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Antimicrobial Agents and Chemotherapy, November 2001, p. 3098-3103, Vol. 45, No. 11
0066-4804/01/$04.00+0 DOI: 10.1128/AAC.45.11.3098-3103.2001
Copyright © 2001, American Society for Microbiology. All rights reserved.
BMS-284756 in Experimental Cephalosporin-Resistant
Pneumococcal Meningitis
Violeta
Rodriguez-Cerrato,*
Faryal
Ghaffar,
Jesus
Saavedra,
Ian C.
Michelow,
Robert D.
Hardy,
Janie
Iglehart,
Kurt
Olsen, and
George H.
McCracken Jr.
Department of Pediatrics, The University of
Texas Southwestern Medical Center, Dallas, Texas
Received 6 February 2001/Accepted 30 July 2001
 |
ABSTRACT |
BMS-284756 is a novel des-fluoro(6) quinolone with a broad
antimicrobial activity, including Streptococcus pneumoniae.
The purpose of this study was to evaluate the pharmacodynamic profile and effectiveness of BMS-284756 for therapy of experimental meningitis caused by penicillin- and cephalosporin-resistant S. pneumoniae (CRSP). Meningitis was induced in rabbits by
intracisternal inoculation of CRSP. BMS-284756 was given intravenously
16 h after intracisternal inoculation in single doses of 2.5 (n = 5 animals), 5 (n = 6), 10 (n = 6), 20 (n = 8), and 30 mg/kg
(n = 6), in two doses of 10 mg/kg each separated by
5 h (n = 4), and as a 20-mg/kg dose followed
5 h later by 10 mg/kg (n = 5). The MICs and MBCs
of BMS-284756, ceftriaxone, and vancomycin were 0.06 and 0.06, 4 and 4, and 0.25 and 0.25 µg/ml, respectively. After single doses of 10, 20, and 30 mg/kg, the maximum concentrations in cerebrospinal fluid (CSF) (mean ± standard deviation) were 0.32 ± 0.12, 0.81 ± 0.38, and 1.08 ± 0.43 µg/ml, respectively; the elimination
half-life in CSF was 4.5 to 6.3 h. The CSF bacterial killing rates
(BKR) at 5 h of the single-dose regimens of 10, 20 and 30 mg/kg
were 
0.84 ± 0.48, 1.09 ± 0.32, and 1.35 ± 0.05 
log10 CFU/ml/h. The BKR0-5 of the divided
regimens (10 mg/kg twice and 20 mg/kg followed by 10 mg/kg) was
0.82 ± 0.52 and 1.24 ± 0.34 log10
CFU/ml/h, respectively. The BKR0-5 of the combined therapy
with vancomycin and ceftriaxone was 1.09 ± 0.39 log10 CFU/ml/h. The penetration of BMS-284756 into
purulent CSF relative to plasma was 14 to 25%. The bactericidal effect
of BMS-284756 in CSF was concentration dependent. BMS-284756 at 30 mg/kg as a single or divided dose was as effective as standard therapy
with vancomycin and ceftriaxone.
| |
INTRODUCTION |
Pneumococcal meningitis is
associated with a case fatality rate of 10% in children and up to 30%
in adults. Among survivors the morbidity rate is approximately 30%,
with neurologic sequelae in 25% of patients and moderate to severe
hearing loss in 32% (1, 4, 8, 16).
The emergence of multidrug-resistant strains of Streptococcus
pneumoniae indicates the need to develop and evaluate new
antipneumococcal agents. BMS-284756 (formerly T-3811ME) is a novel
quinolone agent that lacks the fluorine at the C-6 position typical of
existing fluoroquinolones. This des-F(6) quinolone displays a broad
antimicrobial spectrum and exhibits enhanced in vitro activity against
S. pneumoniae (6, 19). The aims of this study
were to evaluate the pharmacodynamics and bacteriologic effectiveness
of BMS-284756 in experimental meningitis caused by a penicillin- and
ceftriaxone-resistant pneumococcal strain and to compare results with
standard therapy with vancomycin and ceftriaxone.
(This study was presented in part at the 40th Interscience
Conference on Antimicrobial Agents and Chemotherapy
[ICAAC], Toronto, Canada, 21-24 September 2000.)
| |
MATERIALS AND METHODS |
Bacterial strain.
A highly penicillin- (MIC = 2 µg/ml) and cephalosporin-resistant (ceftriaxone MIC = 4 µg/ml)
strain of S. pneumoniae type 6B was used for induction of
meningitis in the rabbit model. This strain was originally isolated
from an infant with meningitis (5). After intrathecal
passage in rabbits, the strain was grown overnight on blood agar
plates. The plates were washed with endotoxin-free phosphate-buffered
saline (PBS), and aliquots of the resultant suspension were frozen at
70°C. For preparation of the inoculum, aliquots were thawed and
diluted in endotoxin-free PBS to a concentration of approximately
1 × 105 to 5 × 105 CFU/ml. The
inoculum size was confirmed by quantitative cultures in each experiment.
Susceptibility tests.
The MICs and MBCs of antibiotics for
this strain were determined using a microdilution method, as
recommended by the National Committee for Clinical Laboratory Standards
(11).
Meningitis model.
The rabbit meningitis model, modified from
the original description by Dacey and Sande, was used (3).
Young male New Zealand White rabbits weighing 2 to 2.5 kg were
anesthetized with intramuscular ketamine (50 mg/kg of body weight) and
acepromazine (4 mg/kg) before every procedure and frequently while
restrained in the stereotactic frames. Flunixin meglumine (1.1 mg/kg)
was administered intramuscularly every 12 h for analgesia.
Meningitis was induced by intracisternal injection of 250 µl of a
pneumococcal suspension containing 1 × 105 to 5 × 105 CFU/ml. Approximately 16 h later, anesthetized
animals underwent intracisternal taps to quantify the baseline
bacterial concentration in the cerebrospinal fluid (CSF), and then
antibiotic therapy was administered via a marginal vein (0 h). Animals
were immobilized in stereotactic frames, and a spinal needle remained
in the cisterna magna for frequent CSF sampling during the first 3 h after receiving antibiotics. The rate of removal of CSF did not
exceed the rate of CSF formation, which is approximately 0.4 ml/h
(18). Blood samples were drawn from a central ear artery.
The animals were sacrificed with pentobarbital (120 mg/kg) at the end
of each experiment or earlier if they were severely lethargic or not recumbent.
Treatment.
BMS-284756 (Bristol-Myers Squibb Co., Princeton,
N.J.) was administered in single-dose regimens at 2.5 mg/kg
(n = 5 animals), 5 mg/kg (n = 6), 10 mg/kg (n = 6), 20 mg/kg (n = 8), and 30 mg/kg (n = 6). Multiple-dose regimens were given as 10 mg/kg twice separated by 5 h (n = 4) and 20 mg/kg
followed by 10 mg/kg 5 h later (n = 5). For
comparison, four animals received the combination of vancomycin (20 mg/kg every 5 h, three doses) and ceftriaxone (125 mg/kg, single
dose). As controls, five animals were inoculated with S. pneumoniae and did not receive antibiotic therapy.
Sample collection and processing.
After a single dose of
antibiotic was given, CSF (150 µl) and blood (700 µl) samples were
obtained at 0.5, 1, 2, 3, 5, 10, and 24 h. In the case of multiple-dose
regimens, CSF and blood were also collected at 6 h (1 h
post-second dose). Blood and CSF samples were centrifuged at
5,000 × g for 10 and 5 min, respectively, and the
supernatants were stored at 70°C for determination of antibiotic
concentrations. An additional 100 to 150 µl of CSF was collected at
3, 5, 10, and 24 h after initiation of therapy for quantification
of bacterial titers. Bacterial concentrations were determined by
plating undiluted and serial dilutions of CSF (100 µl) on sheep blood
agar and incubating in 5% CO2 at 35°C for 24 h. The
lowest bacterial concentration detectable by this method was 10 CFU/ml.
For purposes of analysis, specimens with <10 CFU/ml were assigned a
value of 1 (0 log10) CFU/ml. Bacterial killing rates (BKR)
were calculated as the difference between bacterial concentrations at
the start of therapy and 3, 5, 10, and 24 h later divided by time.
Antibiotic concentration determination.
BMS-284756
concentrations in CSF and plasma were measured by disk diffusion
bioassay using Bacillus subtilis ATCC 6633 as described
previously (17). BMS-284756 standards for CSF and plasma
values were calculated to be between 0.1 and 4.0 and between 0.2 and
10.0 µg/ml, respectively. Some samples showed zones of inhibition
that could be extrapolated to calculate concentrations lower than the
limits of detection. The lowest extrapolated values for plasma and CSF
were 0.04 and 0.02 µg/ml, respectively. Values lower than the limit
of detection were not used for the pharmacokinetic calculations.
BMS-284756 standards for CSF and plasma were prepared with rabbit CSF
and plasma, respectively. The intra- and interassay coefficients of
variation were 2.3 and 7.4% for plasma and 2.7 and 6.8% for CSF, respectively.
Pharmacokinetic and pharmacodynamic indices.
The maximum
concentrations (Cmax) of BMS-284756 in plasma
and CSF were the highest measured values. Pharmacokinetic analyses were
performed using the computer program TopFit V2 (Karl Thomae, Boehringer, Ingelheim, Germany). A noncompartmental model was used for
calculations of CSF pharmacokinetic indices, and a two-compartment model was used for plasma pharmacokinetics. The areas under the concentration-time curves (AUC) for plasma and CSF were estimated from
0 h (initial antibiotic therapy) to the last quantifiable concentration
(24 h) using the linear trapezoidal rule and the logarithmic
trapezoidal rule, respectively. The log-trapezoidal method was used for
CSF values because it is believed to have less distortion of the AUC
computation at both the ascending and descending parts of the
concentration-time curve (7). The percentage of time above
the MBC (T > MBC) was calculated as described by Turnidge (20). The ratio of CSF
Cmax to MBC (Cmax/MBC)
and the AUC/MBC ratio were calculated. The MBC value was used in this study because bactericidal activity is critical for clearance of
organisms from CSF (14). The penetration of BMS-284756
across the blood-brain barrier (expressed as a percentage) was
calculated as the ratio of CSF to plasma AUC0-24.
The relationship between pharmacodynamic indices
(
Cmax/MBC and AUC/MBC) and BKR was established
according to a sigmoid
Emax model with the
computer program WinNonlin version 1.5. (Scientific
Consulting, Inc.).
The following formula was used:
E = (
Emax ×
C
)/(
C +
EC50), where
E is the
estimated bacterial killing
rate,
Emax is the
maximum BKR,
C is the mean
Cmax/MBC
or AUC/MBC,
EC50 is the
C producing
half-maximal BKR, and
is the Hill coefficient
indicating the slope
of the sigmoid curve. Linear regression analysis
was used to express
the relationship between
T > MBC and
BKR.
Statistical analysis.
Comparisons between two groups were
performed by t test or Mann-Whitney test if normally
distributed or not, respectively. Comparisons among three or more
groups were performed by Kruskal-Wallis test followed by Dunn's
multiple-comparisons test among groups when they were significantly
different. A P value of <0.05 was considered significant.
Data are expressed as mean ± standard deviation (SD).
| |
RESULTS |
In vitro susceptibility.
The MICs and MBCs of the study
antibiotics for this strain of S. pneumoniae were as
follows: BMS-284756, 0.06 and 0.06 µg/ml, respectively; ceftriaxone,
4 and 4 µg/ml, respectively; and vancomycin, 0.25 and 0.25 µg/ml, respectively.
Single-dose pharmacokinetics.
Mean serum and CSF
concentrations of BMS-284756 after single-dose regimens are presented
in Table 1. The concentration-time curves
of BMS-284756 in plasma and CSF after single-dose regimens are shown in
Fig. 1. Maximum CSF concentrations of
BMS-284756 were reached between 30 min and 1 h after receiving
therapy. The highest serum concentrations were measured at 30 min after
drug administration. Initial mean bacterial concentrations were similar for all groups. Pharmacokinetic indices over a 24-h period after single-dose regimens of BMS-284756 are shown in Table
2. Among infected animals, the
penetration rate of BMS-284756 into the CSF, expressed as
AUCCSF/AUCplasma, was 14 to 25% with doses of 10 to 30 mg/kg. A good linear correlation was found between the total
dose and CSF Cmax values (r = 0.84),
AUC (r = 0.84), and T > MBC
(r = 0.94; P < 0.001).
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TABLE 1.
Concentrations of BMS-284756 in serum and CSF after
single-dose regimens during experimental meningitis caused by
cephalosporin-resistant S. pneumoniae
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FIG. 1.
Concentration-time curves of BMS-284756 in plasma (left)
and CSF (right) after single intravenous doses for experimental
cephalosporin-resistant pneumococcal meningitis. Mean concentrations
(± SD) of BMS-284756 are illustrated at 5 mg/kg ( ), 10 mg/kg ( ),
20 mg/kg ( ), and 30 mg/kg ( ).
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TABLE 2.
Pharmacokinetic indices over 24 h after single doses
of BMS-284756 for therapy of experimental cephalosporin-resistant
pneumococcal meningitis
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Pharmacodynamics and effectiveness of single-dose therapy.
The
CSF pharmacodynamic indices after single and combined dose regimens are
shown in Table 3. Bacterial killing over
a 24-h period after different regimens of BMS-284756 is shown in Table 4. The CSF bacterial concentrations after
single doses of BMS-284756 are illustrated in Fig.
2. All antibiotic-treated groups had
significantly higher reductions in CSF bacterial titers than the
untreated group (P < 0.05). Bacterial regrowth
occurred after 10 h in rabbits treated with all single-dose
regimens. At 2.5 and 5 mg/kg, only a slow reduction in bacterial titers
was observed; therefore, we considered these regimens inadequate.
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TABLE 3.
CSF pharmacodynamic indices over 24 h with different
dosing regimens of BMS-284756 therapy for cephalosporin-resistant
pneumococcal meningitis
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TABLE 4.
Bacterial killing in CSF over 24 h with different
dosing regimens of BMS-284756 therapy for experimental S. pneumoniae meningitis and comparison with standard therapy
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FIG. 2.
Mean bacterial (bact) concentrations (± SD) in CSF
after single doses of BMS-284756 for experimental
cephalosporin-resistant pneumococcal meningitis. Animals were treated
with BMS-284756 at 5 mg/kg (), 10 mg/kg (), 20 mg/kg (), and
30 mg/kg ().
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The bacteriologic effectiveness of BMS-284756 was concentration
dependent at all time points except at 3 h, when the bacterial
clearance was greater with the 20-mg/kg regimen than with 30-mg/kg
one.
This could be a result of the small difference in the baseline
bacterial count (0 h) between these therapeutic groups (6.3 versus
6.7 log
10 CFU/ml, respectively). The maximal BKR of
1.35
CFU/ml/h
was observed with the 30-mg/kg dose, which produced an AUC/MBC
of 128,
Cmax/MBC of 18, and
T > MBC of 87.7%. For 5 h after administration,
the concentrations of
BMS-284756 in CSF after the 20-mg/kg and
30-mg/kg doses were 6.2- to
8.2-fold higher than the MBC. The
three CSF pharmacodynamic indices,
AUC/MBC,
Cmax/MBC, and
T >
MBC,
were highly interrelated (
r = 0.91). Using the
Emax model
for the first two indices and linear
regression for
T > MBC, all
indices correlated
significantly with BKR from 5 h (
r = 0.79,
r = 0.76, and
r = 0.71, respectively)
to 24 h (
r = 0.87,
r = 0.79,
and
r = 0.77,
respectively).
Pharmacodynamics and bacteriologic response with divided-dose
regimens.
The pharmacodynamic indices in CSF and the bacteriologic
effectiveness are summarized in Tables 3 and 4. The CSF concentrations of BMS-284756 were below the MBC at 24 h for all animals treated with 10 mg/kg given twice and for three of five animals treated with 20 mg/kg followed by 10 mg/kg. However, bacterial clearance (<10 CFU/ml)
in the CSF was obtained at 24 h for all animals treated with
divided-dose regimens. At 10 h, three of four animals treated with
10-mg/kg × 2 therapy and all animals treated with the 20-mg/kg followed by 10-mg/kg regimen achieved CSF sterilization. The bacterial killing rate of BMS-284756 with divided-dose regimens was concentration dependent at all time points.
Comparison of BMS-284756 with standard therapy.
The bacterial
killing of the 20-mg/kg plus 10-mg/kg regimen was slightly higher than
that of vancomycin and ceftriaxone, but the difference was not
statistically significant (Table 4). The CSF bacterial concentrations
after the 30-mg/kg single dose and 20-mg/kg plus 10-mg/kg regimen of
BMS-284756 are displayed and compared to that of vancomycin and
ceftriaxone in Fig. 3.
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FIG. 3.
Mean bacterial (bact) concentrations (± SD) in CSF
after BMS-284756 given at 20 mg/kg followed by 10 mg/kg after 5 h
(), 30-mg/kg single dose (), and vancomycin plus ceftriaxone
( ) therapy for cephalosporin-resistant pneumococcal meningitis. 1, bacterial concentrations in control animals ( ) compared to all
antibiotic groups was significant (P < 0.05).
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| |
DISCUSSION |
Because of their excellent antibacterial activity and favorable
CSF penetration, the new fluoroquinolones (e.g., trovafloxacin, gatifloxacin, and moxifloxacin) have been shown to be effective for
treatment of resistant pneumococcal meningitis in rabbits (9, 12,
15). We demonstrated that BMS-284756 is highly active against
cephalosporin-resistant S. pneumoniae in this meningitis model. BMS-284756 displayed good penetration into inflamed meninges. Protein binding of BMS-284756 has been described to be as high as 80%
(D. P. Nicolau, H. M. Mattoes, M. A. Banevicius, D. Xuan, and
C. H. Nightingale, Program Abstr. 40th ICAAC, 2000, abstr. 290).
As with other fluoroquinoles, the bacterial killing of BMS-284756 was
concentration dependent (2). The effectiveness of
BMS-284756 in CSF was correlated with the three pharmacodynamic
indices, AUC/MBC, Cmax/MBC, and
T > MBC, but the AUC/MBC ratio correlated best with
bacterial killing in CSF.
In the neutropenic thigh infection model, maximal bactericidal activity
of BMS-284756 was achieved when serum AUC/MIC ratios were 150 to 200 and therefore the free drug AUC/MIC was 30 to 40 (Nicolau et al.,
abstr.). In our study, total drug AUC/MBC ratios of 114 to 128 (free
AUC/MBC of 23 to 26) produced maximal bactericidal activity in CSF.
In this study, bacterial clearance at 24 h was observed despite
the fact that CSF concentrations of BMS-284756 were below the MBC for
this strain at 24 h in animals treated with the divided-dose regimens. This suggests a potential sub-MBC effect in CSF, contrary to
previous observations for other quinolones (9, 10, 13).
Recently, data have been presented on safety, tolerability, and
pharmacokinetics in humans after prolonged oral administration (D. Grasela, D. Gajjar, A. Bello, Z. Ge, and L. Christopher, Program Abstr.
40th ICAAC, 2000, abstr. 2260). Mean plasma concentrations ranged from
1.7 to 25 µg/ml after oral doses of 100 to 1,200 mg. Based on the
long elimination t1/2 in plasma (13 to 17 h), once-daily dosage of BMS-284756 may be suitable in humans. However,
the CSF pharmacokinetics of BMS-284756 has not been studied in humans. Based on our findings of similar t1/2 values in
serum and CSF of rabbits, a single daily dose equivalent to our 30 mg/kg or a regimen equivalent to 20 mg/kg followed by 10 mg/kg dose in rabbits given every 12 h could be effective for therapy of
pneumococcal meningitis. Clinical trials are necessary to confirm this hypothesis.
In conclusion, we demonstrated that BMS-284756 as a single agent was as
effective as the standard regimen with vancomycin and ceftriaxone for
therapy of experimental highly cephalosporin-resistant pneumococcal meningitis.
| |
ACKNOWLEDGMENTS |
Violeta Rodriguez-Cerrato is the recipient of a Fellowship Grant
from the European Society of Paediatric Infectious Diseases (ESPID)
sponsored by Wyeth-Lederle Vaccines and Pediatrics. This work was
supported in part by a grant from Bristol-Myers Squibb Co., Princeton,
N.J.
| |
FOOTNOTES |
*
Corresponding author. Mailing address: Department of
Pediatrics, University of Texas Southwestern Medical Center, 5323 Harry Hines Blvd., Dallas, TX 75390-9063. Phone: (214) 648-3720. Fax: (214)
648-2961. E-mail: rodriguez_cerrato{at}yahoo.com.
| |
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Antimicrobial Agents and Chemotherapy, November 2001, p. 3098-3103, Vol. 45, No. 11
0066-4804/01/$04.00+0 DOI: 10.1128/AAC.45.11.3098-3103.2001
Copyright © 2001, American Society for Microbiology. All rights reserved.
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Noreddin, A. M., Haynes, V. L., Zhanel, G. G.
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Abstract
Introduction
