central nervous infection for clinical pharmacists and other medical students this contains management of cns infections how it can be diagnosed and how to chose appropriate drug treatment based on age of patient.

2. Central nervous system infections
prepared by
Sima siyamand Hussein
Near east university –clinical pharmacy department –master

3. ➢Outline
• Anatomy of the brain
• CNS infections
• Epidemiology
• Etiology
• pathophysiology
• Clinical presentations
• Diagnosis
• Pharmacological treatments
• References

4. Central nervous system infection (CNS infection )
CNS infection encephalitiscerebral
abscess
cerebritis
meningitis

5. Anatomy of the brain

6. Anatomy of the brain
• The brain is suspended in these structures by cerebrospinal fluid (CSF)
and is surrounded by the meninges.
• The meninges are made up of three separate membranes: pia mater ,
arachnoid, and dura mater.
• Pia mater and arachnoid called leptomeninges.

7. CNS infection
• meningitis
Leptomeningites
Pia mater
Arachnoid
CSF

8. CNS infection
• Encephalitis is an inflammation of the brain
tissue itself (brain parenchyma).

9. CNS infection
• Cerebritis is localized inflammation of brain parenchyma
• Cerebral abscess is localized inflammation of brain parenchyma

10. Epidemiology
• Approximately 4,100 cases of acute community-acquired bacterial meningitis,
excluding epidemics, occurred annually in the United States between 2003 and
2007, resulting in approximately 500 deaths
• Risk factors and mortality rates widely vary depending on the causative
microorganism and age group
• Neurologic sequelae frequently associated with bacterial meningitis include
seizures, sensorineural hearing loss, and hydrocephalus
• Risk for the development of neurologic sequelae depends on the infecting
organism, pneumococcal meningitis is typically associated with the highest
risk.

11. Etiology
• CNS infections are caused by a variety of microorganisms. Historically, infections
were primarily community-acquired however, an increasing number of cases are
now nosocomial.
• Top 5 causes of meningitis
1.Streptococus pneumonia
2.group B Streptococcus
3.Neisseria meningitidis
4.Listeria monocytogenes
5.Haemophllus influenza

12. Etiology
• Haemophilusinfluenzae type b (Hib) was the most commonly identified cause of
bacterial meningitis until the introduction of the Hib conjugate vaccine in 1990.
• Streptococcus pneumoniae became the most commonly identified cause
Between 2003 and 2007 in the United States
• S. pneumoniae accounted for 58% of all bacterial meningitis cases, followed by
group B Streptococcus (18.1%),
• Neisseria meningitidis (13.9%), H. influenzae (6.7%), and L. monocytogenes
(3.4%).1 Other causative organisms included gram-negative organisms and
Staphylococcus spp.

13. Etiology
Hib s.pneumoniae group B streptococus N.meningitis L.monocytogens other

14. Etiology
• Following the release of the pneumococcal heptavalent protein-
polysaccharide conjugate vaccine (PCV7) in 2000, the rate of invasive
pneumococcal disease (IPD), including pneumococcal meningitis,
steadily dropped from 24.3 cases per 100,000 people
• in 1999 to 17.3 cases per 100,000 in 2001 and 13.5 cases per
100,000
• in 2007.7 The largest impact was in children younger than 2 years of
age,where a nearly 70% decline in infection rate was reported as a
result of implementation in the routinechildhood vaccination
schedule.

15. Pathophysiology
• The development of bacterial meningitis occurs following bacterial
invasion of the host and CNS, bacterial multiplication with
subsequent inflammation of the CNS specifically the subarachnoid
and the ventricular spaces pathophysiologic alterations owing to
progressive inflammation, and the resulting neuronal damage

16. Pathophysiology
nasopharyngeal
colonization
secretory IgA, are found in
high concentrations within
nasopharyngeal secretions
and work to inhibit bacterial
colonization.
mucus barrier is
deteriorated by IgA
proteases secreted
by bacteria
Bacterial pathogens
tightly attach to
nasopharyngeal
epithelial cells and are
then phagocytized into
the host’s bloodstream
bacteria must
overcome the
host’s defense
mechanisms.
the exact site and
mechanism of
bacterial invasion
into the CNS is
unknown,

17. Pathophysiology
• Studies suggest invasion into the subarachnoid space occurs by
continuous exposure of the CNS to large bacterial inoculum.
Bacteremia with inoculum densities of at least 103 colony-forming
units (CFU)/mL [106 CFU/L] appears to be essential for subarachnoid
space invasion.
• the ensuing neurologic damage, are not necessarily a direct result of
the pathogens themselves.
• The neurologic sequelae occur due to the activation of the host’s
inflammatory pathways, a process induced by the pathogen or its
products.

18. Pathophysiology

19. Clinical presentations
• Clinical presentation varies with age, and generally, the younger the
patient, the more atypical and the less pronounced the clinical
picture.
• Receiving antibiotic in the outpatient setting before diagnosis of
meningitis made may cause the gram stain and CSF culture to be
negative but rarely affects CSF protein or glucose.

20. Signs and symptoms
Fever Nuchal rigidity Altered mental status
chills
photophobia severe headache

21. Signs and symptoms
• Kernig’s and Brudzinski’s signs may also be present but are poorly
sensitive and frequently absent in children.
• clinical signs and symptoms in young children may include bulging
fontanelle, apneas, purpuric rash, irritability, refusal to eat, and
convulsions.
• Purpuric and petechial skin lesions may indicate meningococcal
involvement, although lesions may also be present with H. influenzae
meningitis and skin rashes rarely occur with pneumococcal
meningitis.

22. Signs and symptoms
➢ Kernig’s and Brudzinski’s signs may also be
present but are poorly sensitive and frequently absent in children

23. Diagnosis
• Bacterial Meningitis Score
• Bacterial Meningitis Score is a validated clinical decision tool aimed to
identify children older than 2 months with CSF pleocytosis who are at
low risk of acute bacterial meningitis.
• This tool incorporates clinical features such as

24. Diagnosis
positive CSF gram stain
presence of seizure
neutrophil count 10,000 cells/mm3 or more (10 ×
109/L or more)
CSF protein 80 mg/dL or more (800
mg/L or more)
CSF neutrophil count 1,000 cells/mm3 or more (1
× 109/L or more).

25. Diagnosis
o MRI is considered the preferred imaging modality for the diagnosis of
encephalitis due to higher specificity and sensitivity than CT.
oGram stain and culture of the CSF should be performed for suspected
meningitis, and gram stain continues to be the most rapid and accurate
method for presumptive diagnosis.
oPolymerase chain reaction (PCR) techniques can be used to diagnose
meningitis caused by N. meningitidis, S. pneumoniae, and Hib. PCR is
considered to be highly sensitive and specific, but expense and availability
can be limiting.
oLatex agglutination is considered most useful for patients who have been
previously treated with antimicrobials and whose CSF gram stain and
culture remain negative

26. Laboratory findings
➢Analysis of CSF chemistries includes measurement of glucose and
total protein concentrations.
➢An elevated CSF protein of more than or equal to 50 mg/dL (500
mg/L or more) and a CSF glucose concentration of less than 50% of
the simultaneously obtained peripheral value suggest bacterial
meningitis

27. Desired Outcome
➢ Goals for the treatment of CNS infections should include
• eradication of infection,
• amelioration of signs and symptoms
• prevention or reduction of morbidity and mortality
• initiation of appropriate antimicrobials
• supportive care, and prevention of disease through timely
introduction of vaccination and chemoprophylaxis

28. Pharmacologic treatment
▪ Empiric antimicrobial therapy should be instituted as soon as possible
to eradicate the causative organism.
▪ Antimicrobial therapy should last at least 48 to 72 hours or until the
diagnosis of bacterial meningitis can be ruled out.
▪ Continuedtherapy should be based on the assessment of clinical
improvement, cultures, and susceptibility testing results.

30. • With increased meningeal inflammation, there will be greater
antibiotic penetration.
• Problems of CSF penetration were traditionally overcome by direct
instillation of antibiotics intrathecally, intracisternal, or
intraventricularly.

34. Dexamethasone as an Adjunctive Treatment for
Meningitis
• dexamethasone is a commonly used therapy for the treatment of
pediatric meningitis.
• Current recommendations call for the use of adjunctive
dexamethasone in infants and children with H. influenzae meningitis
• The recommended IV dose is 0.15 mg/kg every 6 hours for 2 to 4
days, initiated 10 to 20 minutes prior to or concomitant with
antibiotics , but not after, the first dose of antimicrobials
• If adjunctive dexamethasone is used, careful monitoring of signs and
symptoms of gastrointestinal (GI) bleeding and hyperglycemia should
be employed.

35. Neisseria meningitidis (Meningococcus)
• The presence of petechiae may be the primary clue that the
underlying pathogen is N.meningitidis.
• Approximately 60% of adults and up to 90% of pediatric patients with
meningococcal meningitis have purpuric lesions, petechiae, or both.

36. Neisseria meningitidis (Meningococcus)
• Approximately 10 to 14 days after the onset of the disease and
despite successful treatment, the patient develops a characteristic
immunologic reaction of fever, arthritis (usually involving large joints),
and pericarditis. The synovial fluid is characterized by a large number
of polymorphonuclear cells, elevated protein concentrations, normal
glucose concentrations, and sterile cultures.
• N. meningitidis is spread by direct person-to-person close contact,
including respiratory droplets and pharyngeal secretions. Close
contacts of patients contracting meningococcal meningitis are at an
increased risk of developing meningitis.

37. Neisseria meningitidis (Meningococcus)
• Empiric treatment for meningococcal meningitis Third-generation cephalosporins such
as
• and
• When final culture results are available, penicillin G or ampicillin is recommended
• Meropenem and fluoroquinolones are also suitable alternatives for the treatment of
penicillin non susceptible meningococci
cefotaxime ceftriaxone

38. Neisseria meningitidis (Meningococcus)
➢Prophylaxis
• In general, rifampin, ceftriaxone, ciprofloxacin, or azithromycin is
given for prophylaxis.
• For regions with reported ciprofloxacin resistance, one dose of
azithromycin 500 mg is recommended for prophylaxis
• Prophylaxis of contacts should be started only after
consultation with the local health department

39. Streptococcus pneumoniae
(Pneumococcus or Diplococcus)
• S. pneumoniae is the leading cause of meningitis in patients 2 months
of age or older in the United States.
• Neurologic complications, such as coma and seizures, are common.
Empirical treatment until the results of antimicrobial susceptibility
testing are available is the combination of
vancomycin + ceftriaxone

40. Streptococcus pneumoniae
(Pneumococcus or Diplococcus)
• Penicillin may be used for drug-susceptible isolates with minimum
inhibitory concentrations of 0.06 mcg/mL or less , but for
intermediate isolates ceftriaxone is used, and for highly drug-resistant
isolates combination of ceftriaxone and vancomycin should be used.
• Meropenem is recommended as an alternative to a third-generation
cephalosporin in penicillin non susceptible isolates.
• IV linezolid and daptomycin have emerged as therapeutic options for
treating multidrug-resistant gram-positive infections.

41. Streptococcus pneumoniae
(Pneumococcus or Diplococcus)
• Prophylaxis
• The Centers for Disease Control and Prevention (CDC) recommends use of 23-
valent pneumococcal vaccine (PPV 23).
• PCV13 should be used in series with PPV23 for all adults who are 65 years of age
or older.
persons over 65 years of age
persons 2 to 64
years of age who have a chronic illness,
persons over 2 years, including
those with human immunodeficiency virus
(HIV) infection
All healthy infants
younger than 2 years of
ageat (2, 4, 6, and 12 to 15
months) should be
immunized with the 13-
valent pneumococcal
conjugate vaccine (PCV13)

42. Haemophilus influenzae
• In the past, H. influenzae was the most common cause of meningitis
in children 6 months to 3 years of age, but this has declined
dramatically since the introduction of effective vaccines.
• Because approximately 20% of H. influenzae are ampicillin resistant,
many clinicians use a third-generation cephalosporin for initial
antimicrobial therapy
OR
cefotaxime ceftriaxone

43. • Cefepime and fluoroquinolones are suitable alternatives regardless
of β-lactamase activity.
➢Prophylaxis
• Close contacts should be started only after consultation with the local
health department and the CDC.
• Vaccination with Hib conjugate vaccines is usually begun in children
at 2 months and in patients older than 5 years with sickle cell disease,
asplenia, or immunocompromising diseases.

44. Listeria monocytogenes
• L. monocytogenes is a gram-positive, diphtheroid-like organism and is
responsible for 10% of all reported cases of meningitis in those older
than 65 years.
• The combination of penicillin G or ampicillin with an aminoglycoside
results in abactericidal effect.
• Patients should be treated a minimum of 3 weeks.
• Combination therapy is given for the first 7 to 10 days with the
remainder completed with penicillin G or ampicillin alone

45. Listeria monocytogenes
• Trimethoprim–sulfamethoxazole and meropenem may be an
effective alternative because adequate CSF penetration is achieved
with these agents.

46. Gram-Negative Bacillary Meningitis
• Elderly debilitated patients are at an increased risk of gram-negative
meningitis but typically lack the classic signs and symptoms of the
disease.

47. Gram-Negative Bacillary Meningitis
• Meningitis caused by Pseudomonas aeruginosa is initially treated
with an extended-spectrum β-lactam such as
OR OR alternatively
• The addition of an aminoglycoside usually tobramycin to one of the
above agents should also be considered
ceftazidime cefepime
aztreonam,
ciprofloxacin, or
meropenem

48. Gram-Negative Bacillary Meningitis
• If the pseudomonad is suspected to be antibiotic resistant or becomes
resistant during therapy an intraventricular aminoglycoside (preservative-
free) should be considered along with IV aminoglycoside.
• Gram-negative organisms, other than P. aeruginosa, that cause meningitis
can be treated with a third- or fourth-generation cephalosporin such as
cefotaxime, ceftriaxone, ceftazidime, or cefepime.
• Therapy for gram-negative meningitis is continued for a minimum of 21
days.
• CSF cultures may remain positive for several days or more on a regimen
that will eventually be curative.

49. References
• Pharmacotherapy handbook 10thedition
• Pharmacotherapy a pathophysiologic approach 10th edition