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Previous Article | Next Article 
Antimicrobial Agents and Chemotherapy, April 2000, p. 879-884, Vol. 44, No. 4
0066-4804/00/$04.00+0
Copyright © 2000, American Society for Microbiology. All rights reserved.
Comparative Pharmacodynamics of Gatifloxacin and
Ciprofloxacin in an In Vitro Dynamic Model: Prediction of
Equiefficient Doses and the Breakpoints of the Area under the
Curve/MIC Ratio
Sergey N.
Vostrov,
Olga V.
Kononenko,
Irene Y.
Lubenko,
Stephen H.
Zinner,
and
Alexander A.
Firsov*
Division of Infectious Diseases, Roger
Williams Medical Center, Rhode Island Hospital, Brown University,
Providence, Rhode Island
Received 8 April 1999/Returned for modification 18 September
1999/Accepted 10 January 2000
 |
ABSTRACT |
To demonstrate the impact of the pharmacokinetics of gatifloxacin
(GA) relative to those of ciprofloxacin (CI) on the antimicrobial effect (AME), the killing and regrowth kinetics of two differentially susceptible clinical isolates each of Staphylococcus
aureus, Escherichia coli, and Klebsiella
pneumoniae were studied. With each organism, a series of
monoexponential pharmacokinetic profiles of GA (half-life [t1/2], 7 h) and CI
(t1/2 = 4 h) were simulated to mimic
different single doses of GA and two 12-h doses of CI. The respective
eightfold ranges of the ratios of the area under the concentration-time curve (AUC) to the MIC were 58 to 466 and 116 to 932 (µg · h/ml)/(µg/ml). The species- and strain-independent linear
relationships observed between the intensity of AME
(IE) and log AUC/MIC were not superimposed for
GA and CI (r2 = 0.99 in both cases). The
predicted AUC/MIC ratio for GA that might be equivalent to a clinically
relevant AUC/MIC breakpoint for CI was estimated to be 102 rather than
125 (µg · h/ml)/(µg/ml). The respective MIC breakpoints were
0.32 µg/ml (for a 400-mg dose of GA) and 0.18 µg/ml (for two 500-mg
doses of CI). On the basis of the IE-log
AUC/MIC relationships, equiefficient 24-h doses (D24hs) of GA and CI were calculated for
hypothetical strains of S. aureus, E. coli, and
K. pneumoniae for which the MICs were equal to the MICs at
which 50% of isolates are inhibited. To provide an "acceptable"
IE equal to 200 (log CFU/ml) · h, i.e.,
the IE provided by AUC/MIC of 125 (µg
· h/ml)/(µg/ml) for ciprofloxacin, the
D24hs of GA for all three organisms were much
lower (115, 30, and 60 mg) than the clinically proposed 400-mg dose.
Although the usual dose of CI (two doses of 500 mg) would be in excess for E. coli and K. pneumoniae
(D24h = two doses of 40 mg and two doses
of 115 mg, respectively), even the highest clinical dose of CI (two
doses of 750 mg) might be insufficient for S. aureus (D24h, > two doses of 1,000 mg). The method of
generalization of data obtained with specific organisms to other
representatives of the same species described in the present report
might be useful for prediction of the AMEs of new quinolones.
| |
INTRODUCTION |
We recently described a new approach
to the in vitro comparison of fluoroquinolones on the basis of an
analysis of relationships between the intensity of the antimicrobial
effect (IE; the area between control growth and
bacterial killing and regrowth curves [4, 8]) and the
ratio of the area under the concentration-time curve (AUC) to the MIC
as established over a wide range of AUC/MIC ratios (9). This
approach allowed accurate comparisons of the antimicrobial effects of
trovafloxacin and ciprofloxacin in terms of the
IE versus log AUC/MIC relationships. On the
basis of these relationships that were bacterial species and strain
independent but that were specific for each quinolone, the
equiefficient AUC/MIC breakpoint of trovafloxacin relative to that of
ciprofloxacin was predicted (9). Later, the described
approach was expanded to generalize the data obtained with specific
bacterial strains to predict the equiefficient doses of the quinolones
adjusted by the MIC at which 50% of isolates are inhibited
(MIC50) (7).
A similar approach was applied in the present study to compare the
antimicrobial effects of gatifloxacin and ciprofloxacin on
Staphylococcus aureus, Escherichia coli, and
Klebsiella pneumoniae. Also, an attempt to predict a
clinical equiefficient dose of the newer quinolone was conducted.
| |
MATERIALS AND METHODS |
Antimicrobial agents.
Gatifloxacin and ciprofloxacin lactate
powders (kindly provided by Bristol-Myers Squibb and Bayer Corporation,
respectively) were used in the study.
Bacterial strains.
Two clinical isolates each of S. aureus (methicillin-resistant S. aureus [MRSA]
strains), E. coli, and K. pneumoniae were selected for the study. The MICs for these organisms were determined as
described elsewhere (6) and are presented in Table
1. For the prediction of the
antimicrobial effects of the quinolones on hypothetical representatives
of the species mentioned above (see the Results section), weighted
geometric means of the reported MIC50s of gatifloxacin
(1) and ciprofloxacin (1, 3, 15, 16; D. Adam, Proc. 20th Int. Congr. Chemother., abstr. 2237, 1997; S. Kocagoz,
D. Gur, A. Karademir, H. Akalin, and S. Unal, Abstract 1st Eur. Congr.
Chemother. and 7th Biennial Conf. Antiinfective Agents Chemother.,
abstr. F 148, 1997; M. Takahata, J. Mitsuyama, Y. Yamashiro, M. Yonezawa, H. Araki, H. Yamada, Y. Todo, S. Minami, Y. Watanabe, and H. Narita, Abstr. 37th Intersci. Conf. Antimicrob. Agents Chemother.,
abstr. F 159, p. 173, 1997; M. Visali, M. Jacobs, and P. Appelbaum,
Proc. 20th Int. Congr. Chemother., abstr. 2233, 1997) were calculated.
Since the MIC50s for MRSA reported in one study
(3) differed substantially from the estimates reported in
five other studies (1, 15; Adam, Proc., 20th Int.
Congr. Chemother., 1997; Kocagoz et al., Abstr. 1st Eur. Congr.
Chemother and 7th Biennial Conf. Antiinfective Agents Chemother., 1997; Takahata et al., 37th ICAAC), only MIC50s for
methicillin-susceptible strains reported in the study of Felmingham et
al. (3) were considered. The respective geometric mean
values of the MIC50s of gatifloxacin for S. aureus, E. coli, and K. pneumoniae were 0.08, 0.02, and 0.04 µg/ml, respectively, and those of ciprofloxacin were 0.52, 0.01, and 0.03 µg/ml, respectively.
In vitro dynamic model and simulated pharmacokinetic
profiles.
A previously described dynamic model (8) was
used in the study. The operation procedure, reliability of simulations
of the quinolone pharmacokinetic profiles, and the high degree of reproducibility of the time-kill curves provided by the model have been
reported elsewhere (6).
A series of monoexponential profiles that mimic single-dose
administration of gatifloxacin and twice-daily dosing of ciprofloxacin were simulated. The simulated half-lives (7 h for gatifloxacin and
4.0 h for ciprofloxacin) were consistent with values reported for
humans: 6.0 to 8.4 h (10-12) and 3.2 to 5.0 h
(2, 13, 17), respectively. The respective rates of fresh
nutrient medium influx into the 40-ml central compartment and
antibiotic- and bacterium-containing medium efflux from this
compartment were 4 ml/h (gatifloxacin) and 7 ml/h (ciprofloxacin).
With both strains of S. aureus and with E. coli
37, the simulated AUC/MIC ratios for gatifloxacin were 58, 116, 233, and 466 (µg · h/ml)/(µg/ml) and those for ciprofloxacin were
116, 233, 466, and 932 (µg · h/ml)/(µg/ml). With E. coli 11557 or K. pneumoniae 56, the respective AUC/MIC
ratios were 58, 116, and 233 and 116, 233, and 466 (µg · h/ml)/(µg/ml). With K. pneumoniae 128, the AUC/MIC ratios
for gatifloxacin were 58 and 233 (µg · h/ml)/(µg/ml), and
those for ciprofloxacin were 116 and 466 (µg · h/ml)/(µg/ml). To provide comparable AUC/MIC ratios for gatifloxacin
and ciprofloxacin, the latter of which has a shorter half-life, the sum
of the peak concentration/MIC ratios produced by the two doses of
ciprofloxacin was higher than the respective value for gatifloxacin at
the same simulated AUC/MIC ratio. The overall range of the simulated
peak concentration-to-MIC ratios for gatifloxacin was 5.8 to 46.4, and
that for ciprofloxacin was 10.2 to 81.3 (Fig.
1). For ciprofloxacin, the designed
AUC/MIC ratios reflect the sum of two AUC/MIC ratios provided by the
two doses of the quinolone administered at 12-h intervals.
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FIG. 1.
In vitro simulated pharmacokinetic profiles of
gatifloxacin (bold line) and ciprofloxacin (thin line). The simulated
AUC/MIC ratios [in (µg · h/ml)/(µg/ml)] are indicated by
the boxed numbers.
|
|
Quantitation of time-kill curves and antimicrobial effect.
In each experiment multiple samples of bacterium-containing media from
the central compartment were obtained throughout the observation
period. The duration of the experiments was defined in each case as the
time until regrowing antibiotic-exposed bacteria reached the maximum
numbers observed in the absence of antibiotic (
1010
CFU/ml). The procedure used for quantitation of viable counts has been
reported elsewhere (6).
As described earlier (8), the antimicrobial effect
(E) at each time point (t) was expressed by the
difference between logarithms of the respective viable counts in the
control growth curve (Nc) and in the time-kill
curve (NA): E(t) = log Nc 
log NA (Fig. 2). As seen in Fig. 2, either the area
between the log Nc-t and log
NA-t curves (Fig. 2A) or the area under the
E-t curve (Fig. 2B) describes the total antimicrobial effect
as expressed by IE. The upper limit of bacterial
numbers, i.e., the cutoff level on the regrowth and control growth
curves used to determine the IE, was
1011 CFU/ml. In case of lower counts, they were
extrapolated to the cutoff level by using a logistic function
(STATISTICA software, version 4.3; StatSoft, Inc.).
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FIG. 2.
Determination of IE: S. aureus 944 was exposed to gatifloxacin at an AUC/MIC of 116 (µg · h/ml)/(µg/ml). IE describes the
dashed area between the control growth and time-kill curves (A) or
under the E-t curves (B).
|
|
Relationships between effect and AUC/MIC or dose.
The
IE-versus-log AUC/MIC data sets obtained with
each quinolone against S. aureus, E. coli, and
K. pneumoniae were fitted by the equation
IE = a + b log AUC/MIC (equation 1).
When predicting the AUC/MIC breakpoint for gatifloxacin, the reported
breakpoint value for ciprofloxacin, 125 (µg · h/ml)/(µg/ml), that correlated with bacterial eradication in patients with respiratory tract infections (14) was used. This reference breakpoint
reflects the critical value of the area under the inhibitory curve that is very similar to the AUC/MIC.
To express the antimicrobial effects as a function of quinolone dose
(D), the AUC in the linear relationship between
IE and log AUC that corresponds to equation 1 written for a given quinolone-pathogen pair was replaced by
D according to the polynomial equation AUC = c + dD + eD2 (equation 2). The values
of c, d, and e for gatifloxacin (0, 7.0 × 10
2, and 3.6 × 105,
respectively) and for ciprofloxacin (0.10, 1.4 × 102, and 7.5 × 106, respectively)
were calculated by considering the curvilinear pattern of the
AUC-D plots constructed from pharmacokinetic data for
gatifloxacin (AUCs at Ds from 100 to 600 mg
[10-12]) and ciprofloxacin (AUCs at Ds
from 100 to 1,000 mg [2]).
Correlation and regression analyses of the relationships between
IE and log AUC/MIC for each quinolone were
performed at a level of significance of P equal to 0.05.
| |
RESULTS |
The time courses of viable counts that reflect killing and
regrowth of S. aureus, E. coli, and K. pneumoniae exposed to monoexponentially decreasing concentrations
of gatifloxacin and ciprofloxacin yielded similar patterns. At the
AUC/MIC ratios studied, regrowth followed a rapid and considerable
reduction in bacterial numbers. The rapid onset of the antimicrobial
effect is reflected by steep ascending branches of the E-t
curves (Fig. 3). As a rule, the maximal
Es (Emaxs) produced by both
quinolones were greater at higher AUC/MIC ratios, although the
AUC/MIC-induced differences in Emaxs were less
pronounced than those in the descending branches of the E-t curves. As seen in Fig. 3, these shifts were distinctly dependent on
the simulated AUC/MIC: the higher the AUC/MIC, the later the disappearance of the antimicrobial effect.
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FIG. 3.
Kinetics of the antimicrobial effect of gatifloxacin
(left panels) and ciprofloxacin (right panels). The simulated AUC/MIC
ratio [in (µg · h/ml)/(µg/ml)] is indicated by the number
on each curve.
|
|
The respective IEs correlated well with log
AUC/MIC ratios for both gatifloxacin and ciprofloxacin (Fig.
4). The IE-log
AUC/MIC plots fitted by equation 1 were linear, bacterial species and strain independent, but quinolone specific. As seen in Fig. 4, at
AUC/MIC ratios of >75 (µg · h/ml)/(µg/ml), the effects
produced by gatifloxacin were greater than those produced by
ciprofloxacin at the same AUC/MIC ratio. For example, at an AUC/MIC
ratio of 250 (µg · h/ml)/(µg/ml), the
IE of gatifloxacin was 14% higher than that of
ciprofloxacin. Furthermore, an equivalent AUC/MIC ratio for
gatifloxacin which corresponds to a clinically established AUC/MIC
ratio of 125 (µg · h/ml)/(µg/ml) for ciprofloxacin
(14) and which produces the same IE
of 200 (log CFU/ml) · h was lower, 102 (µg · h/ml)/(µg/ml). This estimated value might be proposed as an
equivalent AUC/MIC breakpoint that in turn might be used to predict the
MIC breakpoint of gatifloxacin. As follows from equation 2, a
clinically accepted dose of gatifloxacin (400 mg) provides an AUC of 33 µg · h/ml. So, the MIC breakpoint is equal to 33/102, which is
equal to 0.32 µg/ml. The respective value for two 500-mg doses of
ciprofloxacin estimated by using equation 2 is lower: 22/125, which is
equal to 0.18 µg/ml. As shown in Fig.
5, the MIC ranges limited from above by
the respective MIC50s for E. coli and K. pneumoniae are lower than the MIC breakpoint lines for both
gatifloxacin and ciprofloxacin. Unlike the two gram-negative bacteria,
the usual clinical dose of ciprofloxacin (two 500-mg doses) might be
insufficient to kill many strains of S. aureus, including
those for which the MIC is less than the MIC50, whereas the
proposed dose of gatifloxacin (400 mg) might kill any strain for which
the MIC is less than or equal to the MIC50.
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FIG. 4.
AUC/MIC-dependent antimicrobial effects of gatifloxacin
(bold line) and ciprofloxacin (thin line) on S. aureus,
E. coli, and K. pneumoniae as fitted by equation
1, in which a is equal to 190 and b is equal to
194 for gatifloxacin and a is equal to 53 and b
is equal to 121 for ciprofloxacin. The transparent numbers indicate the
equivalent AUC/MIC.
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FIG. 5.
MIC50s for S. aureus
(S.a.), E. coli (E.c.), and K. pneumoniae (K.p.) compared with the MIC breakpoints of
gatifloxacin and ciprofloxacin as predicted in this study.
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| |
DISCUSSION |
This comparative study demonstrating a bacterial species- and
strain-independent but quinolone-specific pattern of the
IE-log AUC/MIC relationships is consistent with
our earlier findings for trovafloxacin and ciprofloxacin (7,
9). A similar strain-independent AUC/MIC-response relationship
can be derived from another dose-range study with gatifloxacin (A. Bauernfeind, E. Eberlein, and I. Schneider, Abstr. 2nd Eur. Congr.
Chemother. and the 7th Biennial Conf. Antiinfective Agents Chemother.,
poster T 135, 1996). To establish the respective relationship, on the
basis of reported data (Bauernfeind et al., Abstr. 2nd Eur. Congr.
Chemother. and 7th Biennial Conf. Antiinfective Agents Chemother,
1996), the antimicrobial effects of gatifloxacin against three
differentially susceptible strains of Streptococcus pneumoniae (MICs, 0.25, 0.5, and 1 µg/ml) were expressed by
areas between the control growth and time-kill curves (ABBC)
(5), i.e., by IE determined within
24 h, when regrowth may or may not be seen. The AUC/MIC ratios
that correspond to the doses used in the study by Bauernfeind et al.
(Abstr. 2nd Eur. Congr. Chemother. and 7th Biennial Conf. Antiinfective
Agents Chemother., 1996), from 100 to 800 mg, were calculated by using
equation 2. As seen in Fig. 6, ABBC
correlates well with log AUC/MIC in a strain-independent fashion. So,
these data confirm the interstrain predictability of the antimicrobial
effects of gatifloxacin in terms of the AUC/MIC-response relationship.
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FIG. 6.
AUC/MIC-dependent antimicrobial effects of gatifloxacin
on S. pneumoniae constructed from reported data (Bauernfeind
et al., Abstr. 2nd Eur. Congr. Chemother. and 7th Biennial Conf.
Antiinfective Agents Chemother., 1996). The data obtained with three
strains of S. pneumoniae are indicated by different
symbols.
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|
Due to the strain-independent pattern of the
IE-log AUC/MIC relationships that were
established in the present study with gatifloxacin and ciprofloxacin,
equation 1 may be applied to any strain of a given species, including a
hypothetical strain for which the MIC is equal to the
MIC50. In this case equation 1 may be rearranged as
follows: IE = a' + b log AUC (equation 3),
where a' is a b log MIC50.
With the MIC50s specified in the Materials and Methods
section, a specific a' can be calculated and the respective species-specific AUC/MIC relationship of IE can
be obtained for each quinolone-bacterial species pair. Then, by
combining equations 3 and 2, the respective MIC50-adjusted
dose-response relationships, IE = a' + b
log (c + dD + eD2) (equation 4), can
be derived. The plots of the dose-dependent IEs
that might be produced by gatifloxacin and ciprofloxacin for hypothetical representatives of the three bacterial species for which
MICs are equal to the respective MIC50s are shown in Fig. 7.
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FIG. 7.
Dose-dependent antimicrobial effects of gatifloxacin
(bold curves) and ciprofloxacin (thin curves) on hypothetical strains
of E. coli, K. pneumoniae, and S. aureus. The doses that provided the same IE
are indicated by the transparent symbols.
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|
As seen in Fig. 7, the IE-log D plots
for gatifloxacin are positioned to the left of those for ciprofloxacin,
showing that the same antimicrobial effect might be provided by much
lower absolute doses of the new quinolone. For example, to provide an IE of 200 (log CFU/ml) · h that
corresponds to an AUC/MIC of 125 (µg · h/ml)/(µg/ml) for
ciprofloxacin for the gram-negative organisms, the 24-h doses
(D24hs) of gatifloxacin might be 2.7-fold
(E. coli) and 3.9-fold (K. pneumoniae) lower than
the respective D24hs of ciprofloxacin. Due to
the more striking contrast between the intrinsic activities of the
quinolones against S. aureus (MIC50s, 0.08 µg/ml for gatifloxacin and 0.52 µg/ml for ciprofloxacin), the
difference between the equiefficient D24hs is
even more pronounced: 115 mg versus two doses of 1,080 mg,
respectively. On the other hand, to provide the
IE of 314 (log CFU/ml) · h produced by
the clinically accepted 400-mg D24h of
gatifloxacin against S. aureus, a
D24h of two doses of 3,700 mg of ciprofloxacin
would be necessary, and this dose exceeds the ciprofloxacin
D24hs that might be given clinically. As the
extrapolated relationship between D and AUC of
ciprofloxacin, two doses of 3,700 mg, which is equal to a
D24h of 7,400 mg, is out of the actual
D range in the AUC-D set fitted by equation 2, the latter estimate is more conditional than the estimates for the
other organisms. However, it does reflect the order of difference
between the quinolone doses that might be necessary to provide the same
antimicrobial effect.
The MIC50-adjusted relationships between
IE and D24h may be useful
for the generalization of the findings obtained with specific representatives of a given species. However, they may or may not predict a clinical D24h of the newly developed
quinolone that should be at least as efficient as a clinically accepted
D24h of the older quinolone against similarly
susceptible species, i.e., against gram-negative bacteria. Indeed, the
estimated equiefficient D24hs of gatifloxacin
and ciprofloxacin against E. coli and K. pneumoniae strains for which the MICs are equal to the
MIC50s appeared to be much lower (Fig. 7) than, for
example, the clinical D24h of ciprofloxacin.
With E. coli, the gatifloxacin and ciprofloxacin equiefficient D24hs were 30 mg and two doses of
40 mg, respectively, and with K. pneumoniae they were 60 mg
and two doses of 115 mg, respectively, which are much lower than a
400-mg dose for the D24h of gatifloxacin or two
doses of 500 mg for the D24h of ciprofloxacin. Moreover, even if the D24hs were compared at the
highest level of IE observed in our experiments
[ca. 300 (log CFU/ml) · h for ciprofloxacin], they would still
be lower, i.e., 100 mg of gatifloxacin and two doses of 220 mg of
ciprofloxacin for E. coli and 190 mg of gatifloxacin and two
doses of 520 mg of ciprofloxacin for K. pneumoniae, than the
clinically relevant D24hs, at least of
gatifloxacin. These differences are so substantial that any
extrapolation of the estimated equiefficient
D24hs to the clinical
D24hs would be quite speculative.
To avoid incorrect extrapolations, the antimicrobial effects of the
quinolones might be compared by using bacteria for which the
MIC50s are comparable to the established MIC breakpoint for ciprofloxacin (0.18 µg/ml). Among the organisms studied, E. coli 37 (MIC50s, 0.3 and 0.2 µg/ml for gatifloxacin
and ciprofloxacin, respectively) and K. pneumoniae 56 (MIC50s, 0.2 and 0.12 µg/ml for gatifloxacin and
ciprofloxacin, respectively) meet this requirement most easily. On the
basis of the respective dose-response curves, the predicted
D24hs of gatifloxacin (354 mg with E. coli 37 and 330 mg with K. pneumoniae 56) that might
produce the same effects [IEs of 194 and 221 (log CFU/ml) · h, respectively] as two doses of 500 mg for the
D24h of ciprofloxacin are close to the proposed 400-mg dose for the D24h of the new
quinolone. A similar analysis might also be applied not only to
the specific strains studied but also to a more representative organism
for which the MIC50 meets the requirement described above.
Serratia marcescens may be an appropriate example:
susceptibility testing performed with both quinolones in the same
experimental setting (1) reported MIC50s of
gatifloxacin (0.25 µg/ml) and ciprofloxacin (0.13 µg/ml) which are
comparable to ciprofloxacin's MIC breakpoint (0.18 µg/ml). By
assuming species-independent patterns of the
IE-log AUC/MIC relationships, the
D24h of gatifloxacin that might produce the same
effect [IE = 217 (log CFU/ml) · h] as
two doses of 500 mg for the D24h of
ciprofloxacin is also close to the proposed 400-mg dose for the
D24h of the new quinolone (380 mg). Perhaps the
estimated D24hs of trovafloxacin, equivalent to
two doses of 500 mg for the D24h of
ciprofloxacin, appeared to be so close to the clinically accepted
trovafloxacin D24h, 199, 226, and 203 mg versus
200 mg (9), because for the three gram-negative strains
studied the MICs were comparable (0.18 µg/ml). However, the apparent
similarity of the predicted and clinically accepted quinolone doses may
only be a chance observation, as the results depend highly on the MICs for arbitrarily selected organisms. Additional in vitro-in vivo correlations are needed to verify the clinical relevance of these predictions.
It should be noted in the present study that greater antimicrobial
effects of gatifloxacin were demonstrated both in terms of
D-response and AUC/MIC-response relationships. As with
trovafloxacin and ciprofloxacin (7, 9), a given AUC/MIC
ratio of the longer-acting quinolone (gatifloxacin) provided a more
pronounced antimicrobial effect than the same AUC/MIC ratio of the
shorter-acting quinolone (ciprofloxacin). These data highlight the
important role of the longer half-lives of the newer extended-spectrum
quinolones whose pharmacokinetic profiles result in a greater
antimicrobial effect.
In conclusion, this study supports the applicability of our approach to
the prediction of equivalent AUC/MIC breakpoints and equiefficient
doses of quinolones on the basis of the species- and strain-independent
AUC/MIC relationships of the antimicrobial effect over a wide range of
in vitro simulated AUC/MIC ratios (7, 9). Further studies
with other pharmacokinetically different quinolones are needed to
verify this approach.
| |
ACKNOWLEDGMENTS |
This study was supported by Bristol-Myers Squibb.
We are grateful to Yury A. Portnoy for assistance with computer
presentation of the data.
| |
FOOTNOTES |
*
Corresponding author. Present 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.
Present address: Mount Auburn Hospital, Cambridge MA, 02138.
| |
REFERENCES |
| 1.
|
Bauernfeind, A.
1997.
Comparison of the antibacterial activities of the quinolones Bay 12-8039, gatifloxacin (AM 1155), trovafloxacin, clinafloxacin, levofloxacin and ciprofloxacin.
J. Antimicrob. Chemother.
40:639-651[Abstract/Free Full Text].
|
| 2.
|
Bergan, T., and S. B. Thorsteinsson.
1986.
Pharmacokinetics and bioavailability of ciprofloxacin, p. 111-121.
In
H. C. Neu, and H. Weuta (ed.), Proceedings of the 1st International Ciprofloxacin Workshop, Current Clinical Practice series 34. Elsevier Science Publishers B.V. (Excerpta Medica), Amsterdam, The Netherlands.
|
| 3.
|
Felmingham, D.,
M. J. Robbins,
K. Ingley,
I. Mathias,
H. A. Bhogal,
G. L. Leakey,
G. L. Ridgway, and R. N. Grüneberg.
1997.
In-vitro activity of trovafloxacin, a new fluoroquinolone, against recent clinical isolates.
J. Antimicrob. Chemother.
39(Suppl. B):43-49[Abstract/Free Full Text].
|
| 4.
|
Firsov, A. A.,
V. M. Chernykh, and S. M. Navashin.
1991.
Quantitative analysis of antimicrobial effect kinetics in an in vitro dynamic model.
Antimicrob. Agents Chemother.
34:1312-1317.
|
| 5.
|
Firsov, A. A.,
D. Savarino,
M. Rubble,
D. Gilbert,
B. Manzano,
A. A. Medeiros, and S. H. Zinner.
1996.
Predictors of effect of ampicillin-sulbactam against TEM-1  -lactamase-producing Escherichia coli in an in vitro dynamic model: enzyme activity versus MIC.
Antimicrob. Agents Chemother.
40:734-738[Abstract].
|
| 6.
|
Firsov, A. A.,
A. A. Shevchenko,
S. N. Vostrov, and S. H. Zinner.
1998.
Inter- and intraquinolone predictors of antimicrobial effect in an in-vitro dynamic model: new insight into a widely used concept.
Antimicrob. Agents Chemother.
42:659-665[Abstract/Free Full Text].
|
| 7.
|
Firsov, A. A.,
S. N. Vostrov,
O. V. Kononenko,
I. Y. Lubenko, and S. H. Zinner.
1999.
Prediction of the antimicrobial effects of trovafloxacin and ciprofloxacin on staphylococci using an in-vitro dynamic model.
J. Antimicrob. Chemother.
43:483-490[Abstract/Free Full Text].
|
| 8.
|
Firsov, A. A.,
S. N. Vostrov,
A. A. Shevchenko, and G. Cornaglia.
1997.
Parameters of bacterial killing and regrowth kinetics and antimicrobial effect examined in terms of area under the concentration-time curve relationships: action of ciprofloxacin against Escherichia coli in an in-vitro dynamic model.
Antimicrob. Agents Chemother.
41:1281-1287[Abstract].
|
| 9.
|
Firsov, A. A.,
S. N. Vostrov,
A. A. Shevchenko,
S. H. Zinner, and Y. A. Portnoy.
1998.
A new approach to in vitro comparisons of antibiotics in dynamic models: equivalent area under the curve/MIC breakpoints and equiefficient doses of trovafloxacin and ciprofloxacin against bacteria of similar susceptibilities.
Antimicrob. Agents Chemother.
42:2841-2847[Abstract/Free Full Text].
|
| 10.
|
Grasela, D. M.,
M. Nakashima,
T. Uematsu, et al.
1996.
Pharmacokinetics of BMS-206584; 200 mg oral dose with concurrent probenecid in humans. Report no. 910058296.
Bristol-Myers Squibb Pharmaceutical Research Institute.
|
| 11.
|
Grasela, D. M.,
M. Nakashima,
T. Uematsu, et al.
1996.
Phase I trial of a single intravenous infusion of BMS-206584 (AM-1155) in healthy male volunteers. Report no. 910058297.
Bristol-Myers Squibb Pharmaceutical Research Institute.
|
| 12.
|
Grasela, D. M.,
T. Uematsu,
M. Nakashima, et al.
1996.
Oral dose phase I study of AM-1155 (BMS-206584). Report no. 910058295.
Bristol-Myers Squibb Pharmaceutical Research Institute.
|
| 13.
|
Hoffken, G.,
H. Lode,
C. Prinzing,
K. Borner, and P. Koeppe.
1985.
Pharmacokinetics of ciprofloxacin after oral and parenteral administration.
Antimicrob. Agents Chemother.
27:375-379[Abstract/Free Full Text].
|
| 14.
|
Schentag, J. J.,
D. E. Nix, and A. Forrest.
1993.
Pharmacodynamics of the fluoroquinolones, p. 259-271.
In
D. C. Hooper, and J. S. Wolfson (ed.), Quinolone antimicrobial agents, 2nd ed. American Society for Microbiology, Washington, D.C.
|
| 15.
|
Seftone, A. M.,
J. P. Maskell,
A. M. Rafay,
A. Whiley, and J. D. Williams.
1997.
The in-vitro activity of trovafloxacin, a new fluoroquinolone, against gram-positive bacteria.
J. Antimicrob. Chemother.
39(Suppl. B):57-62[Abstract/Free Full Text].
|
| 16.
|
Seifert, H.
1997.
Comparative in-vitro activities of trovafloxacin, ciprofloxacin, ofloxacin, and fleroxacin against gram-negative blood isolates.
Clin. Microbiol. Infect.
3(Suppl. 2):91.
|
| 17.
|
Wise, R.,
D. Lister,
C. A. M. McNulty,
D. Griggs, and J. M. Andrews.
1986.
The comparative pharmacokinetics of five quinolones.
J. Antimicrob. Chemother.
18(Suppl. D):71-81.
|
Antimicrobial Agents and Chemotherapy, April 2000, p. 879-884, Vol. 44, No. 4
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Copyright © 2000, American Society for Microbiology. All rights reserved.
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Abstract
Introduction
