Transcript S. pneumoniae - Duke University

Meningitis
David A. Wilfret, MD
Pediatric Infectious Diseases
Duke University Medical Center
Meningitis
• Meningitis – Inflammation of
the membranes that surround
the brain and spinal cord
(the dura mater, archnoid
mater, and pia mater)
• Encephalitis – Inflammation of
the cerebral cortex
• Meningoencephalitis –
Inflammation of the meninges
and the cerebral cortex
Pathogenesis
• Bacteria
– Maternal genital secretions or
nasopharyngeal colonization
– Mucosal invasion and penetration
into the blood stream
– Hematogenous spread through the
BBB (choroid plexus) or direct
inoculation
• Virus
– Upper respiratory tract or
gastrointestinal tract
– Primary viremia
– Proliferation in other organs
(lymph nodes, liver, spleen)
– Secondary viremia through the
BBB
Chavez-Bueno S, Pediatr Clin N Am 52;795-810.
Pathogenesis
• Inflammation within the
subarachnoid space
• Cell wall or membrane
components
– Gram positive - Peptidoglycan
– Gram negative - Lipopolysaccharides
• Inflammatory mediators
– TNF-alpha, IL-1, IL-6, IL-8, IL-10,
PAF, NO, prostaglandins, and
macrophage induced proteins
• Cerebral edema, increased ICP, and toxic oxygen
radicals causing apoptosis
Chavez-Bueno S. Pediatr Clin N Am 52;795-810.
Neonatal Meningitis
• Patient is a 3 wk old formerly full-term, vaginal delivery
who presents to the ED
• He has been irritable throughout the day with poor
feeding throughout the day
• One hour prior to arrival, he developed a rectal
temperature of 100.6 F
• In the ED he appears fussy and difficult to console, but
otherwise stable
• On physical examination he has a temperature of 101 F,
a flat fontanelle, no nuchal rigidity, and no Kernig’s nor
Brudzinski’s sign
Neonatal Meningitis
• Incidence 0.25 – 1 per 1000 live births
• Risk factors
– Perinatal and intrauterine infection (T > 100.4oC), prolonged
rupture of membranes (> 18 hours), prematurity (< 37 wks), low
birth weight, previous infant with GBS disease, maternal urinary
tract infection
• Early and late onset meningitis
• Neonatal sepsis arises < 1 %,
• Meningitis 25 % of septic neonates
– One percent of lumbar punctures
Clinical Manifestations - Neonate
Signs and Symptoms
Temperature Instability
Fussy / Lethargy
Poor Feeding and Vomiting
Seizures
Respiratory Distress
Apnea
Bulging Fontanelle
Diarrhea
Nuchal Rigidity
Incidence (%)
60
60
48
42
33
31
25
20
13
Signs of meningitis are often subtle in the neonate
Classic symptoms of meningitis not until 18 – 24 months
What Laboratory Studies
Would you Order?
• CBC with Differential
• Blood Culture
• Electrolytes and LFTs
• Urine Culture
• Urinalysis
• CSF Culture
• Cerebrospinal Fluid
• Viral Culture CSF and
surfaces
–
–
–
–
–
WBC with Differential
RBC
Protein
Glucose
Gram-stain
• HSV and Enterovirus
PCR
Laboratory Results
• CBC: WBC 8000 cells/mm3, N 60% B 10% L 23%, H/H
11.2 / 30 and Platelets 150,000
• Electrolytes: CO2 18 and Glucose 80, LFTs normal
• Urinalysis: Protein 1+, Ketones 1+, Nitrites neg,
LE neg, WBC 1, RBC 0, Bacteria 0-5
• CSF: WBC 120, P 80% L 10% M 10%, RBC 5,
Protein 240, Glucose 30
Is this consistent with meningitis?
Cerebrospinal Fluid - Neonates
Normal Cerebrospinal Fluid of Neonates and Children
CSF Study
Premature
Infants
Term to 7
days old
Term 8 – 30
days old
Term > 1
month old
WBC / ul
0 – 21
0 – 21
0 – 21
0–6
< 20 %
(0 - 2)
0
Neutrophils / ul < 40 – 60 % < 50 – 60 %
RBC / ul
0-2
0–2
0–2
0–2
Glucose
(mg/dl)
30 - 100
35 – 80
40 – 80
40 – 80
Protein (mg/dl)
45 - 200
20 - 140
15 - 100
10 - 45
• Evaluated 9111 neonates > 34 weeks gestation to
establish concordance of CSF culture, CSF parameters,
and blood culture in culture-proven neonatal meningitis
• Thirty-eight percent of neonates with culture-proven
meningitis had a negative blood culture
• Peripheral WBCs were neither sensitive nor specific for
bacterial meningitis
Due to the variability in CSF parameters, unable to develop
an algorithm to accurately and precisely predict
meningitis based on CSF parameters alone
Ten percent of neonates with bacterial meningitis had
3 CSF WBCs/mm3
<
A threshold value of 21 cells as the upper limit of normal
would have missed 12.6% of meningitis cases
Meningitis can occur in the presence of normal CSF WBC,
protein, and glucose levels
Culture Results
• Gram Stain
Gram-positive cocci in pairs / chains
• CSF Culture
Group B Streptococcus
• Blood Culture
Negative
• Urine Culture
Negative
• Virus Culture,
Cancelled after Gram-stain Positive
and HSV and
Enterovirus PCR
What are the most Common
Organisms that cause Bacterial
Meningitis in Neonates?
• Group B Streptococcus (30 – 40 %)
• Gram-negative enteric bacilli (30 – 40 %)
– Escherichia coli, Klebsiella, Enterobacter, Salmonella, Serratia
marcesans, Citrobacter, and Proteus mirabilis
• Listeria monocytogenes (10 %)
• Others include Staphylococcus aureus, viridans
streptococci, and coagulase-negative staphylococci
What Antibiotics would you
Empirically Start?
Ampicillin
Plus an Aminoglycoside
Or Cefotaxime
Infants (> 1 month)
Vancomycin plus Cefotaxime
Specific Therapy
Organism
GBS
Sensitive
Antibiotic
Duration
Penicillin or Ampicillin
14 – 21 days
L. Monocytogenes
Ampicillin plus Aminoglycoside
14 - 21 days
Gram-Negative
Enteric Organisms
3rd Cephalosporin
plus Aminoglycoside
21 days
14 days after Negative
Staphylococcus
Sensitive
Resistant
Nafcillin or Oxacillin
Vancomycin plus Rifampin
21 days
Neonatal Complications
• Development Delay 26%
• Brain Abscess
13%
• Hydrocephalus
24%
• Hearing Loss
12%
• Ventriculitis
20%
• Subdural Effusion
11%
• Late Seizure
19%
• Cortical Blindness <10%
• Cerebral Palsy
17%
Mortality 15 – 20 %
Meningitis
• Patient is a 4 year old Hispanic male without past
medical history who presents to the ED
• He complains of fevers (T 103.8 F), headaches,
photophobia, neck stiffness, vomiting, myalgias, and
drowsiness over the past 24 hours
• On physical examination, he is febrile (T 102.4 F), but
vitals are otherwise stable. He is alert and irritable, but
able to cooperate with the examination. He is without
focal neurologic signs and there is no rash.
What would you look for on
Physical Examination that
is Specific for Meningitis?
Nuchal Rigidity
Kernig’s Sign
Brudzinski’s Sign
Kernig and Brudzinski’s Sign
Kernig and Brudzinski’s
sign present 5% of adults
with meningitis
Nuchal rigidity present in
30% of adults with
meningitis
What Laboratory Studies
Would you Order?
• CBC with Differential
• Blood Culture
• Electrolytes and LFTs
• CSF Culture
• Cerebrospinal Fluid
• Viral Culture CSF,
Nasopharyngeal, and
Perirectal
–
–
–
–
–
–
–
Opening Pressure
WBC with Differential
RBC
Protein
Glucose
Gram-stain
India Ink / Cryptococcal
Antigen if Immunocompromised
• Enterovirus PCR
Would you Order a Head CT
prior to the LP?
• Head CT should be performed if signs of increased
intracranial pressure on physical examination and should
not result in delay of blood tests nor start of antibiotics
• Abnormalities detected on CT scan were already
suspected by neurological examination and did not effect
clinical management
Signs of Increased Intracranial Pressure
focal neurologic signs, altered level of consciousness,
bradycardia, hypertension or hypotension, and altered
respiratory pattern (papilledema late sign)
Cabral DA. J Pediatr 1987;111:201.
Laboratory Results
• CBC: WBC 21,000 cells/mm3, N 70% B 5% L 15%, H/H
14 / 36 and Platelets 470,000
• Electrolytes (Glucose 70) and LFTs Normal
• CSF: Cloudy, WBC 1400, P 80% L 10% M 10%, RBC
120, Protein 180, Glucose 20
Bacterial vs. Aseptic Meningitis
• Bacterial Meningitis
– Meningitis caused by identified bacteria
– Peak in the Fall and Winter
• Aseptic Meningitis
–
–
–
–
Meningitis not caused by identified bacteria
Most common type of meningitis
Peak in the late Spring to Fall
Biphasic fever (especially with enteroviruses)
Cerebrospinal Fluid
Typical Cerebrospinal Fluid Findings
Component
Bacterial
Meningitis
Viral
Meningitis
Herpetic
Meningitis
Tuberculous
Meningitis
Leukocytes /
mcL
> 1000
< 100
10 – 1000
10 – 1000
Cells
Neutrophils
Lymphs
Lymphs
Lymphs
CSF – Serum
Glucose
Normal –
Low
Normal
Normal
Low
Protein
(mg/dL)
> 100
50 – 100
> 75
>100
Erythrocytes /
mcL
0 – 10
0-2
10 – 500
0-2
Cerebrospinal Fluid
• Bacterial meningitis
– WBCs >1000 cells/mm3 with neutrophil predominance > 80%
– Early infection can have a lymphocyte predominance in 10% of
patients with WBCs < 100 cells/mm3 then neutrophil
predominance at 48 h
– Neutrophil predominance related to bacterial meningitis but no
threshold of clinical significance (N 90 % = PPV 25%)
• Viral meningitis
– WBC < 100 cells/mm3 with lymphocyte predominance
– Early infection neutrophil predominance (59%) with WBCs >1000
cells/mm3 then lymphocyte predominance after 24 h
– During the peak season for aseptic meningitis, a patient with
neutrophil predominance is more likely to have aseptic
meningitis than bacterial meningitis
Negrini B. Pediatrics 2000;105:316.
Culture Results
• Gram Stain
Gram-positive cocci in pairs / chains
• CSF Culture
Streptococcus pneumoniae
• Blood Culture
Streptococcus pneumoniae
• Viral Cultures
Negative
and Enterovirus
PCR
Cerebrospinal Fluid
• Gram-stain Sensitivity
–
–
–
–
–
S. pneumoniae
H. influenzae
N. meningitidis
Gram-negative bacilli
L. monocytogenes
– Specificity
90%
86%
75%
50%
33%
> 97%
• Bacterial Culture
– Sensitivity
70-85%
Traumatic Tap
CSF is Uninterpretable
• CSF contaminated with blood in up to 20% of taps
• Both underdiagnose and overdiagnose bacterial meningitis
• Repeat lumbar puncture after 48 hours
Rules
1 WBC/mm3 for every 500 – 1000 RBC/mm3
WBC (CSF) = WBC (CSF) – [WBC (Bld) x RBC (CSF)]/RBC (Bld)
Bonsu BK. PIDJ 2006;25:8.
Partially Treated Meningitis
• Up to 50% of cases may initially
receive oral antibiotics
• CSF WBCs, protein, and glucose
generally remain abnormal for
at least 44 – 68 hours after antibiotics
• CSF Sterilization
– N. meningitidis within 1 – 2 hours
– S. pneumoniae within 4 hours
– Gram-stain sensitivity ~20% lower
Feigen RD. Textbook of Pediatric Infectious Diseases 4th Ed. 1998.
Kanegave JT, et al. Pediatrics 2001;108:1169.
Partially Treated Meningitis
• Latex agglutination
– Detects bacterial capsular antigens, thus results are not affected
by prior antibiotics
– Low PPV and NPV - A positive or negative latex agglutination
does not change clinical therapy or hospital course
• Polymerase Chain Reaction
– Enterovirus and Herpes Simplex Virus
– Sensitivity and specificity > 90%
• Presumed bacterial meningitis treat at least 10 days
Hayden RT. PIDJ 2000;19:290-2
Tunkel AR. IDSA Guidelines Meningitis. CID 2004;39:1267.
• Of pretreated children, Gram-stain was positive in 60% and latex
agglutination was positive in 42%
• Latex agglutination test did not identify any pathogen that was not
identified by blood or CSF culture
• Of culture-negative, pretreated children, none were positive by
latex agglutination
• Negative latex agglutination test did not decrease the risk of
bacterial meningitis
Nigrovic LE, et al. PIDJ 2004;23:786.
What are the most Common
Organisms that cause Bacterial
Meningitis in this Age Group?
Streptococcus pneumoniae
4, 6B, 9, 14, 18F, 19F, 23F
Neisseria meningitidis
B, C, Y, W-135
Haemophilus influenzae type B
Viral Meningitis
• Enteroviruses (Coxsackie
and ECHO viruses)
• Human
Immunodeficiency Virus
• Arboviruses (St. Louis,
Western and Eastern
Equine, West Nile,
California (Lacrosse)
Viruses
• LCMV
• Herpes viruses
• Mumps Virus
Kumar R. Indian J Pediatr 2005;72:57.
• Respiratory Viruses
(Adenovirus, Rhinovirus,
Influenza Virus,
Parainfluenza Virus)
Aseptic Meningitis - Infectious
• Bacteria
–
–
–
–
–
–
–
–
–
Partially Treated
M. tuberculosis
M. pneumoniae
C. pneumoniae
Ehrlichiosis
B. burgdorfi
T. pallidum
Brucella
Leptospirosis
• Fungi
–
–
–
–
–
C. neoformans
H. capsulatum
Coccidioides immitis
Blatomyces dermatitides
Candida
Kumar R. Indian J Pediatr 2005;72:57.
• Parasites
–
–
–
–
–
Toxoplasma gondii
Neurocysticercosis
Trinchinosis
Naeglaria
Bartonella henselae
• Rickettsia
– RMSF
– Typhus
Aseptic Meningitis - Noninfectious
• Postinfectious / Postvaccinial
• Drugs
• Systemic Diseases (Rheumatologic)
• Neoplastic Diseases
• Parameningeal Inflammation
Kumar R. Indian J Pediatr 2005;72:57.
What antibiotics would
you empirically start?
Vancomycin
Third-generation cephalosporin
(Ceftriaxone or Cefotaxime)
PICU Admission and ID Consult
• Definitive Meningitis:
Positive CSF Gram-stain for bacteria
• Probable Meningitis:
Age < 6 months and CSF WBC ≥100 and low glucose in
CSF; or CSF WBC ≥ 500 or;
CSF WBC elevated for age and >70% neutrophils or;
CSF WBC elevated for age and localizing neurologic exam
regardless of age or;
CSF WBC elevated for age and one risk factor:
Seizures
Altered mental status
Hypotension or hemodynamic instability
Age < 12 months and not vaccinated
Immunocompromised; e.g. sickle cell, IgG deficiency, HIV
Specific Therapy
Organism
S. pneumoniae
MIC PCN < 0.1
MIC PCN 0.1-1.0
MIC PCN > 2
(MIC Ceph >1.0)
N. meningitidis
MIC <0.1
MIC 0.1-1.0
H. Influenzae
Sensitive
Resistant
Antibiotic
Duration
Penicillin G or Ampicillin
3rd Gen Cephalosporin
Vancomycin
plus 3rd Gen Cephalosporin
(Rifampin)
10 – 14 days
Penicillin G, Ampicillin
3rd Gen Cephalosporin
Ampicillin
3rd Gen Cephalosporin
Tunkel AR. IDSA Guidelines Meningitis. CID 2004;39:1267.
7 days
7 - 10 days
Specific Therapy
Organism
Gram-Negative
Enteric Organisms
Pseudomonas
S. aureus
Meth Sensitive
Meth Resistant
Enterococcus
Sensitive
Amp Resistant
Vanc Resistant
Antibiotic
Duration
3rd Gen Cephalosporin
plus Aminoglycoside
Ceftazidime, Carbapenem,
Ticarcillin, Piperacillin
plus Aminoglycoside
21 days or
14 days after Negative
Nafcillin or Oxacillin
Vancomycin and Rifampin
21 days
Ampicillin plus Aminoglycoside
Vancomycin plus Aminoglycoside
Linezolid plus Aminoglycoside
Tunkel AR. IDSA Guidelines Meningitis. CID 2004;39:1267.
14 – 21 days
Neurosurgical
Condition
Organism
Antibiotic
Basilar Skull
Fracture
S. pneumoniae
H. influenzae
S. pyogenes
Vancomycin plus
3rd Gen Cephalosporin
Penetrating
Trauma
S. aureus, CoNS
Gram-Neg Bacilli
Vancomycin plus Cefepime,
Ceftazidime, or Meropenem
Postneurosurgery
Gram-neg Bacilli
S. aureus, CoNS
Vancomycin plus Cefepime,
Ceftazidime, or Meropenem
CSF Shunt
CoNS, S. aureus
Gram-Neg Bacilli
P. acnes
Vancomycin plus Cefepime,
Ceftazidime, or Meropenem
Tunkel AR. IDSA Guidelines Meningitis. CID 2004;39:1267.
Steroids
• Dexamethasone
– Decrease inflammatory mediators associated with worsening of
morbidity and mortality (deafness and nerve damage)
– Decrease penetration of antibiotics into the CSF (Vancomycin)
– Mask fever and rebound fever after discontinuation
• Recommendations (prior or with first dose of antibiotics)
– Haemophilus influenzae beneficial effect (hearing loss)
– S. pneumoniae possible effect - “For infants and children 6
weeks of age and older, adjunctive therapy with dexamethasone
may be considered after weighing the potential benefits and
possible risks.”
– N. meningitidis no supporting data
McIntyre PB, et al. JAMA 1997;278:925.
AAP Committee on Infectious Diseases 2003.
Tunkel AR, et al. CID 2004;39:1267.
All S. pneumoniae were susceptible to penicillin
Reduction in risk of an unfavorable outcome (RR, 0.59;
95% CI, 0.37 to 0.94; P=0.03) and mortality (RR of
death, 0.48; 95% CI, 0.24 to 0.96; P=0.04)
No beneficial effect on neurologic sequelae including focal
neurologic abnormalities and hearing loss
Chemoprophylaxis - Meningococus
• High risk: Chemoprophylaxis recommended
– Household contact, Child care or nursery school contact, Direct
exposure to index patient’s secretions (kissing, toothbrushes,
eating utensils), Mouth-to-mouth resuscitation, Unprotected
contact during endotracheal intubation, Frequently slept or ate in
same dwelling, Passengers seated directly next to the index
case during airline flights lasting more than 8 hours
• Low risk: Chemoprophylaxis not recommended
– Casual contact: No history of direct exposure to index patient’s
oral secretions (eg, school or work), Indirect contact - only
contact is with a high-risk contact, Health care professionals
without direct exposure to patient’s oral secretions
• In Outbreak or cluster
– Chemoprophylaxis for people other than people at high risk
should be administered only after consultation with local public
health authorities
Red Book 27th Ed. 2006.
Chemoprophylaxis - Meningococcus
Age
Dose
Duration
Efficacy
5 mg/kg q12
10 mg/kg q12
(max 600 mg)
2 days
2 days
90-95%
125 mg
250 mg
Single dose
Single dose
90-95%
90-95%
500 mg
Single dose
90-95%
Rifampin
< 1 mo
> 1 mo
Ceftriaxone
< 15 yo
> 15 yo
Ciprofloxacin
> 18 yo
Red Book 27th Ed. 2006.
Chemoprophylaxis – Haemophilus
• High risk: Chemoprophylaxis recommended
– For all household contact in the following circumstances:
Household with at least 1 contact < 4 years of age who is
unimmunized or incompletely immunized, Household with a child
< 12 months of age who has not received the primary series,
Household with a contact who is an immunocompromised child,
regardless of that child’s Hib immunization status
– For nursery school and child care center contacts when 2 or
more cases of Hib invasive disease have occurred within 60
days
• Chemoprophylaxis not recommended
– For occupants of households with no children < 4 years of age
– For occupants of households when all household contacts 12 to
48 months of age have completed their Hib immunization series
and when household contacts < 12 months have completed their
primary series of Hib immunizations
– For nursery school and child care contacts of 1 index case
– For pregnant women
Red Book 27th Ed. 2006.
Meningococcal Vaccines
Menomune (MPSV4)
Menactra (MCV4)
Licensed in 1981
Licensed in 2005
> 2 years old
11 – 55 years old
Protection 3 – 5 years
Recommendations:
High-risk groups (2 – 10 yrs old)
- Functional or anatomic
asplenia
- Terminal C’ or properdin
deficient
- Travel to areas where
Meningococcus is epidemic
Protection at least 10 years
Recommendations:
High-risk groups (>10 years old)
11- to 12-year visit
High-school entry or 15 years old
College students living in dorms
A, C, Y, W-135
Red Book 2006
Swartz MN. NEJM 2004;351:18.
Prognosis
• Mortality rate (4 – 10%)
–
–
–
–
Infants and Children
Streptococcus pneumoniae
Neisseria meningitis
Haemophilus influenzae
<5
10
3–5
3–5
%
%
%
%
• Factors associated with a poor outcome
–
–
–
–
–
–
–
–
Extremes of age
Hypotension
Altered mental status
Seizures
S. pneumoniae, GBBS, Gram-negative bacilli
High bacterial burden
Delayed sterilization of CSF
Low CSF glucose (<20 mg/dL)
Chavez-Bueno S. Pediatr Clin N Amer 2005;52:795.
Neurologic Sequelae
• Sensorineural Hearing Loss
– S. pneumoniae
– N. meningitidis
– H. influenzae
•
•
•
•
•
•
•
•
20 - 35 %
5 - 10 %
5 - 10 %
Cranial Nerve Palsies
Vascular Insults (Hemiparesis)
Seizures
Hydrocephalus
Ataxia
Diabetes insipidus
Behavior Disorders
Learning Disabilities
Chavez-Bueno S. Pediatr Clin N Amer 2005;52:795.