Transcript INFECTIOUS DISEASE EPIDEMIOLOGY: INTRODUCTION

DIAGNOSIS AND MANAGEMENT OF
ACUTE BACTERIAL MENINGITIS
Amanda Peppercorn, MD
Assistant Professor of Medicine
Division of Infectious Diseases
Case Example
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25 year old WM presents in July with 4 days of fever (Tm 101F),
malaise, headache, anorexia and mild watery diarrhea
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Presents for evaluation when he starts to notice faint rash on trunk, back
and arms
No known sick contacts
PMHx: episode of gonorrhea 2 years ago
All: PCN—rash
Meds: ibuprofen prn, more recently with onset of HA
Soc Hx: MSM, one new partner, HIV negative one year ago, no
IDU, tob, etoh, no overseas travel, lives in Massachusetts, works
at Starbucks
Fam Hx: unremarkable
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PE: T 100.5F HR 100 BP 105/70 RR 15 Sat 98%
Gen: Ill appearing young man, uncomfortable on stretcher, fatigued
HEENT: +photophobia, no papilledema or conjunctival petechiae or injection,
OP benign, no thrush, mouth sores or pharyngitis, no cervical LAD
Neck: +meningismus with any movement
Lungs: CTA
Cor: tachy, reg, no m/r/g
Abd: slight tenderness diffusely, no HSM
Ext: no c/c/e
Skin: faint macular rash on trunk, back and extremities, spares face and
palms/soles
Genital: no external lesions
Neuro: sleepy but arousable, A&O x 3, CN intact, reflexes 2+ and symmetric,
motor and sensory intact, coordination intact, no asterixis, GCS 13
Labs
WBC 3.2, Hct 38%, Plts 350K, normal diff
 Chemistries: Bun 18 Cr 0.9 LFTs normal
Glucose 75
 PT/PTT/INR normal
 EKG: 1st AVB
 CXR: Clear
 LP: OP 15, TNC 200 50%P 40%L 10%Other
RBC 50 Gluc 45 TP 55
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What does he have?
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Questions to address:
 Meningitis
or encephalitis?
 Bacterial or “aseptic”
Likely
pathogen?
Clues?
 Appropriate isolation?
 Appropriate immediate management?
 Treatment?
 Prognosis?
EPIDEMIOLOGY
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Incidence and pathogens vary by age
Incidence and pathogens vary by host defense factors
(e.g., immunocompromising conditions, neurosurgery)
Incidence and pathogens change over time due to
improvements in immunizations
Conjugate pneumococcal vaccine
 Conjugate H. influenzae vaccine
 Conjugate quadrivalent meningococcal vaccine (covers type
A, C, Y and W-135); omits coverage for type B
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ETIOLOGIES OF SINGLE EPISODE
ACUTE BACTERIAL MENINGITIS, MGH 1962-88
Community Acquired (N=253)
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S. pneumoniae
N. menigitidis
L. monocytogenes
Streptococci
H. influenzae
GNR
Mixed
Other
Culture negative
38%
14%
11%
7%
4%
4%
2%
2%
13%
Nosocomial (n=151)
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GNR
Streptococci
Coag neg staph
S. aureus
S. pneumoniae
H. influenzae
L. monocytogenes
Enterococcus
N. menigitidis
Mixed
Other
Culture negative
38%
9%
9%
9%
5%
4%
3%
3%
1%
7%
3%
11%
Durand M, Calderwood SB, Weber DJ, et al. NEJM 1993;328:21
EPIDEMIOLOGY OF
BACTERIAL MENINGITIS, US, 1996
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Worldwide 1.2 million cases
each year
10th most common cause of
infectious death
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135,000 deaths annually
Neurologic sequelae common
Schuchat A, et al. NEJM 1997;337:970-6
Swartz M, NEJM 2004
MANAGING ACUTE MENINGITIS:
HISTORY
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Duration/pace of symptoms
Recent exposure to someone with meningitis
Tick exposure
Rash (viral exanthems, ulcerations, petechial or palpable purpura)
A recent infection (especially respiratory or otic infection)
A history of recent head trauma, otorrhea or rhinorrhea
Recent travel, particularly to areas with endemic meningococcal disease
such as sub-Saharan Africa
A history of injection drug use
HIV serostatus, sexual history
Any other immunocompromising conditions
Recent use of antibiotics
Serious antibiotic allergies
TB exposure
Pregnancy
Nosocomial
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Risk Factors
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Pathogens
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Head trauma
Neurosurgery
CSF leak
VP shunt, hardware
Underlying illness (DM, luekemia, AIDS, cirrhosis)
Staph aureus (MSSA and MRSA)
Enteric GNRs (E coli, Klebsiella)
Polymicrobial gram negative meningitis: think
Strongyloides hyperinfection syndrome
Mortality
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Up to 35%
CLINICAL FINDINGS IN COMMUNITYACQUIRED BACTERIAL MENINGITIS
Symptom
2 signs present
US, MGH
1962-88 (296)
67%
99% (fever, neck
stiffness,  MS)
NA
Netherlands
1998-92 (N=696)
44%
99% (fever, HA, neck
stiffness,  MS)
95% (as above)
Fever
Neck stiffness
Headache
Rash
95%
88%
NA
11%*
77%
83%
87%
26%
Fever, neck stiffness &  MS
1 sign present:
22/30 N. menigitidis, rash also present with S. pneumoniae, H. influenzae, negative culture
CSF FINDINGS IN COMMUNITY-ACQUIRED
ACUTE BACTERIAL MENINGITIS, MGH
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Opening pressure (mm H20)
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0-139
140-299
300-399
>400
9%
52%
20%
19%
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WBC per mm3
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0-99
100-4999
5000-9999 15%
>10,000
Percent PMNs
13%
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<40
50%
Gram stain
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2%
19%
79%
Glucose mg/dL
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13%
59%
0-19
20-79
>80
Positive
60%
Culture
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Positive
73%
Neurologic Complications
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Systemic
Septic shock
 ARDS
 DIC
 Septic or reactive arthritis
 Death (25%)
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 Older age
 Obtundation at presentation
 Seizures
within 24 hours
 Strep pneumonia
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Neurologic
Impaired mental status
 Increased ICP, herniation
 Seizures (25%)
 CN palsies, focal neurologic
deficits
 Sensorineural hearing loss
 Neurocognitive/intellectual
impairment
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TREATMENT:
GENERAL GUIDELINES
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Use bactericidal drugs
Cover potential for resistance
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S pneumonia: Vanc (20% PCN-R, 5% CTX-R)
Neisseria mening: Ceftriaxone
Use highest safe dose
Use antibiotics that penetrate CNS
Provide all antibiotics by intravenous route
If bacteristatic antibiotic is used (e.g., doxycycline) initiate after
bactericidal drug
Ideally initiate antibiotics within 30 minutes for acute bacterial
meningitis
TREATMENT:
EMPIRIC THERAPY
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Age 18-50
S. pneumoniae, N. meningitidis; much less likely H. influenzae,
L. monocytogenes, Grp B streptococcus
 Ceftriaxone 2 mg IV Q12 hr plus vancomycin 1 gm IV Q12 hr*
 Consider adding doxycycline 100 mg IV Q12 hr (RMSF season)
 Acyclovir if HSV or VZV suspected
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Age >50
S. pneumoniae, N. meningitidis, L. monocytogenes; less often
Grp B streptococcus, H. influenzae, GNR
 Above plus ampicillin 2 gm IV Q4 hr
 Consider adding doxycycline 100 mg IV Q12 hr (RMSF season)
 Acyclovir if HSV or VZV suspected
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30-45 mg/kg per day divided every 8-12 hours
TREATMENT:
EMPIRIC THERAPY
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Impaired cellular immunity
L. monocytogenes, Gram-negative bacilli
 Ceftazidime* 2 g IV Q8 hr plus vancomycin 1 gm IV Q12 hr plus
ampicillin 2 mg IV Q4 hr
 Consider adding doxycycline 100 mg IV Q12 hr (RMSF season)
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Nosocomial meningitis
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Coagulase negative staphylococcus, S. aureus, Gram-negative
bacilli, streptococci
Ceftazidime* 2 g IV Q8 hr plus vancomycin 1 gm IV Q12 hr
* Use ceftazidime instead of ceftriaxone for improved coverage of P. aeruginosa
TREATMENT:
PENICILLIN-ALLERGIC PATIENT
Options
 Replace ceftriaxone or ceftazidime with meropenem (carbapenem
approved for meningitis) – small risk of cross reactivity
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Replace ceftriaxone or ceftazidime with aztreonam (monobactam) –
low risk of cross reactivity (no coverage for pneumococcus)
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Coverage: MSSA, streptococci, penicillin-susceptible pneumococci,
meningococcus, GNRs, P. aeruginosa
Coverage: Meningococcus, GNRs, P. aeruginosa
Replace ceftriaxone with chloramphicol (or moxifloxacin)
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Coverage chloramphenicol: Streptococci, pneumococci, RMSF,
meningococcus, H. influenzae
DURATION OF THERAPY
Neisseria meningitidis
 Hemophilus influenzae
 Streptococcus pneumoniae
 Streptococcus agalactiae
 Aerobic GNR
 Listeria monocytogenes
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7 days
7 days
10-14 days
14-21 days
21 days
>21 days
ETIOLOGIES OF ACUTE MENINGITIS
IN HIV INFECTED PATIENTS
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Usual bacterial agents: S. pneumoniae, N. meningitidis,
H. influenza
Other bacteria: TB, Syphilis, L. monocytogenes
Viruses (acute HIV, CMV, HSV, VZV)
Fungi: Cryptococcus (most common), Histoplasma,
Coccidioides
CASE FATALITY RATE,
BACTERIAL MENINGITIS
Pathogen
MGH (N=493)
1962-88
S. pneumoniae
25% (28%)*
N. meningitidis
10% (10%)
H. Influenza
11% (11%)
L. monocytogenes 21% (32%)
GNR
23% (36%)
S. aureus
28% (39%)
Streptococci
17% (25%)
Enterococcus
25% (50%)
4 states
(N=248) 1995
21%
3%
6%
15%
----7% (GBS)
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Netherlands
(N=696) 1998-02
21%
7%
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NEJM 1993;328:21-28 (* total mortality); NEJM 1997;337:970-6; NEJM 2004;351:1849-59
MANAGEMENT OF MENINGITIS:
KEY CLINICAL DECISIONS
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Clinical presentation
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Onset
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Meningitis: Viral, bacterial, fungal, mycobacterial
Encephalitis (abnl brain function—motor/sensory, change in
MS, personality, speech/movement): Arboviruses, HSV
Acute: S. pneumoniae, N. meningitidis
Chronic: Fungal, mycobacterial
Recurrent: S. pneumoniae
Host
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Normal
Immunocompromised: HIV, organ transplant, steroids
Aseptic Meningitis
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Definition: signs/sx/laboratory evidence of meningitis with
negative standard bacterial cx
Most common cause: enteroviral (summer, coxsackie, echovirus,
nonpolio enteroviruses, dx by PCR)
Other etiologies: spirochetes (lyme, RMSF, syphilis),
mycobacteria (TB), mycoplasma, drugs (NSAIDS, sulfa), cancer,
parameningeal focus, autoimmune (neurosarcoid, behcet’s, SLE)
Viruses: primary HSV, VZV, HHV6, CMV, acute HIV, mumps,
LCM, West Nile virus, adenovirus
Parasites: Angiostrongylus cantonensis (rat lungworm, SE Asia),
CSF eosinophilia
Recurrent aseptic (Mollaret’s) meningitis: HSV-2
ED MANAGEMENT:
SUSPECTED MENINGITIS
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Initiate droplet precautions (N. meningitidis)
Appropriate resuscitation (fluids, airway, etc.)
Blood cultures x 2
LP within 30 minutes
If LP cannot be performed within 30 minutes initiate empiric
antibiotics
Consider dexamethasone for bacterial meningitis, especially if
pneumococcal disease suspected or demonstrated
CT with contrast or MRI with gadolinium if CNS mass lesion
suspected
INDICATIONS FOR BLOOD CULTURES
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Before the use of parenteral or systemic antimicrobial therapy in
ANY hospitalized patient with fever (>38 oC) combined with
leukocytosis or leukopenia
Systemic and localized infections including suspected acute
sepsis, meningitis, osteomyelitis, arthritis, acute untreated
bacterial pneumonia, and fever of unknown origin in which
abscesses or other bacterial infection is possible.
Test of cure: 48-72 hours after initiation of therapy for bacteremia
or fungemia
DOs AND DON’Ts OF
OBTANING BLOOD CULTURES
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Always obtain using strict aseptic technique to prevent
contamination (i.e., a false positive result)
Label bottles properly (name, hospital number)
Fill bottles with proper volume
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Adults: 10 mL per bottle
Children: 0.5-5 mL per bottle (based on weight)
Obtain at least 2 blood cultures
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Yield related to number of cultures obtained
Allows assessment of skin commensals contaminating cultures
DOs AND DON’Ts OF
OBTANING BLOOD CULTURES
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Obtain cultures from different sites (or same site
separated by at least 30 min)
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Never split blood obtained at single time from single site into
multiple blood culture sets
Avoid femoral site (if possible)
Avoid obtaining blood through non-intact skin (if possible)
Obtain via an arterial line only if no other site available
DOs AND DON’Ts OF
OBTANING BLOOD CULTURES
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Do not obtain blood via a peripheral catheter
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Rate of contamination 9.1% (via catheter) vs 2.8% (via
peripheral stick) {Weinstein M. CID 1996;23:40}
Do not change needles between venipuncture and
inoculation of blood culture bottles
CONTAMINATION AND TRUE INFECTION
RATE OF BLOOD CULTURES, UNC
Total contamination rate
ED contamination rate
Total true positives
9.00%
8.00%
7.00%
6.00%
5.00%
4.00%
3.00%
2.00%
1.00%
0.00%
Jan Feb Mar Apr May Jun Jul Aug Sep Oct Nov Dec Jan Feb Mar Apr May
2007
2008
ISOLATION FOR
AIRBORNE/DROPLET DISEASES
Airborne isolation
 Private room, direct out
exhausted air, negative
pressure
 N95 respirator for
entering room
 Diseases: TB, measles,
varicella
Droplet isolation
 Private room
 Mask for entering room
 Diseases: invasive
meningococcal infection,
influenza, pertussis
Any healthcare worker can initiate isolation
Only a physician can discontinue isolation
Post Exposure Prophylaxis
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Regimen options:
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Ciprofloxacin 500 mg PO x 1
Ceftriaxone 250 mg IM x 1 (children, pregnant women)
Rifampin 600 mg PO 2x/day for 2 days (resistance described)
Definition of exposure
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Droplet spread disease
Close contact with respiratory secretions (mouth-to-mouth
resuscitation, intubation, nasotracheal suctioning)
IMPACT OF
DELAYED ANTIBIOTIC THERAPY
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Retrospective study of 269 patients with community
acquired meningitis (Aronin SI, et al. Ann Intern Med 1998;129:862-9)
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Indicators of poor outcome (death, neurologic deficit): Altered
mental status, hypotension and/or seizures
Delay in therapy associated with worse outcome if patient
developed all 3 above signs
Retrospective study of 123 patients with community
acquired meningitis (Proulx N, et al. QJM 2005;98:291-98)
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OR for mortality: Door-to-antibiotics >6 hr, 8.4; afebrile at
presentation, 39.4; severely impaired mental status, 12.6
IMPACT OF
DELAYED ANTIBIOTIC THERAPY
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Prospective study of 156 patients with pneumococcal
meningitis found a delay of >3 hours was independently
associated with 3-month mortality (Crit Care Med 2006;34:2758)
REASONS FOR OBTAINING CSF
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Allows exclusion of meningitis*
Provides diagnosis of meningitis*
Allows specific etiologic diagnosis of acute bacterial
meningitis (e.g., S. pneumoniae, N. meningitidis)
May make alternative diagnosis (e.g., cryptococcus, HSV)
Allows susceptibility testing of isolate (esp. important for
S. pneumoniae)
May have prognostic significance
Rarely CSF may be normal in early bacterial meningitis
EMPIRIC DIAGNOSIS
BASED ON CSF PROFILE
Pattern
Spectrum
PMN predominant Lymphocytic
Low glucose
Normal glucose
Bacterial
Parameningeal
Viral
Pathogens S. pneumonia,
N. meningitidis
Enteroviruses
Brain abscess
Noninfectious
Auto-immune
diseases
Sulfa drugs
Non-steroidals
Lymphocytic
Low glucose
Mycobacterial
Fungal
M. tuberuculosis
Endemic fungi
Mumps, LCM
EFFECTS OF
PRIOR ANTIBIOTICS ON CSF FINDINGS
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A short period of antibiotic therapy prior to LP does not
change cerebrospinal fluid (CSF) white blood cell count,
protein, or glucose
The yield of CSF gram stain and culture may be reduced
by a short period of antibiotic therapy, but these tests
often remain positive
EFFECTS OF
PRIOR ANTIBIOTICS ON CSF FINDINGS
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Retrospective study of 1,316 patients; 54.6% had received antibiotics
before presentation (Geiseler PJ, et al. RID 1980;2:725)
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No significant differences in CSF WBC, glucose, or protein concentrations
for S. pneumoniae, H. influenzae, N. menigitidis
Significantly lower frequency of positive blood and CSF cultures for all 3
organisms, esp. N. meningitidis
Retrospective study of 128 patients (Kanegaye JT. Pediatr 2001;1081:169)
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3/9 patients with N. meningitis were sterile within 1 hour (1 15 min) and all
negative by 2 hours
Pneumococcal disease: first negative at 4.3 hours, 5/7 negative at 4-10
hours
MANAGEMENT ISSUE
CT or MRI before LP
INDICATIONS FOR CT/MRI BEFORE LP
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Immunocompromised state (eg, HIV infection,
immunosuppressive therapy, active cancer, BMT or
organ transplantation)
History of CNS disease (mass lesion, stroke, or focal
infection)
New onset seizure (within one week of presentation)
Papilledema
Abnormal level of consciousness
Focal neurologic deficit
Tunkel AR, et al. CID 2004 39:1267-84 (IDSA)
EVALUATING RISK OF LP WITHOUT CT
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Reports of harm (herniation post-LP) only case reports with
temporal relationship (Ann Neurol 1980;7:524, Pediatr 2003;112:e174, J
Neurol Psychopathol 1933;14:116)
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Even with focal CNS lesions, herniation post-LP uncommon
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200 patients with increased ICP from brain tumor; no adverse
effects of LP (Res Nerv Ment Dis Proc 1927;8:422)
103 patients with increased ICP; death during hospitalization in 4,
no herniation (J Neurol Psychoopath 1933;14:116)
Even with papilledema LP almost always safe (J Mt Sinai Hosp NY
1956;23:808, Neurol 1959;9:290)
EVALUATING RISK OF LP WITHOUT CT
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Among patients dying with meningitis, herniation is a
common cause of death (even with a normal LP herniation
may occur) – MGH 8/27 autopsied patient had herniation
Prediction rules for abnormal CT have been proposed
(Hasbun R, et al. NEJM 2001;345:1727)
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235 patients with CT before LP: 5% had mass effect
Age >60 years, seizure within 7 days, immunocompromised, hx
of CNS disease, altered mental status, gaze or facial palsy,
inability to answer 2 questions or follow 2 commands, visual
field abnormalities, arm or leg drift, or abnormal language
MANAGEMENT ISSUE
Use of dexamethasone
Tunkel AR, et
al. CID 2004;
39:1267-84
Case Answers
HIV Elisa negative, HIV RNA PCR negative
 HSV, VZV pcr negative
 Gram stain, culture negative
 Lyme ab negative, RPR/VDRL negative
 Enteroviral PCR of stool and CSF: positive
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 Rash: viral exanthem
 EKG: myocarditis
 Management: supportive
GENERAL REFERENCES
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Durand ML, et al. Acute bacterial meningitis in adults. NEJM
1993;328:21-28.
Van de Beek, D, et al. Community-acquired bacterial meningitis
in adults. NEJM 2006;354:44-53.
Weisfelt M, et al. Bacterial menigitis: a review of effective
pharmacotherapy. Expert Opin 2007;8:1493-1504.
Fitch MT, et al. Emergency diagnosis and treatment of adult
meningitis. Lancet ID 2007;7:191-200.
Fitch MT, et al. Emergency department management of
meningitis and encephalitis. ID Clin NA 2008;22:33-52.
Tunkel AR, et al. Practice guidelines for the management of
bacterial meningitis. Clin Infect Dis 2004;39:1267-84
Thanks