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Pharmacology

Intrapulmonary Pharmacokinetics of Cefepime and Enmetazobactam in Healthy Volunteers: Towards New Treatments for Nosocomial Pneumonia

Shampa Das, Richard Fitzgerald, Asad Ullah, Marcin Bula, Andrea M. Collins, Elena Mitsi, Jesus Reine, Helen Hill, Jamie Rylance, Daniela M. Ferreira, Karen Tripp, Andrea Bertasini, Samantha Franzoni, Mameli Massimiliano, Omar Lahlou, Paola Motta, Philip Barth, Patrick Velicitat, Philipp Knechtle, William Hope
Shampa Das
aAntimicrobial Pharmacodynamics and Therapeutics, University of Liverpool, Liverpool Health Partners, Liverpool, United Kingdom
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Richard Fitzgerald
bLiverpool University Hospital Foundation Trust, Liverpool Health Partners, Liverpool, United Kingdom
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Asad Ullah
bLiverpool University Hospital Foundation Trust, Liverpool Health Partners, Liverpool, United Kingdom
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Marcin Bula
bLiverpool University Hospital Foundation Trust, Liverpool Health Partners, Liverpool, United Kingdom
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Andrea M. Collins
bLiverpool University Hospital Foundation Trust, Liverpool Health Partners, Liverpool, United Kingdom
cLiverpool School of Tropical Medicine, Liverpool Health Partners, Liverpool, United Kingdom
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Elena Mitsi
cLiverpool School of Tropical Medicine, Liverpool Health Partners, Liverpool, United Kingdom
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Jesus Reine
cLiverpool School of Tropical Medicine, Liverpool Health Partners, Liverpool, United Kingdom
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Helen Hill
cLiverpool School of Tropical Medicine, Liverpool Health Partners, Liverpool, United Kingdom
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Jamie Rylance
bLiverpool University Hospital Foundation Trust, Liverpool Health Partners, Liverpool, United Kingdom
cLiverpool School of Tropical Medicine, Liverpool Health Partners, Liverpool, United Kingdom
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Daniela M. Ferreira
cLiverpool School of Tropical Medicine, Liverpool Health Partners, Liverpool, United Kingdom
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Karen Tripp
bLiverpool University Hospital Foundation Trust, Liverpool Health Partners, Liverpool, United Kingdom
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Andrea Bertasini
dAptuit (Verona) Srl, an Evotec Company, Verona, Italy
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Samantha Franzoni
dAptuit (Verona) Srl, an Evotec Company, Verona, Italy
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Mameli Massimiliano
dAptuit (Verona) Srl, an Evotec Company, Verona, Italy
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Omar Lahlou
eAllecra Therapeutics SAS, St-Louis, France
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Paola Motta
eAllecra Therapeutics SAS, St-Louis, France
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Philip Barth
eAllecra Therapeutics SAS, St-Louis, France
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Patrick Velicitat
eAllecra Therapeutics SAS, St-Louis, France
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Philipp Knechtle
eAllecra Therapeutics SAS, St-Louis, France
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William Hope
aAntimicrobial Pharmacodynamics and Therapeutics, University of Liverpool, Liverpool Health Partners, Liverpool, United Kingdom
bLiverpool University Hospital Foundation Trust, Liverpool Health Partners, Liverpool, United Kingdom
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DOI: 10.1128/AAC.01468-20
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ABSTRACT

Cefepime-enmetazobactam is a novel β-lactam–β-lactamase inhibitor combination with broad-spectrum antimicrobial activity against a range of multidrug-resistant Enterobacteriaceae. This agent is being developed for a range of serious hospital infections. An understanding of the extent of partitioning of β-lactam–β-lactamase inhibitor combinations into the human lung is required to better understand the potential role of cefepime-enmetazobactam for the treatment of nosocomial pneumonia. A total of 20 healthy volunteers were used to study the intrapulmonary pharmacokinetics of a regimen of 2 g cefepime-1 g enmetazobactam every 8 h intravenously (2 g/1 g q8h i.v.). Each volunteer contributed multiple plasma samples and a single epithelial lining fluid (ELF) sample, obtained by bronchoalveolar lavage. Concentrations of cefepime and enmetazobactam were quantified using liquid chromatography-tandem mass spectrometry. The pharmacokinetic data were modeled using a population methodology, and Monte Carlo simulations were performed to assess the attainment of pharmacodynamic targets defined in preclinical models. The concentration-time profiles of both agents in plasma and ELF were similar. The mean ± standard deviation percentage of partitioning of total drug concentrations of cefepime and enmetazobactam between plasma and ELF was 60.59% ± 28.62% and 53.03% ± 21.05%, respectively. Using pharmacodynamic targets for cefepime of greater than the MIC and free enmetazobactam concentrations of >2 mg/liter in ELF of 20% of the dosing interval, a regimen of cefepime-enmetazobactam of 2 g/0.5 g q8h i.v. infused over 2 h resulted in a probability of target attainment of ≥90% for Enterobacteriaceae with cefepime-enmetazobactam MICs of ≤8 mg/liter. This result provides a rationale to further consider cefepime-enmetazobactam for the treatment of nosocomial pneumonia caused by multidrug-resistant Enterobacteriaceae.

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Intrapulmonary Pharmacokinetics of Cefepime and Enmetazobactam in Healthy Volunteers: Towards New Treatments for Nosocomial Pneumonia
Shampa Das, Richard Fitzgerald, Asad Ullah, Marcin Bula, Andrea M. Collins, Elena Mitsi, Jesus Reine, Helen Hill, Jamie Rylance, Daniela M. Ferreira, Karen Tripp, Andrea Bertasini, Samantha Franzoni, Mameli Massimiliano, Omar Lahlou, Paola Motta, Philip Barth, Patrick Velicitat, Philipp Knechtle, William Hope
Antimicrobial Agents and Chemotherapy Dec 2020, 65 (1) e01468-20; DOI: 10.1128/AAC.01468-20

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Intrapulmonary Pharmacokinetics of Cefepime and Enmetazobactam in Healthy Volunteers: Towards New Treatments for Nosocomial Pneumonia
Shampa Das, Richard Fitzgerald, Asad Ullah, Marcin Bula, Andrea M. Collins, Elena Mitsi, Jesus Reine, Helen Hill, Jamie Rylance, Daniela M. Ferreira, Karen Tripp, Andrea Bertasini, Samantha Franzoni, Mameli Massimiliano, Omar Lahlou, Paola Motta, Philip Barth, Patrick Velicitat, Philipp Knechtle, William Hope
Antimicrobial Agents and Chemotherapy Dec 2020, 65 (1) e01468-20; DOI: 10.1128/AAC.01468-20
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KEYWORDS

ESBL
Monte Carlo simulation
beta-lactams
cefepime
enmetazobactam
pneumonia
population pharmacokinetics

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