Cargando…
In-Vitro Selection of Ceftazidime/Avibactam Resistance in OXA-48-Like-Expressing Klebsiella pneumoniae: 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...
Autores principales: | , , , , , |
---|---|
Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
MDPI
2021
|
Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8614831/ https://www.ncbi.nlm.nih.gov/pubmed/34827256 http://dx.doi.org/10.3390/antibiotics10111318 |
_version_ | 1784603956403503104 |
---|---|
author | Palwe, Snehal Bakthavatchalam, Yamuna Devi Khobragadea, Kshama Kharat, Arun S. Walia, Kamini Veeraraghavan, Balaji |
author_facet | Palwe, Snehal Bakthavatchalam, Yamuna Devi Khobragadea, Kshama Kharat, Arun S. Walia, Kamini Veeraraghavan, Balaji |
author_sort | Palwe, Snehal |
collection | PubMed |
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 K. pneumoniae expressing OXA-48-like β-lactamases (n = 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 K. pneumoniae 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 | Online Article Text |
id | pubmed-8614831 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2021 |
publisher | MDPI |
record_format | MEDLINE/PubMed |
spelling | pubmed-86148312021-11-26 In-Vitro Selection of Ceftazidime/Avibactam Resistance in OXA-48-Like-Expressing Klebsiella pneumoniae: In-Vitro and In-Vivo Fitness, Genetic Basis and Activities of β-Lactam Plus Novel β-Lactamase Inhibitor or β-Lactam Enhancer Combinations Palwe, Snehal Bakthavatchalam, Yamuna Devi Khobragadea, Kshama Kharat, Arun S. Walia, Kamini Veeraraghavan, Balaji Antibiotics (Basel) Article 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 K. pneumoniae expressing OXA-48-like β-lactamases (n = 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 K. pneumoniae 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. MDPI 2021-10-29 /pmc/articles/PMC8614831/ /pubmed/34827256 http://dx.doi.org/10.3390/antibiotics10111318 Text en © 2021 by the authors. https://creativecommons.org/licenses/by/4.0/Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/). |
spellingShingle | Article Palwe, Snehal Bakthavatchalam, Yamuna Devi Khobragadea, Kshama Kharat, Arun S. Walia, Kamini Veeraraghavan, Balaji In-Vitro Selection of Ceftazidime/Avibactam Resistance in OXA-48-Like-Expressing Klebsiella pneumoniae: In-Vitro and In-Vivo Fitness, Genetic Basis and Activities of β-Lactam Plus Novel β-Lactamase Inhibitor or β-Lactam Enhancer Combinations |
title | In-Vitro Selection of Ceftazidime/Avibactam Resistance in OXA-48-Like-Expressing Klebsiella pneumoniae: 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 Klebsiella pneumoniae: 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 Klebsiella pneumoniae: 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 Klebsiella pneumoniae: 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 Klebsiella pneumoniae: 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 klebsiella pneumoniae: in-vitro and in-vivo fitness, genetic basis and activities of β-lactam plus novel β-lactamase inhibitor or β-lactam enhancer combinations |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8614831/ https://www.ncbi.nlm.nih.gov/pubmed/34827256 http://dx.doi.org/10.3390/antibiotics10111318 |
work_keys_str_mv | AT palwesnehal invitroselectionofceftazidimeavibactamresistanceinoxa48likeexpressingklebsiellapneumoniaeinvitroandinvivofitnessgeneticbasisandactivitiesofblactamplusnovelblactamaseinhibitororblactamenhancercombinations AT bakthavatchalamyamunadevi invitroselectionofceftazidimeavibactamresistanceinoxa48likeexpressingklebsiellapneumoniaeinvitroandinvivofitnessgeneticbasisandactivitiesofblactamplusnovelblactamaseinhibitororblactamenhancercombinations AT khobragadeakshama invitroselectionofceftazidimeavibactamresistanceinoxa48likeexpressingklebsiellapneumoniaeinvitroandinvivofitnessgeneticbasisandactivitiesofblactamplusnovelblactamaseinhibitororblactamenhancercombinations AT kharataruns invitroselectionofceftazidimeavibactamresistanceinoxa48likeexpressingklebsiellapneumoniaeinvitroandinvivofitnessgeneticbasisandactivitiesofblactamplusnovelblactamaseinhibitororblactamenhancercombinations AT waliakamini invitroselectionofceftazidimeavibactamresistanceinoxa48likeexpressingklebsiellapneumoniaeinvitroandinvivofitnessgeneticbasisandactivitiesofblactamplusnovelblactamaseinhibitororblactamenhancercombinations AT veeraraghavanbalaji invitroselectionofceftazidimeavibactamresistanceinoxa48likeexpressingklebsiellapneumoniaeinvitroandinvivofitnessgeneticbasisandactivitiesofblactamplusnovelblactamaseinhibitororblactamenhancercombinations |