CNS infections

1. Infectious diseases Pharmacotherapy
Lesson 4
Central Nervous system infection
tsegayemlk@yahoo.com or tsegaye.melaku@ju.edu.etJuly, 2018 +251913765609+251913765609
Central Nervous system infection
By: Tsegaye Melaku[MSc]

2.  Session Tips:Session Tips:
 Clinical pictures of CNS infections……
 Pathophysiology of CNS infections
 Most common pathogens & risk factors
 Antibiotic selection issues
 Appropriate empirical antimicrobial regimens
 Prevention strategies
 Adjunctive therapy
 Components of monitoring plan
2

3. A 75 yr old woman presents to ER yesterday with new onset seizures.
She had been well until 4 days prior when she developed a URTI. One
day ago she developed a fever and headache. Last evening the
headache worsened and she appeared confused at times. There is no hx
of travel and she has no other significant medical history. PE reveals anof travel and she has no other significant medical history. PE reveals an
acutely ill, irritable patient. She is oriented to place and time. T=38.7ºC,
PR=100/min, RR =24/min and BP= 110/60 mm Hg. There is no rash.
Pupils are equal and reactive, neck is moderately stiff to passive motion.
There are no localizing neurologic findings.
3

4. Laboratory Studies
Hematocrit 36%
WBC 16000 (85% PMNs, 12% lymphs, 3% monos)
BUN 12 mg/dL
Plasma glucose 105, Electrolytes normal
Head CT: low-density temporal lobe lesion
CSF analysis:CSF analysis:
Normal OP, cell count 200 (65% lymphs, 35% PMNs), 2 RBCs
Glucose and protein are normal.
Gram stain: negative for bacteria
Which antimicrobials would you start empirically?
a) Ampicillin and ceftriaxone
b) Ampicillin, vancomycin and ceftriaxone
c) Ampicillin, ceftriaxone and acyclovir
d) Ampicillin and metronidazole
4

5.  The brain and spinal cord are ensheathed by a
protective covering known as the meninges and
suspended in CSF
– Acts as a “shock absorber” to outside trauma
 The meninges consist of three layers of fibrous The meninges consist of three layers of fibrous
tissue: pia mater, arachnoid, and dura mater
 Subarachnoid space:
– Separates the pia mater from the more
loosely enclosed arachnoid membrane
– CSF resides here
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6.  Membrane lining CNS:
– Dura mater
– Arachnoid
– Pia mater
 BBB
– Maintaining homeostasis
within CNS.
– Isolates & protects the CNS
from pathogens, toxins, etc
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9.  CNS infections describes a variety of infections involving the
brain and spinal cord and associated tissues, fluids, and
membranes:
– Meningitis, Encephalitis,– Meningitis, Encephalitis,
– Brain Abscess, Shunt Infections, &
– Post-operative Infections
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10.  Meningitis
 Encephalitis
 Myelitis
 Meningoencephalitis
 Other: brain abscess, subdural
empyema, and epidural abscess
 Meningoencephalitis
 Meningomyelitis
 Encephalomyelitis
 Meningo-encephalomyelitis
 Brain abscess
10

11.  CNS infections are caused by a variety of pathogens,
including bacteria, viruses, fungi, & parasites
 Infections are the result :
– Hematogenous spread from a primary infection site
– Seeding from a parameningeal focus.
– Reactivation from a latent site, trauma or
– Congenital defects within the CNS
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12.  Meningitis
– Describes inflammation(often the result of infection) of the
subarachnoid space
 Subdural empyema
– Collection of purulent material (pus) in the region separating the– Collection of purulent material (pus) in the region separating the
dura and arachnoid
 Abscesses also can form outside the dural space (epidural abscess),
often with devastating consequences
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13.  Inflammation of the membranes (meninges) which surround the brain
and spinal cord by bacteria.
 Impact:
– 25% mortality
– Substantial morbidity (learning deficits, hearing loss, seizure
disorder, hydrocephalus)
– Eradication of bacteria is essential.
– It is only one of the variables that affect mortality from CNS
infections
– Partial treatment *****
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15.  Sources of bacteria:
– Translocation /inoculation (trauma,
surgery)
– Parameningeal seeding (otitis media,
sinusitis…..)
– Hematogenous
Host
immune
defense
mechanisms
– Hematogenous
• Mucosal colonization
– Local Invasion
» Bacteremia
• Meningeal Invasion (Cross
BBB)
• Bacterial Replication
• Inflammation
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Bacterial
virulence

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18. BacteriaBacteria
Colonize
Nasopharyngeal
epithelial cells
Colonize
Nasopharyngeal
epithelial cells
Multiply, absence of
Immune defences
Multiply, absence of
Immune defences
Inflammatory
reaction
Inflammatory
reaction
Lysis of
bacteria,
cytokines
Lysis of
bacteria,
cytokines
TNF,IL1TNF,IL1
Intravascular
space
Intravascular
space
Polysaccharide capsule
Avoids phagocytosis
Polysaccharide capsule
Avoids phagocytosis
Intraventricular
Choroid plexus
Intraventricular
Choroid plexus
Gain access
To CSF
Gain access
To CSF
COMPLICATIONSCOMPLICATIONS
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19.  Much of the pathophysiology is due to direct consequence of
chemokines, cytokines.
TNF
IL1
TNF
IL1
VascularVascular IncreasedIncreasedVascular
permeabilitiy
Vascular
permeabilitiy
Vasogenic
edema
Vasogenic
edema
Exudate in
CSF
Exudate in
CSF
Obstructive
hydrocephalus
Obstructive
hydrocephalus
Increased
Leukocyte adherence
Increased
Leukocyte adherence
Leakage into
CSF
Leakage into
CSF
Degranulation
of neutrophils
Degranulation
of neutrophils
chemokineschemokines
Excitatory
Aminoacids
Excitatory
Aminoacids
Death Of brain
cells
Death Of brain
cells
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20. The white appearance of this calf brain is caused by neutrophils within the meninges – a
condition known as meningitis. This is usually due to a bacterial infection.

21. This calf brain shows similar pathology. If a glass slide is pressed to the
surface of the brain and stained it would show high numbers of neutrophils.

22. This brain shows irregular red spots which are areas of hemorrhage
and necrosis caused by the bacteria, Histophilus somni.

23. Brain: Meningitis

24. a) Environmental—recent exposures (such as close contact with
meningitis or respiratory tract infection, contaminated foods,
close living conditions)
b) Recent infection in the patient—respiratory infection, otitis media,
sinusitis, mastoiditis
c) Immunosuppression—anatomic or functional asplenia, sickle cellc) Immunosuppression—anatomic or functional asplenia, sickle cell
disease, alcoholism, cirrhosis, immunoglobulin or complement
deficiency, cancer, HIV/AIDS, debilitated state of health
d) Surgery, trauma—neurosurgery, head trauma, CSF shunt, cochlear
implant
24

25.  Acute (s/s within 24hrs) vs Subacute (1 week)
 Neonates: lethargy, irritability, poor feeding
 Children & Adults: fever, headache, photophobia, leukocytosis (with
left shift), stiff neck (nucal rigidity) and back pain, nausea, vomiting, &
altered mental status
 Elderly: fever & altered mental status
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26. + Brudzinski’s sign: flexing neck of supine patient causes
flexion of hips & knees
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Hip and knee

27. + Kernigs’s sign: Can’t passively extend leg after touching
thigh to abdomen with knee flexed
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28.  Classic clinical triad of meningitis: fever, headache, and nuchal rigidityfever, headache, and nuchal rigidity
 Altered mental status: >75% of patients can vary from lethargy to
coma
 Nausea, vomiting, and photophobia : common complaints
 Seizures
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31.  Leukocytosis with left shift (bandemia)
 Bacteremia (reseeding CNS)
 CSF analysis in all patients suspected of Meningitis
– (unless papilledema, trauma, or coagulopathy)
 +/- CT Scan (do if can’t do lumbar tap)
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32.  The characteristics of normal CSF
– Open pressure: 50-200 mmHg
– Clear color
– Protein 20-45 mg/dl– Protein 20-45 mg/dl
– CSF sugar/ Serum sugar > 50%
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35.  Gram Stain (examples)
– Gram-positive diplococci pneumococcal infection
– Gram-negative diplococci meningococcal infection
– Small pleomorphic gram-negative coccobacilli 
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– Small pleomorphic gram-negative coccobacilli 
Haemophilus influenzae
– Gram positive rods listerial infection

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37.  The most important initial issues:
– Avoidance of delay
– Choice of drug regimen
 Avoidance of delay:
– Antibiotics should be started immediately– Antibiotics should be started immediately
 Components of delay
– Time from triage to contact with a physician
– Time from LP until administration of antibiotic
– Performance of CT to exclude mass lesion
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38. Supportive care
– Administration of fluids, electrolytes, antipyretics, analgesics,
and other supportive measures
 Appropriate antibiotic therapy (empirical or definitive): ASAP
 Goals:
– Eradication of infection with amelioration of S & SXS
– Prevention of neurologic sequelae, such as seizures, deafness,
coma, and death
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39.  Optimal outcome demands bactericidal effect in the CSF
– Penetration into the fluid & concentration there
• Inflamed meninges allow increased permeability of BBB
– Characteristics of the antibiotic
• Small molecular size, Low degree of binding to protein
• Low degree of ionization at physiologic pH, High solubility in
lipids
 Prompt institution of appropriate antimicrobial therapy is essential
when treating meningitis
– Delay in antibiotic administration is associated with increased
morbidity and mortality
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43. 43

44. Organism DOC Alternative Duration of
Therapy
Gram-positive
Streptococcus pneumoniae 10–14 days
Penicillin susceptible Penicillin G or
Ampicillin
Cefotaxime,
Ceftriaxone,
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Ampicillin Ceftriaxone,
Chloramphenicol
Penicillin
intermediate
Cefotaxime or
Ceftriaxone
Cefepime, Meropenem ,
Moxifloxacin , Linezolid
Penicillin resistant Vancomycin plus
Cefotaxime or
Ceftriaxone

45. Organism DOC Alternative Duration of
Therapy
Gram-negative
Neisseria meningitis 7 days
Penicillin susceptible Penicillin G or
Ampicillin
Cefotaxime,
Ceftriaxone,
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Ampicillin Ceftriaxone,
Chloramphenicol
Penicillin resistant Cefotaxime or
Ceftriaxone
Chloramphenicol ,
Meropenem,
Fluoroquinolone

46. Organism DOC Alternative Duration of
Therapy
Gram-negative
Haemophilus influenzae 7 days
Beta-lactamse(-) Ampicillin Cefotaxime,
Ceftriaxone,
Chloramphenicol
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Chloramphenicol
Beta lactamase(+) Cefotaxime or
Ceftriaxone
Cefepime ,
Meropenem,
Fluoroquinolone
L. monocytogenes Penicillin G or
Ampicillin ±
Gentamicin
Trimethoprim-
sulfamethoxazole ,
Meropenem
21 days

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48. • Ampicillin
– Infants and Children: 75 mg/kg
every 6 h
– Adults: 2-3 g every 4/6h
• Ceftriaxone
– Infants and Children: 100 mg/kg
once daily
• Gentamicin
– Infants and Children: 2.5 mg/kg
every 8 h
– Adults: 2 mg/kg every 8 h
• Penicillin G
– Infants and Children: 0.05
million Units/kg every 4–6 h
– Adults: 2 g every 12–24 h
• Chloramphenicol
– Infants and Children: 25 mg/kg
every 6 h
– Adults: 1–1.5 g every 6 h
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million Units/kg every 4–6 h
– Adults: 4 million Units every 4 h
• Vancomycin
– Infants and Children: 15 mg/kg
every 6 h
– Adults: 15 mg/kg every 8–12 h

49.  Children with documented H. Influenzae
 Adults with documented S. pneumoniae
– Dexamethasone10 mg (0.15 mg/kg) 4 times daily for 2-4
days before or with first dose of antibiotic.
 Still controversial for empiric therapy Still controversial for empiric therapy
 Neonatal meningitis???
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50.  S. pneumoniae:…………10-14 days
 H. influenzae:…………... 7 days
 N. meningitidis:…………7 days
 L. monocytogenes: …….14-21 days L. monocytogenes: …….14-21 days
 S. agalactiae: …………14-21 days
 Enterobacteriaceae: …..21 days
 P. aeruginosa:………….21+ days
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51.  H. influenzae type b (invasive)
– Rifampin 20mg/kg PO (max 600mg) Q day x 4 doses
 N. meningitidis
– Ciprofloxacin 500mg PO x 1 dose or– Ciprofloxacin 500mg PO x 1 dose or
– Ceftriaxone 250mg IM x 1 dose or
– Rifampin 600mg PO Q12hrs x 4 doses
– Close contacts (droplets): > 4 hrs or exposure to
nasopharyngeal secretions
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52.  S. pneumoniae:
– Pneumovax 23, Pnu-Immune, Pneumo23
• Immunocompromised (HIV, Malignancy, or nephrotic
syndrome) , Asplenic, >65y/o
– Prevnar (7 valent conjugate vaccine)
• Children: 3 doses at 2-6 months, 4th at 12-15 months• Children: 3 doses at 2-6 months, 4th at 12-15 months
 H. influenzae type b:
• Children: 4 shot series
 N . Meningitidis:
– ?Asplenia, epidemics, at risk (college, military)
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53.  Decreased level of consciousness on admission
 Onset of seizures within 24 h of admission
 Signs of increased ICP
 Young age (infancy) and age >50yrs
 The presence of comorbid conditions including shock and/or the need for The presence of comorbid conditions including shock and/or the need for
mechanical ventilation, and
 Delay in the initiation of treatment.
 Decreased CSF glucose concentration [<2.2 mmol/L (<40 mg/dL)] and
 Markedly increased CSF protein concentration [>3 g/L (>300 mg/dL)]
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54.  Decreased intellectual function
 Memory impairement
 Seizures
 Hearing loss/blindness
 Gait disturbances Gait disturbances
 Hemiparesis
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55.  HSV encephalitis: Acyclovir 10mg/kg IV Q8h
 Tuberculosis: INH, RIF, ETB, PZA
 Cryptococcal: Ampho B + 5FC (HIV: +/- 5FC)
 Brain Abscess: Streptococci & Bacteroides
– Metronidazole Plus (Ceftriaxone or high dose Penicillin G)– Metronidazole Plus (Ceftriaxone or high dose Penicillin G)
 Drug-induced Aseptic
– NSAID’s especially if patient has lupus
– Trimethoprim / Sulfamethoxazole
– Penicillin, Cephalosporins
– Isonazid, Pyrazinamide
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56.  Signs and Symptoms
– High potential for rapid deterioration associated with meningitis:
 Signs and symptoms of fever, headache, meningismus (e.g.,
nuchal rigidity, Brudzinski's or Kernig's sign),
 Vital signs, and signs of cerebral dysfunction every 4 hours for
the initial 3 days and then daily thereafter
 Microbiologic Findings
 CSF Examination
56

57. A 75 year old woman presents to ER yesterday with new onset
seizures. She had been well until four days prior when she
developed a URTI. One day ago she developed a fever and
headache. Last evening the headache worsened and she appeared
confused at times. There is no history of travel and she has no otherconfused at times. There is no history of travel and she has no other
significant medical history. PE reveals an acutely ill, irritable patient.
She is oriented to place and time. Temp is 38.7 C, PR=100/min, RR
=24/min and BP= 110/60 mm Hg. . There is no rash. Pupils are
equal and reactive, neck is moderately stiff to passive motion. There
are no localizing neurologic findings.
57

58. Laboratory Studies
Hematocrit 36%
WBC 16000 (85% PMNs, 12% lymphs, 3% monos)
BUN 12 mg/dL
Plasma glucose 105, Electrolytes normal
Head CT: low-density temporal lobe lesion
CSF analysis:CSF analysis:
Normal OP, cell count 200 (65% lymphs, 35% PMNs), 2 RBCs
Glucose and protein are normal.
Gram stain: negative for bacteria
Which antimicrobials would you start empirically?
a) Ampicillin and ceftriaxone
b) Ampicillin, vancomycin and ceftriaxone
c) Ampicillin, ceftriaxone and acyclovir
d) Ampicillin and metronidazole
58

59.  Neurosyphilis
 Viral meningitis
 TB meningitis
 Cryptococcosis
 Herpes Simplex Encephalitis
 Poliomyelitis Poliomyelitis
 Rabies (Rhabdovirus)
 Toxoplasmosis
 Progressive multifocal leukoencephalopathy …papovavirus
(polyomavirus)
 Neurocysticercosis…T. solium/tape worm
 Tetanus
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