High-intensity meropenem combinations with polymyxin B

new strategies to overcome carbapenem resistance in Acinetobacter baumannii

Justin R Lenhard, Jürgen B. Bulitta, Terry D. Connell, Natalie King-Lyons, Cornelia Landersdorfer, Soon-Ee Cheah, Visanu Thamlikitkul, Beom Soo Shin, Gauri Rao, Patricia N Holden, Thomas J. Walsh, Alan Forrest, Roger L Nation, Jian Li, Brian T Tsuji

Research output: Contribution to journalArticleResearchpeer-review

19 Citations (Scopus)

Abstract

Objectives: The pharmacodynamics of polymyxin/carbapenem combinations against carbapenem-resistant Acinetobacter baumannii (CRAB) are largely unknown. Our objective was to determine whether intensified meropenem regimens in combination with polymyxin B enhance killing and resistance suppression of CRAB. Methods: Time-kill experiments for meropenem and polymyxin B combinations were conducted against three polymyxin B-susceptible (MIC of polymyxin B=0.5 mg/L) CRAB strains with varying meropenem MICs (ATCC 19606, N16870 and 03-149-1; MIC of meropenem=4, 16 and 64 mg/L, respectively) at 108 cfu/mL. A hollowfibre infection model was then used to simulate humanized regimens of polymyxin B and meropenem (2, 4, 6 and 8 g prolonged infusions every 8 h) versus N16870 at 108 cfu/mL over 14 days. New mathematical mechanismbased models were developed using S-ADAPT. Results: Time-kill experiments were well described by the mathematical mechanism-based models, with the presence of polymyxin B drastically decreasing the meropenem concentration needed for half-maximal activity against meropenem-resistant populations from 438 to 82.1 (ATCC 19606), 158 to 93.6 (N16870) and 433 to 76.0 mg/L (03-149-1). The maximum killing effect of combination treatment was similar among all three strains despite divergent meropenem MIC values (Emax=2.13, 2.08 and 2.15; MIC of meropenem=4, 16 and 64 mg/L, respectively). Escalating the dose of meropenem in hollow-fibre combination regimens from 2 g every 8 h to 8 g every 8 h resulted in killing that progressed from a >2.5 log10 cfu/mL reduction with regrowth by 72 h (2 g every 8 h) to complete eradication by 336 h (8 g every 8 h). Conclusion: Intensified meropenem dosing in combination with polymyxin B may offer a unique strategy to kill CRAB irrespective of the meropenem MIC.

Original languageEnglish
Pages (from-to)153-165
Number of pages13
JournalJournal of Antimicrobial Chemotherapy
Volume72
Issue number1
DOIs
Publication statusPublished - 2017

Cite this

Lenhard, Justin R ; Bulitta, Jürgen B. ; Connell, Terry D. ; King-Lyons, Natalie ; Landersdorfer, Cornelia ; Cheah, Soon-Ee ; Thamlikitkul, Visanu ; Shin, Beom Soo ; Rao, Gauri ; Holden, Patricia N ; Walsh, Thomas J. ; Forrest, Alan ; Nation, Roger L ; Li, Jian ; Tsuji, Brian T. / High-intensity meropenem combinations with polymyxin B : new strategies to overcome carbapenem resistance in Acinetobacter baumannii. In: Journal of Antimicrobial Chemotherapy. 2017 ; Vol. 72, No. 1. pp. 153-165.
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title = "High-intensity meropenem combinations with polymyxin B: new strategies to overcome carbapenem resistance in Acinetobacter baumannii",
abstract = "Objectives: The pharmacodynamics of polymyxin/carbapenem combinations against carbapenem-resistant Acinetobacter baumannii (CRAB) are largely unknown. Our objective was to determine whether intensified meropenem regimens in combination with polymyxin B enhance killing and resistance suppression of CRAB. Methods: Time-kill experiments for meropenem and polymyxin B combinations were conducted against three polymyxin B-susceptible (MIC of polymyxin B=0.5 mg/L) CRAB strains with varying meropenem MICs (ATCC 19606, N16870 and 03-149-1; MIC of meropenem=4, 16 and 64 mg/L, respectively) at 108 cfu/mL. A hollowfibre infection model was then used to simulate humanized regimens of polymyxin B and meropenem (2, 4, 6 and 8 g prolonged infusions every 8 h) versus N16870 at 108 cfu/mL over 14 days. New mathematical mechanismbased models were developed using S-ADAPT. Results: Time-kill experiments were well described by the mathematical mechanism-based models, with the presence of polymyxin B drastically decreasing the meropenem concentration needed for half-maximal activity against meropenem-resistant populations from 438 to 82.1 (ATCC 19606), 158 to 93.6 (N16870) and 433 to 76.0 mg/L (03-149-1). The maximum killing effect of combination treatment was similar among all three strains despite divergent meropenem MIC values (Emax=2.13, 2.08 and 2.15; MIC of meropenem=4, 16 and 64 mg/L, respectively). Escalating the dose of meropenem in hollow-fibre combination regimens from 2 g every 8 h to 8 g every 8 h resulted in killing that progressed from a >2.5 log10 cfu/mL reduction with regrowth by 72 h (2 g every 8 h) to complete eradication by 336 h (8 g every 8 h). Conclusion: Intensified meropenem dosing in combination with polymyxin B may offer a unique strategy to kill CRAB irrespective of the meropenem MIC.",
author = "Lenhard, {Justin R} and Bulitta, {J{\"u}rgen B.} and Connell, {Terry D.} and Natalie King-Lyons and Cornelia Landersdorfer and Soon-Ee Cheah and Visanu Thamlikitkul and Shin, {Beom Soo} and Gauri Rao and Holden, {Patricia N} and Walsh, {Thomas J.} and Alan Forrest and Nation, {Roger L} and Jian Li and Tsuji, {Brian T}",
year = "2017",
doi = "10.1093/jac/dkw355",
language = "English",
volume = "72",
pages = "153--165",
journal = "Journal of Antimicrobial Chemotherapy",
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Lenhard, JR, Bulitta, JB, Connell, TD, King-Lyons, N, Landersdorfer, C, Cheah, S-E, Thamlikitkul, V, Shin, BS, Rao, G, Holden, PN, Walsh, TJ, Forrest, A, Nation, RL, Li, J & Tsuji, BT 2017, 'High-intensity meropenem combinations with polymyxin B: new strategies to overcome carbapenem resistance in Acinetobacter baumannii', Journal of Antimicrobial Chemotherapy, vol. 72, no. 1, pp. 153-165. https://doi.org/10.1093/jac/dkw355

High-intensity meropenem combinations with polymyxin B : new strategies to overcome carbapenem resistance in Acinetobacter baumannii. / Lenhard, Justin R; Bulitta, Jürgen B.; Connell, Terry D.; King-Lyons, Natalie; Landersdorfer, Cornelia; Cheah, Soon-Ee; Thamlikitkul, Visanu; Shin, Beom Soo; Rao, Gauri; Holden, Patricia N; Walsh, Thomas J.; Forrest, Alan; Nation, Roger L; Li, Jian; Tsuji, Brian T.

In: Journal of Antimicrobial Chemotherapy, Vol. 72, No. 1, 2017, p. 153-165.

Research output: Contribution to journalArticleResearchpeer-review

TY - JOUR

T1 - High-intensity meropenem combinations with polymyxin B

T2 - new strategies to overcome carbapenem resistance in Acinetobacter baumannii

AU - Lenhard, Justin R

AU - Bulitta, Jürgen B.

AU - Connell, Terry D.

AU - King-Lyons, Natalie

AU - Landersdorfer, Cornelia

AU - Cheah, Soon-Ee

AU - Thamlikitkul, Visanu

AU - Shin, Beom Soo

AU - Rao, Gauri

AU - Holden, Patricia N

AU - Walsh, Thomas J.

AU - Forrest, Alan

AU - Nation, Roger L

AU - Li, Jian

AU - Tsuji, Brian T

PY - 2017

Y1 - 2017

N2 - Objectives: The pharmacodynamics of polymyxin/carbapenem combinations against carbapenem-resistant Acinetobacter baumannii (CRAB) are largely unknown. Our objective was to determine whether intensified meropenem regimens in combination with polymyxin B enhance killing and resistance suppression of CRAB. Methods: Time-kill experiments for meropenem and polymyxin B combinations were conducted against three polymyxin B-susceptible (MIC of polymyxin B=0.5 mg/L) CRAB strains with varying meropenem MICs (ATCC 19606, N16870 and 03-149-1; MIC of meropenem=4, 16 and 64 mg/L, respectively) at 108 cfu/mL. A hollowfibre infection model was then used to simulate humanized regimens of polymyxin B and meropenem (2, 4, 6 and 8 g prolonged infusions every 8 h) versus N16870 at 108 cfu/mL over 14 days. New mathematical mechanismbased models were developed using S-ADAPT. Results: Time-kill experiments were well described by the mathematical mechanism-based models, with the presence of polymyxin B drastically decreasing the meropenem concentration needed for half-maximal activity against meropenem-resistant populations from 438 to 82.1 (ATCC 19606), 158 to 93.6 (N16870) and 433 to 76.0 mg/L (03-149-1). The maximum killing effect of combination treatment was similar among all three strains despite divergent meropenem MIC values (Emax=2.13, 2.08 and 2.15; MIC of meropenem=4, 16 and 64 mg/L, respectively). Escalating the dose of meropenem in hollow-fibre combination regimens from 2 g every 8 h to 8 g every 8 h resulted in killing that progressed from a >2.5 log10 cfu/mL reduction with regrowth by 72 h (2 g every 8 h) to complete eradication by 336 h (8 g every 8 h). Conclusion: Intensified meropenem dosing in combination with polymyxin B may offer a unique strategy to kill CRAB irrespective of the meropenem MIC.

AB - Objectives: The pharmacodynamics of polymyxin/carbapenem combinations against carbapenem-resistant Acinetobacter baumannii (CRAB) are largely unknown. Our objective was to determine whether intensified meropenem regimens in combination with polymyxin B enhance killing and resistance suppression of CRAB. Methods: Time-kill experiments for meropenem and polymyxin B combinations were conducted against three polymyxin B-susceptible (MIC of polymyxin B=0.5 mg/L) CRAB strains with varying meropenem MICs (ATCC 19606, N16870 and 03-149-1; MIC of meropenem=4, 16 and 64 mg/L, respectively) at 108 cfu/mL. A hollowfibre infection model was then used to simulate humanized regimens of polymyxin B and meropenem (2, 4, 6 and 8 g prolonged infusions every 8 h) versus N16870 at 108 cfu/mL over 14 days. New mathematical mechanismbased models were developed using S-ADAPT. Results: Time-kill experiments were well described by the mathematical mechanism-based models, with the presence of polymyxin B drastically decreasing the meropenem concentration needed for half-maximal activity against meropenem-resistant populations from 438 to 82.1 (ATCC 19606), 158 to 93.6 (N16870) and 433 to 76.0 mg/L (03-149-1). The maximum killing effect of combination treatment was similar among all three strains despite divergent meropenem MIC values (Emax=2.13, 2.08 and 2.15; MIC of meropenem=4, 16 and 64 mg/L, respectively). Escalating the dose of meropenem in hollow-fibre combination regimens from 2 g every 8 h to 8 g every 8 h resulted in killing that progressed from a >2.5 log10 cfu/mL reduction with regrowth by 72 h (2 g every 8 h) to complete eradication by 336 h (8 g every 8 h). Conclusion: Intensified meropenem dosing in combination with polymyxin B may offer a unique strategy to kill CRAB irrespective of the meropenem MIC.

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U2 - 10.1093/jac/dkw355

DO - 10.1093/jac/dkw355

M3 - Article

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EP - 165

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JF - Journal of Antimicrobial Chemotherapy

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