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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
Pharmacokinetics and Disposition
  • 24 Downloads

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

Ertapenem Antimicrobial bone concentrations Bone to plasma ratio Osteoarticular infections Diabetic foot infection Osteomyelitis 

Notes

Funding

This study was funded through a Fremantle Hospital Medical Research Foundation grant and NHMRC project grant 1047105. TMED is supported by an NHMRC Practitioner Fellowship.

Compliance with ethical standards

Ethical approval

This prospective, single group, longitudinal PK study of single-dose intravenous ertapenem was approved by the Fremantle Hospital Human Research Ethics Committee (13/4) and all patients gave informed consent.

Supplementary material

228_2018_2597_Fig3_ESM.png (184 kb)
Supplementary Figure 1

Extraction efficiency of ertapenem from bone according to time. (PNG 184 kb)

228_2018_2597_MOESM1_ESM.tif (49 kb)
High Resolution Image (TIF 49 kb)
228_2018_2597_Fig4_ESM.png (435 kb)
Supplementary Figure 2

Goodness-of-fit plots for ertapenem in plasma (A) and bone (B), including observed concentrations against population and individual predicted concentrations, and weighted residuals against time from dose and population predicted concentrations. (PNG 435 kb)

228_2018_2597_MOESM2_ESM.tif (1.6 mb)
High Resolution Image (TIF 1628 kb)
228_2018_2597_MOESM3_ESM.docx (31 kb)
ESM 3 (DOCX 30 kb)

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Copyright information

© Springer-Verlag GmbH Germany, part of Springer Nature 2018

Authors and Affiliations

  • Jonathan Chambers
    • 1
  • Madhu Page-Sharp
    • 2
  • Sam Salman
    • 3
  • John Dyer
    • 1
  • Timothy M. E. Davis
    • 3
  • Kevin T. Batty
    • 2
  • Laurens Manning
    • 4
  1. 1.Department of Infectious DiseasesFiona Stanley HospitalMurdochAustralia
  2. 2.School of Pharmacy and Biomedical SciencesCurtin UniversityBentleyAustralia
  3. 3.Faculty of Health and Medical SciencesUniversity of Western Australia, Fremantle HospitalFremantleAustralia
  4. 4.Faculty of Health and Medical Sciences, Harry Perkins Research Institute, Fiona Stanley HospitalUniversity of Western AustraliaMurdochAustralia

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