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Antimicrobial Agents and Chemotherapy, November 2006, p. 3763-3769, Vol. 50, No. 11
0066-4804/06/$08.00+0     doi:10.1128/AAC.00480-05
Copyright © 2006, American Society for Microbiology. All Rights Reserved.

Pharmacokinetic-Pharmacodynamic Relationship of Arbekacin for Treatment of Patients Infected with Methicillin-Resistant Staphylococcus aureus

Reiko Sato,¹ Yusuke Tanigawara,^1* Mitsuo Kaku,² Naoki Aikawa,³ and Kihachiro Shimizu⁴

Department of Pharmacy, Keio University Hospital, Tokyo, Japan,¹ Division of Molecular Diagnostics, Department of Clinical Medicine, Tohoku University, Graduate School of Medicine, Sendai, Japan,² Department of Emergency and Critical Care Medicine, Keio University Hospital, Tokyo, Japan,³ The Kitasato Institute, Tokyo, Japan⁴

Received 12 April 2005/ Returned for modification 24 July 2005/ Accepted 11 July 2006

Arbekacin is widely used in Japan for the treatment of patients infected with methicillin-resistant Staphylococcus aureus (MRSA). In this study, we have determined the optimal concentration targets of arbekacin for both efficacy and safety. A pharmacokinetic-pharmacodynamic analysis was performed to relate exposure to the drug and clinical cure/improvement or nephrotoxicity. Since we have reported the population pharmacokinetic parameters for arbekacin in the preceding paper (Y. Tanigawara, R. Sato, K. Morita, M. Kaku, N. Aikawa, and K. Shimizu, Antimicrob. Agents Chemother. 50:3754-3762, 2006), individual exposure parameters, such as area under the concentration-time curve (AUC), peak concentration (C_max), AUC/MIC, C_max/MIC, and trough concentration (C_min) were estimated by the Bayesian method. Logistic regression was used to describe the relationship between exposure to the drug and the probability of clinical cure/improvement or nephrotoxicity. For the clinical efficacy analysis, 174 patients confirmed to have an MRSA infection were evaluated. The C_max, C_min, and AUC of arbekacin were associated with the probability of clinical cure/improvement during monotherapy. It was shown that the probability of cure/improvement rose when the C_max of arbekacin was increased, with an odds ratio of 6.7 for a change in C_max from 7.9 to 12.5 µg/ml (P = 0.037). For the nephrotoxic risk analysis, 333 patients were included, regardless of whether a pathogen was identified. Logistic regression analysis revealed C_min and AUC as risk factors of nephrotoxicity (P < 0.005). The estimated probabilities of arbekacin-induced nephrotoxicity were 2.5, 5.2, and 13.1% when the C_min values were 1, 2, and 5 µg/ml, respectively. The present findings are useful for optimizing the individual dose of arbekacin for the treatment of MRSA-infected patients.

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* Corresponding author. Mailing address: Department of Hospital Pharmacy, School of Medicine, Keio University, Tokyo 160-8582, Japan. Phone: 81-(0)3-5363-3847. Fax: 81-(0)3-5269-4576. E-mail: tanigawa{at}sc.itc.keio.ac.jp.

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Antimicrobial Agents and Chemotherapy, November 2006, p. 3763-3769, Vol. 50, No. 11
0066-4804/06/$08.00+0     doi:10.1128/AAC.00480-05
Copyright © 2006, American Society for Microbiology. All Rights Reserved.

This article has been cited by other articles:

• Tanigawara, Y., Sato, R., Morita, K., Kaku, M., Aikawa, N., Shimizu, K. (2006). Population Pharmacokinetics of Arbekacin in Patients Infected with Methicillin-Resistant Staphylococcus aureus. Antimicrob. Agents Chemother. 50: 3754-3762 [Abstract] [Full Text]