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Efficacy of mecillinam against clinical multidrug-resistant Escherichia coli in a murine urinary tract infection model

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Zykov, Ilya Nikolaevich ; Frimodt-Møller, Niels ; Småbrekke, Lars ; Sundsfjord, Arnfinn ; Samuelsen, Ørjan. / Efficacy of mecillinam against clinical multidrug-resistant Escherichia coli in a murine urinary tract infection model. In: International Journal of Antimicrobial Agents. 2020 ; Vol. 55, No. 2. pp. 105851.

Bibtex

@article{3c47ab00c09944d489bc173f1011e3d9,
title = "Efficacy of mecillinam against clinical multidrug-resistant Escherichia coli in a murine urinary tract infection model",
abstract = "Pivmecillinam, a pro-drug of mecillinam, has been used extensively in Scandinavia for the treatment of acute lower urinary tract infections (UTIs) caused by Enterobacterales. It is still an attractive first-line drug for the empirical treatment of UTIs owing to the low prevalence of resistance as well as its favourable impact on the intestinal microbiota as a pro-drug and good in vitro efficacy against extended-spectrum β-lactamase (ESBL)- and plasmid-mediated AmpC β-lactamase-producing Escherichia coli. However, optimal dosing of pivmecillinam as well as its in vivo efficacy against UTIs caused by multidrug-resistant (MDR) broad-spectrum β-lactamase-producing E. coli has not been thoroughly studied. In this study, the efficacy of two mimicked human dosing regimens of pivmecillinam (200 mg and 400 mg three times daily) against clinical E. coli strains, including isolates producing ESBLs (CTX-M-14 and CTX-M-15), plasmid-mediated AmpCs (CMY-4 and CMY-6) and carbapenemases (NDM-1 and VIM-29), in a murine UTI model was compared. Both dosing regimens reduced the number of CFU/mL in urine for all strains, including mecillinam-resistant strains. Combining the effect for all six strains showed no significant differences in effect between doses for all three fluids/organs, but for each dose there was a highly significant effect in urine, kidney and bladder compared with vehicle-treated mice. Overall, this highlights the need for further studies to elucidate the role of mecillinam in the treatment of infections caused by MDR E. coli producing broad-spectrum β-lactamases, including specific carbapenemases.",
keywords = "Carbapenemase, ESBL, In vivo, Mecillinam, Multidrug-resistant, UTI model",
author = "Zykov, {Ilya Nikolaevich} and Niels Frimodt-M{\o}ller and Lars Sm{\aa}brekke and Arnfinn Sundsfjord and {\O}rjan Samuelsen",
note = "Copyright {\circledC} 2019 The Author(s). Published by Elsevier B.V. All rights reserved.",
year = "2020",
month = "2",
doi = "10.1016/j.ijantimicag.2019.11.008",
language = "English",
volume = "55",
pages = "105851",
journal = "International Journal of Antimicrobial Agents",
issn = "0924-8579",
publisher = "Elsevier BV",
number = "2",

}

RIS

TY - JOUR

T1 - Efficacy of mecillinam against clinical multidrug-resistant Escherichia coli in a murine urinary tract infection model

AU - Zykov, Ilya Nikolaevich

AU - Frimodt-Møller, Niels

AU - Småbrekke, Lars

AU - Sundsfjord, Arnfinn

AU - Samuelsen, Ørjan

N1 - Copyright © 2019 The Author(s). Published by Elsevier B.V. All rights reserved.

PY - 2020/2

Y1 - 2020/2

N2 - Pivmecillinam, a pro-drug of mecillinam, has been used extensively in Scandinavia for the treatment of acute lower urinary tract infections (UTIs) caused by Enterobacterales. It is still an attractive first-line drug for the empirical treatment of UTIs owing to the low prevalence of resistance as well as its favourable impact on the intestinal microbiota as a pro-drug and good in vitro efficacy against extended-spectrum β-lactamase (ESBL)- and plasmid-mediated AmpC β-lactamase-producing Escherichia coli. However, optimal dosing of pivmecillinam as well as its in vivo efficacy against UTIs caused by multidrug-resistant (MDR) broad-spectrum β-lactamase-producing E. coli has not been thoroughly studied. In this study, the efficacy of two mimicked human dosing regimens of pivmecillinam (200 mg and 400 mg three times daily) against clinical E. coli strains, including isolates producing ESBLs (CTX-M-14 and CTX-M-15), plasmid-mediated AmpCs (CMY-4 and CMY-6) and carbapenemases (NDM-1 and VIM-29), in a murine UTI model was compared. Both dosing regimens reduced the number of CFU/mL in urine for all strains, including mecillinam-resistant strains. Combining the effect for all six strains showed no significant differences in effect between doses for all three fluids/organs, but for each dose there was a highly significant effect in urine, kidney and bladder compared with vehicle-treated mice. Overall, this highlights the need for further studies to elucidate the role of mecillinam in the treatment of infections caused by MDR E. coli producing broad-spectrum β-lactamases, including specific carbapenemases.

AB - Pivmecillinam, a pro-drug of mecillinam, has been used extensively in Scandinavia for the treatment of acute lower urinary tract infections (UTIs) caused by Enterobacterales. It is still an attractive first-line drug for the empirical treatment of UTIs owing to the low prevalence of resistance as well as its favourable impact on the intestinal microbiota as a pro-drug and good in vitro efficacy against extended-spectrum β-lactamase (ESBL)- and plasmid-mediated AmpC β-lactamase-producing Escherichia coli. However, optimal dosing of pivmecillinam as well as its in vivo efficacy against UTIs caused by multidrug-resistant (MDR) broad-spectrum β-lactamase-producing E. coli has not been thoroughly studied. In this study, the efficacy of two mimicked human dosing regimens of pivmecillinam (200 mg and 400 mg three times daily) against clinical E. coli strains, including isolates producing ESBLs (CTX-M-14 and CTX-M-15), plasmid-mediated AmpCs (CMY-4 and CMY-6) and carbapenemases (NDM-1 and VIM-29), in a murine UTI model was compared. Both dosing regimens reduced the number of CFU/mL in urine for all strains, including mecillinam-resistant strains. Combining the effect for all six strains showed no significant differences in effect between doses for all three fluids/organs, but for each dose there was a highly significant effect in urine, kidney and bladder compared with vehicle-treated mice. Overall, this highlights the need for further studies to elucidate the role of mecillinam in the treatment of infections caused by MDR E. coli producing broad-spectrum β-lactamases, including specific carbapenemases.

KW - Carbapenemase

KW - ESBL

KW - In vivo

KW - Mecillinam

KW - Multidrug-resistant

KW - UTI model

U2 - 10.1016/j.ijantimicag.2019.11.008

DO - 10.1016/j.ijantimicag.2019.11.008

M3 - Journal article

VL - 55

SP - 105851

JO - International Journal of Antimicrobial Agents

JF - International Journal of Antimicrobial Agents

SN - 0924-8579

IS - 2

ER -

ID: 58999798