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Antimicrobial Agents and Chemotherapy, April 1998, p. 942-944, Vol. 42, No. 4
Service de
Microbiologie1 and
Service de
Biostatistiques et Informatique Médicale,
Received 8 July 1997/Returned for modification 14 October
1997/Accepted 4 January 1998
The activities of meropenem, imipenem, ceftriaxone, and vancomycin
were evaluated against 80 penicillin-susceptible and -resistant Streptococcus pneumoniae strains. Meropenem, imipenem,
ceftriaxone, and vancomycin MICs at which 90% of the isolates are
inhibited were 0.5, 0.25, 1, and 0.25 µg/ml, respectively. Against
penicillin-resistant strains, the best killing activity at
cerebrospinal fluid concentrations was obtained with imipenem and
ceftriaxone-vancomycin. However, while the killing activity of imipenem
was significantly greater than that of meropenem, no significant
difference was observed between the activities of meropenem and
ceftriaxone-vancomycin.
Meningitis caused by
Streptococcus pneumoniae carries a high rate of morbidity
and mortality in both children and adults. Treatment used to be based
on penicillin G or aminopenicillins, but the marked increase in
pneumococcal resistance to penicillins in the 1980s (20) led
to the use of extended-spectrum cephalosporins as empiric therapy for
acute bacterial meningitis (15, 28). There have now been
reports of S. pneumoniae strains resistant to
extended-spectrum cephalosporins associated with clinical failure and
delayed sterilization of cerebrospinal fluid (CSF) (6, 7, 13, 16,
26). For example, in France, the rate of isolation of S. pneumoniae strains for which the cefotaxime or ceftriaxone MICs
were greater than >0.5 µg/ml from CSF in patients with meningitis in
1995 was 16.4% (14). This means that antibiotic
combinations or new classes of antibacterial agents must be assessed
for the treatment of pneumococcal meningitis.
The carbapenem class is highly active against common meningeal
pathogens. Imipenem is the first member of this class, and its MICs
against penicillin-resistant pneumococci are lower than those of other
(This work was presented in part at the 36th Interscience Conference on
Antimicrobial Agents and Chemotherapy, New Orleans, La., 15 to 18 September 1996.)
Eighty serotyped S. pneumoniae strains were studied. All
were isolated from CSF of children with meningitis between 1987 and 1997. The MICs of penicillin G, meropenem, imipenem, ceftriaxone, and
vancomycin were determined by the dilution method on Mueller-Hinton agar supplemented with 5% sheep blood as recommended by the National Committee for Clinical Laboratory Standards (23). The
replicator prong delivered approximately 104 CFU per spot
onto a blood agar plate. The concentration at which 90% of the strains
were inhibited was defined as the MIC90. Killing activity
against 26 previously described strains (11) for which the
penicillin G MICs were increased (>0.125 to 2 µg/ml), was determined
with microtiter plates (CML, Nemours, France), with an early-log-phase
culture adjusted to approximately 106 to 107
CFU/ml in Mueller-Hinton broth supplemented with 5% lysed defibrinated sheep blood during 5 h of incubation (10). This
incubation period was chosen because most of the strains underwent a
spontaneous autolysis in vitro. The antimicrobial agents were used at
the mean CSF concentration (CC) and fractions of it (CC/2 and CC/4) after administration (two doses at 4 h) of doses currently
recommended for the treatment of meningitis, as follows: meropenem, 3 µg/ml (8); imipenem-cilastatin, 2 µg/ml each
(21); ceftriaxone, 8.8 µg/ml (17); vancomycin,
2 µg/ml (9). Ceftriaxone was tested alone and in
combination with vancomycin, as recommended for the treatment of
penicillin-resistant pneumococcal meningitis (24). Colonies
were counted by the quadrant method after 1:10 dilution, by plating of
50 µl of each dilution onto blood agar plates with a Spiral Plater
system and incubation for 18 h at 37°C with 5% CO2.
The detection limit was 4,000 CFU/ml. With the dilutions and the Spiral
system used, antimicrobial agent carryover does not interfere with
bacterial counts (30). The microdilution method used was
initially compared with the macromethod with five strains. The mean
difference in bactericidal activity of the antibiotics tested for each
strain between the two methods was 0.2 log10 CFU/ml, with a
range of The penicillin, meropenem, imipenem, ceftriaxone, and vancomycin MICs
are reported in Table 1. The serotypes of
strains for which penicillin MICs were increased were 6A, 6B, 9V, 14, 15C, 19A, 19F, 23A, and 23F. According to National Committee for
Clinical Laboratory Standards criteria, strains were classified as
intermediate (0.1 µg/ml The killing activities of the antibiotics at the mean CSF antibiotic
concentration and fractions of it are reported in Table 2. With all antibiotics tested, alone or
in combination, bactericidal activity was observed at 5 h against
all strains with penicillin G MICs of <0.5 µg/ml. Against strains
with penicillin G MICs of
0066-4804/98/$04.00+0
Copyright © 1998, American Society for Microbiology. All rights reserved.
Comparative In Vitro Killing Activities of Meropenem, Imipenem,
Ceftriaxone, and Ceftriaxone plus Vancomycin at
Clinically Achievable Cerebrospinal Fluid Concentrations
against Penicillin-Resistant Streptococcus pneumoniae
Isolates from Children with Meningitis
ABSTRACT
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-lactam agents (27). However, the use of imipenem in
meningitis is limited by its adverse effects (29).
Meropenem, a novel carbapenem antibiotic structurally related to
imipenem, but with fewer adverse effects, penetrates efficiently into
the central nervous system (8). Because meropenem is
reported to have good activity against penicillin-intermediate and
-resistant S. pneumoniae strains (27), we tested
its activity against such strains isolated from children with
meningitis. We used the time-killing curve method with clinically
achievable CSF antibiotic concentrations and a large inoculum to mimic
clinical conditions (4). Meropenem was compared to imipenem
and, against the most-resistant strains, to ceftriaxone alone and to
the ceftriaxone-vancomycin combination, which is recommended for the
treatment of penicillin-resistant pneumococcal meningitis
(24).
0.15 to +0.5 log10 CFU/ml. Student's paired
t test shows that there was no significant difference
between the two methods. Bactericidal activity was defined as a
reduction of more than 3 log10 CFU/ml after 5 h of
incubation. Results were expressed as means ± standard
deviations. One-way analysis of variance was used to compare the
killing activities of the antibiotics. Post hoc tests with Bonferroni
correction were used to test the killing activities of all possible
pairs of antibiotics (P values were two tailed and were
considered significant when probabilities were less than 0.012).
MIC 1 µg/ml) or resistant
(MIC of 
2 µg/ml) to penicillin, susceptible (MIC of 0.12 µg/ml)
or intermediate (0.25 µg/ml MIC 0.5 µg/ml) to
meropenem (data not yet published) and imipenem, susceptible (MIC
of 0.05 µg/ml) or intermediate (MIC of 1 µg/ml) to
ceftriaxone, and susceptible (MIC of 1 µg/ml) to vancomycin.
The meropenem, imipenem, ceftriaxone, and vancomycin MIC90s
were 0.5, 0.25, 1, and 0.25 µg/ml, respectively.
TABLE 1.
Susceptibility of pneumococcal CSF isolates to
antimicrobial agents by penicillin susceptibility
1 µg/ml, killing was significantly lower
for the three CSF concentrations for each agent (P = 0.008). The strains for which penicillin G MICs were 2 µg/ml were
intermediate to ceftriaxone. The best killing activity against these
strains was obtained at 5 h with imipenem and
ceftriaxone-vancomycin at the mean concentrations of antibiotic in the
CSF (no significant difference between the two [P = 0.04]). However, while the killing activity of imipenem was
significantly greater than that of meropenem against the strains for
which the penicillin G MICs were highest (P = 10
4), no significant difference was observed between
meropenem and ceftriaxone-vancomycin (P = 0.05).
Ceftriaxone alone was the least active antibiotic (P > 0.01). For all antibiotics, whether with the mean concentrations in the
CSF or fractions of it, we did not observe a significant difference in
the killing (P = 0.7).
TABLE 2.
Killing activity of meropenem, imipenem, ceftriaxone, and
ceftriaxone-vancomycin against the 26 S. pneumoniae isolates
according to the penicillin G MIC
Changes in -lactam susceptibility among S. pneumoniae
isolates have led to recommendations that high-dose cefotaxime or
ceftriaxone, combined with vancomycin, be used to treat meningitis in
children (24). Alternatively, new therapeutic compounds must
be evaluated. In our study, the MIC90s of meropenem,
imipenem, ceftriaxone, and vancomycin of penicillin-sensitive,
-intermediate, and -resistant pneumococci were consistent with those
reported elsewhere (3, 27). On the basis of the MICs,
imipenem was the most active -lactam agent. The MIC90 of
meropenem for penicillin-resistant pneumococci was 0.5 µg/ml; it is
half that of ceftriaxone. Although small, such a difference may
influence the therapeutic response in meningitis, because the
concentration of -lactams in CSF is close to the relevant MICs
(12). This is even more important in dexamethasone
administration, which by reducing meningeal inflammation, reduces
antibiotic diffusion into the CSF (25).
Optimal treatment requires rapid bactericidal activity within the CSF, because delayed CSF sterilization is associated with a poor prognosis and a high risk of sequelae in children (19). We therefore used the time-killing curve method after 5 h of incubation with clinically achievable concentrations in CSF (CC, CC/2, and CC/4) to predict antimicrobial activity in CSF during the first few hours of treatment. The best killing activity of imipenem is in agreement with those of previous reports (1, 10). However, its use for treatment of meningitis is limited because of its seizure activity (29). In contrast, with meropenem, no greater incidence of neurological toxicity in patients with meningitis was reported (5, 18). Meropenem at the mean CSF concentration and fractions of it gave a mean killing activity superior to 2.3 log10 CFU/ml against penicillin-resistant pneumococcal strains after 5 h of incubation. Barakett et al. reported comparable results, despite the use of a different methodology (1, 2). Meropenem had significantly superior killing activity to that of ceftriaxone used alone. Nairn et al. reported similar results in experimental pneumococcal meningitis with resistant strains (22). The bactericidal activity of meropenem was similar to that of ceftriaxone-vancomycin. However, there are concerns over the moderate penetration of the glycopeptide with significant interpatient variability (5). Meropenem has already been tested for the treatment of meningitis in both adults and children (5, 18), but only a very few data for patients infected by cephalosporin-resistant pneumococci are available. Our in vitro data suggest that meropenem may be effective in the treatment of cephalosporin-resistant pneumococcal meningitis; more clinical data are required in this setting.
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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, April 1998, p. 942-944, Vol. 42, No. 4
0066-4804/98/$04.00+0
Copyright © 1998, American Society for Microbiology. All rights reserved.
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