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Antimicrobial Agents and Chemotherapy, March 2001, p. 673-678, Vol. 45, No. 3
0066-4804/01/$04.00+0 DOI: 10.1128/AAC.45.3.673-678.2001
Copyright © 2001, American Society for Microbiology. All rights reserved.
Comparative Bactericidal Activities of
Ciprofloxacin, Clinafloxacin, Grepafloxacin, Levofloxacin,
Moxifloxacin, and Trovafloxacin against Streptococcus
pneumoniae in a Dynamic In Vitro Model
Michael E.
Klepser,1,*
Erika J.
Ernst,1
C. Rosemarie
Petzold,1
Paul
Rhomberg,2 and
Gary V.
Doern2
University of Iowa Colleges of
Pharmacy1 and
Medicine,2 Iowa City, Iowa
Received 8 March 2000/Returned for modification 26 August
2000/Accepted 27 November 2000
 |
ABSTRACT |
Several new quinolones that exhibit enhanced in vitro activity
against Streptococcus pneumoniae have been developed. Using a dynamic in vitro model, we generated time-kill data for
ciprofloxacin, clinafloxacin, grepafloxacin, levofloxacin,
moxifloxacin, and trovafloxacin against three isolates of
quinolone-susceptible S. pneumoniae. Three pharmacokinetic
profiles were simulated for each of the study agents (0.1, 1, and 10 times the area under the concentration-time curve [AUC]). Target 24-h
AUCs were based upon human pharmacokinetic data resulting from the
maximal daily doses of each agent. Ciprofloxacin was the least active
agent against all three isolates. With regimens that simulated the
human 24-h AUC, ciprofloxacin resulted in an initial, modest decline in
the numbers of CFU per milliliter; however, by 48 h the numbers of CFU
per milliliter returned to or exceeded the starting inoculum. At the
AUC, levofloxacin resulted in variable bacteriostatic and bactericidal
activities against the isolates. The remaining agents yielded
bactericidal (99.9% reduction) activity by 48 h with regimens that simulated the AUC. At 0.1 time the AUC ciprofloxacin and levofloxacin produced no inhibitory effect, grepafloxacin exhibited bacteriostatic activity, trovafloxacin had mixed static and cidal activities, and clinafloxacin and moxifloxacin caused significant reductions in the numbers of CFU per milliliter by 48 h. All six agents produced cidal activity at 10 times the AUC. In this dynamic in
vitro model of infection, the quinolones demonstrated various degrees
of activity against S. pneumoniae. The rank order of
activity, with respect to bactericidal effect, was ciprofloxacin (least active) 
levofloxacin < grepafloxacin, trovafloxacin < clinafloxacin and moxifloxacin (most active). The rank order of the
agents with respect to the selection of resistance was ciprofloxacin
(most likely) > grepafloxacin, moxifloxacin, and
trovafloxacin > levofloxacin > clinafloxacin.
| |
INTRODUCTION |
The frequency of isolation of
penicillin-nonsusceptible strains of Streptococcus
pneumoniae increased dramatically during the 1990s (1, 5,
21). Additionally, cross-resistance of these isolates to other
classes of antimicrobials such as the cephalosporins,
trimethoprim-sulfamethoxazole, macrolides, chloramphenicol, and
tetracyclines is extremely common (6). As a result,
selection of antimicrobials for the treatment of pneumococcal
infections, especially selection of empiric therapy, has become more
complicated. The resistance of pneumococci to fluoroquinolones occurs
infrequently, even among isolates exhibiting high-level resistance to
penicillin (2, 20). Over the past few years, a variety of
new fluoroquinolones with enhanced activity against gram-positive
pathogens including S. pneumoniae have been developed.
Experience with ciprofloxacin in the treatment of pneumococcal
infections has left many clinicians wary of using quinolones for the
management of pneumococcal respiratory tract infections. These
individuals cite reports of treatment failures that have resulted in
breakthrough bacteremia among patients receiving ciprofloxacin therapy
(3, 9, 10, 12, 18); E. Perez-Trallero, J. M. Garcia-Arenzana, J. A. Jimenez, and A. Peris, Letter, Eur. J. Clin. Microbiol. Infect. Dis. 9:905-906, 1990).
Proponents of the newer quinolones, however, argue that these treatment
failures were not the result of emergence of resistance but were the
result of suboptimal dosing of the drug and failure to achieve optimal pharmacodynamic conditions. The superior potencies of the newer quinolones generally result in improved pharmacodynamic parameters and
are therefore thought to lessen the likelihood of treatment failure and
reduce the emergence of quinolone-resistant isolates (7, 14,
15).
In vitro dynamic models are tools used to evaluate the killing kinetics
of antimicrobials under controlled conditions that allow the simulation
of human pharmacokinetic parameters. Although the data generated via
these models are extremely useful, the models are time-consuming and
costly to run. As a result, investigators frequently test only a
limited number of antimicrobials and isolates. Additionally,
variability among test conditions and models may make comparison of the
data generated by various investigators difficult to compare. The goal
of the current study was to describe and compare the killing dynamics
of six fluoroquinolones (ciprofloxacin, clinafloxacin, grepafloxacin,
levofloxacin, moxifloxacin, and trovafloxacin) under three different
simulated pharmacokinetic profiles against three clinical isolates of
S. pneumoniae by using a dynamic in vitro model of infection.
(This study was presented at the 39th Interscience Conference on
Antimicrobial Agents and Chemotherapy, 26 to 29 September 1999, San
Francisco, Calif.).
| |
MATERIALS AND METHODS |
Antimicrobial agents.
An analytical-grade powder of each
quinolone was obtained from the respective manufacturer: ciprofloxacin,
Bayer Corporation (West Haven, Conn.); clinafloxacin, Parke-Davis
(Morris Plains, N.J.); grepafloxacin, GlaxoWellcome (Research Triangle
Park, N.C.); levofloxacin, Ortho-McNeil Pharmaceutical (Raritan, N.J.);
moxifloxacin, Bayer Corporation; and trovafloxacin, Pfizer
Pharmaceutical (New York, N.Y.). Aqueous stock solutions were prepared
for each agent and stored in unit-of-use aliquots at 
80°C. Dimethyl
sulfoxide (9% [vol/vol]) was used to aid the solubilization of trovafloxacin.
Study isolates.
Three clinical strains of S. pneumoniae strains (R1, R11, and R20) were selected for testing.
Strains R1 and R11 were resistant to penicillin (MICs, 2 and 8 µg/ml,
respectively). All isolates were macrolide susceptible. The MIC of each
of the quinolones for the test isolates was determined by broth
microdilution techniques (19). MICs were determined prior
to the initiation of the time-kill experiments and each day the isolate
was used in the model.
Time-kill model.
A one-compartment glass model consisting of
a central culture compartment, medium and waste reservoirs, and a
peristaltic pump was used. Mueller-Hinton broth supplemented with 5%
lysed horse blood (PML Microbiologicals, Wilsonville, Oreg.) served as
the culture medium. Prior to the initiation of the time-kill experiments, the pharmacokinetics of each quinolone in the model were
verified. Each of the study agents was examined under three simulated
pharmacokinetic profiles: (i) human area under the concentration-time curve (AUC) from time zero to 24 h (AUC0-24), (ii)
0.1 time the human AUC0-24, and (iii) 10 times the human
AUC0-24. The target pharmacokinetic parameters for each
agent are provided in Table 1.
Time-kill analysis was performed with each of the pneumococcal isolates
against each of the fluoroquinolone agents under all
three simulated
pharmacokinetic conditions. Prior to use, the
test isolate was
subcultured twice on blood agar plates (Remel,
Lexana, Kans.).
Immediately prior to the initiation of the study,
a standardized
bacterial suspension was prepared by suspending
colonies from a 24-h
culture plate in normal saline and adjusting
the suspensions to a 3.0 McFarland turbidity standard. An appropriate
volume of the standardized
suspension was then introduced into
the central compartment of the
model. This resulted in a starting
inoculum of approximately 5 × 10
5 to 1 × 10
6 CFU/ml. The central
compartment was then placed in a water bath
on a magnetic stirring
plate. At time zero, an appropriate amount
of quinolone was added to
the central compartment. Four models
were run simultaneously: (i)
control (no drug), (ii) the human
AUC
0-24, (iii) 0.1 time
the human AUC
0-24, and (iv)
10 times the human
AUC
0-24. A peristaltic pump was then
programmed and
activated. The model was allowed to run for 48
h. Additional doses
of drug were added to the central compartment
when appropriate to
simulate the dosing regimens of the test agents
(times 12, 24, and
36 h for ciprofloxacin and clinafloxacin and
time 24 h for
the remainder of the quinolones). The temperature
of the central
compartment was maintained at 37°C throughout the
study period. At
predetermined time points over the 48-h study
period, samples of the
culture medium were removed from the central
compartment and serially
diluted as appropriate, and 100 µl was
plated on to blood agar
plates. Determinations of viable colony
counts were performed following
incubation of the culture plates
in the presence of CO
2 at
37°C for 24 h. Additionally, at 24 and
48 h, 100 µl was
removed from the central compartment and plated
without dilution onto
agar plates containing the fluoroquinolone
being tested at
concentrations equal to two and four times the
preexperiment MIC. If
growth was noted on drug-containing agar,
colonies were selected and
MICs were redetermined for all of the
quinolones. All experiments were
performed in
duplicate.
According to the sampling methods used, no antibiotic carryover was
noted over the range of concentrations over which samples
were removed
from the central compartment and plated directly
without dilution
(
13). The lower limit of accurately and reproducibly
countable bacteria obtained with a 100-µl sampling volume was
determined to be 30 CFU/ml (
13). The variability
associated
with sampling techniques was determined to range from 12 to
20%
for the various
isolates.
Drug analysis.
Samples removed from the model for drug
concentration determination were analyzed by microbiological assay
methods with Klebsiella pneumoniae ATCC 10031 as the
indicator organism. Standard curves were constructed for each quinolone
over a concentration range of 0.125 to 25 µg/ml. Briefly, antibiotic
medium 5 (Difco, Detroit, Mich.) agar plates (150 mm) were prepared.
Immediately prior to use, the entire surface of the culture plate was
swabbed with a 0.5 McFarland suspension of K. pneumoniae
ATCC 10031. Upon drying, 6-mm sterile paper disks were aseptically
placed on the surface of the plate. Twenty microliters of the
antibiotic standard or unknown sample was placed on each paper disk.
Each standard or sample was placed on three separate disks (in
triplicate). The plates were then incubated at 37°C for 16 to 18 h. Following incubation, zone size diameters were determined and
recorded. These procedures resulted in standard curves with correlation
coefficients (r2) of >0.97. Intra- and interday
coefficients of variation (CVs) were 
10%.
Data analysis.
For each quinolone regimen, a
concentration-versus-time profile was constructed. Drug concentration
data were fitted by using WinNonlin (Scientific Consulting, Inc.), and
the AUC0-24, half-life (t1/2), maximum
concentration of drug, and minimum concentration of drug were calculated.
Time-kill data from duplicate runs were averaged and plotted as a
function of time. The rate of killing observed with each
quinolone was
compared with the medium flow rate to determine
whether the reduction
in the numbers of CFU was due to the killing
effect of the drug or a
dilution effect. If the rate of reduction
was less than that which
would have been predicted by flow rate
alone, the reduction was
attributed to the effect of the drug.
However, if the reduction in the
numbers of CFU was greater than
or equal to that predicted by the flow
rate, a mathematical model
that allowed correction for this dilutional
effect was used (
11).
The changes in the log number of CFU
per milliliter from the starting
inocula at times of 24 and 48 h were
determined for each regimen
and isolate. Bacteriostatic or inhibitory
was defined as a <99.9%
reduction in the numbers of CFU per
milliliter versus the starting
inoculum. Bactericidal was defined as a
99.9% reduction in the
numbers of CFU per milliliter versus the
starting inoculum. The
presence or absence of regrowth over the study
period was noted.
The AUC:MIC and peak:MIC were calculated for each
regimen and
isolate by using calculated pharmacokinetic values.
Composite
parameter-response curves were then constructed by plotting
AUC:MIC
or peak:MIC as a function of the change in the
log
10 numbers of
CFU per milliliter at 24 h from the
starting inoculum. Data were
then fitted with SigmaPlot (SPSS, Inc.) by
using a four-parameter
Hill equation:
f =
y0 +
a(
xb)/(
cb +
xb), where
f is the observed effect (change in numbers of CFU per
milliliter),
y0 is the minimal change in the
numbers of CFU per
milliliter noted,
a is the difference
between the minimal and
maximal changes in the numbers of CFU per
milliliter,
x is the
pharmacodynamic parameter of interest,
c is equal to 50% of
x,
and
b is a
constant. The 50, 90, and 99% effective ratio (ERs;
ER
50,
ER
90, and ER
99, respectively) were calculated
for each
plot.
| |
RESULTS |
Susceptibility data.
All of the isolates were quinolone
susceptible on the basis of the ciprofloxacin and levofloxacin MICs.
Also, these isolates were found to lack mutations in the quinolone
resistance-determining regions of parC and gyrA.
The median MICs of the quinolones for each of the pneumococcal isolates
are presented in Table 2.
Time-kill data.
All of the test strains of S. pneumoniae remained viable in the model over the 48-h study
period. At the 48-h time point each of the three strains exhibited >2
log10 CFU/ml of growth. A summary of the change in the
log10 number of CFU per milliliter at times of 24 and 48 h
versus the starting inoculum are presented in Fig. 1. All regimens resulted in colony count
reductions that were slower than those that would have been predicted
by a dilutional effect alone. Therefore, no mathematical corrections
were used. With regimens that simulated 0.1 time the
AUC0-24, only clinafloxacin was consistently bactericidal
against all three isolates of S. pneumoniae tested.
Moxifloxacin exhibited bactericidal activity against two of the three
isolates when it was tested under conditions that simulated 0.1 time
the AUC0-24. For the remaining four quinolones, slight
growth or a reduction in the numbers of CFU per milliliter followed by
subsequent regrowth was observed following exposure to 0.1 time the
AUC0-24. With regimens that simulated the observed
human AUC0-24, all of the agents except ciprofloxacin
reached the bactericidal endpoint by 48 h. In contrast,
ciprofloxacin resulted in growth over the starting inoculum for two of
the three isolates and a <2-log10 CFU/ml reduction for the
third isolate. At 10 times the simulated human AUC0-24,
all of the agents with the exception of ciprofloxacin against isolate
R11 caused 3-log10 reductions in the numbers of CFU of the
test isolates per milliliter by 48 h.
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FIG. 1.
Summary of change in the log10 number of CFU
per milliliter at time 24 and 48 h versus the starting inoculum.
*, regrowth.
|
|
Table
3 summarizes the data regarding
observed the changes in the MICs of each of the quinolones at 24 and
48 h following
drug exposure. With the exception of clinafloxacin,
all of the
quinolones demonstrated the ability to select for resistant
isolates.
This effect was most pronounced with regimens that simulated
exposure
to 0.1 time the AUC
0-24. Exposure to
ciprofloxacin regimens
resulted in the emergence by 48 h of
isolates for which MICs were
from four- to eightfold higher than those
for the preexposure
isolate. This phenomenon occurred following
exposure to regimens
that simulated both 0.1 and 1 time the
AUC
0-24 for ciprofloxacin.
For isolates for which
ciprofloxacin-induced changes in the MICs
were demonstrated, similar
magnitudes of increases in MICs of
all other quinolones were also
detected (data not shown).
Composite plots of AUC:MIC and peak:MIC versus the change in the
log
10 numbers of CFU per milliliter for the
fluoroquinolones
against the three test isolates are presented in Fig.
2. Good
correlations were noted between
both AUC:MIC (
r2 = 0.81) and peak:MIC
(
r2 = 0.80) and the observed reduction in
the numbers of viable colonies
at 24 h. The ratios (AUC:MIC and
peak:MIC) that produced 50, 90,
and 99% of the maximal effect were
calculated. For the AUC:MIC
these ratios were 18, 54, and 175 for
ER
50, ER
90, and ER
99, respectively
(standard error of the estimate, 0.97). Values for peak:MIC were
determined to be 1.5, 5.8, and 25, respectively (standard error
of the
estimate, 0.98). The standard error is a measure of the
actual
variability about the regression plane of the population.
The
underlying population generally falls within 2 standard errors
of the
calculated value.
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|
FIG. 2.
Composite plots of peak:MIC (A) and AUC:MIC (B) versus
change in the numbers of CFU per milliliter at 24 h. T, time.
|
|
| |
DISCUSSION |
In vitro systems capable of simulating human pharmacokinetic
parameters are useful tools that provide insight into the killing kinetics of antimicrobial agents under conditions of constantly changing antimicrobial concentrations. In the current study, we examined the activities of six different fluoroquinolones, tested with
three different simulated pharmacokinetic profiles, against three
isolates of S. pneumoniae. In our model we simulated the total drug concentration profile of each of the agents. Although some
investigators promote the use of a correction based on the percentage
of protein binding, we are not sure that these corrections are
appropriate on the basis of the dynamic nature of this binding (personal data). Instead, we opted to test several regimens that cover
a range of simulated concentration profiles for each agent.
Other investigators have previously examined the activities of various
quinolones against S. pneumoniae in dynamic in vitro models
(14-16). Those studies evaluated the activities of
various fluoroquinolone agents under pharmacokinetic conditions that
simulate parameters likely to occur in humans following administration of a commonly used dose. In the current study, we not only simulated typical serum pharmacokinetic parameters but we also examined pharmacokinetic profiles that resulted in AUC0-24 values that were 1 log10 higher and lower than the standard
AUC0-24 for serum (i.e., 0.1 and 10 times the
AUC0-24). As a result, we were able to evaluate the
antipneumococcal activities of the quinolones under extremes of drug
exposure conditions, providing ourselves with more complete data with
which to conduct a pharmacodynamic analysis.
Regimens that simulate 10 times the AUC0-24 exhibited the
most rapid and complete activity against the test isolates. Additionally, under these conditions, none of the quinolones selected for strains for which MICs were elevated at 48 h. In contrast, under suboptimal exposure conditions, 0.1 time the
AUC0-24, only clinafloxacin consistently exhibited
bactericidal activity. Furthermore, at this level of exposure, isolates
for which MICs were increased were recovered from runs with each of the
quinolones except clinafloxacin. Of particular interest, resistant
isolates were recovered from runs with ciprofloxacin following 24 and
48 h of exposure even when they were tested with regimens that
simulate the AUC0-24. Similar findings were reported by
Lacy and colleagues (14) with respect to the ability of
ciprofloxacin to select for resistant strains of pneumococci following
exposure to regimens that simulate exposure to AUC0-24.
Also, even though we recovered isolates for which MICs were elevated
following exposure to moxifloxacin under all simulated regimens,
administration of the second dose of moxifloxacin was able to eradicate
these bacteria. This finding lends support to the belief that the use of quinolones that demonstrate low MICs or low mutant protection concentrations (MPCs) might be beneficial in slowing the emergence of
resistance (7). Even if selective pressures do result in the emergence of isolates for which MICs are two- to fourfold higher
than those for the parent strain, these organisms still appear to be
susceptible to the killing effect of the quinolone if the MICs or MPCs
remain below achievable concentrations. It has been suggested that the
use of compounds which possess a methoxy substitution at the C-8
position may result in enhanced killing of isolates that express low
levels of quinolone resistance owing to their ability to stimulate the
release of DNA breaks (22).
In an effort to examine the correlation between drug exposure and
bactericidal activity, we constructed plots of AUC:MIC and peak:MIC
versus the change in the log10 numbers of CFU per
milliliter at 24 h. It should be noted that the characteristics of
exposure-effect curves are dependent on the time point evaluated. For
instance, a steeper curve might be expected if data from later times
are examined because more of the regimens would have exerted the
maximal effect. Analysis at such a time point would allow optimal
evaluation of the magnitude of the effect. However, this analysis
provides little insight into the relationship between exposure and the rate of activity because most of the regimens would already be at a
point of maximal activity. Conversely, a shallower curve might be noted
if an analysis had been undertaken with earlier data. At this time one
might be able to characterize the relationship between drug exposure
and the rate of activity. However, since few regimens would have yet to
exert the maximal bactericidal effect, any pharmacodynamic analysis
would not be complete with respect to extent of activity. We elected to
evaluate antibacterial activity at 24 h because at this time point
the various agents provided us with a relatively good spread of
activity (i.e., change in the log10 numbers of CFU per
milliliter). That is, we were able to garner information regarding the
relationships between drug exposure and both the rate and extent of activity.
According to our pharmacodynamic analysis, both AUC:MIC and peak:MIC
were significantly correlated (r2 > 0.80)
with the reduction in the numbers of CFU per milliliter. With respect
to peak:MIC, we calculated ER90 and ER99 to be
approximately 5.8 and 25, respectively. These appear to be consistent
across the quinolones. These ratios were similar to the peak:MIC of
12.2 prospectively determined to correlate with clinical and
microbiological outcomes by Preston (17). With respect to
AUC:MIC correlation, several investigators have proposed that ratios
that range from 15:1 to >100:1 exhibit the best in vivo correlation
with quinolone activity against pneumococci. When we calculated the
ER50, or the ratio that results in a static effect, we
found the ratio to be 18:1. The ratios that produced 90 and 99% of the
maximal effect were calculated to be 54:1 and 175:1, respectively.
Therefore, in the absence of host defense effects, it appears
reasonable to target an AUC:MIC between 50 and 100 for the quinolones
against S. pneumoniae to obtain near-maximal antibacterial
effects. These data suggest that in vitro dynamic models are useful for
the conduct of pharmacodynamic analyses and generate values that are
clinically relevant.
We did attempt to correlate pharmacodynamic parameters with the
emergence of resistance; however, we were unable to detect a good
correlation between either ratio and the emergence of resistance. Despite this apparent lack of correlation, we did note that there appear to be differences with respect to the various agents regarding their ability to select for resistant strains. Clinafloxacin
demonstrated the least selective effect. Levofloxacin appeared to be
the next least likely agent to select for isolates for which MICs were elevated. Although isolates were recovered at 48 h following
exposure to 0.1 time the AUC0-24 for two of the
pneumococci, the observed increase in the MICs were only 1 dilution.
For the remainder of the quinolones, when resistant strains were
recovered, increases in the MICs were from 4 to 32 times higher than
those for the preexposure isolates, with the median increase being
8-fold. This observation appears to suggest differences among the
quinolones with respect to MPCs, affinity for the target site, or
affinity for an efflux pump-mediated mechanism of resistance. Similar, discordant findings with regard to the ability of levofloxacin to
select for pneumococcal isolates with reduced quinolone susceptibility have been reported by Fukuda and Hiramatsu (8) and Davies
et al. (4). According to our data, we would rank the
ability of the agents to select for isolates with reduced
susceptibility as ciprofloxacin (most likely) > grepafloxacin,
moxifloxacin, and trovafloxacin > levofloxacin > clinafloxacin.
In summary, the fluoroquinolones, with the exception of ciprofloxacin,
appear to exhibit excellent activity against quinolone-susceptible isolates of S. pneumoniae. The activities of these agents
appear to be optimized either when an AUC:MIC of between 50 and 100 is achieved or when a peak:MIC of >6 is reached. If the drug
concentrations at the site of infection approximate or exceed those
observed in the serum, all of the quinolones tested except
ciprofloxacin would appear to be reasonable therapeutic selections.
However, if lower drug concentrations at the site of infection are
possible, then treatment failure and/or the selection of resistant
pneumococci is likely.
| |
ACKNOWLEDGMENT |
This project was funded by a grant from Pfizer, Inc.
| |
FOOTNOTES |
*
Corresponding author. Mailing address: S412 Pharmacy
Building, The University of Iowa College of Pharmacy, Iowa City, IA
52242-1112. Phone: (319) 335-8861. Fax: (319)353-5646. E-mail:
michael-klepser{at}uiowa.edu.
| |
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Antimicrobial Agents and Chemotherapy, March 2001, p. 673-678, Vol. 45, No. 3
0066-4804/01/$04.00+0 DOI: 10.1128/AAC.45.3.673-678.2001
Copyright © 2001, American Society for Microbiology. All rights reserved.
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Abstract
Introduction
