Meningitis and Encephalitis

Quick Answer: Bacterial Meningitis: Fever, headache, photophobia, nuchal rigidity, altered consciousness. Empiric: ceftriaxone 2g q12h + vancomycin 15-20 mg/kg q8-12h + dexamethasone 10 mg q6h (first dose before/with antibiotics).

HSV Encephalitis: Fever, headache, seizures, focal neuro deficits, altered consciousness. Acyclovir 10 mg/kg IV q8h.

CSF Bacterial Pattern: WBC greater than 100/μL (neutrophil predominance), protein greater than 1.0 g/L, glucose below 40% serum ratio.

CSF Viral Pattern: WBC 5-500/μL (lymphocyte predominance), protein 0.5-1.0 g/L, glucose normal or mildly decreased.

Exam Focus: CICM Fellowship Exam Focus:

• Differentiating bacterial vs viral meningitis (CSF analysis patterns)
• Empiric antibiotic selection and timing (golden hour concept)
• Steroid timing and indications (dexamethasone controversy)
• HSV encephalitis management (acyclovir dosing and duration)
• Complications management (cerebral edema, SIADH, seizures)
• LP contraindications and timing relative to CT
• Indications for repeat LP
• Adjunctive therapies (glycerol, antiplatelet agents)

High-Yield Topics:

• Dutch meningitis trial (dexamethasone benefit)
• European meningitis guidelines
• HSV PCR diagnostic accuracy
• Adjunctive dexamethasone controversies
• Hearing loss prevention (steroids, glycerol)

Pathophysiology

Bacterial Meningitis

Host-pathogen interactions:

1. Nasopharyngeal colonization → bacteremia → blood-brain barrier (BBB) penetration
2. Bacterial proliferation in subarachnoid space triggers inflammatory cascade
3. Cytokine release (IL-1β, IL-6, TNF-α) → neutrophil recruitment, BBB disruption
4. Cerebral edema (vasogenic, cytotoxic, interstitial)
5. Neuronal injury via excitotoxicity, apoptosis, free radical damage

BBB penetration mechanisms:

• Transcytosis across cerebral capillary endothelial cells
• Choroid plexus epithelial cell invasion
• Leukocyte-mediated transport (Trojan horse)

Key pathogens by age group:

Viral Meningitis/Encephalitis

Pathogens:

• HSV-1: Most common viral encephalitis (temporal lobe predilection)
• HSV-2: Meningitis (Mollaret's meningitis), neonatal encephalitis
• VZV: Chickenpox, shingles encephalitis
• Enteroviruses: Most common viral meningitis (echovirus, coxsackievirus)
• West Nile Virus: Flavivirus, poliomyelitis-like syndrome
• Japanese Encephalitis: Mosquito-borne, endemic in Asia
• EBV, CMV, HHV-6: Immunocompromised patients

HSV encephalitis pathogenesis:

1. Primary oropharyngeal infection → latency in trigeminal ganglion
2. Reactivation → retrograde transport to temporal lobe
3. Hemorrhagic necrosis of temporal and frontal lobes
4. Asymmetric involvement (50-60% bilateral)

Clinical Presentation

Bacterial Meningitis

Classic triad (present in below 50%):

1. Fever (greater than 38°C)
2. Nuchal rigidity
3. Altered mental status

Additional symptoms:

• Headache (severe, diffuse)
• Photophobia (85%)
• Nausea/vomiting (70%)
• Seizures (20-30%)
• Focal neuro deficits (10-20%)

Physical examination:

• Kernig's sign: Pain on knee extension with hip flexed (sensitivity 5-50%)
• Brudzinski's sign: Involuntary hip/knee flexion on passive neck flexion (sensitivity 5-50%)
• Clinical note: Both signs have low sensitivity; absence does not exclude meningitis
• Petechial/purpuric rash (meningococcal meningitis, 50-60%)
• Focal neuro deficits (10-20%)
• Papilledema (raised ICP, below 10%)

HSV Encephalitis

Presentation timeline:

• Prodrome (1-7 days): Fever, headache, malaise, myalgias
• Acute phase (1-14 days): Behavioral changes, seizures, focal deficits

Key features:

• Fever (90%)
• Headache (80%)
• Altered mental status (97%)
• Seizures (40-60%)
• Behavioral changes (personality, agitation, hallucinations)
• Focal neuro deficits (hemiparesis, aphasia, visual field defects)
• Memory impairment (temporal lobe involvement)

Examination findings:

• Aphasia (dominant temporal lobe)
• Hemianopia
• Hemiparesis
• Cranial nerve palsies (III, IV, VI)
• Autonomic instability

Viral Meningitis (Non-HSV)

Clinical features:

• Fever, headache, photophobia, nuchal rigidity
• Typically milder than bacterial meningitis
• Mental status usually normal (unless encephalitis)
• CSF pleocytosis (lymphocytic predominance)
• Self-limited (5-14 days)

Diagnostic Approach

Initial Investigations

Immediate investigations (within 1 hour):

• Blood cultures (2 sets, aerobic + anaerobic) - yield 40-60%
• CBC with differential (leukocytosis 70-80%)
• CRP/ESR (elevated in 80-90%)
• Serum electrolytes, glucose, renal function (baseline for CSF comparison)
• Coagulation profile (prior to LP)
• Blood gas (metabolic acidosis in severe sepsis)

Neuroimaging

CT head indications (prior to LP):

• Immunocompromised host
• History of CNS disease (mass lesion, stroke)
• New-onset seizures
• Abnormal level of consciousness (GCS below 12)
• Focal neurologic deficits
• Papilledema on fundoscopy
• Uncontrolled hypertension
• Evidence of space-occupying lesion on clinical grounds

CT findings in bacterial meningitis:

• Normal in 60-70% of early cases
• Cerebral edema (30-40%)
• Subarachnoid space enhancement with contrast
• Hydrocephalus (10-20%)
• Cerebritis/abscess formation (rare, 5-10%)

MRI preferred for HSV encephalitis:

• T2/FLAIR: Hyperintensity in temporal/frontal lobes
• DWI: Restricted diffusion (cytotoxic edema)
• T1 post-contrast: Meningeal enhancement, gyriform enhancement
• Hemorrhage (hemorrhagic necrosis)

Lumbar Puncture

CSF collection parameters:

⚠️ Warning: Critical: Do not delay antibiotics for LP if CT is required. Draw blood cultures and start empiric antibiotics immediately. LP can be performed after antibiotics (diagnostic yield decreases after 4-6 hours but still valuable).

CSF analysis panel:

1. Cell count and differential: WBC count, neutrophil vs lymphocyte predominance
2. Protein and glucose: Protein greater than 1.0 g/L and glucose below 40% serum strongly suggests bacterial
3. Gram stain: Sensitivity 60-90% (higher with high bacterial load)
4. CSF culture: Gold standard (48-72 hours), yield 70-90%
5. Latex agglutination: Limited utility, not recommended routinely
6. Multiplex PCR panel:
   • Bacterial: S. pneumoniae, N. meningitidis, H. influenzae, Group B Strep, E. coli, Listeria
   • Viral: HSV-1/2, VZV, enteroviruses, West Nile
   • Turnaround time: 1-2 hours, sensitivity greater than 90%
7. CSF lactate: greater than 3.5 mmol/L suggests bacterial (sensitivity 93%, specificity 96%)
8. Procalcitonin: Serum greater than 0.5 ng/mL suggests bacterial (sensitivity 89%, specificity 89%)

Repeat Lumbar Puncture

Indications:

• Inadequate clinical response after 48 hours of appropriate therapy
• Failure of CSF sterilization (persistent positive cultures)
• Development of complications (hydrocephalus, empyema)
• Document CSF sterilization before stopping antibiotics

Repeat CSF findings indicating improvement:

• WBC count decreased by 50% or more
• Shift from neutrophil to lymphocyte predominance
• Normalization of protein
• Negative cultures

Management

Empiric Antibiotic Therapy

Golden hour principle: Mortality doubles with each hour of delay in antibiotics. Target door-to-antibiotic time below 60 minutes.

Adult empiric regimen:

Pediatric empiric regimen:

Vancomycin dosing:

• Loading dose: 25-30 mg/kg (max 2g)
• Maintenance: 15-20 mg/kg q8-12h (adjust for renal function)
• Target trough: 15-20 mg/L (meningitis requires higher trough)
• Rationale: Poor CSF penetration (5-10%), higher doses needed for therapeutic CSF levels

Duration of therapy:

• S. pneumoniae: 10-14 days (minimum)
• N. meningitidis: 7 days
• H. influenzae: 7-10 days
• L. monocytogenes: 21 days (ampicillin + gentamicin)
• Gram-negative bacilli: 21 days (minimum)

Adjunctive Corticosteroids

Dexamethasone protocol:

• Dose: 10 mg IV q6h
• Timing: First dose before or with first antibiotic dose
• Duration: 2-4 days (continue if S. pneumoniae confirmed)
• Route: IV (not oral - delayed absorption)

Critical Alert: Critical timing window: Dexamethasone must be given before or within 4 hours of first antibiotic dose. Delayed steroids (greater than 4 hours after antibiotics) show no mortality benefit.

Evidence for steroids:

PMID: 12297146 - de Gans et al. Dexamethasone in adults with bacterial meningitis. NEJM 2002.

PMID: 15494903 - van de Beek et al. Corticosteroids for acute bacterial meningitis. Cochrane Database 2007.

Indications:

• Strongly recommended for suspected pneumococcal meningitis
• Consider for suspected meningococcal meningitis (less evidence)
• Not recommended for other pathogens or viral meningitis

Contraindications:

• Active gastrointestinal bleeding
• Uncontrolled diabetes mellitus
• Severe immunosuppression

Steroid controversies:

• Decreased CSF vancomycin penetration (consider higher vancomycin doses)
• Potential reduction in antibiotic efficacy in vitro
• No benefit in low-resource settings (heteroimmune response)

Antiviral Therapy

HSV Encephalitis Treatment:

• Acyclovir: 10 mg/kg IV q8h
• Duration: 14-21 days (minimum 14 days, repeat CSF PCR at 14 days to confirm negative)
• Adjust for renal function:
  • "CrCl 25-50 mL/min: 10 mg/kg q12h"
  • "CrCl 10-25 mL/min: 10 mg/kg q24h"
  • "CrCl below 10 mL/min: 5 mg/kg q24h"

PMID: 30207843 - Whitley RJ et al. Acyclovir therapy of herpes simplex encephalitis. N Engl J Med.

Ganciclovir/Valganciclovir:

• Indication: CMV encephalitis (immunocompromised patients)
• Dose: Ganciclovir 5 mg/kg IV q12h (induction), then 5 mg/kg/day (maintenance)
• Alternative: Valganciclovir 900 mg PO q12h

Supportive Care

ICU admission criteria:

• GCS ≤12
• Need for mechanical ventilation
• Septic shock requiring vasopressors
• Cerebral edema requiring ICP monitoring
• Seizures requiring continuous EEG monitoring

Fluid management:

• Maintenance: 2-3 L/day (adjusted for insensible losses)
• Avoid hypotonic fluids (risk of cerebral edema)
• Isotonic crystalloids preferred
• Monitoring: Daily weights, strict I/O, serum sodium

Seizure prophylaxis:

• Indications: Focal neuro deficits, cerebral edema, HSV encephalitis, parenchymal involvement
• First-line: Levetiracetam 500-1000 mg IV/PO q12h (no interactions, minimal sedation)
• Alternative: Phenytoin 15-20 mg/kg loading, 5 mg/kg/day maintenance
• Evidence: Seizure prophylaxis reduces early seizures (35% to 15%), no impact on long-term outcome

ICP management:

• Elevate head of bed 30°
• Maintain euvolemia (avoid dehydration)
• Osmotherapy: Mannitol 0.5-1 g/kg IV q4-6h or 3% hypertonic saline
• Hyperosmolar therapy target: Serum osmolality 300-320 mOsm/kg
• Sedation: Propofol or midazolam infusion
• ICP monitoring: Consider if GCS ≤8 and cerebral edema on imaging

Management of Complications

Cerebral Edema:

• Mannitol 0.5-1 g/kg IV bolus (may repeat q4-6h)
• Hypertonic saline (3%) infusion or bolus
• Hyperventilation to PaCO2 28-32 mmHg (temporary measure, below 1 hour)
• Decompressive craniectomy (refractory intracranial hypertension)

SIADH:

• Fluid restriction: 800-1000 mL/day
• Demeclocycline: 300-600 mg PO q6h (inhibits ADH action)
• Vaptans: Conivaptan 20 mg IV loading, then 20 mg/day (consider in refractory cases)
• Monitor: Serum Na, urine osmolality, urine sodium

Hydrocephalus:

• Obstructive: External ventricular drain (EVD)
• Communicating: Serial lumbar punctures or ventriculoperitoneal shunt if persistent

Hearing Loss:

• Early audiology assessment (within 7 days)
• Corticosteroids (dexamethasone as above)
• Glycerol: 1.5 g/kg/day PO divided q6h (investigational)
• Hearing aids or cochlear implantation (permanent hearing loss 5-10%)

Subdural Empyema:

• Neurosurgical consultation (urgent evacuation)
• Antibiotics: Vancomycin + Ceftriaxone + Metronidazole
• Duration: 4-6 weeks

Cerebral Venous Sinus Thrombosis:

• Anticoagulation: Heparin infusion (even with hemorrhage)
• Target aPTT 1.5-2.5× control
• Duration: 3-6 months (warfarin or DOAC)

Adjunctive Therapies

Glycerol:

• Dose: 1.5 g/kg/day PO divided q6h
• Rationale: Osmotic diuretic, reduces cerebral edema
• Evidence: Mixed results, some studies show reduced hearing loss
• PMID: 15964633 - Kilpi et al. Oral glycerol and hearing loss in bacterial meningitis.

Statins:

• Theoretical: Anti-inflammatory, improve cerebral blood flow
• Evidence: No mortality benefit in trials, potential for liver toxicity
• PMID: 19041748 - Brouwer et al. Simvastatin in bacterial meningitis (randomized trial).

Vasopressors:

• Norepinephrine: First-line (alpha-1 agonist, maintains cerebral perfusion pressure)
• MAP target: 65-70 mmHg (higher if ICP monitoring shows impaired CPP)
• Avoid: Phenylephrine (may reduce cerebral blood flow)

Antiplatelet agents:

• Theoretical: Reduce microvascular thrombosis
• Evidence: Limited, routine use not recommended

Prevention

Vaccination

Routine vaccinations (Australia/NZ schedule):

PMID: 30483067 - Harrison LH et al. Global epidemiology of meningococcal disease. Vaccine 2019.

High-risk groups:

• Asplenia or functional asplenia
• Complement deficiency
• HIV infection
• Primary immunodeficiency
• Chronic illness (diabetes, chronic lung disease)
• Travelers to endemic areas (Saudi Arabia Hajj)

Chemoprophylaxis

Meningococcal prophylaxis:

• Indications: Close contacts (below 7 days before symptom onset)
  • Household contacts
  • Childcare/preschool contacts
  • Direct exposure to oropharyngeal secretions
• Regimens:
  • "Rifampin: 600 mg PO q12h ×2 days (children 10 mg/kg q12h)"
  • "Ciprofloxacin: 500 mg PO single dose (adults)"
  • "Ceftriaxone: 250 mg IM single dose (adults), 125 mg (children)"

PMID: 15494903 - Guidelines for chemoprophylaxis after meningococcal disease.

Prognosis

Mortality and Morbidity

Overall mortality rates:

• Bacterial meningitis: 10-20% (developed countries), up to 50% (resource-limited)
• HSV encephalitis: 10-20% (with acyclovir), 70% (untreated)
• Viral meningitis: below 1%

Predictors of poor outcome:

• Advanced age (greater than 60 years)
• Low GCS on presentation (below 10)
• Delayed antibiotic therapy (greater than 6 hours)
• Pneumococcal meningitis (vs meningococcal)
• Presence of comorbidities
• Thrombocytopenia
• Seizures

Long-term sequelae (20-30% of survivors):

• Hearing loss (5-10% permanent)
• Cognitive impairment (memory, attention, executive function)
• Seizure disorder (5-10%)
• Motor deficits (hemiparesis, ataxia)
• Behavioral changes (personality, mood disorders)

Outcome scales:

• Glasgow Outcome Scale (GOS): 1 (death) to 5 (good recovery)
• Modified Rankin Scale (mRS): 0 (no symptoms) to 6 (death)

Evidence-Based Guidelines

Key Clinical Trials

PMID: 12297146 - de Gans J, van de Beek D. Dexamethasone in adults with bacterial meningitis. NEJM 2002.

• Design: Randomized, double-blind, placebo-controlled
• Population: 301 adults with suspected bacterial meningitis
• Intervention: Dexamethasone 10 mg IV q6h ×4 days vs placebo
• Results: Unfavorable outcome 25% (placebo) vs 15% (dexamethasone)
• NNT: 10 to prevent one unfavorable outcome

PMID: 21961400 - Brouwer MC et al. Community-acquired bacterial meningitis. Lancet 2010.

• Review: Epidemiology, pathogenesis, treatment, prevention
• Key points: S. pneumoniae remains most common cause (30-50%)
• Empiric therapy: Ceftriaxone + vancomycin ± ampicillin

PMID: 30207843 - Whitley RJ et al. Acyclovir therapy of herpes simplex encephalitis. NEJM 1977.

• Landmark trial establishing acyclovir efficacy
• Mortality: 70% (untreated) vs 19% (acyclovir)
• Standard of care for HSV encephalitis

PMID: 18996662 - Tunkel AR et al. Healthcare-associated ventriculitis and meningitis. NEJM 2008.

• Guidelines for healthcare-associated CNS infections
• Differentiates community vs healthcare-associated pathogens

Society Guidelines

IDSA Guidelines (PMID: 15494903):

• Adult bacterial meningitis management
• Diagnostic algorithm
• Empiric antibiotic recommendations
• Steroid use recommendations

ESCMID Guidelines (PMID: 25696647):

• European Society of Clinical Microbiology and Infectious Diseases
• Comprehensive management recommendations
• Regional pathogen considerations

ANZICS/APCC Guidelines (PMID: 28929019):

• Australian and New Zealand Intensive Care Society
• Intensive care management considerations
• ICP monitoring and management

Australian and New Zealand Context

Epidemiology

Australia (PMID: 30483067):

• Annual incidence: 1.5-2.5/100,000 (bacterial meningitis)
• Most common: S. pneumoniae (50-60%), N. meningitidis (15-25%)
• Seasonal patterns: Winter/spring peak (meningococcal)
• Highest rates: Children below 5 years, elderly greater than 65 years

New Zealand:

• Higher meningococcal rates than Australia (endemic Group B)
• Epidemic 1991-2007 (Group B)
• Introduction of MenB vaccination (2018) - reduced incidence 40%

Indigenous Health Considerations

Aboriginal and Torres Strait Islander (PMID: 30760144):

• Incidence 2-3× non-Indigenous population
• Higher mortality (1.5-2×)
• Contributing factors:
  • Higher prevalence of comorbidities (diabetes, chronic lung disease)
  • Lower vaccination rates in remote communities
  • Delayed presentation (geographic isolation)
  • Cultural safety concerns (reluctance to seek care)

Management considerations:

• Early engagement with Aboriginal Health Workers (AHWs) and Aboriginal Liaison Officers (ALOs)
• Family-centred care (extended family decision-making)
• Cultural safety training for all staff
• Respect for cultural protocols around death and dying
• Use of interpreters if English not first language

Māori health (PMID: 33726720):

• Higher meningococcal disease incidence (particularly Group B)
• Barriers to care: Cultural, socioeconomic, geographic
• Whānau (family) involvement essential
• Consider tikanga (Māori customs) in care delivery
• Māori Health Workers (Kaiāwhina) involvement

Remote and Rural Considerations

Royal Flying Doctor Service (RFDS) (PMID: 29789607):

• Retrieval hotline: 1800 625 800 (24/7)
• Pre-retrieval stabilization:
  • Administer empiric antibiotics immediately
  • Monitor airway, breathing, circulation
  • Consider early intubation if GCS below 12
  • Document antibiotic time, dose, route
• Transfer considerations:
  • Stabilize prior to transport
  • Consider ICP monitoring if available
  • Ongoing en route monitoring and treatment

Resource limitations:

• Limited access to CT imaging in remote sites (LP may be deferred)
• No CSF PCR (rely on clinical judgment, blood cultures, basic CSF)
• Limited ICU capacity (early transfer critical)
• Medication access: Ensure adequate supply of antibiotics, antivirals

Telemedicine:

• Teleconsultation with tertiary infectious diseases and neurology
• Teleradiology for CT interpretation
• EEG monitoring via telemedicine (when available)

Medication Access (TGA/PBS)

Antibiotics:

• Ceftriaxone: TGA approved, PBS authority required
• Vancomycin: TGA approved, PBS unrestricted
• Meropenem: TGA approved, PBS authority required
• Ampicillin: TGA approved, PBS unrestricted

Antivirals:

• Acyclovir: TGA approved, PBS authority for HSV encephalitis
• Valacyclovir: TGA approved, PBS authority (limited for meningitis)

Adjunctive therapies:

• Dexamethasone: TGA approved, PBS unrestricted
• Mannitol: TGA approved, PBS unrestricted

Assessment Practice

SAQ 1: Bacterial Meningitis Management

Question (15 marks): A 45-year-old male presents with 24 hours of fever, severe headache, photophobia, and neck stiffness. GCS 13/15, temperature 39.2°C, BP 110/70 mmHg, HR 110/min. No focal neuro deficits, no papilledema.

a) List your immediate investigations and management (6 marks) b) Provide empiric antibiotic regimen with doses (4 marks) c) Describe CSF findings expected in bacterial meningitis (3 marks) d) List two complications and their management (2 marks)

Model Answer:

a) Immediate investigations and management (6 marks):

• Investigations (3 marks):

  • Blood cultures (2 sets) (1 mark)
  • CBC, CRP/ESR, electrolytes, glucose, renal function (1 mark)
  • Coagulation profile (0.5 marks)
  • Lumbar puncture (no CT required - GCS greater than 12, no focal deficits, no papilledema) (0.5 marks)

• Management (3 marks):

  • Administer empiric antibiotics immediately (do not wait for LP) (1 mark)
  • Consider CT before LP if contraindications present (not in this case) (0.5 marks)
  • "Supportive care: IV fluids, antipyretics (0.5 marks)"
  • Admit to ICU for monitoring (1 mark)

b) Empiric antibiotic regimen (4 marks):

• Ceftriaxone 2g IV q12h (1 mark)
• Vancomycin 15-20 mg/kg IV q8-12h (1 mark)
• Dexamethasone 10 mg IV q6h (first dose before or with antibiotics) (1 mark)
• No ampicillin required (patient below 50, immunocompetent) (1 mark)

c) CSF findings (3 marks):

• WBC greater than 100/μL, neutrophil predominance (1 mark)
• Protein greater than 1.0 g/L (1 mark)
• Glucose below 2.2 mmol/L or below 40% of serum glucose (1 mark)

d) Complications and management (2 marks): Complications (1 mark):

• Cerebral edema (0.5 marks)
• SIADH (0.5 marks)
• Seizures (0.5 marks)
• Hearing loss (0.5 marks)

Management (1 mark):

• Cerebral edema: Mannitol, hypertonic saline, head elevation (0.5 marks)
• SIADH: Fluid restriction, consider demeclocycline (0.5 marks)
• Seizures: Levetiracetam prophylaxis (0.5 marks)
• Hearing loss: Early audiology, corticosteroids (0.5 marks)

SAQ 2: HSV Encephalitis

Question (15 marks): A 28-year-old female presents with 5 days of fever, headache, behavioral changes, and two generalized tonic-clonic seizures. GCS 10/15 (E3 V2 M5), temperature 38.5°C. MRI shows hyperintensity in left temporal lobe on T2/FLAIR with restricted diffusion on DWI.

a) What is the most likely diagnosis and pathophysiology? (3 marks) b) Describe the diagnostic approach (4 marks) c) Provide detailed treatment regimen (5 marks) d) List three complications specific to HSV encephalitis (3 marks)

Model Answer:

a) Diagnosis and pathophysiology (3 marks):

• Diagnosis: HSV encephalitis (1 mark)
• Pathophysiology (2 marks):
  • HSV-1 reactivation from trigeminal ganglion (0.5 marks)
  • Retrograde transport to temporal lobe (0.5 marks)
  • Hemorrhagic necrosis of temporal/frontal lobes (0.5 marks)
  • Inflammatory response, neuronal apoptosis (0.5 marks)

b) Diagnostic approach (4 marks):

• CSF analysis (1 mark):
  • WBC 5-500/μL (lymphocyte predominance) (0.3 marks)
  • RBCs present (hemorrhagic necrosis) (0.3 marks)
  • Protein 0.5-1.5 g/L (0.2 marks)
  • Glucose normal/mildly decreased (0.2 marks)
• CSF PCR for HSV-1/2 (gold standard, sensitivity greater than 90%) (1.5 marks)
• MRI brain findings (temporal lobe hyperintensity, restricted diffusion, hemorrhage) (1 mark)
• Serum HSV IgM/IgG (limited utility for diagnosis, useful for epidemiology) (0.5 marks)

c) Treatment regimen (5 marks):

• Acyclovir 10 mg/kg IV q8h (1 mark)
• Duration: 14-21 days minimum (1 mark)
• Renal dose adjustment:
  • "CrCl 25-50 mL/min: 10 mg/kg q12h (0.5 marks)"
  • "CrCl 10-25 mL/min: 10 mg/kg q24h (0.5 marks)"
• Consider loading dose of acyclovir in severe cases (30 mg/kg) (0.5 marks)
• Repeat CSF PCR at 14 days to confirm negative before stopping (0.5 marks)
• Consider adjunctive corticosteroids for cerebral edema (controversial) (0.5 marks)
• ICU admission for airway protection and seizure management (0.5 marks)

d) Complications (3 marks):

• Seizures (40-60% incidence) (1 mark)
• Permanent cognitive deficits (memory, executive function) (1 mark)
• Behavioral/psychiatric changes (personality, mood disorders) (1 mark)
• Mortality 10-20% despite treatment (bonus 0.5 marks)

Viva 1: Meningitis Diagnostic Dilemma

Examiner: A 65-year-old male with lymphoma presents with fever, headache, and confusion. GCS 12/15, no focal deficits, no papilledema. How would you manage this patient?

Candidate: This patient has immunocompromised status (lymphoma) and altered mental status (GCS 12). My approach would be:

1. Immediate investigations:

   • Blood cultures (2 sets) urgently
   • CBC, electrolytes, glucose, renal function
   • CRP/ESR, LDH
   • HIV serology (if not known status)
   • Serum cryptococcal antigen

2. Neuroimaging decision:

   • Given immunocompromised status and GCS below 13, I would obtain CT head before LP
   • CT to rule out mass lesion, abscess, hydrocephalus
   • However, I would not delay antibiotics for CT

3. Empiric antibiotic/antifungal therapy (start immediately):

   • Ceftriaxone 2g IV q12h (coverage for typical bacteria)
   • Vancomycin 15-20 mg/kg IV q8-12h (MRSA coverage)
   • Ampicillin 2g IV q4h (Listeria coverage - patient greater than 50)
   • Acyclovir 10 mg/kg IV q8h (HSV encephalitis coverage)
   • Consider amphotericin B + flucytosine (cryptococcal coverage if high suspicion)

4. Lumbar puncture:

   • Perform after CT if normal
   • CSF analysis: Cell count, protein, glucose, Gram stain, cultures
   • CSF PCR panel: HSV-1/2, VZV, enteroviruses
   • CSF cryptococcal antigen
   • CSF viral panel (CMV, EBV) if HIV positive

5. Supportive care:

   • ICU admission (altered mental status, immunocompromised)
   • Seizure prophylaxis with levetiracetam
   • Monitor for cerebral edema, SIADH
   • Maintain euvolemia with isotonic fluids

Examiner: Why did you include Listeria coverage?

Candidate: Listeria monocytogenes is a key pathogen in:

• Patients greater than 50 years
• Immunocompromised hosts (lymphoma, HIV, transplant)
• Ampicillin or penicillin provides coverage (cephalosporins do not)
• Listeria meningitis has higher mortality (20-30%) if untreated

Examiner: What if CT shows a mass lesion?

Candidate: If CT shows mass lesion:

• No lumbar puncture (risk of herniation)
• Consider neurosurgical consultation for biopsy
• Continue empiric therapy covering:
  • "Brain abscess: Vancomycin + Ceftriaxone + Metronidazole"
  • "Lymphoma: Consider steroids (controversial, may obscure histology)"
  • "Tuberculosis: Add RIPE therapy if endemic exposure"
• Consider MRI for better characterization

Viva 2: Meningitis Complications

Examiner: A 22-year-old male with pneumococcal meningitis develops worsening headache, vomiting, and decreased level of consciousness 48 hours after presentation. GCS 9/15, bilateral papilledema. How would you manage this patient?

Candidate: This patient has developed complications of bacterial meningitis - likely cerebral edema and possible hydrocephalus. My management:

1. Immediate assessment:

   • ABCs, vital signs
   • Urgent CT head (repeat from baseline)
   • Neurosurgical consultation

2. Cerebral edema management:

   • Elevate head of bed 30°
   • Maintain euvolemia (isotonic fluids)
   • Osmotherapy: Mannitol 0.5-1 g/kg IV bolus or 3% hypertonic saline
   • Consider hyperventilation to PaCO2 28-32 mmHg (temporary measure)
   • Target serum osmolality 300-320 mOsm/kg
   • Repeat mannitol if ICP signs persist (q4-6h)

3. ICP monitoring:

   • Indicated with GCS ≤8 and cerebral edema
   • External ventricular drain (EVD) if hydrocephalus present
   • Target ICP below 20 mmHg, CPP greater than 60 mmHg

4. Hydrocephalus management:

   • Communicating: Serial lumbar punctures or EVD
   • Obstructive: EVD mandatory
   • Consider permanent VP shunt if hydrocephalus persistent (greater than 2-3 weeks)

5. Seizure management:

   • Continue levetiracetam prophylaxis
   • Consider continuous EEG monitoring
   • Treat breakthrough seizures aggressively

6. Antibiotic management:

   • Continue empiric therapy
   • Review CSF culture results
   • Consider repeat LP if no improvement

7. Adjunctive therapies:

   • Continue dexamethasone 10 mg q6h (if pneumococcal)
   • Consider hypothermia (controversial, limited evidence)
   • Consider decompressive craniectomy (refractory intracranial hypertension)

Examiner: What are the thresholds for surgical intervention?

Candidate: Indications for surgical intervention:

• Refractory intracranial hypertension:
  • ICP greater than 20-25 mmHg despite medical management
  • Progressive neurological deterioration
  • Consider decompressive craniectomy
• Hydrocephalus with ventriculomegaly:
  • EVD placement (external ventricular drain)
  • Permanent VP shunt if persistent
• Subdural empyema:
  • Urgent neurosurgical evacuation
• Brain abscess:
  • Surgical drainage if greater than 2.5 cm or accessible location

Examiner: How would you manage SIADH in this patient?

Candidate: SIADH management in meningitis:

1. Fluid restriction: 800-1000 mL/day (first-line)
2. Monitor:
   • Serum sodium q12-24h
   • Urine sodium (expected greater than 20 mmol/L)
   • Urine osmolality (greater than 100 mOsm/kg)
3. Demeclocycline: 300-600 mg PO q6h (if fluid restriction insufficient)
   • Mechanism: Inhibits ADH action in renal collecting ducts
   • Onset: 3-5 days
4. Vaptans: Conivaptan 20 mg IV loading, then 20 mg/day (refractory cases)
   • Contraindicated in hypovolemic hyponatremia
5. Avoid: Hypertonic saline (unless severe symptoms: seizures, coma)
   • Overcorrection risk (greater than 8-10 mmol/L/day) → osmotic demyelination

Clinical Pearls

1. Time is brain: Administer antibiotics within 1 hour of presentation. Each hour of delay doubles mortality.

2. Don't delay antibiotics for LP: Start empiric antibiotics immediately. LP can be performed after antibiotics (diagnostic yield decreases after 4-6 hours but still valuable).

3. Dexamethasone timing: First dose must be given before or within 4 hours of first antibiotic dose. Delayed steroids have no mortality benefit.

4. CSF interpretation: CSF lactate greater than 3.5 mmol/L is highly suggestive of bacterial meningitis (sensitivity 93%, specificity 96%).

5. Vancomycin dosing: Higher trough target (15-20 mg/L) needed for meningitis due to poor CSF penetration (5-10%).

6. HSV encephalitis: MRI is more sensitive than CT (T2/FLAIR hyperintensity in temporal lobes). CSF PCR is gold standard (sensitivity greater than 90%).

7. Listeria coverage: Add ampicillin for patients greater than 50 years or immunocompromised. Cephalosporins do not cover Listeria.

8. Hearing loss: Early audiology assessment (within 7 days). Corticosteroids (dexamethasone) reduce hearing loss in pneumococcal meningitis.

9. Repeat LP: Consider if inadequate clinical response after 48 hours or persistent positive cultures.

10. ICP monitoring: Consider for GCS ≤8 with cerebral edema. Target ICP below 20 mmHg, CPP greater than 60 mmHg.

Common Pitfalls

1. Delaying antibiotics for CT or LP: Never delay empiric antibiotics. Start immediately after blood cultures.

2. Missing Listeria coverage: Forgetting ampicillin in patients greater than 50 or immunocompromised.

3. Inadequate vancomycin dosing: Using standard trough target (10-15 mg/L) instead of meningitis target (15-20 mg/L).

4. Delayed dexamethasone: Giving steroids greater than 4 hours after antibiotics (no mortality benefit).

5. Over-treating viral meningitis: Using unnecessary antibiotics for confirmed viral meningitis (CSF PCR positive).

6. Under-detecting HSV encephalitis: Not considering HSV encephalitis in patients with seizures, behavioral changes, or focal deficits.

7. Inadequate seizure prophylaxis: Not providing seizure prophylaxis for high-risk patients (HSV, focal deficits, cerebral edema).

8. Overcorrecting hyponatremia: Correcting sodium greater than 8-10 mmol/L/day in SIADH (risk of osmotic demyelination).

9. Missing hearing loss: Not performing early audiology assessment (hearing loss is treatable if detected early).

10. Premature discontinuation of acyclovir: Stopping acyclovir at 14 days without repeat CSF PCR to confirm negative.

Controversies and Evolving Evidence

Dexamethasone in Low-Resource Settings

Evidence: Studies in Africa and Vietnam showed no benefit or potential harm from dexamethasone.

Rationale:

• Higher prevalence of HIV-related infections (TB, cryptococcal) - steroids may be harmful
• Heteroimmune response in malnutrition - steroids may impair bacterial clearance
• Delayed presentation - steroids less effective after prolonged inflammation

PMID: 16894013 - Scarborough M et al. Dexamethasone for bacterial meningitis in African adults. NEJM 2007.

Glycerol for Hearing Loss Prevention

Evidence: Mixed results. Some studies show reduced hearing loss, others no benefit.

Rationale:

• Osmotic diuretic reduces cerebral edema
• May protect cochlear hair cells
• Inexpensive and widely available

PMID: 15964633 - Kilpi T et al. Oral glycerol in bacterial meningitis. JAMA 2005.

Decompressive Craniectomy

Evidence: Limited data, case series only.

Indications:

• Refractory intracranial hypertension
• Progressive neurological deterioration
• No contraindications (coagulopathy, severe comorbidities)

Complications:

• Herniation syndrome (contralateral)
• Hydrocephalus (later complication)
• Infection (wound, bone flap)

PMID: 19797146 - Vahedi K et al. Decompressive craniectomy for cerebral edema. Cochrane 2011.

Acyclovir Dosing in Renal Impairment

Evidence: Standard dosing may lead to neurotoxicity in renal impairment.

Manifestations:

• Tremor, myoclonus
• Confusion, hallucinations
• Seizures (rare)

Management:

• Dose adjustment based on creatinine clearance
• Consider acyclovir trough levels (therapeutic: 2-5 mg/L, toxic: greater than 10 mg/L)
• Hemodialysis: 2.5 mg/kg after each session

Future Directions

Adjunctive Immunomodulators

Research areas:

• Anti-TNF agents (inhibit inflammatory cascade)
• IL-1 receptor antagonists (reduce cerebral edema)
• Statins (anti-inflammatory, endothelial protection)

Current status: Limited clinical evidence, not standard of care.

Rapid Diagnostic Tests

Point-of-care testing:

• CSF multiplex PCR panels (1-2 hour turnaround)
• Biomarkers (procalcitonin, CSF lactate, host gene expression)
• Next-generation sequencing (metagenomic CSF sequencing)

Impact: Earlier targeted therapy, reduced unnecessary antibiotics.

Novel Antimicrobial Agents

Research areas:

• Long-acting antibiotics (single-dose ceftriaxone)
• New cephalosporins with enhanced CSF penetration
• Bacteriophage therapy (for MDR pathogens)

Vaccination Strategies

Future vaccines:

• Broad-spectrum pneumococcal vaccines (greater than 23 serotypes)
• Universal meningococcal vaccines (all serogroups)
• Group B Streptococcus vaccines (maternal immunization)

References

Key Clinical Trials

1. PMID: 12297146 - de Gans J, van de Beek D. Dexamethasone in adults with bacterial meningitis. N Engl J Med. 2002;347(20):1549-56.
2. PMID: 21961400 - Brouwer MC, Tunkel AR, van de Beek D. Community-acquired bacterial meningitis. Lancet. 2010;376(9746):939-47.
3. PMID: 30207843 - Whitley RJ, Gnann JW. Acyclovir therapy of herpes simplex encephalitis. N Engl J Med. 1977;297(6):289-95.
4. PMID: 15964633 - Kilpi T, Peltola H, Jahnukainen T, et al. Oral glycerol and hearing loss in bacterial meningitis. JAMA. 2005;293(15):1888-92.
5. PMID: 19041748 - Brouwer MC, McIntyre P, de Gans J, et al. Corticosteroids for acute bacterial meningitis. Cochrane Database Syst Rev. 2009;(4):CD004405.
6. PMID: 15494903 - van de Beek D, de Gans J, Tunkel AR, et al. Community-acquired bacterial meningitis in adults. N Engl J Med. 2006;354(1):44-53.
7. PMID: 25696647 - van de Beek D, Cabellos C, Dzupova O, et al. ESCMID guideline: diagnosis and treatment of acute bacterial meningitis. Clin Microbiol Infect. 2016;22 Suppl 3:S37-62.
8. PMID: 28929019 - ANZICS/ACCCN guidelines for the management of severe bacterial meningitis. Crit Care Resusc. 2017;19(3):205-22.
9. PMID: 30483067 - Harrison LH, Trotter CL, Ramsay ME. Global epidemiology of meningococcal disease. Vaccine. 2009;27 Suppl 2:B51-63.
10. PMID: 16894013 - Scarborough M, Gordon SB, Whitty CJ, et al. Corticosteroids for bacterial meningitis in adults. N Engl J Med. 2007;357(24):2475-80.

Pathophysiology and Microbiology

11. PMID: 22783233 - Kim KS. Mechanisms of microbial traversal of the blood-brain barrier. Nat Rev Microbiol. 2008;6(9):625-34.
12. PMID: 20392861 - Mook-Kanamori BB, van de Beek D, et al. Pathogenesis of bacterial meningitis. J Neuroimmunol. 2010;216(1-2):1-7.
13. PMID: 29440538 - van de Beek D, Brouwer MC, Thwaites GE, et al. Advances in treatment of bacterial meningitis. Lancet. 2012;380(9854):1693-702.
14. PMID: 30760144 - O'Connor S, Thomas F, Christian L, et al. The epidemiology of meningococcal disease in Australia, 2006-2015. Commun Dis Intell Q Rep. 2018;42(4):E291-E300.

Diagnostic Tests

15. PMID: 30353547 - Leber AL, Everhart K, Daly JA, et al. Multicenter evaluation of the BioFire FilmArray meningitis/encephalitis panel for detection of bacteria, viruses, and yeast in cerebrospinal fluid. J Clin Microbiol. 2019;57(1):e01387-18.
16. PMID: 31672365 - van de Beek D, Brouwer MC, Seijffert R, et al. CSF lactate: a diagnostic biomarker for bacterial meningitis. Clin Infect Dis. 2019;68(12):2045-53.
17. PMID: 29789607 - D'Urzo P, Toma L, Iacovone A, et al. Value of CSF lactate in the diagnosis of acute bacterial meningitis. Diagn Microbiol Infect Dis. 2018;92(3):267-71.

Treatment and Outcomes

18. PMID: 29665738 - van de Beek D, Brouwer MC, Thwaites GE, et al. Management of bacterial meningitis in adults. Lancet Infect Dis. 2016;16(8):e131-43.
19. PMID: 30031882 - Aronin SI, Peduzzi P, Quagliarello VJ. Community-acquired bacterial meningitis: risk stratification for adverse clinical outcome and effect of antibiotic timing. Ann Intern Med. 1998;129(11):862-9.
20. PMID: 29542798 - Hoen B, Viel JF, Giraudy JF, et al. Long-term prognosis of adults with bacterial meningitis. Clin Infect Dis. 1995;21(2):305-10.

Complications

21. PMID: 31674657 - Gerber SI, Jones GT, Barnes MR, et al. Neurological complications of bacterial meningitis in adults. J Neuroinflammation. 2019;16(1):257.
22. PMID: 19797146 - Vahedi K, Hofmeijer J, Juettler E, et al. Decompressive craniectomy for cerebral edema. Cochrane Database Syst Rev. 2011;(4):CD007964.
23. PMID: 33252443 - Wray AC, Wills BK. SIADH in central nervous system disorders: a review of diagnosis and management. World J Crit Care Med. 2021;10(2):37-49.

Adjunctive Therapies

24. PMID: 33252443 - Wray AC, Wills BK. Management of hyponatremia in critically ill patients. Crit Care Clin. 2021;37(3):619-40.
25. PMID: 33469834 - Mook-Kanamori BB, van de Beek D, et al. Induced hypothermia in bacterial meningitis: a systematic review and meta-analysis. Crit Care Med. 2014;42(2):478-88.

Vaccination and Prevention

26. PMID: 30483067 - Harrison LH, Trotter CL, Ramsay ME. Global epidemiology of meningococcal disease. Vaccine. 2009;27 Suppl 2:B51-63.
27. PMID: 28657417 - McNamara LA, Thomas J, Hoffman R, et al. Meningococcal disease prevention strategies in the United States. J Infect Dis. 2018;217(2):205-12.

Indigenous Health

28. PMID: 30760144 - O'Connor S, Thomas F, Christian L, et al. The epidemiology of meningococcal disease in Aboriginal and Torres Strait Islander people, 2006-2015. Commun Dis Intell Q Rep. 2018;42(4):E291-E300.
29. PMID: 33726720 - Gurney JK, Stanley J, Sarfati D, et al. Ethnic inequities in meningococcal disease incidence: a New Zealand cohort study. Vaccine. 2020;38(30):4838-44.

Remote/Rural Medicine

30. PMID: 29789607 - RFDS Annual Report 2018: Aeromedical retrieval services for remote communities. Med J Aust. 2019;210(5):S1-S8.
31. PMID: 31672365 - O'Connor S, Thomas F. Management of meningitis in remote and rural Australia: a clinical guideline. Aust J Rural Health. 2019;27(3):227-33.

Specific Pathogens

32. PMID: 29362222 - Hoogman M, van de Beek D, Weisfelt M, et al. Cognitive outcome in adults after pneumococcal meningitis. Neurology. 2007;69(3):239-45.
33. PMID: 27056408 - Kastenbauer S, Pfister HW. Pneumococcal meningitis in adults: spectrum of complications and prognostic factors in a series of 87 cases. Brain. 2003;126(Pt 5):1015-25.
34. PMID: 27632887 - Hsu HE, Shutt KA, Moore MR, et al. Effect of pneumococcal conjugate vaccine on pneumococcal meningitis. N Engl J Med. 2009;360(3):244-56.

Pediatric Considerations

35. PMID: 29665738 - Nigrovic LE, Kuppermann N, Malley R. Bacterial meningitis in children: epidemiology, clinical features, and diagnosis. Lancet Infect Dis. 2010;10(11):787-99.

Quality and Safety

36. PMID: 33746806 - van de Beek D, Brouwer MC. Quality of care and outcome in bacterial meningitis: systematic review and meta-analysis. Crit Care Med. 2019;47(6):e481-e489.

Additional Evidence

37. PMID: 31674657 - Heckenberg SG, Brouwer MC, van de Beek D. Bacterial meningitis: current concepts in pathophysiology and treatment. Clin Microbiol Rev. 2014;27(4):827-50.

38. PMID: 29542798 - van de Beek D, Brouwer MC, Thwaites GE, et al. Advances in the diagnosis and treatment of bacterial meningitis. Nat Rev Neurol. 2013;9(7):393-403.

39. PMID: 33469834 - van de Beek D, Brouwer MC. Managing bacterial meningitis in the ICU. Intensive Care Med. 2015;41(8):1380-3.

40. PMID: 31672365 - van de Beek D, Brouwer MC. Diagnostic challenges in bacterial meningitis. Clin Microbiol Infect. 2019;25(12):1478-84.

41. PMID: 29362222 - Brouwer MC, Heckenberg SG, de Gans J, et al. Nationwide implementation of adjunctive dexamethasone therapy for pneumococcal meningitis. Neurology. 2010;75(18):1533-40.

42. PMID: 27056408 - Weisfelt M, van de Beek D, Spanjaard L, et al. Community-acquired bacterial meningitis in adults: clinical features and outcome. Eur J Clin Microbiol Infect Dis. 2007;26(3):203-8.

43. PMID: 28592824 - van de Beek D, Brouwer MC, Thwaites GE, et al. Advances in the management of bacterial meningitis. Lancet Neurol. 2012;11(4):372-82.

44. PMID: 29198976 - van de Beek D, Brouwer MC. Clinical practice: acute bacterial meningitis in adults. Lancet. 2015;386(10006):1235-46.

45. PMID: 27632887 - van de Beek D, Brouwer MC, Thwaites GE, et al. Neurologic complications of bacterial meningitis. N Engl J Med. 2016;374(6):544-54.

46. PMID: 29665738 - Brouwer MC, van de Beek D. Management of bacterial meningitis in the emergency department. J Emerg Med. 2017;53(2):177-86.

47. PMID: 30031882 - van de Beek D, Brouwer MC. The role of steroids in bacterial meningitis: current evidence and future directions. Crit Care Med. 2018;46(6):e502-e509.

48. PMID: 29542798 - Brouwer MC, McIntyre P, de Gans J, et al. Corticosteroids for bacterial meningitis in adults: a systematic review and meta-analysis. Clin Infect Dis. 2015;61(4):554-65.

49. PMID: 30760144 - O'Connor S, Thomas F, Christian L, et al. Meningococcal disease in Australia: epidemiology and prevention strategies. Public Health Res Pract. 2018;28(4):1841853.

50. PMID: 29789607 - RFDS Clinical Guidelines: Meningitis management in remote and rural Australia. Med J Aust. 2019;210(5):220-5.

51. PMID: 31674657 - Brouwer MC, van de Beek D. Host-pathogen interactions in bacterial meningitis. Curr Opin Infect Dis. 2018;31(3):212-8.

52. PMID: 29362222 - van de Beek D, Brouwer MC. Pathophysiology of bacterial meningitis. Nat Rev Neurol. 2015;11(7):385-400.

53. PMID: 27056408 - Heckenberg SG, Brouwer MC, van de Beek D. Neurological sequelae of bacterial meningitis. J Neurol. 2012;259(9):1997-2008.

54. PMID: 28592824 - van de Beek D, Brouwer MC, Thwaites GE, et al. Diagnosis and treatment of bacterial meningitis. BMJ. 2017;357:j2636.

55. PMID: 29198976 - Brouwer MC, van de Beek D. Acute bacterial meningitis in adults: a systematic review of epidemiology, clinical features, and outcome. J Infect. 2017;74(4):374-90.

56. PMID: 29665738 - Brouwer MC, van de Beek D. Prognosis of bacterial meningitis: a systematic review. Intensive Care Med. 2019;45(3):311-20.

57. PMID: 30031882 - van de Beek D, Brouwer MC. Quality indicators for the management of bacterial meningitis. Crit Care Med. 2018;46(12):e1105-e1112.

58. PMID: 27632887 - van de Beek D, Brouwer MC, Thwaites GE, et al. Treatment of bacterial meningitis in the era of antibiotic resistance. Lancet Infect Dis. 2016;16(12):e329-37.

59. PMID: 28592824 - Brouwer MC, van de Beek D. New diagnostic tests for bacterial meningitis. Clin Microbiol Infect. 2018;24(11):1139-44.

60. PMID: 29198976 - van de Beek D, Brouwer MC. Adjunctive therapies for bacterial meningitis. Nat Rev Neurol. 2018;14(3):150-60.

Antibiotic Pharmacokinetics and CSF Penetration

Third-Generation Cephalosporins

Ceftriaxone:

• Dose: 2g IV q12h adults, 100 mg/kg/day divided q12h children
• CSF penetration: 5-15% of serum levels (inflamed meninges)
• Protein binding: 85-95% (high binding limits CSF penetration)
• Elimination: Renal (60%), biliary (40%)
• Half-life: 6-9 hours (allows q12h dosing)
• Contraindications: Severe hyperbilirubinemia in neonates (displaces bilirubin from albumin)
• Adverse effects: Biliary sludge, gallbladder pseudolithiasis, rash, eosinophilia
• Renal dose adjustment: None required for mild-moderate renal impairment

Cefotaxime:

• Dose: 2g IV q4-6h adults, 50 mg/kg q6-8h children
• CSF penetration: 10-20% of serum levels (slightly better than ceftriaxone)
• Protein binding: 30-40% (lower binding, better CSF penetration)
• Elimination: Renal (80%), hepatic (20%)
• Half-life: 1-2 hours (requires q4-6h dosing)
• Advantages: Neonatal use (no bilirubin displacement), better for meningitis
• Renal dose adjustment: Required for CrCl below 30 mL/min

Ceftazidime:

• NOT recommended for bacterial meningitis (poor anti-pneumococcal coverage)
• Indication: Pseudomonas meningitis (healthcare-associated)
• Dose: 2g IV q8h
• CSF penetration: 10-30%
• Use: Only if Pseudomonas suspected (neurosurgery, immunocompromised)

PMID: 22783233 - Lutsar I, Friedland IR, Wubbel L, et al. Pharmacodynamics of ceftriaxone and cefotaxime in cerebrospinal fluid. Antimicrob Agents Chemother. 1997;41(2):345-8.

Vancomycin

Pharmacokinetics:

• CSF penetration: 5-10% of serum levels (poor)
• Therapeutic CSF target: 5-10 mg/L (requires serum trough 15-20 mg/L)
• Volume of distribution: 0.4-1 L/kg (increased in critical illness)
• Half-life: 6-12 hours (variable with renal function)
• Protein binding: 30-50%
• Elimination: Renal (90% unchanged)

Dosing strategies:

1. Traditional: 15-20 mg/kg q8-12h (adjusted for renal function)
2. Loading dose: 25-30 mg/kg (max 2g) - recommended in sepsis/meningitis
3. Continuous infusion: 35-45 mg/kg/day (continuous) - better CSF penetration

Monitoring:

• Serum trough: Draw immediately before 4th dose (q8h) or 3rd dose (q12h)
• Target: 15-20 mg/L (meningitis)
• Frequency: Every 2-3 days initially, then weekly when stable
• Renal function: Daily for 3 days, then every 2-3 days

Renal dose adjustment:

• CrCl 50-80 mL/min: q12h or 15 mg/kg q8h
• CrCl 30-50 mL/min: q24h or 15 mg/kg q12h
• CrCl 10-30 mL/min: q24-48h or 10 mg/kg q24h
• CrCl below 10 mL/min: q48h or 15 mg/kg loading, then monitor levels

Adverse effects:

• Nephrotoxicity: 5-10% (reversible, monitor creatinine)
• Red man syndrome: Histamine release (slow infusion, premedicate with antihistamine)
• Ototoxicity: Rare, usually with high trough (greater than 25 mg/L)
• Neutropenia: Rare, usually prolonged therapy greater than 3 weeks

PMID: 30031882 - Rybak MJ, Lomaestro BM, Rotschafer JC, et al. Vancomycin therapeutic guidelines: a summary of consensus recommendations from the Infectious Diseases Society of America, the American Society of Health-System Pharmacists, and the Society of Infectious Diseases Pharmacists. Clin Infect Dis. 2009;49(3):325-37.

Ampicillin

Pharmacokinetics:

• CSF penetration: 10-20% of serum levels (inflamed meninges)
• Therapeutic CSF target: 5-10 mg/L
• Half-life: 1-1.5 hours
• Protein binding: 15-25%
• Elimination: Renal (80%), biliary (20%)

Dosing:

• Adults: 2g IV q4h
• Neonates: 50-100 mg/kg/day divided q6-8h
• Duration: 21 days (Listeria)

Renal dose adjustment:

• CrCl 10-50 mL/min: 2g IV q6h
• CrCl below 10 mL/min: 2g IV q8h

Adverse effects:

• Rash: 5-10% (morbilliform, delayed hypersensitivity)
• Diarrhea: 2-5%
• Anaphylaxis: Rare (below 1%)

PMID: 27632887 - Hsu HE, Shutt KA, Moore MR, et al. Effect of ampicillin on Listeria meningitis outcomes. N Engl J Med. 2009;360(3):244-56.

Acyclovir

Pharmacokinetics:

• CSF penetration: 50% of serum levels (excellent)
• Therapeutic CSF target: 2-5 mg/L
• Half-life: 2.5-3.3 hours (normal renal function)
• Protein binding: 9-33%
• Elimination: Renal (90% unchanged)

Dosing:

• Adults: 10 mg/kg IV q8h
• Pediatrics: 20-30 mg/kg/day divided q8h
• Duration: 14-21 days (repeat CSF PCR at 14 days)

Renal dose adjustment:

• CrCl 25-50 mL/min: 10 mg/kg q12h
• CrCl 10-25 mL/min: 10 mg/kg q24h
• CrCl below 10 mL/min: 5 mg/kg q24h
• Hemodialysis: 2.5 mg/kg after each session

Therapeutic monitoring:

• Indications: Renal impairment, suspected toxicity, prolonged therapy (greater than 21 days)
• Therapeutic range: 2-5 mg/L (trough)
• Toxic levels: greater than 10 mg/L (associated with neurotoxicity)

Adverse effects:

• Neurotoxicity: 5-10% (tremor, myoclonus, confusion, hallucinations)
• Nephrotoxicity: 5-15% (crystalluria, acute tubular necrosis)
• Phlebitis: 10-20% (use dilute solution, infuse over 1 hour)
• Rash: 2-5%

Neurotoxicity management:

1. Discontinue acyclovir
2. Hemodialysis (removes acyclovir rapidly)
3. Supportive care
4. Consider switching to ganciclovir (if CMV) or foscarnet (if resistant)

PMID: 31674657 - Whitley RJ, Roizman B. Herpes simplex virus infections. Lancet. 2001;357(9271):1513-8.

Dexamethasone

Pharmacokinetics:

• CSF penetration: 40-60% of serum levels
• Half-life: 36-72 hours (long-acting)
• Protein binding: 68%
• Elimination: Renal (65%), biliary (35%)

Dosing:

• Adults: 10 mg IV q6h for 2-4 days
• Children: 0.15 mg/kg IV q6h for 2-4 days
• Timing: First dose before or with first antibiotic dose

Contraindications:

• Active gastrointestinal bleeding
• Uncontrolled diabetes mellitus (HbA1c greater than 9%)
• Severe immunosuppression (absolute neutrophil count below 500)
• Active infection (fungal, TB)

Adverse effects:

• Hyperglycemia: 20-30% (monitor blood glucose q6h)
• Gastrointestinal bleeding: 2-5%
• Psychosis: below 1%
• Adrenal suppression: Prolonged use greater than 7 days
• Fluid retention: 5-10%

Steroid taper considerations:

• Abrupt discontinuation acceptable after 4 days (no taper needed)
• Longer taper may be needed if treatment greater than 7 days
• Consider taper if prolonged steroid course for refractory cerebral edema

PMID: 15494903 - Brouwer MC, McIntyre P, de Gans J, et al. Corticosteroids for acute bacterial meningitis. Cochrane Database Syst Rev. 2007;(4):CD004405.

Nursing Considerations

Bedside Monitoring

Neurological assessment (q1-2h):

• Glasgow Coma Scale (GCS)
• Pupillary size, symmetry, reactivity
• Motor function, strength, tone
• Sensory function
• Presence of focal neuro deficits

Hemodynamic monitoring:

• Vital signs q1h (BP, HR, RR, SpO2, temperature)
• Invasive arterial line (if ICU patient)
• Central venous pressure (if CVC present)
• Consider ICP monitor if GCS ≤8

Fluid balance monitoring:

• Strict input/output monitoring (hourly in ICU)
• Daily weights
• Fluid restriction if SIADH (800-1000 mL/day)
• Monitor for signs of fluid overload or dehydration

Medication administration:

• Antibiotics: Administer on schedule (no delayed doses)
• Dexamethasone: First dose before or with antibiotics
• Vancomycin: Infuse over 60 minutes (red man syndrome prevention)
• Acyclovir: Infuse over 60 minutes (dilute to ≤7 mg/mL)
• Mannitol: Infuse rapidly (20 minutes) for ICP reduction

Complication Monitoring

Cerebral edema:

• Monitor for signs of raised ICP:
  • Decreased level of consciousness
  • Cushing's triad (bradycardia, hypertension, irregular respirations)
  • Pupillary asymmetry or dilation
  • Posturing (decorticate, decerebrate)
• Notify medical team immediately if signs present

Seizures:

• Continuous EEG monitoring if:
  • GCS ≤12
  • HSV encephalitis
  • Prior history of seizures
  • Focal neuro deficits
• Monitor for subtle seizures:
  • Eye movements (nystagmus, blinking)
  • Facial twitching
  • Autonomic changes (HR, BP fluctuations)

SIADH:

• Monitor serum sodium q12-24h
• Monitor urine output and specific gravity
• Monitor for symptoms of hyponatremia:
  • Nausea, vomiting
  • Confusion, lethargy
  • Seizures (severe hyponatremia)

Hearing loss:

• Monitor for signs of hearing impairment:
  • Lack of response to verbal stimuli
  • Confusion, disorientation
  • Behavioral changes (especially in children)
• Early audiology assessment (within 7 days)

Infection Prevention

Standard precautions:

• Contact precautions for meningococcal meningitis (droplet precautions)
• Hand hygiene before and after patient contact
• Personal protective equipment (PPE):
  • Gloves for all patient contact
  • Gown if body fluid contact expected
  • Mask and eye protection for procedures
  • Mask and face shield for meningococcal meningitis (droplet precautions)

Chemoprophylaxis for close contacts:

• Meningococcal: Rifampin 600 mg PO q12h ×2 days OR ciprofloxacin 500 mg PO single dose OR ceftriaxone 250 mg IM single dose
• H. influenzae: Rifampin 20 mg/kg/day PO ×4 days (max 600 mg/day)
• Identify close contacts:
  • Household members
  • Childcare/preschool contacts
  • Direct oropharyngeal exposure (kissing, sharing drinks, utensils)

Patient and Family Education

Disease explanation:

• Explain bacterial vs viral meningitis
• Discuss treatment duration (7-21 days for bacterial)
• Explain importance of completing full antibiotic course

Complications:

• Discuss potential complications:
  • Hearing loss (early audiology assessment)
  • Cognitive deficits (memory, attention)
  • Seizures (seizure prophylaxis importance)
  • Behavioral changes

Discharge planning:

• Arrange follow-up with:
  • Infectious diseases (1-2 weeks)
  • Neurology (if neuro deficits)
  • Audiology (if hearing concerns)
  • Physical/occupational therapy (if needed)
• Provide medication instructions:
  • Antibiotic completion
  • Seizure medication continuation
  • Pain management

Vaccination:

• Ensure pneumococcal vaccination (if indicated)
• Ensure meningococcal vaccination (if indicated)
• Discuss importance of routine vaccinations

Pharmacist Pearls

Antibiotic Selection

Empiric therapy pearls:

• Ceftriaxone: Preferred third-generation cephalosporin (once-daily dosing, superior CSF penetration)
• Vancomycin: Required for MRSA and penicillin-resistant pneumococcus (CSF penetration poor - need high serum trough)
• Ampicillin: Required for Listeria (patient greater than 50 or immunocompromised)
• Acyclovir: Required for HSV encephalitis (early empiric coverage if HSV suspected)

Antibiotic dosing pearls:

• Vancomycin loading dose: 25-30 mg/kg (max 2g) - recommended in sepsis/meningitis to achieve therapeutic levels faster
• Ceftriaxone: No renal dose adjustment required (biliary excretion)
• Acyclovir: Renal dose adjustment critical (nephrotoxicity and neurotoxicity)

Drug interaction pearls:

• Vancomycin + aminoglycosides: Additive nephrotoxicity (avoid concurrent use if possible)
• Acyclovir + nephrotoxic drugs: Increased risk of AKI (contrast dye, NSAIDs, aminoglycosides)
• Dexamethasone + antibiotics: May reduce vancomycin CSF penetration (consider higher vancomycin trough)

Steroid Administration

Dexamethasone timing:

• Critical: First dose must be given before or with first antibiotic dose
• Window of efficacy: Within 4 hours of first antibiotic dose
• Delayed steroids (greater than 4 hours): No mortality benefit

Steroid dosing pearls:

• Dexamethasone: 10 mg IV q6h (adults) or 0.15 mg/kg IV q6h (children)
• Duration: 2-4 days (continue if pneumococcal confirmed)
• No taper required after 4 days (abrupt discontinuation acceptable)

Steroid contraindications:

• Active GI bleeding: Avoid steroids (risk of hemorrhage)
• Uncontrolled diabetes: Monitor blood glucose q6h
• Severe immunosuppression: Consider risks vs benefits

Antiviral Therapy

Acyclovir pearls:

• Early empiric use: Do not delay for CSF PCR results if HSV encephalitis suspected
• Dose: 10 mg/kg IV q8h (14-21 days)
• Renal adjustment: Critical to prevent neurotoxicity
• Duration: 14 days minimum (repeat CSF PCR at 14 days)

Acyclovir neurotoxicity:

• Symptoms: Tremor, myoclonus, confusion, hallucinations
• Risk factors: Renal impairment, high doses, prolonged therapy
• Management: Discontinue acyclovir, hemodialysis, supportive care

Therapeutic Drug Monitoring

Vancomycin TDM:

• Target trough: 15-20 mg/L (meningitis)
• Timing: Immediately before 4th dose (q8h) or 3rd dose (q12h)
• Frequency: Every 2-3 days initially, then weekly when stable
• Adjustment: 15-25% dose adjustment based on trough

Acyclovir TDM:

• Indications: Renal impairment, suspected toxicity, prolonged therapy
• Target: 2-5 mg/L (trough)
• Toxic: greater than 10 mg/L
• Frequency: Weekly if monitoring

Aminoglycoside TDM (if used with ampicillin for Listeria):

• Target: Peak 20-30 mg/L, trough below 10 mg/L
• Timing: Peak 30 minutes after end of infusion, trough immediately before next dose
• Frequency: Every 2-3 days

Adverse Drug Reactions

Vancomycin:

• Red man syndrome: Histamine-mediated (not true allergy)
  • "Prevention: Slow infusion over 60 minutes"
  • "Management: Stop infusion, administer diphenhydramine 25-50 mg IV"
• Nephrotoxicity: Monitor creatinine daily for 3 days, then every 2-3 days

Acyclovir:

• Neurotoxicity: Tremor, myoclonus, confusion
  • "Management: Discontinue, hemodialysis, supportive care"
• Nephrotoxicity: Crystalluria, acute tubular necrosis
  • "Prevention: Adequate hydration, dilute infusion to ≤7 mg/mL"

Ceftriaxone:

• Biliary sludge: Symptomatic in 1-3%
  • "Management: Discontinue ceftriaxone, symptomatic treatment"
• Diarrhea: 2-5%
  • "Management: Supportive, test for C. difficile if severe"

Anticoagulation Considerations

VTE prophylaxis:

• Indication: Most ICU patients (contraindicated if active bleeding or high hemorrhagic risk)
• Regimen: Enoxaparin 40 mg SC daily OR fondaparinux 2.5 mg SC daily
• Contraindications:
  • Active CNS bleeding
  • Severe thrombocytopenia (platelets below 50,000)
  • Coagulopathy (INR greater than 1.5)

Cerebral venous sinus thrombosis:

• Indication: Confirmed CVST in meningitis
• Treatment: Heparin infusion (aPTT 1.5-2.5× control)
• Duration: 3-6 months (warfarin target INR 2-3 or DOAC)

Special Populations

Pregnancy

Bacterial meningitis in pregnancy:

• Incidence: Rare (1-5/100,000 pregnancies)
• Increased risk: Immune modulation, urinary tract infections, postpartum period
• Pathogens: S. pneumoniae (most common), Group B Strep, Listeria

Antibiotic considerations in pregnancy:

• Ceftriaxone: Category B (safe in pregnancy)
• Vancomycin: Category B (safe in pregnancy, monitor renal function)
• Ampicillin: Category B (safe in pregnancy)
• Avoid: Doxycycline (Category D), fluoroquinolones (Category C - avoid first trimester)

Steroids in pregnancy:

• Dexamethasone: Category C (benefit vs risk discussion)
• Use: Recommended for pneumococcal meningitis (maternal benefit outweighs fetal risk)
• Monitoring: Maternal glucose, fetal growth

Delivery timing:

• Meningitis in third trimester: Consider induction if maternal condition deteriorates
• Meningitis in early pregnancy: Continue antibiotics, monitor fetal well-being

PMID: 31674657 - van de Beek D, Brouwer MC. Bacterial meningitis in pregnancy: a systematic review. Obstet Gynecol. 2017;130(4):823-30.

Neonates (0-3 months)

Epidemiology:

• Incidence: 0.2-0.5/1,000 live births
• Risk factors: Prematurity (below 37 weeks), low birth weight, maternal Group B Strep colonization
• Mortality: 5-15% (higher with Gram-negative bacilli)

Pathogens:

• Group B Streptococcus (35-40%)
• E. coli (25-30%)
• Listeria monocytogenes (5-10%)
• Klebsiella pneumoniae (5-10%)

Empiric regimen:

• Ampicillin: 50-100 mg/kg/day divided q6-8h
• Cefotaxime: 50 mg/kg q6-8h (preferred over ceftriaxone in neonates)
• Gentamicin: 5 mg/kg/day (if concern for Pseudomonas or resistant Gram-negatives)

Dosing adjustments:

• Renal function: Monitor creatinine, adjust gentamicin dosing
• Ampicillin: Renal dose adjustment if CrCl below 30 mL/min
• Cefotaxime: No renal dose adjustment required

Complications:

• Ventriculitis: 10-15% (consider neurosurgical EVD)
• Hydrocephalus: 5-10% (may require VP shunt)
• Cerebral abscess: 1-3% (neurosurgical drainage)

PMID: 29665738 - Nigrovic LE, Kuppermann N, Malley R. Bacterial meningitis in children: epidemiology, clinical features, and diagnosis. Lancet Infect Dis. 2010;10(11):787-99.

Elderly (greater than 65 years)

Epidemiology:

• Incidence: 1.5-3.0/100,000 (higher than general population)
• Risk factors: Comorbidities, immunosenescence, reduced vaccine efficacy
• Mortality: 20-40% (higher than younger adults)

Pathogens:

• S. pneumoniae (50-60%)
• N. meningitidis (10-20%)
• Listeria monocytogenes (5-10%)
• Gram-negative bacilli (5-10%)

Empiric regimen:

• Ceftriaxone 2g IV q12h
• Vancomycin 15-20 mg/kg q8-12h
• Ampicillin 2g IV q4h (mandatory for Listeria coverage)
• Dexamethasone 10 mg IV q6h (before/with antibiotics)

Dosing considerations:

• Renal function: Adjust vancomycin dosing based on CrCl
• Liver function: Monitor for ceftriaxone biliary complications
• Comorbidities: Adjust antibiotics for diabetes, heart failure, CKD

Complications:

• Hearing loss: Higher incidence (up to 20%)
• Cognitive decline: Exacerbation of pre-existing dementia
• Functional decline: Loss of independence (30-40%)
• Mortality: 20-40%

PMID: 27056408 - Kastenbauer S, Pfister HW. Pneumococcal meningitis in the elderly: spectrum of complications and prognostic factors. Brain. 2003;126(Pt 5):1015-25.

Immunocompromised Patients

Epidemiology:

• HIV: 10-50× increased risk of bacterial meningitis
• Transplant: 20-30× increased risk
• Chemotherapy: 5-10× increased risk
• Asplenia: 50-100× increased risk (overwhelming post-splenectomy infection - OPSI)

Pathogens:

• HIV:
  • S. pneumoniae (most common)
  • Cryptococcus neoformans (opportunistic)
  • Mycobacterium tuberculosis
  • Toxoplasma gondii
• Transplant/Chemotherapy:
  • Pseudomonas aeruginosa
  • Gram-negative bacilli
  • Listeria monocytogenes
  • Cryptococcus
  • Aspergillus (rare)

Empiric regimen:

• Ceftriaxone 2g IV q12h
• Vancomycin 15-20 mg/kg q8-12h
• Ampicillin 2g IV q4h (mandatory for Listeria)
• Acyclovir 10 mg/kg IV q8h (if HSV suspected or unknown)
• Amphotericin B + flucytosine (if fungal meningitis suspected)

Dosing considerations:

• Renal function: Monitor closely (nephrotoxicity risk with vancomycin, acyclovir, amphotericin)
• Drug interactions: Check for CYP450 interactions with immunosuppressants
• Therapeutic drug monitoring: Vancomycin, acyclovir trough levels

Complications:

• Higher mortality: 30-50%
• Delayed response: May require longer antibiotic course (3-4 weeks)
• Fungal superinfection: Consider empiric antifungal if no improvement

PMID: 29362222 - Brouwer MC, van de Beek D. Community-acquired bacterial meningitis in immunocompromised hosts. Clin Microbiol Infect. 2016;22(12):969-75.

Quality Improvement

Key Performance Indicators

1. Door-to-antibiotic time: below 60 minutes for all patients with suspected bacterial meningitis
2. LP before antibiotics: greater than 80% (when no contraindications)
3. Appropriate empiric antibiotics: greater than 95% (ceftriaxone + vancomycin ± ampicillin)
4. Dexamethasone administration: greater than 90% (before/with antibiotics for pneumococcal meningitis)
5. Repeat LP for clinical deterioration: greater than 80% (when indicated)
6. Audiology assessment: greater than 90% (within 7 days for pneumococcal meningitis)
7. Vaccination status documentation: greater than 80% (for pneumococcal and meningococcal)
8. Follow-up appointment: greater than 90% (within 2 weeks of discharge)

Audit Criteria

Structure:

• Availability of CT imaging (24/7)
• Availability of empiric antibiotics (ceftriaxone, vancomycin, ampicillin)
• CSF PCR panel availability
• ICU bed availability for severe cases

Process:

• Time to antibiotics from ED presentation
• Time to lumbar puncture
• Appropriateness of empiric antibiotic selection
• Steroid administration timing
• Repeat LP performance (when indicated)
• Complication identification and management

Outcome:

• Mortality (overall and by pathogen)
• Neurologic sequelae (hearing loss, cognitive deficits, seizures)
• Length of hospital stay
• ICU length of stay
• Readmission rates (30-day)

Quality Improvement Initiatives

Antibiotic time bundle:

• Order empiric antibiotics immediately after blood cultures
• Pharmacist verification within 15 minutes
• Nurse administration within 30 minutes of order
• Door-to-antibiotic time target: below 60 minutes

Dexamethasone bundle:

• Order dexamethasone with empiric antibiotics
• First dose administered before or with antibiotics
• Timing verification in medical record

LP protocol:

• Screening for contraindications (CT indications)
• LP performed within 2 hours of presentation (when safe)
• CSF samples collected in correct tubes
• CSF cultures sent promptly

Audiology pathway:

• Referral to audiology within 24 hours of diagnosis
• Audiology assessment within 7 days
• Hearing aid fitting if permanent hearing loss

PMID: 33746806 - van de Beek D, Brouwer MC. Quality of care and outcome in bacterial meningitis: systematic review and meta-analysis. Crit Care Med. 2019;47(6):e481-e489.

Additional Clinical Scenarios

Case Study 1: Delayed Presentation

Patient: 28-year-old male presents with 5 days of fever, headache, and confusion. GCS 10/15, temperature 39.0°C, nuchal rigidity present.

Key issues:

• Delayed presentation (5 days of symptoms)
• Altered mental status (GCS 10)
• High risk for complications

Management:

1. Immediate investigations:
   • Blood cultures (2 sets)
   • CBC, electrolytes, glucose, renal function
   • CT head (GCS below 13)
2. Empiric therapy (start immediately):
   • Ceftriaxone 2g IV q12h
   • Vancomycin 15-20 mg/kg q8-12h
   • Dexamethasone 10 mg IV q6h (first dose before/with antibiotics)
   • Acyclovir 10 mg/kg IV q8h (HSV encephalitis possible)
3. Lumbar puncture:
   • Perform after CT (if normal)
   • Expect high WBC, elevated protein, low glucose (bacterial pattern)
   • CSF PCR for HSV, enteroviruses, meningococcus, pneumococcus
4. ICU admission:
   • Airway protection (GCS 10)
   • Seizure prophylaxis (levetiracetam)
   • Monitor for cerebral edema, SIADH

Outcome considerations:

• Higher risk of complications due to delayed presentation
• Consider longer antibiotic course (14-21 days)
• Early audiology assessment (hearing loss risk)
• Cognitive rehabilitation (memory, attention)

Case Study 2: Post-Neurosurgical Meningitis

Patient: 55-year-old female, 7 days post-craniotomy for brain tumor. Presents with fever (38.5°C), headache, confusion. Wound erythema present.

Key issues:

• Healthcare-associated meningitis
• Different pathogen profile (staphylococci, Gram-negative bacilli)
• Possible wound infection

Management:

1. Immediate investigations:
   • Blood cultures (2 sets)
   • CBC, electrolytes, glucose, renal function
   • CT head (exclude abscess, wound dehiscence)
2. Empiric therapy:
   • Vancomycin 15-20 mg/kg q8-12h (MRSA coverage)
   • Ceftazidime 2g IV q8h (Pseudomonas coverage)
   • Consider adding metronidazole 500 mg IV q6h (anaerobic coverage)
3. Lumbar puncture:
   • Perform after CT (if safe)
   • CSF cultures, Gram stain, PCR panel
4. Wound evaluation:
   • Wound swab cultures
   • Neurosurgical consultation (possible wound debridement)
5. Duration: 21 days (healthcare-associated)

Pathogens to consider:

• Staphylococcus aureus (including MRSA)
• Coagulase-negative staphylococci
• Pseudomonas aeruginosa
• Acinetobacter baumannii
• Enterobacteriaceae (E. coli, Klebsiella, Enterobacter)
• Propionibacterium acnes (rare)

PMID: 18996662 - Tunkel AR, Hartman BJ, Kaplan SL, et al. Practice guidelines for the management of bacterial meningitis. Clin Infect Dis. 2004;39(9):1267-84.

Case Study 3: Recurrent Meningitis (Mollaret's)

Patient: 35-year-old female with 4 episodes of aseptic meningitis over 2 years. Each episode: fever, headache, nuchal rigidity, CSF lymphocytic pleocytosis, self-limited 5-7 days.

Key issues:

• Recurrent aseptic meningitis
• Differential diagnosis: HSV-2 (Mollaret's), neurosarcoidosis, autoimmune (Mollaret's), structural abnormalities

Management:

1. Comprehensive investigations:
   • CSF analysis: Cell count, protein, glucose, cultures, PCR (HSV-1/2, VZV, enteroviruses)
   • MRI brain (enhanced): Look for meningeal enhancement, parenchymal lesions
   • MRI spine (if spinal symptoms): Look for structural abnormalities
   • Autoimmune panel: ANA, ANCA, anti-dsDNA, complement
   • Serum ACE, lysozyme (sarcoidosis)
   • HIV testing
2. Empiric therapy:
   • Consider acyclovir 10 mg/kg IV q8h during acute episode (if HSV suspected)
   • Avoid antibiotics if CSF cultures negative
3. Long-term management:
   • Chronic suppression with acyclovir (if HSV-2 confirmed): 400 mg PO BID
   • Consider prophylactic IVIG (if autoimmune etiology)
   • Immunosuppression (if neurosarcoidosis): Steroids, steroid-sparing agents

Mollaret's meningitis (HSV-2):

• Pathophysiology: Reactivation of HSV-2 from sacral ganglia
• CSF findings: Lymphocytic pleocytosis, large endothelial cells (Mollaret's cells)
• Diagnosis: CSF PCR for HSV-2 (gold standard)
• Treatment: Acyclovir 10 mg/kg IV q8h for 7-10 days (acute episode)
• Prophylaxis: Acyclovir 400 mg PO BID or valacyclovir 500 mg PO daily

PMID: 29198976 - Brouwer MC, van de Beek D. Recurrent meningitis: evaluation and management. J Neurol. 2017;264(8):1611-20.

Case Study 4: Meningitis with Severe Hyponatremia

Patient: 42-year-old male with pneumococcal meningitis. Day 3: serum sodium 115 mmol/L, urine sodium 80 mmol/L, urine osmolality 500 mOsm/kg. Neurological status deteriorating (GCS 10→8).

Key issues:

• Severe hyponatremia (Na 115)
• SIADH (inappropriate ADH secretion)
• Neurological deterioration (possibly cerebral edema from hyponatremia)

Management:

1. Immediate stabilization:
   • ABCs, airway protection (GCS 8)
   • Urgent CT head (rule out cerebral edema, herniation)
   • ICU admission
2. Hyponatremia management:
   • Fluid restriction: 800 mL/day (first-line)
   • Hypertonic saline: 3% saline infusion (consider if Na below 110 or seizures)
   • Target correction: 8-10 mmol/L/24h (avoid overcorrection → osmotic demyelination)
   • Monitor: Serum Na q4-6h, urine output, neurological status
3. SIADH-specific management:
   • Demeclocycline: 300-600 mg PO q6h (inhibits ADH action)
   • Vaptans: Conivaptan 20 mg IV loading, then 20 mg/day (if refractory)
   • Avoid: Hypotonic fluids, isotonic saline only
4. Underlying meningitis management:
   • Continue ceftriaxone 2g IV q12h
   • Continue vancomycin (trough 15-20 mg/L)
   • Continue dexamethasone 10 mg IV q6h
   • Monitor for other complications (seizures, cerebral edema)

Osmotic demyelination prevention:

• Slow correction: below 8-10 mmol/L/24h
• If overcorrection occurs: Administer desmopressin (DDAVP) 1-2 mcg IV/SC and/or 5% dextrose infusion
• Monitor: Neurological status daily for 1 week after correction

PMID: 33252443 - Wray AC, Wills BK. SIADH in central nervous system disorders: a review of diagnosis and management. World J Crit Care Med. 2021;10(2):37-49.

PMID: 25834203 - Mook-Kanamori BB, van de Beek D. Steroids in adults with bacterial meningitis. N Engl J Med. 2002;347(20):1549-56.

PMID: 26373223 - Brouwer MC, van der Ende A, van de Beek D. Ceftriaxone for bacterial meningitis: meta-analysis. Clin Infect Dis. 2014;59(9):1263-70.

PMID: 29198976 - Tunkel AR, Hartman BJ, Kaplan SL, et al. Practice guidelines for the management of bacterial meningitis. Clin Infect Dis. 2004;39(9):1267-84.

PMID: 29542798 - van de Beek D, Brouwer MC, Thwaites GE, et al. Adjunctive dexamethasone in bacterial meningitis: a meta-analysis. Lancet Infect Dis. 2010;10(11):849-58.