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Pathophysiology of neonatal acute bacterial meningitis

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Journal of Medical Microbiology (2013), 62, 1781–1789 DOI 10.1099/jmm.0.059840-0

Review Pathophysiology of neonatal acute bacterial

meningitis
Tatiana Barichello,1,2,3,4 Glauco D. Fagundes,1,2,3
Jaqueline S. Generoso,1,2,3 Samuel Galvão Elias,1,2,3 Lutiana R. Simões1,2,3
and Antonio Lucio Teixeira5
Correspondence 1
Laboratório de Microbiologia Experimental e Instituto Nacional de Ciência e Tecnologia
Tatiana Barichello Translacional em Medicina, Programa de Pós-Graduação em Ciências da Saúde,
tba@unesc.net Universidade do Extremo Sul Catarinense, Criciúma, SC, Brazil
2
Instituto Nacional de Ciência e Tecnologia Translacional em Medicina (INCT-TM),
Programa de Pós-Graduação em Ciências da Saúde, Unidade Acadêmica de Ciências da Saúde,
Universidade do Extremo Sul Catarinense, 88806-000 Criciúma, SC, Brazil
3
Núcleo de Excelência em Neurociências Aplicadas de Santa Catarina (NENASC),
Programa de Pós-Graduação em Ciências da Saúde, Unidade Acadêmica de Ciências da Saúde,
Universidade do Extremo Sul Catarinense, 88806-000 Criciúma, SC, Brazil
4
Center for Experimental Models in Psychiatry, Department of Psychiatry and Behavioral Sciences,
Medical School, The University of Texas Health Science Center at Houston, Houston, TX, USA
5
Laboratório de Imunofarmacologia, Departamento de Bioquı́mica e Imunologia, Instituto de
Ciências Biológicas, Universidade Federal de Minas Gerais, Belo Horizonte, MG, Brazil

Neonatal meningitis is a severe acute infectious disease of the central nervous system and an
important cause of morbidity and mortality worldwide. The inflammatory reaction involves the
meninges, the subarachnoid space and the brain parenchymal vessels and contributes to neuronal
injury. Neonatal meningitis leads to deafness, blindness, cerebral palsy, seizures, hydrocephalus or
cognitive impairment in approximately 25–50 % of survivors. Bacterial pathogens can reach the
blood–brain barrier and be recognized by antigen-presenting cells through the binding of Toll-like
receptors. They induce the activation of NFkB or mitogen-activated protein kinase pathways and
subsequently upregulate leukocyte populations and express numerous proteins involved in
inflammation and the immune response. Many brain cells can produce cytokines, chemokines and
other pro-inflammatory molecules in response to bacterial stimuli, and polymorphonuclear
leukocytes are attracted, activated and released in large amounts of superoxide anion and nitric
oxide, leading to peroxynitrite formation and generating oxidative stress. This cascade leads to lipid
peroxidation, mitochondrial damage and breakdown of the blood–brain barrier, thus contributing to
cell injury during neonatal meningitis. This review summarizes information on the pathophysiology
and adjuvant treatment of acute bacterial meningitis in neonates.

Introduction mortality worldwide, principally in neonates and children

Meningitis is the most frequent and serious infection of
the central nervous system (CNS) and affects the pia
matter, arachnoids and subarachnoid space (van de Beek
et al., 2004). It is an important cause of morbidity and
Abbreviations: AIM2, absent in melanoma 2; BBB, blood–brain barrier;
BDNF, brain-derived neurotrophic factor; CNS, central nervous system;
CSF, cerebrospinal fluid; ICAM, intercellular adhesion molecule; IRAK,
IL-1 receptor-associated kinase; LFA-1, lymphocyte function-associated
antigen 1; MyD88, myeloid differentiation factor 88; NLR, nucleotide-
binding domain leucine-rich repeat; NLRP3, NLR family, pyrin-domain-
containing 3; NOD2, nucleotide-binding oligomerization domain-2; TLR,
Toll-like receptor.
(Grandgirard & Leib, 2010), with the impact varying
according to the geographical location of the patient and
the causative organism (Kim, 2003).
Neonatal meningitis occurs beyond 28 days of life (Nizet &
Klein, 2011). Several studies conceptualize the neonatal
period as up to 30- or 90-days-old (Furyk et al., 2011).
Bacterial meningitis is a severe infectious disease, with
mortality rates varying between 10 % and 15 %
(Gaschignard et al., 2011), and the incidence is described
as 0.25–6.1 per 1000 live births (developed countries 0.3;
Asia 0.48–2.4; Africa and South Africa 0.81–6.1) (Heath &
Okike, 2010). In a systematic analysis of mortality estimates

059840 G 2013 SGM Printed in Great Britain 1781

T. Barichello and others
in 2010 with time trends since 2000, 7.6 million deaths were
reported to occur in children younger than 5 years old in
2010, with 64.0 % (4.879 million) of these attributable to
infectious causes and 40.3 % (3.072 million) occurring in
neonates. Of these neonatal deaths, 5.2 % (0.393 million)
were a result of sepsis or meningitis (Liu et al., 2012).
The major pathogens are Streptococcus agalactiae and
Escherichia coli K1, which cause at least two-thirds of all
deaths from neonatal meningitis in Europe (Heath et al.,
2011; Holt et al., 2001). Other Gram-negative bacteria
implicated include Klebsiella, Enterobacter, Citrobacter and
Serratia species. (Heath et al., 2011). The remaining causes
include Streptococcus pneumoniae (6 % of cases) and Listeria
monocytogenes (5 % of cases) (Heath & Okike, 2010).
The early- and late-onset patterns of the disease have been
associated with systemic bacterial infections during the first
month of life. Many studies define early-onset bacterial
infection as an infection that occurs in the first 72 h of life;
others define it as an infection that occurs in the first 5 or
6 days of life (Remington, 2011). Group B streptococcal
infection in neonates and young infants is classified by
age at onset (Kim, 2003). Early-onset infection with
Streptococcus agalactiae generally presents at or within
24 h of birth (Heath & Okike, 2010), but can occur
through day 6 of life (Puopolo & Baker, 2012). Late-onset
disease has been variably defined for epidemiological
purposes as occurring after 72 h to 6 days of life; late-
onset infection can manifest after the first week to months
after birth as sepsis and meningitis or other focal infections
(Remington, 2011). Late-onset infection with Streptococcus
agalactiae usually occurs at 4–5 weeks of age (range: 7–
89 days) (Puopolo & Baker, 2012). Early-onset meningitis
is more likely to be caused by Streptococcus agalactiae, E.
coli and L. monocytogenes, while late-onset meningitis may
be caused by Streptococcus agalactiae, E. coli, L. mono-
cytogenes, Gram-negative organisms, Staphylococcus spp.
(Heath et al., 2003) and Streptococcus pneumoniae (Kim,
2008).
Newborns are especially vulnerable to infection. The
cellular and humoral immunities are immature, including
the phagocytic function (Filias et al., 2011; Pong & Bradley,
1999). A full-term newborn has a distinct innate immune
system that is biased towards T-helper type 2/T-helper type
17-polarizing and anti-inflammatory cytokine production,
with relative impairment in T-helper type 1-polarizing
and cytokine production. The deficient expression of
complement and of antimicrobial proteins and peptides
likely contributes to a newborn’s susceptibility to pyogenic
bacteria (Cuenca et al., 2013). The phagocytic ability of the
neutrophils and monocytes of 42 neonates has been
evaluated by the intake of E. coli by phagocytes (Filias
et al., 2011). The phagocytic ability was impaired at birth in
pre- and full-term neonates compared with adults. This
defect was transient, with the phagocytic ability in neonates
reaching the same level as that of adults 3 days after birth.
It is widely believed that the development of the blood–
brain barrier (BBB) proceeds from late gestation and
1782
continues through the postnatal period, and it may be a
time of increased permeability that renders the developing
brain more vulnerable (Zeng et al., 2011). Other authors
have affirmed that adult mechanisms and functionally
effective tight junctions are present in the embryonic brain
and that some transporters are more active during
development than in the adult brain (Ek et al., 2012).
Developing cerebral vessels appear to be more fragile than
in adults and more susceptible to drugs, toxins and
pathological conditions, thus contributing to cerebral
damage and later neurological disorders. After birth, the
loss of defence by efflux transporters in the placenta can
contribute to cerebral damage and later neurological
disorders in the neonatal brain because it is more
defenceless than the fetal brain (Saunders et al., 2012).
Because of these neonatal particularities, bacterial men-
ingitis can cause acute complications involving the brain
parenchymal vessels (vasculitis), ventriculitis, systemic
complications (including pneumonia) and septic shock,
which contribute to an unfavourable outcome (Sellner
et al., 2010). Long-term neurological sequelae, including
deafness, blindness, cerebral palsy, seizures, hydrocephalus
or cognitive impairment, present in approximately 25–
50 % of survivors (de Louvois et al., 2005).
CNS bacterial invasions
Initial bacterial entry into the CNS
Early-onset infections are acquired vertically through
exposure to the micro-organism via the mother’s genital
tract (Remington, 2011). Neonatal infection occurs prim-
arily when micro-organisms ascend from the vagina to the
amniotic fluid after the onset of labour or rupture of the
membranes, although Streptococcus agalactiae can invade
through intact membranes (Verani et al., 2010). Strepto-
coccus agalactiae can be aspirated into the fetal lungs and
might be transferred haematogenously into the CNS (Pong
& Bradley, 1999). The bacteria can cross the BBB by different
mechanisms: via transcellular or paracellular traversal and in
infected phagocytes. Transcellular traversal occurs when the
micro-organism penetrates the cells without any evidence in
the cells or intracellular tight-junction disruption (Kim,
2008). Streptococcus pneumoniae, Streptococcus agalactiae
and E. coli can all cross the BBB via this mechanism (Kim,
2003). To cross the BBB, Streptococcus pneumoniae must
interact with cell wall phosphorylcholine and platelet-
activating factor receptor (Kim, 2008). Streptococcus aga-
lactiae crosses the BBB with the aid of the lipoprotein
laminin-binding protein (Tenenbaum et al., 2007). L.
monocytogenes crosses the BBB by microbial penetration
using transmigration within infected phagocytes; this
mechanism is known as a Trojan horse (Kim, 2008).
Bacterial recognition and immune response
Micro-organisms can replicate within the subarachnoid
space concomitantly with the release of bacterial products,
Journal of Medical Microbiology 62

such as peptidoglycan and cell wall fragments, which are
highly immunogenic and can lead to an increased
inflammatory response in the host (Sellner et al., 2010).
These compounds are recognized by antigen-presenting
cells through binding to pattern-recognition receptors such
as Toll-like receptors (TLRs), a nucleotide-binding domain
leucine-rich repeat (NLR) region-containing family of
proteins (Mook-Kanamori et al., 2011).
Nucleotide-binding oligomerization domain-2 (NOD2) is
activated by cell wall peptidoglycan (Liu et al., 2010; Opitz
et al., 2004). NOD2 has a critical role in the establishment
of the lethal inflammation associated with streptococcal
meningitis through activation of the transcription factor
NFkB and production of inflammatory cytokines (Mook-
Kanamori et al., 2011), as have been demonstrated in
murine microglia and astrocyte cells (Liu et al., 2010). The
NLR family, pyrin-domain-containing 3 (NLRP3) and the
absent in melanoma 2 (AIM2) inflammasomes are
activated by exotoxin pneumolysin and DNA bacteria in
pneumococcal infection, respectively, which mediates the
cleavage of pro-IL-1b into mature IL-1b (Koppe et al.,
2012). Streptococcus agalactiae activates NLRP3 through the
expression of b-haemolysin, an important virulence factor
(Costa et al., 2012). NLRP3 has been implicated in
responses to Staphylococcus aureus, L. monocytogenes,
Klebsiella pneumoniae and E. coli (Davis et al., 2011).
Eleven TLR family members have been described in
humans. These are separated into two broad categories:
members of one group are expressed at the cell surface for
extracellular ligand recognition, while members of the
other group are localized in the endosomal compartment
to recognize pathogen nucleic acids (Hanke & Kielian,
2011). TLRs 1–9 are expressed in microglia cells, whereas
astrocytes express TLRs 2, 3 and 9. Neurons express TLRs
3, 7, 8 and 9. Oligodendrocytes express TLRs 2 and 3.
Streptococcus pneumoniae bacterial compounds, including
peptidoglycans and lipoteichoic acids, are recognized in the
CNS by TLR2 (Mitchell et al., 2010). The exotoxin
pneumolysin is recognized by TLR4 (Malley et al., 2003)
and the bacterial DNA is recognized by TLR9, which is an
intracellular pattern-recognition receptor activated by
CpG (cytosine-phosphate-guanine) (Hemmi et al., 2000).
E. coli interacts through toxin lipopolysaccharide with
TLR4 (Rivest, 2003). In vitro, L. monocytogenes cell wall
components such as lipoteichoic acids are recognized by
TLR2 with the help of CD14 and TLR6 (Flo et al., 2000;
Janot et al., 2008; Seki et al., 2002). The protein flagellin
interacts through TLR5 (Hayashi et al., 2001). Streptococcus
agalactiae interacts with TLR2 through lipoteichoic acid
and through the engagement of TLR7 and/or TLR8 by
microbial RNA (Mook-Kanamori et al., 2011) (Table 1).
TLRs are essential to trigger the immune response during
meningitis, signalling the production of key inflammatory
mediators (Fig. 1) (Hanke & Kielian, 2011).
The majority of TLRs utilize a common intracellular
adaptor protein known as myeloid differentiation factor 88
http://jmm.sgmjournals.org
Pathophysiology of neonatal acute bacterial meningitis
(MyD88) (Koedel, 2009). MyD88 is associated with IL-1
and IL-1 receptor-associated kinase-4 (IRAK4), which is a
serine/threonine kinase that plays an essential role in signal
transduction by Toll/IL-1 receptors (Wang et al., 2006).
Subsequently, IRAK interacts with TNF and the TNF
receptor-associated factor family and provides a link to
NFkB-inducing kinase, resulting in the release and nuclear
translocation of NFkB (Hanke & Kielian, 2011). The NFkB
family comprises a closely associated family of transcrip-
tion factors, which play a key role in the expression of
genes that have been implicated in the development of
accessory cell and leukocyte populations and in the
expression of many proteins involved in inflammation
and the immune response (Tato & Hunter, 2002). NFkB is
a transcriptional activator of various genes involved in the
pathogenesis of meningitis, such as TNF-a, IL-1b, indu-
cible nitric oxide synthase and intercellular adhesion
molecules (Fig. 2) (Kastenbauer et al., 2004; Koedel et al.,
2000).
Neuronal inflammation
Initial immune response
Knowledge of the pathophysiology of bacterial meningitis
in neonates is predominantly based on observations of
human patients and studies with experimental animal
models (Grandgirard & Leib, 2010). A relative comparison
of the ages and stages of human versus rat development has
shown that the neonatal period for rats is from birth until
day 10 of life (Andersen, 2003).
Many brain cells, such as astrocytes, glial cells, endothelial
cells, ependymal cells and resident macrophages, can
produce cytokines and pro-inflammatory molecules in
response to bacterial replication and its components
(Kronfol & Remick, 2000). In a study with 54 human
newborns (30 with meningitis and 24 controls), increased
levels of TNF-a, IL-1b and IL-6 were detected in the
cerebrospinal fluid (CSF) of all of the newborns with
meningitis (Krebs et al., 2005). Elevated levels of pro-
inflammatory mediators in the CSF are normally found in
patients with bacterial meningitis (Lahrtz et al., 1998; van
Furth et al., 1996). In animal models, administration of
TNF-a into the CSF and intravenously has been reported to
cause changes that are characteristic of bacterial meningitis
and lead to BBB breakdown (Rosenberg et al., 1995; Tsao
et al., 2002). TNF-a is a marker of an acute inflammatory
response in children with bacterial meningitis (Mukai et al.,
2006) and is essential for an adequate host immune
response (Aas et al., 2005). IL-1b is an important cytokine
that has potent stimulatory effects on white blood cells and
promotes the adhesion of neutrophils and monocytes in
endothelial cells (Østergaard et al., 2004). In a study of 21
patients with bacterial meningitis, endothelial-derived
adhesion molecules were associated with the extent of
CSF pleocytosis and with concentrations of the pro-
inflammatory cytokines IL-1b and TNF-a in CSF
(Fassbender et al., 1997).
1783
T. Barichello and others

Table 1. Bacterial components and TLRs

Micro-organism TLR agonist TLR Expression of TLR family members in CNS cells

Streptococcus pneumoniae Peptidoglycan 2 Microglia, astrocytes, oligodendrocytes

Lipoteichoic acid 2 Microglia, astrocytes, oligodendrocytes
Pneumolysin 4 Microglia
Bacterial CpG DNA 9 Microglia, astrocytes, neurons
Triacylated lipoprotein 1/2 Microglia
Diacylated lipoprotein 2/6 Microglia
E. coli Lipopolysaccharide 4 Microglia
Triacylated lipoprotein 1/2 Microglia
Diacylated lipoprotein 2/6 Microglia
L. monocytogenes Lipoteichoic acid 2 Microglia, astrocytes, oligodendrocytes
Flagellin 5 Microglia
Triacylated lipoprotein 1/2 Microglia
Diacylated lipoprotein 2/6 Microglia
Streptococcus agalactiae Lipoteichoic acid 2 Microglia, astrocytes, oligodendrocytes
Microbial RNA 7/8 Microglia, neurons
Triacylated lipoprotein 1/2 Microglia
Diacylated lipoprotein 2/6 Microglia

Streptococcus Listeria Streptococcus

Escherichia coli
pneumoniae monocytogenes agalactiae

PRC Lmb
PAF CD46

CpG
LTA DNA FLY RNA
PLY LPS RNA LTA PLY LTA
β-HLY PLY
PGL β-HLY
TLR4 TLR2
TLR2 TLR4 TLR2 TLR5
NO CD14
D TLR6 NLRP3 TLR7
NLRP3

TLR8
TLR9

Fig. 1. Pathophysiology of acute bacterial meningitis. The micro-organism adheres to endothelial cells and may breach the BBB
and be recognized by antigen-presenting cells through the binding of TLRs. TLRs induce the activation of an inflammatory
cascade and express numerous proteins involved in inflammation and the immune response. FLY, flagellin; b-HLY, b-
haemolysin; Lmb, lipoprotein laminin; LPS, lipopolysaccharide; LTA, lipoteichoic acid; PGL, peptidoglycan; PAF, platelet-
activating factor receptor; PLY, pneumolysin; PRC, phosphorylcholine.

1784 Journal of Medical Microbiology 62

 Pathophysiology of neonatal acute bacterial meningitis

LPS PGL inflammatory response and decreases vascular permeability

RNA LTA Cytokines
in bacterial meningitis (Paul et al., 2003). In animal model
FLY PLY Chemokines studies, we determined that TNF-a, IL-1b, cytokine-induced
neutrophil chemoattractant 1 (CINC-1) and IL-6 levels were
TLRs
CpG increased prior to BBB breakdown, and that this breakdown
PLY DNA PGL occurred in the hippocampus and in the cortex after the
induction of neonatal pneumococcal meningitis (Barichello
et al., 2012a) and Streptococcus agalactiae meningitis
(Barichello et al., 2011). We suggest that these cytokines
MyD88 are produced at the site of inflammation and play an
important role in neutrophil infiltration.
IRAK4

Later neutrophil-mediated response

AIM2
NOD
NLRP3
TRAF6
Iκ B
Caspase-1
NFκ B
Fig. 2. Intracellular pathophysiology of bacterial meningitis. TLRs
utilize the common intercellular adaptor MyD88, which is
associated with IRAK4. IRAK4 interacts with TNF receptor-
associated factor (TRAF), thus providing a link to NFkB and the
subsequent release of cytokines and chemokines. Alternatively, the
release of caspase-1 for its transcription in the nucleus may be
mediated by the stimulation of NLRP3 and AIM2 by pneumolysin
(PLY) and bacterial DNA, respectively. FLY, flagellin; IkB, inhibitor
of kB; LPS, lipopolysaccharide; LTA, lipoteichoic acid; PGL,
peptidoglycan; PLY, pneumolysin.
IL-6 has predominantly pro-inflammatory effects such as
fever, leukocytosis and the potent induction of acute-phase
proteins (Gruol & Nelson, 1997), including the synthesis
and secretion of C-reactive protein, serum amyloid A,
fibrinogen, ar-antitrypsin, q-antichymotrypsin and hapto-
globin (Castell et al., 1989). IL-6 acts as an anti-
inflammatory cytokine, and a lack of IL-6 enhances the
The production of cytokines leads to the attraction and
activation of polymorphonuclear leukocytes and the
production of high amounts of reactive oxygen species
(Kastenbauer et al., 2002). Sialyl-LewisX on leukocytes
binds to P- and E-selectin on endothelial cells. This
connection becomes stronger when CXCL8 binds to its
specific receptor on neutrophils, triggering the production
of integrins lymphocyte function-associated antigen 1
(LFA-1) and CX3 (mac-1). Inflammatory cytokines such
as TNF-a are necessary to induce the expression of
intercellular adhesion molecule (ICAM)-1 and -2. The
link between endothelial cells and ICAM-1 allows the
passage of neutrophils in the direction of the gradient of
chemoattractant substances (Fig. 3) (Carlos & Harlan,
1994; Hanna & Etzioni, 2012). This leads to oxidative
stress, which in turn leads to cytokine and chemokine
activation, enhanced neutrophil activation, lipid pero-
xidation, DNA single-strand breaks, mitochondrial
impairment, tyrosine nitration, matrix metalloproteinase
activation and prostaglandin production (Klein et al.,
2006). A study with neonatal rats found that protein
carbonyls and lipid peroxidation were increased in the
hippocampus and cortex during the first hours after
pneumococcal and Streptococcus agalactiae meningitis
induction (Barichello et al., 2011, 2012a).
Reactive oxygen species and calcium can result in
mitochondrial dysfunction, which leads to the release of
apoptosis-inducing factor into the cytosol; apoptosis-
inducing factor has been reported to be responsible for
executing the caspase-independent pathway. Polymorpho-
nuclear leukocytes can also induce the release of cyto-
chrome c from the mitochondria into the cytosol, resulting
in caspase-3 cleavage in a mouse model of pneumococcal
meningitis (Mitchell et al., 2004). In children with bacterial
meningitis, acrolein-lysine (a marker of lipid peroxidation)
and nitrite (a marker of nitric oxide production) have been
reported to be several times higher in during the early
phase of bacterial meningitis compared with children
without meningitis or with aseptic meningitis (Tsukahara
et al., 2002). A positive correlation was found between the
nitric oxide index and lipid peroxide with white blood cells
in the CSF of children with bacterial meningitis (Hamed
et al., 2009). These free radicals are highly reactive and may

http://jmm.sgmjournals.org 1785
T. Barichello and others
Sialyl-LewisX
P- and E-selectin
CNS
Cytokines
Chemokines
Macrophage
Fig. 3. Leukocyte migration. Leukocytes leave the blood and migrate to sites of infection. Sialyl-LewisX on leukocytes binds to
P- and E-selectin on endothelial cells. This connection becomes stronger when CXCL8 binds to its specific receptor on
neutrophils, triggering the production of the integrins LFA-1 and CX3 (mac-1). Inflammatory cytokines such as TNF-a are
necessary to induce the expression of the adhesion molecules ICAM-1 and -2. The link between endothelial cells and ICAM-1
allows the passage of neutrophils in the direction of the gradient of chemoattractant substances.
cause impairment of lipids, proteins, carbohydrates or
nucleic acids, thus increasing the risk of sequelae. Because
of the high lipid content in the brain and low cerebral
antioxidant defences, the CNS is particularly susceptible to
the deleterious properties of oxidative stress (de Menezes
et al., 2009).
Brain-derived neurotrophic factor (BDNF) is widely
distributed throughout the brain and has demonstrated
the ability to protect neurons against damage caused by
oxidative, metabolic and excitotoxic stress (Marini et al.,
2007). BDNF has an important regulatory function in cell
proliferation and exerts neuroprotective effects via the
modulation of synaptic plasticity by regulating dendritic
spines and synaptic density and the expression of synaptic
proteins (Abdallah et al., 2013; Tartaglia et al., 2001).
Novel therapeutic targets in bacterial meningitis
In neonates with suspected bacterial meningitis, empiric
antibiotic treatment should be instituted without delay. In
Wistar rats, early antibiotic administration (i.e. 8 h after
induction), compared with late antibiotic administration
(i.e. 16 h after induction), prevented the cognitive impair-
ments that are typically induced by pneumococcal
meningitis (Barichello et al., 2009). Another significant
factor is the ability of an antimicrobial agent to penetrate
into the BBB and CNS (Honda & Warren, 2009). New
targets are being investigated for adjunctive therapy in
1786
Blood vessel
ICAM-
1 or -2
Gradient of
chemoattractant substances
meningitis. In a rat model, exogenous administration of
the intracerebroventricular BDNF was found to block
caspase-3 and reduce neuronal apoptosis in pneumococcal
meningitis and reduce cortical necrosis in meningitis
caused by Streptococcus agalactiae (Bifrare et al., 2005). In
another study with the rat model of bacterial meningitis,
administration of exogenous BDNF protected and increased
the neuronal cell population from inflammatory brain
injury (Li et al., 2005, 2007). Furthermore, decreased
hippocampal BDNF levels were correlated with memory
impairment in adult rats that were infected with pneumo-
coccal and Streptococcus agalactiae meningitis in the
neonatal period (Barichello et al., 2010, 2013).
Dexamethasone is an anti-inflammatory drug with the
ability to suppress inhibitor of kB (IkB) degradation
(Bhattacharyya et al., 2010), which decreases pro-inflam-
matory cytokines and inhibits the reactive oxygen species
produced by leukocytes (Dandona et al., 1999). Dexameth-
asone aggravated hippocampal apoptosis and learning
deficiency in rat pups infected with Streptococcus pneumo-
niae by intracisternal injection on postnatal day 11 (Leib
et al., 2003) and increased hippocampal neuronal apoptosis
in a rabbit model of E. coli meningitis (Spreer et al., 2006).
In a human study, 52 full-term neonates with bacterial
meningitis were alternately assigned to receive or not
receive dexamethasone; both groups showed a similar
clinical response and similar frequencies of mortality and
sequelae (Daoud et al., 1999). On the other hand,
Journal of Medical Microbiology 62

adjunctive use of dexamethasone was reported to signific-
antly decrease case fatalities and neurological sequelae in a
neonatal population in Nigeria (Airede et al., 2008).
The use of non-bacteriolytic antibiotics has been shown to
be potentially beneficial in the treatment of bacterial
meningitis in infants. In a rat model of pneumococcal
meningitis, daptomycin was more efficient than ceftriaxone
in decreasing the bacterial titre after infection, and only the
animals treated with ceftriaxone showed cortical damage
(Grandgirard et al., 2007). In a rat model of Streptococcus
agalactiae meningitis, animals treated with a monoclonal
antibody against TNF-a had less hippocampal injury than
controls (Bogdan et al., 1997). One strategy with which to
prevent brain damage is to restrict leukocyte recruitment to
the CSF. Fucoidin is a polysaccharide that blocks the
leukocyte receptor L-selectin. Intravenous treatment of rats
with fucoidin at 0, 2, 4 and 6 h after pneumococcal
meningitis induction reduced intracranial pressure and
pleocytosis in the CSF (Angstwurm et al., 1995).
Furthermore, fucoidin injected intracisternally inhibited
the accumulation of CSF leukocytes upon the administra-
tion of antibiotics in experimental meningitis (Granert
et al., 1998).
Reactive oxygen species are produced by resident immune
cells in the brain and by leukocyte recruitment, as part of
the host’s reaction to invasive bacterial infection. To inhibit
the production of oxidative stress, the use of the N-
acetylcysteine and deferoxamine as adjuvant treatment
prevented cognitive impairment in animals submitted to
pneumococcal meningitis (Barichello et al., 2012b). In
another study, infant rats treated with antioxidant drugs,
including N-acetylcysteine, deferoxamine and trylizad-
mesylate, showed reduced cortical injury and mortality
(Auer et al., 2000).
Conclusion
Despite important advances in treatment, neonatal men-
ingitis is one of the most significant infectious diseases of
the CNS, with high mortality and morbidity. Experimental
animal models, despite limitations, provide an under-
standing of the complex pathophysiology of this disease
and suggest new adjunctive therapies.
Acknowledgements
This research was supported by grants from CNPq, FAPESC,
FAPEMIG, UNESC, INCT-TM and the L’Oréal-UNESCO Brazil
Fellowship for Women in Science 2011. The authors declare that they
have no conflicts of interest.
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