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JAC Advance Access published online on September 19, 2007
Journal of Antimicrobial Chemotherapy, doi:10.1093/jac/dkm371
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© The Author 2007. Published by Oxford University Press on behalf of the British Society for Antimicrobial Chemotherapy. All rights reserved. For Permissions, please e-mail: journals.permissions@oxfordjournals.org

Peritoneal penetration of doripenem after intravenous administration in abdominal-surgery patients

Kazuro Ikawa1,*, Norifumi Morikawa1, Nami Urakawa1, Kayo Ikeda1, Hiroki Ohge2 and Taijiro Sueda2

1 Department of Clinical Pharmacotherapy, Graduate School of Biomedical Sciences, Hiroshima University, 1-2-3 Kasumi, Minami-ku, Hiroshima 734-8551, Japan 2 Department of Surgery, Graduate School of Biomedical Sciences, Hiroshima University, 1-2-3 Kasumi, Minami-ku, Hiroshima 734-8551, Japan

Received 22 May 2007; returned 4 August 2007; revised 30 August 2007; accepted 31 August 2007

* Corresponding author. Tel/Fax: +81-82-257-5320; E-mail: ikawak{at}hiroshima-u.ac.jp

Objectives: This study aimed to examine the peritoneal penetration of intravenous doripenem, a novel carbapenem used for the treatment of intra-abdominal infections.

Patients and methods: Doripenem (500 mg) was administered to 10 patients before abdominal surgery. Venous blood and peritoneal exudate samples were obtained at the end of infusion (0.5 h) and every hour for 6 h afterwards. The drug concentrations in serum and exudate were measured using HPLC, estimated by non-compartmental pharmacokinetic analysis and fitted to a three-compartment pharmacokinetic model in order to assess the exposure time that the drug concentration remained above MIC.

Results: The AUC0–{infty} was 59.3 ± 7.2 mg·h/L (mean ± SD) in serum and 49.3 ± 6.5 mg·h/L in exudate, and the exudate/serum ratio was 0.84 ± 0.13. The observed maximum concentration was 46.9 ± 7.4 mg/L at 0.5 h in serum and 24.5 ± 6.5 mg/L at 0.7 ± 0.4 h in exudate, and the exudate/serum ratio was 0.53 ± 0.17. The compartmental analysis showed that the average concentrations remained higher in exudate than in serum after 0.81 h post-dose, and the average drug-exposure times in serum (91% fraction unbound) and exudate were: 73.6% and 78.2% at an MIC of 1 mg/L; 37.0% and 41.5% at 4 mg/L; and 12.7% and 13.1% at 16 mg/L.

Conclusions: Following intravenous administration, doripenem penetrated well into peritoneal exudate of abdominal-surgery patients, and the drug-exposure times in exudate were greater than or equal to those estimated from serum data.

Key Words: pharmacokinetics , peritoneal exudate , carbapenems


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