DIAGNOSIS AND MANAGEMENT OF ACUTE BACTERIAL MENINGITIS

Amanda Peppercorn, MD Assistant Professor of MedicineDivision of Infectious Diseases

Case Example

25 year old WM presents in July with 4 days of fever (Tm 101F), malaise, headache, anorexia and mild watery diarrhea 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

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

What does he have?

Questions to address: Meningitis or encephalitis? Bacterial or “aseptic”

Likely pathogen?Clues?

Appropriate isolation? Appropriate immediate management? Treatment? Prognosis?

EPIDEMIOLOGY

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

ETIOLOGIES OF SINGLE EPISODE ACUTE BACTERIAL MENINGITIS, MGH 1962-88

Community Acquired (N=253) S. pneumoniae 38% N. menigitidis 14% L. monocytogenes 11% Streptococci 7% H. influenzae 4% GNR 4% Mixed 2% Other 2% Culture negative 13%

Nosocomial (n=151) GNR 38% Streptococci 9% Coag neg staph 9% S. aureus 9% S. pneumoniae 5% H. influenzae 4% L. monocytogenes 3% Enterococcus 3% N. menigitidis 1% Mixed 7% Other 3% Culture negative 11%

Durand M, Calderwood SB, Weber DJ, et al. NEJM 1993;328:21

EPIDEMIOLOGY OFBACTERIAL MENINGITIS, US, 1996

Worldwide 1.2 million cases each year

10th most common cause of infectious death 135,000 deaths annually Neurologic sequelae common

Schuchat A, et al. NEJM 1997;337:970-6

Swartz M, NEJM 2004

MANAGING ACUTE MENINGITIS:HISTORY

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

Risk Factors Head trauma Neurosurgery CSF leak VP shunt, hardware Underlying illness (DM, luekemia, AIDS, cirrhosis)

Pathogens Staph aureus (MSSA and MRSA) Enteric GNRs (E coli, Klebsiella)

Polymicrobial gram negative meningitis: think Strongyloides hyperinfection syndrome

Mortality Up to 35%

CLINICAL FINDINGS IN COMMUNITY-ACQUIRED BACTERIAL MENINGITIS

Symptom US, MGH1962-88 (296)

Netherlands1998-92 (N=696)

Fever, neck stiffness & MS 67% 44%1 sign present: 99% (fever, neck

stiffness, MS)99% (fever, HA, neck stiffness, MS)

2 signs present NA 95% (as above)

Fever 95% 77%Neck stiffness 88% 83%Headache NA 87%Rash 11%* 26%

22/30 N. menigitidis, rash also present with S. pneumoniae, H. influenzae, negative culture

CSF FINDINGS IN COMMUNITY-ACQUIRED ACUTE BACTERIAL MENINGITIS, MGH

Opening pressure (mm H20) 0-139 9% 140-299 52% 300-399 20% >400 19%

WBC per mm3 0-99 13% 100-4999 59% 5000-9999 15% >10,000 13%

Percent PMNs 0-19 2% 20-79 19% >80 79%

Glucose mg/dL <40 50%

Gram stain Positive 60%

Culture Positive 73%

Neurologic Complications

Systemic Septic shock ARDS DIC Septic or reactive arthritis Death (25%)

Older age Obtundation at presentation Seizures within 24 hours Strep pneumonia

Neurologic Impaired mental status Increased ICP, herniation Seizures (25%) CN palsies, focal neurologic

deficits Sensorineural hearing loss Neurocognitive/intellectual

impairment

TREATMENT:GENERAL GUIDELINES

Use bactericidal drugs Cover potential for resistance

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

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

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

30-45 mg/kg per day divided every 8-12 hours

TREATMENT:EMPIRIC THERAPY

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)

Nosocomial meningitis 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 Coverage: MSSA, streptococci, penicillin-susceptible pneumococci,

meningococcus, GNRs, P. aeruginosa

Replace ceftriaxone or ceftazidime with aztreonam (monobactam) – low risk of cross reactivity (no coverage for pneumococcus) Coverage: Meningococcus, GNRs, P. aeruginosa

Replace ceftriaxone with chloramphicol (or moxifloxacin) Coverage chloramphenicol: Streptococci, pneumococci, RMSF,

meningococcus, H. influenzae

DURATION OF THERAPY

Neisseria meningitidis 7 days Hemophilus influenzae 7 days Streptococcus pneumoniae 10-14 days Streptococcus agalactiae 14-21 days Aerobic GNR 21 days Listeria monocytogenes >21 days

ETIOLOGIES OF ACUTE MENINGITISIN HIV INFECTED PATIENTS

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

4 states (N=248) 1995

Netherlands (N=696) 1998-02

S. pneumoniae 25% (28%)* 21% 21%N. meningitidis 10% (10%) 3% 7%H. Influenza 11% (11%) 6% ---L. monocytogenes 21% (32%) 15% ---GNR 23% (36%) --- ---S. aureus 28% (39%) --- ---Streptococci 17% (25%) 7% (GBS) ---Enterococcus 25% (50%) ---- ---

NEJM 1993;328:21-28 (* total mortality); NEJM 1997;337:970-6; NEJM 2004;351:1849-59

MANAGEMENT OF MENINGITIS:KEY CLINICAL DECISIONS

Clinical presentation Meningitis: Viral, bacterial, fungal, mycobacterial Encephalitis (abnl brain function—motor/sensory, change in

MS, personality, speech/movement): Arboviruses, HSV Onset

Acute: S. pneumoniae, N. meningitidis Chronic: Fungal, mycobacterial Recurrent: S. pneumoniae

Host Normal Immunocompromised: HIV, organ transplant, steroids

Aseptic Meningitis

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

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

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

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

Adults: 10 mL per bottle Children: 0.5-5 mL per bottle (based on weight)

Obtain at least 2 blood cultures Yield related to number of cultures obtained Allows assessment of skin commensals contaminating cultures

DOs AND DON’Ts OF OBTANING BLOOD CULTURES

Obtain cultures from different sites (or same site separated by at least 30 min) 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

Do not obtain blood via a peripheral catheter 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

0.00%1.00%2.00%3.00%4.00%5.00%6.00%7.00%8.00%9.00%

Jan Feb Mar Apr May Jun Jul Aug Sep Oct Nov Dec Jan Feb Mar Apr May

Total contamination rate ED contamination rate Total true positives

2007 2008

ISOLATION FORAIRBORNE/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 isolationOnly a physician can discontinue isolation

Post Exposure Prophylaxis

Regimen options: 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 Droplet spread disease Close contact with respiratory secretions (mouth-to-mouth

resuscitation, intubation, nasotracheal suctioning)

IMPACT OF DELAYED ANTIBIOTIC THERAPY

Retrospective study of 269 patients with community acquired meningitis (Aronin SI, et al. Ann Intern Med 1998;129:862-9) 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) 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

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

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 DIAGNOSISBASED ON CSF PROFILE

Pattern PMN predominantLow glucose

LymphocyticNormal glucose

LymphocyticLow glucose

Spectrum Bacterial ParameningealViral

MycobacterialFungal

Pathogens S. pneumonia,

N. meningitidis

EnterovirusesBrain abscess

M. tuberuculosisEndemic fungiMumps, LCM

Non-infectious

Sulfa drugsNon-steroidals

Auto-immune diseases

EFFECTS OF PRIOR ANTIBIOTICS ON CSF FINDINGS

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

Retrospective study of 1,316 patients; 54.6% had received antibiotics before presentation (Geiseler PJ, et al. RID 1980;2:725) 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)

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

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

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)

Even with focal CNS lesions, herniation post-LP uncommon 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

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) 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

Rash: viral exanthem EKG: myocarditis Management: supportive

GENERAL REFERENCES

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