In-Vitro Selection of Ceftazidime/Avibactam Resistance in OXA-48-Like-Expressing <i>Klebsiella pneumoniae</i>: In-Vitro and In-Vivo Fitness, Genetic Basis and Activities of β-Lactam Plus Novel β-Lactamase Inhibitor or β-Lactam Enhancer Combinations

Ceftazidime/avibactam uniquely demonstrates activity against both KPC and OXA-48-like carbapenemase-expressing Enterobacterales. Clinical resistance to ceftazidime/avibactam in KPC-producers was foreseen in in-vitro resistance studies. Herein, we assessed the resistance selection propensity of cefta...

Descripción completa

Guardado en:

Detalles Bibliográficos
Autores principales:	Snehal Palwe, Yamuna Devi Bakthavatchalam, Kshama Khobragadea, Arun S. Kharat, Kamini Walia, Balaji Veeraraghavan
Formato:	article
Lenguaje:	EN
Publicado:	MDPI AG 2021
Materias:	ceftazidime/avibactam β-lactams β-lactamase inhibitor multi-drug resistance Therapeutics. Pharmacology RM1-950
Acceso en línea:	https://doaj.org/article/b393954d1a6143759452cbbd2c6768ea
Etiquetas:	Agregar Etiqueta Sin Etiquetas, Sea el primero en etiquetar este registro!

id	oai:doaj.org-article:b393954d1a6143759452cbbd2c6768ea
record_format	dspace
spelling	oai:doaj.org-article:b393954d1a6143759452cbbd2c6768ea2021-11-25T16:22:42ZIn-Vitro Selection of Ceftazidime/Avibactam Resistance in OXA-48-Like-Expressing <i>Klebsiella pneumoniae</i>: In-Vitro and In-Vivo Fitness, Genetic Basis and Activities of β-Lactam Plus Novel β-Lactamase Inhibitor or β-Lactam Enhancer Combinations10.3390/antibiotics101113182079-6382https://doaj.org/article/b393954d1a6143759452cbbd2c6768ea2021-10-01T00:00:00Zhttps://www.mdpi.com/2079-6382/10/11/1318https://doaj.org/toc/2079-6382Ceftazidime/avibactam uniquely demonstrates activity against both KPC and OXA-48-like carbapenemase-expressing Enterobacterales. Clinical resistance to ceftazidime/avibactam in KPC-producers was foreseen in in-vitro resistance studies. Herein, we assessed the resistance selection propensity of ceftazidime/avibactam in <i>K. pneumoniae</i> expressing OXA-48-like β-lactamases (<i>n</i> = 10), employing serial transfer approach. Ceftazidime/avibactam MICs (0.25–4 mg/L) increased to 16–256 mg/L after 15 daily-sequential transfers. The whole genome sequence analysis of terminal mutants showed modifications in proteins linked to efflux (AcrB/AcrD/EmrA/Mdt), outer membrane permeability (OmpK36) and/or stress response pathways (CpxA/EnvZ/RpoE). In-vitro growth properties of all the ceftazidime/avibactam-selected mutants were comparable to their respective parents and they retained the ability to cause pulmonary infection in neutropenic mice. Against these mutants, we explored the activities of various combinations of β-lactams (ceftazidime or cefepime) with structurally diverse β-lactamase inhibitors or a β-lactam enhancer, zidebactam. Zidebactam, in combination with either cefepime or ceftazidime, overcame ceftazidime/avibactam resistance (MIC range 0.5–8 mg/L), while cefepime/avibactam was the second best (MIC: 0.5–16 mg/L) in yielding lower MICs. The present work revealed the possibility of ceftazidime/avibactam resistance in OXA-48-like <i>K. pneumoniae</i> through mutations in proteins involved in efflux and/or porins without concomitant fitness cost mandating astute monitoring of ceftazidime/avibactam resistance among OXA-48 genotypes.Snehal PalweYamuna Devi BakthavatchalamKshama KhobragadeaArun S. KharatKamini WaliaBalaji VeeraraghavanMDPI AGarticleceftazidime/avibactamβ-lactamsβ-lactamase inhibitormulti-drug resistanceTherapeutics. PharmacologyRM1-950ENAntibiotics, Vol 10, Iss 1318, p 1318 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	ceftazidime/avibactam β-lactams β-lactamase inhibitor multi-drug resistance Therapeutics. Pharmacology RM1-950
spellingShingle	ceftazidime/avibactam β-lactams β-lactamase inhibitor multi-drug resistance Therapeutics. Pharmacology RM1-950 Snehal Palwe Yamuna Devi Bakthavatchalam Kshama Khobragadea Arun S. Kharat Kamini Walia Balaji Veeraraghavan In-Vitro Selection of Ceftazidime/Avibactam Resistance in OXA-48-Like-Expressing <i>Klebsiella pneumoniae</i>: In-Vitro and In-Vivo Fitness, Genetic Basis and Activities of β-Lactam Plus Novel β-Lactamase Inhibitor or β-Lactam Enhancer Combinations
description	Ceftazidime/avibactam uniquely demonstrates activity against both KPC and OXA-48-like carbapenemase-expressing Enterobacterales. Clinical resistance to ceftazidime/avibactam in KPC-producers was foreseen in in-vitro resistance studies. Herein, we assessed the resistance selection propensity of ceftazidime/avibactam in <i>K. pneumoniae</i> expressing OXA-48-like β-lactamases (<i>n</i> = 10), employing serial transfer approach. Ceftazidime/avibactam MICs (0.25–4 mg/L) increased to 16–256 mg/L after 15 daily-sequential transfers. The whole genome sequence analysis of terminal mutants showed modifications in proteins linked to efflux (AcrB/AcrD/EmrA/Mdt), outer membrane permeability (OmpK36) and/or stress response pathways (CpxA/EnvZ/RpoE). In-vitro growth properties of all the ceftazidime/avibactam-selected mutants were comparable to their respective parents and they retained the ability to cause pulmonary infection in neutropenic mice. Against these mutants, we explored the activities of various combinations of β-lactams (ceftazidime or cefepime) with structurally diverse β-lactamase inhibitors or a β-lactam enhancer, zidebactam. Zidebactam, in combination with either cefepime or ceftazidime, overcame ceftazidime/avibactam resistance (MIC range 0.5–8 mg/L), while cefepime/avibactam was the second best (MIC: 0.5–16 mg/L) in yielding lower MICs. The present work revealed the possibility of ceftazidime/avibactam resistance in OXA-48-like <i>K. pneumoniae</i> through mutations in proteins involved in efflux and/or porins without concomitant fitness cost mandating astute monitoring of ceftazidime/avibactam resistance among OXA-48 genotypes.
format	article
author	Snehal Palwe Yamuna Devi Bakthavatchalam Kshama Khobragadea Arun S. Kharat Kamini Walia Balaji Veeraraghavan
author_facet	Snehal Palwe Yamuna Devi Bakthavatchalam Kshama Khobragadea Arun S. Kharat Kamini Walia Balaji Veeraraghavan
author_sort	Snehal Palwe
title	In-Vitro Selection of Ceftazidime/Avibactam Resistance in OXA-48-Like-Expressing <i>Klebsiella pneumoniae</i>: In-Vitro and In-Vivo Fitness, Genetic Basis and Activities of β-Lactam Plus Novel β-Lactamase Inhibitor or β-Lactam Enhancer Combinations
title_short	In-Vitro Selection of Ceftazidime/Avibactam Resistance in OXA-48-Like-Expressing <i>Klebsiella pneumoniae</i>: In-Vitro and In-Vivo Fitness, Genetic Basis and Activities of β-Lactam Plus Novel β-Lactamase Inhibitor or β-Lactam Enhancer Combinations
title_full	In-Vitro Selection of Ceftazidime/Avibactam Resistance in OXA-48-Like-Expressing <i>Klebsiella pneumoniae</i>: In-Vitro and In-Vivo Fitness, Genetic Basis and Activities of β-Lactam Plus Novel β-Lactamase Inhibitor or β-Lactam Enhancer Combinations
title_fullStr	In-Vitro Selection of Ceftazidime/Avibactam Resistance in OXA-48-Like-Expressing <i>Klebsiella pneumoniae</i>: In-Vitro and In-Vivo Fitness, Genetic Basis and Activities of β-Lactam Plus Novel β-Lactamase Inhibitor or β-Lactam Enhancer Combinations
title_full_unstemmed	In-Vitro Selection of Ceftazidime/Avibactam Resistance in OXA-48-Like-Expressing <i>Klebsiella pneumoniae</i>: In-Vitro and In-Vivo Fitness, Genetic Basis and Activities of β-Lactam Plus Novel β-Lactamase Inhibitor or β-Lactam Enhancer Combinations
title_sort	in-vitro selection of ceftazidime/avibactam resistance in oxa-48-like-expressing <i>klebsiella pneumoniae</i>: in-vitro and in-vivo fitness, genetic basis and activities of β-lactam plus novel β-lactamase inhibitor or β-lactam enhancer combinations
publisher	MDPI AG
publishDate	2021
url	https://doaj.org/article/b393954d1a6143759452cbbd2c6768ea
work_keys_str_mv	AT snehalpalwe invitroselectionofceftazidimeavibactamresistanceinoxa48likeexpressingiklebsiellapneumoniaeiinvitroandinvivofitnessgeneticbasisandactivitiesofblactamplusnovelblactamaseinhibitororblactamenhancercombinations AT yamunadevibakthavatchalam invitroselectionofceftazidimeavibactamresistanceinoxa48likeexpressingiklebsiellapneumoniaeiinvitroandinvivofitnessgeneticbasisandactivitiesofblactamplusnovelblactamaseinhibitororblactamenhancercombinations AT kshamakhobragadea invitroselectionofceftazidimeavibactamresistanceinoxa48likeexpressingiklebsiellapneumoniaeiinvitroandinvivofitnessgeneticbasisandactivitiesofblactamplusnovelblactamaseinhibitororblactamenhancercombinations AT arunskharat invitroselectionofceftazidimeavibactamresistanceinoxa48likeexpressingiklebsiellapneumoniaeiinvitroandinvivofitnessgeneticbasisandactivitiesofblactamplusnovelblactamaseinhibitororblactamenhancercombinations AT kaminiwalia invitroselectionofceftazidimeavibactamresistanceinoxa48likeexpressingiklebsiellapneumoniaeiinvitroandinvivofitnessgeneticbasisandactivitiesofblactamplusnovelblactamaseinhibitororblactamenhancercombinations AT balajiveeraraghavan invitroselectionofceftazidimeavibactamresistanceinoxa48likeexpressingiklebsiellapneumoniaeiinvitroandinvivofitnessgeneticbasisandactivitiesofblactamplusnovelblactamaseinhibitororblactamenhancercombinations
_version_	1718413221548785664

In-Vitro Selection of Ceftazidime/Avibactam Resistance in OXA-48-Like-Expressing <i>Klebsiella pneumoniae</i>: In-Vitro and In-Vivo Fitness, Genetic Basis and Activities of β-Lactam Plus Novel β-Lactamase Inhibitor or β-Lactam Enhancer Combinations

Ejemplares similares