Optimization of a meropenem-tobramycin combination dosage regimen against hypermutable and nonhypermutable pseudomonas aeruginosa via mechanism-based modeling and the hollow-fiber infection model

Cornelia B. Landersdorfer, Vanessa E. Rees, Rajbharan Yadav, Kate E. Rogers, Tae Hwan Kim, Phillip J. Bergen, Soon-Ee Cheah, John D. Boyce, Anton Y. Peleg, Antonio Oliver, Beom Soo Shin, Roger L. Nation, Jürgen B. Bulitta

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Abstract

Hypermutable Pseudomonas aeruginosa strains are prevalent in patients with cystic fibrosis and rapidly become resistant to antibiotic monotherapies. Combination dosage regimens have not been optimized against such strains using mechanism-based modeling (MBM) and the hollow-fiber infection model (HFIM). The PAO1 wild-type strain and its isogenic hypermutable PAOΔmutS strain (MICmeropenem of 1.0 mg/liter and MICtobramycin of 0.5 mg/liter for both) were assessed using 96-h static-concentration time-kill studies (SCTK) and 10-day HFIM studies (inoculum, ∼108.4 CFU/ml). MBM of SCTK data were performed to predict expected HFIM outcomes. Regimens studied in the HFIM were meropenem at 1 g every 8 h (0.5-h infusion), meropenem at 3 g/day with continuous infusion, tobramycin at 10 mg/kg of body weight every 24 h (1-h infusion), and both combinations. Meropenem regimens delivered the same total daily dose. Time courses of total and less susceptible populations and MICs were determined. For the PAOΔmutS strain in the HFIM, all monotherapies resulted in rapid regrowth to >108.7 CFU/ml with near-complete replacement by less susceptible bacteria by day 3. Meropenem every 8 h with tobramycin caused >7-log10 bacterial killing followed by regrowth to >6 log10 CFU/ml by day 5 and high-level resistance (MICmeropenem, 32 mg/liter; MICtobramycin, 8 mg/liter). Continuous infusion of meropenem with tobramycin achieved >8-log10 bacterial killing without regrowth. For PAO1, meropenem monotherapies suppressed bacterial growth to <4 log10 over 7 to 9 days, with both combination regimens achieving near eradication. An MBM-optimized meropenem plus tobramycin regimen achieved synergistic killing and resistance suppression against a difficult-to-treat hypermutable P. aeruginosa strain. For the combination to be maximally effective, it was critical to achieve the optimal shape of the concentration-time profile for meropenem.

Original languageEnglish
Article numbere02055-17
Number of pages13
JournalAntimicrobial Agents and Chemotherapy
Volume62
Issue number4
DOIs
Publication statusPublished - 1 Apr 2018

Keywords

  • Combination therapy
  • Dosage regimen
  • Dynamic infection model
  • Pseudomonas aeruginosa

Cite this

@article{45f864fff0da4a45a5090a83103c099b,
title = "Optimization of a meropenem-tobramycin combination dosage regimen against hypermutable and nonhypermutable pseudomonas aeruginosa via mechanism-based modeling and the hollow-fiber infection model",
abstract = "Hypermutable Pseudomonas aeruginosa strains are prevalent in patients with cystic fibrosis and rapidly become resistant to antibiotic monotherapies. Combination dosage regimens have not been optimized against such strains using mechanism-based modeling (MBM) and the hollow-fiber infection model (HFIM). The PAO1 wild-type strain and its isogenic hypermutable PAOΔmutS strain (MICmeropenem of 1.0 mg/liter and MICtobramycin of 0.5 mg/liter for both) were assessed using 96-h static-concentration time-kill studies (SCTK) and 10-day HFIM studies (inoculum, ∼108.4 CFU/ml). MBM of SCTK data were performed to predict expected HFIM outcomes. Regimens studied in the HFIM were meropenem at 1 g every 8 h (0.5-h infusion), meropenem at 3 g/day with continuous infusion, tobramycin at 10 mg/kg of body weight every 24 h (1-h infusion), and both combinations. Meropenem regimens delivered the same total daily dose. Time courses of total and less susceptible populations and MICs were determined. For the PAOΔmutS strain in the HFIM, all monotherapies resulted in rapid regrowth to >108.7 CFU/ml with near-complete replacement by less susceptible bacteria by day 3. Meropenem every 8 h with tobramycin caused >7-log10 bacterial killing followed by regrowth to >6 log10 CFU/ml by day 5 and high-level resistance (MICmeropenem, 32 mg/liter; MICtobramycin, 8 mg/liter). Continuous infusion of meropenem with tobramycin achieved >8-log10 bacterial killing without regrowth. For PAO1, meropenem monotherapies suppressed bacterial growth to <4 log10 over 7 to 9 days, with both combination regimens achieving near eradication. An MBM-optimized meropenem plus tobramycin regimen achieved synergistic killing and resistance suppression against a difficult-to-treat hypermutable P. aeruginosa strain. For the combination to be maximally effective, it was critical to achieve the optimal shape of the concentration-time profile for meropenem.",
keywords = "Combination therapy, Dosage regimen, Dynamic infection model, Pseudomonas aeruginosa",
author = "Landersdorfer, {Cornelia B.} and Rees, {Vanessa E.} and Rajbharan Yadav and Rogers, {Kate E.} and Kim, {Tae Hwan} and Bergen, {Phillip J.} and Soon-Ee Cheah and Boyce, {John D.} and Peleg, {Anton Y.} and Antonio Oliver and Shin, {Beom Soo} and Nation, {Roger L.} and Bulitta, {J{\"u}rgen B.}",
year = "2018",
month = "4",
day = "1",
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language = "English",
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journal = "Antimicrobial Agents and Chemotherapy",
issn = "1098-6596",
publisher = "American Society for Microbiology",
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}

Optimization of a meropenem-tobramycin combination dosage regimen against hypermutable and nonhypermutable pseudomonas aeruginosa via mechanism-based modeling and the hollow-fiber infection model. / Landersdorfer, Cornelia B.; Rees, Vanessa E.; Yadav, Rajbharan; Rogers, Kate E.; Kim, Tae Hwan; Bergen, Phillip J.; Cheah, Soon-Ee; Boyce, John D.; Peleg, Anton Y.; Oliver, Antonio; Shin, Beom Soo; Nation, Roger L.; Bulitta, Jürgen B.

In: Antimicrobial Agents and Chemotherapy, Vol. 62, No. 4, e02055-17, 01.04.2018.

Research output: Contribution to journalArticleResearchpeer-review

TY - JOUR

T1 - Optimization of a meropenem-tobramycin combination dosage regimen against hypermutable and nonhypermutable pseudomonas aeruginosa via mechanism-based modeling and the hollow-fiber infection model

AU - Landersdorfer, Cornelia B.

AU - Rees, Vanessa E.

AU - Yadav, Rajbharan

AU - Rogers, Kate E.

AU - Kim, Tae Hwan

AU - Bergen, Phillip J.

AU - Cheah, Soon-Ee

AU - Boyce, John D.

AU - Peleg, Anton Y.

AU - Oliver, Antonio

AU - Shin, Beom Soo

AU - Nation, Roger L.

AU - Bulitta, Jürgen B.

PY - 2018/4/1

Y1 - 2018/4/1

N2 - Hypermutable Pseudomonas aeruginosa strains are prevalent in patients with cystic fibrosis and rapidly become resistant to antibiotic monotherapies. Combination dosage regimens have not been optimized against such strains using mechanism-based modeling (MBM) and the hollow-fiber infection model (HFIM). The PAO1 wild-type strain and its isogenic hypermutable PAOΔmutS strain (MICmeropenem of 1.0 mg/liter and MICtobramycin of 0.5 mg/liter for both) were assessed using 96-h static-concentration time-kill studies (SCTK) and 10-day HFIM studies (inoculum, ∼108.4 CFU/ml). MBM of SCTK data were performed to predict expected HFIM outcomes. Regimens studied in the HFIM were meropenem at 1 g every 8 h (0.5-h infusion), meropenem at 3 g/day with continuous infusion, tobramycin at 10 mg/kg of body weight every 24 h (1-h infusion), and both combinations. Meropenem regimens delivered the same total daily dose. Time courses of total and less susceptible populations and MICs were determined. For the PAOΔmutS strain in the HFIM, all monotherapies resulted in rapid regrowth to >108.7 CFU/ml with near-complete replacement by less susceptible bacteria by day 3. Meropenem every 8 h with tobramycin caused >7-log10 bacterial killing followed by regrowth to >6 log10 CFU/ml by day 5 and high-level resistance (MICmeropenem, 32 mg/liter; MICtobramycin, 8 mg/liter). Continuous infusion of meropenem with tobramycin achieved >8-log10 bacterial killing without regrowth. For PAO1, meropenem monotherapies suppressed bacterial growth to <4 log10 over 7 to 9 days, with both combination regimens achieving near eradication. An MBM-optimized meropenem plus tobramycin regimen achieved synergistic killing and resistance suppression against a difficult-to-treat hypermutable P. aeruginosa strain. For the combination to be maximally effective, it was critical to achieve the optimal shape of the concentration-time profile for meropenem.

AB - Hypermutable Pseudomonas aeruginosa strains are prevalent in patients with cystic fibrosis and rapidly become resistant to antibiotic monotherapies. Combination dosage regimens have not been optimized against such strains using mechanism-based modeling (MBM) and the hollow-fiber infection model (HFIM). The PAO1 wild-type strain and its isogenic hypermutable PAOΔmutS strain (MICmeropenem of 1.0 mg/liter and MICtobramycin of 0.5 mg/liter for both) were assessed using 96-h static-concentration time-kill studies (SCTK) and 10-day HFIM studies (inoculum, ∼108.4 CFU/ml). MBM of SCTK data were performed to predict expected HFIM outcomes. Regimens studied in the HFIM were meropenem at 1 g every 8 h (0.5-h infusion), meropenem at 3 g/day with continuous infusion, tobramycin at 10 mg/kg of body weight every 24 h (1-h infusion), and both combinations. Meropenem regimens delivered the same total daily dose. Time courses of total and less susceptible populations and MICs were determined. For the PAOΔmutS strain in the HFIM, all monotherapies resulted in rapid regrowth to >108.7 CFU/ml with near-complete replacement by less susceptible bacteria by day 3. Meropenem every 8 h with tobramycin caused >7-log10 bacterial killing followed by regrowth to >6 log10 CFU/ml by day 5 and high-level resistance (MICmeropenem, 32 mg/liter; MICtobramycin, 8 mg/liter). Continuous infusion of meropenem with tobramycin achieved >8-log10 bacterial killing without regrowth. For PAO1, meropenem monotherapies suppressed bacterial growth to <4 log10 over 7 to 9 days, with both combination regimens achieving near eradication. An MBM-optimized meropenem plus tobramycin regimen achieved synergistic killing and resistance suppression against a difficult-to-treat hypermutable P. aeruginosa strain. For the combination to be maximally effective, it was critical to achieve the optimal shape of the concentration-time profile for meropenem.

KW - Combination therapy

KW - Dosage regimen

KW - Dynamic infection model

KW - Pseudomonas aeruginosa

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U2 - 10.1128/AAC.02055-17

DO - 10.1128/AAC.02055-17

M3 - Article

VL - 62

JO - Antimicrobial Agents and Chemotherapy

JF - Antimicrobial Agents and Chemotherapy

SN - 1098-6596

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