Clin Pharmacokinet (2013) 52:511–542
DOI 10.1007/s40262-013-0062-9
REVIEW ARTICLE
Clinical Pharmacokinetics of Antibacterials in Cerebrospinal
Fluid
Antonello Di Paolo • Giovanni Gori •
Carlo Tascini • Romano Danesi • Mario Del Tacca
Published online: 20 April 2013
Ó Springer International Publishing Switzerland 2013
Abstract In the past 20 years, an increased discrepancy
between new available antibacterials and the emergence of
multidrug-resistant strains has been observed. This condi-
tion concerns physicians involved in the treatment of
central nervous system (CNS) infections, for which clinical
and microbiological success depends on the rapid
achievement of bactericidal concentrations. In order to
accomplish this aim, the choice of drugs is based on their
disposition toward the cerebrospinal fluid (CSF), which is
influenced by the physicochemical characteristics of anti-
bacterials. A reduced distribution into CSF has been doc-
umented for beta-lactams, especially cephalosporins and
carbapenems, on the basis of their hydrophilic nature.
However, they represent a cornerstone of the majority of
combined therapeutic schemes for their ability to achieve
bactericidal concentrations, especially in the presence of
inflamed meninges. The good tolerability of beta-lactams
makes possible high daily dose intensities, which may be
associated with increased probability of cure. Furthermore,
the adoption of continuous infusion seems to be a fruitful
option. Fluoroquinolones, namely moxifloxacin, and anti-
tuberculosis drugs, together with the agents such as lin-
ezolid, reach the highest CSF/plasma concentration ratio,
A. Di Paolo
R. Danesi
Division of Pharmacology, Department of Clinical and
Experimental Medicine, University of Pisa, Via Roma 55, 56126
Pisa, Italy
G. Gori
M. Del Tacca (&)
Clinical Pharmacology Centre for Drug Experimentation, Pisa
University Hospital, Via Roma 67, 56126 Pisa, Italy
e-mail: m.deltacca@med.unipi.it
C. Tascini
Unit of Infectious Diseases, Pisa University Hospital, via
Paradisa 2, 56124 Pisa, Italy
which is greater than 0.8, and for most of these drugs it is
near 1. For all drugs that are currently used for the treat-
ment of CNS infections, the evaluation of pharmacokinetic/
pharmacodynamic parameters, on the basis of dosing reg-
imens and their time-dependent or concentration-depen-
dent pattern of bacterial killing, remains an important
aspect of clinical investigation and medical practice.
1 Introduction
The appropriate treatment of infections of the central ner-
vous system (CNS), namely meningitis, cerebral abscesses,
and encephalitis, represents a difficult goal of modern
chemotherapy. Antibacterial drugs should rapidly achieve
concentrations high enough to exert their killing effect,
which is dependent on their penetration within the CNS.
However, disposition of antimicrobial agents within the
CNS is strongly influenced by several pharmacokinetic
factors related to the drug with its own physicochemical
properties (i.e., molecular weight, hydrophilic nature,
plasma protein binding, etc.) and the pathophysiology of
barriers [both blood–brain and blood–cerebrospinal fluid
(CSF) barriers] surrounding the CNS. Furthermore, the
pharmacokinetic/pharmacodynamic characteristics of che-
motherapeutic agents (i.e., their time-dependent or con-
centration-dependent killing pattern) and the bacterial
sensitivity to the drugs [i.e., resistant versus sensitive
strains, and minimal inhibitory concentration (MIC)] may
be considered as additional pharmacodynamic factors. As a
modern approach to anti-infective chemotherapy, pharma-
cokinetic data from clinical studies have helped clinicians
to improve drug-dosing regimens, while the same infor-
mation is allowing the elaboration and adoption of thera-
peutic drug monitoring protocols, especially for critically
512
ill patients in the presence of severe or life-threatening
diseases.
The presence of barriers surrounding the CNS ensures
protection of encephalic and spinal structures against pos-
sible damage from chemicals, including drugs. All organ-
isms with a well-developed CNS have a blood–brain
barrier (BBB). In the brain and spinal cord of mammals,
including humans, the BBB is constituted by the endo-
thelial cells that form the walls of the capillaries [1]
(Fig. 1). The combined surface area of these microvessels
represents the large interface for blood–brain exchange.
This surface area consists of about 150–200 cm2/g tissue,
giving a total area for exchange in the brain of 12–18 m2
for an adult human [2, 3]. A second interface is formed by
the epithelial cells of the choroid plexus facing the CSF,
which constitute the blood–CSF barrier (BCSFB). The CSF
is secreted across the choroid plexus epithelial cells into the
brain ventricular system [3, 4], while the remainder of the
brain extracellular fluid, the interstitial one, is derived, at
least in part, by secretion across the capillary endothelium
of the BBB [5, 6].
The third interface is represented by the avascular
arachnoid epithelium, underlying the dura mater, and
completely enclosing the CNS (Fig. 1). This completes the
seal between the extracellular fluids of the CNS and the rest
of the body [7].
At all three interfaces, the barrier function results from a
combination of a physical barrier (the tight junctions
between cells reduce the flux through the intercellular cleft
of paracellular pathway), a transport barrier (specific
transport mechanisms mediating solute flux), and a meta-
bolic barrier (enzymes metabolizing molecules in transit).
The barrier function is not fixed, but can be modulated both
under physiological and pathological conditions [3, 7, 8].
Based on this premise, the two barriers (BBB and BCSFB)
must be regarded not only as anatomical barriers, but also as
dynamic structures that express multiple transporters, recep-
tors, and enzymes. The two main functions of these barriers
are to inhibit free diffusion between brain fluids and blood, as
well as to provide transport processes for essential nutrients,
ions, metabolic waste products, and drugs.
The aim of the present review is to describe the CSF
disposition of antibacterial drugs currently employed for
the treatment of CNS infections, with special attention to
the pharmacokinetic/pharmacodynamic characteristics of
these agents, particularly in the clinical management of
bacterial meningitis.
PubMed database was reviewed up to January 2013
using the following keywords: antibacterials, pharmacoki-
netics, CSF, pharmacokinetic(s)/pharmacodynamic(s).
Moreover, names of antibacterials (i.e., moxifloxacin,
aminoglycosides, etc.) were included within the keywords
and references of retrieved papers were further examined.
A. Di Paolo et al.
1.1 The Blood Brain and Cerebrospinal Fluid (CSF)
Barriers
1.1.1 Morphology of the Blood–Brain Barrier and Blood–
CSF Barrier (BCSFB)
Although there are several similar features between the
BBB and the BCSFB, the cellular basis of these two
structures as well as their primary functions differ signifi-
cantly. The BBB is located in brain capillaries and thus it is
an endothelial structure with a primary role to protect the
brain from physiological fluctuations in plasma levels of
various solutes and from blood-generated substances that
could interfere with neurotransmission. However, at the
same time it acts to provide mechanisms for exchange of
nutrients, metabolic waste products, signaling molecules,
and ions between the blood and the brain. By contrast, the
BCSFB consists of a layer of modified cuboidal epithelium
and the choroid plexus that secretes CSF and this process
could be considered as the main function of this epithe-
lium. The differences concerning the principal functions
are derived from variations in morphology and molecular
biology [8].
Brain endothelial cells and choroid plexus epithelial
cells are connected at a junctional complex by tight junc-
tions and adherens junctions (Fig. 2) [7, 9, 10]. Brain
endothelial cells also express gap junctions, but their
functional significance is not clear.
All tight junctions and adherens junctions are composed
of transmembrane proteins and cytoplasmic plaque pro-
teins. Plaque proteins cluster integral tight junction proteins
and form a platform for interaction with scaffolding and
signaling proteins. In addition, a circumferential actin belt
that encircles each endothelial/epithelial cell at the level of
tight junctions is important for the formation and the nor-
mal function of tight junctions [8].
1.1.2 Physiology of BCSFB Barrier
At the end of the nineteenth century, Paul Ehrlich demon-
strated for the first time the existence of the blood–brain/
blood–CSF barrier by injecting aniline dye into the blood of
preclinical models, observing that all the organs, with the
exception of the brain, were stained [11, 12]. At the
beginning of the twentieth century, Edwin Goldmann, a
pupil of Ehrlich, injected trypan blue both intravenously
and subcutaneously in experimental animals. Trypan blue
stained both the choroid plexus and the dura mater without
entering the CSF. On the contrary, after direct injection of
trypan blue into the CSF, the brain and spinal cord were
stained, indicating the absence of a tight diffusional barrier
between the CSF and brain tissues [12, 13]. Large hydro-
philic molecules, which cannot penetrate tight junctions and
Pharmacokinetics of Antibacterials in CSF
Fig. 1 Sites of the blood–brain barrier (BBB). The BBB includes
tight junctions between: a the endothelial cells of brain capillaries;
b epithelial cells of the choroid plexus; and c epithelial cells of the
arachnoid membrane. ECF extracellular fluid, CSF cerebrospinal
cell membranes, enter the interstitial space of the brain and
the CSF. The surface area of brain capillaries without tight
junctions is approximately 1/5,000 of the total capillary
surface area in the brain. The morphological equivalent of
the blood–CSF barrier consists of the cylindrical epithelium
of the choroid plexus linked by tight junctions [12, 14].
This evidence indicates that the central nervous com-
partments are bordered by a diffusional barrier consisting
of at least one lipid membrane with the exception of a few
leaky regions allowing even large hydrophilic molecules,
such as immunoglobulins, to enter the extracellular space
of the brain and the CSF. Several compounds with low
molecular weight are cleaved enzymatically at the blood–
brain/blood–CSF barrier [15]. By contrast, several active
drug efflux transporters contribute markedly to the function
of the blood–brain/blood–CSF barrier [16, 17].
513
fluid. Reproduced from Taylor [1] with permission from Springer
International Publishing AG (ÓAdis Data Information BV 2002. All
rights reserved)
1.1.3 Meningeal Inflammation
Penetration of antimicrobial agents into the CSF depends
on numerous factors, including their serum protein binding,
molecular size, lipid solubility, and the degree of local
inflammation that could affect BBB permeability. Some
molecules with appropriate lipophilicity, small molecular
weight, and suitable charge could well diffuse from blood
into the CNS. However, the overwhelming majority of
small molecules (500 daltons), proteins, and peptides do
not cross the BBB by diffusion. The BBB permeability
alterations in the presence of meningeal inflammation
could affect CNS and tissue antimicrobial drug concen-
trations in a more doubtful manner. Under the conditions of
a severe disruption of the blood–brain/blood–CSF barrier,
the physicochemical properties of drugs, which govern
514
Fig. 2 Various transport processes occurring at the blood–brain
barrier (BBB) and schematic diagram of the endothelial cells that
form the BBB and main routes for molecular traffic across the BBB
are shown. a Water-soluble compounds, including polar drugs, are
usually unable to reach astrocytes through tight junction restriction,
while the lipid membranes of the endothelium offer an effective
diffusive route for lipid-soluble agents. Ion channels, transport
carriers (e.g., for glucose, amino acids, purine bases, nucleosides,
choline) or energy-dependent proteins (e.g., P-glycoprotein) and
receptor-mediated transporters (for insulin, transferrin) are also
represented. b Molecular composition of endothelial tight and
drug entry into the CNS in the absence of meningeal
inflammation, become a secondary aspect [12].
Usually, drug concentrations measured in the absence of
meningeal inflammation represent the minimum concen-
trations that can be encountered early in the course of a
CNS infection, when the whole BBB morpho-physiologi-
cal structure is still uninjured. In the case of inflamed
meninges, the BBB could become leaky by the opening of
intercellular tight junctions [18]. Moreover, the CSF out-
flow resistance increases, leading to a moderate reduction
of the CSF production and absorption rates [19]. The
activity of P-glycoprotein, a transmembrane transporter
that determines cellular drug efflux, can also be modulated
by proinflammatory cytokines, thus reducing the antibac-
terial drug efflux from the endothelial cells of the BBB and
from the neuronal cells [20, 21]. All these mechanisms
synergistically lead to a rise of the CSF concentrations of
the drugs, particularly those that do not enter the CSF
readily in the absence of meningeal inflammation [12].
A. Di Paolo et al.
adherens junctions. Occludin and claudins are the most important
membranous components and are represented with their four trans-
membrane domains and two extracellular loops. In the figure,
vascular endothelial cadherin (VE-cadherin), the principal molecule
of endothelial adherens junctions, and the platelet–endothelial cell
adhesion molecule (PECAM), which mediates homophilic adhesion,
are also shown. Primary linker molecules between adherens junctions
and the cytoskeleton are represented by catenine and actin filaments.
Modified and reprinted by permission from Macmillan Publishers
Ltd: [Nat Rev Neurosci.] (Abbott et al. [7], copyright (2010)
Given that meningitis is characterized by an inflamma-
tory process, it could be reasonable to expect that the BBB
disruption could significantly jeopardize the pharmacoki-
netic/pharmacodynamic features of an antimicrobial agent.
Actually, the knowledge of CSF penetration of an antibi-
otic across inflamed meninges is still unclear. Meningeal
inflammation may be moderate and even absent in the early
stage of a meningitis when antibiotic penetration into the
CSF is extremely important to inhibit the progress of the
disease. Moreover, immunocompromised patients may
have little or no inflammatory response throughout their
entire course of infection [22]. Furthermore, a subject
affected by meningitis usually represents a critically ill
patient at risk of sepsis. The pathophysiological changes
occurring during sepsis, such as alterations in plasma
proteins, renal perfusion, capillary permeability, and organ
failure could lead to modification of the pharmacokinetic
properties of antimicrobials, because their volume of dis-
tribution and clearance could be affected [23]. During a
Pharmacokinetics of Antibacterials in CSF 515

Table 1 CSF penetration of

Antimicrobial class/ CSF/plasma AUC ratioa Inflammation/
antimicrobial drugs according to
compound noninflammation ratiob
meningeal status (adapted from Normal/mildly affected Inflamed
[12, 154]) meninges meninges

Penicillins 0.02 0.2 10

Beta-lactamase 0.07 0.1 1.4
inhibitors
Cephalosporins 0.007–0.1 0.15 21–1.5
Carbapenems 0.2 0.3 1.5
Fluoroquinolones 0.3–0.7 0.7–0.9 2.3–1.3
Chloramphenicol 0.6–0.7 0.6–0.7 1
Tetracyclines 0.2 0.2 1
Tigecycline n.a. 0.5 n.c.
Trimethoprim 0.18 0.42–0.51 2.8–2.3
Sulfamethoxazole 0.12 0.24–0.30 2–2.5
Glycopeptides 0.14–0.18 0.30 2.1–1.6
AUC area under the Macrolides n.a. 0.18 n.c.
concentration-time curve, CSF Aminoglycosides 0.2 0.1 n.c.
cerebrospinal fluid, n.a. not Fosfomycin 0.18 n.a. n.c.
available, n.c. not computable
a
Linezolid 0.5–0.9 0.7 n.c.
Estimated CSF penetration
Daptomycin n.a. 0.05 n.c.
ratio based on the arithmetic
mean of available data Colistin 0.03–0.05 0.06–0.68 0.5–0.07
b
Ratio between CSF/plasma Metronidazole n.a. 0.87 n.c.
AUC calculated in the presence/ Rifamycins 0.22 0.3 n.c.
absence of meningeal Antitubercular drugs n.a. 0.86 n.c.
inflammation

septic process, an increased volume of distribution could
decrease peak serum concentrations of aminoglycosides,
beta-lactams, and carbapenems, thus requiring a dose
adjustment in order to reach active plasma and/or CSF
concentrations [24, 25].
For a better analysis of the permeability of antibacterials
into the CNS with or without meningeal inflammation, a
summary of data is presented in Table 1.
1.2 Infections of CNS: The Most Common Pathogens
and Drugs of Choice
A wide variety of bacterial species is responsible for CNS
infections, including meningitis and abscesses (Table 2),
which may render difficult the early adoption of the most
appropriate chemotherapy regimen. For this reason, the
choice of empiric combination treatments against most
bacterial infections is the first step toward therapeutic
success when the identification of bacterial species is not
yet available. Then, a specific chemotherapy is chosen in
order to increase the probability of an early cure
attainment.
In the case of meningitis, Gram-positive and Gram-
negative bacterial strains may be responsible for the
infection, whereas in the case of brain abscesses anaerobic
bacilli may play a role. The epidemiology of meningitis has
been changed in the recent past because of the introduction
of routine vaccination of children against Haemophilus
influenzae and some strains of Streptococcus pneumoniae.
Despite these efforts, S. pneumoniae still represents the
major cause of the most severe diseases at all ages, with an
increasing incidence of antibiotic-resistant strains, espe-
cially those resistant to penicillin [26, 27]. Neisseria
meningitidis, Group B Streptococcus, H. influenzae, and
Listeria monocytogenes are other microorganisms respon-
sible for community-acquired infections, sometimes in the
presence of risk factors (i.e., immunocompromised
patient). Nosocomial infections are characterized by a
different epidemiology, depending on the adoption of
required neurosurgical procedures and devices (i.e., ven-
tricular drainages). In these cases, Gram-negative bacteria,
including Escherichia coli, Klebsiella spp., Pseudomonas
aeruginosa, Enterobacter spp., and Acinetobacter spp.,
may be identified, as well as staphylococci and streptococci
other than S. pneumoniae. Chronic meningitis displays a
different pattern of causative microorganism, with Myco-
bacterium tuberculosis one of the major causes, while
Brucella, Treponema, and Borrelia spp. may represent
516 A. Di Paolo et al.

Table 2 Common bacterial pathogens responsible for CNS infections and current recommended antimicrobial treatment (adapted from [31, 115,
213])
Disease Bacterial pathogens Antimicrobial treatments

Abscess Primary Aerobic and anaerobic bacilli Cefotaxime1/ceftriaxone ? metronidazole

Postsurgery S. aureus, ConS, Enterobacteriaceae, Cefotaxime1/ceftriaxone ? nafcillin/oxacillin/
Haemophilus spp., Fusobacterium spp. vancomycin*,2
Nocardia spp. Trimethoprim-sulfamethoxazole ? ceftriaxone
Acute meningitis
Empiric Preterm–1 month S. agalactiae, E. coli, L. monocytogenes Ampicillin3 ? cefotaxime
therapy 1–3 months As above plus S. pneumoniae, Ampicillin3 ? vancomycin4,5 ? ceftriaxone/cefotaxime
N. menigitidis, H. influenzae
3 months–50 years S. pneumoniae, N. meningitidis, Vancomycin4,5 ? ceftriaxone/cefotaxime
S. agalactiae, H. influenzae, E. coli
Immunocompromised S. pneumoniae, L. monocytogenes, Vancomycin4 ? (ampicillin3/cefotaxime/ceftriaxone or
H. influenzae meropenem)
Postsurgery/infected S. aureus, ConS, Enterobacteriaceae, Vancomycin2,6 ? (cefepime/ceftazidime or meropenem)
shunt Haemophilus spp., Streptococcus spp.,
P. aeruginosa, Clostridium spp.
Infection due to: S. pneumoniae Ceftriaxone/cefotaxime ? vancomycin**
N. meningitidis Ceftriaxone/cefotaxime
L. monocytogenes (Ampicillin ? gentamicin) or trimethoprim-
sulfamethoxazole or meropenem
H. influenzae, Coliforms, P. aeruginosa Ceftriaxone/cefotaxime ? gentamicin
Specific H. influenzae Ampicillin or ceftriaxone/cefotaxime or cefepime or
therapy fluoroquinolones or chloramphenicol
L. monocytogenes (Ampicillin ? gentamicin/trimethoprim-
sulfamethoxazole7) or meropenem or
(linezolid ? rifampicin)
N. meningitidis Penicillin G/ampicillin or cefotaxime/ceftriaxone or
meropenem or moxifloxacin
S. pneumoniae MIC [0.1 Penicillin G or ampicillin or ceftriaxone or cefotaxime
MIC 0.1–1 Ceftriaxone/cefotaxime or cefepime or meropenem
MIC [2 (Vancomycin ? ceftriaxone/cefotaxime) or
fluoroquinolones
MICceftriaxone [1 (Vancomycin ? ceftriaxone/cefotaxime) or
fluoroquinolones
E. coli Cefepime/ceftazidime or aztreonam or meropenem or
ciprofloxacin
P. aeruginosa Cefepime/ceftazidime or aztreonam
Prophylaxis N. meningitidis, H. influenzae Rifampicin8,9/ceftriaxone10/ciprofloxacin11/azithromycin12
Chronic meningitis
Specific M. tuberculosis Isoniazid ? rifampicin13 ? ethambutol ? pyrazinamide
therapy Brucella spp. Gentamicin ? (doxycycline/ trimethoprim-
sulfamethoxazole14)***
T. pallidum Penicillin G
Borrelia spp. Ceftriaxone
Pharmacokinetics of Antibacterials in CSF 517

Table 2 continued
Disease Bacterial pathogens Antimicrobial treatments

Encephalitis# M. pneumonia Azithromycin, doxycycline, fluoroquinolones

B. bacilliformis Chloramphenicol, ciprofloxacin, doxycycline, ampicillin,
or trimethoprim-sulfamethoxazole
B. henselae Doxycycline or azithromycin, with or without rifampicin
L. monocytogenes Ampicillin plus gentamicin; trimethoprim-
sulfamethoxazole
T. whipplei Ceftriaxone, followed by either trimethoprim-
sulfamethoxazole or cefixime
M. tuberculosis 4-Drug antituberculous therapy should be initiated;
dexamethasone should be added in patients with
meningitis
B. burgdorferi Ceftriaxone, cefotaxime, or penicillin G
R. rickettsii Doxycycline; chloramphenicol can be considered an
alternative
C. burnetii Doxycycline plus a fluoroquinolone plus rifampicin
A. phagocytophilum Doxycycline
E. chaffeensis Doxycycline
T. pallidum Penicillin G; ceftriaxone
ConS coagulase-negative staphylococci, MIC minimum inhibitory concentration
* In case of methicillin-resistant S. aureus
** plus dexamethasone
*** age: \8 years/[8 years. Recommended dosages of antimicrobials: penicillin G, 2 g intravenously every 4 h; ampicillin, 2 g intravenously
every 4 h, 50 mg/kg intravenously every 6/12 h
#
No recommended dosages are reported by the authors [213]
1
200 mg/kg per day in 3–4 doses
ceftriaxone, 2 g intravenously every 12 h, 100 mg/kg per day in two doses, 250 mg intramuscularly
2
500–750 mg intravenously every 6 h
3
nafcillin and oxacillin, 2 g intravenously every 4 h; cefotaxime, 2 g intravenously every 6 or 4 h
4
15 mg/kg intravenously every 6 h
5
azythromycin, 500 mg orally
6
or every 12 h
7
5/25 mg/kg orally every 12 h
8
or 600 mg every 24 h for 4 days
9
10 mg/kg intravenously or orally every 24 h (up to 600 mg/day)
10
ceftazidime and cefepime, 2 g intravenously every 8 h
meropenem, 2 g intravenously every 8 h; vancomycin, 1 g intravenously every 6 h
11
moxifloxacin, 400 mg orally every 24 h
trimethoprim/sulfamethoxazole, 15/75 mg/kg per day in 2–4 doses, 5 mg/kg intravenously every 6–8 h
12
gentamicin, 2 mg/kg intravenously loading dose, then 1.7 mg/kg intravenously every 8 h; ciprofloxacin, 400 mg intravenously every 8–12 h,
500 mg orally
13
isoniazid, 10 mg/kg every 24 h (up to 300 mg/day)
ethambutol, 25 mg/kg every 24 h
pyrazinamide, 25 mg/kg every 24 h (up to 2.5 g/day)
metronidazole, 7.5 mg/kg intravenously every 6 h
linezolid, 600 mg intravenously every 12 h
chloramphenicol, 1–1.5 g intravenously every 6 h
14
doxycycline, 100 mg orally every 12 h
rifampicin, 600 mg every 12–24 h, 20 mg/kg orally every 24 h
518
further causes of infection. Among the bacteria responsible
for meningitis, L. monocytogenes may also be a cause of
encephalitis [28].
In order to start antibiotic therapy as soon as possible,
the empiric treatment should begin before identification of
the causative microorganism. Drugs used for empiric
therapy include beta-lactams (penicillins, third- and fourth-
generation cephalosporins, carbapenems), glycopeptides
(vancomycin), and other agents [gentamicin, trimethoprim/
sulfamethoxazole, fluoroquinolones, linezolid, rifampicin
(rifampin)]. The same agents should then be administered
as a specific therapy for the time required to obtain clinical
and microbiological response when the causative pathogen
has been identified. Finally, some drugs like metronidazole,
doxycycline, and colistin have a very narrow use in the
presence of a limited number of susceptible bacterial
strains, while they may be considered as alternative choices
in the case of multi-drug-resistant bacteria [29, 30].
The use of adjunctive corticosteroid therapy is another
aspect that should be evaluated. Adjuvant dexamethasone
is recommended with or shortly before the first intravenous
dose of antibiotic in both immunocompetent and immu-
nosuppressed adults with pneumococcal meningitis at a
dose of 10 mg every 6 h for 4 days and in children at a
dose of 0.15 mg/kg every 6 h for 4 days for H. influenzae
B and pneumococcal meningitis [31].
The results of a European controlled trial demonstrated
that adjunctive dexamethasone, given before or with the
first dose of antibiotic therapy, was associated with a slight
reduction in mortality [relative risk (RR) 0.48, 95 % CI
0.24–0.96] [32]. However, the last Cochrane meta-analysis,
performed on 4,041 patients affected by bacterial menin-
gitis to evaluate the effect of adjuvant corticosteroid ther-
apy versus placebo, showed that corticosteroids were
associated with lower rates of severe hearing loss (RR 0.67,
95 % CI 0.51–0.88), any hearing loss (RR 0.76, 95 % CI
0.64–0.89), and low rates of neurological sequelae (RR
0.83, 95 % CI 0.69–1.00) with no effect on mortality (RR
0.74, 95 % CI 0.53–1.05, p = 0.09) [33].
By reducing subarachnoid space inflammation and
BBB permeability, corticosteroids could decrease CSF
penetration of antibiotics; thus, patients receiving vanco-
mycin for penicillin-resistant pneumococcal meningitis
require close clinical and CSF drug concentration moni-
toring [31]. Some authors, however, reported that con-
comitant dexamethasone infusion did not affect
vancomycin [34] or ceftriaxone [35, 36] CSF concentra-
tion in infected patients (Table 3).
Clinical data concerning teicoplanin–steroid interaction
are lacking. When administered in experimental animal
models with dexamethasone, teicoplanin resulted in lower
CSF concentrations in the face of the single agent admin-
istration, but not in pharmacological failures [37].
A. Di Paolo et al.
During antimicrobial treatment of bacterial meningitis,
an inflammatory response to antibiotics (Jarisch-Herxhei-
mer reaction) can occur, particularly in the case of spiro-
chetal infections, especially Treponema pallidum, when
antibacterial concentrations are sustained [38]. This reac-
tion may be the result of both an endotoxin-like bacterial
substance release as well as cytokine elevation, but the
exact mechanism behind the Jarisch-Herxheimer reaction
is still unknown, so that possible preventative measures are
lacking.
In the Taiwan prospective observational study on
patients affected by the Jarisch-Herxheimer reaction,
multivariate analysis showed that risk factors for its
development include high rapid plasma reagin titers, early
syphilis, and prior penicillin exposure [39]. A randomized,
controlled trial, performed to prevent Jarisch-Herxheimer
reaction, showed that pretreatment with sheep anti-TNF-
alpha antigen-binding fragment (Fab) suppressed the
reaction that can occur after penicillin treatment for louse-
borne relapsing fever and reduced the associated increase
in plasma concentrations of interleukin-6 and interleukin-8
[40]. In some cases, pharmacological treatment with cor-
ticosteroids showed a significant role in the prevention [41]
or in the limitation [42] of the systemic effects caused by
the Jarisch-Herxheimer response.
1.3 Key Issues of Antibacterials Within CNS
The study of pharmacokinetics of antibacterial agents
within the CNS represents an important area of research for
possible translation of results into clinical practice, with the
aim to improve treatment efficacy and to reduce the
development of mutant strains. For these reasons, the early
achievement of bactericidal concentrations of drugs
appears as an urgent requirement in modern antimicrobial
chemotherapy. However, while reading and discussing
results obtained in several studies aimed at evaluating
pharmacokinetic and pharmacodynamic characteristics of
antibacterials, it is likely that comparison of data is
difficult.
1.3.1 Pharmacokinetics of Antibacterials in CSF
The antibacterial drug distribution into the CSF depends on
several factors that characterize the biological matrix (i.e.,
ventricular or lumbar CSF, brain abscess) and its features
(protein content, pH, presence of leukocytes), and on the
barriers (inflamed or uninflamed meninges, the use of
corticosteroids) and the pharmacological properties of each
drug, along with its physicochemical characteristics,
plasma protein binding, etc. The following discussion
examines some of these aspects, while Sect. 2 discusses the
pharmacokinetics of each class of drugs.
Table 3 Penetration of antibacterials in CSF following standard dosage regimens
Drug Daily dose Regimen1 Patients Age2 (years) Way of Inflamed Serum4 Cmax (mg/l)5 tmax (h)5 AUCCSF AUC ratio6 Note Reference
sampling3 meninges (mg
h/l)5

Amoxicillin 50 mg/kg IV, 0.5 21 adults 14–76 L Yes Free 2.53 ± 0.59 &2 6.21° 0.06° AUC4 51a
Potassium 5 mg/kg IV, 0.5 21 adults 14–76 L Yes Total 0.27 ± 0.04 &2 0.84° 0.084° AUC4 51
clavulanate
Cefepime 2g IV, 0.5 7h ? 2i 41–79 V No Free 7.4, 15.8i 1, 2i – 0.08h AUC?g 92b, 96c
adults
Ceftriaxone 2g IV, 0.5, S 7 adults 65–90 V No Total 0.18–1.04 1–16 5.8–41.3 0.006–0.018 AUC? 80d
e
Ceftriaxone 75 mg/kg* IV, 0.5, M 30 0.08–16.5 L, V Yes Total 7.2/2.5 6 – – – 97e
children
Cefotaxime 2g IV, 0.5, S 7 adults 60–90 V No Total 0.14 ± 1.81 0.5–8 3.6–16.3 0.03–0.21 80d
Pharmacokinetics of Antibacterials in CSF

AUC?
Ceftazidime 3g IV, 0.5, S 8 adults 45–65 V No Free – – 0.02–0.08 AUC? 66f
Meropenem 2g IV, 0.5, M 10 adults 48–75 V No Total 0.63 ± 0.50 4.1 ± 2.6 8.55 ±6.73 0.047 ± 0.022 AUC? 53g
Amikacin 7.5 mg/kg IV, 0.5, M 16 0.33–8 L Yes Total 1.65 ± 1.6 3 – – – 102h
children
Moxifloxacin 400 mg OS, –, S 50 adults 66.5 ± 10.6 L No Total 4.07 ± 1.15 4–6 – – – 105i
Moxifloxacin 400 mg OS, –, M 4 adults 30–65* L Yes Total 1.29 4 (3.8–5.5) 18.1 0.82 AUC24 104j
(1.04–1.50) (14.8–19.8) (0.70–0.94)
Moxifloxacin 800 mg OS, –, M 4 adults 30–65* L Yes Total 2.22 4 (3.8–5.5) 28.4 0.71 AUC24 104j
(1.72–2.63) (24.9–28.9) (0.58–0.84)
Ciprofloxacin 500 mg 9 2 OS, –, M 2 adults 17–75 L Yes Total – – 6.97 0.31 AUC24 109k
(4.45, 9.49) (0.31, 0.31)
Ciprofloxacin 750 mg 9 2 OS, –, M 13 adults 17–75 L Yes Total – – 6.95 0.26 AUC24 109k
(2.30, 14.9) (0.11, 0.77)
Gatifloxacin 400 mg OS, –, M 14 adults 16–70 L Yes Total – – 20.0 0.48 AUC24 109k
(16.5, 41.5) (0.47, 0.50)
Levofloxacin 500 mg 9 2 OS, –, M 14 adults 18–68 L Yes Total – – 94.1 0.74 AUC24 109k
(53.1, 208) (0.58, 1.03)
Levofloxacin 500 mg 9 2 IV, 1, M 10 adults 26–74 V No Total 4.06 ± 1.26 2.70 ± 1.32 33.42 ± 10.69 0.71 ± 0.07 AUC12 110l
Colistin 2.61 mg/ IVen, 9 adults 18–73 V – – 6.2–22.1 2.4–5.5 72.5–293.3 – AUC24 55m
24 h– bolus, M
5.22 mg/
12 h
Tigecycline 100 mg IV, 0.5, S 17 adults 43 ± 13 L No Total 0.46 0.12 AUC24 113n
Linezolid 600 mg 9 2 IV, 1, M 9 adults 58.7 ± 17.3* V No Total 10.8 ± 5.7 2.6 ± 0.9 101.6 ± 59.6 0.7 ± 0.1 AUC24 160p
519
Table 3 continued
520

Drug Daily dose Regimen1 Patients Age2 (years) Way of Inflamed Serum4 Cmax (mg/l)5 tmax (h)5 AUCCSF AUC ratio6 Note Reference
sampling3 meninges (mg
h/l)5

Daptomycin 10 mg/kg IV, 1, S 6 adults 26–67 L, V Yes Total – – 1.01–19.35 0.001–0.017, AUC24 164q
0.11*
1
Route of administration (IV, intravenous OS, oral IVen, intraventricular), duration of infusion (h), single (S) or multiple doses (M)
2
range (minimum–maximum) or mean ± standard deviation
3
L lumbar, V ventricular
4
drug concentrations in serum were measured as total or free, unbound fraction
5
pharmacokinetic parameters of drugs within CSF: Cmax, tmax, and AUC, maximum concentration, time to Cmax and area under the concentration-time curve, respectively
6
CSF/serum AUC ratio
a
sampling was performed 48–96 h after starting the therapy while maximum daily dose was 2 g, results are expressed as mean values (°)
b
Monte Carlo simulation
c
Cmax and tmax values in two patients
d
values are expressed as range (minimum–maximum)
e
drug concentration 6 h postdose, at the beginning/end of infectious disease while maximum daily dose was 2 g
f
Monte Carlo simulation, drug concentrations in plasma were corrected for plasma protein binding
g
results are expressed as mean ± standard deviation
h
CSF was obtained 3 h postdosing at putative tmax value, while Cmax values are expressed as mean ± standard deviation
i
results are expressed as mean ± standard deviation
j
abnormal mononuclear cell count (but not glucose and protein concentrations) in CSF was observed, while results are expressed as median value (interquartile range)
k
population/pharmacokinetic analysis on sparse sampling time points, results are expressed as mean value (minimum–maximum)
l
results are expressed as mean ± standard deviation
m
colistimethate sodium was administered and results are expressed as range (minimum–maximum)
n
results are expressed as mean values
p
results are expressed as mean ± standard deviation
q
results are expressed as range (minimum–maximum), while the free fraction of the drug in plasma was considered for calculation (*)
A. Di Paolo et al.
Pharmacokinetics of Antibacterials in CSF
Fig. 3 Plot of concentrations in serum and ventricular cerebrospinal
fluid (CSF) of linezolid 600 mg given intravenously twice daily
infused over 1 h (open circles) [52], intravenous levofloxacin 500 mg
twice a day (filled squares) [110], 2 g intravenous meropenem infused
over 30 min (open triangles) [53], 3 g intravenous ceftazidime
infused over 30 min (filled circles) [212]. Points of each plot
represent the CSF/plasma concentration ratio at different times after
dosing (i.e., numbers next to symbols represent the time of sampling
expressed in hours after the end of drug administration). For each
drug, the variable ratio is due to the delay of drug entry into CSF (the
hysteresis phenomenon). Furthermore, the high and more rapid
penetration of antibacterials within the central nervous system
characterizes the drugs (namely linezolid and levofloxacin) whose
curve lies on the left part of the graph. For clarity, dashed lines
represent the CSF/serum ratio of 1 (on the left) and 0.1 (on the right)
In the case of bacterial meningitis, CSF should be
considered as a suitable matrix to investigate drug dispo-
sition and pharmacokinetics of antibacterial agents, at
variance with that occurring in the cerebral tissue infection.
In this case, the time profile of CSF concentrations may not
reflect the antibacterial drug diffusion within the infected
tissue, because several factors (i.e., extension of the lesion,
increased interstitial pressure, changes in pH, etc.) may
influence tissue penetration of the drugs [43]. Furthermore,
the availability of cerebral tissue is restricted to particular
events and clinical cases (i.e., when a surgical curettage
or drainage is required) and published data are limited
[44–47].
One of the most important factors, responsible for the
variability among the studies, could be the method of CSF
sample collection. CSF undergoes a concentration process
as it passes along ventricles and the spinal cord mainly due
to the extracellular fluid of nervous tissue together with
CSF diffusing from meninges and produced by the choroid
plexus [48]. Therefore, an increase in drug concentration
should be expected when a lumbar puncture is chosen to
collect CSF instead of using an external ventricular drain
(EVD). However, another consequence of this process is a
significant ventricular-lumbar increase in protein and
albumin [49], but whether this condition could have a
significant influence on the free fraction of the drug within
521
the CSF remains questionable, because it may occur in
purulent CSF [50].
Another factor responsible for result variability is the
delay of the time profile of antimicrobial drug concentra-
tions in the CSF with respect to plasma (the hysteresis
phenomenon), a delay which could be smallest when the
CSF is sampled through an EVD (according to the rate of
drug diffusion through barriers), and highest when using a
lumbar puncture. In this manner, when CSF is harvested
through a lumbar puncture, the calculation of CSF/plasma
concentration ratio at the same time point after drug
administration does not completely reflect the real dispo-
sition of the drug within the CNS [51], or at least within the
upper part of CSF spaces (i.e., ventricles). The hydrophilic/
lipophilic properties of drugs may concur to the above-
described hysteresis phenomenon also within ventricular
CSF when passage of drugs through the BBB is delayed by
poor lipid solubility, as in the case of beta-lactams (Fig. 3).
For these reasons, the assessment of drug disposition
into ventricular CSF has the dual advantage of making
feasible both a dense sampling scheme [52] and the sub-
sequent calculation of area under the concentration–time
curve (AUC) ratios between CSF and plasma. Use of AUC
ratios is superior to use of the CSF/plasma ratio at a single
time point, and can be more definitive for evaluation of
drug disposition into CSF. However, the presence of an
EVD is not a common condition, because it depends on the
clinical status and management of patients; therefore,
several studies have adopted lumbar puncture to obtain
CSF [53, 54]. Other strategies to improve the pharmaco-
kinetic analysis of drugs within CSF are external lumbar
drainage [54] and the application of population pharma-
cokinetic modeling. The latter approach ensures a complete
pharmacokinetic analysis on the basis of a more feasible,
sparse sampling protocol, instead of a dense one [55]. A
possible drawback in these studies occurs when drug
administration through the EVD is adopted to obtain CSF
drug concentrations that are not achievable after extra-
ventricular administration. This strategy may influence the
pharmacokinetics of antibacterials, inasmuch that the drain
is closed for a variable length of time (i.e., from 1 up to
3 h) after drug administration, hence affecting drug clear-
ance. On the other hand, the volume of CSF drained from
the EVD before drug administration may play a consider-
able role in interpatient variability of drug pharmacoki-
netics [56].
From a general point of view, studies that deal with the
distribution of antibacterials from systemic circulation into
the CSF should only consider the free fraction of drugs in
plasma, which is responsible for the pharmacological effect
in tissues. However, in many studies the laboratory end-
point is represented by the measurement of total plasma
concentration, whereas, in a limited number of studies,
522
drug concentrations are measured in plasma ultrafiltrate
[57]; otherwise, the plasma protein binding percentage is
considered a posteriori [52].
Several factors may significantly influence the diffusion
of drugs from plasma into CSF. During bacterial menin-
gitis, the reduction of CSF pH from 7.3 to 7.0 (or lower)
may increase the diffusion of weak acid antibacterials,
namely penicillins and cephalosporins, from CNS com-
partments to blood [58]. In addition, the increased protein
content in purulent CSF may reduce the free portion of
antibacterials [59, 60]. These two factors are potentially
associated with reduced treatment effectiveness.
Age plays an important role in the variability of protein
content of CSF and its produced volume. In fact, the pro-
tein content may change from 1,770 and 1,350 mg/l in
preterm neonates at 26–28 and 38–40 weeks of age,
respectively, up to 900 mg/l in healthy-term neonates [61].
However, the CSF-to-serum albumin ratio is a direct
function of the BBB permeability, while CSF flow is high
in newborns and in elderly people and is lowest in children
at the age of 4 years [62, 63]. Therefore, an increased CSF-
to-serum albumin ratio reflects an augmented disposition
into CSF of substances and drugs, whose concentrations
are often higher in infants and old people when compared
with those measured in children and young adults [12]. By
contrast, no relationship between amikacin disposition and
protein content in CSF has been found in neonates [64].
Finally, the choice of methods and techniques for the
measurement of drug concentrations within the matrix
could affect the results. In fact, the use of high-perfor-
mance liquid chromatography (HPLC) or agar diffusion
methods could lead to different results, as observed when
the free fraction of ceftriaxone was measured in plasma
[65]. At variance with plasma, the measurement of CSF
drug concentrations was not affected by the method, sug-
gesting that the analytical methodology employed for the
prediction and/or calculation of antibacterial penetration
into CNS should be carefully evaluated [65].
1.3.2 Pharmacodynamics of Antibacterials in CSF
The classification of drugs in terms of concentration-
dependent or time-dependent bacterial killing activity
offers the basis for use of antibacterials at doses and
schemes that should maximize therapeutic effects. Fur-
thermore, the post-antibiotic effect and/or inhibitory effect
when concentrations are below the bacterial MIC (the so-
called sub-MIC effect) are adjunctive factors that may
influence the overall antimicrobial effects of drugs.
Overall, the definition of the most predictive pharmaco-
kinetic/pharmacodynamic parameter in terms of clinical and/
or microbiological efficacy has been based on plasma phar-
macokinetics, because plasma represents a compartment that
A. Di Paolo et al.
can be easily accessed and investigated, in contrast with CSF
or cerebral tissue. Therefore, a major question to arise is
whether antibacterials maintain their plasma pharmacoki-
netic/pharmacodynamic characteristics (i.e., time-dependent
or concentration-dependent killing effect) in other compart-
ments such as CSF. In addition to this, because the treatment
of CNS infections requires the attainment of bactericidal
concentrations, the minimal bactericidal concentration
(MBC) should be considered rather than the MIC value.
Furthermore, in some studies there was no distinction
between MIC and MBC, and the maximal difference between
MBC and MIC values was within one dilution [66].
For beta-lactams displaying a time-dependent bacterial
killing activity, the most predictive pharmacokinetic/phar-
macodynamic parameter is represented by the time
between two consecutive doses during which the drug
concentration is higher than the MIC value of the causative
bacteria (T[MIC). The value of T[MIC should be greater
than 40 % in the case of carbapenems, which are charac-
terized by a postantibiotic effect, or 60–70 % for penicil-
lins and cephalosporins. However, preclinical studies
suggest that the beta-lactam bactericidal concentration in
the CSF may be predicted by the maximum concentration
(Cmax)/MIC (or Cmax/MBC) ratio. In fact, ampicillin Cmax
in the CSF must correspond to 10–30 times the MBC value
in order to obtain a bacterial killing activity of approxi-
mately 1 log10 CFU/ml per hour [67, 68]. This apparent
difference of pharmacodynamic behavior has been
explained by the fact that high Cmax values in the presence
of longer terminal half-lives of drugs in CSF with respect
to plasma half-lives, are associated with higher minimum
concentration (Cmin), and hence higher T[MIC values.
Moreover, the Cmax/MBC, AUC/MBC, and T[MBC ratios
of ceftriaxone could strictly depend on each other, but the
highest predictive value was retained by T[MBC [69]. The
same conclusions were drawn by Lodise and colleagues for
meropenem [66].
For antibacterial drugs with a concentration-dependent
killing potency, both Cmax and AUC pharmacokinetic
parameters may be predictive of bacterial killing. For
example, in experimental meningitis induced by E. coli,
moxifloxacin was effective when the AUC/MBC ratio in
CSF was 220–720 for total drug and 160–500 for the free
drug [70]. For fluoroquinolones, a Cmax equal to 30–40
times MBC has been suggested to obtain the best thera-
peutic benefit. As in the case of antimicrobials with a time-
dependent activity, all three pharmacokinetic/pharmaco-
dynamic parameters were found to be interrelated when
bacterial killing of gatifloxacin was evaluated, even if the
AUC/MBC ratio had the highest correlation with drug
activity [71].
Several antimicrobial drugs, currently used for the
treatment of bacterial meningitis, are characterized by a
Pharmacokinetics of Antibacterials in CSF
post-antibiotic effect of variable length when measured in
plasma, including carbapenems [72] and quinolones [73].
Whether this characteristic is still present when the drugs
diffuse into CSF is still under investigation. In vitro
studies have demonstrated that the post-antibiotic effect in
CSF may be higher than that observed in culture medium
for cefotaxime, gentamicin, and ciprofloxacin [74], while
for trovafloxacin similar post-antibiotic effect values were
observed in human pooled CSF samples and in culture
media against S. pneumoniae, H. influenzae, and
N. meningitidis [75]. For other drugs, like beta-lactams,
the delay in bacterial regrowth may depend on CSF
concentrations lower than MIC (sub-MIC effect) rather
than on the post-antibiotic effect [76, 77]. For example,
the inhibitory effect of ampicillin on bacterial growth was
reduced when the drug was removed from the medium or
inactivated, suggesting that the overall ‘‘post-exposure’’
inhibitory effect was mainly due to sub-MIC concentra-
tions rather than to a post-antibiotic effect [78]. Further-
more, for the exhaustive analysis of the phenomenon, it
should be considered that several antibacterial drugs dis-
play longer half-lives in CSF than in plasma (e.g., blood
and CSF half-lives were 0.7–1.4 and 2.1–3.6 h for
ampicillin and 0.9–1.7 and 9.3 h for ceftriaxone, respec-
tively) [79, 80]. Of note, the antimicrobial activity of
fosfomycin was found to be impaired in CSF [81].
In vitro experiments demonstrated that sustained bacterial
killing activity in human pooled CSF samples was found
when drug concentrations of fosfomycin greatly exceeded
MIC values (i.e., at least eightfold MIC, 16 mg/l),
whereas bacterial regrowth was observed 24 h after
exposure at lower drug concentrations (i.e., from one up
to fourfold MIC). This result was not evident under the
same experimental conditions in plasma, when bacterial
regrowth occurred only for drug concentrations lower
than the MIC. Therefore, an effective regimen (at least for
S. aureus infections) should be aimed at attaining CSF
antibacterial concentrations higher than eightfold MIC
during the entire dosing interval [81].
Finally, CSF is devoid of an effective immune
response against bacteria [59]; therefore, drug concen-
trations should achieve the bactericidal range as early as
possible. However, in the presence of an infectious
meningitis, several cytokines and degradation products
from bacteria act as chemoattractant stimuli for leuko-
cyte recruitment [82], with the subsequent CSF pleocy-
tosis and tissue damage. Under these conditions, changes
of pH and high protein content may play a role in
reducing the activity of antibacterial drugs. For example,
preclinical studies demonstrated that bactericidal activity
of drugs like most macrolides and quinolones was
reduced at CSF pH values lower than the physiological
pH [83, 84].
523
2 Pharmacokinetic/Pharmacodynamic Profile
of Antibacterials in the CSF
2.1 Beta-Lactams
Drugs belonging to the class of beta-lactams display some
features that could be responsible for their poor penetration
into CSF. Although they are characterized by low molec-
ular weight, their hydrophilicity, the marked variability in
plasma protein binding, and substrate affinity for trans-
membrane transporters [85] may explain their limited
penetration into CSF, unless meningeal inflammation is
present. Although the rate of penetration does not change,
some studies suggest that beta-lactam concentrations into
CNS may be increased by administering higher doses with
respect to standard regimens, without a corresponding
increased risk of severe toxicities. Beta-lactams have a
time-dependent activity and the division of the total daily
dose in multiple doses or the adoption of extended infu-
sions may give some advantages in terms of both greater
T[MIC values and increased susceptibility [86, 87]. Nev-
ertheless, how this approach could be transferred to CSF
should be carefully evaluated. In general, T[MIC values of
40–70 % of the time interval between two consecutive
doses are considered predictive of treatment efficacy even
if, in some selected cases, the attainment of a T[MIC value
equal to 100 % should be reached in order to reduce the
risk of treatment failure and to prevent the selection of
mutant strains. Overall, beta-lactams are widely used for
the treatment of CNS infections, for empiric or specific
therapies. These drugs are also employed to prevent CNS
infections after trauma and neurosurgical procedures, but
the analysis of available randomized controlled trials led to
the conclusion that the benefit for the patient is negligible
[88].
2.1.1 Penicillins
2.1.1.1 Amoxicillin Although the use of amoxicillin in
combination with clavulanic acid is not a first choice
therapeutic option for bacterial meningitis, a CSF/free-
plasma AUC ratio for amoxicillin, administered at the
intravenous dose of 50 mg/kg body weight, was 0.06 in
patients aged 14–76 years with inflamed meninges, and the
magnitude of the flogistic process seemed to directly and
significantly influence drug disposition when CSF was
obtained by lumbar puncture [51]. In particular, the time
profile of CSF levels revealed that drug concentration
peaked as early as 2 h postdose, and a plateau was evident
at 3–4 h postinfusion, with concentrations ranging from
approximately 0.7 up to 3 mg/l (mean 2.25 mg/l), with
68 % of values exceeding 1 mg/l. This level is sufficiently
high to be effective, in combination with clavulanate,
524
against beta-lactamase-producing pathogens [51]. Clavu-
lanic acid disposition into CSF was also investigated. The
major findings were that clavulanate reached higher CSF/
plasma AUC ratio (0.08) than amoxicillin and the degree of
inflammation did not significantly influence drug penetra-
tion. Furthermore, the amoxicillin/clavulanate ratio in CSF
ranged between 6.87 and 12.44, suggesting different
pharmacokinetic behaviors of the two drugs [51]. These
data suggest that amoxicillin plus clavulanic acid could
have a limited role in treating staphylococcal and strepto-
coccal meningitis.
2.1.1.2 Ampicillin Ampicillin is used for empiric and
specific therapy of meningitis in children and adults.
Ampicillin may be employed for the treatment of bacterial
meningitis caused by Group B Streptococci, and other
pathogens (L. monocytogenes, N. meningitidis) [89]. The
usual intravenous daily dose of 150–250 mg/kg should be
given at various time intervals of 3–4 h in adult patients, up
to a total dose of 6–12 g/day. At these dosages, and con-
sidering a pharmacokinetic/pharmacodynamic target of
T[MIC C50 %, Monte Carlo simulation demonstrates that
more than 90 % of N. meningitidis isolates is susceptible to
ampicillin at the plasma and CSF breakpoints of 4 and
0.5 mg/l, respectively [89], even if the clinical breakpoint
for susceptibility for ampicillin against N. meningitidis is
0.125 mg/l [90, 91].
In summary, the use of penicillins to treat meningitis is
widely recognized in empiric and specific treatments,
regardless of the age of the patients. These drugs are lar-
gely prescribed despite their relatively poor permeability of
the BBB, which may be increased by the presence of a
flogistic process.
2.1.2 Cephalosporins
Cephalosporins are largely used in combination with other
antibacterial drugs for the treatment of CNS infections,
both in children and adults (Table 2). As already discussed
in the above paragraph, beta-lactams display poor pene-
tration into the CNS, with the attainment of low concen-
trations when a minimal meningeal inflammation is present
(‘‘the worst case scenario’’) [92], and this condition also
affects cephalosporin pharmacokinetics. For a general
overview regarding properties of cephalosporins and their
passage into CSF through the BBB, see the review by
Lutsar and Friedland [93].
2.1.2.1 Cefepime In the case of cefepime, a fourth-gen-
eration cephalosporin, its pharmacokinetic and pharmaco-
dynamic profiles in ventricular CSF and plasma were
evaluated in patients treated with the drug at doses of 2 g
every 12 h by 30-min intravenous infusion [94]. When the
A. Di Paolo et al.
same parameters were analyzed using a population phar-
macokinetic approach and a subsequent Monte Carlo
simulation [92], it was found that the mean CSF/plasma
AUC from time zero to infinity (AUC?) ratio for cefepime
was 0.23 and none of the dosing regimens evaluated (2 g
intravenous as a 30-min infusion every 8 or 12 h) allowed
attainment of T[MIC values of 50 and 100 % in CSF for at
least 90 % of patients when a MIC value of 0.5 mg/l was
obtained. However, when researchers took into consider-
ation both a reduced probability of target achievement
(80 %) and MIC values lower than 0.5 mg/l, as in the case
of S. pneumoniae, a cefepime dosing regimen of 2 g
intravenously every 8 h proved to be effective [95], in
agreement with previous data [96]. In fact, a T[MIC
value [90 %, which is predictive of treatment efficacy,
was observed in one of two patients given 2 g cefepime
intravenously every 8 h, whereas six subjects, receiving
1 g cefepime intravenously every 8 h, had no measurable
drug concentrations in CSF [96].
Of interest, Monte Carlo simulation indicated that the
best target attainment for cefepime CSF concentrations was
associated with a dosing regimen using an intravenous
loading dose of 2 g followed by continuous infusion at a
rate of 250 mg/h for a daily total dose of 8 g [92]. On the
basis of these results, continuous infusion after a loading
dose could be associated with increased clinical effec-
tiveness, in agreement with the results obtained when
cefepime was administered by prolonged intravenous
infusions for infections other than those involving the CNS
for which a metastatic spreading to the CNS could be
possible [87]. The study by Lodise and colleagues [92] also
showed that the enrolled patients had a minimal meningeal
inflammation, suggesting that in the case of meningitis the
distribution of cefepime into CSF should be increased, thus
allowing prompt achievement of bactericidal concentra-
tions within the CNS. Moreover, beta-lactam effectiveness
could be best predicted by the Cmax/MIC or the ratio
between Cmax and MBC rather than the T[MIC parameter,
because the Cmax/MBC ratio could be considered a surro-
gate marker of T[MIC [92]. It is noteworthy that cefepime
Cmax in CSF ranged from 7.4 up to 15.8 mg/l after the
intravenous administration of a 2-g dose [96], and these
concentrations were always higher than MICs for most
common pathogens [90].
2.1.2.2 Ceftriaxone Ceftriaxone shows a CSF/serum
AUC ratio \0.02 after an intravenous 30-min infusion of
2 g [80]; however, its probability of reaching target con-
centrations may be comparable to that of the fourth-gen-
eration cephalosporins for low MIC values [95], as those
reported for S. pneumoniae [90]. Indeed, ceftriaxone
remains one of the most used drugs for the treatment of
meningitis (Table 2). In children given a single dose of
Pharmacokinetics of Antibacterials in CSF
ceftriaxone 75 mg/kg intravenously (maximum dose 2
g/day), the presence of an infection or the early adminis-
tration of the drug ensured higher lumbar CSF drug con-
centrations with respect to a late administration when the
infective process, as well as the flogistic meningeal reac-
tion, were decreased [97]. In particular, at 6 h postdose, the
mean lumbar CSF concentrations were 7.2 and 2.5 mg/l at
the beginning or at the end of the infectious disease,
respectively. CSF concentrations were higher than MIC
values against the most common bacterial isolates observed
in children (B0.03 mg/l) and the EUCAST breakpoints
(0.125–0.5 mg/l) [90]. These results were partially con-
firmed in adult patients without inflamed meninges who
received a 2-g intravenous dose of ceftriaxone [80]. In
particular, ventricular CSF Cmax values were in the range
of 0.18–1.04 mg/l, exceeding MIC values for highly sen-
sitive bacteria, such as H. influenzae, N. meningitidis, and
penicillin-sensitive S. pneumoniae (0.125–0.5 mg/l).
When ceftriaxone fails to inhibit bacterial species
characterized by high MICs, like Enterobacteriaceae (MIC
1 mg/l), the dose should be increased up to 4 g/day;
otherwise, a carbapenem must be employed [80].
2.1.2.3 Cefotaxime Compared with ceftriaxone, cefotax-
ime showed a greater ventricular CSF distribution in adults
(CSF/total-serum AUC? ratio range, 0.03–0.21) for the
same single 2-g intravenous dose [80]. However, according
to clinical indications, daily doses can be augmented up to
12 g/day without increasing the risk of CNS toxicity.
Taking into account the efficacy predictive value of the
Cmax/MIC ratio, a single 2-g intravenous dose of cefotax-
ime was associated with ventricular CSF Cmax values of
0.14–1.81 mg/l. As stated above for ceftriaxone, these
Cmax values were higher than MIC values for the strains
most commonly involved in meningitis, but ineffective
against Enterobacteriaceae. Therefore, the cefotaxime dose
should be increased or a carbapenem must be selected in
the presence of less sensitive bacterial strains [80].
2.1.2.4 Ceftazidime Adult patients treated with ceftazi-
dime (3 g, 30-min intravenous infusion) for extracerebral
infections were enrolled in a pharmacokinetic study aimed
at evaluating the probability of achieving bactericidal
concentrations within the CSF for the most frequent bac-
terial strains encountered in clinical practice [66]. Serum
pharmacokinetic results were calculated by considering a
10 % protein binding. The disposition of the drug into
ventricular CSF was poor, as witnessed by the low median
value of the CSF/free-serum AUC ratio of 0.04 (inter-
quartile range 0.02–0.08). Furthermore, when a regimen
consisting of 3 g of ceftazidime every 8 h as intravenous
infusion (30 min) was applied, the probability of achieving
a T[MIC value of 50 and 100 % was higher than 80 %
525
only for MIC values of 0.5 and 0.25 mg/l, respectively,
indicating a moderate bactericidal activity of ceftazidime
against P. aeruginosa isolates (breakpoint 8 mg/l) among
other Gram-negative bacteria [66].
In summary, the new cephalosporins represent the
backbone of several antimicrobial regimens for the treat-
ment of bacterial meningitis. From our survey of the lit-
erature, their penetration into CSF is high enough to
achieve bactericidal concentrations against the most com-
monly involved pathogens (H. influenzae, N. meningitidis,
and penicillin-sensitive S. pneumoniae), especially in the
case of cefepime. However, in some cases, MIC values
make bacterial strains less sensitive to these drugs, thus
requiring an increase in dosage.
2.1.3 Carbapenems
Meropenem, the most documented carbapenem derivative,
is selectively used for the treatment of severe CNS infec-
tions caused by Gram-positive and Gram-negative bacteria,
including species producing beta-lactamases (extended-
spectrum beta-lactamase and AmpC-producing strains).
Furthermore, at variance with imipenem, its use for the
treatment of severe bacterial meningitis is supported by a
minor incidence of seizures, which allows the use of high
doses [98]. The administration of intravenous doses of 20
and 40 mg/kg is associated with meropenem peaks in CSF
of about 0.1–2.8 and 0.3–6.5 mg/l, respectively, approxi-
mately 2–3 h after dosing [99, 100].
The absence of meningeal inflammation is concomitant
with a reduced penetration of meropenem into CSF, despite
the negligible plasma protein binding of approximately
2 % [53]. In adult patients exposed to meropenem for non-
CNS infections and provided with an EVD, the adminis-
tration of 2 g as a short 30-min infusion led to CSF Cmax
mean values of 0.63 ± 0.50 mg/l, with a range varying
from 0.13 up to 1.60 mg/l. These values were much lower
than the corresponding mean plasma levels (84.7 ±
23.7 mg/l). Moreover, time to reach Cmax (tmax) values in
ventricular CSF were 4.1 ± 2.6 h, suggesting a slow dis-
tribution of meropenem into the CNS [53]. Interestingly,
AUC? values for CSF were found to be related with those
calculated for serum; hence, the increase in dosage could
be associated with an augmented disposition of meropenem
from plasma to CSF. Furthermore, the analysis of the most
predictive pharmacokinetic/pharmacodynamic parameter
for meropenem showed that T[MIC values were C8 h in
patients with uninflamed meninges when MIC values of
0.125–0.5 mg/l were taken into consideration. These
results suggest that, in the presence of uninflamed meninges,
meropenem could not reach bactericidal concentrations in
CSF of some patients, and high doses (up to 12 g/day) are
required [53].
526
In agreement with these results, Lodise and colleagues
[66] found that the probability of a T[MIC target attain-
ment equal to 50 and 100 % was 80 % when MICs were
B0.25 and B0.125 mg/l, respectively, in patients equipped
with an EVD and in the absence of meningeal inflamma-
tion. In agreement with a preclinical model [69], Lodise
and colleagues suggested that the pharmacodynamic target
of meropenem might be represented by a T[MIC value
ranging from 50 to 100 % [66]. Nevertheless, various
reports showed that meropenem was effective in the
treatment of infections caused by microorganisms less
susceptible to cephalosporins like Enterobacteriaceae,
which are considered resistant if MIC values are C1 mg/l
[90].
A more recent pharmacokinetic study of meropenem
was performed by Tsumura and colleagues [54] in neuro-
surgical adult patients fitted with an external lumbar drain.
Several CSF and blood samples were collected over 16 h
after the first meropenem dose (0.5 g every 8 h infused in
30 min), and drug concentrations were then fitted by using
a three-compartment model. A Monte Carlo simulation was
performed considering both a T[MIC target equal to
100 % and a probability of target attainment of 95 %; then
the CSF pharmacodynamic-derived breakpoint was calcu-
lated. Although higher concentrations of meropenem
should be expected when CSF is harvested by lumbar
puncture instead of ventricular drainage, results showed
that the administration of intravenous meropenem 1.5–2 g
every 8 h was associated with a pharmacodynamic break-
point of 0.25 mg/l against S. pneumoniae, N. meningitidis,
and H. influenzae [54], a value similar to that adopted by
EUCAST for sensitive bacterial strains of the three species,
in the case of meningitis [90].
Moreover, the BBB was not expected to be damaged or
inflamed in the above-mentioned study [54], suggesting a
putative increased disposition of meropenem into CSF in
the presence of bacterial meningitis. However, the disrup-
tion of barriers due to a surgical procedure requiring EVD
equipment still remains a matter of debate. Finally, changes
in drug administration modalities (i.e., 3-h rather than 0.5-h
infusions) could improve target attainment, as demon-
strated in previous studies [101].
In summary, meropenem represents a drug for which the
recommended dosage is 2 g every 8 h as an intravenous
3-hour infusion, with MIC values B0.25 mg/l. Its disposi-
tion into CSF may increase in the presence of inflamed
meninges.
2.2 Aminoglycosides
The limited penetration of aminoglycosides in several tis-
sues such as the CNS, lung, and bone and their poor toler-
ability should be viewed as the main factors responsible for
A. Di Paolo et al.
the decreased clinical use of these drugs in the past 10 years.
Although intrathecal administration can overcome the poor
distribution into CSF, the availability of more effective and
safer drugs justifies the diminished request of aminoglyco-
sides for the treatment of CNS infections.
Antimicrobial therapy with amikacin (7.5 mg/kg intra-
venously twice a day) in children affected by community-
acquired bacterial meningitis led to a mean concentration
in lumbar CSF of 1.65 mg/l at 3 h postdose, which was
considered the expected time to peak [102]. The corre-
sponding Cmax values in total serum (obtained 30 min after
the end of infusion) was 19.6 mg/l, for a Cmax CSF/total
serum ratio of 0.08.
Furthermore, serum and CSF samples (from lumbar
puncture performed to exclude or to document meningitis)
from newborns were analyzed for amikacin concentrations
by using a population pharmacokinetic approach that
demonstrated significant correlation between total serum
and CSF concentrations of amikacin [64] when the drug was
administered on a weight-adjusted basis as a 20-min intra-
venous infusion. Median CSF concentration of the drug was
1.08 mg/l (range 0.34–2.65 mg/l), while Cmax and Cmin
serum values were 35.7 ± 5.9 and 3.8 ± 2.5 mg/l,
respectively, with a partition coefficient between CSF and
total serum of 0.103. These results suggest that after the
third dose, the amikacin mean peak concentration in CSF
could be 2.5 mg/l, a value that could ensure a Cmax/MIC
ratio of 10 for bacterial MICs of 0.25 mg/l or lower, while
other sensitive strains show pharmacodynamic breakpoints
B8 mg/l [90]. It is of interest that ototoxicity, given repe-
ated doses, showed higher occurrence in preterm newborns,
in whom an inflamed status of meninges is a known factor
of increased risk of hearing loss, because of higher BBB
permeability [64, 103]. Therefore, the use of amikacin in
bacterial meningitis should be carefully evaluated.
2.3 Fluoroquinolones
The administration of fluoroquinolones in one dose or in
two refracted doses per day could increase their penetration
into the CSF, with the achievement of bactericidal con-
centrations both in terms of Cmax/MIC and/or AUC/MIC,
because fluoroquinolones are characterized by a concen-
tration-dependent bactericidal activity. Moreover, a major
advantage of fluoroquinolones is their capability to cross
the BBB for the treatment of CNS infections due to their
rapid penetration and appearance in CSF, making intra-
thecal administration unnecessary. In fact, when CSF and
plasma concentrations were calculated at the same time
points, pharmacokinetic analysis revealed the achievement
of CSF/plasma AUC ratio values of 0.4–0.6 or higher,
suggesting a rapid disposition of the drugs within the CNS
[104].
Pharmacokinetics of Antibacterials in CSF
2.3.1 Moxifloxacin
Among fluoroquinolones, moxifloxacin has demonstrated a
marked penetration into CSF. A pharmacokinetic analysis
of moxifloxacin was carried out in adult male patients
given moxifloxacin in a 400-mg oral dose as prophylaxis
for a short urological surgical procedure, and CSF was
obtained from lumbar puncture [105]. The highest total
plasma concentrations (6.55 ± 3.61 mg/l) were obtained
within 2–4 h postdose, whereas in CSF, Cmax (4.07 ±
1.15 mg/l) was observed between 4 and 6 h postdose, thus
explaining why the highest CSF/plasma ratio was observed
in the range of 4–6 h postdose. The 400-mg oral dose of
moxifloxacin suggests the attainment of Cmax/MIC values
of nearly 10 for Klebsiella spp., Enterobacter spp., and
Proteus [90].
Four patients affected by tubercular meningo-encepha-
litis received moxifloxacin at oral doses of 400 and
800 mg/day in association with other antituberculosis
drugs, including rifampicin [104]. The coadministration of
rifampicin may be able to negatively influence plasma
concentrations of moxifloxacin, probably by inducing
glucuronidation or sulfation processes [106]. However,
results showed that the mean value of CSF/total-plasma
AUC from 0 to 24 h (AUC24) ratio ranged from 0.82 to
0.71 at oral doses of 400 and 800 mg/day, respectively,
suggesting a good penetration of the drug within the CNS
[104]. Because CSF was sampled through an external
lumbar drain, tmax in CSF was observed approximately 4 h
after drug administration [104]. The free fraction of
moxifloxacin was 40–60 % in plasma and up to 90–95 %
in CSF, while in two out of four enrolled patients the CSF/
plasma AUC24 ratio for ultrafiltrate ranged from 0.85 to
1.16 and from 1.31 to 1.75 for oral doses of 800 and
400 mg/day, respectively [104]. Furthermore, the geomet-
ric mean values of AUC24/MIC in CSF were 84 and 132 at
doses of 400 and 800 mg, respectively [104], and these
values were associated with at least a 2-log10 CFU decrease
in experimental models of lung tuberculosis [107]. More
recently, Pranger et al. [108] described the pharmacoki-
netics of moxifloxacin (400 mg orally) in a patient affected
by tubercular meningitis. In this case report, a CSF/plasma
AUC24 ratio of approximately 60 % was calculated, with
an AUC24/MIC ratio of 208 in plasma (the unbound frac-
tion) and 175 in CSF, with the subsequent achievement of
bactericidal concentrations within the CNS.
2.3.2 Levofloxacin, Ciprofloxacin, and Gatifloxacin
Interesting results have been reported by Thwaites et al.
[109], who evaluated the penetration into the CNS and the
therapeutic role of three different fluoroquinolones (levo-
floxacin 500 mg or ciprofloxacin 750 mg every 12 h and
527
gatifloxacin 400 mg every 24 h) as add-on oral therapy in
association with standard antitubercular chemotherapy.
Plasma and corresponding CSF samples from lumbar
puncture were obtained and pharmacokinetic parameters
were compared among the three groups. Oral levofloxacin
displayed the highest mean value of the CSF/plasma
AUC24 ratio at steady state (median 0.74; range 0.58–1.03),
whereas the ratio value was lower for gatifloxacin (median
0.48; range 0.47–0.50) and ciprofloxacin (median 0.26;
range 0.11–0.77). Interestingly, U-shaped relationships
between drug exposure and clinical outcome were identi-
fied, for which the major benefit from chemotherapy was
associated with intermediate rather than high exposure
levels (i.e., in the case of levofloxacin, the AUC24/MIC
ratio was in the ranges of 112–220 and 14–252 in plasma
and CSF, respectively). The study further showed that the
penetration ratios for levofloxacin and ciprofloxacin were
more variable than those for gatifloxacin [109]. Indeed, Pea
and coworkers [110] reported levofloxacin pharmacoki-
netics at steady state in adult patients endowed with an
EVD and treated with the drug at the dose of 500 mg twice
a day administered as a 1-h infusion. On the basis of a
dense sampling schedule of both blood and ventricular
CSF, the disposition of the drug within CSF was demon-
strated to be substantial also in the absence of inflamed
meninges, with an AUC from 0 to 12 h (AUC12) CSF/total
plasma ratio of 0.71, and a Cmax ratio ranging from 0.32 up
to 0.79 (i.e., a coefficient of variation of approximately
30 % for both parameters). However, the CSF AUC12
values ranged from 20.31 up to 48.73 mg
h/l, suggesting
that the adopted schedule (intravenous 500 mg every 12 h)
could not be effective in some patients when MIC values
are higher than 1 mg/l (i.e., AUC24/MIC values lower than
100) [110]. Therefore, the authors suggest the administra-
tion of levofloxacin in combination with a beta-lactam
when the causative microorganism is unknown [110].
In conclusion, fluoroquinolones may be regarded as
antimicrobials able to achieve bactericidal concentrations
in CSF, even if at higher MIC values these drugs should be
used in combination therapy with other antibacterials.
2.4 Colistin
Although the use of colistin has been reduced in the past
mainly because of the occurrence of severe toxicitiy, the
emergence of multidrug resistant strains of P. aeruginosa,
Acinetobacter, and Klebsiella pneumoniae has renewed the
interest for this drug, whose more reliable pharmacoki-
netic/pharmacodynamic parameter seems to be represented
by AUC/MIC of the unbound fraction of the drug [111].
The introduction of colistimethate sodium, as a more tol-
erable prodrug, has allowed the use of colistin in pediatric
patients. Antachopoulos et al. [112] investigated colistin
528
penetration into the CNS of infants and adolescents, who
were affected by Gram-negative infections and fitted with
an EVD. Colistin and colistimethate sodium concentrations
were measured both in plasma and CSF before and 30 min
after intravenous drug administration at doses ranging from
60,000 to 225,000 IU/kg per day. The drug did not reach
effective concentrations in CSF when MIC values for
Acinetobacter baumannii, P. aeruginosa, and K. pneumo-
niae were C2–4 mg/l, in accordance with EUCAST
guidelines [90]. In particular, peak and trough values in
CSF ranged from 0.05 to 0.15 mg/l, but they increased up
to 0.50 and 0.46 mg/l, respectively, in the presence of
meningitis. Overall, the CSF/total serum penetration ratio
at the ventricular level ranged from 0.03 to 0.67, in
agreement with previous studies [113]. Interestingly, all
these values are below the MIC values of multidrug-
resistant Gram-negative rods.
Similar results were obtained by Markantonis and
coworkers [114] in adults exposed to colistimethate sodium
(150–225 mg daily intravenous dose) for infections caused
by multiresistant Gram-negative bacilli. The CSF samples
were obtained by lumbar puncture, and CSF/total-serum
ratio was found in the range of 0.051–0.057 1–3 h after
drug administration, while CSF/total-serum AUC ratio at
steady state was 0.051.
The systemic administration of colistin or colistimethate
sodium was associated with low CSF concentrations, sug-
gesting that in the presence of multidrug-resistant bacteria
the drug could be ineffective [114]. The availability of a
more tolerable prodrug, like colistimethate sodium, allows
intraventricular administration, thus increasing the proba-
bility of achieving bactericidal concentrations in the CSF.
A recent investigation by Imberti et al. [55] evaluated
the pharmacokinetics of colistin in CSF from patients given
intraventricular colistimethate sodium for CNS infections
due to pan-resistant Gram-negative bacteria. Colistimethate
sodium was administered as an intraventricular bolus
(1–2 min) at doses ranging from 2.61 mg every 24 h up to
5.22 mg every 12 h, a dose level close to the schedule of
10 mg/day recommended by Tunkel et al. [115]. The
average steady-state concentrations of active colistin in the
ventricular CSF ranged between 3 and 12.2 mg/l, while the
mean tmax value was 3.7 h. Minimum CSF concentrations
ranged from 2.0 up to 9.7 mg/l, and these values were not
observed when intravenous delivery was used in pediatric
patients [112]. Cmin values were higher than MICs of pan-
resistant bacteria for all evaluated dose regimens, with the
exception of the lowest dose (i.e., 2.61 mg intraventricu-
larly every 24 h). Finally, the dense CSF sampling sche-
dule showed that the estimated AUC24 ranges were
72.5–248.6 and 149.1–282.9 mg
h/l at doses of 2.61 mg
every 24 h and 5.22 mg every 12 h, respectively. These
pharmacokinetic results were associated with the
A. Di Paolo et al.
achievement of clinical response in eight out of nine
patients in the absence of CNS toxicity [55].
Recently, physicians have faced the outbreak of severe
infection caused by K. pneumoniae carbapenemase (KPC)-
producing bacteria, which is a condition characterized by a
high mortality rate among patients. Both colistin and
colistimethate sodium have been shown to have a signifi-
cant role in combination with rifampicin and tigecycline
[116]. Although MIC for colistin may be higher than the
drug breakpoint, these regimens display a synergic bacte-
ricidal activity, resulting in clinical cure of patients.
Moreover, in order to obtain the highest concentrations as
early as possible, the intravenous regimen of colistimethate
sodium should use a loading dose of 9–12 9 106 IU fol-
lowed by maintenance doses of 4.5 9 106 IU every 12 h in
association with other drugs [117].
In summary, colistin and colistimethate sodium repre-
sent drugs of choice when the causative microorganisms
are multidrug-resistant strains. However, these drugs
should be used in combination with other antibacterials,
and, in selected cases, intraventricular administration
should be adopted to augment the probability of cure
because of modest and variable drug penetration into CSF.
2.5 Macrolides
The limited penetration of macrolides into CSF is related to
their high molecular weight and affinity for P-glycoprotein;
consequently, they do not reach sufficient active concen-
trations in the CSF when meningeal inflammation is lack-
ing [118, 119]. Because of a failure of bactericidal activity
in experimental S. pneumoniae meningitis, the role of
macrolides in the treatment of CNS infection is limited to
Legionella pneumophila infections.
2.5.1 Azithromycin
Azithromycin, a 15-membered ring azolide antibiotic
related to macrolide erythromycin, differs in antimicrobial
activity and pharmacokinetic properties from the prototype
macrolide [120] and is superior to erythromycin against
some pathogens, including H. influenzae, Moraxella ca-
tarrhalis, and L. pneumophila [121, 122]. The antibiotic
has excellent pharmacokinetic properties, including wide
distribution in body fluids or tissues and high intracellular
storage [123–125].
Concentrations of azithromycin in the CNS were mea-
sured in patients with brain tumors receiving multiple oral
doses of antibiotic prior to the surgery [120]. Brain tissue
samples were taken from the periphery of the tumor mass,
specifically from the cerebral cortex and cerebellum. The
mean concentrations of azithromycin in brain tissue at 24,
48, 72, and 96 h after dosing were 2.63 ± 2.58,
Pharmacokinetics of Antibacterials in CSF
3.64 ± 3.81, 0.74 ± 0.37, and 0.41 lg/g, respectively,
whereas the mean levels in serum at the same times were
0.031 ± 0.044, 0.016 ± 0.011, 0.012 ± 0.005, and
0.008 mg/l, respectively. The mean ratios of the concen-
tration of the drug in brain tissue to that in serum at 24, 48,
72, and 96 h after dosing were 255.76 ± 429.39,
199.06 ± 188.90, 62.71 ± 5.60, and 51.25, respectively.
The CSF levels of azithromycin ranged from undetectable
to 0.015 mg/l at 24 and 48 h after a single 500-mg oral
dose [120].
2.5.2 Clarithromycin
Clarithromycin is the most active macrolide against rapidly
growing mycobacteria. Monotherapy with clarithromycin
has been successfully employed, although resistance has
been observed among isolates of M. abscessus from
patients with disseminated disease treated with clarithro-
mycin monotherapy. Resistance has been associated with a
point mutation in the gene encoding pr23SRNA [126]. For
this reason, the combination of two drugs might be indi-
cated, like the addition of amikacin, which showed sig-
nificant additive effect especially for disseminated disease
[127].
Limited information is available concerning the pene-
tration of clarithromycin into CSF in humans. In a post-
traumatic meningitis due to M. abscessus, a patient was
treated initially with oral clarithromycin at a dosage of
1,000 mg twice daily and intravenous amikacin plus
intrathecal amikacin. In the presence of meningeal
inflammation, intraventricular CSF concentrations of clar-
ithromycin increased to 15–18 % of the simultaneous
serum levels and to 25–27 % for its metabolite, after 4 and
9 h, respectively, and they were significantly higher (15- to
17-fold) than the MIC for clarithromycin (0.125 mg/ml).
Despite CSF levels of clarithromycin and amikacin in
excess of their in vitro MIC for the microorganism,
the CSF cultures remained continuously positive for
M. abscessus [128].
In experimental pneumococcal meningitis, clarithro-
mycin lacks bactericidal activity in CSF despite its CSF
levels exceeding the MBC of the test strains and a bacte-
ricidal in vitro effect in time–kill studies [84]. A possible
explanation may be related to the fact that the MBC of
clarithromycin is substantially increased when the pH of
the medium is acidified, which is the case for CSF during
meningitis [129].
2.5.3 Erythromycin
In neurosurgical patients, erythromycin penetrates into the
CSF after oral administration of a 300–500 mg dose or
intravenous administration of 200 mg. However, the
529
penetration of the macrolide was low, regardless of the
administration route (oral or intravenous). The highest CSF
levels were found 3–6 h after drug administration; the
maximum index of penetration from the blood into the CSF
was about 10 %. In cases of meningeal inflammation,
erythromycin penetration significantly increases [130].
In conclusion, because of their relatively high molecular
weight, protein binding, lipophilic properties, and P-gly-
coprotein affinity, the entry of macrolides into the CSF is
limited. Despite great activity against S. pneumonia
in vitro, clarithromycin was only bacteriostatic in experi-
mental pneumococcal meningitis. At various times fol-
lowing oral treatment with azithromycin, high levels of the
macrolide are found in cerebral tissues whereas low con-
centrations are detected in CSF. Due to the poor CSF
penetration of macrolides, some authors recommend the
addition of rifampicin or amikacin to macrolide regimens
when CNS symptoms are manifested [50].
2.6 Tetracyclines and Tigecycline
Tetracyclines display a time-dependent killing pattern and
exhibit a considerable postantibiotic effect [131, 132]. This
is also the case for tigecycline, which is a new member of
this class [133]; the best pharmacokinetic/pharmacody-
namic index is the AUC24/MIC ratio. In fact, in clinical
trials on patients affected by complicated skin or intra-
abdominal infections, the AUC24/MIC ratio was chosen as
the pharmacokinetic/pharmacodynamic index for target
development. Owing to the prolonged postantibiotic effect
and AUC24/MIC ratios of 17.9 and 6.96 for skin and intra-
abdominal infections, respectively, good clinical efficacy
was observed [134, 135]. However, the time above the
MIC of free drug level versus effect had a high correlation
coefficient [133].
2.6.1 Doxycycline
Among tetracyclines, the most effective treatment of
CNS infections is with doxycycline. Clinical studies
indicate that doxycycline is slowly absorbed after oral
administration, taking 2–3 h to reach peak concentra-
tions. The elimination half-life is long, ranging from 12
to 25 h. Average AUCs for oral doses of 200 mg/day
range from 40–123 and 61–112 mg
h/l for intravenous
doses [136].
Doxycycline appears to be an effective agent for the
treatment of early syphilis and neurosyphilis [137, 138],
and appears to have both antimicrobial and anti-inflam-
matory activities against Borrelia burgdorferi in Lyme
disease [139, 140].
After single oral or intravenous doses of doxycycline
(100 mg), the concentrations found in the lumbar CSF did
530
not exceed 0.1 mg/l, while daily oral administration for
2–10 days gave a level of 0.1–0.76 mg/l, whose mean
value (0.37 mg/l) corresponded to 14 % of the serum
concentration [141].
Based on these data, Yim and colleagues [142] inves-
tigated doxycycline concentrations in the lumbar CSF from
patients affected by neurosyphilis treated with oral doses of
200 mg twice a day for 21 days. The mean doxycycline
total serum level was 5.8 mg/l, and the mean CSF level
was 1.3 mg/l, which exceeded the standard MIC for
Treponema pallidum. Penetration into CSF varied from 11
to 56 %, with a mean of 26 % [142].
In patients treated with oral doxycycline (200 mg once
daily) for neuroborreliosis, the median concentration in
lumbar CSF was 0.6 mg/l after 4 h, corresponding to
3–36 % (mean 15 %) of the simultaneous concentration
in total serum [143]. Although patients with a peak
doxycycline concentration below the median of 6.1 mg/l
in serum had a mean concentration in CSF of 0.62 mg/l
compared with 0.97 mg/l for patients with a higher
concentration in serum, no significant correlation
between the concentrations of doxycycline in serum and
CSF was observed [143]. By contrast, Dotevall et al.
[144] found significantly higher concentrations of CSF
doxycycline when the antimicrobial was administered as
oral doses of 100 mg twice a day (serum mean concen-
trations 4.7 mg/l; CSF mean concentration 0.6 mg/l) or
200 mg twice a day (serum mean concentrations 7.5 mg/
l; CSF mean concentration 1.1 mg/l), showing a steady
state of CSF doxycycline levels on day 7. The penetra-
tion of doxycycline into CSF, compared with serum
concentrations, was lower (15 %) than that reported by
Yim et al. (26 %) [142], probably due to differences in
the time of sampling [144]. Although it is generally
agreed that patients with a damaged BBB have increased
CSF concentrations of antibiotics, the mean concentra-
tion of doxycycline in CSF has been found to be similar
in patients with BBB dysfunction (calculated as the CSF/
serum albumin ratio) (mean 0.77 mg/l with a CSF/serum
concentration ratio of 0.18) and those without BBB
dysfunction (mean 0.83 mg/l with a CSF/serum concen-
tration ratio of 0.13) [144].
2.6.2 Tigecycline
Tigecycline is a glycylglycine antimicrobial with bacte-
riostatic activity. In in vitro evaluations, tigecycline is
active against the most prevalent pathogens including
Gram-positive, Gram-negative, aerobic, and anaerobic
bacteria isolated from diabetic foot infections with 95 % of
MICs B2 mg/l [145]. It is considered an emerging anti-
microbial for the treatment of multidrug-resistant strains,
especially A. baumannii.
A. Di Paolo et al.
Despite its high efficacy against multidrug-resistant
pathogens, tigecycline is not usually recommended in
cases of meningeal infections, based on data showing
modest penetration into the CSF in healthy volunteers
[146, 147]. After intravenous administration of a single
100-mg dose of tigecycline to subjects with noninflamed
meninges [146], mean lumbar CSF and serum AUC24
values, obtained from a total of 17 cases, were 0.46 and
4.18 mg
h/l, respectively, with an AUC24 ratio of 0.11. In
the same study, mean and median CSF concentrations of
tigecycline, measured between 0.92 and 2.1 h after the
start of infusion, were 0.015 and 0.014 mg/l (range
0.011–0.020 mg/l). Individual ratios of CSF-to-serum
concentrations during the sampling period ranged from
0.016 to 0.095, with a mean of 0.055. In comparison, the
respective mean and median CSF concentrations of the six
samples obtained between 18.4 and 26 h after the start of
infusion were 0.025 and 0.022 mg/l (range 0.021–0.033
mg/l). Individual ratios of CSF-to-serum concentration
during this sampling period ranged from 0.33 to 0.52,
with a mean of 0.41 [146].
In contrast to the moderate penetration ratio observed in
subjects with noninflamed meninges, successful treatment
has been reported in patients with multidrug-resistant
pathogen-induced meningitis, receiving parenteral tigecy-
cline [148–150]. Moreover, in a case report, Lengerke et al.
[151] investigated tigecycline brain penetration after
11 days of parenteral administration of 50 mg every 12 h
in a neutropenic patient affected by Enterococcus faecium-
induced meningitis, and carrying an EVD. The authors
observed comparable mean total plasma and CSF steady-
state levels in samples collected within 5–9 h after expo-
sure to 50 mg tigecycline (plasma 0.0366 ± 0.0014 mg/l;
CSF 0.031 ± 0.0045 mg/l) and identical mean trough
levels of tigecycline (plasma 0.0254 mg/l; CSF 0.0250 mg/l).
The reported AUC and the CSF/plasma ratio of tigecycline
concentrations yielded comparable values (0.85) and
peak levels assessed in plasma 30 min after infusion
(0.232 mg/l) could not be reproduced in CSF analyzed at a
corresponding time point (0.0386 mg/l). These data sug-
gest a higher penetration of tigecycline into CSF in cases of
inflamed meninges than that reported in patients with
noninflamed meninges, where CSF peak levels reached,
respectively, 52 and 41 % of the corresponding total
plasma levels [146, 148].
Furthermore, two case reports have been published for
patients with cerebral and meningeal infections. The case
reported by Ray et al. [152] presented a patient affected by
A. baumannii-induced cerebritis that was treated with an
intravenous 100-mg loading dose of tigecycline followed
by 50 mg twice daily. The patient showed CSF concen-
trations at the steady state slightly higher (range
0.035–0.048 mg/l, with a penetration ratio between 0.09
Pharmacokinetics of Antibacterials in CSF
and 0.52) than those reported in patients with noninflamed
meninges at 1.5 and 24 h after dosing (mean
0.015–0.025 mg/l) [146], suggesting a facilitated tigecy-
cline penetration through the compromised BBB. These
data are similar to those reported for a patient affected by
K. pneumoniae meningitis [153], in whom tigecycline
penetration was about 0.35 after the parenteral adminis-
tration of 100 mg every 12 h. The authors suggested a 1:1
tigecycline dose:concentration response in CSF, because
they found twofold higher CSF tigecycline levels when the
patient was treated with a twofold higher dose. Although
these concentrations were less than the MIC determined for
tigecycline, the patient responded clinically and the culture
of CSF, obtained by EVD, became sterile [153].
In conclusion, tigecycline is active against many Gram-
negative and Gram-positive bacteria, but data about its use
in meningitis are limited to some case reports. In these
cases, tigecycline offers good CSF penetration even if
concentrations achieved at current standard doses could be
insufficient to ensure bacterial killing [154].
2.7 Oxazolidinones
Linezolid is the first member of a synthetic class of anti-
microbials, the oxazolidinones, which are effective against
Gram-positive pathogens commonly responsible for CNS
infections. Linezolid has gained attention for the treatment
of CNS infections because of its effectiveness against
multiresistant Gram-positive microorganisms such as
methicillin-resistant Staphylococcus aureus, methicillin-
resistant coagulase-negative Staphylococcus, and vanco-
mycin-resistant Enterococcus with MIC values ranging
from 0.5 up to 4 mg/l [90, 155]. For these reasons, the drug
is often used to prevent or to treat severe Gram-positive
infections at the CNS level, as may occur after neurosur-
gical interventions. The maximal (i.e., bactericidal) thera-
peutic efficacy corresponds to free AUC/MIC values of
80–120 and T[MIC values greater than 80 %, even if the
highest probability to obtain a bactericidal effect is asso-
ciated with T[MIC values of 100 % or Cmin values 4–5
times the MIC value [156]. To date, some studies have
investigated drug pharmacokinetics in plasma and CSF,
which are characterized by wide interpatient variability.
Indeed, careful analysis shows that some patients seem not
to receive a therapeutic benefit on the basis of established
pharmacokinetic/pharmacodynamic cutoff values [52, 57,
157, 158], even in the absence of known factors associated
with pharmacokinetic variability [159].
Despite the observed clinical response variability, the
role of linezolid as a therapeutic option for severe CNS
infections cannot be doubted. Of note, Myrianthefs and
colleagues [160] demonstrated on neurosurgical patients
carrying an EVD and treated with linezolid (600 mg twice
531
daily by 1-h intravenous infusion) that the antimicrobial
achieved maximum and minimum CSF concentrations of
10.8 ± 5.7 and 6.1 ± 4.2 mg/l, respectively, with a mean
penetration ratio of 0.66. This roughly corresponds to the
free plasma fraction of the drug and the mean Cmin value
was higher than the pharmacodynamic breakpoint of 2 mg/l
[90].
Interestingly, the adoption of a different schedule of
drug administration in children (i.e., 10 mg/kg intrave-
nously every 12 h for 3 days instead of every 8 h for
2 days) was associated with a similar linezolid penetration
into ventricular CSF after the last dose [CSF/total plasma
AUC12 ratio 0.98 and CSF/total plasma AUC from 0 to 8 h
(AUC8) ratio 0.95], with a small advantage in terms of
increased mean Cmin values (1.26 vs 1.94 mg/l, respec-
tively) [158]. Furthermore, meningeal inflammation did not
play a role concerning linezolid penetration into CSF. In
agreement with the above-mentioned studies, a wide range
of values from analyzed cases was observed, in terms of
both Cmax and Cmin range, further supporting the variable
disposition of linezolid into CSF. In a case report on lin-
ezolid and rifampicin interaction, Gebhart et al. [128]
hypothesized a role for ABCB1/P-glycoprotein, for which
the drug could represent a substrate, thus explaining in-
terpatient variability. However, results from other studies
do not support ABCB1 or organic anion-transporting
polypeptide (OATP) as transporters involved in trans-
membrane passage of linezolid [161].
In summary, CSF linezolid concentrations have been
found similar to those of the free fraction in plasma [162],
whereas the presence of inflammation seems not to influ-
ence linezolid penetration into CSF. When strains sensitive
to linezolid are identified as causative bacteria, then the
drug represents a possible choice for the treatment of CNS
infections.
2.8 Daptomycin
Daptomycin, a lipopeptide antibiotic with significant
activity against a wide range of Gram-positive bacteria,
offers the possibility to treat infections caused by resistant
Gram-positive strains that could be less sensitive to lin-
ezolid. Its concentration-dependent activity makes the
AUC/MIC parameter the best predictor of drug effective-
ness, ranging from 400 (bacteriostatic effect) up to 800
(bactericidal effect) against methicillin-resistant Staphylo-
coccus aureus and vancomycin-resistant Enterococcus
strains. However, the Cmax/MIC value should be regarded
as an additional parameter when a dense sampling schedule
is not feasible, taking into account a lower limit of thera-
peutic range equal to 100, as suggested by preclinical
studies [163]. Experimental evidence supports the possible
use of daptomycin for the treatment of severe meningitis
532
caused by fluoroquinolone-resistant and/or penicillin-
resistant pneumococcal strains [164]. However, previous
studies described the relatively low penetration of dapto-
mycin into CSF (approximately 6 %), when high peak and
trough concentrations were observed. In fact, in a case
report, intravenous daptomycin (9 mg/kg) reached con-
centrations in total plasma and lumbar CSF of 11.21 and
0.52 mg/l, respectively, with a CSF/plasma ratio of 0.05 in
the presence of inflamed meninges [165]. More recently,
the disposition of a single intravenous dose (10 mg/kg) of
daptomycin has been investigated in neurosurgical patients
with indwelling external CSF shunts (lumbar or ventricular
drainages) [166]. The results demonstrated a CSF/plasma
AUC24 ratio of 0.08, which increased up to 0.11 when the
ratio took into account only the free fraction (approxi-
mately 0.30) of plasma daptomycin. The reduced disposi-
tion of daptomycin into CSF was probably due to the
variability of meningeal inflammation and it was witnessed
by high tmax values (6 h after administration) and reduced
Cmax values (0.12 mg/l), which suggest the difficult
achievement of effective bactericidal concentrations in
CSF. In view of the low variability of daptomycin phar-
macokinetics, further studies are required to assess the role
of the drug for the treatment of CNS infections, even if
bacterial strains are found to be sensitive.
In summary, penetration of daptomycin into CSF is
limited, even if an increased penetration has been docu-
mented in the presence of inflamed meninges. Future
studies should investigate CSF disposition of the drug
when administered at high dosages (i.e., 12 mg/kg).
2.9 Glycopeptides
Glycopeptides possess some characteristics that could be
responsible for their low disposition into CSF. In particular,
hydrophilicity, a molecular mass approaching 1.4 kDa, and
protein binding ranging from 50 % (vancomycin) up to
90 % (teicoplanin) explain why drug disposition into CNS
should be considered inadequate. On the other hand, the
administration of excessively high doses may expose
patients to intolerable toxic effects. However, inflamed
meninges enhance the distribution of vancomycin into CSF
when the drug is administered in suitable doses. In fact,
vancomycin 500–750 mg intravenously every 6 h may be
employed in association with a cephalosporin for the
empiric therapy of acute bacterial meningitis [167]
(Table 2).
Although the effectiveness of vancomycin and teicopl-
anin is time dependent, the vancomycin effect is better
predicted by AUC/MIC values higher than 400, whereas
for teicoplanin a Cmin value greater than the bacterial MIC
is considered predictive of bactericidal effect. In particular,
a trough value higher than 10 and 20 mg/l is required for
A. Di Paolo et al.
moderate and severe infections, respectively. On the basis
of these considerations, some studies have examined the
advantage of continuous infusions over intermittent brief
infusions. In some cases, the adoption of a continuous
infusion may give a benefit [168, 169], while in other cases,
the adoption of an increased dose intensity (at least at the
beginning of the treatment) may be associated with an
improved efficacy [170]. Whether these results may be
transferred or extrapolated to CSF should be carefully
evaluated.
2.9.1 Vancomycin
In patients who have undergone neurosurgery, disruption
of the BBB allows the achievement of therapeutic levels of
vancomycin in CSF [171]. In adult patients, the intrave-
nous administration of vancomycin (1 g) was associated
with mean CSF concentrations of 6.24 ± 3.46 and
2.55 ± 1.13 mg/l in ventricles and 4.49 ± 3.14 and
2.43 ± 0.41 mg/l in the spinal cord at 15–30 min (Cmax)
and 12 h (Cmin) after the end of drug infusion, respectively.
The mean Cmax values were higher than MIC values of
methicillin-resistant S. aureus and methicillin-resistant
coagulase-negative staphylococci strains (2 and 4 mg/l,
respectively) [90, 171].
After administration of a single intravenous dose
(15–20 mg/kg) of vancomycin before insertion of a CNS
shunt in pediatric patients, over 40 % of ventricular CSF
samples had undetectable drug concentrations [172]. On
the contrary, the administration of doses of 10–20 mg/kg
every 6–12 h for a documented or suspected shunt infec-
tion led to mean CSF concentrations of 2.48 ± 0.52 mg/l,
even if the range of variability in both CSF concentrations
(0–6.58 mg/l) and CSF/total plasma AUC ratio
(0.077–0.18) was large enough to assume that in some
patients the schedule was clinically ineffective. These
results suggest poor penetration of vancomycin into CSF,
with concentrations equal or less than 10 % of those
measured in plasma [172]. In summary, the penetration of
vancomycin into CSF depends on both the integrity of the
BBB and the inflammatory meningeal status, which
ensures greater penetration of the drug within CSF when
administered at adequate doses.
2.10 Antituberculosis Drugs
Tuberculous meningitis represents a particular form of
meningitis, often characterized by its occurrence in
immunocompromised patients, especially those affected by
HIV infection in developing countries, where it is a com-
mon cause of bacterial meningitis. As for the pulmonary
form of tuberculosis, several drugs are available for the
treatment of tuberculous meningitis, displaying important
Pharmacokinetics of Antibacterials in CSF
advantages in terms of CSF disposition and achievement of
bactericidal concentrations.
2.10.1 Isoniazid
Isoniazid, which is still indicated as a first-line therapy for its
capability to protect other drugs from mycobacterium
resistance, has been demonstrated to be an agent with a
concentration-dependent activity with AUC/MIC being the
best pharmacokinetic/pharmacodynamic predictive param-
eter [173], even if monitoring of drug effectiveness has been
performed on the basis of maximal CSF concentrations. In
fact, the drug showed its major effectiveness with plasma
Cmax values of 3 mg/l (or better 5 mg/l) [174], while the
achievement of these Cmax values in CSF is possible when
the drug is administered at oral doses of 5 mg/kg, or better at
8–10 mg/kg. Indeed, a study in children affected by tuber-
culous meningitis showed that CSF tmax ranged from 2 to 4 h
postdose and mean ± SD Cmax values were 4.6 ± 2.4 and
11.6 ± 2.7 mg/l following oral doses of 10 and 20 mg/kg,
respectively. Of interest, acetylator genotype significantly
influence Cmax values of isoniazid in CSF [175].
2.10.2 Rifampicin
Rifampicin exerts its bactericidal activity in a concentra-
tion-dependent manner [176], and in particular the maxi-
mal bacterial killing activity is associated with AUC24/MIC
ratio values of approximately 24. Because its plasma pro-
tein binding is about 80 %, it is expected that only 20 % of
the total plasma concentration could be responsible for the
bactericidal effect. Of interest, the emergence of drug
resistance may compromise treatment outcome and a free
drug Cmax/MIC ratio greater than 175 has been found to
prevent the selection of resistant strains of M. tuberculosis
[176]. Further analysis demonstrated that the postantibiotic
effect of more than 5 days was related to the free rifam-
picin Cmax/MIC ratio. Therefore, the achievement of
total and free Cmax concentrations of C9 mg/l (for
MIC & 0.05 mg/l) should be effective for bacterial killing
and mutant strain prevention, respectively [174]. When
rifampicin was administered at doses of 600 mg as 3-h
intravenous infusion, median Cmax values of 0.73 mg/l
were obtained, whereas higher CSF concentrations were
found in children receiving intravenous dosages up to
20 mg/kg [177].
2.10.3 Pyrazinamide
The third antitubercular drug indicated for a classic com-
bination for the treatment of tuberculous meningitis is
pyrazinamide, which displays a good CSF disposition, with
lumbar CSF/total plasma ratios greater than 0.75 [178,
533
179]. In particular, mean Cmax values, occurring 3–5 h
postdose, were higher than 30 mg/l at oral doses of 30 mg/kg
per day. Pyrazinamide shows a concentration-dependent
effect, whose 90 % maximal effect of bacterial killing
occurs with an AUC24/MIC ratio of about 209 in the case
of pulmonary tuberculosis, while T[MIC is associated
with the prevention of mutant strains [176, 180]. However,
Monte Carlo simulation demonstrated that pyrazinamide at
oral doses of 15–30 mg/kg per day led to an AUC0–24/MIC
value in epithelial lining fluid of about 209 in 15–53 % of
patients, suggesting that daily doses of 60 mg/kg ([2
g/day) have greater probability of target attainment [180].
Whether these results can be transposed to pyrazinamide
pharmacokinetics in CSF should be carefully evaluated.
2.10.4 Other Antituberculosis Drugs
Among the other drugs used for the treatment of tubercu-
lous meningitis, streptomycin may be employed at doses of
12–18 mg/kg intramuscularly, and the most appropriate
pharmacokinetic/pharmacodynamic parameter to predict
the best antibacterial effect is the Cmax/MIC ratio, which
should be equal or greater than 8 [181]. For example,
streptomycin CSF levels ranged between 1.6 and 2.2 mg/l
at 2–6 h after a dose of 13 mg/kg, while at higher dosages,
CSF concentrations ranged between 3 and 16 mg/l.
Amikacin and kanamycin show similar pharmacokinetic
behavior for CSF disposition, with Cmax values of 4–8 mg/l
and a Cmax/MIC ratio of 10, after administration of doses of
15 mg/kg per day intravenously. However, in the presence
of MIC values of 0.5–1 and 2–4 mg/l for amikacin and
kanamycin, respectively, it is likely that a bactericidal
effect could be achieved in a minority of patients [182].
A poor penetration into CSF characterizes ethambutol,
for which CSF concentrations ranged from 0 up to
1.98 mg/l at 3–4 h after administration of oral standard
doses [183]. In the case of ethionamide, a time-dependently
active drug with a T[MIC value of &4 h, daily oral doses
of 250 mg in adults were associated with CSF concentra-
tions of 1.0–2.6 mg/l at 3 h after dosing [184]. In children,
a regimen consisting of oral ethionamide at 15 or 20 mg/kg
led to mean lumbar CSF concentrations of 2.17 or 2.83 mg/l,
respectively, 3–4.5 h after drug administration [185], sug-
gesting that high dosing regimens could offer a better
therapeutic benefit.
Finally, cycloserine is characterized by a good CFS
penetration, with mean trough CSF concentrations of
12.8 mg/l after oral doses of 250–500 mg, while Cmax
values of 22.5 and 19.9 mg/l at 9 and 6 h after dosing were
observed in a child and an adult patient, respectively [186].
In conclusion, pyrazinamide and cycloserine display the
highest penetration into CSF with respect to isoniazid,
rifampicin, and other antituberculosis agents, especially
534
ethambutol, which is characterized by a poor disposition.
For some drugs, like ethionamide and isoniazid, increased
dosage has been suggested to increase the probability of
target attainment.
2.11 Fosfomycin, Trimethoprim,
and Sulfamethoxazole
Fosfomycin is used for the treatment of multiresistant
Gram-positive and Gram-negative infections. Despite its
hydrophilic nature, its disposition into CSF is more rapid
than beta-lactams because of its small molecular weight
and negligible plasma protein binding. The pharmacoki-
netics of the drug have been evaluated in patients carrying
an EVD who received the drug at doses of 8 g intrave-
nously three times a day [187]. After single and multiple
intravenous doses, the CSF/total plasma AUC8 ratio was
0.23 ± 0.07 and 0.27 ± 0.08, while CSF Cmax values were
43 ± 20 and 62 ± 38 mg/l, respectively. Fosfomycin is a
time-dependently active agent, and T[MIC values range
from 98 to 61 % for MIC values of 8 and 32 mg/l,
respectively. Therefore, in the presence of bacterial strains
with lower MIC values (i.e., 2 mg/l), the T[MIC may
approach 100 %, suggesting that the drug could be effec-
tive even against ‘‘difficult-to-treat’’ bacteria [29].
The disposition of trimethoprim and sulfamethoxazole
into CSF is higher than beta-lactams, also in the presence
of uninflamed meninges because of their lipophilic nature.
Trimethoprim and sulfamethoxazole are time-dependently
active agents, for which a T[MIC value of 50 % has been
tentatively established [55], even if no differences were
found between T[MIC and AUC/MIC parameters. Lumbar
CSF penetration (calculated as CSF/total serum AUC?
ratio) accounts for 0.18 and 0.12 for trimethoprim and
sulfamethoxazole after oral and 2-h intravenous doses of 5
and 25 mg/kg, respectively [188]. Moreover, only 46 % of
bacterial isolates from N. meningitidis infections were
susceptible to trimethoprim and sulfamethoxazole [55].
In conclusion, trimethoprim and sulfamethoxazole dis-
play a penetration into CSF higher than beta-lactams. For
these reasons, they are currently used for the treatment of
meningitis caused by L. monocytogenes. In the case of
fosfomycin, its rapid disposition into CSF supports its use
in the treatment of multiresistant Gram-positive and Gram-
negative infections as well as ‘‘difficult-to-treat’’ bacterial
infections.
3 Methods to Increase Antibacterial Penetration
into CNS
To circumvent the multitude of barriers inhibiting CNS
penetration of potential therapeutic agents, numerous drug
A. Di Paolo et al.
delivery strategies have been developed [189]. These
strategies generally fall into one or more of the following
categories: [190] manipulation of drugs; disruption of the
BBB; coadministration of antimicrobials with compounds
affecting drug influx/efflux; alternative routes for drug
delivery.
Manipulation of drugs includes the possibility of mod-
ifying molecules, originally unable to enter the BBB, into
more permeable compounds. To date, various models have
been attempted, mainly in oncological settings, to increase
the lipophilicity of a drug by the use of lipophilic analogs
[191] or a lipophilic precursor or prodrug of a parent
compound [192, 193]. Another method is the use of lipo-
somes or lipid-based nanocarriers [194] to surround a
hydrophilic molecule with a sphere of lipids to allow them
to flow through the BBB, as demonstrated for ciprofloxacin
[195]. Polymeric micelles self-assembled from cholesterol-
conjugated polyethylene glycol and anchored with trans-
activator of transcription peptide have been created with a
size of less than 180 nm. Ciprofloxacin was loaded into the
micelles by membrane dialysis and sustained release of the
antimicrobial drug was observed both in vitro (human
astrocytes) and in animal models, providing a promising
carrier of antibiotics across the BBB in a clinical setting
[195].
A further invasive strategy to enhance CNS drug entry
involves the systemic administration of drugs in conjunc-
tion with transient BBB disruption. Entry of drugs into
brain tissue and CSF can be facilitated by the artificial
temporary disruption of the diffusional barriers among
blood, CSF, and brain tissue, by the intra-arterial injection
of hyperosmotic compounds or alkyl glycerols [12].
However, the exact benefit/risk ratio of these procedures is
still under examination and several risk factors, like the
passage of plasma proteins, altered glucose uptake,
expression of heat shock proteins, microembolism, or
abnormal neuronal function [165], suggest a cautious
approach.
Recently, new and potentially safer biochemical tech-
niques have been developed to disrupt the BBB. Ultra-
sounds can be noninvasively delivered to the brain through
the intact skull. When combined with preformed micro-
bubbles, ultrasounds can safely induce transient, localized,
and reversible disruption of the BBB, allowing antibacte-
rial drugs to be delivered. Investigations to date have
shown positive response to ultrasound BBB disruption
combined with therapeutic agent delivery in preclinical
models of Alzheimer’s disease and in neuro-oncological
settings [196–199], and could represent a promising tool
for release of antibacterials into the brain.
All these categories have been shown to work in proof-
of-principle experiments and some have increased the
efficacy of drugs that have very little ability to enter the
Pharmacokinetics of Antibacterials in CSF
brain [190, 200, 201]. However, two factors have limited
the use of these promising approaches: toxicity and
inability to deliver enough drug into the CNS; conse-
quently, these procedures are not yet included in routine
clinical use for treating CNS disorders.
Some authors have reported increased penicillin pene-
tration into CSF when administered together with proben-
ecid, an inhibitor of the multidrug resistance-associated
proteins and of the renal tubular excretion of organic acids,
which enhances the CSF concentrations of penicillins and
cephalosporins [202, 203]. Although this pharmacological
association is not recommended by actual guidelines, this
procedure represents a theoretical aspect of specific trans-
porter blockade that could be a useful tool in cases unre-
sponsive to antimicrobial treatment, secondary to an
insufficient drug concentration at a level of target tissue.
Recent experimental research showed nasal-to-CNS
drug release as a new and promising drug administration
route. Data from preclinical models and investigatory
human clinical trials have shown efficacy and tolerability
of this technique [204], suggesting the feasibility of this
mode of releasing antibacterials, such as cefotaxime, into
the brain [205]. Indeed cefotaxime levels, attained in the
brain following intravenous and intranasal administrations,
were comparable, suggesting that intranasal administration
of the antibacterials could be a potential noninvasive
method of drug transfer that might improve patient com-
pliance [205].
An effective but invasive method to obtain high drug
concentrations within the CNS is intraventricular injection
in addition to intravenous administration, as discussed in
Sect. 1.3. This method is most useful with antibiotics with
a low penetration rate into the CSF and/or with a high
systemic toxicity, which precludes any increase of the daily
systemic dose (e.g., aminoglycosides, vancomycin). It
should be noted that the administration of antibacterials
into the ventricular or lumbar CSF is almost always an off-
label use, and therefore requires a clear indication. For a
large hydrophilic compound such as vancomycin, the
apparent volume of distribution after intraventricular
injection was 250 ml [206]. Vancomycin and other mole-
cules with high molecular weight and strong hydrophilicity
have a long elimination half-life in CSF, because they do
not readily cross the BBB by diffusion after intracisternal
injection. The long half-lives in CSF ensure therapeutic
CSF concentrations with once-daily dosing. The high
interpatient variation of CSF elimination half-lives is
caused by the heterogeneity of critically ill patients (e.g.,
CSF outflow from an external ventriculostomy, obstruction
of ventricles or the subarachnoid space by blood, or drugs
affecting the CSF secretion) [206].
In treatment of infants with Gram-negative meningitis
and ventriculitis by routine use of intraventricular
535
aminoglycosides, in addition to intravenous antibiotics, a
threefold increase in mortality was observed when com-
pared to standard treatment with only intravenous antibi-
otics [207, 208]. However, in a more recent retrospective
study [209], the efficacy of treatment with intraventricular
gentamicin was compared with that of systemic antibiotics
in patients with Gram-negative bacillary ventriculitis or
meningitis after neurosurgery. The intravenous antibacte-
rials were meropenem, cefotaxime, ceftazidime, imipenem,
and trimethoprim-sulfamethoxazole. The patients treated
with intraventricular gentamicin had a significantly higher
cure rate and a lower relapse rate than did those treated
with other intravenous antibiotics with a similar mortality
rate of 19 %.
Because of their relatively low systemic toxicity and high
potential to induce epileptic seizures after intraventricular
application [210], beta-lactam antibiotics are not good can-
didates for this route of administration. However, whether
intrathecal administration of antibacterials should be used to
treat CNS infections is a topic requiring careful evaluation
[208, 211], even though it represents the only chance to treat
infections in the presence of multiresistant organisms,
requiring high antimicrobial CSF concentrations.
4 Conclusions
CNS infections, caused by bacteria with reduced sensitivity
to antimicrobial drugs, represent an increasing challenge
worldwide. Effective treatments of these infections require
careful consideration of several factors that may signifi-
cantly affect the therapeutic activity of antibacterials.
The uneven distribution of anti-infective drugs within
the various CNS compartments, including CSF, is an
important issue, even if simple analysis of drug penetration
cannot sufficiently predict clinical and microbiological
success. The choice of appropriate laboratory and clinical
endpoints (i.e., the measurement of a pharmacokinetic/
pharmacodynamic parameter) may improve the manage-
ment of antibacterial chemotherapy, at both initial acute/
empiric and maintenance stages for long-term periods.
However, some hurdles remain present and will need to be
solved before obtaining maximum effectiveness. Low BBB
permeability mainly affects hydrophilic drugs, namely
beta-lactams and glycopeptides, for which the presence of
inflamed meninges is associated with an increase in CNS
penetration. However, cephalosporins, namely ceftriaxone,
ceftazidime, and the more recent cefepime, play an
important role in modern chemotherapeutic regimens for
the treatment of CNS infections. Interestingly, these drugs
may achieve therapeutic concentrations in CSF, supporting
their use to attain high clinical and microbiological cure
rates, often in association with other drugs. At the same
536
time, meropenem still represents an antimicrobial of choice
in several infections because of the achievement of T[MIC
values associated with a bactericidal effect even in the
presence of a reduced CSF disposition. For beta-lactams,
alternative regimens (i.e., continuous instead of short
infusions) could give a significant advantage in terms of
cure rates. Furthermore, even these drugs have a time-
dependent bactericidal pattern (for which the T[MIC
parameter should be the best predictor of treatment effec-
tiveness) and clinical pharmacological studies suggest that
their efficacy could be monitored and predicted by calcu-
lating the Cmax/MIC ratio.
In comparison with beta-lactams, other classes of anti-
bacterial drugs display better penetration into CSF, as in
the case of fluoroquinolones, antitubercular drugs, and
other compounds, such as linezolid, for which the CSF/
plasma ratio is greater than 0.8 or is approaching 1 in the
case of meningitis. In spite of these relevant characteristics,
it is well known that some drugs display a significant in-
terpatient variability that becomes evident from a survey of
literature and that could be responsible for individual
treatment failures. Among the other drugs, colistin repre-
sents a useful option for the treatment of multidrug-resis-
tant strains of P. aeruginosa, Acinetobacter, and
Klebsiella. However, due to its poor penetration into CSF,
it often should be administered intrathecally while a
loading dose should be considered.
Concerning the drugs under evaluation, the best way to
measure their distribution includes the calculation of the
ratio between AUC-time curves in CSF and in serum,
although a dense sampling schedule is not always feasible.
Similarly, the CSF/plasma ratio, obtained from single time
point concentrations, is susceptible to misinterpretation
when there is a delayed passage of drugs into the liquor
(hysteresis phenomenon). Indeed, the penetration of anti-
biotics from serum into CSF is a complex pharmacokinetic
process, because the concentrations of antibiotics in CSF
are not always parallel to those in serum. The elimination
of an antibacterial from CSF may be two or three times
slower than from serum, while the CSF undergoes a con-
centration process when it passes from ventricles to the
spinal cord. Finally, technical issues (i.e., methods of
measurement, EVD vs lumbar puncture for CSF sampling)
are further points that should be taken into consideration.
The attained concentrations of antimicrobial drugs in
CSF are influenced not only by the degree of meningeal
inflammation but also by the method of administration and
the dose regimens adopted. Further studies are required to
elucidate the relationship between the concentrations and
the bacterial killing rates for available and novel
antibiotics.
In order to facilitate the entry and attainment of bacte-
ricidal concentrations of antimicrobials in the CNS, novel
A. Di Paolo et al.
strategies have been proposed. Among them, alternative
routes of drug administration or BBB disruption appear to
be associated with efficient penetration of antibiotics into
the CSF. However, the duration of this effect seems to be
limited and complete information is still lacking.
Acknowledgments No source of funding was used in the prepara-
tion of this review. The authors have no conflict of interest with
respect to the manuscript.
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