Population Pharmacokinetics of Intravenous Amoxicillin Combined With Clavulanic Acid in Healthy and Critically Ill Dogs

Background: Data regarding antimicrobial pharmacokinetics (PK) in critically ill dogs are lacking and likely differ from those of healthy dogs. The aim of this work is to describe a population PK model for intravenous (IV) amoxicillin–clavulanic acid (AMC) in both healthy and sick dogs and to simula...

Descripción completa

Guardado en:

Detalles Bibliográficos
Autores principales:	Maria D. Vegas Cómitre, Stefano Cortellini, Marc Cherlet, Mathias Devreese, Beatrice B. Roques, Alain Bousquet-Melou, Pierre-Louis Toutain, Ludovic Pelligand
Formato:	article
Lenguaje:	EN
Publicado:	Frontiers Media S.A. 2021
Materias:	antimicrobial MIC clinical breakpoint Augmentin ICU VetCast Veterinary medicine SF600-1100
Acceso en línea:	https://doaj.org/article/3709d17f3feb47fe83bbefd066e8d366
Etiquetas:	Agregar Etiqueta Sin Etiquetas, Sea el primero en etiquetar este registro!

id	oai:doaj.org-article:3709d17f3feb47fe83bbefd066e8d366
record_format	dspace
spelling	oai:doaj.org-article:3709d17f3feb47fe83bbefd066e8d3662021-11-15T06:57:55ZPopulation Pharmacokinetics of Intravenous Amoxicillin Combined With Clavulanic Acid in Healthy and Critically Ill Dogs2297-176910.3389/fvets.2021.770202https://doaj.org/article/3709d17f3feb47fe83bbefd066e8d3662021-11-01T00:00:00Zhttps://www.frontiersin.org/articles/10.3389/fvets.2021.770202/fullhttps://doaj.org/toc/2297-1769Background: Data regarding antimicrobial pharmacokinetics (PK) in critically ill dogs are lacking and likely differ from those of healthy dogs. The aim of this work is to describe a population PK model for intravenous (IV) amoxicillin–clavulanic acid (AMC) in both healthy and sick dogs and to simulate a range of clinical dosing scenarios to compute PK/PD cutoffs for both populations.Methods: This study used a prospective clinical trial in normal and critically ill dogs. Twelve client-owned dogs hospitalized in the intensive care unit (ICU) received IV AMC 20 mg/kg every 8 h (0.5-h infusion) during at least 48 h. Eight blood samples were collected at predetermined times, including four trough samples before the next administration. Clinical covariates and outcome were recorded, including survival to discharge and bacteriologic clinical failure. Satellite PK data were obtained de novo from a group of 12 healthy research dogs that were dosed with a single AMC 20 mg/kg IV. Non-linear mixed-effects model was used to estimate the PK parameters (and the effect of health upon them) together with variability within and between subjects. Monte Carlo simulations were performed with seven dosage regimens (standard and increased doses). The correlation between model-derived drug exposure and clinical covariates was tested with Spearman's non-parametric correlation analysis. Outcome was recorded including survival to discharge and bacteriologic clinical failure.Results: A total of 218 amoxicillin concentrations in plasma were available for healthy and sick dogs. A tricompartmental model best described the data. Amoxicillin clearance was reduced by 56% in sick dogs (0.147 L/kg/h) compared with healthy dogs (0.336 L/kg/h); intercompartmental clearance was also decreased (p <0.01). None of the clinical data covariates were significantly correlated with individual exposure. Monte Carlo simulations showed that higher PK/PD cutoff values of 8 mg/L could be reached in sick dogs by extending the infusion to 3 h or doubling the dose.Conclusions: The PK of AMC is profoundly different in critically ill dogs compared with normal dogs, with much higher interindividual variability and a lower systemic clearance. Our study allows to generate hypotheses with regard to higher AMC exposure in clinical dogs and provides supporting data to revise current AMC clinical breakpoint for IV administration.Maria D. Vegas CómitreStefano CortelliniMarc CherletMathias DevreeseBeatrice B. RoquesAlain Bousquet-MelouPierre-Louis ToutainPierre-Louis ToutainLudovic PelligandLudovic PelligandFrontiers Media S.A.articleantimicrobialMICclinical breakpointAugmentinICUVetCastVeterinary medicineSF600-1100ENFrontiers in Veterinary Science, Vol 8 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	antimicrobial MIC clinical breakpoint Augmentin ICU VetCast Veterinary medicine SF600-1100
spellingShingle	antimicrobial MIC clinical breakpoint Augmentin ICU VetCast Veterinary medicine SF600-1100 Maria D. Vegas Cómitre Stefano Cortellini Marc Cherlet Mathias Devreese Beatrice B. Roques Alain Bousquet-Melou Pierre-Louis Toutain Pierre-Louis Toutain Ludovic Pelligand Ludovic Pelligand Population Pharmacokinetics of Intravenous Amoxicillin Combined With Clavulanic Acid in Healthy and Critically Ill Dogs
description	Background: Data regarding antimicrobial pharmacokinetics (PK) in critically ill dogs are lacking and likely differ from those of healthy dogs. The aim of this work is to describe a population PK model for intravenous (IV) amoxicillin–clavulanic acid (AMC) in both healthy and sick dogs and to simulate a range of clinical dosing scenarios to compute PK/PD cutoffs for both populations.Methods: This study used a prospective clinical trial in normal and critically ill dogs. Twelve client-owned dogs hospitalized in the intensive care unit (ICU) received IV AMC 20 mg/kg every 8 h (0.5-h infusion) during at least 48 h. Eight blood samples were collected at predetermined times, including four trough samples before the next administration. Clinical covariates and outcome were recorded, including survival to discharge and bacteriologic clinical failure. Satellite PK data were obtained de novo from a group of 12 healthy research dogs that were dosed with a single AMC 20 mg/kg IV. Non-linear mixed-effects model was used to estimate the PK parameters (and the effect of health upon them) together with variability within and between subjects. Monte Carlo simulations were performed with seven dosage regimens (standard and increased doses). The correlation between model-derived drug exposure and clinical covariates was tested with Spearman's non-parametric correlation analysis. Outcome was recorded including survival to discharge and bacteriologic clinical failure.Results: A total of 218 amoxicillin concentrations in plasma were available for healthy and sick dogs. A tricompartmental model best described the data. Amoxicillin clearance was reduced by 56% in sick dogs (0.147 L/kg/h) compared with healthy dogs (0.336 L/kg/h); intercompartmental clearance was also decreased (p <0.01). None of the clinical data covariates were significantly correlated with individual exposure. Monte Carlo simulations showed that higher PK/PD cutoff values of 8 mg/L could be reached in sick dogs by extending the infusion to 3 h or doubling the dose.Conclusions: The PK of AMC is profoundly different in critically ill dogs compared with normal dogs, with much higher interindividual variability and a lower systemic clearance. Our study allows to generate hypotheses with regard to higher AMC exposure in clinical dogs and provides supporting data to revise current AMC clinical breakpoint for IV administration.
format	article
author	Maria D. Vegas Cómitre Stefano Cortellini Marc Cherlet Mathias Devreese Beatrice B. Roques Alain Bousquet-Melou Pierre-Louis Toutain Pierre-Louis Toutain Ludovic Pelligand Ludovic Pelligand
author_facet	Maria D. Vegas Cómitre Stefano Cortellini Marc Cherlet Mathias Devreese Beatrice B. Roques Alain Bousquet-Melou Pierre-Louis Toutain Pierre-Louis Toutain Ludovic Pelligand Ludovic Pelligand
author_sort	Maria D. Vegas Cómitre
title	Population Pharmacokinetics of Intravenous Amoxicillin Combined With Clavulanic Acid in Healthy and Critically Ill Dogs
title_short	Population Pharmacokinetics of Intravenous Amoxicillin Combined With Clavulanic Acid in Healthy and Critically Ill Dogs
title_full	Population Pharmacokinetics of Intravenous Amoxicillin Combined With Clavulanic Acid in Healthy and Critically Ill Dogs
title_fullStr	Population Pharmacokinetics of Intravenous Amoxicillin Combined With Clavulanic Acid in Healthy and Critically Ill Dogs
title_full_unstemmed	Population Pharmacokinetics of Intravenous Amoxicillin Combined With Clavulanic Acid in Healthy and Critically Ill Dogs
title_sort	population pharmacokinetics of intravenous amoxicillin combined with clavulanic acid in healthy and critically ill dogs
publisher	Frontiers Media S.A.
publishDate	2021
url	https://doaj.org/article/3709d17f3feb47fe83bbefd066e8d366
work_keys_str_mv	AT mariadvegascomitre populationpharmacokineticsofintravenousamoxicillincombinedwithclavulanicacidinhealthyandcriticallyilldogs AT stefanocortellini populationpharmacokineticsofintravenousamoxicillincombinedwithclavulanicacidinhealthyandcriticallyilldogs AT marccherlet populationpharmacokineticsofintravenousamoxicillincombinedwithclavulanicacidinhealthyandcriticallyilldogs AT mathiasdevreese populationpharmacokineticsofintravenousamoxicillincombinedwithclavulanicacidinhealthyandcriticallyilldogs AT beatricebroques populationpharmacokineticsofintravenousamoxicillincombinedwithclavulanicacidinhealthyandcriticallyilldogs AT alainbousquetmelou populationpharmacokineticsofintravenousamoxicillincombinedwithclavulanicacidinhealthyandcriticallyilldogs AT pierrelouistoutain populationpharmacokineticsofintravenousamoxicillincombinedwithclavulanicacidinhealthyandcriticallyilldogs AT pierrelouistoutain populationpharmacokineticsofintravenousamoxicillincombinedwithclavulanicacidinhealthyandcriticallyilldogs AT ludovicpelligand populationpharmacokineticsofintravenousamoxicillincombinedwithclavulanicacidinhealthyandcriticallyilldogs AT ludovicpelligand populationpharmacokineticsofintravenousamoxicillincombinedwithclavulanicacidinhealthyandcriticallyilldogs
_version_	1718428488593047552

Population Pharmacokinetics of Intravenous Amoxicillin Combined With Clavulanic Acid in Healthy and Critically Ill Dogs

Ejemplares similares