Pharmacodynamics of dose-escalated ‘front-loading’ polymyxin B regimens against polymyxin-resistant mcr-1-harbouring Escherichia coli

Nicholas M. Smith, Zackery P. Bulman, Arthur O Sieron, Jurgen B Bulitta, Patricia N Holden, Roger L Nation, Jian Li, Gerard D. Wright, Brian Tsuji

Research output: Contribution to journalArticleResearchpeer-review

3 Citations (Scopus)

Abstract

Objectives: Gram-negative bacteria harbouring the mcr-1 plasmid are resistant to the ‘last-line’ polymyxins and have been reported worldwide. Our objective was to define the impact of increasing the initial polymyxin B dose intensity against an mcr-1-harbouring strain to delineate the impact of plasmid-mediated polymyxin resistance on the dynamics of bacterial killing and resistance.
Methods: A hollow fibre infection model (HFIM) was used to simulate polymyxin B regimens against an mcr-1-harbouring Escherichia coli (MIC 8 mg/L) over 10 days. Four escalating polymyxin B ‘front-loading’ regimens(3.33, 6.66, 13.3 or 26.6 mg/kg for one dose followed by 1.43 mg/kg every 12 h starting 12 h later) simulating human pharmacokinetics were utilized in the HFIM. A mechanism-based, mathematical model was developed using S-ADAPT to characterize bacterial killing.
Results: The 3.33 mg/kg ‘front-loading’ regimen resulted in regrowth mirroring the growth control. The 6.66,13.3 and 26.6mg/kg ‘front-loading’ regimens resulted in maximal bacterial reductions of 1.91, 3.79 and6.14 log10 cfu/mL, respectively. Irrespective of the early polymyxin B exposure (24 h AUC), population analysis profiles showed similar growth of polymyxin B-resistant subpopulations. The HFIM data were well described by the mechanism-based model integrating three subpopulations (susceptible, intermediate and resistant). Compared with the susceptible subpopulation of mcr-1-harbouring E. coli, the resistant subpopulation had an approximately 10-fold lower rate of killing due to polymyxin B treatment.
Conclusions: Manipulating initial dose intensity of polymyxin B was not able to overcome plasmid-mediated resistance due to mcr-1 in E. coli. This reinforces the need to develop new combinatorial strategies to combat these highly resistant Gram-negative bacteria.
Original languageEnglish
Article numberdkx121
Pages (from-to)2297-2303
Number of pages7
JournalJournal of Antimicrobial Chemotherapy
Volume72
Issue number8
DOIs
Publication statusPublished - 1 Aug 2017

Cite this

Smith, Nicholas M. ; Bulman, Zackery P. ; Sieron, Arthur O ; Bulitta, Jurgen B ; Holden, Patricia N ; Nation, Roger L ; Li, Jian ; Wright, Gerard D. ; Tsuji, Brian. / Pharmacodynamics of dose-escalated ‘front-loading’ polymyxin B regimens against polymyxin-resistant mcr-1-harbouring Escherichia coli. In: Journal of Antimicrobial Chemotherapy. 2017 ; Vol. 72, No. 8. pp. 2297-2303.
@article{1f48e74b4838437b9d20fe4a7a0eefca,
title = "Pharmacodynamics of dose-escalated ‘front-loading’ polymyxin B regimens against polymyxin-resistant mcr-1-harbouring Escherichia coli",
abstract = "Objectives: Gram-negative bacteria harbouring the mcr-1 plasmid are resistant to the ‘last-line’ polymyxins and have been reported worldwide. Our objective was to define the impact of increasing the initial polymyxin B dose intensity against an mcr-1-harbouring strain to delineate the impact of plasmid-mediated polymyxin resistance on the dynamics of bacterial killing and resistance.Methods: A hollow fibre infection model (HFIM) was used to simulate polymyxin B regimens against an mcr-1-harbouring Escherichia coli (MIC 8 mg/L) over 10 days. Four escalating polymyxin B ‘front-loading’ regimens(3.33, 6.66, 13.3 or 26.6 mg/kg for one dose followed by 1.43 mg/kg every 12 h starting 12 h later) simulating human pharmacokinetics were utilized in the HFIM. A mechanism-based, mathematical model was developed using S-ADAPT to characterize bacterial killing.Results: The 3.33 mg/kg ‘front-loading’ regimen resulted in regrowth mirroring the growth control. The 6.66,13.3 and 26.6mg/kg ‘front-loading’ regimens resulted in maximal bacterial reductions of 1.91, 3.79 and6.14 log10 cfu/mL, respectively. Irrespective of the early polymyxin B exposure (24 h AUC), population analysis profiles showed similar growth of polymyxin B-resistant subpopulations. The HFIM data were well described by the mechanism-based model integrating three subpopulations (susceptible, intermediate and resistant). Compared with the susceptible subpopulation of mcr-1-harbouring E. coli, the resistant subpopulation had an approximately 10-fold lower rate of killing due to polymyxin B treatment.Conclusions: Manipulating initial dose intensity of polymyxin B was not able to overcome plasmid-mediated resistance due to mcr-1 in E. coli. This reinforces the need to develop new combinatorial strategies to combat these highly resistant Gram-negative bacteria.",
author = "Smith, {Nicholas M.} and Bulman, {Zackery P.} and Sieron, {Arthur O} and Bulitta, {Jurgen B} and Holden, {Patricia N} and Nation, {Roger L} and Jian Li and Wright, {Gerard D.} and Brian Tsuji",
year = "2017",
month = "8",
day = "1",
doi = "10.1093/jac/dkx121",
language = "English",
volume = "72",
pages = "2297--2303",
journal = "Journal of Antimicrobial Chemotherapy",
issn = "0305-7453",
publisher = "Oxford University Press",
number = "8",

}

Pharmacodynamics of dose-escalated ‘front-loading’ polymyxin B regimens against polymyxin-resistant mcr-1-harbouring Escherichia coli. / Smith, Nicholas M.; Bulman, Zackery P.; Sieron, Arthur O; Bulitta, Jurgen B; Holden, Patricia N; Nation, Roger L; Li, Jian; Wright, Gerard D.; Tsuji, Brian.

In: Journal of Antimicrobial Chemotherapy, Vol. 72, No. 8, dkx121, 01.08.2017, p. 2297-2303.

Research output: Contribution to journalArticleResearchpeer-review

TY - JOUR

T1 - Pharmacodynamics of dose-escalated ‘front-loading’ polymyxin B regimens against polymyxin-resistant mcr-1-harbouring Escherichia coli

AU - Smith, Nicholas M.

AU - Bulman, Zackery P.

AU - Sieron, Arthur O

AU - Bulitta, Jurgen B

AU - Holden, Patricia N

AU - Nation, Roger L

AU - Li, Jian

AU - Wright, Gerard D.

AU - Tsuji, Brian

PY - 2017/8/1

Y1 - 2017/8/1

N2 - Objectives: Gram-negative bacteria harbouring the mcr-1 plasmid are resistant to the ‘last-line’ polymyxins and have been reported worldwide. Our objective was to define the impact of increasing the initial polymyxin B dose intensity against an mcr-1-harbouring strain to delineate the impact of plasmid-mediated polymyxin resistance on the dynamics of bacterial killing and resistance.Methods: A hollow fibre infection model (HFIM) was used to simulate polymyxin B regimens against an mcr-1-harbouring Escherichia coli (MIC 8 mg/L) over 10 days. Four escalating polymyxin B ‘front-loading’ regimens(3.33, 6.66, 13.3 or 26.6 mg/kg for one dose followed by 1.43 mg/kg every 12 h starting 12 h later) simulating human pharmacokinetics were utilized in the HFIM. A mechanism-based, mathematical model was developed using S-ADAPT to characterize bacterial killing.Results: The 3.33 mg/kg ‘front-loading’ regimen resulted in regrowth mirroring the growth control. The 6.66,13.3 and 26.6mg/kg ‘front-loading’ regimens resulted in maximal bacterial reductions of 1.91, 3.79 and6.14 log10 cfu/mL, respectively. Irrespective of the early polymyxin B exposure (24 h AUC), population analysis profiles showed similar growth of polymyxin B-resistant subpopulations. The HFIM data were well described by the mechanism-based model integrating three subpopulations (susceptible, intermediate and resistant). Compared with the susceptible subpopulation of mcr-1-harbouring E. coli, the resistant subpopulation had an approximately 10-fold lower rate of killing due to polymyxin B treatment.Conclusions: Manipulating initial dose intensity of polymyxin B was not able to overcome plasmid-mediated resistance due to mcr-1 in E. coli. This reinforces the need to develop new combinatorial strategies to combat these highly resistant Gram-negative bacteria.

AB - Objectives: Gram-negative bacteria harbouring the mcr-1 plasmid are resistant to the ‘last-line’ polymyxins and have been reported worldwide. Our objective was to define the impact of increasing the initial polymyxin B dose intensity against an mcr-1-harbouring strain to delineate the impact of plasmid-mediated polymyxin resistance on the dynamics of bacterial killing and resistance.Methods: A hollow fibre infection model (HFIM) was used to simulate polymyxin B regimens against an mcr-1-harbouring Escherichia coli (MIC 8 mg/L) over 10 days. Four escalating polymyxin B ‘front-loading’ regimens(3.33, 6.66, 13.3 or 26.6 mg/kg for one dose followed by 1.43 mg/kg every 12 h starting 12 h later) simulating human pharmacokinetics were utilized in the HFIM. A mechanism-based, mathematical model was developed using S-ADAPT to characterize bacterial killing.Results: The 3.33 mg/kg ‘front-loading’ regimen resulted in regrowth mirroring the growth control. The 6.66,13.3 and 26.6mg/kg ‘front-loading’ regimens resulted in maximal bacterial reductions of 1.91, 3.79 and6.14 log10 cfu/mL, respectively. Irrespective of the early polymyxin B exposure (24 h AUC), population analysis profiles showed similar growth of polymyxin B-resistant subpopulations. The HFIM data were well described by the mechanism-based model integrating three subpopulations (susceptible, intermediate and resistant). Compared with the susceptible subpopulation of mcr-1-harbouring E. coli, the resistant subpopulation had an approximately 10-fold lower rate of killing due to polymyxin B treatment.Conclusions: Manipulating initial dose intensity of polymyxin B was not able to overcome plasmid-mediated resistance due to mcr-1 in E. coli. This reinforces the need to develop new combinatorial strategies to combat these highly resistant Gram-negative bacteria.

UR - http://www.scopus.com/inward/record.url?scp=85027126651&partnerID=8YFLogxK

U2 - 10.1093/jac/dkx121

DO - 10.1093/jac/dkx121

M3 - Article

VL - 72

SP - 2297

EP - 2303

JO - Journal of Antimicrobial Chemotherapy

JF - Journal of Antimicrobial Chemotherapy

SN - 0305-7453

IS - 8

M1 - dkx121

ER -