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Infect Dis Clin N Am 18 (2004) 581602

Antimicrobial agents in the treatment


of bacterial meningitis
Scott W. Sinner, MDa, Allan R. Tunkel, MD, PhDb,*
a

Division of Infectious Diseases, Drexel University College of Medicine,


245 North 15th Street, Mail Stop 487, Philadelphia, PA 19102-1101, USA
b
Department of Medicine, Drexel University College of Medicine,
245 North 15th Street, Mail Stop 487, Philadelphia, PA 19102-1101, USA

Although signicant advances have been made in the management of


bacterial meningitis, the disease has unacceptably high morbidity and
mortality [1]. Clinical success in treating patients with bacterial meningitis
relies on familiarity with the pharmacologic principles of the commonly
used antimicrobial agents, which includes penetration of drug into the
cerebrospinal uid (CSF) and the drugs activity in purulent CSF. These
properties, along with the mode of administration of the drug and the
intrinsic pharmacodynamic relationships of CSF drug concentrations to
bactericidal activity, help to dene the potential ecacy of a given
antimicrobial agent in the treatment of bacterial meningitis. Much of what
is known about these principles has been derived from the experimental
rabbit model of meningitis, rst described three decades ago [2].
Many changes in the epidemiology and etiology of bacterial meningitis
have dictated modications in antimicrobial therapy over the last several
years. One of the most important changes has been the dramatic decline in
the incidence of meningitis caused by Haemophilus inuenzae type b, as
a result of the widespread use of the H inuenzae type b conjugate vaccine
[3]. Since licensure of the pneumococcal conjugate vaccine, there has also
been a dramatic decline in the incidence of invasive pneumococcal infections
[4], which may further change the epidemiology of pneumococcal meningitis
in areas where vaccine use has been implemented. Another important
development has been the rise in the incidence of antimicrobial-resistant
meningeal pathogens, particularly Streptococcus pneumoniae, which has

* Corresponding author. Oce of Admissions, Drexel University College of Medicine,


2900 Queen Lane, Philadelphia, PA 19129.
E-mail address: allan.tunkel@drexel.edu (A.R. Tunkel).
0891-5520/04/$ - see front matter 2004 Elsevier Inc. All rights reserved.
doi:10.1016/j.idc.2004.04.005

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been observed in the United States and throughout the world [5]. As a result
of this increasing problem of drug resistance, research in recent years has
focused on nding new antimicrobial agents for the therapy of meningitis
caused by penicillin- and cephalosporin-resistant pneumococci.
Rather than attempt to review all aspects of the therapy of bacterial
meningitis, this article reviews the pharmacologic principles of use of
antimicrobial therapy, summarizes the specic animal data for selected
antimicrobial agents, and gives specic recommendations for therapy of
bacterial meningitis based on the isolated meningeal pathogen.

Basic pharmacologic principles


Cerebrospinal uid penetration
The rst pharmacologic factor that determines whether an antimicrobial
agent is able to clear bacteria from the CSF is the drugs penetration across
the blood-brain barrier and into the subarachnoid space. In general, the
following drug characteristics aect the blood-brain barrier penetration and
subsequent CSF concentrations of the antimicrobial agent [1,69]:
1. Lipophilic agents (eg, uoroquinolones, chloramphenicol [Chloromycetin], rifampin [Rifadin, Rimactane], and the sulfonamides) diffuse
across the blood-brain barrier by transcellular pathways, reach peak CSF
concentrations (Cpeak) quickly, and penetrate relatively well, even in the
absence of meningeal inammation. Hydrophilic agents (eg, b-lactams
and vancomycin [Vancocin]), must enter the CSF through paracellular
tight junctions, reach Cpeak more slowly, and have decreased penetration
(sometimes markedly so) if the meninges are not inamed.
2. Drugs with a low molecular weight and relatively simple structure (eg,
the uoroquinolones and rifampin) enter the CSF more readily than
larger compounds or those with more complex chemical structures (eg,
vancomycin).
3. Drugs that are highly protein-bound in serum (eg, ceftriaxone [Rocephin])
display a lower degree of CSF penetration, because only the unbound
fraction of the drug is available to cross the blood-brain barrier.
4. The choroid plexus contains an active transport system that can pump
penicillins and cephalosporins (and potentially aminoglycosides and
uoroquinolones) from the CSF into the blood. Conversely, an active
transport system present in central nervous system capillaries can
transport penicillins and cephalosporins from the blood into the CSF,
although this systems low afnity and capacity for drugs limits its
importance in being able to achieve adequate CSF concentrations of
a specic agent [10].
The percent CSF penetration of an individual antimicrobial agent may be
measured in a number of dierent ways. If simultaneous CSF and serum

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concentrations are measured to determine the percent penetration calculated


by the formula, (CSF concentration/serum concentration)  100, the results
may be misleading because the concentration-time curve of an antimicrobial
in CSF usually lags behind that in serum [8]. This was demonstrated in
a study of pediatric patients with meningitis in which the CSF penetration of
meropenem (Merrem) was calculated at 7.8% when measured within 2
hours of antimicrobial administration, but was recalculated at 23.9% when
measured after 2 hours [11]. Alternatively, one can calculate a percent CSF
penetration based on the Cpeak attained in both serum and in CSF. This
method is the one by which many of the published CSF penetration gures
were determined (Table 1). A more meaningful parameter for many
antimicrobial agents is the ratio of the area under the concentration curve
(AUC) in CSF to that in serum. This method, however, requires multiple
concentration measurements in both CSF and serum, and is impractical for
human pharmacokinetic studies.
Antimicrobial activity in purulent cerebrospinal uid
The second pharmacologic property of an antibacterial that helps to
determine its usefulness in treating meningitis is the activity of that agent in
the purulent environment of infected CSF. This may depend on a number of
parameters [1,69]:
1. The decreased CSF pH in bacterial meningitis contributes, at least in part,
to the poor response seen with aminoglycosides, and perhaps also with
clarithromycin (Biaxin), in experimental animal models of meningitis.
Table 1
Pharmacologic parameters of common antimicrobial agents used to treat bacterial meningitis
Percent CSF penetration

Half-life (hours) in humans

Animals

Humans

Serum

CSF

Penicillin G
2.66
Ampicillin
818.4
Ceftriaxone
2.712
Gentamicin
18.928.7
Ciprooxacin
1527.5

510
1335
1.516
030
637

0.5
0.71.4
5.410.9
23
2.54

ND
2.13.6
16.8b
ND
4.37.2b

Vancomycin
Rifampin
TMP-SMX

153
756
2435

48
25.8
11/9

2.84.1b
9.121b
ND

Drug

8.413
17.222
1739

Pharmacologic
a
Parameters
Time above MBC
Time above MBC
Time above MBC
CSFpeak/MBC
Time above MBC,
AUC-MBC
Time above MBC
Paradoxicalc
ND

Abbreviations: AUC, area under the concentration curve; CSF, cerebrospinal uid; MBC,
minimum bactericidal concentration; ND, not determined; TMP-SMX, trimethoprim-sulfamethoxazole.
a
Parameters that are most related to eective bactericidal activity in meningitis models.
b
Half-lives determined in patients with external ventriculostomies.
c
Paradoxical dose-response relationship has been seen with rifampin; see text for details.
Data from references [8,1226].

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2. Highly protein-bound antimicrobial agents may have somewhat diminished activity as a result of the high CSF protein concentrations
often seen in bacterial meningitis, which result in decreased CSF
concentrations of free drug available to kill bacteria.
3. The relatively slow growth of bacteria in CSF may reduce the activity of
b-lactam agents, which are dependent on a brisk bacterial growth rate
for maximal activity.
4. Some antibacterials may be metabolized in the CSF space to less active
compounds (eg, cephalothin [Kein] to desacetylcephalothin). In
contrast, some antimicrobial agents still retain signicant antibacterial
activity after metabolism (eg, cefotaxime [Claforan] to desacetylcefotaxime) that may be equal to that of the parent compound.
5. Certain antimicrobial combinations may be synergistic when co-administered (eg, ampicillin [Omnipen, Principen] plus gentamicin [Garamycin]
for Listeria monocytogenes and Streptococcus agalactiae meningitis),
whereas others may be antagonistic (eg, chloramphenicol combined with
either penicillin or gentamicin).
6. The activity of some antimicrobial agents against certain bacterial strains
may be decreased in the presence of high bacterial densities, the so-called
inoculum effect, in which high bacterial densities may result in
signicant increases in the minimum inhibitory concentration (MIC) of
certain antimicrobial agents against a specic microorganism.
Mode of administration
The choice of mode of antimicrobial administration is a third factor
inuencing the potential success of a given agent in the treatment of
bacterial meningitis [1,6]. Intravenous antimicrobial agents may be administered by intermittent bolus or by continuous infusion. The success of one
method over another depends on the specic agent and the microorganism
being studied because, just as in serum, various CSF pharmacodynamic
parameters are important for dierent antibacterial agents (see Table 1)
[8,1226]. Bolus administration of an antimicrobial agent leads to a higher
Cpeak, but may not maintain concentrations above the microorganisms
minimum bactericidal concentration (MBC) for the entire dosing interval,
whereas continuous infusion produces a lower Cpeak, but may maintain
concentrations above the MBC during nearly 100% of the dosing interval.
The MBC, rather than the MIC, is often used in experimental meningitis
studies, because of the need for true bactericidal activity in this environment
where there is relatively little immune system function (ie, as a result of low
CSF concentrations of immunoglobulins and complement).
Antimicrobial pharmacodynamics in cerebrospinal uid
A nal factor that may contribute to the response to antimicrobial
therapy in bacterial meningitis is pharmacodynamics, which is concerned

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585

with the time course of antimicrobial activity at the site of infection (see
Table 1). For b-lactam agents, the following pharmacodynamic measures
seem to be interrelated: the ratio of Cpeak to the MBC for the isolate, the
ratio of the CSF AUC to the MBC, and the time that the b-lactam CSF
concentration remains above the MBC [8]. In a study of ceftriaxone therapy
in the experimental rabbit model of cephalosporin-resistant pneumococcal
meningitis, these three parameters were interconnected, although the time
above the MBC was the only factor that was independently correlated with
the bacterial killing rate (BKR) [27]; maximal BKR was only attained when
the CSF ceftriaxone concentration exceeded the MBC for 95% to 100% of
the dosing interval. Although not completely conrmed, vancomycin killing
in CSF also seems to be mostly a time-dependent process [12].
For aminoglycosides, the concentration-dependent killing observed in
serum is also seen in CSF, as was demonstrated in an experimental model of
Escherichia coli meningitis [20]. The CSF pharmacodynamics of uoroquinolones is more complicated, however, in that features of both timedependency and concentration-dependency have been observed. The
expected concentration-dependency of uoroquinolone killing was demonstrated in an experimental rabbit model of pneumococcal meningitis [21],
but time above the MBC was also found to be important for bacterial killing
by both trovaoxacin (Trovan) [28] and gatioxacin (Tequin) [29] in later
experimental studies. The pharmacodynamics of rifampin are unusual, in
that a paradoxical decrease in BKR has been demonstrated at infusion rates
of 20 mg/kgh compared with 10 mg/kgh [13], possibly as a result of the
need for some amount of ongoing protein synthesis to maintain bacterial
killing.
Other pharmacodynamic properties of antimicrobial agents in CSF that
have been examined are the postantibiotic eect, which describes delayed
regrowth of bacteria after removal of an antimicrobial agent [6], and the
post sub-MIC eect, which describes continued suppression of bacterial
regrowth once antimicrobial concentrations fall below the MIC [8]. In in
vitro studies, most antibacterial agents display a signicant postantibiotic
eect against gram-positive organisms, whereas only aminoglycosides,
uoroquinolones, and carbapenems exert a postantibiotic eect against
gram-negative organisms [30]. Studies of ampicillin in experimental animal
models of pneumococcal meningitis suggest that slowly declining sub-MIC
antimicrobial concentrations in CSF are important in delaying bacterial
regrowth, but that a true postantibiotic eect is unlikely to exist to any
signicant degree in CSF [31,32].
Experimental data for selected antibacterial agents
It is beyond the scope of this article to discuss all antimicrobial agents that
have been studied in experimental animal models of bacterial meningitis.
Rather, the focus is on specic agents that are most commonly used in current

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treatment regimens, and agents that may become important in the future.
When relevant, the eects of adjunctive dexamethasone on ecacy of specic
agents in experimental animal models are discussed, because this may have
relevance in the treatment of patients with bacterial meningitis.
b-Lactams
The b-lactam agents are among the most commonly used classes of
antibacterials in the treatment of bacterial meningitis. Despite some of the
potential drawbacks to their use (eg, low CSF penetration, hydrophilic
chemistry, and optimal killing only at times when bacteria are in log phase
growth), they have proved to be eective against a wide variety of meningeal
pathogens. This is because high systemic doses of b-lactams are generally
well-tolerated and can achieve CSF concentrations that are well above the
MIC of sensitive pathogens. For example, high-dose intravenous penicillin
G therapy (24 million units daily) can achieve serum penicillin concentrations of 20 lg/mL, which translate to initial CSF concentrations of
approximately 1 lg/mL in patients with meningitis. In the past, pneumococci were uniformly susceptible to penicillin, with virtually all isolates
having an MIC of less than or equal to 0.06 lg/mL, such that penicillin G
had good microbiologic success in treating patients with pneumococcal
meningitis caused by susceptible strains [1]. Given the emergence of
antimicrobial resistance in meningeal pathogens, however, other agents
have been evaluated for their ecacy in the treatment of bacterial
meningitis.
Newer b-lactams that have been evaluated for the treatment of bacterial
meningitis include the carbapenems and advanced-generation cephalosporins. Of the carbapenems, imipenem-cilastatin (Primaxin) was the rst
studied. Although imipenem has excellent in vitro activity against many
of the important meningeal pathogens, a high frequency of seizures in
children receiving imipenem for meningitis [33] has largely precluded its use
for this infection. Meropenem is a carbapenem with less seizure proclivity
than imipenem [34], and is a therapeutic option in some patients with
bacterial meningitis. In one in vitro study of the use of various antimicrobials against penicillin- and cephalosporin-resistant S pneumoniae, meropenem had comparable bactericidal activity with the combination of
vancomycin plus a third-generation cephalosporin, suggesting a possible
role for meropenem in resistant pneumococcal meningitis [35]. Penicillinresistant isolates, however, that have demonstrated reduced susceptibility to
carbapenems have been described. In one in vitro study [36], penicillinnonsusceptible pneumococci displayed a higher likelihood of resistance to
the carbapenems (47%49%) than to either cefotaxime (15%) or chloramphenicol (31%). In another in vitro study that examined 20 cefotaximeresistant S pneumoniae isolates [37], 4 were intermediate and 13 were
resistant to meropenem, suggesting that meropenem is not a useful

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587

alternative for treatment of pneumococcal isolates that are highly resistant


to penicillin and cephalosporins. Meropenem has also been evaluated in an
animal model of bacterial meningitis, and was found to be more eective
than ceftriaxone for therapy of penicillin-resistant S pneumoniae (PRSP);
more eective than ceftazidime (Fortaz, Tazicef, Tazidime) for meningitis
caused by Pseudomonas aeruginosa; and equivalent to the combination of
ampicillin and gentamicin for meningitis caused by L monocytogenes [38].
Ceftazidime is a third-generation cephalosporin with enhanced in vitro
activity against P aeruginosa, and has been shown to be ecacious in an
animal model of Klebsiella pneumoniae meningitis [39]. Cefepime (Maxipime), a fourth-generation cephalosporin with excellent in vitro activity
against a variety of meningeal pathogens, including aerobic gram-negative
bacilli and PRSP, has also been studied in experimental animal models of
bacterial meningitis. Two experimental studies have demonstrated the
ecacy of cefepime in treatment of meningitis caused by PRSP. In the rst
study [40], the BKR of cefepime was superior to that of ceftriaxone or
vancomycin against a PRSP strain (MIC values: penicillin, 4 lg/mL;
ceftriaxone, 0.5 lg/mL; vancomycin, 0.120.25 lg/mL; cefepime, 0.5 lg/
mL); statistical signicance was reached in the comparison of cefepime with
ceftriaxone, even though the in vitro activities of ceftriaxone and cefepime
were similar against the test strain. The in vivo superiority of cefepime may
be secondary to the enhanced CSF penetration of cefepime (20%) versus
ceftriaxone (9%) [41]. The addition of vancomycin to either cephalosporin
increased the BKR as compared with monotherapy, but combination
therapy was not synergistic. In a second study [42], a PRSP isolate with
induced uoroquinolone resistance was evaluated (MIC values: penicillin, 4
lg/mL; ceftriaxone, 0.5 lg/mL; cefepime, 0.5 lg/mL; vancomycin, 0.120.25
lg/mL; trovaoxacin, 4 lg/mL; ciprooxacin [Cipro], 32 lg/mL); the BKR
for cefepime was similar to that for the combination of ceftriaxone and
vancomycin, which is the current standard of care for treatment of patients
with meningitis caused by PRSP [1]. The uoroquinolone-resistant PRSP
strain was killed more slowly by ceftriaxone and cefepime in vitro than the
parent uoroquinolone-susceptible strain; the in vitro killing rates for
vancomycin were not dierent for the two strains. The underlying
mechanism linking uoroquinolone resistance in pneumococci to decreased
in vitro killing rates for the cephalosporins remains unclear.
Glycopeptides
As a result of drug resistance in pneumococci, vancomycin has become an
important antimicrobial agent in the treatment of bacterial meningitis. One
important consideration in the use of vancomycin in experimental meningitis is the decreased and unreliable CSF penetration in the presence of
dexamethasone. In some cases, this decreased penetration caused a decreased
BKR and delay in CSF sterilization compared with animals that did not

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receive adjunctive dexamethasone [16,43]. In another study, the addition of


dexamethasone led to signicantly lower CSF vancomycin concentrations,
but also signicantly decreased brain edema, without considerable alteration
of the BKR [44]. Of additional concern is the description of a strain of S
pneumoniae that displayed vancomycin tolerance [45,46], which is the ability
of the microorganism to survive in the presence of antimicrobial agent
through loss of autolysin activity or triggering; experimental meningitis
caused by this tolerant strain was not responsive to vancomycin therapy. In
1998, an evaluation of 138 pneumococcal isolates from patients with
meningitis revealed that 12 isolates were at least moderately vancomycintolerant [47]; although the mortality of patients with tolerant isolates was
not signicantly increased, there was a prolonged length of hospital stay.
Vancomycin has retained an important role in the treatment of pneumococcal meningitis, and combination therapy with vancomycin and ceftriaxone has been demonstrated to be synergistic against ceftriaxone-resistant
pneumococcal meningitis in experimental animals without the adjunctive
use of dexamethasone [48], and potentially additive in the killing of
ceftriaxone-resistant pneumococci in an in vitro model that did include
dexamethasone [49]. The combination of vancomycin and gentamicin was
found to be synergistic against penicillin-resistant pneumococci in vitro and
in a rabbit model of meningitis [50]; the BKR of vancomycin plus
gentamicin was similar to that of vancomycin plus ceftriaxone. Interestingly,
these results were achieved with an average Cpeak of gentamicin of 4.3 lg/
mL, against a pneumococcal strain with a gentamicin MIC of 4 lg/mL.
A newer glycopeptide, oritavancin (LY333328), has been examined in
experimental meningitis caused by b-lactamsusceptible S pneumoniae [51].
In this study, oritavancin was shown to release lower amounts of lipoteichoic acid and teichoic acid in vitro than ceftriaxone, although this was
not found in the in vivo model, possibly because of more rapid bactericidal
activity of oritavancin in vivo. The MIC and MBC of oritavancin in
a representative b-lactamsusceptible pneumococcal isolate were very low
(0.015 and 0.03 lg/mL, respectively); a 10 mg/kg dose of oritavancin
achieved similar BKRs to a 12-hour infusion of ceftriaxone at 10 mg/kgh in
rabbits, despite very low (1%5%) CSF penetration of this glycopeptide. Of
note, the 40 mg/kg dose of oritavancin achieved signicantly higher BKRs,
but the safety of this dose in humans has not yet been established.
Rifampin
Rifampin has been studied in experimental models of bacterial meningitis, mostly in the setting of combination therapy because rapid emergence
of bacterial resistance precludes the use of rifampin monotherapy in clinical
settings. In a mouse model of pneumococcal meningitis, rifampin released
lower amounts of lipoteichoic acid and teichoic acid, and had an improved
mortality rate, compared with ceftriaxone [52]. In an in vitro study of

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589

combination antimicrobials, lipoteichoic acid and teichoic acid release was


found to be diminished in the setting of pneumococcal exposure to
ceftriaxone, if the pneumococcal isolate was pre-exposed to rifampin [53];
analogous results were demonstrated in the rabbit model of pneumococcal
meningitis, and this was associated with decreased numbers of apoptotic
neurons at autopsy in animals in which ceftriaxone therapy was preceded by
rifampin. In an earlier animal study of rifampin and ceftriaxone, with or
without adjunctive dexamethasone, for pneumococcal meningitis, combination therapy led to CSF sterilization, even with the pneumococcal MIC to
ceftriaxone of 4 lg/mL [16]. Another study revealed that the in vivo killing
curves for rifampin alone, rifampin plus ceftriaxone, and rifampin plus
vancomycin were nearly identical for a penicillin- and ceftriaxone-resistant
pneumococcal isolate [48]; each of these three rifampin-containing regimens
had killing rates at 24 hours similar to the vancomycin plus ceftriaxone
combination, and had higher BKRs than either ceftriaxone or vancomycin
alone. In contrast, an in vitro model of antimicrobial therapy for
amoxicillin-resistant S pneumoniae showed that the addition of rifampin
to ceftriaxone resulted in at least a 10-fold decrease in killing rates compared
with ceftriaxone monotherapy [49]. One additional study examined rifampin
or vancomycin, or both, with or without dexamethasone, for the treatment
of PRSP and ceftriaxone-resistant S pneumoniae meningitis in rabbits [54].
Without the addition of dexamethasone, the three antimicrobial regimens
displayed similar BKRs, with no additive eect seen with use of the
combination regimen; the addition of rifampin to vancomycin, however,
was able to reduce the negative eect of dexamethasone on vancomycin
Cpeak.
Fluoroquinolones
The uoroquinolones have recently undergone intensive study in
experimental animal models of PRSP meningitis, and for therapy of
meningitis caused by other meningeal pathogens. Trovaoxacin, for
example, showed great promise for the treatment of bacterial meningitis
in view of its broad in vitro activity and CSF pharmacokinetics [55], and was
studied in experimental animal models of meningitis caused by S pneumoniae [28], L monocytogenes [56], and other microorganisms. Reports of
serious liver toxicity, however, have limited its clinical usefulness. Since
then, a number of newer uoroquinolones, particularly those with enhanced
in vitro activity against S pneumoniae, have been evaluated for meningitis
therapy in various experimental animal models (Table 2).
Clinaoxacin demonstrated excellent potency against S pneumoniae in
a rabbit model of pneumococcal meningitis [48], displaying signicantly
more rapid bactericidal activity than either ceftriaxone, vancomycin,
meropenem, or cefpirome, even against a more sensitive pneumococcal
isolate. In a mouse model, clinaoxacin was found to have equal activity

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against both ceftriaxone-susceptible and -resistant pneumococci [57],


although ceftriaxone was 11- to 12-fold more potent than clinaoxacin
against the ceftriaxone-susceptible strain, as measured by the median
curative dose of the antimicrobial agent used in this study.
Gemioxacin (Factive) was found to be active against pneumococci in
the rabbit meningitis model, with bactericidal activity at a 5 mg/kgh
infusion rate being almost equal to that of ceftriaxone at 10 mg/kgh [58].
Coadministration of dexamethasone did not decrease the CSF penetration
of gemioxacin, nor did it alter its bactericidal activity. Lower degrees of
initial lipoteichoic acid and teichoic acid release, as compared with
ceftriaxone therapy, were not accompanied by attenuation of the inammatory response, as assessed by the CSF white blood cell count; CSF
concentrations of protein, lactate, or neuron-specic enolase; or by neuronal
apoptosis.
Table 2
Summary of data for quinolones as monotherapy for experimental meningitis
Drug

Dose
(mg/kg)

Clinaoxacin
Gemioxacin

20
5

Moxioxacin

10

Garenoxacin

540
20

18
9a
28b
20c
44 without
dexamethasoneb
34 with
dexamethasoneb
78 with meningitisc
50 without
meningitisc
50 with meningitisc
ND

7.530
15
15
1030

2738a
ND
49c
1425c

20 then 10

ND

20 then 10

ND

20 or 40

Gatioxacin

CSF
penetration (%)

BKR
(log10 CFU/mL/h)

Isolate studied

ND
0.25 from 012 h

PSSP
PSSP

0.32 from 012 h

PSSP

ND

PSSP and PRSP

1.72.4 from 03 h
0.92 from 03 h
0.50 from 010 h
ND
0.83 from 05 h
0.75 from 08 h
0.81.3 from 05 h
0.50.7 from 010 h
0.81.5 from 03 h
0.5 from 010 h
0.95 from 03 h
0.65 from 010 h

Escherichia coli
VTSP
CRSP
E coli
PRSP
CRSP
VTSP
CRSP

Abbreviations: AUC, area under the concentration curve; BKR, bacterial killing rate; CFU,
colony-forming units; CRSP, ceftriaxone-resistant Streptococcus pneumoniae; CSF, cerebrospinal uid; ND, not determined; PRSP, penicillin-resistant S pneumoniae; PSSP, penicillinsusceptible S pneumoniae; VTSP, Vancomycin-tolerant S pneumoniae.
a
Determined as (peak CSF concentration/peak serum concentration)  100.
b
Determined as (CSF/serum concentrations at 12 h after a dose)  100.
c
Determined as (CSF AUC/serum AUC)  100.
Data from references [29,48,57,5966].

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Moxioxacin (Avelox) was evaluated in two separate rabbit models for


the treatment of meningitis caused by both penicillin-susceptible S pneumoniae (PSSP) and PRSP. Against PSSP [59], the bactericidal activity of a 10
mg/kgh infusion of moxioxacin, with or without dexamethasone, was
almost as great as the bactericidal activity of ceftriaxone; doubling the dose
of moxioxacin did not result in any measurable increase in the BKR. As
with many other uoroquinolones, lipoteichoic acid and teichoic acid
release were not signicantly decreased in comparison with ceftriaxone,
but the Cpeak of lipoteichoic acid and teichoic acid were delayed. In an
animal model study that examined the ecacy of moxioxacin in PRSP
meningitis [60], moxioxacin was found to be as eective as ceftriaxone or
vancomycin in sterilizing the CSF, and displayed dose-dependent bactericidal activity. In addition, the bactericidal action of moxioxacin was more
rapid than that of vancomycin, a nding that had been previously
demonstrated [48]. Moxioxacin has also been evaluated in an animal
model of E coli meningitis [61], in which the drug was shown to have
excellent CSF penetration. As with most other uoroquinolones, the
AUC:MBC ratio and the Cpeak:MBC ratio were interrelated in this study,
and the time above the MBC was less strongly correlated with the BKR.
Moxioxacin was found to be at least as eective as ceftriaxone, and more
eective than meropenem, in eradicating E coli from the CSF.
Gatioxacin has been evaluated in experimental rabbit models of both S
pneumoniae and E coli meningitis. In a study of gatioxacin in experimental
cephalosporin-resistant pneumococcal meningitis, several interesting pharmacodynamic properties were noted [29]. The Cpeak:MBC, AUC:MBC, and
time above MBC were all signicantly interrelated (r = 0.94), and each
correlated signicantly with the BKR. Divided-dose regimens of gatioxacin, resulting in greater time over the MBC but lower Cpeak:MBC ratios,
were more eective in terms of bacterial clearance, as compared with singledose regimens; maximal activity was achieved only when drug concentrations exceeded the MBC for the entire dosing interval. Gatioxacin was
found to be as eective as the combination of vancomycin plus ceftriaxone
against this cephalosporin-resistant isolate. Gatioxacin has also been
studied alone and in combination with cefepime in experimental PRSP
meningitis [62]. The bactericidal activity of gatioxacin monotherapy in this
model was excellent, and was signicantly greater than the standard
combination of ceftriaxone plus vancomycin (BKR of 0.75 versus 0.53
log10 CFU/mL/h, respectively). The addition of cefepime in this animal
model increased the BKR slightly (to 0.84 log10 CFU/mL/h), but true
synergy was demonstrated only in vitro. In an experimental model of blactamaseproducing E coli meningitis [63], gatioxacin was more rapidly
bactericidal than cefotaxime, but similar to meropenem (bacterial killing
rates at 5 hours were 0.83  0.26, 0.46  0.3, and 0.73  0.17 log10 CFU/
mL/h, respectively, for gatioxacin, cefotaxime, and meropenem; P = .03
for gatioxacin versus cefotaxime).

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Garenoxacin (BMS-284756 or T-3811ME), a des-uoroquinolone, is the


newest of the quinolone class to be evaluated for therapy of bacterial
meningitis. One study evaluated both the CSF pharmacokinetics of
garenoxacin and its ecacy in experimental pneumococcal meningitis [64];
CSF penetration and BKRs were similar for garenoxacin compared with
other uoroquinolones, and bacterial killing was most closely correlated
with the CSF AUC:MBC ratio. In contrast to other uoroquinolones
[29,65], a potential sub-MBC eect was displayed with garenoxacin, because
bacterial clearance was observed at the 24-hour time period, despite
garenoxacin concentrations below the MBC. A regimen of 20 mg/kg of
garenoxacin followed by a second dose of 10 mg/kg displayed similar
bactericidal activity to the standard combination of vancomycin plus
ceftriaxone for ceftriaxone-resistant S pneumoniae. Garenoxacin and moxioxacin were also tested in an experimental model of vancomycin-tolerant S
pneumoniae [66]; BKRs for both uoroquinolones exceeded that for the
combination of vancomycin plus ceftriaxone, although the dierences were
not statistically signicantly.

Specic antimicrobial therapy in patients with meningitis


Use of specic antimicrobial agents in patients with bacterial meningitis
takes into account in vitro and animal model data in selecting the optimal
therapeutic regimen. Rather than giving treatment recommendations for
every bacterial pathogen that causes meningitis, the authors concentrate on
the specic microorganisms that have provided challenges for antimicrobial
selection based on recent trends in in vitro susceptibility testing.
Streptococcus pneumoniae
Current guidelines from the National Committee for Clinical Laboratory
Standards dene a pneumococcus as susceptible, intermediate, or highly
resistant to penicillin when the isolate has a penicillin MIC of less than or
equal to 0.06 lg/mL, 0.1 to 1 lg/mL, or greater than or equal to 2 lg/mL,
respectively [1]. Because of the emergence of PRSP and cephalosporinresistant S pneumoniae [5], penicillin can no longer be considered appropriate therapy for suspected or proved pneumococcal meningitis until in vitro
susceptibility testing is performed. The combination of vancomycin and
ceftriaxone is currently accepted as the standard for empiric therapy of
suspected pneumococcal meningitis in locations where pneumococcal resistance to b-lactams is common. Once the organism and its in vitro
antimicrobial susceptibilities are known, therapy may be appropriately
modied (Table 3). High-dose parenteral penicillin therapy had been
successfully used for pneumococcal meningitis in the era of predictable
penicillin susceptibility, and is still appropriate therapy for pneumococci
with a penicillin MIC of less than or equal to 0.06 lg/mL. If one chooses to

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593

Table 3
Specic antimicrobial therapy for pneumococcal meningitis
In vitro susceptibility

Standard therapy

Alternative therapies

Penicillin MIC  0.06 lg/mL

Penicillin G or ampicillin

Penicillin MIC 0.11 lg/mL

3rd P-Ceph

Penicillin MIC  2 lg/mL

Vancomycin plus 3rd P-Cepha

Ceftriaxone MIC  1 lg/mL

Vancomycin plus 3rd P-Cepha

3rd P-Ceph,
chloramphenicol
Meropenem,
cefepime
3rd P-Ceph plus
uoroquinoloneb
3rd P-Ceph plus
uoroquinoloneb

Abbreviations: 3rd P-Ceph, Third-generation parenteral cephalosporin, ceftriaxone, or


cefotaxime; MIC, mean inhibitory concentration.
a
The addition of rifampin might be considered in select patients. See text for details.
b
Currently available uoroquinolones with data for experimental pneumococcal meningitis
include gemioxacin, moxioxacin, and gatioxacin. Although recommended as alternative
agents in combination with standard therapy, there are currently no clinical data to support this
recommendation.

use a third-generation cephalosporin as alternative therapy for PSSP, the


cephalosporin MIC should still be determined, because cases of ceftriaxonenonsusceptible PSSP have been reported [67].
The third-generation cephalosporins, ceftriaxone and cefotaxime, are
considered the agents of choice against pneumococci with intermediate
susceptibility to penicillin [1]. Cephalosporin monotherapy may also be
adequate for pneumococci that are intermediately susceptible to the thirdgeneration cephalosporins (MIC = 1 lg/mL) [68,69], although failures have
been reported with high-dose cefotaxime therapy in children with meningitis
caused by cephalosporin-resistant S pneumoniae [70]. Vancomycin also has
a role in therapy of penicillin- or cephalosporin-resistant pneumococcal
meningitis, in combination with a third-generation cephalosporin. Vancomycin monotherapy cannot be recommended, because of unpredictable CSF
penetration (particularly in the presence of dexamethasone); poor performance in experimental animal models; and reports of clinical failures
[16,43,44,71]. The combination of vancomycin plus a third-generation
cephalosporin, in addition to demonstrating ecacy in animal models
[48], has had an additive or synergistic eect in children with bacterial
meningitis [18,72].
For those patients allergic to, intolerant of, or nonresponsive to standard
therapies, there are a number of potential alternatives for the treatment of
pneumococcal meningitis. Meropenem has been studied for the treatment of
meningitis both in children and adults, with microbiologic and clinical
outcomes similar to the third-generation cephalosporins [73,74]. There are
little data on use of meropenem, however, in patients with meningitis caused
by penicillin- or cephalosporin-resistant pneumococci, such that routine use
of meropenem cannot yet be recommended for patients with meningitis
caused by these resistant strains. Cefepime has been evaluated for empiric

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therapy in children with bacterial meningitis [75]. Of the 345 children


studied, 26 had S pneumoniae isolated, 17 children received cefepime, and 9
received a third-generation cephalosporin. Sixteen of the 17 children who
received cefepime cleared their CSF cultures promptly, and one had delayed
eradication. All pneumococcal isolates in this study were penicillinsusceptible. Clinical data for the addition of rifampin to vancomycin or
a third-generation cephalosporin for patients with pneumococcal meningitis
are lacking, and there are conicting results of the benets of rifampin in in
vitro and animal model studies [16,48,49,53,54]. It has been suggested that
rifampin be used for patients in whom the pneumococcal isolate is sensitive
to rifampin in vitro, and in patients who are not responding appropriately to
standard therapy [76].
Although animal model data for use of uoroquinolones in pneumococcal meningitis are impressive, there is a paucity of clinical data to warrant
their routine use in patients with bacterial meningitis. In a single trial
examining trovaoxacin as empiric therapy for childhood meningitis, a 94%
microbiologic cure rate for trovaoxacin versus a 96% rate for the
comparator drug (ceftriaxone with or without vancomycin) was demonstrated in the 27% of the 311 children who had proved S pneumoniae
meningitis [77]. As more clinical trials are performed, the newer uoroquinolones may nd a role in the therapy of pneumococcal meningitis in
patients who are either intolerant of current therapies, or in those with
penicillin- or cephalosporin-resistant strains. Ongoing monitoring of uoroquinolone susceptibility patterns is crucial, because uoroquinoloneresistant S pneumoniae have been reported [78], including one case of fatal
pneumococcal meningitis caused by a levooxacin (Levaquin)-resistant
strain [79].
One important issue is whether adjunctive dexamethasone is appropriate
in the treatment of patients with pneumococcal meningitis, given concerns
that dexamethasone may decrease antimicrobial penetration into CSF. A
recently published trial in adult patients with acute bacterial meningitis
demonstrated reduced mortality in patients with pneumococcal meningitis
who received adjunctive dexamethasone [80]. On the basis of these results,
the use of adjunctive dexamethasone (given concurrently with or just before
the rst dose of an antimicrobial agent) is recommended in adults with
suspected or proved pneumococcal meningitis [81]. It should be noted,
however, that only 72% of pneumococcal isolates were tested for antimicrobial susceptibility in this trial and all were susceptible in vitro to
penicillin, a nding that is not expected in the United States or in many
other parts of the world. Because corticosteroids can decrease the CSF
penetration of many antimicrobials, particularly vancomycin, there are
concerns regarding the routine use of adjunctive dexamethasone in the
treatment of patients with penicillin- or cephalosporin-resistant pneumococcal meningitis, in which vancomycin becomes a very important component of therapy. In some experimental rabbit models of meningitis,

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595

decreased CSF penetration of vancomycin has been demonstrated in the


presence of dexamethasone and this has led to a delay in CSF sterilization
[16,43]. Decreased CSF penetration of vancomycin was not seen in one
experimental model [44], however, or in a study in children with bacterial
meningitis who received adjunctive dexamethasone [18]. Because of these
concerns, a repeat lumbar puncture 36 to 48 hours after initiation of
antimicrobial therapy is recommended for any patient receiving adjunctive
dexamethasone who is not improving as expected, or who has a pneumococcal isolate for which the cefotaxime or ceftriaxone MIC is 2 lg/mL or
greater [76,82]. In patients receiving dexamethasone for penicillin- or
cephalosporin-resistant pneumococcal meningitis, careful observation and
follow-up are critical to determine whether use of dexamethasone may be
associated with adverse clinical outcome in these patients [81].
Neisseria meningitidis
Penicillin G and ampicillin have been the agents of choice for treating
meningococcal meningitis, but emerging resistance to penicillin throughout
the world [83] may necessitate a change in this choice of antimicrobial
therapy. One study from Spain [84] documented a rise in penicillin-resistant
N meningitidis from 9.1% in 1986 to 71.4% in 1997. High-level penicillin
resistance caused by b-lactamase activity, producing MICs as high as 256
lg/mL, has also been reported [85], although not in the United States.
Many, but not all, patients with penicillin-intermediate-resistant N meningitidis have responded well to penicillin therapy. One series from Spain [86],
however, showed that reduced susceptibility to penicillin was signicantly
associated with an increased risk of death or neurologic sequelae. Based on
these data, some authorities recommend a third-generation cephalosporin as
the most appropriate therapy for meningococcal meningitis [1], pending
results of in vitro susceptibility testing. Resource-deprived areas of the
world have continued to use a single intramuscular dose of chloramphenicol
in an oil-suspension for treatment of meningococcal meningitis. One large
observational study from Sudan [87] demonstrated a 92.8% clinical success
rate with chloramphenicol, compared with an 87.1% success rate for a 5-day
course of parenteral penicillin, during a large outbreak of meningococcal
meningitis. High-level chloramphenicol resistance in meningococci has also
been described [88], however, mandating continued surveillance for these
isolates. Other options for the treatment of meningococcal meningitis may
include meropenem or the uoroquinolones, pending further study.
Aerobic gram-negative bacilli
The third-generation cephalosporins have revolutionized the treatment of
gram-negative bacillary meningitis, and are now the standard for therapy
because of signicantly improved mortality when compared with previous
regimens (usually an aminoglycoside with or without chloramphenicol) [1].

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Therapy with ceftazidime resulted in a 79% cure rate in a small series of


patients with Pseudomonas meningitis, when used with or without an
aminoglycoside [89]. A more recent study documented a 94.4% survival
rate for gram-negative meningitis in neonates when treated with the
combination of a third-generation cephalosporin and amikacin (Amikin)
[90], although the study was retrospective and uncontrolled. The addition of
intrathecal or intraventricular aminoglycoside to a cephalosporin may still
be considered in patients not responding to intravenous therapy [1]. There
was one report of poorer outcomes, however, when intraventricular
gentamicin was used in infants [91].
Several other antimicrobial agents have been evaluated for patients with
meningitis caused by aerobic gram-negative bacilli, mostly published as case
reports or small case series. These have included cefepime for a cephalosporinase-hyperproducing Enterobacter aerogenes [92], aztreonam (Azactam) for
various gram-negative bacilli [93], meropenem for P aeruginosa [94,95],
high-dose ampicillin-sulbactam (Unasyn) for a multidrug-resistant Acinetobacter baumannii [96], colistin sulfomethate sodium (Coly-Mycin M) for
multidrug-resistant P aeruginosa and A baumannii [97,98], and the uoroquinolones for a variety of gram-negative bacilli [99,100]. The primary
area of use for all of these agents is for therapy of multidrug-resistant
organisms, in which more standard therapies are not an option, or when the
patient is not responding as expected. Choice of empiric antimicrobial
therapy for meningitis caused by aerobic gram-negative bacilli should take
into account the local susceptibility patterns of these microorganisms. In
vitro susceptibility testing must then be performed on isolates to determine
the optimal therapeutic regimen.

Summary
Success in treating bacterial meningitis relies on familiarity with the
pharmacology of the commonly used antimicrobial agents and the likely
microbiologic etiology of the meningitis. Important pharmacologic parameters relevant to acute bacterial meningitis include CSF penetration, the
drugs activity in purulent CSF, the mode of administration of the drug, and
the intrinsic pharmacodynamic relationships of CSF drug concentrations to
bactericidal activity. The key changes in the microbiology of the syndrome
have been the dramatic decline in the incidence of meningitis caused by H
inuenzae type b, the emergence of b-lactamresistant pneumococci, and the
increasing problem of resistant gram-negative bacilli in nosocomial meningitis. Many of the recent in vitro and animal model studies have focused on
newer antimicrobial agents (especially the uoroquinolones) that may be used
to ght resistant pathogens, although their use in humans has largely been
conned to observational experience, as opposed to large controlled studies.

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597

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