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JAC Advance Access originally published online on September 26, 2006
Journal of Antimicrobial Chemotherapy 2006 58(6):1215-1220; doi:10.1093/jac/dkl389
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© The Author 2006. Published by Oxford University Press. All rights reserved. For Permissions, please e-mail: journals.permissions@oxfordjournals.org
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Pharmacokinetic and pharmacodynamic assessment of co-amoxiclav in the treatment of melioidosis

Wirongrong Chierakul1,*, Jinda Wangboonskul2, Thida Singtoroj3, Wirichada Pongtavornpinyo3, Jennifer M. Short3,4, Bina Maharjan3, Vanaporn Wuthiekanun3, David A. B. Dance5, Prapit Teparrukkul6, Niklas Lindegardh3,4, Sharon J. Peacock3,4, Nicholas P. Day3,4, Wipada Chaowagul6 and Nicholas J. White3,4

1 Department of Clinical Tropical Medicine, Faculty of Tropical Medicine Mahidol University, Bangkok, Thailand 2 Department of Pharmaceutical Chemistry, Faculty of Pharmaceutical Sciences Khon Kaen University, Khon Kaen, Thailand 3 Faculty of Tropical Medicine, Mahidol University Bangkok, Thailand 4 Centre for Clinical Vaccinology and Tropical Medicine, Nuffield Department of Clinical Medicine University of Oxford, Churchill Hospital, Oxford OX3 7LJ, UK 5 Health Protection Agency (South West) Tamar Science Park, 1 Davy Road, Plymouth, Devon PL6 8BX, UK 6 Medical Department, Sappasithiprasong Hospital Ubon Ratchathani, Thailand

Received 16 March 2006; returned 11 May 2006; revised 24 August 2006; accepted 31 August 2006

*Corresponding author. Tel: +66-2-354-1395; Fax: +66-2-354-9169; E-mail: tmwcr{at}mahidol.ac.th

Objectives: We conducted a prospective pharmacokinetic study of oral co-amoxiclav in patients with melioidosis to determine the optimal dosage and dosing interval in this potentially fatal infection.

Patients and methods: Serial plasma concentrations were measured after administration of two 1 g tablets of Augmentin® (1750 mg of amoxicillin and 250 mg of clavulanate) to 14 adult patients with melioidosis. Monte Carlo simulation was used to predict the concentration of each drug following multiple doses of co-amoxiclav at different dosages and dose intervals. The proportion of the dose-interval above MIC (T > MIC) was calculated from 10 000 simulated subject plasma concentration profiles together with chequerboard MIC data from 46 clinical isolates and four reference strains of Burkholderia pseudomallei.

Results: The median (range) observed maximum plasma concentrations of amoxicillin and clavulanate were 11.5 (3.3–40.2) mg/L and 5.1 (0.8–12.1) mg/L, respectively. The median (range) elimination half-lives were 94 (73–215) and 89 (57–140) min, respectively. Simulation indicated that co-amoxiclav 1750/250 mg given at 4, 6, 8 or 12 hourly dosing intervals would be associated with a T > MIC of ≤50% in 0.7%, 2.8%, 8.6% and 33.2% of patients, respectively. Corresponding proportions for T > MIC of ≥90% were 95.8%, 78.6%, 50.2% and 10.8%, respectively.

Conclusions: The dosing interval for co-amoxiclav (750/250 mg) in melioidosis should not be greater than 6 h.

Keywords: Monte Carlo simulation , Burkholderia pseudomallei , amoxicillin , clavulanate , PK/PD


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