Bacterial Meningitis – Summary

Introduction:

  • inflammation of the leptomeninges (arachnoid mater + CSF)
  • among 10 most common infectious causes of death (135,000 deaths/world/year)

Epidemiology

  • Community or Healthcare associated
    • Community: Strep pneumo, Neisseria meningitidis, Listeria monocytogenes (pt over 50-60 yr old or cell-mediated immunity)
    • Healthcare-associated: generally staphylococci or anaerobic gram-negative
      • Risks: neurosurgery, VP drain placement, trauma w/ leakage of CSF

Clinical Features — pts often present soon after symptom onset

  • Classic triad: fever + nuchal rigidity + AMS, though most pts do not have all 3
    • Review of 279 episodes of community acquired meningitis
      • Most common is fever with temp > 38C (95% at presentation, another 4% w/n 24h)
      • Nuchal rigidity (88% on initial examination)
      • AMS (78%, confusion + lethargy most common)
    • Three other large series showed:
      • Fever (77-85%), neck stiffness (83-94%), headache (79-94%), AMS (83%)
    • 2004 Review of 696 cases of community-acquired bacterial meningitis
      • Classic triad in only 44% patients (fever, neck stiffness, AMS)
        • More common in pneumococcal than meningococcal meningitis (58% vs 27%)
      • 95% had 2 out of 4: fever, neck stiffness, AMS, HA, 99-100% with at least one sign
        • Therefore, absence of all findings essentially excludes the diagnosis of bacterial meningitis
  • Kernig’s & Brudzinski signs
    • Brudzinski: spontaneous flexion of hips w/ passive neck flexion
    • Kernig: inability or reluctance to allow full extension of knee when hip is flexed to 90 degrees
    • Prospective study of 297 patients in 2002 – meningitis defined as > 6 WBCs in CSF
      • Low sensitivity (5% each kernig/brudz and 30% nuchal rigidity), specificity 95% for kernig/brudz and 68% for nuchal rigidity

Course

  • Determinants of pace are related to hot and microbial virulence factors
    • If late to treatment, course is almost uniformly fatal

Assessment of Risk

  • Prognostic model of 176 adults and another cohort of 93 patients
    • 9% with neurologic deficit at discharge
    • Baseline clinical features (hypotension, AMS, sz) independently assoc w/ adverse outcome
      • Low risk (no clinical risk factors) – 9% adverse outcome
      • Intermediate (1 clinical risk factor) – 33% adverse outcome
      • High (2-3 risk factors) – 56% adverse outcome

Laboratory Features – often unrevealing

  • CBC: generally elevated WBC with left shift, though severe infxn may present w/ leukopenia
    • Plt: may be reduced
    • Leukopenia + thrombocytopenia associated with poorer outcomes
  • Coags: may be consistent with DIC
  • BMP: AGMA or hyponatremia
  • Blood Cultures: often positive and useful if CSF cannot be obtained p/t abx
    • 50-90% pts w/ bacterial meningitis will have (+) cultures
  • LP: crucial for diagnosis
    • May delay for CT scan in order to r/o mass lesion or increased ICP — would lead to herniation w/ removal of large amount of CSF
      • However, screening CT not necessary for majority of patients
        • Prospective Study of 301 w/ suspected meningitis: 235 underwent CT before LP —24% had abn finding, but only 5% had mass effect
          • Risk of abn finding often predicted by suspicious hx (ex. impaired cellular immunity, hx prior CNS disease or seizure in past week) as well has PE (reduced LOC, focal motor weakness or cranial abn)
            • Among 96 pts with none of these features, only 3 had abn CT, 0 w/ herniation
        • Compared w/ pts who did not have CT before LP, those who did had average 2 hours delay in dx and 1 hour delay in tx
    • ISDA Guidelines of CT before LP — get CT if:
      • Immunocompromised state (HIV, immunosuppressive tx, solid organ or hematopoietic stem cell txp)
      • Hx CNS disease (mass lesion, stroke, focal infection)
      • New onset seizure
      • Papilledema
      • Abn LOC
      • Focal neurologic deficit
    • Clinical signs of impending herniation: deteriorating LOC (GCS < 11), brainstem signs (ie. pupillary changes, posturing, irregular respirations), very recent seizure
      • suggest delaying LP
    • If Delayed LP
      • 1) Obtain blood cx immediately
      • 2) Begin empiric abx + dexamethasone (0.15 mg/kg IV) s/p blood cultures
        • Important to begin dexamethasone BEFORE or AT SAME TIME as ABX, not after
        • Pathogen may still be cultured from CSF in most patients up to several hours after administration of abx
      • 3) Obtain LP as soon as possible after imaging study
    • Opening Pressure — typically elevated in bacterial meningitis
      • Series of 301 adults: mean opening pressure 350 mmH2O (normal up to 200)

CSF Analysis

  • What to get
    • Cell count + differential, glucose, protein, gram stain + culture
  • Clinical findings will suggest meningitis, the CSF will differentiate the type
    • Normal CSF: < 50mg/dL protein, CSF to serum glucose ratio > 0.6, < 5 WBCs, lactate concentration < 3.5 mEq/L
  • Bacterial Meningitis
    • WBC: 1000 – 5000/microliter, Neutrophils > 80%, Protein > 200 mg/dL, glucose < 40 mg/dL
      • CSF:serum glucose </= 0.4)
    • Observational study: 99% probability of bacterial meningitis if one of following present:
      • CSF glucose < 34 mg/dL, Protein > 220 mg/dL, WBC > 2000, neutrophil count > 1180
    • Lactate: 2 meta-analyses including 25 & 31 studies
      • determined that CSF lactate superior to WBC, glucose and protein in differentiating bacterial from aseptic meningitis — lower sensitivity if abx p/t LP & falsely elevated if concurrent CNS disease present
    • Pleocytosis: false-positive elevate of WBC found in few instances
      • traumatic LP, intracerebral or SAH (both RBC and WBC introduced to arachnoid space), generalized seizures (temporary pleocytosis)
    • Gram Stain
      • G (+) diplococci suggests pneumococcal infection
      • G (-) diplococci suggests meningococcal infection
      • Small pleomorphic G (-) coccobacilli suggests Haemophilus influenzae infection
      • G (+) rods + coccobacilli suggets listeria
      • Reported sensitivity of gram stain 60-90%, but specificity approaches 100%
        • Study of 696 patients w/ community-acquired bacterial meningitis
          • Sensitivity of gram stain 80%, specificity 97%
      • Gram stain may be positive in 10-15% patients who have a negative culture
    • Limited Utility in repeat LP to assess response to therapy
      • Repeat if: 1) no evidence of improvement by 48 hours 2) 2-3 days after initiation of tx due to microorganisms resistant to standard agents and are not responding as expected or for infection caused by gram-negative bacillus 3) persistent fever for more than 8 days w/o other explanation

Treatment

Effects of Delay to Treatment

  • Retrospective study of 269 adults with bacterial meningitis
    • 3 baseline prognostic markers (HoTN, AMS, Sz) predictive of adverse outcome (in-hospital mortality or neuro deficit at discharge)
      • Delay to tx in ER (median time 4 hours) associated with worsening of these markers in 15% patients
  • Prospective study of 156 patients w/ pneumococcal meningitis
    • Delay more than 3 hours after hospital admission = independent risk for mortality (odds ratio 14.1: 95% CI 3.9 – 50.9)
  • Retrospective cohort of 286 patients with community-acquired bacterial meningitis
    • Early/adequate ABX in r/t onset of overt s/s —> favorable outcome (mild or no disability) (OR 11.2, 95% CI 4.4 – 32.6)

Why would there be a delay?

  • Atypical presentation = absence of fever on presentation, lack of headache/neck stiffness
  • Imaging delay to exclude presence of mass lesion or risks for cerebral herniation
    • If going to delay LP, MUST begin ABX/Steroids while obtaining blood cultures

Antibiotics

  • Three general requirements
    • 1) bactericidal drugs effective against organism 2) drugs entering CSF 3) structuring regimen to optimize bactericidal efficacy
    • Bactericidal drugs: CSF = space of impaired humoral immunity
    • CSF entry: normal BBB = blockage of beta-lactams (ex. PCN), if meningeal inflammation —> separation of intercellular tight junctions but decr. permeability as inflammation decreases blocking antimicrobial entry
      • Therefore, maximal parenteral doses must be continued throughout course to maintain adequate CSF concentration
    • Pharmacodynamics: bactericidal activity depends on time above minimal inhibitory concentration for time-dependent drugs (ex. beta-lactams, vancomycin)
      • Concentration-dependent antimicrobials (ex. aminoglycosides), killing of bacteria occurs over wide range of antimicrobial concentrations w/ prolonged recovery period
  • Empiric Therapy
    • Causative Organisms — CDC study of 1083 cases meningitis 2003 – 2007
      • S. pneumo 71%, N. meningitidis 12%, Group B Strep 7%, H influenzae 6%, Listeria monocytogenes 4%
        • Incidence of Listeria increases with age — empirically tx if age > 50 (ampicillin)
    • Regimens
      • 1) Third generation cephalosporins (ex. cefotaxime + ceftriaxone)
        • Consistent CSF penetration + potent activity against major bacterial pathogens (exception being L. monocytogenes & some PCN-resistant S. pneumo strains)
      • 2) Vancomycin
        • Empiric tx for pcn-resistant strains until cultures & susceptibilities return
      • Others:
        • Ceftazidime (3rd generation ceph w/ broad activity against gram-negative bacteria including Pseudomonas
          • Much less active against PCN-resistant pneumococci than cefotaxime & ceftriaxone
        • 4th Generation cephs including cefepime — safe & equivalent to cefotaxime for bacterial meningitis in infants and children
    • No known Immune Deficiency
      • Bugs: S. pneumo, N. meningitidis, less often H. flu & GBS — up to 60 yo
        • 1) Ceftriaxone 2g IV q 12h OR Cefotaxime 2g IV q4-6h, PLUS
        • 2) Vancomycin 15-20 mg/kg IV q 8-12h (not to exceed 2 g per dose or total daily of 60 mg/kg, IF
        • 3) Adults > 50 also get Ampicillin 2 g IV q 4h
    • Impaired Cellular Immunity — ex. lymphoma, cytotoxic chemotx, high-dose glucocorticoids
      • Bugs: Listeria monocytogenes, gram-negative bacilli (including Pseudomonas), S. pneumo
        • 1) Vancomycin – 15-20 mg/kg IV q 8-12h — not to exceed 2 g per dose, PLUS
        • 2) Ampicillin – 2 g IV q 4h, PLUS EITHER
        • 3) Cefepime 2 g IV q 8h OR Meropenem 2 g IV q 8h
    • Healthcare-associated Infection (i.e. s/p trauma, surgery, pts w/ VP drains)
      • Bugs: Gram-positive & gram-negative (i.e. Kleb, Pseudo)
        • 1) Vancomycin (dosing as above), PLUS
        • 2) Ceftazidime 2 g IV q 8h OR Cefepime 2 g IV q8h OR Meropenem 2g IV q8h
      • Question of withdrawing abx if CSF culture negative & suggest aseptic picture vs bacterial s/p neurosurgery
        • Consensus is to continue abx in all patients w/ clinical & lab features suggesting meningitis and discontinue 48-72 hours s/p CSF culture negative
    • Beta-Lactam Allergy
      • 1) Vancomycin (dosing as above), PLUS
      • 2) Moxifloxacin 400 mg IV qD, PLUS
      • 3) TMP-SMX 5 mg/kg IV q6-12h if age > 50 or listeria otherwise suspected

Adjunctive Dexamethasone

  • Early IV administration of glucocorticoids evaluated as adjunctive tx in attempt to diminish hearing loss, other neuro complications and mortality
  • Main indication: pneumococcal meningitis
    • Since etiology often not known at time of presentation, administer prophylactically
  • Rationale provided by animal studies — decreased hearing loss temporarily associated with severe inflammatory changes induced by meningitis — decreased w/ dexamethasone
  • Regimen: 0.15 mg/kg q6h x 4 days
    • Consider adding rifampin to abx if pneumococcal meningitis and receiving dexamethasone
      • if susceptibility studies show intermediate susceptibility (MIC >/= 2) to ceftriaxone and cefotaxime

Prognosis

  • Mortality: increases linearly with age
    • 16.4% mortality in adults (8.9% 18-34 yo vs 22.7 in adults > 65)
    • Higher rates of mortality with healthcare-associated infection vs. community acquired (35 vs 25%), higher with infection due to S. pneumo & L. monocytogenes vs N. meningitidis (28 & 32% vs 10%)
  • Neurologic
    • 28% community acquired patients in study of 493 episodes resulted in neuro sequelae
      • Includes: impaired mental status, increased ICP & cerebral edema, seizures, focal neuro deficits, cerebrovascular abnormalities, sensorineural hearing loss, intellectual impairment

Source: Bacterial Meningitis – UptoDate

Advertisements

Leave a Reply

Fill in your details below or click an icon to log in:

WordPress.com Logo

You are commenting using your WordPress.com account. Log Out / Change )

Twitter picture

You are commenting using your Twitter account. Log Out / Change )

Facebook photo

You are commenting using your Facebook account. Log Out / Change )

Google+ photo

You are commenting using your Google+ account. Log Out / Change )

Connecting to %s