Bacterial

Meningoencephalitis
RITA YU MD
DEPARTMENT OF PEDIATRICS
KANGDONG SACRED HOSPITAL, SEOUL
HALLYM UNIVERSITY, COLLEGE OF MEDICINE
Name :Rita Yu, MD

Position: Clinical Assistant Professor
Department of Pediatrics, Kangdong Sacred Heart Hospital
Hallym University Medical Center

Education:
2006 M.D.  Yonsei University, College of Medicine

Post‐graduate Training:
2006 ‐ 2007 Internship, Severance Hospital
2008 ‐ 2011 Residency, Department of Pediatrics, Severance 
Children’s Hospital 
2012 ‐ 2014.09 Clinical Fellow, Division of Pediatric Neurology, 
Department of Pediatrics, Severance Children’s Hospital
2014.10 ‐ 2015.02 Clinical Fellow, Department of Pediatrics, 
Kangdong Sacred Heart Hospital, Hallym University, School of Medicine
2015.03 Clinical Assistant Professor, Department of Pediatrics, Kangdong, 
Sacred Heart Hospital, Hallym University, School of Medicine 
Bacterial Infections of Nervous System

 normally sterile brain

 protected from infection by specialized barriers
 bony skull and the blood–brain barrier
 central nervous system infection : comparatively rare.
 bacterial meningitis 3–5/ 100,000 vs sepsis > 200 /100,000
in USA, 1995
 Schuchat et al., 1997

 Devastating results of CNS infection

 death or significant neurologic sequelae
 vulnerability of brain to infection
 deficient local host defenses : do not suppress multiplication of
pathogens,
 detrimental effects of cerebral blood flow alterations
 when cerebral vasculature involved
 harmful effects of increased intracranial pressure
 due to brain swelling and mass lesions,
 destruction of brain tissue by inflammatory process
 limited repair mechanisms of neuronal tissue

 damage to brain
 not primarily of pathogen invasion
 rather of overwhelming inflammatory response
 Meningitis and meningoencephalitis
 two separate diseases

 Meningitis
 abrupt onset of fever, headache, photophobia, nuchal
rigidity and other meningeal signs predominate

 Meningoencephalitis
 features of both encephalitis and meningitis.
 Meningoencephalitis and Encephalitis
 uncommon responses to common infections.
 most infected patients : mild syndrome of
meningoencephalitis rather than severe encephalitis
 Whitley R. Viral encephalitis. N Engl J Med 1990;323:242-50.

 many cases : viral origin.

Bacterial meningitis
 ‘Meningoencephalitis’ is more appropriate term

 Acute purulent infection within subarachnoid space  CNS

inflammatory reaction
 meninges, subarachnoid space, brain parenchyma all involved in
inflammatory reaction
 coma, seizure activity, increased intracranial pressure, and ischaemic
infarcts.
 (Madhusudan M., 2003.)

 Still die or suffer permanent neurologic sequelae as a result of

meningitis
 Have changed only little
 5~30% to of 50~60% death in adults : high to low income countries
 (De Louvois et al., 2007)
 5~40% cases : only partial recovery with disability sequelae
 (Van de Beek D et al., 2002)
 High mortality predominately seen in
 Streptococcus pneumoniae (S pneumoniae) infections
 Neisseria meningitidis (N meningitidis) : lower mortality

 Children
 Wider range of pathogens
 Lower case fatality rate
 Outcome from bacterial meningitis is influenced by
 Pathogen
 geographical area,
 patient’s access to healthcare and quality of healthcare
system.

 Very few data on risk factors for poor outcomes in low-

income countries.
 anemia and delayed presentation to hospital are
probably important (McCormick 2012; Sudarsanam 2017)
 HIV may influence outcome?
 Goal
 Prevention or prompt diagnosis and aggressive management

 Antibiotics treatment : mainstay!

 High mortality rates, despite effective antibiotics : efforts to
minimise neurological inflammation with adjunctive therapies.
 Adjunctive therapy : corticosteroids, osmotic treatment
 Vaccination
Initial Antibiotic treatment

 Early administration
 Increases survival and reduce morbidity!
 Prospective study of 156 patients with pneumococcal
meningitis in ICU
 Delayed antibiotics tx for > 3 hr  3 mo mortality ↑
 (Auburtin M et al., 2006)

 Empirical antibiotics should be based

 local epidemiology
 patient’s age
 presence of specific underlying diseases or risk factors
Age Bacterial Pathogens

Age <1 month Streptococcus agalactiae, Escherichia coli,

Listeria monocytogenes

Age 1–23 months S agalactiae, E coli, S pneumoniae, Neisseria

meningitidis

Age 2–50 years S pneumoniae, N meningitidis

Immunocompromised S pneumoniae, N meningitidis,

state L monocytogenes, Staphylococcus aureus,
Salmonella spp, aerobic Gram-negative bacilli
(including Pseudomonas aeruginosa)
Recurrent S pneumoniae, N meningitidis,
Haemophilus infl uenzae

Basilar skull fracture S pneumoniae, H infl uenzae, group A

β-haemolytic streptococci

Head trauma; Staphylococci (S aureus and

post-neurosurgery coagulase-negative staphylococci), aerobic
Gram-negative bacilli (including P aeruginosa)
van de Beek, D et al., 2012
Empirical antibiotic therapy

 Vancomycin and ceftriaxone > ceftriaxone alone

 no RCT comparing the combination
 evidence of ceftriaxone resistance more prevalent
amongst penicillin resistant S. pneumoniae isolates
 little or no resistance vancomycin (0% intermediate and
resistance) detected
 Sham DF et al., 2000
Age Bacterial Pathogens Empirical Thearpy

Age <1 month Streptococcus agalactiae, Escherichia coli, Amoxicillin/ampicillin plus

Listeria monocytogenes cefotaxime, or amoxicillin/
ampicillin plus an aminoglycoside
Age 1–23 months S agalactiae, E coli, S pneumoniae, Neisseria Vancomycin plus a third-generation
meningitidis cephalosporin (either cefotaxime or
ceftriaxone)*

Age 2–50 years S pneumoniae, N meningitidis Vancomycin plus a third-generation

cephalosporin (either cefotaxime or
ceftriaxone)*

Immunocompromised S pneumoniae, N meningitidis, Vancomycin plus ampicillin plus

state L monocytogenes, Staphylococcus aureus,
Salmonella spp, aerobic Gram-negative bacilli
(including Pseudomonas aeruginosa)
Recurrent S pneumoniae, N meningitidis,
Haemophilus infl uenzae
either cefepime or meropenem
Vancomycin plus a third-generation
cephalosporin (either cefotaxime or
ceftriaxone)

Basilar skull fracture S pneumoniae, H infl uenzae, group A
β-haemolytic streptococci
Head trauma; Staphylococci (S aureus and
post-neurosurgery coagulase-negative staphylococci), aerobic
Gram-negative bacilli (including P aeruginosa)
Vancomycin plus a third-generation
cephalosporin (either cefotaxime or
ceftriaxone)
Vancomycin plus ceftazidime,
cefepime, or meropenem
van de Beek, D et al., 2012
To optimize antibiotics tx

 Delivery and Effectiveness

 Penetration across the blood–brain barrier

 Amount of disrupted BBB integrity by inflammation,
 Antibiotics size, charge, lipophilicity, protein-binding
ability, and interaction with efflux pumps
 Antibiotic CSF concentration, its bactericidal activity
against causative bacteria
 β-lactam antibiotics
 Slow penetration into CSF,
 very effective bactericidal concentrations by frequent and
high systemic dose
 generally well tolerated (Nau R et al., 2010)

 Aminoglycosides, glycopeptides, and polymyxins :

toxicity with dose escalation
 intrathecal or intraventricular administration?
 Better understanding of CSF concentration and antibiotic
effectiveness could improve clinical outcome

 Continuous infusions?
 Randomized study of 723 African children with bacterial meningitis
 cefotaxime boluses vs. continuous infusion for first 24 h of therapy
 mode of cefotaxime administration did not change morbidity or
mortality
 pneumococcal meningitis group given continuous infusion
 significantly less likely to die or have sequelae
When organism identified

 CSF Gram stain, issolated and in-vitro susceptibility testing

 antibiotic therapy can be modified for optimum treatment
Streptococcus pneumoniae

 Emergence of strains with reduced susceptibility to penicillin

 reduced susceptibility ranges from 25% ~ 50% in some US regions
and even higher in many other countries
 decreased susceptibility to other antibiotics  tx failures in
pneumococcal meningitis

 heptavalent pneumococcal conjugate vaccine

 Overall pneumococcal meningitis rate declined
 Not covered serotypes rates increased
 more susceptible to antibiotics than vaccine serotypes, ex serotype 19A.
 (Hsu HE et al., 2009;)
 Cephalosporin resistance areas
 Vancomycin + cefotaxime or ceftriaxone
 Pending results of in-vitro susceptibility testing

 Vancomycin Doses
 adjunctive dexamethasone  reduce vancomycin penetration into CSF
 A study of 14 patients with bacterial meningitis with adjunctive dexamethasone
 IV vancomycin 15 mg/kg loading  continuous infusion of 60 mg/kg/d
 adequate CSF vancomycin concentrations (mean 7・9 μg/mL)
 (Ricard JD et al., 2007)

 Rifampicin
 few study on efficacy
 combination with a 3rd generation cephalosporin, With or without vancomycin
 When suspected of highly resistant to penicillin or cephalosporins.
 Minimum inhibitory concentration (MIC) of penicillin
and 3rd generation cephalosporins
 treatment can be modified accordingly
 in-vitro susceptibility breakpoints redefined by The
Clinical and Laboratory Standards Institute

 For pneumococcal isolates from patients with meningitis

 Susceptible (MIC ≤0・06 μg/mL)
 Resistant (MIC ≥0・12 μg/mL) to penicillin

 therapeutic approach depends on degree of in-vitro

susceptibility to 3rd generation cephalosporins.
Source : Van de Beek D et al., Advances in treatment of bacterial meningitis Lancet 2012;380:1693-1702
Neisseria meningitidis

 Meningococcal strains with reduced susceptibility to

penicillin have been identified in many countries.
 Spanish study : increased from 9.1% in 1986 to 71.4% in 1997
 Latorre C et al., 2000
 intermediate susceptibility to penicillin (MIC >0・1 μg/mL)
 in 3–4% of US meningococcal isolates (Rosenstein NE et al., 2000)
 2% of isolates in sub-Saharan Africa. (Hedberg ST, et al., 2009)

 increased risk of death or neurological sequelae!

 Current treatment recommendation for meningococcal
meningitis
 penicillin G, amoxicillin, or ampicillin.
 van de Beek D et al., 2006; Brouwer MC et al., 2010; Tunkel AR et al., 2004
 empirically with 3rd-generation cephalosporin (cefotaxime or
ceftriaxone) until results of in-vitro susceptibility

 Reports of
 High-level resistance to chloramphenicol (MIC ≥64 μg/mL)
 ciprofloxacin resistance in some regions of USA
 (Galimand M et al., 1998 ), (Wu HM et al., 2009)

 meningococcal meningitis epidemics in resource-poor settings,

 one IM of long-acting chloramphenicol is sufficient
 Injection of ceftriaxone is equally effective
Haemophilus influenzae

 standard treatment of
 3rd generation cephalosporins > 2nd generation
(cefuroxime), chloramphenicol

 β-lactamase-producing strains of H influenzae

 Chloramphenicol-resistant strains of H influenzae
 resource-poor settings : where often used as 1st line
 β-lactamase-negative ampicillin-resistant strain
 increased rapidly from 6%, 2000  35%, 2004
 also resistant to ceftriaxone.
 Hirakata Y et al., 2009
Bacterial Pathogens Currently Recommended Therapy Comments

Listeria monocytogenes Amoxicillin, ampicillin, or penicillin Gentamicin can reduce mortality.

G + aminoglycoside Trimethoprim-sulfamethoxazole as
alternative treatment.

Streptococcus agalactiae amoxicillin or ampicillin Vancomycin and 3rd generation

penicillin G + aminoglycoside cephalosporins as alternatives

Aerobic Gram-negative bacilli Acinetobacter baumannii meningitis resistant to carbapenems  IV colistin

 meropenem

Staphylococcus aureus Vancomycin and more?

Listeria monocytogenes

 Current treatment recommendation : Amoxicillin, ampicillin, or penicillin G

 addition of an aminoglycoside recommended

 Amoxicillin or Ampicillin alone vs. Amoxicillin or Ampicillin + gentamicin,

 No comparison study done, gentamicin can reduce mortality
 (Mylonakis E, et al., 1998)

 Aminoglycoside can increase rate of kidney injury and mortality.

 (Mitja O et al., 2009)

 Trimethoprim-sulfamethoxazole as alternative treatment

 If allergic to or intolerant of penicillin.
 Trimethoprim-sulfamethoxazole + ampicillin vs. Aminoglycoside + ampicillin
 lower antibiotic failure rate and fewer neurological sequelae (Merle-Melet M et al., 1996)
Streptococcus agalactiae

 Standard treatment of meningitis by group B streptococci

 amoxicillin or ampicillin
 penicillin G + aminoglycoside
 Brouwer MC et al., 2010

 Vancomycin and 3rd generation cephalosporins are alternatives

 Some group B streptococci less sensitive to penicillin (MIC 0・

12–1・0 μg/mL)
 optimum regimen not clear
 efficacy of 3rd generation cephalosporins not established
Aerobic Gram-negative
bacilli
 Multidrug-resistant Gram-negative bacilli emerging
 patients with health-care associated bacterial meningitis
 resistance to 3rd, 4th generation cephalosporins, and carbapenems
 Small range of antibiotic options available

 Outbreaks of meningitis by Escherichia coli strains producing extended-

spectrum β-lactamases
 In neonatal wards can be difficult to control.

 Acinetobacter baumannii meningitis: m/c empirical antibiotic is meropenem

 with or without gentamicin or amikacin given IV or intrathecally (Andes DR et
al., 1999)
 If resistant to carbapenems  IV colistin (usually formulated as colistimethate
sodium) or polymyxin B
 Also given by the intrathecal or intraventricular route.
Staphylococcus aureus

 S aureus meningitis
 usually after neurosurgical procedures or placement of
CSF shunts.

 Standard treatment
 local prevalence of methicillin resistant S aureus;
 Vancomycin?
 Anti-staphylococcal penicillins more for severe S aureus
 empirical use until susceptibility testing results
 (DeLeo FR et al., 2010)
Duration of antibiotic therapy
 Sufficient time necessary
 to kill all bacteria and prevent disease recurrence
 causative bacteria, disease severity, and antimicrobial agent used.

 Uncomplicated meningococcal disease

 one dose of IM ceftriaxone or oily chloramphenicol : WHO rec in
African meningococcal meningitis epidemics
WHO. Standardized treatment of bacterial meningitis in Africa in
epidemic and non-epidemic situations. Geneva: World Health
Organization, 2007

 at least 5 days of treatment for non-epidemic situations, younger

than 24 months, fever/coma/convulsions lasting longer than 24 h
 meta-analysis of 5 controlled trials : shorter (4–7 d) vs longer (7–14d)

 Many authorities in high-income countries

 10–14 days of treatment for pneumococcal meningitis.
 least 7 days for haemophilus and meningococcal meningitis
New antibiotics for meningitis

 Increasing prevalence of resistant bacteria caused meningitis

 New antimicrobial agents!
 data limited to from experimental animal models & case reports.

 Those clinically assessed in patients with bacterial meningitis.

 Cefepime
 Carbapenems
 Fluoroquinolones
 Daptomycin
 Linezolid
 Tigecycline
Cefepime

 4th generation cephalosporin

 broad-range activity and greater stability against β-lactamases,
 including β-lactamases produced by Pseudomonas aeruginosa
 Compared to ceftriaxone and cefotaxime

 better CSF activity? than ceftriaxone, including against penicillin-

resistant S pneumoniae

 Infectious Diseases Society of America (IDSA) guidelines

 cefepime as a second-line agent for H influenzae meningitis,
 cefepime or ceftazidime as empirical 1st tx for post-
neurosurgical meningitis
Carbapenems

 Broadest range of in-vitro activity against Gram (+) and Gram(-)

bacteria amongst β-lactams

 Meropenem
 better CSF penetration than imipenem and doripenem.
 Nau R et al., 2010; Nalda-Molina R et al., 2012

 similar efficacy and safety to cefotaxime or ceftriaxone

 Increased prevalence of carbapenem-resistant Enterobacteriaceae

 novel β-lactamases with direct carbapenem-hydrolysing activity
 Gupta N et al., 2011
Fluoroquinolones

 gatifloxacin and moxifloxacin

 penetrate CSF effectively
 have greater in-vitro activity against Gram (+) bacteria than ciprofloxacin.
 But no clinical trials reported in human beings.
 Only one controlled study in ped bacterial meningitis
 fluoroquinolone trovafloxacin mesilate

 hepatic toxicity and dysglycaemia

 Trovafloxacin and gatifloxacin : withdrawn from many markets.

 IDSA guidelines recommend moxifloxacin

 alternative to 3rd generation cephalosporins + vancomycin
 for meningitis of S pneumoniae strains resistant to penicillin & 3rd generation ] cephalosporins
 absence of supportive clinical data
 Tunkel AR et al., 2004
Daptomycin

 cyclic lipopeptide with solely Gram (+) activity.

 Poor CSF penetration

 could have greater bactericidal activity than vancomycin
against β-lactam-resistant bacteria.

 only case reports

 Daptomycin 6–12 mg/kg once daily), usually with rifampicin,
 for meningitis caused by meticillin-resistant S aureus and
vancomycin-resistant Enterococcus spp.
 Lee DH et al., 2008; Le J et al., 2008
Linezolid

 oxazolidinone that acts only on Gram(+) bacteria.

 never assessed in a controlled trial for bacterial meningitis,
only some case reports
 penetrates CSF well
 associated with cure rates of about 90%.

 standard doses (600 mg every 12 h) might not

achievetherapeutic CSF concentrations  Higher doses and
CSF concentration measurements might be necessary
Tigecycline

 glycycline antibiotic, active against many Gram-(+)

and Gram (-) bacteria.

 Data on bacterial meningitis

 limited mainly to case reports
 Treating multidrug-resistant Acinetobacter meningitis,
 Kim BN et al., 2009

 Standard IV tigecycline doses

 produce subtherapeutic CSF concentrations
Adjunctive
dexamethasone therapy
 Benefit of modulating inflammatory response of
bacterial meningitis
 Experimental animal models : outcome related to
severity of inflammation in subarachnoid space

 randomized controlled trials in Malawian and South

American children
Molyneux EM et al., 2002;
 No benefit of dexamethasone. Peltola H et al., 2007

 one randomised, but not placebo-controlled trial

 no benefit in neonates Scarborough M et al., 2007
 Better reports for adults?
 European controlled trial : adj. dexa given before/with 1st anti
 Reduced risk of unfavourable outcome (15% vs 25%)
 reduction in mortality (7% vs 15%)
 most obvious in pneumococcal meningitis : mortality rate 34% to 14%
 de Gans J et al., 2002

 randomised controlled trials in Malawi and Vietnam

 No benefits? Scarborough M et al., 2007
 increased survival in microbiologically confirmed bacterial meningitis
Nguyen TH et al., 2007

 individual patient data meta-analysis of trials published since 2000

 2029 patients of all age groups from five trials
van de Beek D et al., 2010
 Cochrane review on 2015
 corticosteroid dexamethasone did not significantly reduce death rate
(17.8% versus 19.9%).
 corticosteroids had significantly lower rates of
 severe hearing loss (6.0% versus 9.3%), any hearing loss (13.8% versus
19.0%) and neurological sequelae (17.9% versus 21.6)

 Streptococcus pneumoniae : lower death rate (29.9% versus 36.0%)

 Haemophilus influenzae and Neisseria meningitidis : no effect on
mortality

 high-income countries reduced severe hearing loss, any hearing loss and
short-term neurological sequelae.

 low-income countries : no beneficial effect

 Children
 H. influenzae : decreased hearing loss (4% versus 12%),
 not in other bacteria.
Dexamethasone guidelines

 Adjunctive dexamethasone in patients with suspected or proven

community-acquired bacterial meningitis
 but only in high- income countries?

 Start with or before 1st dose of antibiotics

 for 4 days at a dose of 0.6 mg/kg IV every day
 for children / 10 mg IV every 6 h for adults.

 Stop if not bacterial meningitis, bacterium to be other than H

influenzae or S pneumoniae
 Some advise to continue irrespective of bacterium. (van de Beek D
et al., 2006), given to meningococcal meningitis (Heckenberg SG et
al., 2012), pneumococcal meningitis (Brouwer MC et al., 2010)
 Cognitive deficits aggravated by corticosteroid?
 Animal studies : aggravate learning deficiencies?
 Mook-Kanamori BB et al., 2011

 European study in adults

 no differences in dexamethasone vs. placebo
 Weisfelt M et al., 2003
 potential rare complication of dexamethasone therapy
 pneumococcal meningitis : delayed cerebral thrombosis,
 Delayed cerebral thrombosis can occur 7–19 days after
hospital admission in patients with excellent initial
recovery (Schut ES et al. 1988)
 is dexamethasone effective after first antibiotic dose?
 is dexamethasone effective in patients with septic shock?

 In experimental pneumococcal meningitis, CSF bacterial concentrations at the

start of treatment : more important factor affecting antimicrobial-induced
inflamatory response
 than when dexamethasone therapy was started.

 dexamethasone reduced hearing loss, irrespective of dexa timing

 individual patient data meta-analysis showed
 van de Beek D et al., 2010

 survival benefit in severe sepsis or septic shock in pneumococcal meningitis

 outweighed the risks associated with high-dose steroids
 Brouwer MC et al., 2010; Moran JL et al., 2010
Other adjunctive therapies
 Osmotic therapy : Glycerol
 hyperosmolar agent used to decrease intracranial pressure : oral
or IV

 No beneficial effect in experimental meningitis models (Mook-Kanamori BB et al.,

2011)
 Randomised clinical trial, Finland : might protect against sequelae in children
with bacterial meningitis. (Kilpi T et al., 1995)
 Randomised controlled trial of 654 bacterial meningitis children, South
American countries
 significant decrease in sequelae. (Peltola H et al., 2007)
 Randomised controlled trial of 265 Malawian adults
 adjuvant glycerol : harmful and increased mortality (Ajdukiewicz KM et al., 2011)

 Insufficient evidence to justify routine glycerol treatment in children

 No evidence to support use of glycerol as adjunctive treatment
for acute bacterial meningitis.

 Some beneficial effects of monitoring & lowering of intracranial

pressure use of osmotic diuretics to lower intracranial pressure
 For patients with impending cerebral herniation
 outcomes generally poor in critically ill group of patients
 Reducing deafness in surviving children

 Cochrane 2013, updated 2018

 Antipyretic treatments
 often administered in severely ill patients
 effect on outcome uncertain.

 Randomised controlled trial of 723 children with bacterial meningitis in

Luanda, Angola
 paracetamol for the first 48 hr did not increase survival (Pelkonen T et al., 2011)

 Active cooling leading to hypothermia : beneficial effects in animals with

pneumococcal meningitis. (Mook-Kanamori BB et al., 2011)
 Randomised clinical trial of moderate hypothermia in patients with
severe bacterial meningitis
 Stopped due to safety issues (excess mortality of 51%) (Mourvillier B et al., 2013)
Supportive management
 Close monitoring is mandatory!
 Frequent seizures associated with high mortality rate  consider
anticonvulsant therapy early (Zoons E et al., 2008)
 Blood glucose concentrations need to be monitored : normoglycaemia
 Schut ES et al., 2009

 Goal of fluid management : normovolaemic state

 severe hyponatraemia : fluid maintenance than restriction
 (van de Beek D et al., 2006)

 Kidney function : especially septic shock or pre-existing kidney disease

 Repeat CSF analysis?

 only in those not responded clinically after 48 h of appropriate antimicrobial
therapy.
Take Home Message

 Antibiotics are mainstream treatment

 Earlier the better
 Be aware of antibiotics resistant pathogens

 Adjunctive therapies can be considered

 Dexamethasone
 Osmotic Therapy still controversial

 More therapies to reduce inflammation are underway

Novel therapeutic
approaches
 experimental meningitis models to study modulation of damage
by reactive oxygen species, inhibition of caspase, or other
mediators in the inflammatory, coagulant, or complement
cascades.
 role of non-bacteriolytic antibiotics in contrast

 common non-synonymous single nucleotide poly morphism in

complement component 5 (C5) gene
 unfavourable clinical outcome
 Mook-Kanamori BB et al., 2011
 C5a receptor-deficient mice with pneumococcal meningitis
 decreased brain damage
 adjuvant treatment with C5-specific monoclonal Ab
 prevented death in all wild-type mice with pneumococcal meningitis.
 Woehrl B et al., 2011