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Naunyn-Schmiedeberg's Archives of Pharmacology

, Volume 392, Issue 2, pp 229–241 | Cite as

After standard dosage of piperacillin plasma concentrations of drug are subtherapeutic in burn patients

  • Katharina Olbrisch
  • Tobias Kisch
  • Julia Thern
  • Evelyn Kramme
  • Jan Rupp
  • Tobias Graf
  • Sebastian G. Wicha
  • Peter Mailänder
  • Walter RaaschEmail author
Original Article

Abstract

Infections are a major problem in patients with burn diseases. Mortality is high despite antibiotic therapy as studies are controversial concerning drug underdosing. The aims of this prospective, observational study were to monitor plasma concentrations of piperacillin during standard piperacillin/tazobactam treatment in 20 burn patients and 16 controls from the intensive care unit (ICU) and to optimize doses by in silico analyses. Piperacillin/tazobactam (4/0.5 g, tid) was administered over 0.5 h. Blood samples were taken at 1, 4, and 7.5 h after the end of the infusion. Free piperacillin plasma concentrations were determined. Pharmacokinetic parameters and in silico analysis results were calculated using the freeware TDMx. The primary target was defined as percentage of the day (fT>1xMIC; fT>4xMIC) when piperacillin concentrations exceeded 1xMIC/4xMIC (minimum inhibitory concentration), considering a MIC breakpoint of 16 mg/L for Pseudomonas aeruginosa. In an off-label approach, two burn patients were treated with 8/1 g piperacillin/tazobactam, 3 h qid. fT>1xMIC (55 ± 22% vs. 77 ± 24%) and fT>4xMIC (17 ± 11% vs. 30 ± 11%) were lower in burn than in ICU patients after 4/0.5 g, 0.5 h, tid. In silico analyses indicated that fT>1xMIC (93 ± 12% burn, 97 ± 4% ICU) and fT>4xMIC (62 ± 23% burn, 84 ± 19% ICU) values increase by raising the piperacillin dosage to 8/1 g qid and prolonging the infusion time to 3 h. Off-label treatment results were similar to in silico data for burn patients (84%fT>1xMIC and 47%fT>4xMIC). Standard dosage regimens for piperacillin/tazobactam resulted in subtherapeutic piperacillin concentrations in burn and ICU patients. Dose adjustments via in silico analyses can help to optimize antibiotic therapy and to predict respective concentrations in vivo. Trial registration: NCT03335137, registered 07.11.2017, retrospectively.

Keywords

Burn patients Piperacillin Dosing simulation Pharmacokinetic In silico analyses 

Abbreviations

ABSI

Abbreviated Burn Severity Risk Index

AKI

Acute kidney injury

ARC

Augmented renal clearance

CL

Clearance

CLCr

Creatinine clearance

D

Day

ICU

Intensive care unit

MIC

Minimal inhibition concentration

PIP

Piperacillin

PK

Pharmacokinetic

SAPS II score

Simplified Acute Physiology Score

SCr

Serum creatinine

t1/2

Half-life time

TAZ

Tazobactam

TBSA

Total burn surface area

TDM

Therapeutic drug monitoring

TISS

Therapeutic Intervention Scoring System

Vd

Volume of distribution

PBB

Plasma protein binding

tid

Three times a day

qid

Four times a day

sid

Once a day

Notes

Acknowledgments

The authors gratefully acknowledge Prof. Dr. Frieder Kees (Institute of Pharmacology, University of Regensburg) for his support in establishing HPLC analysis, Dr. Reinhard Vonthein (Institute of Medical Biometry and Statistics, University of Lübeck) for assistance in power analysis, Ines Stölting for assistance in HPLC analysis, and Sherryl Sundell for improving the English style.

Authors’ contributions

KO, TK, EK, JT, PM, and WR conceived the study. KO, JT, TK, EK, PM, TG, and WR were involved in protocol development, ethical approval, and implementation. KO, TK, TG, and WR collected the data. KO and WR completed the laboratory analysis and quality assurance. KO, SW, and WR performed the statistical and pharmacokinetic analyses. KO and WR wrote the manuscript draft, and all of the remaining authors contributed to subsequent revisions. WR takes responsibility for archiving the data and guarantees the integrity of the paper from inception to publication. All of the authors have read and approved the article for publication.

Funding

The study was funded by the Department of Pharmacy of the University Hospital Schleswig-Holstein, Campus Lübeck, Lübeck, Germany.

Compliance with ethical standards

Ethics approval and consent to participate

This study was approved by the ethics committee of the University (reference number 13-275).

Conflict of interest

The authors declare that they have no conflict of interest.

Supplementary material

210_2018_1573_MOESM1_ESM.docx (183 kb)
ESM 1 (DOCX 183 kb)

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Copyright information

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

Authors and Affiliations

  1. 1.Institute of Experimental and Clinical Pharmacology and ToxicologyUniversity of LübeckLübeckGermany
  2. 2.Department of PharmacyUniversity Hospital Schleswig-HolsteinLübeckGermany
  3. 3.Clinic of Plastic SurgeryUniversity Hospital Schleswig-HolsteinLübeckGermany
  4. 4.Department of Infectious Diseases and MicrobiologyUniversity Hospital Schleswig-HolsteinLübeckGermany
  5. 5.University Heart Centre Lübeck, Department of Cardiology, Angiology and Intensive Care MedicineUniversity Hospital Schleswig-HolsteinLübeckGermany
  6. 6.Clinical Pharmacy, Institute of PharmacyUniversity of HamburgHamburgGermany
  7. 7.DZHK (German Centre for Cardiovascular Research), partner site Hamburg/Kiel/LübeckLübeckGermany
  8. 8.CBBM (Center of Brain, Behavior and Metabolism)University of LübeckLübeckGermany

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