Polymyxin B in combination with meropenem against carbapenemase-producing Klebsiella pneumoniae

pharmacodynamics and morphological changes

Rajnikant Sharma, Saloni Patel, Cely Abboud, John Diep, Neang S Ly, Jason M Pogue, Keith S Kaye, Jian Li, Gauri G Rao

Research output: Contribution to journalArticleResearchpeer-review

16 Citations (Scopus)

Abstract

Combination therapy provides a useful therapeutic approach to overcome resistance until new antibiotics become available. In this study, the pharmacodynamics, including the morphological effects, of polymyxin B (PMB) and meropenem alone and in combination against KPC-producing Klebsiella pneumoniae clinical isolates was examined. Ten clinical isolates were obtained from patients undergoing treatment for mediastinitis. KPCs were identified and MICs were measured using microbroth dilution. Time–kill studies were conducted over 24 h with PMB (0.5–16 mg/L) and meropenem (20–120 mg/L) alone or in combination against an initial inoculum of ca. 106 CFU/mL. Scanning electron microscopy (SEM) was employed to analyse changes in bacterial morphology after treatment, and the log change method was used to quantify the pharmacodynamic effect. All isolates harboured the blaKPC-2 gene and were resistant to meropenem (MICs ≥8 mg/L). Clinically relevant PMB concentrations (0.5, 1.0 and 2.0 mg/L) in combination with meropenem were synergistic against all isolates except BRKP28 (polymyxin- and meropenem-resistant, both MICs >128 mg/L). All PMB and meropenem concentrations in combination were bactericidal against polymyxin-susceptible isolates with meropenem MICs ≤16 mg/L. SEM revealed extensive morphological changes following treatment with PMB in combination with meropenem compared with the changes observed with each individual agent. Additionally, morphological changes decreased with increasing resistance profiles of the isolate, i.e. increasing meropenem MIC. These antimicrobial effects may not only be a summation of the effects due to each antibiotic but also a result of differential action that likely inhibits protective mechanisms in bacteria.

Original languageEnglish
Pages (from-to)224-232
Number of pages9
JournalInternational Journal of Antimicrobial Agents
Volume49
Issue number2
DOIs
Publication statusPublished - 1 Feb 2017

Keywords

  • Combination
  • Klebsiella pneumoniae
  • KPC carbapenemase
  • Meropenem
  • Pharmacodynamics
  • Polymyxin B

Cite this

Sharma, Rajnikant ; Patel, Saloni ; Abboud, Cely ; Diep, John ; Ly, Neang S ; Pogue, Jason M ; Kaye, Keith S ; Li, Jian ; Rao, Gauri G. / Polymyxin B in combination with meropenem against carbapenemase-producing Klebsiella pneumoniae : pharmacodynamics and morphological changes. In: International Journal of Antimicrobial Agents. 2017 ; Vol. 49, No. 2. pp. 224-232.
@article{e94cd28f2956489491e19a8b4af0aebb,
title = "Polymyxin B in combination with meropenem against carbapenemase-producing Klebsiella pneumoniae: pharmacodynamics and morphological changes",
abstract = "Combination therapy provides a useful therapeutic approach to overcome resistance until new antibiotics become available. In this study, the pharmacodynamics, including the morphological effects, of polymyxin B (PMB) and meropenem alone and in combination against KPC-producing Klebsiella pneumoniae clinical isolates was examined. Ten clinical isolates were obtained from patients undergoing treatment for mediastinitis. KPCs were identified and MICs were measured using microbroth dilution. Time–kill studies were conducted over 24 h with PMB (0.5–16 mg/L) and meropenem (20–120 mg/L) alone or in combination against an initial inoculum of ca. 106 CFU/mL. Scanning electron microscopy (SEM) was employed to analyse changes in bacterial morphology after treatment, and the log change method was used to quantify the pharmacodynamic effect. All isolates harboured the blaKPC-2 gene and were resistant to meropenem (MICs ≥8 mg/L). Clinically relevant PMB concentrations (0.5, 1.0 and 2.0 mg/L) in combination with meropenem were synergistic against all isolates except BRKP28 (polymyxin- and meropenem-resistant, both MICs >128 mg/L). All PMB and meropenem concentrations in combination were bactericidal against polymyxin-susceptible isolates with meropenem MICs ≤16 mg/L. SEM revealed extensive morphological changes following treatment with PMB in combination with meropenem compared with the changes observed with each individual agent. Additionally, morphological changes decreased with increasing resistance profiles of the isolate, i.e. increasing meropenem MIC. These antimicrobial effects may not only be a summation of the effects due to each antibiotic but also a result of differential action that likely inhibits protective mechanisms in bacteria.",
keywords = "Combination, Klebsiella pneumoniae, KPC carbapenemase, Meropenem, Pharmacodynamics, Polymyxin B",
author = "Rajnikant Sharma and Saloni Patel and Cely Abboud and John Diep and Ly, {Neang S} and Pogue, {Jason M} and Kaye, {Keith S} and Jian Li and Rao, {Gauri G}",
year = "2017",
month = "2",
day = "1",
doi = "10.1016/j.ijantimicag.2016.10.025",
language = "English",
volume = "49",
pages = "224--232",
journal = "International Journal of Antimicrobial Agents",
issn = "0924-8579",
publisher = "Elsevier - Mosby",
number = "2",

}

Polymyxin B in combination with meropenem against carbapenemase-producing Klebsiella pneumoniae : pharmacodynamics and morphological changes. / Sharma, Rajnikant; Patel, Saloni; Abboud, Cely; Diep, John; Ly, Neang S; Pogue, Jason M; Kaye, Keith S; Li, Jian; Rao, Gauri G.

In: International Journal of Antimicrobial Agents, Vol. 49, No. 2, 01.02.2017, p. 224-232.

Research output: Contribution to journalArticleResearchpeer-review

TY - JOUR

T1 - Polymyxin B in combination with meropenem against carbapenemase-producing Klebsiella pneumoniae

T2 - pharmacodynamics and morphological changes

AU - Sharma, Rajnikant

AU - Patel, Saloni

AU - Abboud, Cely

AU - Diep, John

AU - Ly, Neang S

AU - Pogue, Jason M

AU - Kaye, Keith S

AU - Li, Jian

AU - Rao, Gauri G

PY - 2017/2/1

Y1 - 2017/2/1

N2 - Combination therapy provides a useful therapeutic approach to overcome resistance until new antibiotics become available. In this study, the pharmacodynamics, including the morphological effects, of polymyxin B (PMB) and meropenem alone and in combination against KPC-producing Klebsiella pneumoniae clinical isolates was examined. Ten clinical isolates were obtained from patients undergoing treatment for mediastinitis. KPCs were identified and MICs were measured using microbroth dilution. Time–kill studies were conducted over 24 h with PMB (0.5–16 mg/L) and meropenem (20–120 mg/L) alone or in combination against an initial inoculum of ca. 106 CFU/mL. Scanning electron microscopy (SEM) was employed to analyse changes in bacterial morphology after treatment, and the log change method was used to quantify the pharmacodynamic effect. All isolates harboured the blaKPC-2 gene and were resistant to meropenem (MICs ≥8 mg/L). Clinically relevant PMB concentrations (0.5, 1.0 and 2.0 mg/L) in combination with meropenem were synergistic against all isolates except BRKP28 (polymyxin- and meropenem-resistant, both MICs >128 mg/L). All PMB and meropenem concentrations in combination were bactericidal against polymyxin-susceptible isolates with meropenem MICs ≤16 mg/L. SEM revealed extensive morphological changes following treatment with PMB in combination with meropenem compared with the changes observed with each individual agent. Additionally, morphological changes decreased with increasing resistance profiles of the isolate, i.e. increasing meropenem MIC. These antimicrobial effects may not only be a summation of the effects due to each antibiotic but also a result of differential action that likely inhibits protective mechanisms in bacteria.

AB - Combination therapy provides a useful therapeutic approach to overcome resistance until new antibiotics become available. In this study, the pharmacodynamics, including the morphological effects, of polymyxin B (PMB) and meropenem alone and in combination against KPC-producing Klebsiella pneumoniae clinical isolates was examined. Ten clinical isolates were obtained from patients undergoing treatment for mediastinitis. KPCs were identified and MICs were measured using microbroth dilution. Time–kill studies were conducted over 24 h with PMB (0.5–16 mg/L) and meropenem (20–120 mg/L) alone or in combination against an initial inoculum of ca. 106 CFU/mL. Scanning electron microscopy (SEM) was employed to analyse changes in bacterial morphology after treatment, and the log change method was used to quantify the pharmacodynamic effect. All isolates harboured the blaKPC-2 gene and were resistant to meropenem (MICs ≥8 mg/L). Clinically relevant PMB concentrations (0.5, 1.0 and 2.0 mg/L) in combination with meropenem were synergistic against all isolates except BRKP28 (polymyxin- and meropenem-resistant, both MICs >128 mg/L). All PMB and meropenem concentrations in combination were bactericidal against polymyxin-susceptible isolates with meropenem MICs ≤16 mg/L. SEM revealed extensive morphological changes following treatment with PMB in combination with meropenem compared with the changes observed with each individual agent. Additionally, morphological changes decreased with increasing resistance profiles of the isolate, i.e. increasing meropenem MIC. These antimicrobial effects may not only be a summation of the effects due to each antibiotic but also a result of differential action that likely inhibits protective mechanisms in bacteria.

KW - Combination

KW - Klebsiella pneumoniae

KW - KPC carbapenemase

KW - Meropenem

KW - Pharmacodynamics

KW - Polymyxin B

UR - http://www.scopus.com/inward/record.url?scp=85009266839&partnerID=8YFLogxK

U2 - 10.1016/j.ijantimicag.2016.10.025

DO - 10.1016/j.ijantimicag.2016.10.025

M3 - Article

VL - 49

SP - 224

EP - 232

JO - International Journal of Antimicrobial Agents

JF - International Journal of Antimicrobial Agents

SN - 0924-8579

IS - 2

ER -