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Antimicrobial Agents and Chemotherapy, May 1999, p. 1118-1123, Vol. 43, No. 5
0066-4804/99/$04.00+0
Copyright © 1999, American Society for Microbiology. All rights reserved.
Pharmacodynamics of Trovafloxacin, Ofloxacin, and
Ciprofloxacin against Streptococcus pneumoniae in an In
Vitro Pharmacokinetic Model
Philip D.
Lister* and
Christine C.
Sanders
Center for Research in Anti-Infectives and
Biotechnology, Department of Medical Microbiology and Immunology,
Creighton University School of Medicine, Omaha, Nebraska 68178
Received 25 June 1998/Returned for modification 21 October
1998/Accepted 20 February 1999
 |
ABSTRACT |
An in vitro pharmacokinetic model was used to simulate the
pharmacokinetics of trovafloxacin, ofloxacin, and ciprofloxacin in
human serum and to compare their pharmacodynamics against eight Streptococcus pneumoniae strains. The MICs of ofloxacin and
ciprofloxacin ranged from 1 to 2 µg/ml. Trovafloxacin was 8- to
32-fold more potent, with MICs of 0.06 to 0.12 µg/ml.
Logarithmic-phase cultures were exposed to peak concentrations of
trovafloxacin, ofloxacin, or ciprofloxacin achieved in human serum
after 200-, 400-, and 750-mg oral doses, respectively. Trovafloxacin
was dosed at 0 and 24 h, and ofloxacin and ciprofloxacin were
dosed at 0, 12, and 24 h. Human elimination pharmacokinetics were
simulated, and viable bacterial counts were measured at 0, 2, 4, 6, 8, 12, 24, and 36 h. Trovafloxacin was rapidly and significantly
bactericidal against all eight strains evaluated, with viable bacterial
counts decreasing at least 5 logs to undetectable levels. Times to
99.9% killing were only 1 to 3 h. Although the rate of killing
with ofloxacin was substantially slower than that with trovafloxacin, ofloxacin was also able to eradicate all eight strains from the model,
despite a simulated area under the inhibitory curve/MIC ratio (AUC/MIC)
of only 49. In contrast, ciprofloxacin eradicated only five strains
(AUC/MIC = 44) from the model. Against the other three strains
(AUC/MIC = 22), the antibacterial activity of ciprofloxacin was
substantially diminished. These data corroborate clinical data and
suggest that trovafloxacin has a pharmacodynamic advantage over
ciprofloxacin and ofloxacin against S. pneumoniae in
relation to its enhanced antipneumococcal activity.
| |
INTRODUCTION |
Streptococcus pneumoniae
is a leading cause of pneumonia, bacteremia, otitis media, and
sinusitis (24). Since the 1970s, 
-lactam resistance and
resistance to multiple antibiotics have been steadily increasing
worldwide, limiting the therapeutic options for treatment of some
infections (19). It is essential, therefore, that the search
for more-effective antipneumococcal drugs continue.
The fluoroquinolones are one class of antibiotics currently being
developed for improved therapy of pneumococcal infections. In the past,
the role of ciprofloxacin and ofloxacin in treatment of pneumococcal
infections has been controversial because of their marginal in vitro
activity. Ciprofloxacin and ofloxacin MICs at which 90% of the
isolates are inhibited against S. pneumoniae are generally
two- to fourfold above the susceptible breakpoints (14, 27,
36). Trovafloxacin is a new fluoroquinolone that exhibits
enhanced potency against S. pneumoniae. In comparisons with
ciprofloxacin and ofloxacin, trovafloxacin is generally 8- to 16-fold
more potent, with MICs at which 90% of the isolates are inhibited of
0.12 to 0.25 µg/ml (27, 33, 40). The purpose of this study
was to compare the in vitro pharmacodynamics of trovafloxacin with
those of ofloxacin and ciprofloxacin against S. pneumoniae
and to determine if trovafloxacin's enhanced potency would translate
to enhanced pharmacodynamic killing when serum pharmacokinetics were
simulated. With an in vitro pharmacokinetic model (IVPM), oral doses of
200 mg of trovafloxacin, 400 mg of ofloxacin, and 750 mg of
ciprofloxacin were simulated and time-kill pharmacodynamic interactions
were evaluated over 36 h.
| |
MATERIALS AND METHODS |
Bacterial strains and culture conditions.
Eight clinical
isolates of S. pneumoniae were selected for this study, four
of which were resistant to penicillin (MICs of 2 to 4 µg/ml).
Logarithmic-phase cultures were prepared by suspending 10 colonies from
a 14-h culture on Trypticase soy agar supplemented with 5% sheep blood
(BBL Microbiology Systems, Cockeysville, Md.) into 6 ml of Todd-Hewitt
broth (Unipath/Oxoid, Ogdensburg, N.Y.) supplemented with 0.5% yeast
extract (THY) (20). Viable bacterial counts after 10 h
of incubation at 37°C in 5% CO2 ranged from 1 × 108 to 5 × 108 CFU/ml.
Antibiotic preparations.
Trovafloxacin powder was supplied
by Pfizer Inc., Groton, Conn. Ofloxacin powder was supplied by R. W. Johnson Pharmaceutical Research Institute, Raritan, N.J.
Ciprofloxacin powder was supplied by Bayer Corporation, West Haven,
Conn. Trovafloxacin and ofloxacin powders were dissolved in 0.2 ml of
0.1 M NaOH, diluted to final volume with distilled water, and
sterilized by passage through a 0.20-µm-pore-size Acrodisc syringe
filter membrane (Gelman Sciences, Ann Arbor, Mich.). Ciprofloxacin
powder was reconstituted with distilled water and filter sterilized as
described above.
Antimicrobial susceptibility testing.
Susceptibility tests
with trovafloxacin, ofloxacin, and ciprofloxacin were performed by
microbroth dilution methodology according to the procedure recommended
by the National Committee for Clinical Laboratory Standards
(25).
IVPM.
The IVPM used in these studies was a modification of
the original model described by Blaser and colleagues (3)
and has been described in detail previously (21). The
hollow-fiber cartridges (model BR130; Unisyn Fibertech, San Diego,
Calif.) used in these studies consisted of 2,250 cellulose acetate
hollow fibers contained within a polycarbonate housing, with each fiber
having 30,000-molecular-weight pores within its wall. The surface area
of exchange between the hollow fibers and the extracapillary space
(peripheral compartment) was 1.5 ft2. Medium containing
antibiotic was pumped through the lumen of the fibers at a flow rate of
20 ml/min with Masterflex computerized peristaltic pumps (model
7550-90; Cole-Parmer Instrument Company, Vernon Hills, Ill.) and
Easy-Load pump heads (model 7518-00; Cole-Parmer). In addition, the
bacterial culture within the peripheral compartment was continuously
circulated with similar peristaltic pumps at a rate of 20 ml/min
through a loop of silicone tubing attached to two ports entering and
exiting the peripheral compartment. The initial volume of culture
circulated through the peripheral compartment and loop of silicone
tubing was 35 to 40 ml. When samples were required from the peripheral
compartment, 0.5-ml volumes were removed through a four-way sterile
stopcock (Medex, Hilliard, Ohio) positioned within the loop of silicone
tubing. The volume of THY within the central reservoir varied with each drug depending upon the elimination half-life, such that the rate of
dilution and elimination could be set at the minimum 0.7 ml/min allowed
by the peristaltic pumps. The elimination half-lives simulated were
11 h for trovafloxacin (38, 39), 6.5 h for
ofloxacin (16), and 4 h for ciprofloxacin
(16). The corresponding central reservoir volumes were 700 ml for studies with trovafloxacin, 450 ml for ofloxacin, and 250 ml for
ciprofloxacin. In drug-free control experiments, the volume of THY in
the central reservoir was 500 ml and the flow rates for addition of
fresh medium and elimination from the central reservoir were 2 ml/min.
Pharmacokinetics in the IVPM.
Peak concentrations of
trovafloxacin, ofloxacin, and ciprofloxacin achieved in human serum
after single oral doses of 200 mg of trovafloxacin, 400 mg of
ofloxacin, and 750 mg of ciprofloxacin were targeted in these studies
(16, 42). To evaluate the pharmacokinetics of trovafloxacin,
ofloxacin, and ciprofloxacin in uninfected chambers, peak
concentrations were dosed into the central reservoir at 0 h for
trovafloxacin and 0 and 12 h for ciprofloxacin and ofloxacin. Samples were removed from the peripheral compartment at 0, 0.5, 1, 2, 4, 8, 12, 12.5, 16, 20, and 24 h, and drug concentrations were
measured by disk diffusion bioassay with a susceptible strain of
Escherichia coli. Areas under the concentration-time curves over 24 h (AUC0-24) for trovafloxacin, ofloxacin, and
ciprofloxacin were calculated by the trapezoidal rule. The AUC/MIC
ratios (AUC/MICs) were calculated by dividing the AUC0-24
by the MIC (31).
Pharmacodynamics against S. pneumoniae.
Logarithmic-phase cultures were diluted into fresh 37°C THY for a
final inoculum of 106 to 107 CFU/ml; introduced
into the peripheral compartment of the IVPM; and exposed to
trovafloxacin, ofloxacin, or ciprofloxacin as described above.
Pharmacodynamic experiments were performed in ambient air at 37°C. At
0, 2, 4, 6, 8, 12, 24, and 36 h, samples were removed from the
peripheral compartment and viable bacterial counts were measured by
plating serial 10-fold dilutions of each sample into Todd-Hewitt agar
(THA: BBL) and incubating plates overnight at 37°C in 5%
CO2. The lowest dilution plated was 0.1 ml of undiluted sample from the peripheral compartment. Since 30 colonies per plate is
the lower limit of accurate quantitation by pour plate methodology, the
lowest number of bacteria that could be accurately counted was 300 CFU/ml. The lowest level of detection was 10 CFU/ml.
To prevent antibiotic carryover, 2.5 mM ferric chloride was added to
the THA and mixed by inversion before plating (35). Preliminary experiments demonstrated that 2.5 mM ferric chloride was
the optimum concentration which would allow for the growth of all the
S. pneumoniae strains in the presence of peak concentrations of each quinolone (data not shown). In studies with ciprofloxacin and
ofloxacin, ferric chloride was added to THA for the undiluted samples
only. Because of the enhanced potency of trovafloxacin, ferric chloride
was added to the THA used to plate the undiluted sample, as well as the
first 10-fold dilution. Ferric chloride was not required for any other
dilutions since the fluoroquinolones were diluted to a concentration at
least 200-fold below the MIC.
To evaluate for the selection of mutants with decreased susceptibility
to quinolones, samples removed from the IVPM at 36
h were also
plated into THA containing the antibiotic at a concentration
4× the
MIC.
| |
RESULTS |
Characterization of test strains and the IVPM.
Ofloxacin and
ciprofloxacin MICs ranged from 1 to 2 µg/ml for all eight strains.
When a difference in MIC was observed, the MICs of ofloxacin were
always twofold higher than those of ciprofloxacin. Trovafloxacin was 8- to 32-fold more potent than ofloxacin and ciprofloxacin, with MICs of
0.06 to 0.12 µg/ml.
The pharmacokinetic profiles of trovafloxacin, ofloxacin, and
ciprofloxacin within the peripheral compartment of the IVPM
are shown
in Fig.
1. Peak concentrations (mean ± standard deviation
[SD]) in the peripheral compartment were
achieved 0.5 h after
dosing into the central reservoir and were
2.9 ± 0.1 µg/ml for
trovafloxacin, 6.3 ± 0.3 µg/ml for
ofloxacin, and 4.6 ± 0.1 µg/ml
for ciprofloxacin.
AUC
0-24 were 37 µg · h/ml for trovafloxacin,
44 µg · h/ml for ciprofloxacin, and 96 µg · h/ml for
ofloxacin.
Calculated peak/MIC ratios and AUC/MICs are shown in Table
1.
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FIG. 1.
Pharmacokinetics of trovafloxacin, ofloxacin, and
ciprofloxacin in the peripheral compartment of the IVPM after dosing
into the central reservoir. Drug levels were measured by bioassay. Each
datum point represents the mean drug level in the peripheral
compartment (in micrograms per milliliter) for three experimental runs.
Error bars show SDs.
|
|
Pharmacodynamic studies.
The pharmacodynamics of
trovafloxacin, ofloxacin, and ciprofloxacin against three
representative strains are shown in Fig. 2. Trovafloxacin was rapidly bactericidal
against all eight strains of S. pneumoniae, with viable
counts falling 5 to 6 logs to undetectable levels (eradication) within
4 to 6 h after the first dose (Fig. 2 and Table 1). Thereafter, no
viable bacteria were detected in trovafloxacin-treated cultures through
36 h. The time required for trovafloxacin to achieve a significant
99.9% killing of the S. pneumoniae ranged from 1.5 to
3.5 h (Table 1).
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FIG. 2.
Time-kill pharmacodynamics of ofloxacin and
ciprofloxacin against representative strains of S. pneumoniae, 3935 (A), 213 (B), and 256 (C). Each datum point
represents the mean CFU per milliliter of THY from the peripheral
compartment for duplicate experiments. Error bars show SDs.
|
|
The times required to achieve 99.9% killing and eradication with
ofloxacin were consistently longer than those observed with
trovafloxacin (Table
1). In studies with
S. pneumoniae 212,
S. pneumoniae 257,
S. pneumoniae 213, and
S. pneumoniae 3956, it
took ofloxacin between 2 and 4 h
longer than trovafloxacin to
achieve a significant 99.9% killing. In
studies with the other
S. pneumoniae strains, the
differences between ofloxacin and trovafloxacin
in times to 99.9%
killing were
1.5 h. Although ofloxacin eventually
eradicated all
eight
S. pneumoniae strains from the IVPM, viable
counts of
six strains did not decrease below the 10-CFU/ml limit
of detection
until 12 to 24 h, or after the second dose of ofloxacin
had been
added to the
IVPM.
Similar to ofloxacin, the rates of killing with ciprofloxacin were
consistently slower than those observed with trovafloxacin.
In studies
with six of the eight strains, ciprofloxacin required
2 to 5 h
longer to achieve significant 99.9% killing than did
trovafloxacin. In
contrast to trovafloxacin and ofloxacin, ciprofloxacin
failed to
eradicate three of the eight strains from the IVPM and
failed to even
achieve a significant 99.9% killing of
S. pneumoniae 213 (Fig.
2B) and
S. pneumoniae 256 (Fig.
2C). Furthermore, in
studies with
S. pneumoniae 213 and
S. pneumoniae
256, the antibacterial
activities of the second and third doses of
ciprofloxacin were
substantially diminished such that net
bacteriostasis or slight
net increases in viable counts were observed
over the second and
third dose intervals. No mutants with decreased
susceptibility
to ciprofloxacin were detected on drug selection plates
at 36
h.
| |
DISCUSSION |
An IVPM was used to simulate maximum oral doses of trovafloxacin,
ofloxacin, and ciprofloxacin and to compare their pharmacodynamics against eight clinical isolates of S. pneumoniae. Although
all three quinolones bind to serum proteins (70% protein binding for trovafloxacin compared to 20 to 40% protein binding for ciprofloxacin and ofloxacin [23]), these pharmacodynamic studies
were performed in the absence of serum proteins. While the degree of
protein binding has been shown previously to influence the movement of antibiotics from the bloodstream to extravascular spaces
(41), the impact of protein binding on antibacterial
activity remains unsettled. The interaction between antibiotics and
serum proteins is a dynamic reversible process, and drug molecules are
constantly binding and unbinding at a rapid pace (1). In MIC
studies, the presence of 40 to 50% serum does not alter the in vitro
potency of ciprofloxacin (2, 6) or ofloxacin (4,
18). However, in studies with trovafloxacin, intra- and
interspecies variations have been observed, ranging from no effect at
all to significant 32-fold reductions in activity (5). Using
an IVPM similar to the one in this study, Dudley and colleagues
(11a) reported that killing of Staphylococcus
aureus with dicloxacillin (~96% protein bound) was
significantly altered over the initial 6 h when 25% serum was
present in the medium. How these data relate to this study is
uncertain, especially since the impact of protein binding is 8- to
20-fold greater for dicloxacillin than for the quinolones evaluated in
this study. Furthermore, the impact of protein binding on -lactam
antibiotics may be much different from that for fluoroquinolones.
Trovafloxacin was rapidly and significantly bactericidal against all
eight S. pneumoniae strains and eradicated all strains from
the IVPM within 4 to 6 h after the first dose. The significant killing observed with trovafloxacin in this study confirms other pharmacodynamic data in similar pharmacokinetically based models (43, 44). Furthermore the significant bactericidal activity observed with trovafloxacin in this study correlates with the in vivo
efficacy of trovafloxacin against S. pneumoniae in clinical trials. Three separate studies have evaluated trovafloxacin for patients with community-acquired pneumococcal pneumonia and have reported rates of clinical efficacy from 90 to 100% at the end of
treatment and 86 to 92% at the end of the studies (22, 26, 37). When bacteremia was evaluated, trovafloxacin successfully eradicated S. pneumoniae from the blood of 92 to 96% of
patients (22, 26). While similar rates of clinical efficacy
and bacterial eradication have been observed with ofloxacin (28,
30) and in some cases with ciprofloxacin (17, 29), the
more rapid rates of bacterial killing observed with trovafloxacin in
this study suggest that the trovafloxacin possesses a pharmacodynamic advantage over ofloxacin and ciprofloxacin against S. pneumoniae. The increased rate of killing observed with
trovafloxacin most likely reflects increased peak/MIC ratios obtained
with the 200-mg dose, compared to the peak/MIC ratios obtained with
maximum oral doses of ofloxacin and ciprofloxacin. The dose-response
relationship associated with the bactericidal activity of
fluoroquinolones has been well established previously (11,
34), and in this study, the peak/MIC ratios simulated with
trovafloxacin were 4- to 16-fold higher than those simulated for
ofloxacin and 5- to 24-fold higher than those simulated for
ciprofloxacin. Even if protein binding was not dynamic and the amount
of these quinolones bound was no longer available, peak/MIC ratios for
trovafloxacin would still be 5- to 10-fold higher than those for
ciprofloxacin and 4- to 8-fold higher than those for ofloxacin for the
majority of the strains in this study. Although the rates of killing
observed for ciprofloxacin and ofloxacin may have been more comparable to those of trovafloxacin if their pharmacokinetics in the IVPM had
been adjusted to provide similar peak/MIC ratios, the purpose of this
investigation was to determine if the enhanced in vitro potency of
trovafloxacin would translate into enhanced pharmacodynamic activity.
Although the rates of killing observed with ofloxacin and ciprofloxacin
were slower than that with trovafloxacin, ofloxacin still eradicated
all eight strains from the IVPM. These data corroborate clinical
experience with ofloxacin in the treatment of community-acquired pneumococcal pneumonia, in which the eradication of S. pneumoniae from the lower respiratory tract is 97%
(30). In contrast, ciprofloxacin failed to eradicate three
of the eight strains from the IVPM. In studies with two of these
strains, gradual net increases in viable counts were observed over the
second and third dose intervals. Since no resistant mutants were
detected on drug selection plates at 36 h, the decreased
antibacterial activity of the second and third doses of ciprofloxacin
most likely represents adaptive resistance or the reversible decrease
in susceptibility after first exposure to an antibiotic (8,
9). Similar to the variability in killing observed in the IVPM,
clinical experience with ciprofloxacin against S. pneumoniae
has been variable. In some clinical trials, ciprofloxacin has
eradicated 95 to 100% of S. pneumoniae bacteria from the
lower respiratory tract, including the eradication of strains
exhibiting resistance to ciprofloxacin (17, 29, 32).
However, in other clinical studies ciprofloxacin has failed to
eradicate 30 to 45% of S. pneumoniae bacteria from the
respiratory tract (17, 32), and the development of
pneumococcal bacteremia or pneumococcal superinfection has been
reported during therapy with ciprofloxacin (7, 15).
The eradication of six strains from the IVPM with ofloxacin and five
strains with ciprofloxacin was observed despite simulated AUC/MICs of
only 44 to 49. These data suggest that the minimum AUC/MIC required for
effective treatment of pneumococcal infections with ofloxacin or
ciprofloxacin may be well below the 125 breakpoint suggested by studies
with ciprofloxacin against gram-negative bacteria (13). This
conclusion is supported by data with oral grepafloxacin in the
treatment of acute exacerbations of chronic bronchitis (12).
Although the number of patients infected with S. pneumoniae
was small, Forrest and colleagues reported an 87.5% (seven of eight)
bacteriologic cure when AUC/MICs were in the range of 0 to 92 (12). More systematic studies comparing the antipneumococcal
pharmacodynamics of fluoroquinolones over a range of AUC/MICs are
required to determine the minimum required for clinical efficacy. This
is especially true for those fluoroquinolones which frequently do not
provide peak/MIC ratios of 10:1 or greater, since pharmacodynamic data
have suggested that the AUC/MIC ratio is most closely linked to
treatment outcome when the peak/MIC ratio is less than 10:1
(10).
In summary, the pharmacodynamics of trovafloxacin were enhanced over
those of ofloxacin and ciprofloxacin against S. pneumoniae when maximum oral doses were simulated in an IVPM. The higher rates of
killing observed with trovafloxacin were most likely the result of the
increased potency of trovafloxacin compared to that of the other
quinolones, thus providing higher peak/MIC ratios with maximum oral
doses. Data from this study and recent clinical data support the use of
a once-daily dose of 200 mg of trovafloxacin for the treatment of
pneumococcal infections. Furthermore, the consistent eradication of
pneumococci from the IVPM with simulated AUC/MICs of 44 to 49 warrants
an in-depth investigation into the minimum AUC/MICs required for
efficacy of fluoroquinolones against S. pneumoniae.
| |
ACKNOWLEDGMENTS |
This work was supported by a grant from Roerig-Pfizer, New York,
N.Y.
We thank Stacey Edward for her excellent technical assistance.
| |
FOOTNOTES |
*
Corresponding author. Mailing address: Center for
Research in Anti-Infectives and Biotechnology, Department of Medical
Microbiology and Immunology, Creighton University School of Medicine,
2500 California Plaza, Omaha, NE 68178. Phone: (402) 280-1881. Fax: (402) 280-1225. E-mail: pdlister{at}creighton.edu.
| |
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Abstract
Introduction
