Bacterial Meningitis in Adults

25/7/22, 11:46 Bacterial Meningitis in Adults
Bacterial Meningitis in Adults

Overview and Recommendations
Background
● Bacterial meningitis refers to bacterial infection of the meninges resulting in inflammation that can be life-
threatening.
⚬ Community-acquired bacterial meningitis is caused by invasion of the central nervous system (CNS) by
bacteria in the setting of bacteremia or by direct extension though dural defects or local infection.
⚬ Nosocomial or postsurgical bacterial meningitis occurs after manipulation of the CNS space allowing for
entry of pathogenic organisms.
● Community-acquired bacterial meningitis is most commonly due toStreptococcus pneumoniae (about 50%)
and Neisseria meningitidis (about 30%).
● Listeria monocytogenes accounts for about 5% of cases and is more common in those > 50 years old and
immunocompromised patients. See Listeria meningitis for details.
● The most common causes in patients with neurosurgical infections include Staphylococcus aureus,
coagulase-negative staphylococci (including methicillin-resistant strains), and gram-negative bacilli
(especially Enterobacteriaceae).
● Risk factors include older age, immunosuppression, parameningeal sources of infection, recent
neurosurgical procedures, and close living quarters.
● Complications include septic shock, increased intracranial pressure and syndrome of inappropriate diuresis
during acute illness, and focal neurologic deficits, hearing loss, and cognitive impairment after recovery.
Evaluation
● Prompt diagnosis and management is critical to avoid significant morbidity and mortality.
● Presenting signs and symptoms vary.
⚬ Presentation can be indolent at the extremes of age, in patients with immunocompromise, and in
patients with partially treated infections.
⚬ A small percentage of patients experience fulminant bacterial meningitis, with sudden onset, rapid
deterioration, abrupt cerebral edema, intracranial hypertension, and brain herniation.
⚬ A classic triad of fever, neck stiffness, and altered mental status is seen in about 40% of patients,
although it is more common in the elderly and in those with pneumococcal meningitis.
⚬ A rapidly evolving petechial or purpuric rash may indicate meningococcal disease.
● Brudzinski and Kernig signs of meningeal irritation appear unreliable for diagnosis or ruling out of
meningitis.
● Testing prior to lumbar puncture (LP):
⚬ obtain blood cultures, complete blood count, and coagulation studies.

⚬ obtain a noncontrast head CT prior to LP to assess for the risk of herniation if the patient is
immunocompromised, has papilledema, a history of central nervous system (CNS) disease, focal
neurologic deficit on exam, new-onset seizure ≤ 1 week prior, or an abnormal level of consciousness
(Strong recommendation).
● Diagnosis is confirmed by LP.

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⚬ Perform in all patients unless contraindicated.

⚬ Consider initiation of empiric antibiotics once the blood cultures are drawn if LP is delayed for any
reason (head CT, reversal of anticoagulation, thrombocytopenia, etc).
⚬ Measure:
– opening pressure, usually > 180 mm H2O in bacterial meningitis

– cell counts with differential, usually > 1 × 109/L in bacterial meningitis
– cerebrospinal fluid (CSF) glucose, usually low
– CSF protein, usually high
– CSF for immediate Gram stain and bacterial cultures
– herpes simplex virus (HSV) by polymerase chain reaction (PCR), as HSV meningoencephalitis can
present in a similar fashion to bacterial meningitis
● Differential diagnosis includes viral meningitis, particularly due to HSV, fungal meningitis, other infections
(such as acute HIV, Lyme disease, or leptospirosis), drug-induced meningitis, stroke, subarachnoid
hemorrhage, and central nervous system vasculitides.
Management
● Delays in treatment are associated with an increased mortality.
● For community-acquired bacterial meningitis, empiric treatment in patients with normal renal function
often includes:
⚬ for adults < 50 years old, ceftriaxone 2 g IV every 12 hours plus vancomycin 15-20 mg/kg IV every 8-12
hours
⚬ for adults > 50 years old or immunocompromised patients, ceftriaxone 2 g IV every 12 hours plus
vancomycin 15-20 mg/kg IV every 8-12 hours plus ampicillin 2 g IV every 4 hours
● Add acyclovir 10 mg/kg IV every 8 hours for all patients until herpes simplex meningoencephalitis is ruled
out (Strong recommendation).
● Add adjunctive dexamethasone for known or suspected Streptococcus pneumoniae meningitis (Strong
recommendation):
⚬ 0.15 mg/kg IV every 6 hours beginning 10-20 minutes before or during the antibiotic administration and
continuing for 2-4 days
⚬ may improve survival in adults with bacterial meningitis due to S. pneumoniae
⚬ Consider adding rifampin 600 mg every 24 hours when dexamethasone is given (Weak
recommendation), even with vancomycin which may not adequately penetrate the central nervous
system.
⚬ Insufficient evidence to recommend adjunctive dexamethasone for meningitis caused by other bacteria.
● For postsurgical bacterial meningitis, or meningitis associated with head trauma or shunt:
⚬ Empiric treatment often includes coverage for methicillin-resistant Staphylococcus aureus (MRSA) and
aerobic gram-negative organisms, such as Pseudomonas spp. and Enterobacteriaceae.
⚬ Infectious Diseases Society of America recommends vancomycin 15-20 mg/kg IV every 8-12 hours plus
either ceftazidime 2 g IV every 8 hours or cefepime 2 g IV every 8 hours (Strong recommendation).
● A definitive therapy and the duration of therapy should be based on cerebrospinal fluid (CSF) culture
results (Strong recommendation).
Prevention
● Preventive measures recommended by the Centers for Disease Control and Prevention for meningococcal
meningitis include:
⚬ droplet precautions for hospitalized patients as soon as diagnosis is suspected through the first 24
hours of antimicrobial therapy
⚬ chemoprophylaxis for close contacts of patients with confirmed meningococcal meningitis:
– closer than 3 feet for > 8 hours or those exposed to oral secretions and exposed during the 7 days
prior to and 1 day after the start of antibiotics
– ciprofloxacin 500 mg single dose unless there is concern for quinolone-resistant Neisseria meningitidis
(rare but has been reported)
● For vaccination information, see Meningococcal disease or Pneumococcal vaccination.
General Information
Description
● potentially life-threatening medical, neurologic, and sometimes neurosurgical emergency due to bacterial
infection and inflammation of meninges 1 , 3
Epidemiology
Who is most affected
● bacterial meningitis shifted from pediatric to adult population in United States following childhood
vaccinations
⚬ previously more common in children, but estimated 2,793 cases in infants and children and 2,962 cases
in adults in 1995 (N Engl J Med 1997 Oct 2;337(14):970 full-text )
⚬ median age of affected patients increased from 30.3 years in 1998-1999 to 41.9 years in 2006-2007 in
United States, based on surveillance data (N Engl J Med 2011 May 26;364(21):2016 )
Incidence/Prevalence
● worldwide incidence of bacterial meningitis varies, ranging from 1-2 cases per 100,000 people annually in
the United Kingdom and western Europe to 1,000 cases per 100,000 people annually in the Sahel region of
Africa 1
● introduction of conjugate vaccine programs has results in large reductions in incidence over last few
decades 1 , 3
● United States
⚬ 15,000-25,000 cases occur in US annually 3
STUDY
⚬ SUMMARY
annual incidence of bacterial meningitis in United States in 2006-2007
POPULATION-BASED SURVEILLANCE: N Engl J Med 2011 May 26;364(21):2016
Details
– based on surveillance study
– 3,188 patients with bacterial meningitis were identified in 8 surveillance areas of Emerging Infections
Programs Network between 1998 and 2007
– incidence of bacterial meningitis per 100,000 adults between 2006 and 2007
● 0.66 at age 18-34 years

● 1.92 at age ≥ 65 years
– Reference - N Engl J Med 2011 May 26;364(21):2016
STUDY
⚬ SUMMARY
> 72,000 meningitis-related hospitalizations in United States in 2006
POPULATION-BASED SURVEILLANCE: Healthcare Cost and Utilization Project 2008 Jul | Full Text
Details
– based on surveillance study

– > 72,000 meningitis-related hospitalizations were reported to Healthcare Cost and Utilization Project
in 2006
– overall rate 24.1 hospitalizations per 100,000 persons
– cause of meningitis-related hospital stays
● virus in 54.6%
● bacterial meningitis in 21.8%
⚬ streptococcal meningitis in 3.9%

⚬ staphylococcal meningitis in 3%
⚬ gram-negative meningitis in 2.5%
⚬ pneumococcal meningitis in 2.3%
● unspecified cause in 17.2%

● fungi and other microorganisms in 7.3%
⚬ cryptococcal meningitis in 5.7%
– in-hospital mortality
● 9.1% with fungal meningitis

● 8% with bacterial meningitis
● 6% with nonspecific meningitis
● 0.6% with viral meningitis
● substantially higher for patients ≥ 45 years old
– Reference - Healthcare Cost and Utilization Project 2008 Jul full-text
● "meningitis belt"
⚬ meningitis belt refers to a region that spans sub-Saharan Africa from Senegal and Gambia to Kenya and
Ethiopia that experiences cyclic meningococcal meningitis epidemics (East Afr J Public Health 2010
Mar;7(1):20 )
⚬ reports of meningococcal disease outbreaks
– 608 suspected cases of meningitis, including 161 deaths, reported in Banalia Health Zone in
Democratic Republic of the Congo as of September 18, 2021 (WHO Disease Outbreak News 2021 Sep
20 )
– Nigeria
● 541 suspected cases of cerebrospinal meningitis (47 confirmed out of 119 tested) and 48 deaths
reported from October 1, 2018 to March 27, 2019 (Nigeria Centre for Disease Control Situation
Report 2019 Mar 27 PDF )
● 14,518 suspected cases, mainly due to serogroup C, reported from December 13, 2016 to June 15,
2017 (MMWR Morb Mortal Wkly Rep 2017 Dec 15;66(49):1352 full-text )
● 1,543 suspected cases and 147 deaths reported from January 1 to April 25, 2015, mainly due to
serogroup C (WHO Disease Outbreak News 2015 Apr 29 )
– Togo - 1,975 cases and 127 deaths reported in 2016 in the northern part of country, mostly due to
serogroup W (WHO Disease Outbreak News 2017 Feb 23 )
– outbreaks with 11,647 reported cases and 960 deaths reported from January 1 to April 17, 2012 in
Benin, Burkina Faso, Chad, Central African Republic, Côte d'Ivoire, Gambia, Ghana, Mali, Nigeria, and
Sudan; mainly due to serogroup W135 (WHO Disease Outbreak News 2012 May 24 )
– for earlier outbreak data see WHO Global Alert and Response (GAR) archive
● the Netherlands
STUDY
⚬ SUMMARY
incidence of bacterial meningitis decreasing in Netherlands, and may be in part due to pediatric
vaccination
POPULATION-BASED SURVEILLANCE: Lancet Infect Dis 2016 Mar;16(3):339
Details
– based on national surveillance data from the Netherlands Reference Laboratory of Bacterial
Meningitis 2006-2014
– annual incidence of community-acquired bacterial meningitis
● 1.72 cases per 100,000 adults in 2007-2008

● 0.94 cases per 100,000 adults in 2013-2014
– Streptococcus pneumoniae most common pathogen (72%)

– routine vaccination with 7-valent vaccine in infants introduced in 2006
● incidence of pneumococcal serotypes included in 7-valent vaccine decreased from 0.42 per
100,000 adults in 2006 to 0.02 per 100,000 adults in 2013
● no evidence of serotypes replacement
– Reference - Lancet Infect Dis 2016 Mar;16(3):339 , commentary can be found in Lancet Infect Dis
2016 Mar;16(3):271
STUDY
⚬ SUMMARY
annual incidence of invasive meningococcal disease 0.6 per 100,000 population in 2012 in the
Netherlands
POPULATION-BASED SURVEILLANCE: Lancet Infect Dis 2014 Sep;14(9):805
Details
– based on national surveillance data from the Netherlands Reference Laboratory of Bacterial
Meningitis 1960-2013
– annual incidence of invasive meningococcal disease
● 0.5 per 100,000 population in 1960

– median age increased from 1.8 years in 1960 to 6.1 years in 2012
– rate of reduced penicillin susceptibility increased to 37% from 1993 to 2012
– Reference - Lancet Infect Dis 2014 Sep;14(9):805
STUDY
● SUMMARY
prevalence of meningococcal carriage peaks around age 19 years
SYSTEMATIC REVIEW: Lancet Infect Dis 2010 Dec;10(12):853
Details
⚬ based on systematic review of observational studies

⚬ systematic review of 110 studies reporting pharyngeal carriage of all meningococcal serogroups in
defined age groups
⚬ 82 studies with 143,114 persons were included in meta-analysis
⚬ prevalence of asymptomatic Neisseria meningitidis carriers
– 4.5% in infants
– 7.7% in children aged 10 years
– 23.7% in persons aged 19 years
⚬ Reference - Lancet Infect Dis 2010 Dec;10(12):853
Possible risk factors
● abnormal communication between nasopharynx and subarachnoid space
⚬ due to congenital anatomic abnormality

⚬ due to trauma
⚬ Reference - Cleve Clin J Med 2012 Jun;79(6):393
● externally communicating dural fistula or other dural defects 1 , 3 , 5
● immunosuppression (particularly asplenic patients or those with immunoglobulin deficiencies) 3 , 5
● parameningeal sources of infection such as 3 , 5
⚬ otitis
⚬ sinusitis
⚬ mastoiditis
● prior neurosurgery 3 , 5
● skull fracture 2 , 5
● pneumonia 3
● cochlear implants (Curr Opin Otolaryngol Head Neck Surg 2014 Oct;22(5):359 )
● living and social situations involving high-likelihood of close-person-to-person contact, such as living in
college dorms or military barracks, associated with increased risk of invasive meningococcal disease (Curr
Opin Pediatr 2009 Aug;21(4):437 )
STUDY
● SUMMARY
current opioid use associated with increased invasive Streptococcus pneumoniae infection
CASE-CONTROL STUDY: Ann Intern Med 2018 Mar 20;168(6):396
Details
⚬ based on nested case-control study

⚬ 221,096 persons ≥ 5 years old enrolled in Medicaid program who did not have invasive pneumococcal
disease and no contraindications to opioid prescription (documented by filling ≥ 1 opioid prescription)
were assessed
⚬ 1,233 patients who developed invasive S. pneumoniae infection were compared to 24,399 age-, index
date-, and residence-matched controls
⚬ among patients with invasive S. pneumoniae infection, 73.9% had pneumonia, and remainder had
meningitis, or primary or secondary bacteremia
⚬ current use defined as opioid prescription overlapping with index date
⚬ remote use defined as last opioid prescription > 182 days before index date
⚬ patients with invasive S. pneumoniae infection were more likely to be current opioid users compared to
controls (adjusted odds ratio 1.62, 95% CI 1.36-1.92)
⚬ associations were strongest for long-acting opioids, high potency opioids, and use of ≥ 50 morphine
milligram equivalents/day
⚬ Reference - Ann Intern Med 2018 Mar 20;168(6):396 , editorial can be found in Ann Intern Med 2018
Mar 20;168(6):444
STUDY
● SUMMARY
stress-related disorders associated with increased risk of meningitis
COHORT STUDY: BMJ 2019 Oct 23;367:l5784 | Full Text
Details
⚬ based on retrospective cohort study

⚬ 144,919 Swedish-born patients with stress-related disorders identified from 1987 to 2013 were
evaluated in 2 separate analyses
– 103,072 patients were compared to 184,612 siblings without stress-related disorders
– 144,919 patients were compared to 1,449,190 matched persons from general population without
stress-related disorders
⚬ among patients with stress-related disorders, 8% had posttraumatic stress disorder (PTSD), 46% had
acute stress disorder, and 46% had adjustment disorder or other stress reaction
⚬ incidence per 1,000 person-years comparing any stress disorder vs. no stress disorder
– in sibling-based analysis
● meningitis 0.15 vs. 0.09 (hazard ratio [HR] 1.63, 95% CI 1.23-2.16)
● life-threatening infections 2.7 vs. 1.69 (HR 1.47, 95% CI 1.37-1.58)
– in population-based analysis
● meningitis 0.16 vs. 0.08 (HR 1.7, 95% CI 1.43-2.02)

● life-threatening infections 2.9 vs. 1.34 (HR 1.58, 95% CI 1.51-1.65)
⚬ comparing PTSD vs. no PTSD, risk of meningitis was significantly increased in population-based analysis,
but not in sibling-based analysis
⚬ Reference - BMJ 2019 Oct 23;367:l5784 full-text
Etiology and Pathogenesis

Causes
● causes in immunocompetent adults 5
⚬ 80% caused by
– Streptococcus pneumoniae
– Neisseria meningitidis
⚬ other organisms
– Listeria monocytogenes
– staphylococci
⚬ < 10% of cases due to gram-negative bacilli including
– Escherichia coli
– Klebsiella
– Enterobacter
– Pseudomonas aeruginosa
● most common pathogens in immunocompromised adults 5
⚬ S. pneumoniae
⚬ L. monocytogenes
⚬ gram-negative bacilli such as P. aeruginosa
● mixed bacterial infection in < 1% of all cases of community-acquired bacterial meningitis 5
● common pathogens in neurosurgical infections 1 , 5
⚬ Staphylococcus aureus or coagulase negative staphylococci, including methicillin-resistant strains

⚬ gram-negative bacilli (especially Enterobacteriaceae)
● other bacteria 1
⚬ Haemophilus influenzae
– significant cause of meningitis (especially in infants and children) before widespread immunization
– incidence of nontype b strains (types e and f) has increased
⚬ Streptococcus suis
– occurs in parts of Asia, especially Vietnam and Thailand

– increased risk in people with close contact to pigs or pork
– > 50% of survivors develop some degree of hearing loss
STUDY
● SUMMARY
Streptococcus pneumoniae most common cause of bacterial meningitis in United States in 2010
COHORT STUDY: Lancet Infect Dis 2014 Sep;14(9):813
Details
⚬ based on analysis of HealthCare Cost Utilization Project network database records from 1997 to 2010
⚬ 50,822 patients hospitalized with bacterial meningitis evaluated
⚬ incidence by identified bacterial pathogen in 2010
– 0.306 per 100,000 people for Streptococcus pneumoniae

– 0.123 per 100,000 people for Neisseria meningitidis
– 0.058 per 100,000 people for Haemophilus influenzae
– 0.114 per 100,000 people for staphylococcal species
– 0.127 per 100,000 people for gram-negative bacteria
⚬ Reference - Lancet Infect Dis 2014 Sep;14(9):813
STUDY
● SUMMARY
S. pneumoniae and N. meningitidis are most common organisms associated with community-acquired
acute bacterial meningitis, but organism frequency varies by age group
COHORT STUDY: N Engl J Med 2004 Oct 28;351(18):1849 | Full Text

COHORT STUDY: Arch Intern Med 1997 Feb 24;157(4):425
COHORT STUDY: J Am Geriatr Soc 2006 Oct;54(10):1500
Details
⚬ based on 3 population-based cohort study

⚬ 671 patients > 16 years old with 696 episodes of community-acquired acute bacterial meningitis
confirmed by cerebrospinal fluid (CSF) cultures from 1998 to 2002 in the Netherlands were assessed
– pathogens isolated
● 51% S. pneumoniae
● 37% N. meningitidis
● 4% L. monocytogenes
● 8% other bacteria
– Reference - N Engl J Med 2004 Oct 28;351(18):1849 full-text , correction can be found in N Engl J
Med 2005 Mar 3;352(9):950, commentary can be found in N Engl J Med 2005 Feb 3;352(5):512 , Am
Fam Physician 2005 Sep 15;72(6):1113
⚬ 127 patients ≥ 16 years old with 132 cases of acute bacterial meningitis in Iceland from 1975 to 1994
were assessed
– most common causative agents were
● N. meningitidis in 56%
● S. pneumoniae in 20%
● L. monocytogenes in 6%
● H. influenzae in 5%
– in subgroup analyses by age,
● in patients aged 16-20 years, N. meningitidis was responsible for 93% of infections
● in patients ≥ 45 years old, causative agent was N. meningitidis in 25%, S. pneumoniae in 38%, and L.
monocytogenes in 14%
– Reference - Arch Intern Med 1997 Feb 24;157(4):425
⚬ patients ≥ 16 years old with 696 episodes of community-acquired acute bacterial meningitis confirmed
by CSF culture from 1998 to 2002 in Dutch Meningitis Cohort Study were evaluated
– culture results by age group
● in 257 patients ≥ 60 years old
⚬ S. pneumoniae in 68%
⚬ N. meningitidis in 14%
⚬ L. monocytogenes in 7%
● in 439 patients aged 17-59 years
⚬ S. pneumoniae in 40%
⚬ N. meningitidis in 50%
⚬ L. monocytogenes in 3%
– Reference - J Am Geriatr Soc 2006 Oct;54(10):1500 , commentary can be found in J Am Geriatr Soc
2007 Apr;55(4):628
Pathogenesis
● although much of the pathogenesis of community-acquired bacterial meningitis is not well understood,
four main steps have been described 1 , 3

⚬ colonization - bacteria that cause meningitis often first colonized respiratory tract mucous membranes
⚬ invasion into blood stream - pathogens may enter the bloodstream by traversing through cells
(transcellularly) or between cells (pericellularly)
⚬ survival in bloodstream - immune evasion is required for bloodstream survival
⚬ entry into subarachnoid space - most commonly occurs following bacteremia, but direct entry into
central nervous system may be possible
● mechanisms of central nervous system entry 1 , 5
⚬ in patients with community acquired bacterial meningitis
– many bacteria associated with bacterial meningitis are capable of nasopharyngeal colonization,
which can lead to blood stream invasion and bacteremia
– only certain bacteria can cross the blood-brain barrier and enter the subarachnoid space, such as
Neisseria meningitidis and Streptococcus pneumoniae
– direct spread to central nervous also likely to occur, as suggested by high incidence of pneumococcal
meningitis in patients with sinusitis and otitis media
– direct entry through dural defects also possible
⚬ nosocomial meningitis occurs when surgical manipulation or penetration of the subarachnoid space
results in inoculation of pathogenic organisms
● bacterial multiplication in subarachnoid space ultimately causes release of proinflammatory mediators,
breakdown of blood-brain barrier, and recruitment of leukocytes to subarachnoid space 1 , 5
● inflammation and neurological damage is caused by combination of host and bacterial factors 1 , 5
⚬ bacterial invasion of subarachnoid space results in release of pro-inflammatory cytokines and

consequent inflammation of subarachnoid space (which may result in fever and headache)
⚬ cytokines and other chemical mediators induce subpial encephalopathy (which may result in
meningismus, confusion, reduced cerebrospinal fluid [CSF] glucose)
⚬ breakdown in blood-brain barrier and transendothelial migration of leukocytes can lead to cerebral
edema (which may result in impaired consciousness, elevated CSF pressure, increased CSF protein, focal
symptoms)
⚬ impaired cerebral blood flow, rising intracranial pressure, and vasculitis may cause obtundation,
seizures, focal neurologic symptoms, and signs (such as cranial nerve palsies)
⚬ focal neuronal injury may cause paralysis, cognitive impairment, coma, and possibly death in untreated
cases
● higher levels of inflammatory cytokines (common in pneumococcal meningitis) could result in worse
prognosis 1
History and Physical

History
Chief concern (CC)
● patients may have 1 , 2 , 3 , 5
⚬ altered mental status

⚬ fever
⚬ headache
⚬ neck stiffness
⚬ lethargy
⚬ nausea and vomiting
⚬ rash
● in a small percentage of cases, fulminant bacterial meningitis may occur with sudden onset, rapid
deterioration, abrupt cerebral edema, intracranial hypertension, and brain herniation (Pediatr Infect Dis J
2014 Feb;33(2):204 )
STUDY
● SUMMARY
classic triad of fever, neck stiffness, and altered mental status has low sensitivity for bacterial
meningitis in adults
COHORT STUDY: Lancet Infect Dis 2016 Mar;16(3):339
Details
⚬ based on 3 cohort studies

⚬ classic triad defined as
– fever
– neck stiffness
– alteration in mental status
⚬ cohort of 1,412 Dutch patients with community-acquired acute bacterial meningitis confirmed by
cerebrospinal fluid (CSF) culture or combination of positive CSF PCR or antigen test plus ≥ 1 finding
predictive of bacterial meningitis

– 41% had classic triad
– 74% had fever ≥ 38 degrees C (100.4 degrees F)
– 74% had neck stiffness
– 71% had altered mental status
⚬ Reference - Lancet Infect Dis 2016 Mar;16(3):339 , commentary can be found in Lancet Infect Dis 2016
Mar;16(3):271 ; consistent results found
⚬ prospective cohort of 696 Dutch patients with community-acquired acute bacterial meningitis confirmed
by cerebrospinal fluid cultures
– 95% had at least 2 of 4 symptoms of headache, fever, neck stiffness, and altered mental status
– 44% had classic triad
– classic triad more likely to be present in patients with pneumococcal meningitis vs. in patients with
meningococcal meningitis (58% vs. 27%, p < 0.001)
– Reference - N Engl J Med 2004 Oct 28;351(18):1849 full-text , commentary can be found in N Engl
J Med 2005 Feb 3;352(5):511
⚬ consistent results found in a cohort of 132 adult patients in Iceland (Arch Intern Med 1997 Feb
24;157(4):425 )
● in elderly patients
⚬ classic triad more common in elderly patients ≥ 60 years old (58% of 257 episodes) than in patients aged
17-59 years (36% of 439 episodes) (J Am Geriatr Soc 2006 Oct;54(10):1500 ), commentary can be found
in J Am Geriatr Soc 2007 Apr;55(4):628
⚬ presentation may be insidious in elderly patients with lethargy, obtundation, absence of fever, and
variable signs of meningeal irritation (Arch Intern Med 1989 Jul;149(7):1603 )
History of present illness (HPI)
● early signs and symptoms 1 , 2 , 5
⚬ fever
⚬ headache
⚬ lethargy
⚬ nausea and vomiting
⚬ confusion
⚬ altered consciousness
● intermediate signs and symptoms 5
⚬ obtundation
⚬ seizures
⚬ focal neurologic symptoms
● late signs and symptoms 5
⚬ paralysis
– unilateral or bilateral hemiparesis

– weakness of eye movements
– paraparesis or quadriparesis with corresponding sensory signs suggesting spinal cord involvement
⚬ cognitive impairment
– depression
– chronic fatigue
⚬ coma
Physical
General physical
● check vital signs for evidence of sepsis or shock 3
● in elderly patients, presentation may be insidious with lethargy, obtundation, no fever, and variable signs of
meningeal irritation (Arch Intern Med 1989 Jul;149(7):1603 )
STUDY
● SUMMARY
normal mental status and absence of fever and neck stiffness may rule out bacterial meningitis in
immunocompetent adults
SYSTEMATIC REVIEW: JAMA 1999 Jul 14;282(2):175
Details
⚬ based on systematic review

⚬ systematic review of 10 studies of clinical exam in diagnosis of objectively confirmed bacterial or viral
meningitis in immunocompetent adults
⚬ presence of any of fever, neck stiffness, or altered mental status has 99%-100% sensitivity for meningitis
⚬ absence of fever, neck stiffness, and altered mental status effectively eliminates meningitis
⚬ pooled sensitivity for individual findings was
– 85% for fever (733 patients)

– 70% for neck stiffness (733 patients)
– 67% for altered mental status (811 patients)
– 46% for all 3 of fever/neck stiffness/altered mental status (3 studies with 426 patients)
– 23% for focal neurologic findings (794 patients)
– 22% for rash (3 studies with 446 patients)
⚬ among patients with fever and headache, jolt accentuation of headache had 97%-100% sensitivity and
54%-60% specificity in 1 study of 34 patients
⚬ Reference - JAMA 1999 Jul 14;282(2):175 , commentary can be found in JAMA 2000 Feb 23;283(8):1004
, Ann Emerg Med 2004 Jul;44(1):71 , Evidence-Based Medicine 2000 Jan-Feb;5(1):28, summary can
be found in Am Fam Physician 2000 Jan 15;61(2):493 (correction can be found in Am Fam Physician
2000 Aug 1;62(3):508)
Skin
● rapidly evolving petechial rash (purpura or ecchymosis) 3 , 5
⚬ also called purpura fulminans

⚬ more common in meningococcal disease
Image 1 of 4
Purpura fulminans
Purpura fulminans is a severe complication of meningococcal disease. Meningococcal-induced

microvascular thrombosis and disseminated intravascular coagulation produces widespread
hemorrhage into the skin, evolving into painful purple papules which may become necrotic, with
the formation of bullae and vesicles.
Used with permission from the American College of Physicians.
HEENT
● papilledema 3
● associated infections that may serve as source of infection such as 1
⚬ sinus tenderness
⚬ acute otitis media
⚬ posterior auricular lymphadenopathy as seen with mastoiditis
Neck
● neck stiffness, meningismus may be early signs 1 , 3 , 5
Neuro
● assess for focal neurologic deficits, such as cranial nerve palsies or paralysis 3 , 4 , 5
● assess for mental status changes, which may range from mild cognitive impairment or altered
consciousness, to obtundation and coma 4 , 5
● focal or generalized seizures can occur 5
● individual meningeal signs do not appear to be reliable for diagnosing or ruling out meningitis (JAMA 1999
Jul 14;282(2):175 )
⚬ signs of meningeal irritation
– nuchal rigidity
– Brudzinski sign - passive flexion of neck elicits involuntary flexing of knees in supine patient
– Kernig sign - resistance or pain to knee extension following 90-degree hip flexion by clinician in
supine patient
Image 2 of 4
Brudzinski sign
Provocative maneuver assessing for signs of meningitis. (A) Patient lying supine; (B) neck passively
flexed by examiner; (C) patient spontaneously flexes hips and knees to mitigate pain from meningeal
stretching; Brudzinski sign is therefore positive.
Copyright© 2021 EBSCO Information Services.
STUDY
⚬ SUMMARY
meningeal signs do not appear to be reliable for diagnosing or ruling out meningitis DynaMed Level 2
DIAGNOSTIC COHORT STUDY: Clin Infect Dis 2002 Jul 1;35(1):46 | Full Text
Details
– based on diagnostic cohort study with tests under investigation not performed in all patients
– prospective study of meningeal signs in 301 patients > 16 years old with symptoms of meningitis in
single emergency department over 4 years
● 297 patients had lumbar puncture (4 patients excluded based on computed tomography results)
● 80 (27%) had diagnosis of meningitis based on ≥ 6 white blood cells/mL cerebrospinal fluid
– 236 patients were examined for Brudzinski's sign and 237 patients were examined for Kerning sign
and
Table 1. Diagnostic Accuracy of Meningeal Signs
Nuchal Rigidity Kernig Sign Brudzinski Sign
Sensitivity 30% 5% 5%
Specificity 68% 95% 95%
Nuchal Rigidity Kernig Sign Brudzinski Sign
Positive 26% 27% 27%

predictive value
Negative 73% 72% 72%

predictive value
– likelihood ratios for all 3 signs were about 1 (positive likelihood ratios 0.94-0.97) which means that
neither positive nor negative findings change the likelihood of the patient having meningitis
– Reference - Clin Infect Dis 2002 Jul 1;35(1):46 full-text , summary can be found in Am Fam
Physician 2002 Nov 15;66(10):1952 , commentary can be found in Clin Infect Dis 2003 Jan
1;36(1):125
Diagnosis
Making the diagnosis
● diagnosis of bacterial meningitis may be difficult as symptoms are similar in many other illnesses 1
● once there is clinical suspicion of acute bacterial meningitis, immediately obtain blood and CSF samples for
culture and initiate empiric antimicrobial therapy 4

⚬ delays in blood culture or lumbar puncture may result in delayed diagnosis
⚬ if diagnosis and initiation of therapy are delayed, risk of morbidity and mortality increases
⚬ do not delay empiric therapy if lumbar puncture delayed
● diagnosis based on clinical suspicion and identification of causative bacteria from any of 3
⚬ cerebrospinal fluid (CSF) cultures (positive in up to 80% of patients not pretreated with antibiotics)
⚬ CSF Gram stain (identifies causative organism in 50%-90% of patient)
⚬ CSF polymerase chain reaction (PCR) for specific pathogens
⚬ CSF latex agglutination for specific pathogens
⚬ blood cultures (positive in 50%-90% in patients no pretreated with antibiotics and 30%-70% in patients
receiving pretreatment)
● Centers for Disease Control and Prevention/National Healthcare Safety Network (CDC/NHSN) surveillance
definition of meningitis or ventriculitis
⚬ patient must meet ≥ 1 of following criteria
– organism identified from CSF by culture or nonculture-based testing method, performed for clinical
diagnosis or treatment, not surveillance
– in patients > 1 year old, both of following criteria
● ≥ 2 of following without other cause
⚬ fever (> 38 degrees C [100.4 degrees F]) or headache

⚬ meningeal signs
⚬ cranial nerve signs
● ≥ 1 of following
⚬ increased white cells, elevated protein, and decreased glucose in CSF

⚬ organism on Gram stain of CSF
⚬ organism identified from blood by culture or nonculture-based testing method, performed for
clinical diagnosis or treatment, not surveillance
⚬ diagnostic single antibody titer (IgM) or 4-fold increase in paired sera (IgG) for organism
⚬ Reference - CDC/NHSN surveillance definitions for specific types of infections (CDC/NHSN 2018 Jan PDF
)
● Infectious Diseases Society of America (IDSA) recommendations for diagnosis of healthcare-associated
ventriculitis and meningitis in patients with recent neurosurgery or head trauma 2

⚬ new headache, fever, seizures, worsening mental status, and/or evidence of meningeal irritation suggest
ventriculitis or meningitis (IDSA Strong recommendation, Moderate-quality evidence)
⚬ consider central nervous system infection in patients with fever and no other clear source of infection
(IDSA Weak recommendation, Low-quality evidence)
⚬ symptoms of infection plus positive CSF culture and CSF pleocytosis indicate ventriculitis or meningitis
(IDSA Strong recommendation, High-quality evidence)
⚬ elevated CSF protein concentration plus hypoglycorrhachia suggest ventriculitis or meningitis (IDSA
Weak recommendation, Low-quality evidence)
Differential diagnosis
● causes of aseptic meningitis, including
⚬ viral meningitis
– enteroviral meningitis
– arbovirus (mosquito borne), such as West Nile virus or Eastern equine encephalitis virus
– herpes viruses, such as herpes simplex virus or varicella-zoster virus
– acute HIV infection
⚬ Lyme disease with central nervous system involvement

⚬ neurosyphilis
⚬ tuberculous meningitis
⚬ leptospirosis
⚬ fungal meningitis
⚬ drug-induced meningitis due to
– nonsteroidal anti-inflammatory drugs (NSAIDs)

– antimicrobials such as
● co-trimoxazole (trimethoprim-sulfamethoxazole)
● amoxicillin
● cephalosporins
● isoniazid
– intrathecal injections
⚬ inflammatory (noninfectious) conditions such as
– Behcet disease
– systemic lupus erythematosus (SLE)
– sarcoidosis
– migraine
⚬ malignancy
⚬ chemical meningitis (such as after subarachnoid hemorrhage, leaking craniopharyngioma, or IV
immunoglobulin therapy)
⚬ partially treated bacterial meningitis
⚬ parameningeal foci of infection, such as
– sinusitis
– mastoiditis
– osteomyelitis
– subdural empyema
– spinal epidural abscess
– brain abscess
⚬ see Aseptic meningitis for details
● stroke
● rapidly evolving petechial rash (purpura or ecchymosis) may indicated disseminated intravascular
coagulation (DIC) or occur with other bacterial and viral infections including 3 , 5
⚬ Staphylococcus aureus
⚬ Rocky Mountain spotted fever
⚬ Capnocytophaga (Clin Neurol Neurosurg 2007 Jun;109(5):393 )
⚬ Vibrio vulnificus (Clin Infect Dis 2011 Mar 15;52(6):788 full-text )
⚬ enteroviruses (see Enteroviral meningitis)
Testing overview
● perform blood tests including
⚬ blood cultures
⚬ complete blood counts with differential
⚬ glucose
⚬ consider C-reactive protein or procalcitonin level
● perform lumbar puncture to evaluate cerebrospinal fluid (CSF)
⚬ opening pressure
⚬ cell counts with differential
⚬ glucose and protein
⚬ STAT Gram stain and bacterial cultures
⚬ herpes simplex virus (HSV) by polymerase chain reaction (PCR) if noted CSF pleiocytosis
● obtain specimens for cultures before starting antibiotics (obtain blood culture before starting antibiotics if
lumbar puncture is delayed) 2
● head computed tomography (CT) may be indicated prior to lumbar puncture in specific patients
Blood tests
● Infectious Diseases Society of America (IDSA) guideline for management of bacterial meningitis
recommendations for blood testing include 4

⚬ blood cultures - collect blood sample for culture emergently before starting antimicrobial treatment
– 53% prevalence of bacteremia in cohort of 118 adults with acute bacterial meningitis (QJM 2005
Apr;98(4):291 full-text )
⚬ white blood cell count
⚬ blood glucose (for correlation with cerebrospinal fluid [CSF] level)
⚬ C-reactive protein (CRP) concentration
– CRP may help distinguish bacterial from viral meningitis, but is not diagnostic and should not be used
alone to determine need for antibiotics
– normal CRP has high-negative predictive value for bacterial meningitis (IDSA Grade B-II) which may
be helpful if considering withholding antibiotics in patient with negative CSF Gram stain but CSF
findings consistent with meningitis
● IDSA recommendations for blood testing to diagnose healthcare-related ventriculitis and meningitis in
patients with neurosurgery or head trauma 2

⚬ blood cultures should be obtained prior to initiation of antimicrobial therapy (IDSA Strong
recommendation, Moderate-quality evidence)
⚬ elevated serum procalcitonin levels may help differentiate CSF abnormalities due to surgery or
intracranial hemorrhage from those due to bacterial meningitis (IDSA Weak recommendation, Low-
quality evidence)
Imaging studies
recommendations for head computed tomography (CT) 4

⚬ indications for head CT prior to lumbar puncture (IDSA Grade B-II)
– immunocompromised
– history of central nervous system disease (such as stroke, mass lesion, focal infection)
– papilledema
– focal neurologic deficit including
● fixed dilated pupil

● gaze palsy
● weakness of extremity
● visual field cut
– new onset seizure ≤ 1 week prior to presentation

– abnormal level of consciousness
⚬ consider providing antibiotics prior to head CT as diagnosis may be delayed
Image 3 of 4
Computed tomography (CT) of the brain
CT of the brain showing diffuse swelling in a patient with meningococcal meningitis.
Contributed by Richard A Murphy, M.D. Copyrighted by Partners Healthcare System Inc. and available from the
Partners Infectious Disease Images website: http://www.idimages.org. Reproduced with permission of The General
Hospital Corporation. The image may NOT be reproduced for any other purpose without permission.
● IDSA recommendations for imaging in patients with suspected healthcare-related ventriculitis and
meningitis in patients with neurosurgery or head trauma 2

⚬ perform neuroimaging in patients with suspected healthcare-associated ventriculitis and meningitis
(IDSA Strong recommendation, Moderate-quality evidence)
⚬ perform magnetic resonance imaging (MRI) with gadolinium enhancement and diffusion-weighted
imaging to detect abnormalities in patients with healthcare-associated ventriculitis and meningitis (IDSA
Strong recommendation, Moderate-quality evidence)
● American College of Radiology (ACR) Appropriateness Criteria for intracranial infections can be found in
Radiology 2000 Jun;215 Suppl:535
Cerebrospinal fluid (CSF) analysis

Lumbar puncture (LP) indications, contraindications and timing
● LP indicated in all patients with suspicion of meningitis, unless contraindicated 1
● timing of LP 2 , 5
⚬ recommendation to delay LP
– for 30 minutes in adults with short, convulsive seizures or not performing LP in adults with prolonged
seizures (assuming no contraindications on head computed tomography [CT])
– in patients with signs and symptoms of raised intracranial pressure or increased risk of cerebral
herniation following LP (EFNS Level I-A)
⚬ consider starting antibiotics if LP delayed or head CT required before LP
⚬ performing lumbar puncture without CT scan is reasonable if patients do not meet any of the following
– patients with new-onset seizures

– immunocompromise
– signs of space-occupying lesions (papilledema or focal neurologic signs, not including cranial nerve
palsy)
– severe impairment of consciousness
● contraindications for LP in cases of suspected bacterial meningitis 3
⚬ absolute contraindications - LP puncture not recommended
– signs of increased intracranial pressure
● decerebrate posturing
● papilledema
– skin infection at site of lumbar puncture

– CT or magnetic resonance imaging evidence of
● obstructive hydrocephalus
● cerebral edema
● herniation
⚬ relative contraindications - therapy or investigations indicated prior to LP
– sepsis
– hypotension (systolic blood pressure < 100 mm Hg, diastolic blood pressure < 60 mm Hg)
– coagulation disorders including
● platelet count < 50,000/mm3

● warfarin therapy
● disseminated intravascular coagulopathy
– focal neurologic lesions (risk of brain herniation)
● posterior fossa lesion suspected

● expanding masses including
⚬ brain abscess
⚬ necrotic temporal lobe (herpes simplex encephalitis)
⚬ subdural empyema
– Glasgow coma score < 10

– seizures
– severe immunodeficiency (such as HIV)
● repeat CSF analysis indicated in certain situations 1 , 2
⚬ unclear diagnosis
⚬ partially treated patients
⚬ poor clinical response without explanation
⚬ gram-negative bacillary cause of meningitis
⚬ patients not responding following 48 hour of antimicrobial treatment and dexamethasone
⚬ meningitis in patient with CSF shunt
⚬ need for intrathecal antibiotics
Lumbar puncture (LP) technique
● contraindications include increased intracranial pressure due to mass lesion, local infection at puncture site
● computed tomography may be unnecessary before LP in absence of clinical risk factors
● positioning of patient important to success of procedure
● important to determine what testing and volume of CSF is needed BEFORE performing LP
● interventions associated with reduced risk of post-LP headache
⚬ use of atraumatic needles

⚬ smaller needle diameter
⚬ bevel orientation parallel to dural fibers
⚬ reinsertion of stylet before needle removal
● bedrest for 4 hours following LP does not reduce risk for post-LP headache
● see Lumbar puncture (LP) for details
Recommendations for diagnostic testing

Infectious Diseases Society of America (IDSA)
● IDSA guideline for management of bacterial meningitis recommendations for diagnostic CSF testing 4
⚬ glucose
⚬ protein
⚬ white blood cell count and differential
⚬ culture
⚬ Gram stain in all patients with suspected meningitis (IDSA Grade A-III)
⚬ polymerase chain reaction (PCR)
– broad-based PCR may be useful to exclude bacterial meningitis or influence decisions to start or
discontinue antibiotics (IDSA Grade B-II)
– enteroviral PCR may reduce length of hospital stay, use of antibiotics, and ancillary diagnostic testing
(IDSA Grade B-II)
⚬ lactate concentration
– not recommended for patients with suspected community-acquired bacterial meningitis (IDSA Grade
D-III)
– in postoperative neurosurgical patient, consider initiation of empirical antimicrobial therapy for CSF
lactate concentration ≥ 4 mmol/L (36 mg/dL), pending other study results (IDSA Grade B-II)
● IDSA recommendations for diagnostic CSF testing in patients with suspected healthcare-related ventriculitis
and meningitis in patients with neurosurgery or head trauma 2

⚬ obtain CSF culture before initiation of antimicrobial therapy (IDSA Strong recommendation, Moderate-
quality evidence)
– CSF culture is most important test to confirm diagnosis (IDSA Strong recommendation, High-quality
evidence)
– if initial CSF cultures are negative, extend incubation for ≥ 10 days to allow growth of slow-growing
organisms such as Propionibacterium acnes (IDSA Strong recommendation, High-quality evidence)
– healthcare-associated ventriculitis and meningitis cannot be excluded if CSF culture is negative in a
patient with prior antimicrobial therapy (IDSA Strong recommendation, Moderate-quality evidence),
and cultures should be repeated if infection is likely
– indication of infection
● symptoms of infection plus positive CSF culture and CSF pleocytosis (IDSA Strong
recommendation, High-quality evidence)
● isolation of Staphylococcus aureus or aerobic Gram-negative bacilli (IDSA Strong recommendation,
Moderate-quality evidence)
● CSF culture with growth of fungal pathogens (IDSA Strong recommendation, Moderate-quality
evidence)
● elevated CSF protein concentration plus hypoglycorrhachia suggests ventriculitis or meningitis
(IDSA Weak recommendation, Low-quality evidence)
– growth of pathogen commonly considered a contaminant (such as coagulase-negative
staphylococcus) in enrichment broth only or 1 of multiple cultures plus normal CSF and no fever is
not indicative of ventriculitis or meningitis (IDSA Strong recommendation, Low-quality evidence)
– if CSF culture from a single sample is positive for multiple organisms and patient has no symptoms of
infection or CSF pleocytosis, consider sample contamination (IDSA Weak recommendation, Low-
quality evidence)
⚬ other CSF testing
– consider CSF Gram stain, but a negative result cannot exclude infection, especially in patients with
prior antimicrobial therapy (IDSA Strong recommendation, Moderate-quality evidence)
– if fungal ventriculitis or meningitis is suspected, obtain beta-D-glucan and galactomannan
measurements (IDSA Strong recommendation, Moderate-quality evidence)
– consider assessing CSF lactate and procalcitonin levels, elevated levels of either or both may suggest
bacterial ventriculitis or meningitis (IDSA Weak recommendation, Moderate-quality evidence)
– elevated serum procalcitonin levels may help differentiate CSF abnormalities due to surgery or
quality evidence)
– consider polymerase chain reaction (PCR) or other nucleic acid amplification tests to identify infecting
pathogen and allow faster diagnosis (IDSA Weak recommendation, Low-quality evidence)
– consider CSF cell count, glucose and protein tests, but these may have limited utility
● abnormalities may not reliably indicate infection and normal values may not reliably exclude
infection (IDSA Weak recommendation, Moderate-quality evidence)
● abnormalities may be secondary to neurosurgery or existing conditions
European Federation of Neurological Societies (EFNS) guideline on management of community-

acquired bacterial meningitis
● EFNS recommendations for diagnostic testing 5
⚬ perform lumbar puncture as soon as possible if no clinical contraindications (EFNS Level III-C)
⚬ postpone diagnostic lumbar puncture in patients with signs and symptoms of raised intracranial
pressure or increased risk of cerebral herniation following lumbar puncture (EFNS Level I-A)
Cerebrospinal fluid (CSF) test findings
● opening pressure typically elevated in patients with bacterial meningitis (compared to normal opening
pressure of 10-20 cm CSF) 2
● CSF may appear cloudy, turbid, or purulent if significant concentrations of white or red blood cells, bacteria,
or protein present 1
● white blood cell count and differential
⚬ in patients with bacterial meningitis, typically > 1,000 cells/mcL (> 90% of patients present with > 100
cells/mcL) 3
⚬ neutrophil predominance usually present (80%-95%) 1 , 3
⚬ lymphocyte predominance may be observed, but typically occurs in viral meningitis 1
⚬ normal or marginally elevated CSF white cell counts occur in 5%-10% of patients with bacterial
meningitis and are associated with adverse outcomes (N Engl J Med 2004 Oct 28;351(18):1849 full-text
), correction can be found in N Engl J Med 2005 Mar 3;352(9):950, commentary can be found in N Engl
J Med 2005 Feb 3;352(5):512-5
● glucose
⚬ concentration usually ≤ 45 mg/dL (2.5 mmol/L) 3
⚬ CSF glucose levels < 40% of simultaneously measured serum glucose 3
● protein
⚬ elevated protein concentration (> 50 mg/dL) 3
⚬ mean concentration in bacterial meningitis 418 mg/dL (4.18 g/L)
– may be adjusted for increased protein caused by traumatic tap (subtract 1 mg/dL [0.01 g/L] protein
per 1,000 red blood cells/mm3)
– reference range may vary by laboratory
– Reference - Am Fam Physician 2003 Sep 15;68(6):1103 full-text
Table 2. Cerebrospinal Fluid Profiles
Investiga Normal Bacterial Viral/ADE Tubercul Fungal

tion M osis
Opening 10-20 cm High Normal/hig High High/very

pressure (50-180 h high
mm H2O)
Color Clear Cloudy Clear/cloud Cloudy/y Clear/cloud

y ellow y
Cells < 5 mm3 1,000-50,000 50-1,000 50-500 0-1,000

mm3 mm3 mm3 mm3
Differenti Mononucle Neutrophilic* Mononucle Mononuc Mononucle

al ar ar lear ar
Glucose > 45 mg/dL < 40 mg/dL > 45 mg/dL < 45 > 45 mg/dL
(2.5 (2.2 mmol/L) (2.5 mg/dL (2.5
mmol/L) mmol/L) (2.5 mmol/L)
mmol/L)
Protein < 45 mg/dL 100-500 < 200 50-300 > 45 mg/dL

mg/dL mg/dL = mg/dL
Investiga Normal Bacterial Viral/ADE Tubercul Fungal

tion M osis
Abbreviation: ADEM, acute disseminated encephalomyelitis.
* Neutrophils may predominate early in the course of
viral infections and may persist in cases of West Nile virus,
tick-borne encephalitis, and Eastern equine encephalitis.
Reference - Tunkel AR. Approach to the patient with
central nervous system infection. In: Mandell GL, Bennett JE,
Dolin R, eds. Mandell, Douglas, and Bennett’s Principles and
Practice of Infectious Diseases. 7th ed. Elsevier Health
Sciences; 2009.
J Infect 2012 Apr;64(4):347 .
● procalcitonin 2
⚬ elevated serum procalcitonin levels may help differentiate CSF abnormalities due to surgery or
quality evidence)
⚬ consider assessing CSF lactate and procalcitonin levels, elevated levels of either or both may suggest
bacterial ventriculitis or meningitis (IDSA Weak recommendation, Moderate-quality evidence)
● CSF lactate 2 , 4
⚬ develops during bacterial meningitis due to tissue anoxia but not routinely recommended
⚬ consider empiric antimicrobial treatment in postoperative neurosurgical patient if lactate level ≥ 4
mmol/L (36 mg/dL) (IDSA Grade B-II)
STUDY
⚬ SUMMARY
CSF lactate may be useful for diagnosis of bacterial meningitis in postneurosurgical patients
DynaMed Level 2
SYSTEMATIC REVIEW: BMC Infect Dis 2016 Sep 13;16:483 | Full Text
Details
– based on systematic review of studies without reliable reference standard

– systematic review of 5 studies evaluating CSF lactate for diagnosis of bacterial meningitis in 404
postneurosurgical patients
– reference standards varied between studies, but typically included positive CSF culture or Gram stain,
elevated CSF white blood cell count, and/or decreased glucose
– 130 patients (32%) had bacterial meningitis
– diagnostic performance of CSF lactate in pooled analyses of all studies
● sensitivity 92% (95% CI 85%-96%)

● specificity 88% (95% CI 84%-92%), result limited by significant heterogeneity
● positive likelihood ratio 7.7 (95% CI 3.94-15.05), result limited by significant heterogeneity
● negative likelihood ratio 0.11 (95% CI 0.06-0.19)
– Reference - BMC Infect Dis 2016 Sep 13;16:483 full-text
STUDY
⚬ SUMMARY
CSF lactate may help differentiate bacterial meningitis from viral meningitis DynaMed Level 2
DIAGNOSTIC COHORT STUDY: Eur J Clin Microbiol Infect Dis 2015 Oct;34(10):2049
Details
– based on diagnostic cohort study without reliable reference standard

– 61 patients with meningitis had evaluation of cerebrospinal fluid (CSF) parameters and microbiologic
testing
● assessed CSF parameters were leukocyte and neutrophil count, protein, glucose, and lactate
● microbiologic testing of CSF included Gram stain, bacterial culture, and bacterial and multiple viral
polymerase chain reaction (PCR) tests
● additional diagnostic procedures performed based on clinical presentation, including blood
serologies for viruses and bacteria
– 45 patients with microbiologically documented meningitis included in analysis
● 18 patients had bacterial meningitis

● 27 patients had viral meningitis
– diagnostic accuracy of CSF parameters for diagnosis of bacterial meningitis
● lactate > 3.5 mmol/L had sensitivity 100%, specificity 100%

● CSF glucose/blood glucose ratio < 0.35 had sensitivity 92%, specificity 100%
● neutrophils > 260 cells/mm3 had sensitivity 92%, specificity 100%
● leukocytes > 388 cells/mm3 had sensitivity 81%, specificity 92%
● protein > 1,934 mg/L had sensitivity 88%, specificity 100%
– Reference - Eur J Clin Microbiol Infect Dis 2015 Oct;34(10):2049
recommends repeat lumbar puncture (LP) for CSF analysis for patients not responsive to antimicrobial
therapy after 48 hours (IDSA Grade A-III) 4
Detection of specific organisms in cerebrospinal fluid (CSF)
● microbiology tests to identify specific bacteria include 1 , 2 , 3
⚬ culture
⚬ Gram stain
⚬ counterimmunoelectrophoresis (CIE)
⚬ radioimmunoassay (RIA)
⚬ latex particle agglutination (LPA)
⚬ enzyme-linked immunosorbent assay (ELISA)
⚬ polymerase chain reaction (PCR)
● culture 2 , 3
⚬ CSF culture is most important test to confirm diagnosis (IDSA Strong recommendation, High-quality
evidence)
⚬ if initial CSF cultures are negative, extend incubation for ≥ 10 days to allow growth of slow-growing
organisms such as Propionibacterium acnes (IDSA Strong recommendation, High-quality evidence)
⚬ healthcare-associated ventriculitis and meningitis cannot be excluded if CSF culture is negative in a
patient with prior antimicrobial therapy (IDSA Strong recommendation, Moderate-quality evidence), and
cultures should be repeated if infection is likely
⚬ positive CSF cultures reported in 70%-85% of bacterial meningitis in patients not on antimicrobial
therapy
– pediatric data demonstrates that complete sterilization of CSF can occur within 2 hours for Neisseria
meningitidis and within 4 hours for Streptococcus pneumoniae (Pediatrics 2001 Nov;108(5):1169 ),
commentary can be found in Pediatrics 2002 Nov;110(5):1028
● Gram stain
⚬ identifies causative bacteria in about 50%-90% of patients with community-acquired bacterial meningitis
and has ≥ 97% specificity 3

⚬ Gram stain for diagnosis of bacterial meningitis 3
– sensitivity 60%-90%
– specificity ≥ 97%
⚬ likelihood of visualizing bacteria 4
– increased with cytospin techniques

– depends on pathogen
● 90% for S. pneumoniae

● 86% for Haemophilus influenzae
● 75% for N. meningitidis
● 50% for gram-negative bacilli
● about 33% for Listeria monocytogenes
– decreased by about 20% if antimicrobial given before lumbar puncture
Image 4 of 4
Gram stain of CSF
Gram stain showing abundant polymorphonuclear leukocytes and moderate numbers of gram-
negative diplococci (bacteria indicated by arrows). Abbreviation: CSF, cerebrospinal fluid.
Contributed by Richard A. Murphy. Copyrighted by Partners Healthcare System Inc and available from the
Partners Infectious Disease Images website: http://www.idimages.org. Reproduced with permission of the
General Hospital Corporation. The image may NOT be reproduced for any other purpose without permission.
● rapid diagnostic tests of CSF to determine bacterial etiology of meningitis
⚬ consider polymerase chain reaction (PCR) or other nucleic acid amplification tests to identify infecting
pathogen and allow faster diagnosis (IDSA Weak recommendation, Low-quality evidence)
– FilmArray Meningitis/Encephalitis (ME) Panel nucleic acid-based test FDA approved for simultaneous
detection of 14 pathogens from a single sample of cerebrospinal fluid in patients with suspected
meningitis or encephalitis
● simultaneously tests for 14 bacterial, viral and yeast pathogens
⚬ bacteria identified include Escherichia coli K1, H. influenzae, L. monocytogenes, N. meningitidis,

Streptococcus agalactiae, and S. pneumoniae
⚬ viruses identified include cytomegalovirus, enterovirus, herpes simplex virus 1, herpes simplex
virus 2, human herpesvirus 6, human parechovirus, and varicella zoster virus
⚬ yeasts identified include Cryptococcus neoformans and Cryptococcus gattii
● test does not detect all causes of central nervous system infections or provide information about
antimicrobial susceptibility
⚬ standard cerebrospinal fluid bacterial and fungal cultures should still be obtained due to
– possibility of false negative and false positive results

– need for bacterial growth for drug susceptibility testing following positive results
⚬ false negative results may occur when the concentration of organisms in the CSF specimen is
below the limit of detection
● Reference - FDA Press Release 2015 Oct 8
– perform herpes simplex virus (HSV) PCR, as HSV meningoencephalitis can present in a similar fashion
to bacterial meningitis (Clin Infect Dis 2008 Aug 1;47(3):303 full-text )
STUDY
– SUMMARY
PCR has potential to provide diagnosis of bacterial meningitis within 2 hours after lumbar
puncture DynaMed Level 2
COHORT STUDY: Clin Infect Dis 2003 Jan 1;36(1):40 | Full Text
Details
● based on prospective cohort study with blinding of reference standard or test under investigation
not stated
● 74 CSF specimens from 70 adults with suspected bacterial meningitis were tested by PCR
● 17 had positive CSF culture or Gram stain
● PCR assay had
⚬ 100% sensitivity
⚬ 98% specificity (1 false positive)
⚬ 94% positive predictive value
⚬ 100% negative predictive value
● Reference - Clin Infect Dis 2003 Jan 1;36(1):40 full-text
⚬ latex agglutination
– Infectious Diseases Society of America (IDSA) guideline for management of bacterial meningitis
recommendations for latex agglutination 4

● not recommended for routine use (IDSA Grade D-II) due to studies showing false-positives and
failure of positive result to alter clinical decisions
● may be useful for patients with negative CSF Gram stain (IDSA Grade C-II)
● may be most useful for patients pretreated with antibiotics who have negative Gram stain and
CSF culture results (IDSA Grade B-III)
● easy to perform, results available in ≤ 15 minutes
● reported sensitivities for detecting antigens for common meningeal pathogens
⚬ 78%-100% for H. influenzae type b

⚬ 67%-100% for S. pneumoniae
⚬ 69%-100% for S. agalactiae
⚬ 50%-93% for N. meningitidis
● positive latex agglutination test establishes diagnosis of bacterial meningitis caused by specific
pathogen, but negative test cannot rule out bacterial meningitis
STUDY
● SUMMARY
metagenomic next-generation sequencing (NGS) using cerebrospinal fluid samples may help diagnose
infectious meningitis and encephalitis DynaMed Level 2
DIAGNOSTIC COHORT STUDY: N Engl J Med 2019 Jun 13;380(24):2327
Details
⚬ based on diagnostic cohort study without independent reference standard

⚬ 204 hospitalized children and adults (mean age 39 years) with isolated meningitis (34.3%), encephalitis
(63.7%), or myelitis (2%) from multiple centers had cerebrospinal fluid sample assayed for bacterial, viral,
and fungal infections using metagenomic next-generation sequencing and conventional testing
– 86.3% had acute condition and 13.7% had acute exacerbation of chronic condition
– 48.5% were in intensive care unit and overall 30-day mortality was 11.3%
⚬ conventional testing included culture, PCR, serologic (antibody), and antigen testing of CSF and other
body fluids or tissues
⚬ reference standard was composite of conventional testing and orthogonal confirmatory testing of
positive tests for pathogens on metagenomic next-generation sequencing only
⚬ metagenomic next-generation sequencing testing performed at single center
⚬ 57 patients had total of 58 cerebrospinal fluid infections
– 26 infections (45%) detected by conventional testing only

– 13 infections (22%) detected by next-generation sequencing only
– 19 infections (33%) detected by both metagenomic NGS and conventional testing
⚬ infections detected by next-generation sequencing only included Nocardia farcinica, Candida tropicalis,
hepatitis E virus, Enterococcus faecalis, Enterobacter aerogenes, Streptococcus mitis, S. agalactiae, Epstein-
Barr virus, N. meningitidis, Echovirus 6, Echovirus 30, MW polyomavirus, and St. Louis encephalitis virus
⚬ extent of conventional diagnostic testing varied across hospitals, precluding unbiased estimates of
sensitivity and specificity so performance measures expressed as positive percent agreement and
negative percent agreement with composite reference standard
⚬ for detection of infectious meningitis and encephalitis
– metagenomic next-generation sequencing had
● 80% positive agreement

● 98.2% negative agreement
– conventional testing (including only culture, PCR, and antigen testing of CSF) had
● 67.5% positive agreement

● 99.4% negative agreement
⚬ Reference - PDAID trial (N Engl J Med 2019 Jun 13;380(24):2327 )
Other diagnostic testing
● body fluid cultures may be tested from 5
⚬ petechial fluid
⚬ sputum
⚬ secretions from oropharynx, nose, and ear
Management
Management overview
● bacterial meningitis is a neurologic emergency and appropriate therapy should be started as soon as
possible after diagnosis is considered to be likely
● treatment recommendations based on Infectious Diseases Society of America (IDSA) and European
Federation of Neurological Societies (EFNS) guidelines
● antibiotics
⚬ start antibiotic therapy as soon as possible after diagnosis of bacterial meningitis is suspected or proven
⚬ empiric antibiotics indicated if lumbar puncture delayed or purulent meningitis (even if negative
cerebrospinal fluid [CSF] Gram stain)
⚬ empiric antibiotic choice depends on likely pathogens (IDSA Grade A-III for drug combination)
– if organisms unknown use both
● vancomycin 15-20 mg/kg IV based on actual body weight (ABW) every 8-12 hours to maintain
serum trough levels 15-20 mg/L
● ceftriaxone (2 g IV every 12 hours or 4 g IV every 24 hours) or cefotaxime (8-12 g/day IV with
dosing every 4-6 hours)
– in adults > 50 years old or in immunocompromised patients, add ampicillin 2 g IV every 4 hours
– consider adding rifampin 600 mg every 24 hours when dexamethasone given
– give empiric acyclovir to all patients with meningoencephalitis pending outcome of diagnostic studies
(IDSA Grade A-III), with dosage 10 mg/kg IV every 8 hours (IDSA Grade A-I) (Clin Infect Dis 2008 Aug
1;47(3):303 full-text )
⚬ modify treatment if
– positive Gram stain implicates likely pathogen
– bacterial pathogen isolated from blood and/or CSF (consider susceptibility testing)
⚬ see IDSA Recommended Doses of Antibiotics once specific antibiotic selected

⚬ recommended duration of antibiotic therapy depends on organism isolated (IDSA Grade A-III)
⚬ selected patients may finish therapy with outpatient antibiotics after ≥ 6 days of inpatient antibiotic
therapy (IDSA Grade A-III)
● dexamethasone 0.15 mg/kg IV every 6 hours for 2-4 days with first dose 10-20 minutes before or with first
antibiotic dose
⚬ recommended in all adults with suspected or proven pneumococcal meningitis (IDSA Grade A-I)
⚬ may reduce mortality in patients with Streptococcus pneumoniae meningitis DynaMed Level 2
⚬ insufficient data to recommend use in adults with meningitis caused by other pathogens (IDSA Grade B-
III)
⚬ do not give to adults who have already received antibiotic therapy (IDSA Grade A-I)
● antimicrobial chemoprophylaxis recommended for close contacts if meningococcal disease
Medications
Antibiotics
Timing of antibiotic therapy
● Infectious Diseases Society of America (IDSA) guideline for management of bacterial meningitis 2004
recommendations 4
⚬ start antibiotic therapy as soon as possible after diagnosis of bacterial meningitis is suspected or proven
⚬ give dexamethasone beginning 10-20 minutes before or during antibiotic administration in cases of
suspected pneumococcal meningitis
⚬ start empiric antibiotics if
– lumbar puncture (LP) delayed or head computed tomography (CT) required before LP
– purulent meningitis (even if negative cerebrospinal fluid [CSF] Gram stain) (IDSA Grade A-III)
⚬ inadequate data for guidelines regarding interval between physician encounter and administration of
first dose of antibiotics (IDSA Grade C-III)
● European Federation of Neurological Societies (EFNS) 2008 recommendations 5
⚬ initial antibiotic therapy should be given parenterally (EFNS Level -IA)

⚬ patients with suspected acute bacterial meningitis should be hospitalized as soon as possible (EFNS
Level III-A)
⚬ proposed timeline for acute management of bacterial meningitis (EFNS Level IV-C)
– admission to hospital within 90 minutes of contact with healthcare provider

– assessment and treatment within 60 minutes of admission and no longer than 3 hours from contact
with healthcare provider
⚬ prehospital antibiotic therapy
– should be started in patients if strong suspicion of disseminated meningococcal infection (EFNS Level
III-C)
– should be considered for patients with anticipated delay in hospital transfer > 90 minutes (EFNS Level
III-C)
⚬ timing of antibiotic administration suggests 3-6 hour cutoff beyond which mortality increases
⚬ if lumbar puncture is delayed, antibiotic therapy should be started immediately after obtaining blood
cultures (EFNS Level III-A)
STUDY
● SUMMARY
delay in antibiotic therapy > 3-6 hours associated with increased mortality in patients hospitalized with
bacterial meningitis DynaMed Level 2
COHORT STUDY: Crit Care Med 2006 Nov;34(11):2758
Details
⚬ based on 2 cohort study

⚬ in prospective cohort of 156 adults hospitalized for pneumococcal meningitis
– case fatality rate 33%

– antibiotic administration > 3 hours from hospital admission associated with increased mortality (odds
ratio 14.12, 95% CI 3.93-50.9)
⚬ Reference - Crit Care Med 2006 Nov;34(11):2758
⚬ in retrospective cohort of 119 patients > 16 years old hospitalized with 123 episodes of acute bacterial
meningitis
– case fatality rate 13%
– antibiotic administration > 6 hours from time of presentation associated with increased mortality
(adjusted mortality ratio 8.4, 95% CI 1.7-40.9)
– Reference - QJM 2005 Apr;98(4):291
STUDY
● SUMMARY
evidence limited and inconsistent regarding prehospital antibiotic therapy
COHORT STUDY: J Infect 1995 Mar;30(2):89
Details
⚬ based on 2 cohort studies

⚬ in cohort of 305 patients aged 1 month to > 80 years hospitalized with bacterial meningitis
– 53 (17.4%) patients treated with antibiotics prior to admission

– mortality 1.9% in patients who had antibiotic therapy prior to hospital admission vs. 12% in patients
who had antibiotic therapy after admission
⚬ Reference - J Infect 1995 Mar;30(2):89
⚬ in cohort of 57 patients with otogenic pneumococcal meningitis
– 45 patients > 21 years old, 12 patients < 12 years old

– no significant difference in mortality in patients who received prehospital antibiotics (50%) vs.
patients who did not (60%)
– most cases treated with prehospital antibiotics considered to have inadequate antibiotic dosing
– Reference - Scand J Infect Dis 2006;38(3):172
Empiric antibiotic treatment
recommendations for empiric antibiotics for purulent meningitis 4
⚬ in all adults use both (IDSA Grade A-III for drug combination)
– vancomycin 15-20 mg/kg IV based on actual body weight (ABW) every 8-12 hours to maintain serum
trough levels 15-20 mg/L (IDSA Grade B-III for vancomycin dosage) (Am J Health Syst Pharm 2009 Jan
1;66(1):82 ), correction can be found in Am J Health Syst Pharm 2009 May 15;66(10):88
– ceftriaxone (2 g IV every 12 hours or 4 g IV every 24 hours) or cefotaxime (8-12 g/day IV with dosing
every 4-6 hours)
⚬ in adults > 50 years old, add ampicillin 2 g IV every 4 hours to above regimen (IDSA Grade A-III)
⚬ consider adding rifampin 600 mg every 24 hours when dexamethasone given (IDSA Grade A-III)
⚬ modifications for specific predisposing conditions (IDSA Grade A-III)
– penetrating head trauma - vancomycin plus 1 of cefepime, ceftazidime, or meropenem

– postneurosurgery - vancomycin plus 1 of cefepime, ceftazidime, or meropenem
– CSF shunt - vancomycin plus 1 of cefepime, ceftazidime, or meropenem
⚬ for initial treatment, assume antimicrobial resistance likely
● IDSA 2008 clinical guideline on management of encephalitis recommends empiric acyclovir for all patients
with suspected encephalitis while awaiting results of diagnostic workup (IDSA Grade A-III), with dosage 10
mg/kg IV every 8 hours (IDSA Grade A-I) (Clin Infect Dis 2008 Aug 1;47(3):303 full-text )
● European Federation of Neurological Societies (EFNS) 2008 recommendations 5
⚬ for empiric therapy - use 1 of 2 therapies
– ceftriaxone 2 g IV every 12-24 hours (EFNS Level III-B)

– cefotaxime 2 g IV every 6-8 hours (EFNS Level III-B)
⚬ alternative therapy - use 1 of 2 therapies
– meropenem 2 g IV every 8 hours (EFNS Level III-C)

– chloramphenicol 1 g IV every 6 hours
⚬ if penicillin or cephalosporin-resistant pneumococcus suspected use combination of (EFNS Level IV-A)
– ceftriaxone or cefotaxime, PLUS

– vancomycin
● loading dose 15 mg/kg IV

● 60 mg/kg/day IV (adjust for creatinine clearance)
⚬ if Listeria suspected use either ampicillin or amoxicillin 2 g IV every 4 hours (EFNS Level IV-A) (amoxicillin
not available as IV formulation in the United States)
STUDY
● SUMMARY
third-generation cephalosporins may be as effective as older antibiotic regimens for empiric treatment
of acute bacterial meningitis in adults and children DynaMed Level 2
COCHRANE REVIEW: Cochrane Database Syst Rev 2007 Oct 17;(4):CD001832
Details
⚬ based on Cochrane review of trials with methodologic limitations

⚬ systematic review of 19 randomized trials comparing ceftriaxone or cefotaxime to older antibiotic
regimens (ampicillin-chloramphenicol or chloramphenicol alone) as empiric therapy for acute bacterial
meningitis in 1,496 adults and children
⚬ unclear allocation concealment in 18 trials, blinding not reported in 1 additional trial
⚬ all trials conducted in 1980s except 3 (1993, 1996, and 2005)

⚬ largest trial with 510 patients had majority of weight (33.8%) in analyses it was included in (mortality and
treatment failure)
⚬ no significant difference between groups in
– mortality in analysis of 19 trials

– deafness in analysis of 10 trials with 501 patients
– treatment failure (either death or deafness) in analysis of 19 trials
– neutropenia (in 10 trials with 472 patients) or skin rash (in 8 trials with 533 patients)
⚬ third-generation cephalosporins associated with
– reduced risk of positive cerebrospinal fluid (CSF) cultures at 10-48 hours after start of treatment (risk
difference [RD] -6%, 95% CI -11% to 0%) in analysis of 12 trials with 442 patients
– increased risk of diarrhea (RD 8%, 95% CI 3%-13%) in analysis of 12 trials with 750 patients, results
limited by significant heterogeneity
⚬ Reference - Cochrane Database Syst Rev 2007 Oct 17;(4):CD001832 (review updated 2011 Oct 5)
Treatment based on isolated pathogen and susceptibility testing

Enterobacteriaceae and other enteric bacteria
recommendations for Enterobacteriaceae and other enteric bacteria 4

⚬ Escherichia coli and other Enterobacteriaceae (see table for recommended dosing)
– in vitro susceptibility test results must guide specific antimicrobial choice (IDSA Grade A-III)
– third-generation cephalosporin (IDSA Grade A-II)
– alternatives - aztreonam, fluoroquinolone, meropenem, trimethoprim-sulfamethoxazole, ampicillin
(IDSA Grade A-III)
– treat for 21 days (IDSA Grade A-III)
⚬ Enterococcus species (see below for recommended dosing)
– ampicillin susceptible - ampicillin plus gentamicin (IDSA Grade A-III)

– ampicillin resistant - vancomycin plus gentamicin (IDSA Grade A-III)
– ampicillin and vancomycin resistant - linezolid (recommended dose not reported) (IDSA Grade B-III)
Haemophilus influenzae
recommendations for H. influenzae (see table for recommended dosing) 4

⚬ treat for 7 days (IDSA Grade A-III)
⚬ beta-lactamase negative (IDSA Grade A-III)
– ampicillin
– alternatives - ceftriaxone, cefotaxime, cefepime, chloramphenicol, or fluoroquinolone
⚬ beta-lactamase positive
– third-generation cephalosporin (IDSA Grade A-I)

– alternatives - cefepime (IDSA Grade A-I), chloramphenicol (IDSA Grade A-III), or fluoroquinolone (IDSA
Grade A-III)
● European Federation of Neurological Societies (EFNS) 2008 recommendations for H. influenzae type B 5
⚬ ceftriaxone or cefotaxime (EFNS Level IV-C)

⚬ alternatives (EFNS Level IV-C)
– chloramphenicol IV plus ampicillin IV

– chloramphenicol IV plus amoxicillin IV (amoxicillin not available as IV formulation in the United
States)
Listeria monocytogenes
recommendations for Listeria monocytogenes (see table for recommended dosing) 4

⚬ ampicillin or penicillin G (IDSA Grade A-III)
⚬ consider addition of aminoglycoside to penicillin G (IDSA Grade A-III)
⚬ alternatives - trimethoprim-sulfamethoxazole (IDSA Grade A-III) or meropenem (IDSA Grade B-III)
⚬ treat for ≥ 21 days (IDSA Grade A-III)
● European Federation of Neurological Societies (EFNS) 2008 recommendations for listerial meningitis 5
⚬ ampicillin or amoxicillin 2 g IV every 4 hours (amoxicillin not available as IV formulation in the United
States)
⚬ consider adding gentamicin 1-2 mg IV every 8 hours for first 7-10 days (EFNS Level IV-C)
⚬ alternatives (EFNS Level IV)
– trimethoprim-sulfamethoxazole (co-trimoxazole) 10-20 mg/kg (of trimethoprim component) IV every

6-12 hours
– meropenem IV
⚬ in patients with risk factor for Listeria meningitis (immunosuppression, old age, signs of
rhombencephalitis) give IV amoxicillin with third-generation cephalosporin as empirical treatment (EFNS
Level IV-C) (amoxicillin not available as IV formulation in the United States)
Neisseria meningitidis
recommendations for N. meningitidis - based on penicillin minimum inhibitory concentration (MIC) (see
table for recommended dosing) 4
⚬ MIC < 0.1 mcg/mL (IDSA Grade A-III)
– penicillin G or ampicillin
– alternatives - ceftriaxone, cefotaxime, or chloramphenicol
⚬ MIC 0.1-1 mcg/mL (IDSA Grade A-III)
– ceftriaxone or cefotaxime
– alternatives - chloramphenicol, fluoroquinolone, or meropenem
● European Federation of Neurological Societies (EFNS) 2008 recommendations for meningococcal
meningitis 5
⚬ benzyl penicillin (penicillin G), ceftriaxone, or cefotaxime (EFNS Level IV)
⚬ alternatives (EFNS Level IV-C)
– meropenem
– chloramphenicol
– moxifloxacin
⚬ in patients with known history of severe beta-lactam allergy use chloramphenicol as alternative for
meningococcal meningitis (EFNS Level IV-C)
● Centers for Disease Control and Prevention (CDC) recommends chemoprophylaxis for close contacts
⚬ contacts closer than 3 feet for > 8 hours or those exposed to oral secretions and exposed during the 7
days prior to and 1 day after start of antibiotics
⚬ ciprofloxacin 500 mg orally once daily (unless concern for quinolone resistant N. meningitidis which is
rare but has been reported)
Pseudomonas aeruginosa
recommendations for P. aeruginosa (see table for recommended dosing) 4

⚬ in vitro susceptibility test results must guide specific antimicrobial choice (IDSA Grade A-III)
⚬ cefepime or ceftazidime (IDSA Grade A-II)
⚬ alternatives - aztreonam, ciprofloxacin, meropenem (IDSA Grade A-III)
⚬ consider addition of aminoglycoside to any of the above (IDSA Grade A-III)
● European Federation of Neurological Societies (EFNS) 2008 recommendations for pseudomonal meningitis
5
⚬ meropenem
⚬ consider adding gentamicin
Staphylococcus
recommendations for Staphylococcus
⚬ Staphylococcus aureus (see table for recommended dosing)
– methicillin susceptible 4
● nafcillin or oxacillin (IDSA Grade A-III)

● alternatives - vancomycin (IDSA Grade A-III) or meropenem (IDSA Grade B-III)
– methicillin resistant
● vancomycin 15-20 mg/kg IV every 8-12 hours for 2 weeks is recommended (IDSA Grade B-II)
● some experts recommend addition of rifampin 600 mg once daily or 300-450 mg twice daily (IDSA
Grade B-III)
● alternatives include either of
⚬ linezolid 600 mg orally or IV twice daily (IDSA Grade B-II)

⚬ Sulfamethoxazole/Trimethoprim 5 mg/kg (trimethoprim component) IV every 8-12 hours (IDSA
Grade C-III)
● Reference - Infectious Diseases Society of America (IDSA) clinical practice guideline on treatment
of methicillin-resistant Staphylococcus aureus (MRSA) infections in adults and children (Clin Infect
Dis 2011 Feb 1;52(3):e18 ), correction can be found in Clin Infect Dis 2011 Aug 1;53(3):319,
commentary can be found in Clin Infect Dis 2011 Jun 15;52(12):1468 , Clin Infect Dis 2011 Jul
1;53(1):98 , Clin Infect Dis 2011 Aug 1;53(3):308 , Clin Infect Dis 2015 Apr 15;60(8):1290
● see also Methicillin-resistant Staphylococcus aureus (MRSA)
⚬ Staphylococcus epidermidis (see below for recommended dosing)
– vancomycin (IDSA Grade A-III)

– consider addition of rifampin to vancomycin (IDSA Grade A-III)
– alternatives - linezolid (recommended dose not reported) (IDSA Grade B-III)
● European Federation of Neurological Societies (EFNS) 2008 recommendations for Staphylococcus 5
⚬ flucloxacillin 2 g every 4 hours (EFNS Level IV) (not available in the United States)
⚬ vancomycin if penicillin allergy suspected (EFNS Level IV)
⚬ consider adding rifampin to either agent and linezolid for methicillin-resistant staphylococcal meningitis
(EFNS Level IV-C)
Streptococcus pneumoniae
recommendations for S. pneumoniae 4

⚬ based on penicillin MIC, but see revised definition of S. pneumoniae susceptibility breakpoints for
penicillin
– MIC < 0.1 mcg/mL (IDSA Grade A-III)
● penicillin G or ampicillin
● alternatives - ceftriaxone, cefotaxime, or chloramphenicol
– MIC 0.1-1 mcg/mL
● ceftriaxone or cefotaxime (IDSA Grade A-III)

● alternatives - cefepime or meropenem (IDSA Grade B-II)
– MIC ≥ 2 mcg/mL (or cefotaxime or ceftriaxone MIC ≥ 1 mcg/mL)
● vancomycin plus ceftriaxone or cefotaxime (IDSA Grade A-III)

● consider addition of rifampin if ceftriaxone MIC > 2 mcg/mL (IDSA Grade A-III)
● alternative - gatifloxacin or moxifloxacin (systemic gatifloxacin not available in the United States)
(IDSA Grade B-II)
⚬ treat for 10-14 days (IDSA Grade A-III) (see below for recommended dosing)
● European Federation of Neurological Societies (EFNS) 2008 recommendations for S. pneumoniae 5
⚬ for penicillin-sensitive pneumococcal meningitis (and other sensitive streptococcal species)
– use 1 of 4 regimens (EFNS Level IV-A)
● penicillin G (benzyl penicillin) 250,000 units/kg/day IV (approximately 2.4 g IV every 4 hours)

● ampicillin or amoxicillin 2 g IV every 4 hours (amoxicillin not available as IV formulation in the
United States)
● ceftriaxone 2 g IV every 12 hours
● cefotaxime 2 g IV every 6-8 hours
– alternative therapy - use 1 of 3 regimens
● meropenem 2 g IV every 8 hours (EFNS Level IV-C)

● rifampin 600 mg IV every 12 hours plus vancomycin (EFNS Level IV-C)
⚬ vancomycin 15 mg/kg IV loading dose

⚬ vancomycin 60 mg/kg/day as continuous infusion (adjusted for creatinine clearance)
⚬ aim for serum level 15-25 mg/L
● moxifloxacin 400 mg/day IV (EFNS Level IV-C)
⚬ pneumococcus with reduced susceptibility to penicillin or cephalosporin

– ceftriaxone or cefotaxime plus vancomycin and consider adding rifampin (EFNS Level IV)
– alternatives - moxifloxacin, meropenem, or linezolid 600 mg plus rifampin (EFNS Level IV)
– in patients with known history of severe beta-lactam allergy use vancomycin as alternative for
pneumococcal meningitis (EFNS Level IV-C)
● revised definition of Streptococcus pneumoniae susceptibility breakpoints for penicillin
Table 3. Susceptibility Category by Minimum Inhibitory Concentration (MIC)
Susceptible Intermediate Resistant
Meningitis, IV ≤ 0.06 mcg/mL Not applicable ≥ 0.12 mcg/mL

penicillin
Not meningitis, IV ≤ 2 mcg/mL 4 mcg/mL ≥ 8 mcg/mL

penicillin
Not meningitis, ≤ 0.06 mcg/mL 0.12-1 mcg/mL ≥ 2 mcg/mL

oral penicillin
⚬ Reference - MMWR Morb Mortal Wkly Rep 2008 Dec 19;57(50):1353 full-text
Other bacteria
recommendations for Streptococcus agalactiae (see table for recommended dosing) 4

⚬ ampicillin or penicillin G (IDSA Grade A-III)
⚬ consider addition of aminoglycoside to penicillin G (IDSA Grade A-III)
⚬ alternatives - ceftriaxone or cefotaxime (IDSA Grade B-III)
⚬ treat for 14-21 days (IDSA Grade A-III)
● treatment of specific organisms identified by culture can be found in Clin Infect Dis 2004 Nov 1;39(9):1267
full-text
Drug-specific information
Table 4. Infectious Diseases Society of America (IDSA) Guideline for Management of

Bacterial Meningitis 2004 Recommended Doses of Antibiotics(4)
Drug Dosing Schedule in Adults
Amikacin 5 mg/kg every 8 hours (monitor serum peak

and trough levels)
Ampicillin 2 g every 4 hours
Aztreonam 1.5-2 g every 6 hours or 2-2.5 g every 8

hours
Cefepime 2 g every 8 hours
Cefotaxime 1.33-2 g every 4 hours or 2-3 g every 6

hours
Ceftazidime 2 g every 8 hours
Ceftriaxone 2 g every 12 hours or 4 g every 24 hours
Chloramphenicol 1-1.5 g every 6 hours (higher dose if

pneumococcal)
Ciprofloxacin 800-1,200 mg/day divided every 8-12 hours
Gatifloxacin 400 mg every 24 hours (no data on optimal

dose)
Gentamicin 5 mg/kg/day divided every 8 hours (monitor

serum peak and trough levels)
Meropenem 2 g every 8 hours
Moxifloxacin 400 mg every 24 hours (no data on optimal

dose)
Nafcillin 1.5-2 g every 4 hours
Oxacillin 1.5-2 g every 4 hours
Penicillin G 4 million units every 4 hours
Rifampin 600 mg every 24 hours
Tobramycin 5 mg/kg/day divided every 8 hours (monitor

serum peak and trough levels)
Trimethoprim-sulfamethoxazole (co- 2.5-5 mg/kg every 6 hours or 5-10 mg/kg

trimoxazole) every 12 hours (dose based on
trimethoprim component)
Vancomycin 15-20 mg/kg every 8-12 hours (maintain

serum trough 15-20 mcg/mL)
Duration of treatment
recommendations for duration of IV antibiotic therapy based on pathogen (IDSA Grade A-III) 4
⚬ H. influenzae - 7 days
⚬ N. meningitidis - 7 days
⚬ S. pneumoniae - 10-14 days
⚬ S. agalactiae - 14-21 days
⚬ aerobic gram-negative bacilli - 21 days
⚬ L. monocytogenes - at least 21 days
● European Federation of Neurological Societies (EFNS) recommendations for duration of IV antibiotic
therapy based on pathogen 5

⚬ unspecified bacterial meningitis - 10-14 days (EFNS Level IV-C)
⚬ H. influenzae meningitis - 7-14 days (EFNS Level IV-B)
⚬ pneumococcal meningitis - 10-14 days (EFNS Level IV-A)
⚬ meningococcal meningitis - 5-7 days (EFNS Level IV-A)
⚬ Listeria meningitis - 21 days (EFNS Level IV-B)
⚬ gram-negative bacilli and Pseudomonas meningitis - 21-28 days (EFNS Level IV-B)
Outpatient antibiotic therapy
● Infectious Disease Society of America (IDSA) guideline for management of bacterial meningitis recommends
that selected patients may be discharged to finish antibiotic therapy as outpatient if (IDSA Grade A-III) 4
⚬ inpatient antibiotic therapy for ≥ 6 days
⚬ improving condition or clinical stability
– no fever for ≥ 24-48 hours prior to starting outpatient treatment

– no seizure activity, significant neurologic dysfunction, or focal findings
– ability to take fluids by mouth
⚬ discharge plan includes healthcare visits, lab monitoring, and emergency plan
⚬ adequate home resources
– access to home healthcare for antimicrobial administration

– daily availability of physician
– reliable access route and infusion device if needed
– patient and/or family compliance with plan
– safe environment with access to phone, utilities, refrigerator, and food
Steroids
recommendations for dexamethasone 4

⚬ dexamethasone may reduce associated cerebral edema, increased intracranial pressure, altered
cerebral blood flow, cerebral vasculitis, and neuronal injury by decreasing inflammatory response, but
does not reverse damage that occurred prior to treatment
⚬ dosing
– 0.15 mg/kg IV every 6 hours for 2-4 days

– give first dose 10-20 minutes before or with first antibiotic dose
⚬ recommended in all adults with suspected or proven pneumococcal meningitis (IDSA Grade A-I), even if
organism subsequently found to be highly resistant to penicillin and cephalosporins (IDSA Grade B-III)
⚬ insufficient data to recommend use in adults with meningitis caused by other pathogens (IDSA Grade B-
III)
⚬ do not give to adults who have already received antibiotic therapy (IDSA Grade A-I) because it is unlikely
to improve outcome
⚬ addition of rifampin to patients receiving dexamethasone may be reasonable (IDSA Grade B-III)
● addition of rifampin recommended when steroids given as vancomycin may not adequately penetrate the
central nervous system when steroids are given to reduce inflammation
Efficacy for corticosteroid use
STUDY
● SUMMARY
adjunctive corticosteroids might reduce hearing loss and mortality in adults and adolescents with acute
bacterial meningitis DynaMed Level 2
COCHRANE REVIEW: Cochrane Database Syst Rev 2015 Sep 12;(9):CD004405
Details
⚬ based on Cochrane review limited by clinical heterogeneity

⚬ systematic review of 25 randomized trials comparing adjunctive corticosteroids vs. placebo or no
corticosteroids (control) in 4,121 adults or children with acute bacterial meningitis
⚬ 7 trials enrolled adults and adolescents
– corticosteroid regimens included dexamethasone (for 3 or 4 days) or hydrocortisone (for 7 days), with
time of first dose varying between trials
– antibiotics included ceftriaxone or empiric antibiotics (2 trials), amoxicillin (2 trials), chloramphenicol
plus ampicillin (1 trial), and chloramphenicol/penicillin or cephalosporin (1 trial), but were not
reported in 1 trial
– 1 trial with 465 patients was conducted in area with high prevalence of HIV infection (below)
⚬ results limited by heterogeneity in corticosteroid and antibiotic regimens, predominant causative

pathogen, and presence of comorbidities
⚬ comparing corticosteroids to control in adults and adolescents, corticosteroids associated with
– reduced risk of hearing loss in analysis of 4 trials with 844 patients
● risk ratio (RR) 0.74 (95% CI 0.56-0.98)

● NNT 11-228 with hearing loss in 22% of control group
– nonsignificant decrease in mortality (RR 0.74, 95% CI 0.53-1.05) in analysis of 7 trials with 1,517
patients, results limited by significant heterogeneity
– nonsignificant decrease in short-term neurological sequelae (RR 0.72, 95% CI 0.51-1.01) in analysis of
4 trials with 542 patients
⚬ Reference - Cochrane Database Syst Rev 2015 Sep 12;(9):CD004405
⚬
DynaMed Commentary
Analysis was heavily weighted by a high proportion of patients with Streptococcus pneumoniae
meningitis.
● 3 trials included in Cochrane and 1 additional cohort study provide data on patients with bacterial
meningitis due to organisms other than S. pneumoniae
STUDY
⚬ SUMMARY
administration of dexamethasone with antibiotics may not improve mortality or hearing loss in
patients with bacterial meningitis due to Neisseria meningitidis DynaMed Level 2
RANDOMIZED TRIAL: N Engl J Med 2002 Nov 14;347(20):1549 | Full Text

RANDOMIZED TRIAL: Pediatr Infect Dis J 1989 Dec;8(12):848
Details
– based on subgroup analyses of 2 randomized trials

– 301 patients ≥ 17 years old with suspected bacterial meningitis in Europe were randomized to
adjunctive dexamethasone 10 mg vs. placebo IV every 6 hours for 4 days and followed for 8 weeks
● all patients received amoxicillin 2 g IV every 4 hours for 7-10 days (but changes allowed at
physician discretion) or empiric antibiotic therapy based on local guidelines
● dexamethasone was given either 15-20 minutes before or at same time as antibiotics
● median symptom duration before admission 24 hours in both groups
● 78% (234 patients) had positive bacterial culture of cerebrospinal fluid (CSF)
● 65% (43 out of 66 patients) with negative CSF culture had ≥ 1 CSF finding predictive of bacterial
meningitis
● most commonly identified pathogens were S. pneumoniae (108 patients) and Neisseria meningitidis
(97 patients)
● stratified results comparing dexamethasone vs. placebo
⚬ all-cause mortality
– N. meningitidis 4% vs. 2% (not significant)

– S. pneumoniae 14% vs. 34% (p = 0.02, NNT 5)
– negative bacterial culture 0% vs. 7% (not significant)
⚬ unfavorable outcome (Glasgow Outcome Scale score < 5)
– N. meningitidis 8% vs. 11% (not significant)

– S. pneumoniae 26% vs. 52% (p = 0.006, NNT 4)
– negative bacterial culture 5% vs. 13% (not significant)
⚬ hearing loss at 8 weeks
– N. meningitidis 7% vs. 11% (not significant) (subgroup of 90 patients)

– S. pneumoniae 14% vs. 21% (not significant) (subgroup of 82 patients)
– negative bacterial culture 3% vs. 4% (not significant) (subgroup of 63 patients)
● Reference - N Engl J Med 2002 Nov 14;347(20):1549 full-text , editorial can be found in N Engl J
Med 2002 Nov 14;347(20):1613 , commentary can be found in Curr Neurol Neurosci Rep 2007
Nov;7(6):459
● mortality benefit sustained at median 13-year follow-up in 93% of patients (Neurology 2012 Nov
27;79(22):2177 )
– in subgroup analysis of randomized trial including 108 patients aged ≥ 13 years with Neisseria
meningitidis meningitis
● mortality was 6% with dexamethasone plus antibiotic therapy vs. 10% with antibiotic therapy
alone (not significant)
● Reference - Pediatr Infect Dis J 1989 Dec;8(12):848
STUDY
⚬ SUMMARY
administration of dexamethasone may reduce mortality and hearing loss in adolescents and adults
with confirmed bacterial meningitis due to Streptococcus suis DynaMed Level 2
RANDOMIZED TRIAL: N Engl J Med 2007 Dec 13;357(24):2431 | Full Text
Details
– based on prespecified subgroup analysis in randomized trial

– 435 patients > 14 years old with suspected bacterial meningitis in Vietnam were randomized to
dexamethasone 0.4 mg/kg vs. placebo IV every 12 hours for 4 days
● all patients received ceftriaxone 2 g IV every 12 hours for 10-14 days, but antibiotics could be
altered at physician discretion
● most patients in dexamethasone group received dexamethasone 15 minutes before first dose of
antibiotics
– median duration of illness 4 days in dexamethasone group vs. 3 days in placebo group
– 69% (300 patients) had confirmed bacterial meningitis, 28% (123 patients) had probable bacterial
meningitis, and 3% (12 patients) had alternative diagnosis (tuberculous meningitis, parasitic
eosinophilic meningitis, or cryptococcal meningitis)
● confirmed bacterial meningitis defined as bacteria detected in cerebrospinal fluid or culture from
cerebrospinal fluid or blood
● probable bacterial meningitis defined as no bacteria detected but no alternative diagnosis
– most commonly identified pathogens were Streptococcus suis (116 patients) and S. pneumoniae (55
patients)
– comparing dexamethasone vs. placebo
● overall 30-day mortality 10.1% vs. 12.4% (not significant)

● 30-day mortality comparing confirmed vs. probable bacterial meningitis
⚬ dexamethasone significantly reduced 30-day mortality in subgroup with confirmed bacterial

meningitis (relative risk [RR] 0.43, 95% CI 0.2-0.94)
⚬ no significant difference in subgroup with probable bacterial meningitis (RR 2.65, 95% CI 0.73-
9.63)
● 30-day mortality by causative pathogen
⚬ S. pneumoniae 0% vs. 17.2% (p = 0.028, NNT 6)

⚬ S. suis 0% vs. 5.4% (p = 0.07)
● hearing loss in patients with
⚬ confirmed bacterial meningitis 9.6% vs. 21.8% (p = 0.008, NNT 9) (subgroup of 254 patients)
⚬ probable meningitis 16.7% vs. 20% (no p value reported) (subgroup of 99 patients)
⚬ S. suis 12.3% vs. 37.7% (p = 0.003, NNT 4) (subgroup of 110 patients)
– Reference - N Engl J Med 2007 Dec 13;357(24):2431 full-text , editorial can be found in N Engl J
Med 2007 Dec 13;357(24):2507 , commentary can be found in N Engl J Med 2008 Mar
27;358(13):1399
STUDY
⚬ SUMMARY
adjunctive dexamethasone associated with decreased mortality in patients with bacterial meningitis
DynaMed Level 2
Details
– based on prospective cohort study

– 1,391 patients > 16 years old with community-acquired bacterial meningitis (1,412 episodes)
identified in Netherlands Reference Laboratory of Bacterial Meningitis between 2006 and 2014
– most common pathogens were Streptococcus pneumoniae (72%), Neisseria meningitidis (11%), and
Listeria monocytogenes (5%)
– initial antibiotic treatments included amoxicillin plus third-generation cephalosporin (36%),
monotherapy with third-generation cephalosporin (29%), and monotherapy with penicillin or
amoxicillin (20%)
– 89% received adjunctive dexamethasone, and 78% of these patients received dexamethasone 10 mg
IV every 6 hours for 4 days started before or with first dose of parenteral antibiotics
– in multivariate analyses, adjunctive dexamethasone associated with
● decreased mortality (adjusted odds ratio [OR] 0.46, 95% CI 0.32-0.66)

● decreased risk of unfavorable outcome (Glasgow Outcome Scale score ≤ 4)
⚬ overall (adjusted OR 0.54, 95% CI 0.39-0.73)

⚬ in patients with pneumococcal meningitis (adjusted OR 0.55, 95% CI 0.38-0.8)
⚬ in patients with meningitis caused by other pathogens (adjusted OR 0.44, 95% CI 0.23-0.85)
– no association between adjunctive dexamethasone and hearing loss detected

– Reference - Lancet Infect Dis 2016 Mar;16(3):339 , commentary can be found in Lancet Infect Dis
2016 Mar;16(3):271
● 1 study in Cochrane review evaluated corticosteroid use in patients with bacterial meningitis in areas with
high HIV prevalence
STUDY
⚬ SUMMARY
administration of dexamethasone before first dose of antibiotics may not reduce mortality or hearing
loss in patients with bacterial meningitis due to Streptococcus pneumoniae in areas with high
prevalence of HIV infection DynaMed Level 2
RANDOMIZED TRIAL: N Engl J Med 2007 Dec 13;357(24):2441 | Full Text
Details
– based on subgroup analysis of randomized trial

– 465 patients ≥ 16 years old (about 90% had HIV infection) with suspected bacterial meningitis in
Malawi randomized to dexamethasone 16 mg vs. placebo IV twice daily for 4 days
● all patients received ceftriaxone 2 g IV or intramuscularly twice daily for 10 days with antibiotic
therapy modified according to antimicrobial sensitivity and clinical progress
● dexamethasone was given immediately before administration of antibiotics
– median time to presentation 72 hours in both groups

– 70% (325 patients) had microbiologically proven bacterial meningitis, 22% (102 patients) had probable
bacterial meningitis, and 8% (38 patients) had alternative diagnosis (cryptococcal meningitis,
tuberculous meningitis, traumatic lumbar puncture)
● proven bacterial meningitis defined as identification of organism from cerebrospinal fluid (CSF) or
from blood culture for patients with CSF white-cell count > 100 per mm3 with > 50% neutrophils
● probable bacterial meningitis defined as CSF with white-cell count > 100 per mm3 with > 50%
neutrophils but without identification of organism
– most commonly identified pathogen was Streptococcus pneumoniae (275 patients)
– comparing dexamethasone vs. placebo at 40 days
● overall results
⚬ mortality 56% vs. 53% (not significant)

⚬ hearing loss in 31% vs. 36% (subgroup of 195 patients with audiometry results at 40 days)
● in patients with proven bacterial meningitis

⚬ hearing loss in 36% vs. 38% (not significant)
● in patients with S. pneumoniae

⚬ hearing loss in 37% vs. 43% (not significant)
– Reference - N Engl J Med 2007 Dec 13;357(24):2441 full-text
Vancomycin dosing and corticosteroid use
STUDY
● SUMMARY
adequate levels of vancomycin in CSF may be reached using continuous infusion in presence of
dexamethasone DynaMed Level 2
COHORT STUDY: Clin Infect Dis 2007 Jan 15;44(2):250 | Full Text
Details
⚬ based on prospective cohort study without clinical outcomes

⚬ 14 patients with meningitis (13 with pneumococcal meningitis, 1 with N. meningitidis meningitis) treated
with all of
– cefotaxime 200 mg/kg/day
– vancomycin continuous infusion 60 mg/kg/day after 15 mg/kg loading dose
– dexamethasone 10 mg every 6 hours
⚬ mean levels of vancomycin on day 2 or 3
– 25.2 mg/L in serum

– 7.2 mg/L in CSF
⚬ Reference - Clin Infect Dis 2007 Jan 15;44(2):250 full-text , commentary can be found in Curr Infect
Dis Rep 2007 Jul;9(4):299
Other management
STUDY
● SUMMARY
induced hypothermia associated with increased mortality in patients with severe bacterial meningitis
DynaMed Level 2
RANDOMIZED TRIAL: JAMA 2013 Nov 27;310(20):2174
Details
⚬ based on randomized trial with early termination

⚬ 98 adults (mean age 59 years) with suspected or proven bacterial meningitis and Glasgow Coma Scale
score ≤ 8 for < 12 hours were randomized to induced hypothermia (body temperature ≤ 33.5 degrees C
[≤ 92.3 degrees F]) vs. usual care and followed for 3 months
⚬ all patients received appropriate antimicrobial therapy plus vital support
⚬ 77% had pneumococcal meningitis
⚬ primary end point was unfavorable outcome at 3 months (Glasgow Outcome Scale score 1-4, including
moderate or severe disability, vegetative state, or death)
⚬ trial terminated early at unplanned interim analysis due to increased mortality in hypothermia group
⚬ comparing induced hypothermia vs. usual care
– mortality 51% vs. 31% (p = 0.04, NNH 5)

– unfavorable outcome in 86% vs. 74% (not significant)
⚬ no significant differences in aspiration or nosocomial pneumonia, hemorrhage, hearing impairment, or

cardiac arrhythmia
⚬ Reference - JAMA 2013 Nov 27;310(20):2174
Management of patients with cerebrospinal fluid (CSF) shunt infection
● management of central nervous system device-associated infection typically includes antimicrobial therapy
and surgery to remove or replace device hardware
● antimicrobial therapy
⚬ antimicrobial choice must penetrate central nervous system, reach adequate concentrations in
cerebrospinal fluid (CSF), and have bactericidal activity against infecting pathogen
⚬ in patients with suspected infection and abnormal CSF test results (CSF pleocytosis, elevated lactate and
protein levels, and decreased glucose CSF/blood ratio), start empiric antimicrobial therapy
– start therapy after obtaining appropriate cultures, but before results are available
– vancomycin IV plus antipseudomonal beta-lactam (such as cefepime, ceftazidime, or meropenem;
choice based on local susceptibility) is recommended for coverage against common causes of CSF
shunt or drain infection
⚬ modify therapy after pathogen is identified and in vitro susceptibility results are available
⚬ recommended duration of antimicrobial therapy depends on organism isolated and response to
therapy
⚬ consider intraventricular antimicrobial therapy in patients who respond poorly to systemic antimicrobial
therapy alone
● device removal and reimplantation
⚬ infected device hardware should be completely removed if possible
– if CSF drain is removed, consider immediate replacement with external ventricular drain
– if device hardware is retained or immediately replaced, consider addition of antibiofilm therapy
(rifampin or ciprofloxacin) for 12 weeks
⚬ timing of CSF shunt replacement depends on isolated organism, severity of disease, and response to
therapy
● see Central nervous system device infections for details
Complications and Prognosis

Complications
● complications are common in patients recovering from bacterial meningitis and may be more common
with pneumococcal meningitis compared to meningococcal meningitis 1 , 3

⚬ up to 50% develop long-term neurological complications (such as cognitive impairment) after
pneumococcal meningitis
⚬ morbidity with meningococcal meningitis reported as approximately 7%
● 15%-20% of patients have cerebrovascular complications, including 1 , 3
⚬ subdural effusion or empyema

⚬ septic sinus thrombosis
⚬ subarachnoid hematoma
⚬ intracranial hypertension
⚬ cerebral edema
⚬ compression of intracranial structures
⚬ temporal lobe or cerebellar herniation
⚬ hydrocephalus
● 20%-40% of patients may experience delayed neurological complications including 1 , 3 , 5
⚬ cognitive impairment
⚬ hearing loss
⚬ behavioral changes
⚬ depression
⚬ paralysis
⚬ motor impairment
⚬ chronic fatigue
⚬ stroke (arterial or venous)
⚬ coma
⚬ epilepsy
⚬ hydrocephalus
⚬ permanent visual impairment
⚬ subarachnoid bleed
⚬ sleep disorders
STUDY
● SUMMARY
20%-30% of patients with bacterial meningitis may experience complications
SYSTEMATIC REVIEW: Lancet Infect Dis 2010 May;10(5):317
Details
⚬ based on 2 systematic reviews

⚬ systematic review of 132 articles reporting complications due to bacterial meningitis
– major complications were cognitive deficit, bilateral hearing loss, motor deficit, seizures, visual
impairment, and hydrocephalus
– minor complications were behavioral problems, learning difficulties, unilateral hearing loss,
hypotonia, and diplopia
– risk for complication
● 19.9% for any complication

● 12.8% for major complication
● 8.6% for minor complication
● 24.7% for major complication in pneumococcal meningitis
● 9.5% for major complication in Haemophilus influenzae type b meningitis
● 7.2% for major complication in meningococcal meningitis
● 25.1% for major complication in Africa
● 21.6% for major complication in southeast Asia
● 9.4% for major complication in Europe
⚬ Reference - Lancet Infect Dis 2010 May;10(5):317

⚬ systematic review of 63 studies reporting complications due to Streptococcus pneumoniae infection
– data based on 3,408 meningitis survivors from high-income countries

– prevalence of complications
● 31% for any complication

● 20.9% for hearing loss
● 6.5% for seizures
● 6.8% for hydrocephalus

● 8.7% for spasticity/paresis
● 12.2% for cranial nerve palsies
● 2.4% for visual impairment
– Reference - J Infect 2010 Jul;61(2):114
● review of neurological sequelae of bacterial meningitis can be found in J Infect 2016 Jul;73(1):18
Prognosis
● mortality is heavily influenced by causative organism
⚬ Streptococcus pneumoniae meningitis associated with highest mortality, with reported fatality rate
19%-37% 3
⚬ meningococcal meningitis has 5% reported mortality 3
⚬ Austrian syndrome (meningitis, endocarditis, and pneumonia) due to invasive pneumococcal disease
associated with high mortality rate 5

⚬ mortality can occur within first 48 hours and sometimes before diagnosis is suspected 5
⚬ deaths associated with Neisseria meningitidis often occur within 12-24 hours of first symptoms 5
STUDY
⚬ SUMMARY
high mortality in patients with culture-proven community-acquired meningitis
COHORT STUDY: N Engl J Med 2004 Oct 28;351(18):1849 | Full Text
Details
– based on prospective cohort study

– 696 Dutch adults with community-acquired acute bacterial meningitis confirmed by cerebrospinal
fluid (CSF) cultures in 1998-2002
– average mortality 21% (Streptococcus pneumoniae 30%, other causes 7%)
– 34% had unfavorable outcome; risk factors for unfavorable outcome
● advanced age
● presence of otitis or sinusitis
● absence of rash
● low Glasgow Coma Scale score
● tachycardia
● positive blood culture
● elevated erythrocyte sedimentation rate
● thrombocytopenia
● low CSF white cell count
– Reference - N Engl J Med 2004 Oct 28;351(18):1849 full-text , correction can be found in
commentary can be found in N Engl J Med 2005 Mar 3;352(9):950, N Engl J Med 2005 Feb 3;352(5):512
– age > 60 years associated with increased mortality
● comparing 257 (37%) patients ≥ 60 years old vs. 439 (67%) patients aged 17-59 years
⚬ mortality 34% vs. 13% (p < 0.001)
⚬ mortality from cardiorespiratory failure 25% vs. 11% (p = 0.06)

⚬ mortality from brain herniation 2% vs. 23% (p = 0.004)
● Reference - J Am Geriatr Soc 2006 Oct;54(10):1500 , commentary can be found in J Am Geriatr

Soc 2007 Apr;55(4):628
STUDY
⚬ SUMMARY
initial focus of infection may affect mortality
COHORT STUDY: BMC Infect Dis 2005 Oct 27;5:93 | Full Text
Details
– based on prospective cohort study in Denmark from 1999 to 2000

– 187 consecutive cases with S. pneumoniae meningitis were evaluated, including 45 children < 16 years
old
– in-hospital mortality 27% in adults vs. 2% in children < 16 years old (p < 0.05)
– overall case fatality based on focus of infection
● 7% with otogenic focus

● 33% with sinusitis focus
● 26% with pneumonic focus
● 50% with other kind of focus
● 21% with no primary infection focus
– Reference - BMC Infect Dis 2005 Oct 27;5:93 full-text
STUDY
⚬ SUMMARY
increased brain ventricle size associated with increased mortality in patients with bacterial
meningitis
COHORT STUDY: BMC Infect Dis 2015 Aug 25;15:367 | Full Text
Details
– based on retrospective cohort study

– 81 patients with bacterial meningitis had computed tomography (CT) scan at time of diagnosis
– overall 30-day mortality 32%
– increased ventricle to brain ratio associated with increased mortality in multivariate analysis
(mortality rate ratio 6.03, 95% CI 1.61-22.64, for highest vs. lowest tertile)
– Reference - BMC Infect Dis 2015 Aug 25;15:367 full-text
STUDY
⚬ SUMMARY
mortality risk may vary by serotype in bacteremic patients with invasive pneumococcal disease
SYSTEMATIC REVIEW: Clin Infect Dis 2010 Sep 15;51(6):692 | Full Text
Details
– based on systematic review

– meta-analysis of 9 studies of serotype-specific disease outcomes in 8,253 patients with pneumococcal
pneumonia and meningitis
– relative risk of mortality in patients with bacteremic pneumonia (referent was serotype 14)
● increased risk of mortality in patients infected with
⚬ serotype 3 (risk ratio [RR] 1.9, 95% CI 1.54-2.35)

⚬ serotype 6A (RR 1.39, 95% CI 1.02-1.91)
⚬ serotype 6B (RR 1.59, 95% CI 1.2-2.11)
⚬ serotype 9N (RR 1.53, 95% CI 1.16-2.02)
⚬ serotype 19F (RR 2.22, 95% CI 1.71-2.88)
● reduced risk of mortality in patients infected with
⚬ serotype 1 (RR 0.48, 95% CI 0.37-0.63)

⚬ serotype 7F (RR 0.58, 95% CI 0.43-0.79)
⚬ serotype 8 (RR 0.68, 95% CI 0.5-0.94)
– no significant difference in risk of mortality by serotype among patients with meningitis

– Reference - Clin Infect Dis 2010 Sep 15;51(6):692 full-text
STUDY
● SUMMARY
older age, alcoholism, cranial nerve palsy, cerebrospinal fluid white cell count, and positive blood
culture associated with increased risk of unfavorable outcome in patients with bacterial meningitis
Details
⚬ based on prospective cohort study

⚬ 1,412 patients with community-acquired bacterial meningitis identified in Netherlands Reference
Laboratory of Bacterial Meningitis between 2006 and 2014
⚬ overall mortality 17%
⚬ unfavorable outcome (Glasgow Coma Scale score 1-4) in 38%
⚬ factors associated with unfavorable outcome in multivariate analysis
– older age (vs. age 16-39 years)
● age 40-70 years (odds ratio [OR] 1.55, 95% CI 1.02-2.35)

● age > 70 years (OR 3.04, 95% CI 1.89-4.89)
– alcoholism (OR 1.98, 1.15-3.41)

– tachycardia (OR 1.1, 95% CI 1.03-1.17 per increase of ten beats/minute)
– cranial nerve palsy (OR 2.55, 95% CI 1.59-4.09)
– lower cerebrospinal fluid white cell count (vs. < 1,000-10,000 cells/mcL)
● < 100 cells/mcL (OR 2.1, 95% CI 1.34-3.29)

● 100-999 cells/mcL (OR 2.04, 95% CI 1.46-2.84)
– positive blood culture (OR 1.44, 95% CI 1.02-2.05)

– higher C-reactive protein (OR 1.02, 95% CI 1.01-1.03 per 10 mg/L increase)
⚬ factors associated with reduced risk of unfavorable outcome in multivariate analysis
– otitis or sinusitis (OR 0.74. 95% CI 0.55-0.99)

– higher Glasgow Coma Scale score (OR 0.91, 95% CI 0.87-0.96 per 1 point increase)
⚬ Reference - Lancet Infect Dis 2016 Mar;16(3):339 , commentary can be found in Lancet Infect Dis 2016
Mar;16(3):271
STUDY
● SUMMARY
age ≥ 45 years, abnormal neurological exam, and mechanical ventilation associated with increased risk
of adverse outcomes in patients with healthcare-associated meningitis or ventriculitis
COHORT STUDY: Open Forum Infect Dis 2016 Apr;3(2):ofw077 | Full Text
Details
⚬ based on retrospective cohort study

⚬ 215 patients (median age 45 years, 77% adults) with healthcare-associated meningitis or ventriculitis,
screened by infection control practitioners and cerebrospinal fluid (CSF) samples had clinical and
demographic data evaluated
– 77% were adults and 23% were children
– indications for neurosurgical procedure included hemorrhage, hydrocephalus, trauma, and brain
tumor
⚬ healthcare-associated meningitis or ventriculitis defined by 2015 Centers of Disease Control and
Prevention (CDC)’s National Healthcare Safety Network (NHSN) surveillance definition
⚬ 49% had positive CSF cultures, 67% of which were gram-positive organisms
⚬ 81.4% had external ventricular drain placed at time of diagnosis
⚬ 78% had adverse clinical outcomes
– death in 9.3%
– persistent vegetative state in 14.4%
– severe disability in 36%
– moderate disability in 18%
⚬ factors associated with higher risk of adverse outcomes (Glasgow Outcome Scale score 1-4) in
multivariable analysis
– age ≥ 45 years (odds ratio [OR] 6.47, 95% CI 2.31-18.11)
– abnormal neurological exam (OR 3.04, 95% CI 1.27-7.29)
– mechanical ventilation (OR 5.34, 95% CI 1.51-18.92)
⚬ Reference - Open Forum Infect Dis 2016 Apr;3(2):ofw077 full-text
STUDY
● SUMMARY
poor outcome in half of adults with S. pneumoniae meningitis DynaMed Level 2
COHORT STUDY: Brain 2003 May;126(Pt 5):1015
Details
⚬ based on retrospective chart review

⚬ retrospective study of 87 adults admitted to intensive care with pneumococcal meningitis, 24% died
before hospital discharge
⚬ 75% had intracranial complications including
– 29% diffuse brain edema

– 22% arterial cerebrovascular complications
– 16% hydrocephalus
– 9% venous cerebrovascular complications
– 9% spontaneous intracranial hemorrhages
⚬ 26% of survivors had hearing loss

⚬ only 48% were discharged with Glasgow Outcome Scale (GOS) score of 5 (considered good outcome)
⚬ factors associated with a bad outcome (GOS 4 or lower) were
– chronic debilitating diseases

– low GOS and focal neurological deficits on admission
– low CSF leucocyte counts
– pneumonia
– bacteriemia and meningitis-associated intracranial
– systemic complications
⚬ Reference - Brain 2003 May;126(Pt 5):1015
STUDY
● SUMMARY
bacterial meningitis associated with deficits of psychomotor and executive functioning in survivors
DynaMed Level 2
J Neurol Neurosurg Psychiatry 2007 Oct;78(10):1092 | Full Text
Details
⚬ based on 3 prospective cohort studies

⚬ 155 adults surviving bacterial meningitis and 72 healthy controls were analyzed
⚬ 79 patients had pneumococcal meningitis, 76 patients had meningococcal meningitis
⚬ median 49.5 months (range 5-164 months) between onset of illness and cognitive testing
⚬ compared to controls, patients with meningitis had
– no significant differences in measures of intelligence

– no significant differences in measures of memory
– worse scores in 2-3 of 8 measures of attention/executive functioning
– worse scores in 5-7 of 8 measures of psychomotor functions
⚬ Reference - J Neurol Neurosurg Psychiatry 2007 Oct;78(10):1092 full-text
Prevention and Screening

Prevention
● preventive measures recommended by the Centers for Disease Control and Prevention for Meningococcal
meningitis include
⚬ droplet precautions for hospitalized patients as soon as diagnosis is suspected through the first 24
hours of antimicrobial therapy (CDC 2007 PDF )
⚬ chemoprophylaxis for close contacts
– closer than 3 feet for > 8 hours or those exposed to oral secretions and exposed during the 7 days
prior to and 1 day after start of antibiotics
– regimens include
● rifampin 600 mg orally every 12 hours for 2 days

● ciprofloxacin 500 mg orally as single dose (unless concern for quinolone resistant N. meningitidis
which is rare but has been reported)
● ceftriaxone 250 mg intramuscularly as single dose
– Reference - N Engl J Med 2006 Oct 5;355(14):1466 full-text , MMWR Recomm Rep 2013 Mar
22;62(RR-2):1 full-text
STUDY
● SUMMARY
antibiotic prophylaxis might not prevent meningitis in patients with basilar skull fractures with or
without cerebrospinal fluid leakage DynaMed Level 2
COCHRANE REVIEW: Cochrane Database Syst Rev 2015 Apr 28;(4):CD004884
Details
⚬ based on Cochrane review of trials with methodologic limitations

⚬ systematic review of 5 randomized trials comparing prophylactic antibiotics vs. placebo or no antibiotics
in 368 patients with basilar skull fractures with or without cerebrospinal fluid leakage
⚬ all trials had unclear allocation concealment and/or small sample size
⚬ prophylactic antibiotics included ceftriaxone, penicillin, ampicillin, cephalothin, and ampicillin plus
sulphadiazine
⚬ no significant differences overall or in subgroups of patients with or without CSF leakage for rates of
– meningitis in analysis of 4 trials with 208 patients

– all-cause mortality in analysis of 4 trials with 208 patients
– meningitis-related mortality in analysis of 4 trials with 208 patients, but 2 events overall
⚬ authors report that 798 total patients needed in randomized trials to demonstrate significant results
with 90% power and 5% probability of type I error
⚬ Reference - Cochrane Database Syst Rev 2015 Apr 28;(4):CD004884
STUDY
● SUMMARY
multidisciplinary program may reduce incidence of meningitis in patients with ventricular and lumbar
cerebrospinal fluid drains DynaMed Level 2
BEFORE AND AFTER STUDY: J Neurosurg 2010 Feb;112(2):345
Details
⚬ based on retrospective before-and-after study of patients who had external ventricular or lumbar
cerebrospinal fluid drains placed
⚬ 43 patients evaluated before program implementation and 112 patients evaluated after program
implementation
⚬ multidisciplinary program included
– increased awareness
– focused standard operating procedures
– diagnostic and therapeutic algorithm
– timely administration of prophylaxis
– improvement of drainage system
⚬ infection rate 37% before implementation vs. 9% after implementation (p < 0.0001)
⚬ Reference - J Neurosurg 2010 Feb;112(2):345
STUDY
● SUMMARY
interventions recommended in pneumococcal disease clusters include prompt use of amoxicillin or

azithromycin chemoprophylaxis, pneumococcal vaccination for close contacts, and implementation of
infection control measures
SYSTEMATIC REVIEW: Lancet Infect Dis 2011 Feb;11(2):119
Details
⚬ based on systematic review of 28 identified cluster reports

⚬ antibiotics to close contacts reduced risk of pneumococcal disease in 1 study
⚬ no further cases seen following rifampicin chemoprophylaxis in 3 of 4 clusters
⚬ no further cases seen following penicillin chemoprophylaxis in 4 of 5 clusters
⚬ no further cases seen following use of infection control measures in 7 of 8 clusters
⚬ pneumococcal polysaccharide vaccine appears to have about 2-week delayed benefit
⚬ Reference - Lancet Infect Dis 2011 Feb;11(2):119
Immunization
● for information on vaccination, see
⚬ Meningococcal Vaccine
⚬ Pneumococcal Vaccine
● pneumococcal conjugate vaccines 1
⚬ sustained reduction in pneumococcal meningitis following the introduction of vaccine has been
observed with modest reductions in adult populations
⚬ substantial herd immunity has also been established in areas following introduction of vaccine
⚬ see Pneumococcal vaccination for details
● meningococcal conjugate vaccine 1
⚬ global reductions in disease have been observed following introduction of serogroup A and C conjugate
vaccines
⚬ see The Meningitis Vaccine Project for additional information
● Haemophilus influenzae is nearly nonexistent in areas where vaccines programs have been implemented
however H. influenzae remains in areas where vaccination is not commonplace 1
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Bacterial Meningitis in Adults

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25/7/22, 11:46 Bacterial Meningitis in Adults

Bacterial Meningitis in Adults

● Presenting signs and symptoms vary.

● Testing prior to lumbar puncture (LP):

⚬ obtain blood cultures, complete blood count, and coagulation studies.

● Diagnosis is confirmed by LP.

⚬ Perform in all patients unless contraindicated.

– opening pressure, usually > 180 mm H2O in bacterial meningitis

● Delays in treatment are associated with an increased mortality.

● For vaccination information, see Meningococcal disease or Pneumococcal vaccination.

infection and inflammation of meninges 1 , 3

⚬ 15,000-25,000 cases occur in US annually 3

POPULATION-BASED SURVEILLANCE: N Engl J Med 2011 May 26;364(21):2016

– based on surveillance study

● 0.66 at age 18-34 years

– Reference - N Engl J Med 2011 May 26;364(21):2016

– based on surveillance study

⚬ streptococcal meningitis in 3.9%

● unspecified cause in 17.2%

⚬ cryptococcal meningitis in 5.7%

● 9.1% with fungal meningitis

– Reference - Healthcare Cost and Utilization Project 2008 Jul full-text

POPULATION-BASED SURVEILLANCE: Lancet Infect Dis 2016 Mar;16(3):339

● 1.72 cases per 100,000 adults in 2007-2008

– Streptococcus pneumoniae most common pathogen (72%)

POPULATION-BASED SURVEILLANCE: Lancet Infect Dis 2014 Sep;14(9):805

● 0.5 per 100,000 population in 1960

SYSTEMATIC REVIEW: Lancet Infect Dis 2010 Dec;10(12):853

⚬ based on systematic review of observational studies

⚬ Reference - Lancet Infect Dis 2010 Dec;10(12):853

Possible risk factors

● abnormal communication between nasopharynx and subarachnoid space

⚬ due to congenital anatomic abnormality

● externally communicating dural fistula or other dural defects 1 , 3 , 5

● immunosuppression (particularly asplenic patients or those with immunoglobulin deficiencies) 3 , 5

● parameningeal sources of infection such as 3 , 5

CASE-CONTROL STUDY: Ann Intern Med 2018 Mar 20;168(6):396

⚬ based on nested case-control study

COHORT STUDY: BMJ 2019 Oct 23;367:l5784 | Full Text

⚬ based on retrospective cohort study

● meningitis 0.16 vs. 0.08 (HR 1.7, 95% CI 1.43-2.02)

Etiology and Pathogenesis

● causes in immunocompetent adults 5

⚬ < 10% of cases due to gram-negative bacilli including

● most common pathogens in immunocompromised adults 5

● mixed bacterial infection in < 1% of all cases of community-acquired bacterial meningitis 5

● common pathogens in neurosurgical infections 1 , 5

⚬ Staphylococcus aureus or coagulase negative staphylococci, including methicillin-resistant strains

– occurs in parts of Asia, especially Vietnam and Thailand

COHORT STUDY: Lancet Infect Dis 2014 Sep;14(9):813

– 0.306 per 100,000 people for Streptococcus pneumoniae

⚬ Reference - Lancet Infect Dis 2014 Sep;14(9):813

COHORT STUDY: N Engl J Med 2004 Oct 28;351(18):1849 | Full Text

⚬ based on 3 population-based cohort study

– in subgroup analyses by age,

● in 257 patients ≥ 60 years old

● in 439 patients aged 17-59 years

four main steps have been described 1 , 3

● mechanisms of central nervous system entry 1 , 5

⚬ in patients with community acquired bacterial meningitis

● bacterial multiplication in subarachnoid space ultimately causes release of proinflammatory mediators,

breakdown of blood-brain barrier, and recruitment of leukocytes to subarachnoid space 1 , 5

⚬ bacterial invasion of subarachnoid space results in release of pro-inflammatory cytokines and

History and Physical