licenses/by-nc-nd/4.0/
eu_rights_str_mv openAccess
dc.publisher.none.fl_str_mv Elsevier
publisher.none.fl_str_mv Elsevier
dc.source.none.fl_str_mv reponame:Repisalud
instname:Instituto de Salud Carlos III (ISCIII)
instname_str Instituto de Salud Carlos III (ISCIII)
reponame_str Repisalud
collection Repisalud
repository.name.fl_str_mv
repository.mail.fl_str_mv
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score 15,811543

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