JAC Advance Access published online on September 20, 2002
Journal of Antimicrobial Chemotherapy, doi:10.1093/jac/dkf177
© 2002 by The British Society for Antimicrobial Chemotherapy
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Original Paper
1 Department of Pharmacokinetics
and Pharmacodynamics, Gause Institute of New Antibiotics, Russian
Academy
of Medical Sciences, 11 Bolshaya Pirogovskaya Street, Moscow, 119992
Russia
* Corresponding author. E-mail: firsov{at}dol.ru.
Received 22 January 2002
; revised 15 May 2002
; accepted 15 July 2002
Most integral endpoints of antimicrobial effect, including
area between the control growth and time-kill curves (ABBC),
area above the curve (AAC) and area under the time-kill
curve (AUBC) are determined over a dosing interval (
AUC/MIC relationships to different endpoints of
the antimicrobial effect: multiple-dose in vitro simulations
with moxifloxacin and levofloxacin
2 Department of Medicine,
Mount Auburn Hospital, Harvard Medical School, Cambridge, MA, USA
),
regardless of the actual effect duration. Unlike these -related endpoints, the intensity of
antimicrobial effect (IE) considers
the area between the control growth and time-kill curves
from time zero to the time when bacterial counts on the regrowth curve
achieve the same maximal numbers as in the absence of antibiotic,
even if this time is greater than .
Recently, important differences between ABBC-, AAC-,
AUBC- and IE-AUC/MIC relationships
were reported in single-dose simulations. The present study was
designed to examine these relationships in multiple-dose simulations.
A clinical isolate of Staphylococcus aureus was
exposed to simulated pharmacokinetics of moxifloxacin (MIC = 0.37
mg/L) and levofloxacin (MIC = 0.6 mg/L), simulating three
consecutive 24 h doses, which varied over a 32-fold range in the
24 h AUC/MIC ratio (AUC/MIC:
14-444 h and 15-484 h, respectively). The cumulative effect
of each treatment was expressed by IE,
determined from time zero to the time after the third dose when
the effect could no longer be detected, and by ABBC, AAC and AUBC
calculated over a 72 h period (i.e. over three dosing intervals).
With all four endpoints, systematic AUC/MIC increase-induced
changes in effect—an increase in IE,
ABBC and AAC, or a decrease in AUBC—were observed and the
log AUC/MIC-response
curves were fitted by an Emax model.
Using IE, the effects of moxifloxacin
and levofloxacin could be distinguished over a wider range of AUC/MIC ratios than with ABBC
and AUBC, whereas no differences between the fluoroquinolones could be
seen based on the AAC-AUC/MIC curves.
Although ABBC and AUBC were more descriptive than AAC, these two
endpoints distinguished the fluoroquinolone effects only over a
relatively narrow AUC/MIC
range (
40-100 h), which includes
therapeutically achievable values for levofloxacin but not for moxifloxacin.
Similar limitations of the -related
endpoints might be critical in comparative studies with other new
fluoroquinolones where therapeutic AUC/MIC ratios are >100
h.
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