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Antimicrobial Agents and Chemotherapy, October 1999, p. 2372-2375, Vol. 43, No. 10
Service de Microbiologie,
Received 8 March 1999/Returned for modification 7 June
1999/Accepted 2 August 1999
The killing activities of trovafloxacin alone and in combination
with Streptococcus pneumoniae
meningitis carries a high rate of morbidity and mortality. Treatment
was previously based on penicillin G or aminopenicillins and on
extended-spectrum cephalosporins (21, 45), but clinical
failures with delayed sterilization of cerebrospinal fluid (CSF) have
been reported with amoxicillin and extended-spectrum cephalosporins
(4-6, 17, 19, 21, 42, 45). The combination of
extended-spectrum cephalosporins and vancomycin is recommended for the
treatment of penicillin-resistant pneumococcal meningitis (1,
39). However, isolates with a high level of resistance to
cefotaxime have recently been reported (13, 20, 28, 30).
Questions as to the appropriateness of this combination have been
raised, given the erratic penetration of vancomycin into the CSF and
the fact that local concentrations of extended-spectrum cephalosporins
are close to the MICs for such isolates (10).
Quinolones have not previously been used for the treatment of
community-acquired meningitis because of their limited activity against
S. pneumoniae. Trovafloxacin, a new fluoroquinolone, is reported to have good activity against S. pneumoniae that is
independent of the penicillin susceptibility of the organism and to
achieve a good concentration in CSF, contrary to older quinolones
(25, 44, 46). We tested the efficacy of trovafloxacin
against genotypically characterized isolates of S. pneumoniae that were recently recovered in France and that had
high-level resistance to amoxicillin (amoxicillin MICs, Twenty-nine serotyped clinical isolates of S. pneumoniae were studied. The serotypes were 6B, 14, 19F, and 23F.
The isolates were obtained from blood, middle-ear fluid, conjunctival
pus, or the lower respiratory tract between 1996 and 1997. The isolates were genotyped on the basis of the rRNA gene restriction pattern and
DNA fingerprinting of the pbp1a, pbp2b, and
pbp2x genes as described previously (12). The
MICs of penicillin G, amoxicillin, cefotaxime, cefpirome, ceftriaxone,
meropenem, trovafloxacin, rifampin, and vancomycin were determined by
the dilution method on Mueller-Hinton agar supplemented with 5% sheep
blood as described in 1997 by the National Committee for Clinical
Laboratory Standards (NCCLS) (33). The replicator prong
delivered approximately 104 CFU per spot. Killing activity
was determined for 20 strains that were genotypically different on the
basis of the rRNA gene restriction pattern and/or DNA fingerprinting of
the pbp1a, pbp2b, and pbp2x genes.
Killing activity was determined in microtiter plates (CML, Nemours,
France) with an early-logarithmic-phase culture adjusted to
approximately 106 to 107 CFU/ml in
Mueller-Hinton broth supplemented with 5% lysed defibrinated sheep
blood as described previously (11, 15). An incubation period
of 6 h was chosen because most of the strains underwent spontaneous autolysis in vitro. The antimicrobial agents were used at
the mean clinically achievable peak concentration in CSF after
administration of doses currently recommended or proposed for the
treatment of meningitis, as follows: amoxicillin, 6 µg/ml (35); cefotaxime, 5 µg/ml (10); ceftriaxone, 5 and 8 µg/ml (regimens of 50 and 100 mg/kg of body weight per day,
respectively) (24, 26); cefpirome, 4 µg/ml
(47); meropenem, 3 µg/ml (8); trovafloxacin, 1 µg/ml (2, 7); rifampin, 1 µg/ml (24, 31); and
vancomycin, 2 µg/ml (10). Each The penicillin, amoxicillin, cefotaxime, ceftriaxone, cefpirome,
meropenem, rifampin, vancomycin, and trovafloxacin MICs are reported in
Table 1. According to NCCLS criteria
(32), the strains were classified as resistant to penicillin
(MICs, The mean killing activities of the antibiotics alone and in combination
are reported in Table 2. The strains were
classified into three groups as susceptible, intermediate, or resistant
to ceftriaxone according to NCCLS breakpoints. Against strains that were susceptible or intermediate to ceftriaxone, the best killing activity of a
0066-4804/99/$04.00+0
Copyright © 1999, American Society for Microbiology. All rights reserved.
Killing Activities of Trovafloxacin Alone and in Combination
with
-Lactam Agents, Rifampin, or Vancomycin against
Streptococcus pneumoniae Isolates with Various
Susceptibilities to Extended-Spectrum Cephalosporins at Concentrations
Clinically Achievable in Cerebrospinal Fluid
ABSTRACT
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Abstract
Introduction
Materials and Methods
Results and Discussion
References
-lactam agents (extended-spectrum cephalosporins, meropenem), rifampin, or vancomycin were evaluated against 20 genotypically characterized Streptococcus pneumoniae isolates for which
amoxicillin MICs were 
4 µg/ml (cefotaxime MICs, 4 µg/ml for six
strains) at concentrations clinically achievable in cerebrospinal
fluid. At 6 h the mean killing activity of trovafloxacin alone
(range, 2.6 to 2.9 log10 CFU/ml) did not vary significantly
according to the susceptibility of the strains to -lactam agents.
The activities of trovafloxacin or vancomycin added to the -lactam
agents and the combination trovafloxacin-vancomycin were additive or
indifferent. Against the ceftriaxone-resistant isolates, the killing
activity of the combination of a -lactam agent and trovafloxacin did
not differ significantly from that of a -lactam agent and vancomycin.
INTRODUCTION
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Abstract
Introduction
Materials and Methods
Results and Discussion
References
4 µg/ml)
but for which cefotaxime MICs were or were not 4 µg/ml. We used the
time-kill curve method with clinically achievable CSF antibiotic
concentrations and a large inoculum to mimic the situation encountered
in the clinical setting (3). Trovafloxacin was tested alone
and in combination with amoxicillin, cefotaxime, ceftriaxone,
cefpirome, meropenem, vancomycin, or rifampin. Combinations of
trovafloxacin with a -lactam agent, rifampin, or vancomycin were
compared with the combination of rifampin or vancomycin with a
-lactam agent, used for the treatment of penicillin-resistant pneumococcal meningitis (1, 39).
MATERIALS AND METHODS
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Abstract
Introduction
Materials and Methods
Results and Discussion
References
-lactam agent was tested
alone and in combination with trovafloxacin, rifampin, or vancomycin.
Colonies were counted by the quadrant method after 1:10 sample dilution
by plating 50 µl of each dilution onto blood agar plates with a
Spiral Plater system and incubating them for 18 h at 37°C with
5% CO2. The detection limit was 4,000 CFU/ml. With the
dilutions and the Spiral Plater system used, antimicrobial carryover
does not interfere with bacterial counts (48). The microdilution method was initially compared with the macrodilution method with five strains. The mean difference between the two methods
in the bactericidal activities of the antibiotics tested against each
strain was 0.2 log10 CFU/ml, with a range of 
0.15 to +0.5
log10 CFU/ml (no significant difference by Student's
paired t test). Additivity and indifference were defined as
a less than 10-fold change (increase or decrease) in killing at 6 h with the combination in comparison with that of the most active
single agent used alone (14). Since the drugs were tested at
a concentration which affected the growth curve of the organism when
each drug was tested alone, synergy could not have been detected.
Results are expressed as means ± standard deviations. Student's
paired t test was used to test for statistical significance,
and P values of less than 0.05 were considered significant.
RESULTS AND DISCUSSION
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Abstract
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Materials and Methods
Results and Discussion
References
2 µg/ml), resistant to amoxicillin (MICs, 2 µg/ml),
intermediate (0.5 µg/ml 
MIC < 1 µg/ml) or resistant
(MICs, 1 µg/ml) to meropenem, susceptible, intermediate (0.5 µg/ml < MIC 1 µg/ml), or resistant (MICs, 2 µg/ml) to
cefotaxime and ceftriaxone, susceptible (MICs, 1 µg/ml) to
vancomycin and rifampin, and susceptible to trovafloxacin (MICs, 1
µg/ml). However, the NCCLS breakpoints for amoxicillin and trovafloxacin are for nonmeningeal infections. The penicillin MIC at
which 90% of isolates are inhibited (MIC90) was half that of amoxicillin. For seven strains the cefotaxime MICs were equal to or
1 dilution higher than the corresponding penicillin MICs. For 17 strains the ceftriaxone MICs were lower than the cefotaxime MICs
(difference of 2 to 4 dilutions for four isolates).
TABLE 1.
Distribution of MICs of penicillin, amoxicillin,
cefotaxime, cefpirome, ceftriaxone, meropenem, vancomycin, rifampin,
and trovafloxacin for 29 S. pneumoniae isolates
-lactam agent used alone was obtained with meropenem (P < 0.05). Against the resistant strains, we observed
no significant difference in the killing activities of the -lactam
agents used alone, excluding amoxicillin but including ceftriaxone at 5 and 8 µg/ml. However, with cefotaxime alone, for two resistant
strains we observed growth at the concentration clinically achievable in CSF; the cefotaxime MIC for these two strains was 8 µg/ml. The
killing activity of trovafloxacin alone did not vary significantly (P > 0.05) according to the strain's susceptibility
to extended-spectrum cephalosporins. For all the strains (including the
two for which the cefotaxime MIC was 8 µg/ml), the effect of the
addition of trovafloxacin or vancomycin to the cephalosporins or to
meropenem was additive or indifferent, while the effect of the addition of rifampin (except to meropenem) was indifferent only against the
strains that were intermediate or resistant to ceftriaxone. The
addition of rifampin to the cephalosporins resulted in at least a
10-fold decrease in killing of the strains that were susceptible to
ceftriaxone. Similarly, the addition of rifampin to meropenem resulted
in a more than 10-fold decrease in the killing of strains that were
susceptible or intermediate to ceftriaxone. Similar results were
obtained for all strains when rifampin was added to trovafloxacin. The
trovafloxacin-vancomycin combination was indifferent. Against the
ceftriaxone-resistant isolates, the killing activity of the
combinations meropenem-trovafloxacin or extended-spectrum cephalosporin-trovafloxacin was not significantly different from that
of the combination meropenem-vancomycin or extended-spectrum cephalosporin-vancomycin (P > 0.05).
TABLE 2.
Killing activities of amoxicillin, cefotaxime,
ceftriaxone, cefpirome, and meropenem alone or in combination with
vancomycin, rifampin, or trovafloxacin after 6 h of incubation,
according to ceftriaxone susceptibilitya
Changes in -lactam susceptibility among S. pneumoniae
isolates have led to recommendations that high-dose cefotaxime or
ceftriaxone in combination with vancomycin be used to treat meningitis
in children (1, 39). However, the recent emergence and
spread of strains with high-level resistance to extended-spectrum
cephalosporins may compromise the efficacy of this treatment in
patients with meningitis (13, 20, 28, 30). So far, S. pneumoniae isolates with high-level resistance to
extended-spectrum cephalosporins have been reported in Spain, the
United States, and the United Kingdom (20, 28, 30).
Recently, pneumococci with high-level resistance to amoxicillin (MICs,
4 µg/ml) and to cefotaxime (MICs, 4 µg/ml) have also been
identified in France (13). Interestingly, the penicillin
MIC90 for those isolates was half that of amoxicillin, suggesting the emergence of high-level resistance to amoxicillin within
preexisting penicillin-resistant clones (13). Although none
of the strains were isolated from CSF, their serotypes were those
usually recovered from patients with meningitis. Given the reported
spread of clonal epidemic strains (12, 28-30, 41), the
killing activities of the antibiotics and their combinations were
tested only against the 20 genotypically different strains among the 29 isolates. In our study the MIC90s of cefotaxime and ceftriaxone were 4 and 2 µg/ml, respectively. Mean clinically achievable peak concentrations in CSF are 5 µg of cefotaxime per ml
after the administration of 300 mg/kg/day and 5 and 8 µg of ceftriaxone per ml after the administration of 50 and 100 mg/kg/day, respectively (10, 24, 26). Even though the difference is minimal, such a difference in antibiotic susceptibility may lead to
delayed sterilization of CSF, as studies of experimental pneumococcal meningitis have shown a correlation between peak CSF antibiotic concentrations and maximal bactericidal efficacy (27, 43). In agreement with the MICs, amoxicillin alone showed a nonefficient killing activity. We observed no significant difference in the killing
activities of ceftriaxone when it was tested at 5 and 8 µg/ml. This
may be explained by the short incubation period and the time-dependent
actions of -lactam drugs. The addition of vancomycin to
cephalosporins or meropenem was additive or indifferent. However,
against the two strains for which the cefotaxime MIC was 8 µg/ml, the
vancomycin-cefotaxime combination prevented growth at concentrations
clinically achievable in CSF. This is consistent with at least additive
activity of extended-spectrum cephalosporin-vancomycin combinations in
an experimental model of pneumococcal meningitis (16). The
use of rifampin has been proposed against such strains for which the
expected clinical or bacteriologic response may be delayed
(1). In our study the addition of rifampin to cephalosporins resulted in at least a 10-fold reduction in the killing of
ceftriaxone-susceptible strains, while this combination was indifferent
against resistant or intermediate strains. Note, however, that the
rifampin-cephalosporin combination is effective in the rabbit model of
pneumococcal meningitis (38).
All the isolates were susceptible to trovafloxacin, regardless of their
-lactam susceptibilities, as reported previously (24, 36,
39). The killing activity of trovafloxacin ranged from 2.6 to 2.9 log10 CFU/ml. Studies based on experimental models of
meningitis have indicated that trovafloxacin has effective bactericidal
activity in CSF against penicillin- or cephalosporin-resistant pneumococci (22, 37, 40). However, selection of
antibiotic-resistant mutants may be a cause for concern when using
quinolone antibiotics alone, and use of a drug combination may be
required to prevent the emergence of resistance. This is why we tested
trovafloxacin in combination. Very few data on the combination of
fluoroquinolones with other drugs against S. pneumoniae are
available. In vitro, the rifampin-fluoroquinolone combination was found
to be indifferent in a study by Klugman et al. (23), while
Giron et al. (18) found that rifampin reduced the killing
activities of quinolones, as supported by our results. However, in an
experimental model of pneumococcal meningitis, Kim et al.
(22) found that the trovafloxacin-rifampin combination was
indifferent. Nicolau et al. (34) reported that the
trovafloxacin-vancomycin and trovafloxacin-ceftriaxone combinations were generally indifferent or synergistic against ceftriaxone-resistant S. pneumoniae strains. In our study both combinations were
indifferent against all the ceftriaxone-resistant strains. This
discrepancy between our data and those from the study of Nicolau et al.
(34) may be explained by methodology considerations (use of
the time-kill curve in our study and the checkerboard method in the
work of Nicolau et al. [34]), although it has been
suggested that the time-kill method is more predictive of the outcome
of antibiotic treatment (9, 40). Against the
ceftriaxone-resistant pneumococcal isolates, no significant difference
in killing activity was observed between the meropenem-vancomycin or
extended-spectrum cephalosporin-vancomycin combination (the
recommended treatment) on the one hand and the meropenem-trovafloxacin
or extended-spectrum cephalosporin-trovafloxacin combination on the
other hand. The last two combinations may thus prove to be satisfactory
alternatives for patients who do not tolerate vancomycin. Experimental
studies and clinical trials are required to corroborate our in vitro data.
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FOOTNOTES |
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* Corresponding author. Mailing address: Service de Microbiologie, Hôpital R. Debré, 48 Bd. Sérurier, 75019 Paris, France. Phone: 33 (1) 40 03 23 40. Fax: 33 (1) 40 03 24 50. E-mail: edouard.bingen{at}rdb.ap-hop-paris.fr.
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Antimicrobial Agents and Chemotherapy, October 1999, p. 2372-2375, Vol. 43, No. 10
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