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PathophysiologyPathophysiology AndAnd Therapeutics Of Meningitis Therapeutics Of Meningitis Robert J. Konop, Robert J.
PathophysiologyPathophysiology AndAnd
Therapeutics Of Meningitis
Therapeutics Of Meningitis
Robert J. Konop,
Robert J. Konop, Pharm.D.
Pharm.D.
Manager, Manager, Clinical Clinical Formulary Formulary Development Development
Pharmacotherapy, Pharmacotherapy, Assessment Assessment & & Policy Policy
Prime Prime Therapeutics Therapeutics Inc. Inc.
ObjectivesObjectives •• IdentifyIdentify thethe mostmost commoncommon organismsorganisms forfor both both viral
ObjectivesObjectives
•• IdentifyIdentify thethe mostmost commoncommon organismsorganisms forfor
both both viral viral and and bacterial bacterial meningitis meningitis
••
UnderstandUnderstand thethe differencedifference betweenbetween viralviral
and and bacterial bacterial meningitis meningitis
••
Know Know the the composition composition of of normal normal and and
abnormalabnormal CSFCSF
ObjectivesObjectives •• ListList thethe riskrisk factorsfactors forfor CNSCNS infectionsinfections •• Describe
ObjectivesObjectives
•• ListList thethe riskrisk factorsfactors forfor CNSCNS infectionsinfections
••
Describe Describe the the clinical clinical presentation presentation and and
laboratory laboratory results results of of characteristic characteristic
meningitismeningitis
••
Know Know both both empiric empiric and and pathogen--specificspecific pathogen
antibiotic antibiotic regimens regimens in in meningitis meningitis
••
Understand Understand the the recommended recommended prophylactic prophylactic
regimens regimens and and their their indications indications for for use use
DefinitionsDefinitions 1.1. MeningitisMeningitis Inflammation Inflammation of the meninges; abnormal WBC in CSF of
DefinitionsDefinitions
1.1. MeningitisMeningitis
Inflammation
Inflammation
of the meninges; abnormal WBC in CSF
of the meninges; abnormal WBC in CSF
2.2.
Septic Septic versus versus Aseptic Aseptic meningitis meningitis
3.
3.
Encephalitis
Encephalitis
Inflammation Inflammation
of of the the brain brain
4.
4.
Meningoencephalitis Meningoencephalitis
Inflammation Inflammation
of of the the brain brain accompanied accompanied by by meningitis meningitis
MeningesMeninges DuraDura MaterMater (pachymeninges)(pachymeninges) Directly beneath and is adherent to the skull
MeningesMeninges
DuraDura MaterMater (pachymeninges)(pachymeninges)
Directly beneath and is adherent to the skull
Directly beneath and is adherent to the skull
Pia Pia Mater Mater
Lies directly over the brain tissue
Lies directly over the brain tissue
ArachnoidArachnoid
The The middle middle layer layer between between the the dura dura mater mater and and the the pia pia mater mater
SubarachnoidSubarachnoid SpaceSpace
Between Between the the pia pia mater mater and and the the arachnoid arachnoid
Anatomy/Physiology of the CNS Anatomy/Physiology of the CNS CerebrospinalCerebrospinal FluidFluid OriginOrigin
Anatomy/Physiology of the CNS
Anatomy/Physiology of the
CNS
CerebrospinalCerebrospinal FluidFluid
OriginOrigin
Infants:Infants: 4040--60ml60ml
Children: Children:
60--100ml100ml
60
Adults:Adults: 110110--160ml160ml
Viral Meningitis 1.1.IncidenceIncidence 2.2. Clinical Clinical presentation presentation
Viral Meningitis
1.1.IncidenceIncidence
2.2.
Clinical Clinical presentation presentation
Viral Meningitis PathogensPathogens A) A) Enteroviruses Enteroviruses -- 85%85% B) Mumps Virus-- 55--10%10% B)
Viral Meningitis
PathogensPathogens
A)
A)
Enteroviruses Enteroviruses -- 85%85%
B) Mumps Virus-- 55--10%10%
B)
Mumps Virus
C)
C)
Lymphocytic Lymphocytic choriomeningitis choriomeningitis virus virus
D)
D)
Herpes Herpes Simplex Simplex Virus Virus
HSVHSV--22
ViralViral MeningitisMeningitis OtherOther PathogensPathogens 10%: 10%: adenoviruses, adenoviruses, poliovirus,
ViralViral MeningitisMeningitis
OtherOther PathogensPathogens
10%: 10%:
adenoviruses, adenoviruses, poliovirus, poliovirus,
rhinoviruses, influenza A&B, rotavirus,
rhinoviruses, influenza A&B, rotavirus,
CMV, CMV,
coronavirus, coronavirus, Varicella--Zoster Varicella Zoster virus, virus,
EpsteinEpstein--BarrBarr virusvirus
EnterovirusesEnteroviruses •• GroupGroup AA coxsackiecoxsackie 2323 serotypesserotypes 14% 14% of of the the cases
EnterovirusesEnteroviruses
•• GroupGroup AA coxsackiecoxsackie
2323 serotypesserotypes
14% 14%
of of the the cases cases
••
Group B coxsackiecoxsackie
Group B
6 6 serotypes serotypes
12% 12%
of of the the cases cases
••
EchovirusesEchoviruses
3131
serotypesserotypes
75
75 %of the cases
%of the cases
EnterovirusesEnteroviruses RespiratoryRespiratory EyeEye CommonCommon coldcold PharyngitisPharyngitis Acute Acute
EnterovirusesEnteroviruses
RespiratoryRespiratory
EyeEye
CommonCommon coldcold
PharyngitisPharyngitis
Acute Acute hemorrhagic hemorrhagic
conjunctivitisconjunctivitis
HeartHeart
PneumoniaPneumonia
MyopericarditisMyopericarditis
GastrointestinalGastrointestinal
SkinSkin
VomitingVomiting
DiarrheaDiarrhea
AbdominalAbdominal painpain
ExanthemExanthem
NeurologicNeurologic
MeningitisMeningitis
EnterovirusesEnteroviruses MostMost commoncommon-- 8585--95%95% ofof thethe casescases SeasonalSeasonal Late summer to
EnterovirusesEnteroviruses
MostMost commoncommon-- 8585--95%95% ofof thethe casescases
SeasonalSeasonal
Late summer to fall
Late summer to fall
Fecal Fecal to to oral oral route route
Effects Effects all all age age groups groups
Typically Typically < < 1 1 year year old old
MumpsMumps VirusVirus ParotitisParotitis Meningitis occurs in 10--30% Meningitis occurs in 10 30% of the cases
MumpsMumps VirusVirus
ParotitisParotitis
Meningitis occurs in 10--30%
Meningitis occurs in 10 30% of the cases
of the cases
Encephalitis is rare
Encephalitis is rare
Second Second most most common common viral viral meningitis meningitis
10 10 to to 20% 20%
Peak Peak late late winter winter to to early early spring spring
Humans Humans only only natural natural hosts hosts
Lymphocytic Lymphocytic Choriomeningitis Choriomeningitis VirusVirus NonspecificNonspecific prodromeprodrome
Lymphocytic Lymphocytic Choriomeningitis Choriomeningitis
VirusVirus
NonspecificNonspecific prodromeprodrome
MeningitisMeningitis
Chronic infection of the house mouse
Chronic infection of the house mouse
Infected Infected rodent rodent
Common Common in in the the winter winter
Herpes Simplex Virus Herpes Simplex Virus HSVHSV--22 Neonates Neonates during during birth birth Sexually active
Herpes Simplex Virus
Herpes Simplex Virus
HSVHSV--22
Neonates Neonates during during birth birth
Sexually active adults
Sexually active adults
Treatment Viral Meningitis Treatment Viral Meningitis SUPPORTIVESUPPORTIVE CARECARE Antibiotics Antibiotics until until
Treatment Viral Meningitis
Treatment Viral Meningitis
SUPPORTIVESUPPORTIVE CARECARE
Antibiotics Antibiotics until until bacterial bacterial meningitis meningitis is is ruled ruled
outout
SeizureSeizure controlcontrol
Symptom control
Symptom control
AcyclovirAcyclovir
Bacterial Meningitis Incidence:Incidence: 0.20.2--2.9 2.9 cases/100,000/year cases/100,000/year (1986) (1986)
Bacterial Meningitis
Incidence:Incidence:
0.20.2--2.9 2.9 cases/100,000/year cases/100,000/year (1986) (1986)
0.20.2--1.1
1.1
cases/100,000/year (1995)
cases/100,000/year (1995)
Very Very Young Young and and Very Very Old Old
Dramatic Dramatic decrease decrease in in H.H. fluflu
MortalityMortality
SequelaeSequelae
Incidence and Mortality Rate Incidence and Mortality Rate Organism % of Total Cases Annual Incidence
Incidence and Mortality Rate
Incidence and Mortality Rate
Organism
% of Total Cases
Annual Incidence
Fatality
Rate (%)
1986
1995
1986
1995
1986
1995
H.
flu
45
7
2.9
0.2
3
6
S.
pneumo
18
47
1.1
1.1
19
21
N.
menin.
14
25
0.9
0.6
13
3
GBS
5.7
12
0.4
0.3
12
7
L.
mono
3.2
8
0.2
0.2
22
15
other
15
1.0
18
* * Bacterial Bacterial Meningitis Meningitis in in the the United United States States in in 1995,NJM, 1995,NJM, October October 2, 2, 1997, 1997, 337 337 (14) (14) 970--976.976. 970
Bacterial Meningitis MostMost commoncommon organismsorganisms byby population:population: 00--4 4 weeks: weeks: GBS,
Bacterial Meningitis
MostMost commoncommon organismsorganisms byby population:population:
00--4 4 weeks: weeks:
GBS, GBS,
E.
E.
coli, coli, L. L. monocytogenes, monocytogenes, other other
gram gram negatives negatives
44--12 weeks:
12 weeks:
GBS,
GBS,
E.
E.
coli, L. monocytogenes, H.
coli, L. monocytogenes, H.
influenzae,influenzae, S.S. pneumoniaepneumoniae
3mo3mo--44 yrsyrs::
N.
N.
meningitidis, meningitidis, S. S.
pneumoniae pneumoniae
, , H. H.
influenzaeinfluenzae
55--99 yrsyrs::
N.
N.
meningitidis, meningitidis, S. S.
pneumoniae/H. pneumoniae/H.
influenzaeinfluenzae
Bacterial Meningitis 99--1818 years:years: N.N. meningitidis,meningitidis, S.S. pneumoniae,pneumoniae, H.H.
Bacterial Meningitis
99--1818 years:years:
N.N. meningitidis,meningitidis, S.S. pneumoniae,pneumoniae, H.H.
influenzaeinfluenzae
1818--60
60 years:
years:
S.
S.
pneumoniae, pneumoniae, N. N.
meningitidis meningitidis
> 60 years:
> 60 years:
S.
S.
pneumoniae, N.
pneumoniae, N.
meningitidis, L.
meningitidis, L.
monocytogenes, monocytogenes, other other gram gram negatives negatives
NeurosurgNeurosurg::
S.
S.
aureus, aureus, S. S. epidermidis, epidermidis, gram gram
negativesnegatives
Closed Closed Head: Head:
S.
S.
pneumoniae, pneumoniae, H. H.
influenzae influenzae
Open Open Head: Head:
S.
S.
aureus, aureus, gram gram negatives negatives
Pathogenesis BacterialBacterial InvasionInvasion ParameningealParameningeal focus/colonizationfocus/colonization
Pathogenesis
BacterialBacterial InvasionInvasion
ParameningealParameningeal focus/colonizationfocus/colonization
Adhesions, binding receptors, pili
Adhesions, binding receptors, pili
HematogenousHematogenous spreadspread
ParameningealParameningeal seedingseeding
Colonization Colonization of of hardware hardware
Direct Direct inoculation inoculation
Pathogenesis BacterialBacterial elementselements -- inflammatoryinflammatory responseresponse
Pathogenesis
BacterialBacterial elementselements -- inflammatoryinflammatory responseresponse
Endotoxin/LipopolysaccharideEndotoxin/Lipopolysaccharide
PeptidoglycanPeptidoglycan
LipoteichoicLipoteichoic acidacid
Release Release of of inflammatory inflammatory mediators mediators by by
astrocytes, astrocytes, microglial/endothelial microglial/endothelial cells cells
TNFTNF alphaalpha
ILIL--11
Pathophysiology •• Reduced cerebral perfusion secondary to edema Reduced cerebral perfusion secondary to edema
Pathophysiology
••
Reduced cerebral perfusion secondary to edema
Reduced cerebral perfusion secondary to edema
••
Cerebral Cerebral ischemia ischemia secondary secondary to to thrombosis thrombosis
•• VasculitisVasculitis
••
Alteration Alteration of of cerebral cerebral blood blood flow flow
••
Direct Direct neuronal neuronal cell cell damage damage secondary secondary to to
bacterial bacterial elements, elements, activated activated leukocytes, leukocytes,
cytokines, cytokines, and and other other inflammatory inflammatory mediators mediators
Pathophysiology IncreasedIncreased intracranialintracranial pressurepressure Vasogenic edema ---- cytokines act on
Pathophysiology
IncreasedIncreased intracranialintracranial pressurepressure
Vasogenic edema ---- cytokines act on
Vasogenic edema
cytokines act on
endothelial endothelial cells cells to to damage damage the the BBB BBB
Cytotoxic edema ---- direct damage to cells allowing
Cytotoxic edema
direct damage to cells allowing
buildup buildup of of intracellular intracellular water water
Interstitial edema ---- obstruction of CSF flow and
Interstitial edema
obstruction of CSF flow and removal
removal
BrainBrain herniationherniation
Risk Factors 1.1. RespiratoryRespiratory tracttract infectioninfection 2.2. OtitisOtitis mediamedia 3.3.
Risk
Factors
1.1. RespiratoryRespiratory tracttract infectioninfection
2.2. OtitisOtitis mediamedia
3.3. MastoiditisMastoiditis
4.
4.
Head Head trauma trauma
5.5.
SplenectomySplenectomy
6.
6.
Sickle Sickle cell cell disease disease
7.
7.
Immunosuppressive Immunosuppressive therapy therapy
8.
8.
Immunocompromised Immunocompromised host host
9.
9.
Alcoholic Alcoholic patients patients
10.Patients 10.Patients with with hardware hardware (shunts, (shunts, etc.) etc.)
Clinical Presentation PhysicalPhysical signs/symptoms:signs/symptoms: FeverFever HeadacheHeadache
Clinical Presentation
PhysicalPhysical signs/symptoms:signs/symptoms:
FeverFever
HeadacheHeadache
PhotophobiaPhotophobia
Nausea/vomitingNausea/vomiting
Mental Mental status status changes changes
StiffStiff neck/backneck/back
Positive Positive Brudzinski's Brudzinski's sign sign
Positive Positive Kernig's Kernig's sign sign
DeafnessDeafness
SeizuresSeizures
Focal Focal neurologic neurologic deficit deficit
HydrocephalusHydrocephalus
LaboratoryLaboratory StudiesStudies LumbarLumbar PuncturePuncture CSF CSF cell cell count count CSFCSF
LaboratoryLaboratory StudiesStudies
LumbarLumbar PuncturePuncture
CSF CSF cell cell count count
CSFCSF chemistrieschemistries
CSF gram stain
CSF gram stain
CSFCSF cultureculture
BloodBlood CultureCulture
Sputum
Sputum Culture/Urine Culture
Culture/Urine Culture
Peripheral Peripheral CBC CBC
and and Electrolytes Electrolytes
Clinical Presentation and Diagnosis Abnormal CSF-findings by type of meningitis ProteinProtein GlucoseGlucose
Clinical Presentation
and
Diagnosis
Abnormal CSF-findings by type of meningitis
ProteinProtein
GlucoseGlucose
TypeType
WBC(mm2)WBC(mm2)
DiffDiff (%)(%)
(mg/L)(mg/L)
(mg/(mg/dLdL))
NMLNML
<
<
10
10
BactBact
>50>50 lymphslymphs
>90>90 PMN'sPMN's
>50>50 lymphslymphs
<< 5050
3030--7070
400400--100,000100,000
8080--500500
ViralViral
55--500500
3030--150150
FungalFungal 4040--400400
>50>50 lymphslymphs
4040--150150
T.B.T.B.
100100--1,000
1,000
>50 >50 lymphs lymphs
4040--400400
<< 3535
NML/lowNML/low
NML/lowNML/low
NML/lowNML/low
Clinical Presentation and Diagnosis BacterialBacterial antigenantigen detectiondetection teststests 69% 69% accurate
Clinical Presentation
and
Diagnosis
BacterialBacterial antigenantigen detectiondetection teststests
69%
69%
accurate when positive cultures
accurate when positive cultures
Useful when antibiotics were given before the CSF
Useful when antibiotics were given before the CSF culture was
culture was
takentaken
May react to other organisms
May react to other organisms
OtherOther teststests
Counterimmunoelectrophoresis Counterimmunoelectrophoresis (CIE) (CIE) and and latex latex fixation fixation
(encapsulated (encapsulated organisms) organisms)
Limulus Limulus lysate lysate assay assay (gram--negativenegative (gram endotoxin)endotoxin)
Common Bacterial Organisms HaemophilusHaemophilus influenzaeinfluenzae Peak Peak incidence: incidence: 6--12 6 12
Common
Bacterial Organisms
HaemophilusHaemophilus influenzaeinfluenzae
Peak Peak incidence: incidence: 6--12 6 12 months months of of age: age:
declines declines after after 24 24
months months of of age age
Deafness =
Deafness = 6%
6%
Coma/seizures Coma/seizures common common
Close Close contacts contacts are are 200--10001000 200 xx riskrisk
Resistance Resistance pattern pattern is is growing growing throughout throughout the the
U.S. U.S.
Dramatic decrease in cases since 1990
Dramatic decrease
in cases since 1990
Common Bacterial Organisms NeisseriaNeisseria meningitidismeningitidis Usually Usually occurs occurs winter/spring
Common
Bacterial Organisms
NeisseriaNeisseria meningitidismeningitidis
Usually Usually occurs occurs winter/spring winter/spring
Five Five main main serogroups: serogroups: A, A, B, B, C, C, Y, Y,
and W--135 (A
and W 135 (A
andand CC----epidemics;epidemics; BB----individual cases; Y
individual cases; Y----
pneumonia)pneumonia)
May May present present with with a a characteristic characteristic immune immune
reactionreaction 1010--14 14 days days after after infection infection (fever, (fever,
arthritis, arthritis, pericarditis). pericarditis). Rx Rx with with NSAID's NSAID's
Common Common Bacterial Organisms Bacterial Organisms NeisseriaNeisseria meningitidismeningitidis 50% 50% die die
Common
Common Bacterial Organisms
Bacterial Organisms
NeisseriaNeisseria meningitidismeningitidis
50% 50%
die die within within
the
the first 24 hours
first 24 hours
Coma and seizures are uncommon
Coma and seizures are uncommon
DeafnessDeafness == 10.5%10.5%
Close Close contacts contacts are are 500--1000x1000x 500 riskrisk
No problem with penicillin resistance yet
No problem with penicillin resistance
yet
Common Bacterial Organisms StreptococcusStreptococcus pneumoniaepneumoniae Gram Gram positive positive diplococci
Common
Bacterial Organisms
StreptococcusStreptococcus pneumoniaepneumoniae
Gram Gram positive positive diplococci diplococci
"Pneumococcus""Pneumococcus"
DeafnessDeafness = 31%
= 31%
Coma Coma and and seizures seizures are are more more common common
Resistance Resistance is is becoming becoming a a problem problem
Common Bacterial Organisms ListeriaListeria monocytogenesmonocytogenes Peak Peak incidence incidence in in summer/early
Common
Bacterial Organisms
ListeriaListeria monocytogenesmonocytogenes
Peak Peak incidence incidence in in summer/early summer/early fall fall
Gram Gram positive positive rod rod (coccobacilli) (coccobacilli)
Most Most common common ages: ages:
Very Very young young (< (< 3 3 months) months)
Older Older (> (> 60 60 years) years)
Susceptible Susceptible to to ampicillin ampicillin
AntibioticAntibiotic TherapyTherapy FactorsFactors EnhancingEnhancing AntimicrobialAntimicrobial PenetrationPenetration
AntibioticAntibiotic TherapyTherapy
FactorsFactors EnhancingEnhancing AntimicrobialAntimicrobial PenetrationPenetration
Small Small MW MW
Unionized Unionized at at physiologic physiologic pH pH
Lipid soluble
Lipid soluble
Large Large Free Free Fraction Fraction
Factors Factors Reduce Reduce Antibiotic Antibiotic Activity Activity
Low Low pH pH
of of fluid fluid
High High concentration concentration of of protein protein in in fluid fluid
High High temperature temperature of of fluid fluid
AntibioticAntibiotic TherapyTherapy WithoutWithout inflamedinflamed meningesmeninges CChloramphenicolhloramphenicol
AntibioticAntibiotic TherapyTherapy
WithoutWithout inflamedinflamed meningesmeninges
CChloramphenicolhloramphenicol
RRifampinifampin
II NHNH
SSulfonamidesulfonamides
TTrimethoprimrimethoprim
TTriazoleriazole antifungalsantifungals-- fluconazole, fluconazole,
itraconazole itraconazole
NeedsNeeds InflammationInflammation PenicillinPenicillin CefuroximeCefuroxime AmpicillinAmpicillin
NeedsNeeds InflammationInflammation
PenicillinPenicillin
CefuroximeCefuroxime
AmpicillinAmpicillin
CeftizoximeCeftizoxime
CarbenicillinCarbenicillin
CeftazidimeCeftazidime
CiprofloxacinCiprofloxacin
TicarcillinTicarcillin (clavulanate)(clavulanate)
QuinolonesQuinolones
MezlocillinMezlocillin
ImipenemImipenem
AztreonamAztreonam
Piperacillin (tazobactam)
Piperacillin (tazobactam)
VancomycinVancomycin
Questionable Questionable concentrations concentrations AminoglycosidesAminoglycosides GentamicinGentamicin
Questionable
Questionable concentrations
concentrations
AminoglycosidesAminoglycosides
GentamicinGentamicin
StreptomycinStreptomycin
AmikacinAmikacin
KanamycinKanamycin
TobramycinTobramycin
PolymyxinPolymyxin

TreatmentTreatment

EmpiricEmpiric choicechoice ofof antibiotic:antibiotic: 00--4 4 weeks: weeks: ampicillin/cefotaxime ampicillin/cefotaxime
EmpiricEmpiric choicechoice ofof antibiotic:antibiotic:
00--4 4 weeks: weeks: ampicillin/cefotaxime ampicillin/cefotaxime or or
ampicillin/gentamicinampicillin/gentamicin
44--12 12 weeks: weeks: ampicillin/cefotaxime ampicillin/cefotaxime
3mo3mo--4 4 years: years: vancomycin/ceftriaxone vancomycin/ceftriaxone or or
cefotaximecefotaxime

TreatmentTreatment

55--99 years:years: vancomycin/ceftriaxonevancomycin/ceftriaxone oror cefotaximecefotaxime 99--18 18 years: years:
55--99 years:years: vancomycin/ceftriaxonevancomycin/ceftriaxone oror cefotaximecefotaxime
99--18 18 years: years: vancomycin/ceftriaxone vancomycin/ceftriaxone or or
cefotaximecefotaxime
1818--60 60 years: years: vancomycin/ceftriaxone vancomycin/ceftriaxone or or
cefotaximecefotaxime
> 60 years: ampicillin/ceftriaxone or
> 60 years: ampicillin/ceftriaxone
or
ampicillin/cefotaximeampicillin/cefotaxime
Treatment DefinitiveDefinitive ChoiceChoice ofof AntibioticAntibiotic H. H. influenzae: influenzae:
Treatment
DefinitiveDefinitive ChoiceChoice ofof AntibioticAntibiotic
H.
H.
influenzae:
influenzae:
ßß--lactamaselactamase ((--) ampicillin ampicillin
)
ßß--lactamase (+) cefotaxime or
lactamase (+) cefotaxime or
ceftriaxoneceftriaxone
N.
N.
meningitidis: meningitidis: penicillin penicillin G G or or ampicillin ampicillin
L. monocytogenes:
L.
monocytogenes:
ampicillin ampicillin
TreatmentTreatment Enterobacteriaceae:Enterobacteriaceae: cefotaximecefotaxime P. P. aeruginosa: aeruginosa:
TreatmentTreatment
Enterobacteriaceae:Enterobacteriaceae: cefotaximecefotaxime
P.
P.
aeruginosa: aeruginosa: ceftazidime/tobramycin ceftazidime/tobramycin
S.S. aureus:aureus:
S.
S.
MSSA:MSSA: nafcillinnafcillin
MRSA:MRSA: vancomycinvancomycin
epidermidis: epidermidis: vancomycin/rifampin vancomycin/rifampin
TreatmentTreatment StreptococcusStreptococcus pneumoniaepneumoniae Sensitive:Sensitive: PenicillinPenicillin Penicillin
TreatmentTreatment
StreptococcusStreptococcus pneumoniaepneumoniae
Sensitive:Sensitive: PenicillinPenicillin
Penicillin MIC < 0.06 µg/mL
Penicillin MIC < 0.06 µg/mL
Intermediate Intermediate Resistance: Resistance: Third Third Generation Generation
Penicillin Penicillin MIC MIC 0.12 0.12 -- 11 µg/mLµg/mL
Ceftriaxone
Ceftriaxone MIC < 0.5 µg/mL
MIC < 0.5 µg/mL
Resistant: Resistant: Vancomycin Vancomycin + + Third Third Generation Generation
Penicillin Penicillin MIC MIC > > 2 2 µg/mL µg/mL
Ceftriaxone
Ceftriaxone MIC > 2 µg/mL
MIC > 2 µg/mL
DexamethasoneDexamethasone •• BlocksBlocks TNFTNF alphaalpha andand ILIL--11 releaserelease •• Decreases ICP,
DexamethasoneDexamethasone
•• BlocksBlocks TNFTNF alphaalpha andand ILIL--11 releaserelease
••
Decreases ICP, CNS edema, fever duration, and
Decreases ICP, CNS edema, fever duration, and
CSF CSF lactate lactate and and protein protein levels levels
••
Increased CSF glucose level
Increased CSF glucose level
••
Decreases Decreases neurologic neurologic complications complications (e.g. (e.g. ataxia, ataxia,
seizures, focal deficit) and hearing loss by
seizures, focal deficit) and
hearing loss by
approximatelyapproximately 50%50%
Children Children with with H.H. influenzaeinfluenzae typetype BB
DexamethasoneDexamethasone Indication:Indication: >> 66 weeksweeks ofof age,age, andand clinicalclinical CSFCSF
DexamethasoneDexamethasone
Indication:Indication: >> 66 weeksweeks ofof age,age, andand clinicalclinical CSFCSF
findings findings of of H. H. flu flu meningitis meningitis
0.15 mg/kg/dose IV Q6H x 4 days
0.15 mg/kg/dose
IV Q6H x 4 days
First dose
First dose given with/before antibiotics
given with/before antibiotics
Dexamethasone/Antibiotic Interaction SignificantSignificant reductionreduction ofof vancomycin/BBBvancomycin/BBB
Dexamethasone/Antibiotic Interaction
SignificantSignificant reductionreduction ofof vancomycin/BBBvancomycin/BBB
penetrationpenetration
Somewhat Somewhat lower lower CSF CSF concentrations concentrations of of
ceftriaxoneceftriaxone

Dexamethasone/AntibioticDexamethasone/Antibiotic

InteractionInteraction ParisParis et.al.et.al. S. S. pneumoniae pneumoniae susceptibility susceptibility in in area area
InteractionInteraction
ParisParis et.al.et.al.
S. S. pneumoniae pneumoniae susceptibility susceptibility in in area area
IfIf resistantresistant isis aa probabilityprobability thenthen useuse ceftriaxoneceftriaxone
or or cefotaxime cefotaxime and and vancomycinvancomycin withwith
dexamethasonedexamethasone
Found Found vancomycin vancomycin significant significant for for killing killing
bacteria bacteria (4 (4 times times MIC MIC ) )
Treat Treat for for minimum minimum of of 10 10 days days
Prevention VaccinesVaccines a.a. N.N. meningitidismeningitidis covers serotypes A, C, Y, W--135135 covers serotypes
Prevention
VaccinesVaccines
a.a.
N.N. meningitidismeningitidis
covers serotypes A, C, Y, W--135135
covers serotypes A, C,
Y, W
type B causes 50% of cases
type B causes 50% of cases
compliment compliment deficiency, deficiency, asplenia asplenia
b.b.
H. influenzae
H.
influenzae
all all children children at at 2 2 months months
PreventionPrevention VaccineVaccine (cont.)(cont.) c.c. S.S. pneumoniaepneumoniae 1) 1) Capsular Capsular
PreventionPrevention
VaccineVaccine (cont.)(cont.)
c.c. S.S. pneumoniaepneumoniae
1) 1)
Capsular Capsular polysaccharide polysaccharide vaccine vaccine
Covers 23 serotypes (88%
Covers 23 serotypes (88%
of cases)
of cases)
patients with chronic disease (e.g. CHF,
patients with chronic disease (e.g. CHF,
COPD, COPD,
diabetes, alcoholism, cirrhosis, > 65 yrsyrs, , asplenia,
diabetes, alcoholism, cirrhosis, > 65
asplenia,
sickle sickle cell cell disease, disease, lymphoma, lymphoma, chronic chronic renal renal failure, failure,
HIV, HIV, transplant transplant patients) patients)
2) 2)
Heptavalent Heptavalent Conjugate Conjugate Vaccine Vaccine
CoversCovers 77 serotypesserotypes
Standard Standard immunization immunization
ProphylaxisProphylaxis A.A. NeisseriaNeisseria meningitidismeningitidis Close Close contacts contacts of of index index
ProphylaxisProphylaxis
A.A. NeisseriaNeisseria meningitidismeningitidis
Close Close contacts contacts of of index index case case
Index Index case case
RifampinRifampin
B.
B.
Haemophilus Haemophilus influenzae influenzae type type B B
Close Close contacts contacts of of index index case case
If If a a contact contact is is 4 4 yo yo and and not not immunized immunized
C. Streptococcus Pneumoniae
C.
Streptococcus Pneumoniae
NotNot recommendedrecommended
Case Presentation Case Presentation EBEB waswas aa 88 momo femalefemale –– 2 2 days days
Case Presentation
Case
Presentation
EBEB waswas aa 88 momo femalefemale
–– 2 2 days days PTA PTA pt pt became became “ill” “ill” with with “cold” “cold”
Sx’sSx’s
–– 1 1
day day PTA PTA pt pt went went into into the the clinic clinic and and was was Dx Dx
with a ROM;
with a ROM;
Rx’dRx’d with Amoxicillin and
with Amoxicillin and
APAP APAP prn prn
–– Morning Morning of of admission admission dad dad was was holding holding her her
and and she she started started cough. cough. EB EB started started to to shake shake
and and then then went went into into a a GTC GTC SzSz
Case Presentation Case Presentation EBEB waswas broughtbrought intointo thethe ERER withwith GTCGTC SzSz –– SzSz
Case Presentation
Case
Presentation
EBEB waswas broughtbrought intointo thethe ERER withwith GTCGTC SzSz
–– SzSz was was stopped stopped with with multiple multiple doses doses of of
midazolam, diazepam, and phenobarbital
midazolam, diazepam, and phenobarbital
•• Lasted Lasted 30 30 minutes minutes
–– Sx’sSx’s: Cough, Cough, anorexia, anorexia, rhinorrhea, rhinorrhea, fussy, fussy,
:
temp temp
(102 (102 F) F)
–– Labs: Labs: CBC, CBC, ABG, ABG, CSF, CSF, LytesLytes,, UA/UCUA/UC
Clinical Presentation PhysicalPhysical signs/symptoms:signs/symptoms: FeverFever HeadacheHeadache
Clinical Presentation
PhysicalPhysical signs/symptoms:signs/symptoms:
FeverFever
HeadacheHeadache
Nausea/vomitingNausea/vomiting
Mental status changes
Mental status changes
StiffStiff neck/backneck/back
Positive Positive Brudzinski's Brudzinski's sign sign
Positive Positive Kernig's Kernig's sign sign
DeafnessDeafness
SeizuresSeizures
Focal Focal neurologic neurologic deficit deficit
HydrocephalusHydrocephalus
AnorexiaAnorexia
Case Case Presentation: Presentation: Labs Labs CSFCSF CBCCBC WBC:WBC: 217217 RBC: RBC: 31 31 WBC:WBC:
Case
Case
Presentation:
Presentation:
Labs
Labs
CSFCSF
CBCCBC
WBC:WBC: 217217
RBC: RBC:
31
31
WBC:WBC: 14.514.5
HGB:HGB: 8.28.2
Glu:Glu: 5757
PLTsPLTs:: 244244
Protein:Protein: 118118
LytesLytes: NL NL
:
Gram Gram stain stain (+) (+) for for GPC GPC
Glu:Glu: 244244
AG AG + +
for for S. S. pneumo pneumo
CxCx pendingpending
Clinical Presentation and Diagnosis Abnormal CSF-findings by type of meningitis ProteinProtein GlucoseGlucose
Clinical Presentation
and
Diagnosis
Abnormal CSF-findings by type of meningitis
ProteinProtein
GlucoseGlucose
TypeType
WBC(mm2)WBC(mm2)
DiffDiff (%)(%)
(mg/L)(mg/L)
(mg/(mg/dLdL))
NMLNML
<
<
10
10
BactBact
>50>50 lymphslymphs
>90>90 PMN'sPMN's
>50>50 lymphslymphs
<< 5050
3030--7070
400400--100,000100,000
8080--500500
ViralViral
55--500500
3030--150150
FungalFungal 4040--400400
>50>50 lymphslymphs
4040--150150
T.B.T.B.
100100--1,000
1,000
>50 >50 lymphs lymphs
4040--400400
<< 3535
NML/lowNML/low
NML/lowNML/low
NML/lowNML/low
CaseCase StudyStudy EBEB waswas startedstarted on:on: Vancomycin Vancomycin 15 15 mg/kg mg/kg IV IV q
CaseCase StudyStudy
EBEB waswas startedstarted on:on:
Vancomycin Vancomycin 15 15 mg/kg mg/kg IV IV q q 6 6 hrshrs
Ceftriaxone 100 mg/kg/day divided BID
Ceftriaxone 100 mg/kg/day divided BID
Phenobarbital Phenobarbital 5 5 mg/kg/day mg/kg/day divided divided BID BID
CaseCase StudyStudy S.S. PneumoPneumo sensitivitiessensitivities PreliminaryPreliminary results:results: KirbyKirby
CaseCase StudyStudy
S.S. PneumoPneumo sensitivitiessensitivities
PreliminaryPreliminary results:results:
KirbyKirby BauerBauer-- resistant to penicillin
resistant to penicillin
Final:Final:
Penicillin Penicillin MIC MIC = =
0.094
0.094
Ceftriaxone Ceftriaxone MIC MIC = = 0.032 0.032
CaseCase StudyStudy VancomycinVancomycin waswas stoppedstopped EB EB continued continued to to improve improve Never
CaseCase StudyStudy
VancomycinVancomycin waswas stoppedstopped
EB EB
continued continued to to improve improve
Never had another seizure to date
Never had another seizure to date
CT CT did did reveal reveal a a small small bilateral bilateral subdural subdural effusion effusion
Follow Follow up up CT: CT: present present but but decreasing decreasing in in size size
No No neurological neurological deficits deficits were were noted noted to to date date
Pt Pt got got a a total total of of 14 14 days days of of antibiotics antibiotics
RepeatRepeat LPLP waswas WNLWNL
Bacterial Components CNS-macrophage Endothelial Cells I L-1 TNF and IL-1 Endothelium-leukocyte PGE 2 PAF Increased
Bacterial Components CNS-macrophage Endothelial Cells I L-1 TNF and IL-1 Endothelium-leukocyte PGE 2 PAF Increased
Bacterial Components CNS-macrophage Endothelial Cells I L-1 TNF and IL-1 Endothelium-leukocyte PGE 2 PAF Increased
Bacterial Components CNS-macrophage Endothelial Cells I L-1 TNF and IL-1 Endothelium-leukocyte PGE 2 PAF Increased
Bacterial Components CNS-macrophage Endothelial Cells I L-1 TNF and IL-1 Endothelium-leukocyte
Bacterial
Components
CNS-macrophage
Endothelial Cells
I L-1
TNF and IL-1
Endothelium-leukocyte
Cells I L-1 TNF and IL-1 Endothelium-leukocyte PGE 2 PAF Increased BBB Thrombosis Permeability Increased
Cells I L-1 TNF and IL-1 Endothelium-leukocyte PGE 2 PAF Increased BBB Thrombosis Permeability Increased
Cells I L-1 TNF and IL-1 Endothelium-leukocyte PGE 2 PAF Increased BBB Thrombosis Permeability Increased
Cells I L-1 TNF and IL-1 Endothelium-leukocyte PGE 2 PAF Increased BBB Thrombosis Permeability Increased
Cells I L-1 TNF and IL-1 Endothelium-leukocyte PGE 2 PAF Increased BBB Thrombosis Permeability Increased
Cells I L-1 TNF and IL-1 Endothelium-leukocyte PGE 2 PAF Increased BBB Thrombosis Permeability Increased
Cells I L-1 TNF and IL-1 Endothelium-leukocyte PGE 2 PAF Increased BBB Thrombosis Permeability Increased

PGE 2

PGE 2
Cells I L-1 TNF and IL-1 Endothelium-leukocyte PGE 2 PAF Increased BBB Thrombosis Permeability Increased
Cells I L-1 TNF and IL-1 Endothelium-leukocyte PGE 2 PAF Increased BBB Thrombosis Permeability Increased
Cells I L-1 TNF and IL-1 Endothelium-leukocyte PGE 2 PAF Increased BBB Thrombosis Permeability Increased
Cells I L-1 TNF and IL-1 Endothelium-leukocyte PGE 2 PAF Increased BBB Thrombosis Permeability Increased
Cells I L-1 TNF and IL-1 Endothelium-leukocyte PGE 2 PAF Increased BBB Thrombosis Permeability Increased
Cells I L-1 TNF and IL-1 Endothelium-leukocyte PGE 2 PAF Increased BBB Thrombosis Permeability Increased
Cells I L-1 TNF and IL-1 Endothelium-leukocyte PGE 2 PAF Increased BBB Thrombosis Permeability Increased

PAF

PAF
Cells I L-1 TNF and IL-1 Endothelium-leukocyte PGE 2 PAF Increased BBB Thrombosis Permeability Increased Vasogenic
Cells I L-1 TNF and IL-1 Endothelium-leukocyte PGE 2 PAF Increased BBB Thrombosis Permeability Increased Vasogenic
Cells I L-1 TNF and IL-1 Endothelium-leukocyte PGE 2 PAF Increased BBB Thrombosis Permeability Increased Vasogenic
Cells I L-1 TNF and IL-1 Endothelium-leukocyte PGE 2 PAF Increased BBB Thrombosis Permeability Increased Vasogenic
Cells I L-1 TNF and IL-1 Endothelium-leukocyte PGE 2 PAF Increased BBB Thrombosis Permeability Increased Vasogenic
Cells I L-1 TNF and IL-1 Endothelium-leukocyte PGE 2 PAF Increased BBB Thrombosis Permeability Increased Vasogenic
Cells I L-1 TNF and IL-1 Endothelium-leukocyte PGE 2 PAF Increased BBB Thrombosis Permeability Increased Vasogenic
Cells I L-1 TNF and IL-1 Endothelium-leukocyte PGE 2 PAF Increased BBB Thrombosis Permeability Increased Vasogenic
Cells I L-1 TNF and IL-1 Endothelium-leukocyte PGE 2 PAF Increased BBB Thrombosis Permeability Increased Vasogenic
Cells I L-1 TNF and IL-1 Endothelium-leukocyte PGE 2 PAF Increased BBB Thrombosis Permeability Increased Vasogenic
Cells I L-1 TNF and IL-1 Endothelium-leukocyte PGE 2 PAF Increased BBB Thrombosis Permeability Increased Vasogenic

Increased BBB

Thrombosis Permeability Increased Vasogenic Edema ICP Decreased Cerebral Blood Flow Increased CSF pleocytosis
Thrombosis
Permeability
Increased
Vasogenic Edema
ICP
Decreased Cerebral
Blood Flow
Increased
CSF pleocytosis
Oxygen
CSF protein
Cytotoxic
Depletion
Edema
CSF outflow
Interstitial
Decreased
Increased
resistance
Edema
CSF glucose
CSF lactate
Cytotoxic Depletion Edema CSF outflow Interstitial Decreased Increased resistance Edema CSF glucose CSF lactate
Cytotoxic Depletion Edema CSF outflow Interstitial Decreased Increased resistance Edema CSF glucose CSF lactate
Cytotoxic Depletion Edema CSF outflow Interstitial Decreased Increased resistance Edema CSF glucose CSF lactate
Cytotoxic Depletion Edema CSF outflow Interstitial Decreased Increased resistance Edema CSF glucose CSF lactate
Cytotoxic Depletion Edema CSF outflow Interstitial Decreased Increased resistance Edema CSF glucose CSF lactate
Cytotoxic Depletion Edema CSF outflow Interstitial Decreased Increased resistance Edema CSF glucose CSF lactate
Cytotoxic Depletion Edema CSF outflow Interstitial Decreased Increased resistance Edema CSF glucose CSF lactate