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Antimicrobial Agents and Chemotherapy, November 1999, p. 2742-2746, Vol. 43, No. 11
0066-4804/99/$04.00+0
Copyright © 1999, American Society for Microbiology. All rights reserved.
Efficacy of Levofloxacin for Experimental
Aortic-Valve Endocarditis in Rabbits Infected with Viridans Group
Streptococcus or Staphylococcus aureus
Henry F.
Chambers,*
Qing
Xiang ,
Liu,
Lucian Liuxin
Chow, and
Corinne
Hackbarth
Department of Medicine, University of
California, and Division of Infectious Diseases, San Francisco
General Hospital, San Francisco, California
Received 13 April 1999/Returned for modification 3 June
1999/Accepted 12 August 1999
 |
ABSTRACT |
Levofloxacin is among the more active fluoroquinolones against
streptococci and staphylococci. It is effective against moderately severe infections caused by these organisms, but its efficacy in the
treatment of bacteremia and serious infections such as endocarditis is
not well defined. We compared the efficacy of levofloxacin to those of
standard agents in the rabbit model of aortic-valve endocarditis caused
by fluoroquinolone-susceptible strains including a
penicillin-susceptible strain of Streptococcus sanguis, a
penicillin-resistant strain of Streptococcus mitis, a
methicillin-resistant strain of Staphylococcus aureus, and
a methicillin-susceptible strain of S. aureus. Levofloxacin
administered intramuscularly at dosages of 20 to 40 mg/kg of body
weight twice daily (b.i.d.) was completely ineffective against the
penicillin-susceptible strain, with mean vegetation titers after 3 days
of therapy not statistically significantly different from those for
controls. Levofloxacin was no more effective than penicillin against
the penicillin-resistant strain. Levofloxacin administered for 4 days at a dosage of 20 mg/kg b.i.d. was at least as effective as vancomycin administered intravenously at a dosage of 25 mg/kg b.i.d. against the
methicillin-resistant S. aureus strain and was as effective as nafcillin administered intramuscularly at 100 mg three times daily
against the methicillin-susceptible strain. Emergence of resistance to
levofloxacin in vitro was less likely to occur than resistance to
ciprofloxacin, and resistance to levofloxacin was not observed in vivo.
Levofloxacin-rifampin combinations were antagonistic in vitro and in
vivo. Levofloxacin was highly effective as a single agent against
experimental staphylococcal endocarditis but was surprisingly
ineffective against streptococcal endocarditis, suggesting that it has
a potential role as treatment for serious S. aureus but not
viridans group streptococcal infections in humans.
| |
INTRODUCTION |
Levofloxacin, a fluoroquinolone with
somewhat enhanced activity against gram-positive cocci, is the
L-stereoisomer of ofloxacin, which is a racemic mixture
that contains equal parts of the L- and
D-stereoisomers. Since the D-stereoisomer has
no antibacterial activity, levofloxacin is twice as potent by weight as
ofloxacin, although their antibacterial spectra are otherwise identical
(10, 32). Levofloxacin is more active in vitro than
ciprofloxacin against gram-positive organisms, including streptococci
and staphylococci (3, 25, 29, 31). The purpose of these
studies was to investigate whether the in vitro activity of
levofloxacin against gram-positive cocci is predictive of in vivo
efficacy. The rabbit model of aortic-valve endocarditis caused by
viridans group streptococci and methicillin-susceptible and
methicillin-resistant strains of Staphylococcus aureus was
used to compare the activity of levofloxacin to those of the first-line
agents used to treat these infections in humans. Emergence of
resistance during therapy has been a concern with fluoroquinolones when
these are used as single agents (13, 14, 19, 26, 28).
Accordingly, selection for levofloxacin-resistant mutants was examined
in vitro and in vivo. Since ciprofloxacin and rifampin in combination
prevent the emergence of resistance and are used clinically (9,
14, 34), the effect of the combination of rifampin and
levofloxacin on the antibacterial activity of rifampin was also examined.
| |
MATERIALS AND METHODS |
Bacterial strains.
Strain M99 is a penicillin-susceptible
(MIC, <0.1 µg/ml) strain of Streptococcus sanguis. Strain
543 is a penicillin-resistant (MIC, 2 µg/ml) strain of
Streptococcus mitis. Strain 76 is a
beta-lactamase-producing, high-level methicillin-resistant strain of
S. aureus. Strain 1-63 is a methicillin-susceptible
beta-lactamase-producing strain of S. aureus. Both S. aureus strains were ciprofloxacin susceptible.
Thirty-six S. aureus clinical isolates, 26 ciprofloxacin-susceptible isolates and 10 ciprofloxacin-resistant
isolates (kindly provided by David Hooper, Harvard Medical School),
were used for in vitro experiments designed to assess susceptibility,
cross-resistance, and frequency of occurrence of mutants with
resistance to ciprofloxacin and levofloxacin.
Susceptibility studies.
MICs were determined by the standard
broth dilution method in 1-ml volumes of cation-supplemented
Mueller-Hinton broth (MHB) for S. aureus strains and in
Todd-Hewitt broth (THB) for viridans group streptococci at an inoculum
of approximately 3 × 105 CFU/ml. MICs were read after
a 24-h incubation at 35°C. Minimal bactericidal concentrations
(MBCs), defined as a 99.9% reduction in the original inoculum, were
determined by subculturing 10 µl from each clear tube onto blood agar
and incubation for 24 h.
Time-kill studies were conducted with the
S. aureus strains
to determine the effect of rifampin on the bactericidal activity
of
levofloxacin. Levofloxacin at a concentration of 4 µg/ml and
rifampin
at a concentration of 1 µg/ml were tested alone and in
combination in
10-ml volumes of Trypticase soy broth (TSB) for
S. aureus at
37°C. Samples of 100 µl taken after 0, 4, and 24
h of
antibiotic exposure were serially diluted 10-fold and were
cultured
onto blood agar. Colonies were counted after incubation
for 24 h
at 37°C.
The frequency of occurrence of resistant mutants among the
S. aureus strains was determined by quantitatively inoculating
an
overnight culture onto Trypticase soy agar (TSA) containing
ciprofloxacin or levofloxacin at concentrations of 0, 2×, 4×,
8×,
16×, and 32× the MIC. The inoculum was prepared by suspending
the
pellet obtained by centrifugation of a 10-ml culture in TSB
into 1 ml
of 0.85% saline. Tenfold serial dilutions were prepared.
Ten-microliter volumes were taken from the suspension and spotted
onto
the agar to give a final inoculum of approximately 10
7 CFU,
a value which approximates the total bacterial burden present
in
aortic-value vegetations of infected rabbits at the start of
antimicrobial therapy. Cultures were incubated for 48 h at 37°C,
and the numbers of colonies that grew at each concentration were
counted. The frequency of occurrence of resistant mutants was
expressed
as the ratio of the number of CFU on antibiotic-containing
agar to the
number of CFU on drug-free
agar.
Rabbit endocarditis model.
To establish endocarditis, a
catheter was positioned across the aortic valve and was secured in
place for the duration of the experiment. After the catheter had been
in place for an hour, 1 ml of approximately 107 CFU in
0.9% saline was injected intravenously. Twenty-four hours later,
antimicrobial therapy was begun. Levofloxacin was administered intramuscularly at a dosage of 20 or 40 mg/kg of body weight twice daily (b.i.d.) to approximate the peak concentrations achievable in the
sera of humans (8, 18). The mean concentration in serum,
which was determined by the agar diffusion bioassay method with
S. aureus 209P, was 5.8 ± 1.0 µg/ml (n = 3) at 1 h after administration of a 20-mg/kg dose and
0.2 ± 0.1 µg/ml at 8 h. The corresponding values for the
40-mg/kg dose were 11.0 ± 1.5 (n = 3) and
0.5 ± 0.3 µg/ml. The half-life was 1.5 h for both doses.
Comparator drugs were administered at doses that have previously been
shown in the rabbit model to approximate concentrations
achievable in
the sera of humans. Penicillin was administered
at a dosage of 150,000 U of penicillin G plus 150,000 U of procaine
penicillin intramuscularly
three times daily (t.i.d.) which achieves
concentrations in serum of
38 ± 8 µg/ml 1 h after dosing, with
a half-life of
3.2 h (
6). Vancomycin was administered intravenously
at
a dosage of 25 mg/kg b.i.d. which produces mean concentrations
in serum
of 43 ± 7 µg/ml 1 h after dosing, with a half-life of
1.3 h (
5). Nafcillin was given at a dosage of 100 mg/kg
t.i.d.,
which achieves concentrations in serum of 28 ± 11 µg/ml
1 h after
dosing, with a half-life of 1.7 h (
5).
Rifampin was administered
intramuscularly at a dosage of 5 mg/kg
b.i.d., which achieves
mean concentrations in serum of 3.6 ± 0.6 µg/ml 1 h after dosing,
with a half-life of 7.7 h
(
7).
Untreated control rabbits were killed 18 to 24 h after infection,
and aortic-valve vegetations were removed for culture. The
remaining
rabbits were given antimicrobial therapy for 3 days
(for viridans group
streptococcal endocarditis) or 4 days (
S. aureus
endocarditis). The rabbits were killed and aortic-valve
vegetations
were harvested 12 h following administration of the
last dose of
drug. The vegetations were homogenized and were quantitatively
subcultured onto blood agar to determine the number of organisms
remaining in the vegetation. Vegetations from rabbits in the
experiments
with
S. aureus in which levofloxacin alone was
compared to levofloxacin
plus rifampin were also cultured onto TSA
containing 5 µg of either
levofloxacin or rifampin per ml to screen
for the emergence of
resistance. The number of organisms remaining in
the vegetation
of each rabbit was expressed as the vegetation titer,
defined
as log
10 CFU per gram of
vegetation.
Statistical analysis.
Differences in frequencies of the
occurrence of resistant mutants was determined by paired Student's
t test. Differences in mean vegetation titers for treated
and untreated rabbits were analyzed for statistical significance
(defined as P < 0.05) by analysis of variance. An
unpaired Student's t test with the Bonferoni correction was
used post hoc to determine statistical significance.
| |
RESULTS |
Susceptibility studies.
The levofloxacin MICs for the
streptococcal strains were determined on two separate occasions in THB
and were 2 and 4 µg/ml, respectively (Table
1), with corresponding MBCs of 2 to 4 and 4 to 8 µg/ml. These MICs were somewhat higher than the published MICs
of 
2 µg/ml for streptococcal strains (3, 25, 31). To
determine whether higher MICs could be due to the use of THB, MIC
determinations were repeated with cation-adjusted MHB plus 2 to 5%
lysed horse blood, according to National Committee for Clinical
Laboratory Standard methods (20). The MICs obtained by this
method were 0.5 and 2 µg/ml, respectively.
The levofloxacin MICs for the
S. aureus strains were 0.5 and
1 µg/ml with MBCs of 1 and 2 µg/ml. In time-kill studies
levofloxacin
alone produced a 3- to 4-log
10 CFU/ml
reduction in the initial
inoculum of each strain after 24 h (Fig.
1). The addition of rifampin
to
levofloxacin resulted in approximately 1-log
10 CFU/ml
increase
in the number of surviving organisms at 24 h compared to
the number
after treatment with levofloxacin alone.
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FIG. 1.
Time-kill curves for methicillin-resistant strain
S. aureus 76 (A) and methicillin-susceptible strain S. aureus 1-63 (B). Black diamond, no drug; black circle, rifampin at
1 µg/ml; white triangle, levofloxacin at 4 µg/ml; black triangle,
levofloxacin plus rifampin.
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|
The MICs for the 36 clinical isolates ranged from 0.12 to >64 µg/ml
for ciprofloxacin and 0.12 to 32 µg/ml for levofloxacin.
The
geometric mean MIC of ciprofloxacin for the 10 ciprofloxacin-resistant
(defined as an MIC of
4 µg/ml) isolates was 18 µg/ml (range,
4 to
128 µg/ml), whereas the mean for levofloxacin was 4 µg/ml
(range, 1 to 32 µg/ml). Three ciprofloxacin-resistant strains
and nine
ciprofloxacin-susceptible strains were chosen for studies
that compared
the frequencies of occurrence of resistant mutants
upon exposure to
ciprofloxacin or levofloxacin. Approximately
1 in 4.58 ± 1.68 log
10 CFU grew on agar containing ciprofloxacin
at 4× the
MIC, whereas 1 in 5.74 ± 1.45 log
10 CFU grew on agar
containing levofloxacin at 4× the MIC (
P < 0.017).
Similar differences
were observed at 2× and 8× the MIC, although
insufficient data
were available to make a direct statistical
comparison due to
overgrowth on some plates with 2× the MIC of
ciprofloxacin and
no growth on plates with a 8× the MIC of
levofloxacin.
The lowest concentrations of ciprofloxacin that permitted no growth of
CFU from a 10
7 inoculum for the three
ciprofloxacin-resistant strains for which
MICs were 4, 16, and 16 µg/ml were 32, 64, and 128 µg/ml, respectively.
The corresponding
concentrations for levofloxacin were MICs of
1, 2, and 8 µg/ml and no
growth at 4, 8, and 32 µg/ml. The geometric
mean ciprofloxacin MIC
for the nine susceptible strains was 0.34
µg/ml (range, 0.12 to 0.5 µg/ml), whereas the mean MIC of levofloxacin
was 0.17 µg/ml (range,
0.12 to 0.25 µg/ml). The geometric mean
of the lowest concentration
of ciprofloxacin that permitted no
growth in susceptible strains was 10 µg/ml (range, 4 to 16 µg/ml),
whereas it was 2 µg/ml for
levofloxacin (range, 1 to 8 µg/ml).
The MICs for resistant mutants
obtained from four representative
susceptible strains after a single
passage on agar containing
either ciprofloxacin at 2× the MIC or
higher demonstrated that
regardless of which fluoroquinolone was used
to select for resistance,
the MICs of ciprofloxacin were approximately
2 to 2.5 times the
MICs of levofloxacin (Table
2).
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TABLE 2.
MICs for parents and first-step fluoroquinolone-resistant
mutants of four ciprofloxacin-susceptible S. aureus
clinical isolates
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|
Endocarditis experiments.
Levofloxacin was relatively
ineffective against both the penicillin-susceptible and the
penicillin-resistant strains of viridans group streptococci. The
densities of the penicillin-susceptible organisms in the vegetations of
rabbits treated with either 20- or 40-mg/kg doses of levofloxacin were
not statistically significantly different from those in the vegetations
of control rabbits and were inferior to those in the vegetations of
rabbits treated with penicillin (Table
3). The 40-mg/kg regimen was more active
than the 20-mg/kg regimen, indicating a dose response. Production of this difference, however, required peak concentrations in serum at the
upper limit of those achievable in humans (8). The efficacy of the 40-mg/kg b.i.d. dosage regimen of levofloxacin was no better and
was perhaps inferior to that of penicillin in rabbits infected with a
penicillin-resistant strain, although the results did not achieve
statistical significance. No further experiments were conducted with
the penicillin-resistant strain because power calculations indicated
that more than 60 rabbits would have to be treated to have an 80%
probability of observing a statistically significant result, which the
trend indicated would likely favor penicillin over levofloxacin. The
possibility that levofloxacin would be better than penicillin even for
rabbits infected with the penicillin-resistant strain seemed remote,
particularly given the results obtained with the penicillin-susceptible
strain.
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TABLE 3.
Titers in vegetations of rabbits treated with
levofloxacin or penicillin for penicillin-susceptible and -resistant
strains of viridans group streptococci
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|
In contrast to the results for streptococcal endocarditis, levofloxacin
was highly effective against
S. aureus infection.
Levofloxacin produced a mean reduction in bacterial density of
6 to 7.5 log
10 CFU/g compared to that for control rabbits infected
with methicillin-resistant strain 76. The vegetation titers in
control
rabbits and rabbits treated with vancomycin at 25 mg/kg
b.i.d.,
levofloxacin at 20 mg/kg b.i.d., and levofloxacin at 40
mg/kg b.i.d.
were 9.2 ± 0.5 (
n = 7), 5.8 ± 3.1 (
n = 8), 3.3 ±
2.1 (
n = 7), and
1.6 ± 1.4 (
n = 9) log
10 CFU/ml,
respectively.
For vancomycin and levofloxacin at 20 and 40 mg/kg,
P was <0.05
versus no treatment. Levofloxacin at the
20-mg/kg dose produced
a 2.5 log
10 greater reduction in CFU
than vancomycin, although
the difference did not achieve statistical
significance. Levofloxacin
at the 40-mg/kg dose, however, was
significantly more effective
than vancomycin (
P < 0.01).
The addition of rifampin to levofloxacin
was antagonistic in vivo.
Treatment with levofloxacin alone in
a separate experiment at the
20-mg/kg b.i.d. dosage resulted in
a mean vegetation titer of 2.3 ± 2.5 log
10 CFU/g (
n = 7), whereas
the
mean vegetation titer was 5.5 + 0.9 log
10 CFU/g
(
n = 7) for
levofloxacin plus rifampin at 5 mg/kg
b.i.d. (
P < 0.01). Emergence
of resistance, indicated
by growth of CFU on antibiotic-containing
agar, was not observed for
either
regimen.
The results for the methicillin-susceptible strain were similar to
those for the resistant strain. The vegetation titers in
control
rabbits and rabbits treated with nafcillin at 100 mg/kg
t.i.d.,
levofloxacin at 20 mg/kg b.i.d., and levofloxacin plus
rifampin at 5 mg/kg b.i.d. were 9.0 ± 0.3 (
n = 6), 0.0 ± 0.0 (
n = 8), 1.3 ± 1.6 (
n = 8),
and 3.3 ± 1.3 (
n = 9) log
10 CFU/g,
respectively.
For nafcillin and levofloxacin alone,
P
was < 0.001 versus the
control. Levofloxacin was about as
effective as nafcillin in reducing
vegetation titers (
P > 0.05 for levofloxacin alone versus nafcillin),
although all vegetations
from the nafcillin-treated group were
sterile, whereas four of the
eight levofloxacin-treated group
were sterile. Vegetation titers in
rabbits given the levofloxacin-rifampin
combination were
significantly higher than vegetation titers in
rabbits given
levofloxacin alone (
P < 0.05). Emergence of
resistance,
indicated by growth of CFU on antibiotic-containing agar,
was
not observed for either levofloxacin or
rifampin.
| |
DISCUSSION |
Lack of coverage of gram-positive cocci is considered an important
weakness in the antibacterial spectrum of fluoroquinolones. The MICs of
many fluoroquinolones for streptococci and staphylococci are just below
the breakpoint for resistance and are just below the concentrations
that are achievable in serum and tissues. Although ciprofloxacin has
been used successfully to treat a variety of respiratory tract and skin
and soft-tissue infections caused by gram-positive cocci (21,
23), the emergence of resistance and reports of treatment
failures (particularly in serious and often high-inoculum infections,
such as endocarditis, osteomyelitis, and meningitis) (2, 13, 16,
17, 24, 30, 33) have led to avoidance of fluoroquinolones for the
treatment of infections caused by gram-positive cocci.
Levofloxacin is slightly more active than ciprofloxacin against
streptococci and staphylococci, and higher peak concentrations in serum
can be achieved with the recommended doses. On the basis of this
profile, levofloxacin was developed and is approved by the U.S. Food
and Drug Administration for use in the treatment of community-acquired
pneumonia, acute maxillary sinusitis, and uncomplicated skin and
skin-structure infections caused by Streptococcus pyogenes,
Streptococcus pneumoniae, and S. aureus. Although
it is active in vitro against viridans group streptococci, the clinical significance of this activity is unknown. Our results with experimental streptococcal endocarditis indicate that this improved activity in
vitro may not translate to in vivo conditions, at least for serious
infections. The reason for this lack of efficacy is not clear.
Emergence of resistance, although not specifically sought in the
experiments with streptococci, is possible but seems unlikely given the
short period of exposure and the complete lack of response at the
20-mg/kg dose with no reduction in vegetation titers compared to the
titers in untreated controls. Notably, the MICs in THB were higher than
those in cation-supplemented MHB with lysed horse blood, suggesting
that viridans group streptococci may be intrinsically more resistant to
fluoroquinolones than other streptococcal species and that standard
susceptibility tests overestimate activity. Further studies with other
isolates are required to determine if this is a general phenomenon or
peculiar to the strains that we used. A lack of efficacy of
trovafloxacin against experimental viridans group streptococcal
endocarditis (27) suggests that the phenomenon could be a
general one and that fluoroquinolones, despite MICs in the susceptible
range, may not be efficacious as treatment for serious infections
caused by strains of viridans group streptococci.
Levofloxacin was at least as effective as comparator drugs and was
perhaps more effective that vancomycin against experimental S. aureus endocarditis. Unlike the experience with ciprofloxacin in
vitro and in animal models, in which emergence of resistance readily
occurs (11, 14, 15), no emergence of resistance occurred
with levofloxacin. These results are consistent with the findings of
other investigators who found no emergence of resistance during
levofloxacin exposure (11, 15, 22). In vitro levofloxacin
selected for resistant mutants at a 10-fold lower frequency than
ciprofloxacin, as others have reported (12). Levofloxacin
MICs for first-step mutants averaged 4 to 5 µg/ml, whereas they were
9 to 14 µg/ml for ciprofloxacin. Levofloxacin MICs for first-step
mutants tended to be below the peak concentrations in serum produced in
the experimental model and achievable in humans, whereas ciprofloxacin
MICs were well above the maximum achievable concentration in serum of
approximately 4 µg/ml. Thus, levofloxacin is slightly more active
than ciprofloxacin, selects for resistance at a lower frequency, and
achieves concentrations in vivo that require two mutations instead of
one mutation to produce resistance at that level. These properties
probably account for the failure to observe resistance in these
experiments, which produced an infection with a pretreatment inoculum
of approximately 107 CFU. Resistance might occur, however,
with higher bacterial burdens, particularly if these persist in the
presence of drug after long periods of exposure.
The results of these experiments are applicable only to fully
fluoroquinolone-susceptible strains of S. aureus. Many
methicillin-resistant strains are also ciprofloxacin resistant
(1). Cross-resistance to other fluoroquinolones is the rule,
and it is therefore unlikely that levofloxacin would be effective
either due to outright failure or due to the emergence of resistance.
Whether or not rifampin should be used in combination with levofloxacin
for the treatment of serious S. aureus infections is
unclear. The rationale for a rifampin-fluoroquinolone combination is
twofold: to take advantage of the excellent antistaphylococcal activity
of rifampin and to prevent the emergence of resistance, which can occur
with either antibiotic when it is used as a single agent. However, in
vitro and during the relatively short period of drug exposure for these
studies, the levofloxacin-rifampin combination was antagonistic, as has
been observed for cephalosporin-rifampin combinations against
experimental staphylococcal endocarditis (4). The
levofloxacin-rifampin combination was still bactericidal in vivo, and
it may be that over longer courses of treatment these differences would
disappear and be of no clinical significance. If the emergence of
resistance proves to be a problem, as it has been with other
fluoroquinolones in high-inoculum infections, osteomyelitis, or
foreign-body infections, there could very well be benefit to the
addition of rifampin to the regimen (2, 9, 34). Further
studies with other animal models of infection and clinical trials and
experience are required to resolve this issue and to define indications
for combination therapy.
| |
ACKNOWLEDGMENT |
This work was supported by a grant from Ortho-McNeil
Pharmaceutical Company.
| |
FOOTNOTES |
*
Corresponding author. Mailing address: Building 30, Room 410, 1001 Potrero Ave., San Francisco General Hospital, San
Francisco, CA 94110. Phone: (415) 206-5437. Fax: (415) 206-6015. E-mail: chipc{at}itsa.ucsf.edu.
| |
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Copyright © 1999, American Society for Microbiology. All rights reserved.
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Abstract
Introduction
