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Antimicrobial Agents and Chemotherapy, July 1999, p. 1805-1807, Vol. 43, No. 7
0066-4804/99/$04.00+0
Copyright © 1999, American Society for Microbiology. All rights reserved.
Efficacy of Gatifloxacin in Experimental Escherichia
coli Meningitis
Irja
Lutsar,*
Ian R.
Friedland,
Hasan S.
Jafri,
Loretta
Wubbel,
Winston
Ng,
Faryal
Ghaffar, and
George H.
McCracken Jr.
The University of Texas Southwestern Medical
Center, Dallas, Texas
Received 10 June 1998/Returned for modification 15 November
1998/Accepted 5 May 1999
 |
ABSTRACT |
The effectiveness of gatifloxacin therapy (15 mg/kg every 5 h
[q5h]) was compared with that of meropenem (75 mg/kg q5h) and cefotaxime (75 mg/kg q5h) therapy in experimental meningitis caused by
a 
-lactamase-producing strain of Escherichia coli.
Gatifloxacin therapy was more rapidly bactericidal than cefotaxime but
similar to meropenem therapy (bacterial killing rates at 5 h,
0.83 ± 0.26, 0.46 ± 0.3, and 0.73 ± 0.17 CFU/ml/h,
respectively; P = 0.03 for gatifloxacin versus
cefotaxime). At 10 h, seven of eight animals treated with
gatifloxacin had <10 CFU/ml in their cerebrospinal fluid, compared
with one of seven treated with cefotaxime therapy (P = 0.01). Gatifloxacin was at least as effective as currently available
antibiotics in this model of E. coli meningitis.
| |
TEXT |
Gram-negative meningitis is rare but
is associated with significant morbidity and mortality (22).
Currently, cefotaxime alone or in combination with an aminoglycoside is
a recommended option for the therapy for Escherichia coli
meningitis. However, therapeutic failures have occurred, especially in
neonates (10, 18). The fluoroquinolones are active against
gram-negative bacilli, and ciprofloxacin, pefloxacin, and ofloxacin
have been shown to be effective in the therapy of gram-negative
meningitis in experimental animals and in humans (19).
Gatifloxacin (AM-1155) is a new 8-methoxy fluoroquinolone. It is well
absorbed and widely distributed into body fluids and tissues and is
primarily excreted unchanged in the urine (3). Gatifloxacin
has excellent bactericidal activity against most gram-negative and
gram-positive microorganisms and, because of its lipophilicity,
penetrates cerebrospinal fluid (CSF) better (8, 9, 21, 24).
We have shown previously that gatifloxacin is highly effective as a
single agent in experimental cephalosporin-resistant pneumococcal
meningitis (17). The present study was conducted to compare
the effectiveness of gatifloxacin therapy with meropenem and cefotaxime
therapy in experimental meningitis caused by a -lactamase-producing
strain of E. coli.
Methods.
E. coli 77-436, a K1:O18 strain (-lactamase
positive) originally isolated from a neonate with bacterial meningitis,
was grown overnight on blood agar. The plates were flooded with
endotoxin-free phosphate-buffered saline, and aliquots of the resultant
suspension were frozen at 
70°C. The MICs and MBCs of antibiotics
for this strain were measured by standard National Committee for
Clinical Laboratory Standards methods (20).
Overnight Mueller-Hinton broth cultures of E. coli were
diluted in fresh broth to final concentrations of 105 to
108 CFU/ml. Antibiotics were added to achieve
concentrations similar to those in the CSF of patients with meningitis,
i.e., cefotaxime at 4 µg/ml, meropenem at 3 µg/ml, and gatifloxacin
at 1 µg/ml. Resultant suspensions were incubated at 37°C for
24 h; serial 100-fold dilutions were plated on blood agar at 6 and
24 h and incubated overnight at 37°C. The lower limit of
detection was 100 CFU/ml.
A rabbit meningitis model originally described by Dacey and Sande was
used (
4). Meningitis was induced in young New Zealand
White
male rabbits by intracisternal inoculation of 0.25 ml of
the
E. coli suspension (approximately 10
5 CFU/ml).
Antibacterial therapy was started 14 h after inoculation of
bacteria. All antibiotics were given intravenously via a marginal
ear
vein. The antibiotics studied were gatifloxacin (Bristol-Myers-Squibb,
Wallingford, Conn.) at 15 mg/kg, cefotaxime (Hoechst-Roussel,
Somerville, N.J.) at 75 mg/kg, and meropenem (Zeneca, Wilmington,
Del.)
at 75 mg/kg. Dosages were chosen to simulate concentrations
achieved in
human CSF (
5,
23). Three doses of each antibiotic
were given
5 h apart. Animals were killed by pentobarbital overdose
24 h
after the initiation of antibacterial therapy. Each treatment
group
consisted of 7 to 10
animals.
CSF samples for measurement of peak and trough drug concentrations were
collected 1 and 10 h after administration of the first
antibiotic
dose. Bacterial concentrations were measured before
therapy and at 5, 10, and 24 h after initiation of therapy by
plating undiluted CSF
and serial dilutions of CSF on sheep blood
agar and incubating them at
35°C for 24 h. The lower limit of
detection was 10 CFU/ml.
Meropenem and cefotaxime concentrations were measured by
high-performance liquid chromatography (
1). Gatifloxacin
concentrations
were determined by disk diffusion bioassay using
Bacillus subtilis ATCC 6633 (
17). Standard curves
were prepared with rabbit CSF
and were linear in the ranges of 1.0 to
10 µg/ml for meropenem
and cefotaxime and 0.1 to 2.0 µg/ml for
gatifloxacin. Concentrations
of each antibiotic were measured in one
run. Intra-assay coefficients
of variance were <5%.
Continuous variables are expressed as means ± standard deviations
(SD). Student's
t test and analysis of variance were used
to compare continuous variables. The Fisher exact test was used
to
compare categorical
values.
Results.
The respective MICs and MBCs for E. coli
are presented in Table 1. Table
2 shows the effect of bacterial
concentration on the bacterial killing rate (BKR) in vitro (inoculum
effect). Gatifloxacin was more rapidly bactericidal than meropenem and
cefotaxime. The BKR of cefotaxime decreased as bacterial concentrations
increased; this did not occur with meropenem or gatifloxacin. At
24 h, all cultures, other than the controls, were sterile.
Antibiotic concentrations in CSF are shown in Table
1. The
bacteriologic effectiveness of the different therapies is demonstrated
in Fig.
1. The BKRs in the first 5 h
were 0.83 ± 0.26, 0.73 ±
0.17, and 0.46 ± 0.3 CFU/ml/h with the gatifloxacin, meropenem,
and cefotaxime therapies,
respectively (
P = 0.03 for gatifloxacin
versus
cefotaxime). As a result of its greater BKR, more animals
had negative
(<10 CFU/ml) CSF cultures at 5 and 10 h with gatifloxacin
therapy
than with cefotaxime therapy (7 of 9 versus 2 of 10 at
5 h
[
P = 0.02] and 7 of 8 versus 1 of 7 at 10 h
[
P = 0.01], respectively).
Meropenem and gatifloxacin
were similarly effective; four of seven
animals had <10 CFU/ml at 5 and 10 h with meropenem therapy. At
24 h, the bacterial
concentrations in CSF were 1.0 ± 0.1, 2.4
± 1.0, and
2.1 ± 1.6 CFU/ml with the gatifloxacin, meropenem,
and cefotaxime
therapies, respectively, and the numbers of animals
with negative
cultures were similar in all groups. However, only
5 of 10 animals
treated with cefotaxime survived compare with
8 of 9 and 7 of 7 treated
with gatifloxacin and meropenem, respectively.
The in vivo BKRs of the
three antibiotics studied were not influenced
by the initial bacterial
concentrations in CSF.
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FIG. 1.
Bacterial concentrations (mean and SD) in CSF of rabbits
with E. coli meningitis treated with cefotaxime ( , 75 mg/kg), meropenem ( , 75 mg/kg), and gatifloxacin ( , 15 mg/kg) at
0, 5, and 10 h. Symbols: *, P = 0.02; and
**, P = 0.01 (for gatifloxacin versus cefotaxime
therapy). Control animals ( ) were euthanized after 10 h. The
dashed line indicates the lower limit of detection.
|
|
Discussion.
Gatifloxacin, a new fluoroquinolone, demonstrated
rapid bacterial killing in this experimental model of E. coli meningitis; its effectiveness was comparable to that of
meropenem and was superior to that of cefotaxime therapy.
In vitro, higher MICs of cefotaxime for
E. coli are measured
in the presence of high initial bacterial concentrations
(
14).
This is thought to be caused by the overproduction of
-lactamase
by dense bacterial populations (
16). This
inoculum effect occurs
to a much lesser extent with gatifloxacin or
meropenem (
8,
11). Our time-kill studies confirmed that the
BKR of cefotaxime
was reduced when the initial bacterial concentrations
were large
whereas the BKR of gatifloxacin was independent of the
initial
bacterial concentration. Similarly, in experimental
E. coli meningitis,
a reduction in the effectiveness of cefotaxime
therapy in the
presence of high bacterial concentrations has been shown
(
12-14)
and was confirmed in this study. In contrast to its
BKR in vitro,
the BKR of cefotaxime was not affected by bacterial
concentrations
in the meningitis model. However, the BKR of cefotaxime
was relatively
slow compared with that of gatifloxacin therapy, and in
the presence
of high bacterial concentrations, this translates into
delayed
CSF sterilization and increased mortality. A similar effect may
occur in humans with meningitis because patients who have bacterial
concentrations in the CSF of >10
6 CFU/ml tend to have
delayed CSF sterilization (
2,
6).
The MBCs of the three antibiotics studied for the
E. coli
strain used were low and antibiotic concentrations in CSF many fold
greater than the respective MBCs were achieved. Thus, we believe
the
slower bacterial clearance with cefotaxime therapy was related
not to
low drug concentrations in CSF but to the drug's mode of
action; the
lower BKR observed in vitro supports this
supposition.
Whether a more rapid BKR, as occurs with gatifloxacin or meropenem
therapy, is of clinical benefit in gram-negative meningitis
is
unproven, although available evidence suggests that this is
likely. In
experimental meningitis, persistence of
E. coli in
the CSF
eventually results in much greater endotoxin release than
that induced
by effective antibacterial therapy (
7). In the
present and
previous experimental studies (
13), lower BKRs were
associated with increased mortality. In children with
Haemophilus influenzae or enteric gram-negative meningitis, failure to
sterilize
the CSF within 24 h of antibacterial therapy is
associated with
a poorer outcome (
15,
18,
25).
In conclusion, gatifloxacin was rapidly bactericidal in this
experimental
E. coli meningitis model. Whether this will
translate
into improved outcome of gram-negative enteric meningitis in
humans
warrants further
investigation.
| |
ACKNOWLEDGMENTS |
This study was supported by a grant from Bristol-Myers Squibb Pharmaceuticals.
| |
FOOTNOTES |
*
Corresponding author. Mailing address: Department of
Pediatrics, UT Southwestern Medical Center, 5323 Harry Hines Blvd.,
Dallas, TX 75235-9063. Phone: (214) 648-3082. Fax: (214) 648-2961. E-mail: ilutsa{at}mednet.swmed.edu.
| |
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Antimicrobial Agents and Chemotherapy, July 1999, p. 1805-1807, Vol. 43, No. 7
0066-4804/99/$04.00+0
Copyright © 1999, American Society for Microbiology. All rights reserved.
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