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Antimicrobial Agents and Chemotherapy, March 2001, p. 927-931, Vol. 45, No. 3
0066-4804/01/$04.00+0   DOI: 10.1128/AAC.45.3.927-931.2001
Copyright © 2001, American Society for Microbiology. All rights reserved.

Relationships of the Area under the Curve/MIC Ratio to Different Integral Endpoints of the Antimicrobial Effect: Gemifloxacin Pharmacodynamics in an In Vitro Dynamic Model

Alexander A. Firsov,1,* Irene Y. Lubenko,1 Yury A. Portnoy,1 Stephen H. Zinner,2 and Sergey N. Vostrov1

Department of Pharmacokinetics, Centre of Science & Technology LekBioTech, Moscow, Russia,1 and Mount Auburn Hospital, Harvard Medical School, Cambridge, Massachusetts2

Received 26 April 2000/Returned for modification 21 October 2000/Accepted 26 December 2000

Most integral endpoints of the antimicrobial effect are determined over an arbitrarily chosen time period, such as the dosing interval (tau ), regardless of the actual effect duration. Unlike the tau -related endpoints, the intensity of the antimicrobial effect (IE) does consider its duration---from time zero to the time when bacterial counts on the regrowth curve achieve the same maximal numbers as in the absence of the antimicrobial. To examine the possible impact of this fundamental difference on the relationships of the antimicrobial effect to the ratio of the area under the concentration-time curve (AUC) to the MIC, a clinical isolate of Staphylococcus aureus was exposed to simulated gemifloxacin pharmacokinetics over a 40-fold range of AUC/MIC ratios, from 11 to 466 h. In each run, IE and four tau -related endpoints, including the area under the time-kill curve (AUBC), the area above the curve (AAC), the area between the control growth and time-kill curves (ABBC), and the ABBC related to the area under the control growth curve (AUGC), were calculated for tau  = 24 h. Unlike the IE, which displayed pseudolinear relationships with the AUC/MIC ratio; each tau -related endpoint showed a distinct saturation at potentially therapeutic AUC/MIC ratios (116 to 466 h) when the antimicrobial effect persisted longer than tau . This saturation results from the underestimation of the true effect and may be eliminated if ABBC, AAC, and AUBC (but not AUGC) are modified and determined in the same manner as the IE to consider the actual effect duration. These data suggest a marginal value of the tau -related endpoints as indices of the total antimicrobial effect. Since all of them respond to AUC/MIC ratio changes less than the IE, the latter is preferable in comparative pharmacodynamic studies.


* Corresponding author. Mailing address: Department of Pharmacokinetics, Centre for Science & Technology LekBioTech, 8 Nauchny Proezd, Moscow 117246, Russia. Phone: 7 (095) 332-3435. Fax: 7 (095) 332-6307. E-mail: firsov{at}dol.ru.


Antimicrobial Agents and Chemotherapy, March 2001, p. 927-931, Vol. 45, No. 3
0066-4804/01/$04.00+0   DOI: 10.1128/AAC.45.3.927-931.2001
Copyright © 2001, American Society for Microbiology. All rights reserved.



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