Pharmacotherapy of Common

Central Nervous Infections

Cecilia C. Maramba-Lazarte, MD, MScID, MScCT
Professor, Dept. of Pharmacology and Toxicology
Clin Prof, Section of Pediatric Infect Dis, Dept. of
Pediatrics
UP College of Medicine
 Summary
• Introduction
• Bacterial Causes
Bacterial meningitis
Brain Abscess
• TB CNS Infections
• Fungal CNS Infections
• Viral CNS infections
• Central nervous system (CNS) infections continue to cause
significant morbidity and mortality worldwide, despite the
advent of antibiotics, vaccines, and other medical
therapies.
• The causative organisms— bacteria, viruses, parasites,
fungi, and prions—
• Types of infections- meningitis, encephalitis, spinal and
cranial abscesses, discitis, epilepsy, and other severe
complications.
• The spread of other CNS infections remains a concern in
light of increased migration and tourism travel, drug-
resistant organisms, and immunosuppressed individuals.
• While medical treatment is necessary for most CNS
infections, neurosurgical involvement can be required for
biopsy, debridement, decompression, or reconstruction.
 Meningitis
• Clinical syndrome
characterized by
inflammation of the
meninges
dura- a tough outer layer
arachnoid- lacy, web like
middle membrane
subarachnoid space- delicate
fibrous inner layer that
contains blood vessels
• Alcoholic with
pneumococcal
meningitis
 Risk factors for meningitis
• Extremes of age (< 5 or >60 years)
• Diabetes mellitus, chronic kidney
failure, adrenal insufficiency,
hypoparathyroidism, or cystic
fibrosis
• Immunosuppression, which
increases the risk of opportunistic
infections and acute bacterial
meningitis
• HIV infection, which predisposes
to Streptococcus pneumoniae,
and opportunistic pathogens
• Crowding (such as that
experienced by military recruits
and college dorm residents),
which increases the risk of
outbreaks of meningococcal
meningitis
• Splenectomy and sickle cell
disease, which increase the risk
of meningitis secondary to
encapsulated organisms
• Alcoholism and cirrhosis
• Contiguous infection (egg,
sinusitis)
• Dural defect (e.g., traumatic,
surgical, or congenital)
• Thalassemia major
• Intravenous (IV) drug abuse
• Bacterial endocarditis
• Ventriculoperitoneal shunt
• Malignancy (increased risk of
Listeria infection)
• Some cranial congenital
deformities
 Function of Meninges
• The brain is naturally protected from the body’s
immune system by the barrier that the meninges
create between the bloodstream and the brain.
Normally, this protection is an advantage because
the barrier prevents the immune system from
attacking the brain.
• In meningitis, the blood-brain barrier can become
disrupted; once bacteria or other organisms have
found their way to the brain, they are isolated
from the immune system and can spread.
 Pathophysiology of meningitis
An infectious agent (i.e., a bacterium, virus, fungus, or
parasite) can gain access to the CNS and cause meningeal
disease via any of the 3 following major pathways:
• Invasion of the bloodstream (i.e., bacteremia, viremia,
fungemia, or parasitemia) and subsequent
hematogenous seeding of the CNS
• A retrograde neuronal (e.g., olfactory and peripheral
nerves) pathway (e.g., Naegleria fowleri or
Gnathostoma spinigerum)
• Direct contiguous spread (e.g., sinusitis, otitis media,
congenital malformations, trauma, or direct
inoculation during intracranial manipulation)
 Signs and Symptoms of Meningitis

• are variable and depend on the age of the

patient, and the duration of illness before
treatment
• neonates and young infants may have minimal
signs and symptoms
• signs of symptoms of neonatal sepsis are
indistinguishable from neonatal meningitis
• all neonates being evaluated for sepsis should
be evaluated for meningitis
 Signs and Symptoms of Bacterial Meningitis

Signs and Neonates Older infants and children

symptoms
Nonspecific Fever or hypothermia, Fever, anorexia, confusion,
abnormally sleepy or lethargic, irritability, photophobia,
disinterest in feeding, poor nausea, vomiting, headache,
feeding, cyanosis, grunting, seizure
apneic episodes, vomiting
Meningeal Neck rigidity, Neck rigidity, Kernig and
inflammation Brudzinski sign
Increased Bulging fontanel, diastasis of Headache, bulging fontanel,
intracranial sutures, convulsions, diastasis of sutures in infants,
pressure opisthotonus papilledema, mental
confusion, altered state of
consciousness
Focal Hemiparesis, ptosis, facial Hemi paresis, ptosis,
neurologic nerve palsy deafness, facial nerve palsy,
signs optic neuritis
What is the definitive test for bacterial
meningitis?
CSF culture is the gold standard for the
diagnosis of acute bacterial meningitis
*Without prior antibiotics, CSF culture is
positive in 95% positive in those with H.
influenzae meningitis, 87% positive in those
with pneumococcal meningitis and 80%
positive in those with meningococcal
meningitis.

*Bohr, V., N. Rasmussen, B. Hansen et al. 875 cases of bacterial meningitis

:diagnostic procedures and impact of preadmission antibiotic therapy.
J. Infectious 1983;7:193-202.
How will you differentiate acute bacterial
meningitis from other CNS infection?
efinitive diagnosis requires culture and CSF
analysis.
A normal CSF analysis does not rule out
bacterial meningitis, especially in the neonatal
age group. However, a CSF protein >1g/L, WBC
of >100/mm3, with predominance of
neutrophils and sugar concentration of < 40%
is indicative of bacterial meningitis.
 Neutrophils Lympho Protein Glucose
(X106/l) (x106/L) (g/L) (CSF:blood
ratio)
Normal term 0 <20 <1.0 >0.6
neonate
Normal 0 <5 <0.4 >0.6
(>1 month)
Bacterial 100-10,000 Usually <100 >1.0 <0.4
meningitis (may be (may be (may be
normal) normal) normal)
Viral Usually <100 10-1000 0.4-1 Usually normal
meningitis (may be (may be
normal) normal)
TB meningitis Usually <100 50-1000 1-5 <0.3
(may normal) (may be (maybe
normal) normal)
Fungal 40% 60% Variable 2.11 (.30-3.12) 0.3 (0.1-0.7)
meningitis cells (10 -1000
cells/µL)
<500cells/µL
What are the ancillary tests in the
diagnosis of bacterial meningitis?

• CBC
• Blood culture
• CRP
• PCR
• Latex agglutination
• Procalcitonin
 What is the role of imaging tests in the
diagnosis of bacterial meningitis?
• Neuroimaging is used to identify the presence of
complications of bacterial meningitis and to rule
out contraindications in doing a lumbar tap.
Neuroimaging is not used to diagnose the
presence or absence of a CNS infection.
• A normal imaging study does not rule out CNS
infection
• Based on systematic reviews on MRI, UTZ and
CT scan
What are the most common pathogens of acute
bacterial meningitis in the different age groups?
Age Common Etiology of Meningitis
0-2 mos Gram negative bacilli
>2mos - <5 years H. Influenzae and S. pneumoniae
>5 yrs S. pneumoniae

• Neisseria meningitides may occur in

epidemics or sporadically, 80-90% of cases
present as meningitis. In infants, children
and young adults, meningococcal
meningitis are caused by Neisseria
meningitides Serotype A or B.
- Based on local data, needs to be continually
updated
Are there signs and symptoms suggestive of
a specific etiology?
There are no signs and symptoms suggestive of
a specific etiology EXCEPT for meningococcal
meningitis
classic symptoms of meningococcal meningitis:
haemorrhagic rash, impaired consciousness, and
meningism; 3 important clinical features were
identified - leg pain, cold hands and feet, and
abnormal skin color
 Empiric Therapy for Bacterial Meningitis

• Adjust therapy based on culture. Start antibiotic therapy immediately after a

lumbar puncture or, if this is delayed, after obtaining blood cultures.
• Early onset usually due to maternal transmission.
• May use Ceftriaxone if Cefotaxime is not available and the neonate is not
jaundiced.
• Repeat lumbar tap in the neonate is necessary to verify sterilization of the CSF in
Gram negative meningitis.
• Dexamethasone has no role in neonatal meningitis.
 Empiric Therapy for Bacterial Meningitis

• Do not use Cefuroxime for treatment of bacterial meningitis because of delayed

sterilization and greater incidence of hearing loss.
• Dexamethasone should be started along or shortly before the 1st antibiotic dose.
The first dose should be administered within 4 hours of starting antibiotic. Do not
start Dexamethasone >12h after starting antibiotics.
• Repeat lumbar puncture (LP) is recommended in patients with poor clinical
response despite 36 hours of appropriate antibiotic treatment or those with Gram-
negative meningitis.
• For H. influenzae and S. pneumoniae meningitis, if the patient is improving, repeat
LP is not necessary.
 Empiric Therapy for Bacterial Meningitis

• Start Dexamethasone before or give with the

first dose of antibiotics at 0.15 mg/kg q6h IV x
2-4 days
 Empiric Therapy for Bacterial Meningitis

• Patients with confirmed meningococcal meningitis and not treated with

Ceftriaxone should receive either:
• Rifampicin 10mg/kg q12h x 2d (for children 1 month of age and older)
OR
Ceftriaxone <15 yrs.: 125mg IM x 1 dose;
>15 yrs.: 250mg IM x 1 dose
OR
Ciprofloxacin 500mg PO x 1 dose
Empiric Therapy for Bacterial
Meningitis
 Definitive Therapy for Bacterial
Meningitis
Culture Isolate Definitive Alternative Duration of
therapy Therapy

E. coli Cefotaxime Ceftriaxone (if 21 days

not jaundiced)
H. influenzae Ceftriaxone Chloramphenicol 7-10 days

S. pneumoniae Penicillin Ceftriaxone or 10-14 days

Chloramphenicol
N. meningitides Penicillin Ampicillin or 7-10 days
Ceftriaxone or
Chloramphenicol
 Prognosis
In bacterial meningitis, several risk factors are
associated with death and with neurologic
disability.
• Older age
• Increased heart rate
• Lower Glasgow Coma Scale score
• Cranial nerve palsies
• CSF leukocyte count lower than 1000/μL
• Gram-positive cocci on CSF Gram stain
 Prognosis
• Advanced bacterial
meningitis can lead to brain
damage, coma, and death.
In 50% of patients, several
complications may develop
in the days to weeks
following infection.
• Long-term sequelae are
seen in as many as 30% of
survivors and vary with
etiologic agent, patient age,
presenting features, and
hospital course.
• Patients usually have subtle
CNS changes.
Serious complications include
the following:
• Hearing loss
• Cortical blindness
• Other cranial nerve
dysfunction
• Paralysis
• Muscular hypertonia
• Ataxia
• Multiple seizures