Ertapenem for osteoarticular infections in obese patients: a pharmacokinetic study of plasma and bone concentrations

Jonathan Chambers, Madhu Page-Sharp, Sam Salman, John Dyer, Timothy M.E. Davis, Kevin T. Batty, Laurens Manning

Research output: Contribution to journalArticle

Abstract

Purpose: Ertapenem is used off-label to treat osteoarticular infections but there are few pharmacokinetic (PK) data to guide optimal dosing strategies in patients who may be obese with multiple co-morbidities including diabetes and peripheral vascular disease. Methods: Participants undergoing lower limb amputation or elective joint arthroplasty received a dose of intravenous ertapenem prior to surgery. Eight plasma samples were collected over 24 h, together with at least one bone sample per patient. Ertapenem concentrations in plasma and bone were measured using liquid-chromatography/mass-spectroscopy and analysed using non-linear mixed effects PK modelling. Results: Plasma and bone concentrations were obtained from 10 participants. The final population PK model showed that a fat free body mass was the most appropriate body size adjustment. Ertapenem diffused rapidly into bone but concentrations throughout the 24 h dosing period were on average 40-fold higher in plasma, corresponding to a bone to plasma ratio of 0.025, and highly variable between individuals. Simulations demonstrated a high probability of target attainment (PTA) for free plasma concentrations when the minimum inhibitory concentrations (MIC) were ≤ 0.25 mg/L. By contrast, at MICs of 0.5 mg/L and ≥ 1 mg/L, the fractions of patients attaining this target was ~ 80% and 40%, respectively. In bone, the PTA was ≤ 45% when the MIC was ≥ 0.25 mg/L. Conclusion: Local bone and free plasma concentrations appear adequate for osteoarticular infections where Enterobacteriaceae are the main causative pathogens, but for Staphylococcus aureus and other bacteria, conventional dosing may lead to inadequate PTA.

Original languageEnglish
Pages (from-to)511-517
Number of pages7
JournalEuropean Journal of Clinical Pharmacology
Volume75
Issue number4
Early online date4 Dec 2018
DOIs
Publication statusPublished - Apr 2019

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Pharmacokinetics
Bone and Bones
Infection
Microbial Sensitivity Tests
Enterobacteriaceae Infections
Peripheral Vascular Diseases
Body Size
ertapenem
Amputation
Liquid Chromatography
Arthroplasty
Staphylococcus aureus
Lower Extremity
Mass Spectrometry
Joints
Fats
Morbidity
Bacteria
Population

Cite this

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title = "Ertapenem for osteoarticular infections in obese patients: a pharmacokinetic study of plasma and bone concentrations",
abstract = "Purpose: Ertapenem is used off-label to treat osteoarticular infections but there are few pharmacokinetic (PK) data to guide optimal dosing strategies in patients who may be obese with multiple co-morbidities including diabetes and peripheral vascular disease. Methods: Participants undergoing lower limb amputation or elective joint arthroplasty received a dose of intravenous ertapenem prior to surgery. Eight plasma samples were collected over 24 h, together with at least one bone sample per patient. Ertapenem concentrations in plasma and bone were measured using liquid-chromatography/mass-spectroscopy and analysed using non-linear mixed effects PK modelling. Results: Plasma and bone concentrations were obtained from 10 participants. The final population PK model showed that a fat free body mass was the most appropriate body size adjustment. Ertapenem diffused rapidly into bone but concentrations throughout the 24 h dosing period were on average 40-fold higher in plasma, corresponding to a bone to plasma ratio of 0.025, and highly variable between individuals. Simulations demonstrated a high probability of target attainment (PTA) for free plasma concentrations when the minimum inhibitory concentrations (MIC) were ≤ 0.25 mg/L. By contrast, at MICs of 0.5 mg/L and ≥ 1 mg/L, the fractions of patients attaining this target was ~ 80{\%} and 40{\%}, respectively. In bone, the PTA was ≤ 45{\%} when the MIC was ≥ 0.25 mg/L. Conclusion: Local bone and free plasma concentrations appear adequate for osteoarticular infections where Enterobacteriaceae are the main causative pathogens, but for Staphylococcus aureus and other bacteria, conventional dosing may lead to inadequate PTA.",
keywords = "Antimicrobial bone concentrations, Bone to plasma ratio, Diabetic foot infection, Ertapenem, Osteoarticular infections, Osteomyelitis",
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Ertapenem for osteoarticular infections in obese patients : a pharmacokinetic study of plasma and bone concentrations. / Chambers, Jonathan; Page-Sharp, Madhu; Salman, Sam; Dyer, John; Davis, Timothy M.E.; Batty, Kevin T.; Manning, Laurens.

In: European Journal of Clinical Pharmacology, Vol. 75, No. 4, 04.2019, p. 511-517.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Ertapenem for osteoarticular infections in obese patients

T2 - a pharmacokinetic study of plasma and bone concentrations

AU - Chambers, Jonathan

AU - Page-Sharp, Madhu

AU - Salman, Sam

AU - Dyer, John

AU - Davis, Timothy M.E.

AU - Batty, Kevin T.

AU - Manning, Laurens

PY - 2019/4

Y1 - 2019/4

N2 - Purpose: Ertapenem is used off-label to treat osteoarticular infections but there are few pharmacokinetic (PK) data to guide optimal dosing strategies in patients who may be obese with multiple co-morbidities including diabetes and peripheral vascular disease. Methods: Participants undergoing lower limb amputation or elective joint arthroplasty received a dose of intravenous ertapenem prior to surgery. Eight plasma samples were collected over 24 h, together with at least one bone sample per patient. Ertapenem concentrations in plasma and bone were measured using liquid-chromatography/mass-spectroscopy and analysed using non-linear mixed effects PK modelling. Results: Plasma and bone concentrations were obtained from 10 participants. The final population PK model showed that a fat free body mass was the most appropriate body size adjustment. Ertapenem diffused rapidly into bone but concentrations throughout the 24 h dosing period were on average 40-fold higher in plasma, corresponding to a bone to plasma ratio of 0.025, and highly variable between individuals. Simulations demonstrated a high probability of target attainment (PTA) for free plasma concentrations when the minimum inhibitory concentrations (MIC) were ≤ 0.25 mg/L. By contrast, at MICs of 0.5 mg/L and ≥ 1 mg/L, the fractions of patients attaining this target was ~ 80% and 40%, respectively. In bone, the PTA was ≤ 45% when the MIC was ≥ 0.25 mg/L. Conclusion: Local bone and free plasma concentrations appear adequate for osteoarticular infections where Enterobacteriaceae are the main causative pathogens, but for Staphylococcus aureus and other bacteria, conventional dosing may lead to inadequate PTA.

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KW - Antimicrobial bone concentrations

KW - Bone to plasma ratio

KW - Diabetic foot infection

KW - Ertapenem

KW - Osteoarticular infections

KW - Osteomyelitis

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U2 - 10.1007/s00228-018-2597-z

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