Professional Documents
Culture Documents
582
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.
583
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].
584
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
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
586
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
587
588
589
590
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
PSSP
ND
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].
591
592
593
Table 3
Specic antimicrobial therapy for pneumococcal meningitis
In vitro susceptibility
Standard therapy
Alternative therapies
Penicillin G or ampicillin
3rd P-Ceph
3rd P-Ceph,
chloramphenicol
Meropenem,
cefepime
3rd P-Ceph plus
uoroquinoloneb
3rd P-Ceph plus
uoroquinoloneb
594
595
596
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.
597
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