Vol.57 No.1 January 2009

Evaluation of levofloxacin dosage regimens to prevent the appearance of resistant mutants in Streptococcus pneumoniae and Escherichia coli using an in vitro simulation model

Hiroko Kanda¹⁾, Megumi Chiba¹⁾, Kazue Inoue¹⁾, Kazuki Hoshino¹⁾, Mayumi Tanaka²⁾, Tsuyoshi Otani¹⁾, Seiji Hori³⁾ and Kyoichi Totsuka⁴⁾

¹⁾Biological Research Laboratories IV, Daiichi Sankyo Co., Ltd., 1-16-13 Kitakasai, Edogawa-ku, Tokyo, Japan
²⁾Global Project Management Group, Daiichi Sankyo Co., Ltd.
³⁾Department of Pharmacology, Jikei University School of Medicine
⁴⁾Department of Infectious Diseases, Tokyo Women's Medical University

Abstract

To determine levofloxacin(LVFX) dosage regimens for preventing the appearance of resistant mutants, we evaluated bactericidal activity and the emergence of resistant subpopulations in Streptococcus pneumoniae and Escherichia coli by simulating human blood concentration after receiving LVFX using an in vitro simulation model. We then evaluated AUC/MIC and C_max/MIC ratios identified as pharmacodynamic predictors of clinical and microbiological outcomes and the appearance of bacterial resistance. For levofloxacin-susceptible strains (MIC ≤2 μg/mL) of S. pneumoniae and E. coli, an AUC/MIC ratio of ≥35.8 and a C_max/MIC ratio of ≥5.45 and an AUC/MIC ratio of ≥47.3 and a C_max/MIC ratio of ≥5.6, respectively, were needed to show potent bactericidal activities without the emergence of subpopulations with decreased susceptibility to LVFX. This means that the emergence of LVFX-resistant subpopulations was prevented in the model of LVFX 500 mg q.d. Subpopulations in which a susceptibility to LVFX decreased from 1/8 to 1/2 appeared in some strains where the MIC of LVFX was 1-2 μg/mL after being treated with 100 mg t.i.d., 250 mg q.d. or 250 mg b.i.d. These subpopulations acquired one quinolone-resistance-associated amino acid substitution in the quinolone-resistance determining region of target enzymes or increased expression of the qionolone efflux pump. This suggested that LVFX 500 mg q.d. would be a more effective dosage regimen than 100 mg t.i.d., 250 mg q.d., and 250 mg b.i.d. to prevent the appearance of resistant mutants.

Key word

levofloxacin, in vitro, simulation, Streptococcus pneumoniae, Escherichia coli

Received

October 29, 2008

Accepted

December 2, 2008

Jpn. J. Chemother. 57 (1): 1-14, 2009