Suboptimal drug exposure leads to selection of different subpopulations of ceftazidime-avibactam-resistant Klebsiella pneumoniae carbapenemase-producing Klebsiella pneumoniae in a critically ill patient

Objectives: Ceftazidime-avibactam (CAZ-AVI) is a promising novel agent with activity against carbapenem-resistant Enterobacteriaceae. Here, we describe the dynamic evolution of a Klebsiella pneumoniae carbapenemase-producing Klebsiella pneumoniae (KPC-Kp) infection in a critically ill patient treate...

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Autores principales:	Paolo Gaibani, Milo Gatti, Matteo Rinaldi, Cristina Crovara Pesce, Tiziana Lazzarotto, Maddalena Giannella, Donatella Lombardo, Stefano Amadesi, Pierluigi Viale, Federico Pea, Simone Ambretti
Formato:	article
Lenguaje:	EN
Publicado:	Elsevier 2021
Materias:	ceftazidime-avibactam-resistance PK/PD critically ill patient whole-genome sequencing Infectious and parasitic diseases RC109-216
Acceso en línea:	https://doaj.org/article/56472403412b4437858c06138af240c6
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spelling	oai:doaj.org-article:56472403412b4437858c06138af240c62021-11-12T04:27:27ZSuboptimal drug exposure leads to selection of different subpopulations of ceftazidime-avibactam-resistant Klebsiella pneumoniae carbapenemase-producing Klebsiella pneumoniae in a critically ill patient1201-971210.1016/j.ijid.2021.10.028https://doaj.org/article/56472403412b4437858c06138af240c62021-12-01T00:00:00Zhttp://www.sciencedirect.com/science/article/pii/S120197122100816Xhttps://doaj.org/toc/1201-9712Objectives: Ceftazidime-avibactam (CAZ-AVI) is a promising novel agent with activity against carbapenem-resistant Enterobacteriaceae. Here, we describe the dynamic evolution of a Klebsiella pneumoniae carbapenemase-producing Klebsiella pneumoniae (KPC-Kp) infection in a critically ill patient treated with CAZ-AVI-tigecycline combination therapy. Methods: Whole-genome sequencing was performed on longitudinal intrapatient KPC-Kp strains isolated from different sites during CAZ-AVI treatment. The pharmacokinetic/pharmacodynamic (PK/PD) analysis was performed on the basis of therapeutic drug monitoring of ceftazidime. Results: The development of resistance due to mutations in the blaKPC gene was observed in KPC-Kp strains isolated from bronchoalveolar lavage and blood during CAZ-AVI treatment. PK/PD analysis demonstrated that during the first days of treatment CAZ- AVI blood exposure was suboptimal (steady-state concentration/minimum inhibitory concentration ratio 2.85). Of note, the low antibiotic pressure may have selected hybrid subpopulations harboring blaKPC-3 and T243M mutation in KPC-Kp isolated from bronchoalveolar lavage and D179Y mutation in those isolated from blood. Conclusion: These results suggest the high adaptability of KPC to CAZ-AVI due to the rapid evolution of resistance and highlight the importance of identifying the optimal PK/PD target to prevent such an event from occurring again in a critically ill patient with pneumonia due to KPC-Kp.Paolo GaibaniMilo GattiMatteo RinaldiCristina Crovara PesceTiziana LazzarottoMaddalena GiannellaDonatella LombardoStefano AmadesiPierluigi VialeFederico PeaSimone AmbrettiElsevierarticleceftazidime-avibactam-resistancePK/PDcritically ill patientwhole-genome sequencingInfectious and parasitic diseasesRC109-216ENInternational Journal of Infectious Diseases, Vol 113, Iss , Pp 213-217 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	ceftazidime-avibactam-resistance PK/PD critically ill patient whole-genome sequencing Infectious and parasitic diseases RC109-216
spellingShingle	ceftazidime-avibactam-resistance PK/PD critically ill patient whole-genome sequencing Infectious and parasitic diseases RC109-216 Paolo Gaibani Milo Gatti Matteo Rinaldi Cristina Crovara Pesce Tiziana Lazzarotto Maddalena Giannella Donatella Lombardo Stefano Amadesi Pierluigi Viale Federico Pea Simone Ambretti Suboptimal drug exposure leads to selection of different subpopulations of ceftazidime-avibactam-resistant Klebsiella pneumoniae carbapenemase-producing Klebsiella pneumoniae in a critically ill patient
description	Objectives: Ceftazidime-avibactam (CAZ-AVI) is a promising novel agent with activity against carbapenem-resistant Enterobacteriaceae. Here, we describe the dynamic evolution of a Klebsiella pneumoniae carbapenemase-producing Klebsiella pneumoniae (KPC-Kp) infection in a critically ill patient treated with CAZ-AVI-tigecycline combination therapy. Methods: Whole-genome sequencing was performed on longitudinal intrapatient KPC-Kp strains isolated from different sites during CAZ-AVI treatment. The pharmacokinetic/pharmacodynamic (PK/PD) analysis was performed on the basis of therapeutic drug monitoring of ceftazidime. Results: The development of resistance due to mutations in the blaKPC gene was observed in KPC-Kp strains isolated from bronchoalveolar lavage and blood during CAZ-AVI treatment. PK/PD analysis demonstrated that during the first days of treatment CAZ- AVI blood exposure was suboptimal (steady-state concentration/minimum inhibitory concentration ratio 2.85). Of note, the low antibiotic pressure may have selected hybrid subpopulations harboring blaKPC-3 and T243M mutation in KPC-Kp isolated from bronchoalveolar lavage and D179Y mutation in those isolated from blood. Conclusion: These results suggest the high adaptability of KPC to CAZ-AVI due to the rapid evolution of resistance and highlight the importance of identifying the optimal PK/PD target to prevent such an event from occurring again in a critically ill patient with pneumonia due to KPC-Kp.
format	article
author	Paolo Gaibani Milo Gatti Matteo Rinaldi Cristina Crovara Pesce Tiziana Lazzarotto Maddalena Giannella Donatella Lombardo Stefano Amadesi Pierluigi Viale Federico Pea Simone Ambretti
author_facet	Paolo Gaibani Milo Gatti Matteo Rinaldi Cristina Crovara Pesce Tiziana Lazzarotto Maddalena Giannella Donatella Lombardo Stefano Amadesi Pierluigi Viale Federico Pea Simone Ambretti
author_sort	Paolo Gaibani
title	Suboptimal drug exposure leads to selection of different subpopulations of ceftazidime-avibactam-resistant Klebsiella pneumoniae carbapenemase-producing Klebsiella pneumoniae in a critically ill patient
title_short	Suboptimal drug exposure leads to selection of different subpopulations of ceftazidime-avibactam-resistant Klebsiella pneumoniae carbapenemase-producing Klebsiella pneumoniae in a critically ill patient
title_full	Suboptimal drug exposure leads to selection of different subpopulations of ceftazidime-avibactam-resistant Klebsiella pneumoniae carbapenemase-producing Klebsiella pneumoniae in a critically ill patient
title_fullStr	Suboptimal drug exposure leads to selection of different subpopulations of ceftazidime-avibactam-resistant Klebsiella pneumoniae carbapenemase-producing Klebsiella pneumoniae in a critically ill patient
title_full_unstemmed	Suboptimal drug exposure leads to selection of different subpopulations of ceftazidime-avibactam-resistant Klebsiella pneumoniae carbapenemase-producing Klebsiella pneumoniae in a critically ill patient
title_sort	suboptimal drug exposure leads to selection of different subpopulations of ceftazidime-avibactam-resistant klebsiella pneumoniae carbapenemase-producing klebsiella pneumoniae in a critically ill patient
publisher	Elsevier
publishDate	2021
url	https://doaj.org/article/56472403412b4437858c06138af240c6
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Suboptimal drug exposure leads to selection of different subpopulations of ceftazidime-avibactam-resistant Klebsiella pneumoniae carbapenemase-producing Klebsiella pneumoniae in a critically ill patient

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