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Central Nervous
System Infections Introduction CNS infections include a wide variety of clinical conditions and etiologies: Meningitis, meningoencephalitis, encephalitis, brain and meningeal abscesses, and shunt infections. CNS infection is caused by virulent pathogen
Antibiotic penetration often is limited and where
host defenses are absent or inadequate • Greater morbidity and mortality Meningitis Meningitis is an inflammatory disease of the leptomeninges, the tissues
surrounding the brain and spinal cord, and is defined by an abnormal
number of WBCs in the cerebrospinal fluid (CSF)
The inflammation is usually caused by an infection of the fluid surrounding
the brain and spinal cord
Meningitis can be life-threatening because of the inflammation's proximity
to the brain and spinal cord; therefore the condition is classified as a
medical emergency. Causes of Meningitis
Bacterial Viral Fungal Ricketsial (Rocky mountain spotted fever) Parasitic/ protozoal Physical injury Cancer Certain drugs ( mainly, NSAID’S) Pathophysiology Infections are the result of: – Hematogenous spread from a primary infection site, – Seeding from a parameningeal focus,
– Reactivation from a latent site,
– Trauma, or congenital defects in the CNS.
Pathophysiology. . .
• The critical first step in the acquisition of
acute bacterial meningitis is – Nasopharyngeal colonization of the host by the bacterial pathogen. Pathophysiology. . .
• Proteolytic products ( from bacterial cell
death) and toxic oxygen radicals cause an alteration of the blood–brain barrier. • While platelet-activating factor activates coagulation and arachidonic acid metabolites stimulate vasodilation. Pathophysiology. . .
End result: • Cerebral edema,
• Elevated intracranial pressure,
• Cerebrospinal fluid (CSF) pleocytosis,
• Decreased cerebral blood flow,
• Cerebral ischemia, and death.
Clinical presentation
GENERAL: • Meningitis causes CSF changes, and these changes can be used as diagnostic markers of infection. Clinical presentation. . . Classic signs and symptoms include: – Fever – Severe headache – Nuchal rigidity (neck stiffness), – Altered mental status, – Chills, – Vomiting, – Photophobia Clinical presentation. . .
• Clinical signs and symptoms in young
children may include bulging fontanelle, apneas, purpuric rash, and convulsions in addition to those just mentioned. • Seizures occur more commonly in children (20% to 30%) than in adults (0% to 12%). Clinical presentation. . . DIFFERENTIAL SIGNS AND SYMPTOMS • Purpuric and petechial skin lesions typically indicate meningococcal involvement, – May be present with H. influenzae meningitis. • Rashes rarely occur with pneumococcal meningitis. Clinical presentation. . .
• H. influenza meningitis and meningococcal
meningitis both can cause involvement of the joints during the illness. • A history of head trauma with or without skull fracture or presence of a chronically draining ear is associated with pneumococcal involvement. Laboratory Tests • CSF Analysis……..Glucose & total protein conc. – CSF protein > 100 mg/dL and
– CSF glucose <50% of the simultaneously
obtained peripheral value suggest……… bacterial meningitis CSF chemistry TYPE NORMAL BACTERIAL VIRAL FUNGAL TUBERC ULOSIS
WBC <5 1,000– 100– 40–400 100–500
(cells/mm3) 5,000 1,000
Differentia >90a 80 PMNs 50 >50 >80
l (%)
Protein <50 100–500 30–150 40–150 40–150
(mg/dL) Glucose 50–66% <40 <30–70 <30–70 <30–70 (mg/dL) simultane simultaneo ous us serum serum value) value Other Diagnostic tests • Gram stain ……… & ………. Culture of the CSF
– Make sure to perform…… before antibiotic
therapy is initiated • Gram stain…….Rapid and sensitive ….75% to 90% • Culture is required to ……………
– differentiate the various bacterial etiologies.
• Polymerase chain reaction (PCR). . . Can also be
used. Other Diagnostic tests. . . • Tuberculosis meningitis:
– Acid-fast staining, culture, and PCR of the CSF.
• Viral meningitis:
– PCR testing of the CSF is the preferred.
• Fungal meningitis
– Direct microscopic examination of stained and
unstained specimens of CSF. TREATMENT GENERAL PRINCIPLES • . GENERAL PRINCIPLES OF THERAPY The administration of fluids, electrolytes, antipyretics, analgesia, and other supportive Antibiotics should be – Avoidance of delay
– Bactericidal drugs
– Drug entry into CSF
– All Pts should be treated with IV antibiotics
– Longer duration of antibiotic therapy
Treatment. . . General Principle
• Meningitis caused by S. pneumoniae is
successfully treated with 10 to 14 days of antibiotic therapy. • Meningitis caused by N. meningitidis usually can be treated with a 7-day course. • A longer course, ≥21 days, is recommended for patients infected with L. monocytogenes . 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. • Once a pathogen is identified, antibiotic therapy should be tailored to the specific pathogen. Pharmacologic. . .
• With increased meningeal inflammation, there
will be greater antibiotic penetration. • Problems of CSF penetration may be overcome by direct instillation of antibiotics by – intrathecal, intracisternal, or intraventricular routes of administration. Dexamethasone as an Adjunctive Treatment for Meningitis
• Even if conflicting, several studies have shown that:
• Dexamethasone causes a significant improvement in
suggests. . . • Dexamethasone be considered for infants and children aged 2 months or older with pneumococcal meningitis and H. influenzae meningitis. Dexamethasone. . .
Commonly: • IV dexamethasone dose is 0.15 mg/kg every 6 hours for 4 days. • Alternatively, dexamethasone given 0.15 mg/kg every 6 hours for 2 days or • 0.4 mg/kg every 12 hours for 2 days is equally effective and a potentially less toxic regimen. Dexamethasone. . .
• Dexamethasone should be administered
prior to the first antibiotic dose and not after antibiotics have already been started. • Serum hemoglobin and stool guaiac should be monitored for evidence of GI bleeding. Neisseria Meningitidis (Meningococcus) • The presence of petechiae…….. 50%
Neisseria Meningitidis (Meningococcus) • Unique characteristics: – After the acute phase, immune reaction occurs
– Immunologic reaction of fever, arthritis
(usually involving large joints), and pericarditis ,10 to 14 days after onset of symptoms. – last 1 week or longer
– no additional antibiotic therapy is required.
Neisseria Meningitidis (Meningococcus) • Transmission – Spread by direct person-to-person close contact, including respiratory droplets and pharyngeal secretions – Daycare center contacts, members of the household (coughing, sneezing, or kissing): 500 to 800 times greater N. Meningitidis Meningitis- Treatment
• Meropenem and fluoroquinolones…….alternatives • Chloramphenicol . . . . . . . Another alternative N. Meningitidis. . . • Prophylaxis……….. Rifampin x 2 days
– Dose: Adult 600 mg every 12 hours
– Children >1 month ………10 mg/kg every 12 hrs
– Children < 1 month………..5 mg/kg every 12 hrs
• IM ceftriaxone
– Adults 250 mg………children < 12 yrs 125 mg
• Oral ciprofloxacin ……….children >12 yrs 500 mg
Streptococcus Pneumoniae (Pneumococcus Or Diplococcus) • Is the leading cause of meningitis in adults.
• 50% cases are Secondary infections from
– Ear or paranasal sinuses, pneumonia,
endocarditis, CSF leak secondary to head trauma, splenectomy, alcoholism, sickle cell disease, and bone marrow transplantation • Neurologic complications, (coma and seizures) are common with pneumococcal meningitis. Streptococcus Pneumoniae. . .
Drug of Choice IV Crystalline penicillin G ……50,000 units/kg q4 hrs. But ……….PCN-resistant pneumococcal strains…. increases in alarming numbers Streptococcus Pneumoniae. . . Current recommendations For intermediate isolates……..Ceftriaxone For highly resistant….Ceftriaxone plus vancomycin Cefotaxime …………..alternatives Role of vancomycin as a monotherapy............... Not recommended Streptococcus Pneumoniae. . . Other options………… Fluoroquinolones (synergistic) with vancomycin Linezolid and daptomycin Vaccine • Heptavalent pneumococcal conjugate vaccine (Prevnar® - 2000)…….. – Active against all knows PCN-resistant organisms – Children aged 2 months to 5 years given at …………. • 2, 4, 6, and 12 to 15 months
• Benefit: 90% reduction
Haemophilus Influenzae • Incidence …………… is decrease by 99%
– Third-generation cephalosporin (cefotaxime and ceftriaxone) ……..preferred as empiric therapy – Cefepime and fluoroquinolones ……alternatives
• Prophylaxis of close contacts
– Children: Rifampin 20 mg/kg/day (maximum
600 mg) – Adults: 600 mg/day in one dose for 4 days Listeria Monocytogenes Mostly affects Neonates, alcoholics, immunocompromised adults, and the elderly. Food-borne pathogen….. Coleslaw, unpasteurized milk, soft cheese, ready-to-eat foods, and raw beef and poultry Start as colonization…then penetrates the GI lumen Listeria Monocytogenes. . . • Treatment: Penicillin G or ampicillin
– plus an aminoglycoside x 10 days and……….
– the remaining course of therapy completed
with penicillin G or ampicillin alone. • Use of other agents:
Dose. . . . . – Tobramycin or gentamicin 0.03 mg/mL of CSF
– Or amikacin 0.1 mg/mL of CSF every 24 hours
Gram-Negative Meningitis. . . • Other gram negative organisms:
– Adults: ceftriaxone 2 g twice daily
– displacement of bilirubin from albumin-
binding sites (neonatal) • Trimethoprim- sulfamethoxazole……Not bactericidal – But…dose not require inflammation for CNS penetration Mycobacterium Tuberculosis meningitis – Is the most life-threatening form of Extrapulmonary tuberculosis . – Associated with significant morbidity and mortality – Difficult to diagnose in a timely manner Incidence increased due to…..... HIV/AIDS spread Mycobacterium Tuberculosis meningitis - Diagnosis
Acid-fast bacilli smears….37% - 87% sensitive
Cultures of CSF………+ve in 45% to 90% but… may take up to 8 weeks Nucleic acid amplification products Amplicor, MTD Gen-Probe Detect within 48 hours and yield higher sensitivity than a smear Drug therapy • CDC recommendation…….4 drug therapy
– Isoniazid, rifampin, pyrazinamide, and
ethambutol 15 to 20 mg/kg/day (maximum 1.6 g/day) for the first 2 months – Followed by isoniazid plus rifampin for the remaining duration of therapy Drug therapy. . .
• Duration………..9 months or longer,
– If rifampin-resistant strains …..18 to 24 month
– Due to isoniazid . . . . .
– Pyridoxine hydrochloride (vitamin B6)
50 mg/day (peripheral neuropathy) Cryptococcus Neoformans C. Neoformans a soil fungus acquired by inhalation of spores from the environment Cause a pneumonia that usually is asymptomatic. Symptoms………….are insidious
– Fever and History of headaches
– Altered mentation and evidence of focal
neurologic deficits Cryptococcus Neoformans. . . Diagnosis is based on….. the presence of a positive CSF, blood, sputum, or urine culture for C. neoformans. Positive CSF cultures…. >90% of cases. Cryptococcus Neoformans. . . Amphotericin B………..first line despite.. Poor penetration into CSF Dose: 0.5 to 1 mg/kg/day PLUS flucytosine 100 mg/kg/day Flucytosine……is poorly tolerated in AIDS pts… b/s of Bone marrow suppression Other alternatives. . . . . . Fluconazole..200 mg/day or Itraconazole 200 mg Cryptococcus Neoformans. . . AIDS-associated cryptococcal meningitis ……… Induction phase: – Amphotericin B 0.7–1 mg/kg/day and flucytosine 100 mg/kg/day for 2 weeks – Consolidation Phase: Fluconazole 400 mg/day for 8 weeks continued thereafter with fluconazole 200 mg/day Viral Encephalitis Causative agents: Nonpolio enteroviruses such as coxsackievirus A and B, echoviruses, and enterovirus 70 and 71 …. Associated w/.. Encephalitis incidence…………….85% Method of transmission: Primarily by hematogenous spread Viral Encephalitis. . . • Common signs in adults:
– Nuchal rigidity……..a resistance to flexion
of the neck, a condition seen in patients with meningitis – Headache, mild fever (<40°C), malaise,
– Drowsiness, nausea, vomiting, and
photophobia. – last 1 to 2 weeks Viral Encephalitis. . .
• Laboratory examination of the CSF:
– Pleocytosis …………presence of a greater than normal number of cells in CSF….100 to 1,000 WBCs/mm3, • Other laboratory findings – Elevated protein concentrations and normal or mildly reduced glucose concentrations Viral Encephalitis. . . • Other causative agents….variety of viral etiology – Enteroviruses: transmitted in the host via the fecal–oral route. – Herpes simplex virus type 1 (HSV-1; adult)
– Herpes simplex virus type 2 (HSV-2; children)
Viral Encephalitis. . . • Treatment: – Acyclovir: 10 mg/kg IV q8 hours for 2 to 3 weeks. – Foscarnet (acyclovir-resistant herpes simplex virus): • 40 mg/kg infused over 1 hr q8-12 hrs for 2 to 3 wks. • Role of adequate hydration…..is a key for both drugs Organism Antibiotic Alternati Recommend Of First ve ed Duration Choice Antibiotic Of Therapy s Gram-positive - streptococcus pneumoniae 10–14 days Penicillin • Penicillin G or • Cefotaxime susceptible • ampicillin • ceftriaxone, • chloramphenic ol Penicillin • Cefotaxime or • Cefepime, intermediat • ceftriaxone • meropenem, e • moxifloxacin, • linezolid Penicillin • Vancomycin plus • Cefepime , resistant cefotaxime or • meropenem ceftriaxone • moxifloxacin, • linezolid Group B • Penicillin G or • Cefotaxime 14–21 Organism Antibiotic of Alternative Recommende First Choice Antibiotics d Duration of Therapy
Gram-positive Staphylococcus aureus 14–21 days
Methicillin Nafcillin or Vancomycin,
susceptible oxacillin meropenem Methicillin Vancomycin Trimethopri resistant m- sulfamethox azole, linezolid Staphylococc Vancomycin Linezolid 14–21 days us epidermidis Listeria Penicillin G Trimethopri 21 days monocytogen or m- es ampicillin ± sulfamethox NEISSERIA MENINGITIS 7 days Penicillin Penicillin G Cefotaxime, ceftriaxone, susceptible or chloramphenicol ampicillin Penicillin Cefotaxim Chloramphenicol, resistant e or meropenem ceftriaxone fluoroquinolone HAEMOPHILUS INFLUENZAE 7 days Beta- Ampicillin Cefotaxime, ceftriaxone, Lactamase chloramphenicol, cefepime, negative fluoroquinolone Beta- Cefotaxim Cefepime , fluoroquinolone, Lactamase e or chloramphenicol positive ceftriaxone Enterobacte Cefotaxim Cefepime, fluoroquinolone,, 21 riaceae e or meropenem, aztreonam days ceftriaxone The End
