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Antimicrobial Agents and Chemotherapy, October 1998, p. 2650-2655, Vol. 42, No. 10
0066-4804/98/$04.00+0
Copyright © 1998, American Society for Microbiology. All rights reserved.
Pharmacodynamics of Gatifloxacin in Cerebrospinal
Fluid in Experimental Cephalosporin-Resistant Pneumococcal
Meningitis
Irja
Lutsar,*
Ian R.
Friedland,
Loretta
Wubbel,
Cynthia C.
McCoig,
Hasan S.
Jafri,
Winston
Ng,
Faryal
Ghaffar, and
George H.
McCracken Jr.
The University of Texas Southwestern Medical
Center, Dallas, Texas
Received 9 February 1998/Returned for modification 31 May
1998/Accepted 20 July 1998
 |
ABSTRACT |
The purpose of this study was to evaluate the cerebrospinal fluid
(CSF) pharmacodynamics of a new fluoroquinolone, gatifloxacin (AM-1155), in experimental pneumococcal meningitis. The penetration of
gatifloxacin into CSF, calculated as the percentage of the area under
the concentration-time curve (AUC) in CSF over the AUC in blood, was 46 to 56%. Gatifloxacin showed linear pharmacokinetics in CSF, and 1 h after intravenous dosages of 7.5, 15, or 30 mg/kg of body weight,
peak CSF concentrations were 0.46 ± 0.08 (mean ± standard
deviation), 0.94 ± 0.16, and 1.84 ± 0.5 µg/ml,
respectively. The elimination half-life of gatifloxacin in CSF was 3.8 to 5.6 h (compared with 2.7 to 3.2 h in blood). There was a
significant interrelationship among the highest measured values of
gatifloxacin in blood and CSF/minimal bactericidal concentration
(Cpeak/MBC), the time antibiotic concentrations
exceeded the MBC (T > MBC), and AUC/MBC
(r = 0.94); in single-dose experiments, each
correlated significantly with the bacterial killing rate. Divided-dose
regimens, resulting in greater T > MBC values but
lower Cpeak/MBC ratios, were more effective in
terms of bacterial clearance compared with corresponding single-dose
regimens. Gatifloxacin therapy was as effective as currently
recommended regimens (e.g., a combination of ceftriaxone and
vancomycin) against this highly cephalosporin-resistant pneumococcal
strain. The bactericidal activity of gatifloxacin in CSF was closely
related to the AUC/MBC ratio, but maximal activity was achieved only
when drug concentrations exceeded the MBC for the entire dosing
interval.
| |
INTRODUCTION |
Current recommendations for empiric
therapy of bacterial meningitis in areas with a high prevalence of
penicillin-resistant pneumococci include the combination of vancomycin
and ceftriaxone (16). However, an effective single agent
that could be given once or twice daily would be preferable. New
fluoroquinolones have a wide antibacterial spectrum against
gram-positive and gram-negative bacteria, including
penicillin-resistant pneumococci, and good penetration into
cerebrospinal fluid (CSF). As single agents, they have been shown to
be effective in experimental meningitis and in a recent clinical
meningitis study (6, 14).
Gatifloxacin (AM-1155) is a new fluoroquinolone with broader in
vitro and in vivo activities than those of older quinolones (7, 8,
20). The pharmacokinetic properties of gatifloxacin are similar
to those of other quinolones. Gatifloxacin is rapidly absorbed and
distributed to target tissues, demonstrates a linear pharmacokinetic
profile in serum, and has a comparatively long serum elimination
half-life (t1/2) (7 to 8 h) in humans
(11). The low protein binding (approximately 20%) and high
lipophilicity (octanol-water partition coefficient, 1.14) predict
favorable penetration into CSF (15). In experimental animals
with noninflamed meninges, the penetration of gatifloxacin into
CSF and brain ranged between 13 and 50% (15).
Gatifloxacin is active in rodents with systemic infections caused
by various gram-positive and gram-negative bacteria (7, 8),
but there are no data on the use of gatifloxacin in the therapy of
meningitis.
This study was conducted to determine the pharmacodynamic profile of
gatifloxacin in the CSF and to evaluate its effectiveness in the
therapy of experimental meningitis caused by cephalosporin-resistant Streptococcus pneumoniae.
| |
MATERIALS AND METHODS |
Bacterial strain.
A highly penicillin- and
cephalosporin-resistant strain of S. pneumoniae type
6B, originally isolated from a patient with bacterial meningitis
(4), was used in all experiments. The MICs and minimal
bactericidal concentrations (MBCs) of antibiotics for this strain were
measured by standard National Committee for Clinical Laboratory
Standards microdilution methods (12).
Meningitis model.
The rabbit meningitis model, originally
described by Dacey and Sande (2), was used. Meningitis was
induced in young New Zealand White male rabbits weighing 1.8 to 2.2 kg
by direct inoculation of 250 µl of a bacterial suspension
(104 to 105 CFU) into the cisterna magna. Once
meningitis was established (16 to 18 h later), rabbits were
anesthetized with ketamine (50 mg/kg of body weight) and acepromazine
(4 mg/kg) and immobilized in stereotactic frames, and a spinal needle
was introduced into the cisterna magna.
Antibacterial therapy was started after collection of the first CSF
sample. Animals were restrained under anesthesia in the stereotactic
frames, and the spinal needle remained in the cisterna for the first
3 h to ensure nontraumatic collection of CSF. To maintain
hydration, 20 ml of 0.9% sodium chloride was given subcutaneously to
all animals while in the frames, and one dose of flunixin meglumine (1.1 mg/kg) was given intramuscularly for analgesia.
Treatment.
All antibiotics were given intravenously via a
marginal ear vein. Gatifloxacin (Bristol-Myers Squibb, Wallingford,
Conn.) was diluted in sterile water (10 mg/ml), and 5 µl of
concentrated hydrochloric acid was added to each 10 ml to improve
solubility. The solution was further diluted in normal saline to a
concentration of 3 mg/ml. In the first set of experiments, gatifloxacin
was given as a single intravenous injection of 7.5, 15, or 30 mg/kg. To
avoid high peak concentrations and to extend the time antibiotic concentrations exceeded the MBC (T > MBC), in the
second set of experiments multiple doses of gatifloxacin were given in
one of two regimens: 7.5 mg/kg followed by 5 and 2.5 mg/kg, each 3 h apart, or three doses of 10 mg/kg given every 5 h (q5h).
Gatifloxacin therapy (three doses of 15 mg/kg/q5h) was compared with
the following treatment regimens: trovafloxacin (Pfizer Inc., Groton,
Conn.), 15 mg/kg; vancomycin (Abbott Laboratories, Chicago, Ill.), 20 mg/kg; and ceftriaxone (Roche, Nutley, N.J.), 125 mg/kg. Animals received three doses of trovafloxacin or vancomycin (given 5 h apart) or one dose of ceftriaxone intravenously. Antibiotic dosages were chosen to simulate serum and CSF peak concentrations achieved in
humans. Each treatment group consisted of 7 to 10 animals.
Sample collection.
For single-dose pharmacokinetic studies,
150 µl of CSF was collected 1, 2, 3, 6, and 10 h and 400 µl of
serum was collected 0.5, 1, 2, 3, and 6 h after the initiation of
therapy. In multiple-dosing studies, only peak and trough CSF
concentrations were measured. All samples were stored at 
70°C and
assayed within 2 months. Visibly bloody CSF samples were not analyzed.
Bacterial concentrations in CSF were measured before and 6, 10, and
24 h after initiation of therapy by plating undiluted
and serial
dilutions of CSF on sheep blood agar and incubating
in 5%
CO
2 at 35°C for 24 h. The lower limit of detection
was 10
CFU/ml, and specimens with <10 CFU/ml were assigned a value of
1 (0 log
10) CFU/ml. Bacterial killing rates (BKR) were
calculated
as the difference between bacterial concentrations at the
start
of therapy and 10 h later divided by time (10 h). No
evidence
of antibiotic carryover was detected with gatifloxacin
concentrations
of 2 µg/ml.
Antibiotic assay.
Gatifloxacin concentrations were
determined by disk diffusion bioassay (19) with
Bacillus subtilis ATCC 6633. Gatifloxacin standards between
0.1 and 2.0 µg/ml were prepared in rabbit CSF or serum. Samples with
concentrations higher than 2.0 µg/ml were diluted to fit within the
standard curve range. The lower limit of detection was 0.1 µg/ml. The
intra- and interassay coefficients of variations were 2.0 and 2.4% for
CSF and 7.9 and 4.2% for serum, respectively.
Pharmacokinetic and pharmacodynamic indices.
The highest
measured values of gatifloxacin in blood and CSF were designated peak
concentrations (Cpeak). Pharmacokinetic analysis
was performed with the computer program TopFit V2. A two-compartment
model (with lag time of 1 min) was used for calculations of blood
pharmacokinetic indices, and a noncompartmental model was used for
calculations of CSF pharmacokinetics. Weighting was not applied in the
models, because data had a constant absolute error (5).
Because of infrequent sampling in the 
phase, the t1/2 and area under the concentration-time
curves (AUC) for serum were calculated based on the mean values for
each dosage group. AUC were estimated to the last quantifiable
concentration with the logarithmic trapezoidal rule and extrapolated to
infinity with the terminal-phase rate constant. The percentage of
T > MBC was calculated as described by Schentag et al.
(18). The relationships between pharmacodynamic indices
(T > MBC, the ratio of CSF
Cpeak to MBC
[Cpeak/MBC], and the AUC/MBC ratio) and BKR
were fitted to a linear regression or sigmoid
Emax model as appropriate with the computer
program WinNonlin version 1.5. For the latter model, the following
formula was used: E = (Emax × C
)/(C + EC50), where E is
estimated BKR, Emax is the maximum BKR,
C is the mean Cpeak/MBC or AUC/MBC
ratio, EC50 is the C producing
half-maximal BKR, and 
is the Hill coefficient indicating
the slope of the sigmoid curve.
Statistics.
Continuous variables were expressed as
means ± standard deviations. Penetration of gatifloxacin through
the blood-CSF barrier (expressed as a percentage) was calculated as the
ratio of CSF to serum concentrations 1 h after drug administration
or as the ratio of CSF to blood AUC0-
. The Student
t test and analysis of variance (ANOVA) were used to compare
continuous normally distributed variables, and the Mann-Whitney test
was used for nonparametric data.
| |
RESULTS |
In vitro susceptibility.
The respective MICs and MBCs of the
study antibiotics for S. pneumoniae were as follows: 4 and 4 µg/ml (ceftriaxone), 0.25 and 0.25 µg/ml (vancomycin), 0.06 and 0.125 µg/ml (trovafloxacin), and 0.125 and 0.25 µg/ml
(gatifloxacin).
Single-dose pharmacokinetics.
The concentration-time curves of
gatifloxacin in CSF and serum after a single intravenous injection are
shown in Fig. 1. Linear pharmacokinetics
were observed in body fluids. A good linear correlation was found
between the administered dosages and CSF Cpeak
(r = 0.84; P = 0.0001), AUC
(r = 0.81; P = 0.0001), and
T > MBC (r = 0.79; P = 0.0001). Pharmacokinetic indices are summarized in Table
1. The elimination
t1/2 of gatifloxacin in CSF was significantly longer after a dose of 30 mg/kg than after 15 mg/kg (ANOVA;
P < 0.05), and the t1/2 in CSF
was 1.2- to 1.7-fold greater than in blood. When calculated as the
ratio of AUCCSF to AUCblood, the penetration of
gatifloxacin into CSF was greater than when calculated as the ratio of
CSF to blood concentration at 1 h. Larger doses of gatifloxacin
tended to result in relatively lower penetration, but this was
significant only when penetration was calculated as the ratio of CSF to
blood concentration at 1 hour (ANOVA; P < 0.05).
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FIG. 1.
Concentration (Concn.)-time curves of gatifloxacin in
blood and CSF after a single dose. Gatifloxacin doses, 7.5 ( ), 15 ( ), or 30 ( ) mg/kg, were given intravenously at 0 h. Data
are shown as means ± standard deviations. The MBC of the
S. pneumoniae strain used in experiments was 0.25 µg/ml.
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TABLE 1.
Pharmacokinetic indices of single-dose gatifloxacin
therapy in rabbits with experimental pneumococcal meningitis
|
|
Pharmacodynamics of single-dose therapy.
The bactericidal
effectiveness of gatifloxacin was dose dependent (Fig.
2). Bacterial regrowth occurred after
6 h in animals treated with 15 mg/kg and after 10 h in those
treated with 30 mg/kg.
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FIG. 2.
Bacterial concentrations (concn.) in CSF in animals
treated with a single dose of gatifloxacin of 7.5 (), 15 (), or
30 () mg/kg.
|
|
The pharmacodynamic indices of single-dose gatifloxacin are summarized
in Table
2. The three CSF pharmacodynamic
indices,
T > MBC, AUC/MBC ratio, and
Cpeak/MBC, were highly interrelated
(
r = 0.94), and each correlated significantly with BKR
(Fig.
3).
The relationships between BKR
and AUC/MBC or
Cpeak/MBC ratios
were best
described by the sigmoid
Emax model
(
r2 = 0.74 and 0.69, respectively); the
T > MBC correlated best with
BKR by
linear regression (
r2 = 0.68). The
maximal BKR of 0.55 CFU/ml/h was reached with AUC/MBC
of 40,
Cpeak/MBC of 6, and
T > MBC
values of 100% (Fig.
3). The
AUC/MBC and
Cpeak/MBC ratios producing 50% of the maximal
BKR
were 14.4 and 2.8, respectively.
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FIG. 3.
Relationship between BKR ( Log10 CFU per
milliliter per hour) and T > MBC (percentage of 10-h
interval), AUC/MBC (ratio of AUC0-10 and MBC) or
Cpeak/MBC in CSF in the first 10-h period.
Animals were treated with a single dose of gatifloxacin of 7.5, 15, or
30 mg/kg. Linear regression analysis was used to express the
relationship between T > MBC and BKR. The correlation
between BKR and AUC/MBC or Cpeak/MBC was fitted
to a sigmoid Emax model.
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|
Bacteriologic efficacy of divided-dose regimens.
The
pharmacodynamic indices after divided dosing are summarized in
Table 3. Divided-dose regimens resulted
in half the peak CSF concentrations but 40 to 60% greater
T > MBC values than those for the same total dosage
given as a single injection. The AUC/MBC values were similar for
divided- and single-dose regimens. Comparison of treatment regimens
with similar AUC/MBC values (group 1 versus 2 and group 3 versus 4) and Cpeak/MBC values (group 1 versus
4) indicated that regimens with greater T > MBC values
(groups 2 and 4) were significantly more effective. Comparison of
treatment regimens with similar T > MBC values (groups
2 and 3) indicated that bacterial clearance for these groups was not
significantly different (P = 0.1) (Table 3).
The bacteriologic effectiveness of divided- compared with that of
single-dose therapy is demonstrated in Fig.
4. During the
first 10 h,
there was no difference in bacterial clearance between
single- or
divided-dose regimens of 15 mg/kg. However, a single
dose of 30 mg/kg
resulted in greater bacterial killing in the
first 6 h compared
with the divided-dose regimen (
P = 0.01). At
the end of
24 h of therapy, both divided-dose regimens demonstrated
greater
bacterial clearance than the corresponding single-dose
regimens
(
P = 0.04 for 15 mg/kg and
P = 0.002 for 30 mg/kg) (Table
3 and Fig.
4).
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FIG. 4.
Bacterial concentrations (concn.) in CSF after single or
divided doses of gatifloxacin. A total of 15 (left) or 30 (right) mg/kg
of gatifloxacin was given as a single dose at 0 h () or in
divided doses ( ) as follows: 7.5 mg/kg followed by 5 mg/kg and 2.5 mg/kg, each 3 h apart (left), or three doses of 10 mg/kg q5h
(right) (*, P = 0.039; **, P = 0.01, and ***, P = 0.002 compared with the same
total dose given as a single injection).
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|
Comparison of gatifloxacin with other antibiotics.
The
bacteriologic effectiveness, including initial BKR, of gatifloxacin,
trovafloxacin, and combined ceftriaxone and vancomycin therapies was
not significantly different (Fig. 5).
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FIG. 5.
Bacterial concentrations (concn.) in CSF after
gatifloxacin () or trovafloxacin () (15 mg/kg/q5h) or a
combination of ceftriaxone (125 mg/kg/q24h) and vancomycin (20 mg/kg/q5h) () therapy. Three doses of each antibiotic (except
ceftriaxone) were given starting 16 to 18 h after inoculation with
S. pneumoniae. Control animals ( ) died or were
euthanized within 12 h.
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|
| |
DISCUSSION |
The new fluoroquinolone, gatifloxacin, demonstrated excellent
penetration into CSF and was highly effective as a single agent in the
therapy of experimental meningitis caused by highly
cephalosporin-resistant S. pneumoniae. The MICs of
gatifloxacin for 15 strains of S. pneumoniae fall
within a narrow range (0.20 to 0.39 µg/ml) (8), and
although only one pneumococcal strain was used in this study, it is
likely that the findings apply to other strains.
The penetration of gatifloxacin into CSF is species dependent
(15) and has not been determined in humans. The blood-CSF penetration expressed as the ratio of simultaneous CSF and serum concentrations can be misleading because antibiotic time-concentration curves in CSF lag behind those in serum. The ratio of
AUCCSF/AUCserum better characterizes CSF
penetration (13). In this study, the ratio of the AUC values
(46 to 56%) was higher than that of 1-h concentrations (27 to 38%),
suggesting that the latter ratio actually underestimates penetration.
The Cpeak/MIC and AUC/MIC ratios have been shown
to be the pharmacodynamic indices that best correlate with the
bacteriologic efficacy of quinolones in Pseudomonas
aeruginosa infections in vitro and in vivo (3, 10).
MBCs rather than MICs were used in this study, because bactericidal
activity is important for clearance of organisms from CSF
(17). The concentration-dependent bacterial killing by
various quinolones, with the exception of trovafloxacin, has been
demonstrated in experimental pneumococcal meningitis (14).
However, in that study, antibiotic therapy was given as a continuous
infusion over a 7-h period, thereby maintaining CSF drug concentrations
above the MBC for the entire study period. Also, the correlation of BKR
with other pharmacodynamic indices such as AUC/MBC and
T > MBC was not presented. In another study by the
same investigators, the BKR of trovafloxacin was significantly greater
during the first 5 h after doses of 30 mg/kg compared with those
after 10 mg/kg; the investigators suggested that bacterial killing was
concentration dependent, but the correlation between BKR and
Cpeak/MBC was not specifically reported
(9). We also demonstrated that higher dosages resulted
in larger CSF concentrations and in greater initial bacterial
killing. However, the high dosages also resulted in longer
T > MBC and greater AUC/MBC values. It is difficult to
determine which pharmacodynamic value best predicts bacteriologic
efficacy in single-dose experiments because T > MBC, Cpeak/MBC, and AUC/MBC are highly
interrelated (r = 0.94 in our study) and the AUC is
especially difficult to manipulate independently.
By administering gatifloxacin in divided doses, we could lower
Cpeak and extend the time that antibiotic
concentrations remained above the MBC without changing the AUC. In our
model, divided-dose regimens were clearly more effective than the same
dose given as a single injection. In animals with similar CSF
Cpeak/MBC or AUC/MBC ratios, bacterial killing
was greater in those with greater T > MBC values.
However, when T > MBC was maintained at 100%, Cpeak/MBC still correlated with initial BKR,
indicating that the influence of drug concentration on bacterial
clearance is superimposed on the effect of T > MBC.
The important influence that T > MBC had on the
bactericidal activity of gatifloxacin was probably the result of
the absence of a postantibiotic effect in the CSF. These findings
support a previous study in which trovafloxacin therapy was
bactericidal only while drug concentrations were maintained above
the MBC (9). In contrast, in a study of levofloxacin therapy in systemic Pseudomonas infection in neutropenic
mice, T > MIC was found to be unimportant
(3).
Experimental studies of pneumonia, peritonitis, and sepsis and
clinical trials evaluating fluoroquinolone therapy have shown that AUC/MIC ratios of 
100 and Cpeak/MIC
ratios of 8 to 10 are almost always associated with satisfactory
outcomes (1). We found that the same relationships applied
in the CSF; AUC/MBC and Cpeak/MBC ratios of 40 and 6, respectively, produced maximal BKR. These ratios would be
twofold greater if they were calculated with MICs rather than MBCs.
The CSF pharmacokinetic profile of gatifloxacin in humans is unknown,
but predictions can be made based on the data in the present study and
on available human serum pharmacokinetic data (11).
Gatifloxacin is eliminated from CSF by simple diffusion (15), and the CSF t1/2 is longer than
that in serum (1.2- to 1.7-fold longer in the present study). The serum
elimination t1/2 of gatifloxacin in humans
is 7 to 8 h (11); the estimated
t1/2 in CSF is 10 to 12 h. Assuming that
the CSF penetration of gatifloxacin in humans is similar to that in
rabbits (at least 30%) and that, as in the present study, peak
concentrations in CSF of 1 µg/ml would be adequate, peak serum
concentrations of 3 to 4 µg/ml in humans should be targeted. Such
concentrations can be achieved after oral doses of 400 mg
(11). Because of the long elimination t1/2, once- or twice-daily administration of
gatifloxacin should be sufficient in humans. This hypothesis requires
verification by clinical pharmacokinetic studies in humans with
meningitis.
In conclusion, gatifloxacin was effective as a single agent for the
therapy of experimental cephalosporin-resistant pneumococcal meningitis. In the CSF the antibacterial activity of gatifloxacin correlated well with AUC/MBC. Because the AUC/MBC is dependent on
T > MBC and Cpeak/MBC, it was
not surprising that these latter indices also correlated with
bactericidal activity. For maximal bactericidal efficacy in meningitis,
the concentrations of gatifloxacin should be maintained above the MBC
for the entire dosing interval.
| |
ACKNOWLEDGMENTS |
This study was supported in part by a grant from Bristol-Myers
Squibb. I. Lutsar is a recipient of a fellowship award of the European
Society for Pediatric Infectious Diseases, supported by Lederle-Praxis
Biologicals.
| |
FOOTNOTES |
*
Corresponding author. Mailing address: Department of
Pediatrics, Southwestern Medical Center, 5323 Harry Hines Blvd.,
Dallas, TX 75235-9063. Phone: (214) 648-3082. Fax: (214) 648-2961. E-mail: GMCCRA{at}mednet.swmed.edu.
| |
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Antimicrobial Agents and Chemotherapy, October 1998, p. 2650-2655, Vol. 42, No. 10
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Abstract
Introduction
