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Antimicrobial Agents and Chemotherapy, March 2001, p. 927-931, Vol. 45, No. 3
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
(
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
), regardless of the actual effect duration. Unlike the
-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
-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
= 24 h. Unlike the IE, which displayed
pseudolinear relationships with the AUC/MIC ratio; each
-related
endpoint showed a distinct saturation at potentially therapeutic
AUC/MIC ratios (116 to 466 h) when the antimicrobial effect
persisted longer than
. 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
-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.
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