CNS Infections

February 20, 2008

George P. Allen, Pharm.D.Assistant Professor, Pharmacy PracticeOSU College of Pharmacy at OHSU

Introduction

• Meningitis: inflammation of the meninges– protective membranes covering the CNS

• Encephalitis: inflammation of the brain– usually viral

Epidemiology

• Incidence: 4-6 / 100,000 / year in U.S.• Mortality ~ 3-33%

– overall mortality remains high (~25%) despite advances in therapy

• Neurologic sequelae are frequent (~61% in Gram -)– seizures– hearing loss– hydrocephalus

Epidemiologic Considerations

• Significant changes in the distribution of causative organisms have occurred

• Rates of infection by specific pathogens are most influenced by patient age

• Morbidity and mortality are influenced by organism, patient age

• Increases in nosocomial CNS infections• Increases in antimicrobial resistance

Predisposing Factors

• Recent respiratory tract infection• Otitis media• Sinusitis• Mastoiditis• Immunosuppression• Splenectomy• Sickle cell disease

Pathophysiology

• Nasopharyngeal colonization• Passage into bloodstream• Bacteria invade subarachnoid space• Subarachnoid defenses limited• Infection and inflammation result

Clinical Considerations

• Age• Time of year• Previous antibiotic therapy • Laboratory analysis

Clinical Presentation: Adults

• Early signs:– photophobia– headache– neck stiffness (nuchal rigidity)

• Late signs:– seizures– focal neurologic deficits– hydrocephalus

Clinical Presentation: Infants

• Non-specific signs and symptoms are common– irritability– altered sleep– vomiting– high-pitched crying– diminished oral intake– seizures

Clinical Presentation: Children

• Decreased activity• Somnolence• Confusion• Lethargy

Diagnosis

Kernig’s Sign

Saberi A et al. Hosp Phys 1999:23-4.

Brudzinski’s Sign

Saberi A et al. Hosp Phys 1999:23-4.

Accuracy of Clinical Signs

95%5%Kernig’s sign

95%5%Brudzinski’s sign

68%30%Nuchal rigidity

SpecificitySensitivityClinical Sign

Thomas KE et al. Clin Infect Dis 2000;35:46-52.

Lumbar Puncture

• 4 tubes collected• Appropriate technique important (contamination,

traumatic LP)

CSF Analysis

• 4 tubes: chemistry, hematology, microbiology, latex agglutination testing

• Normal CSF:– clear– sterile– protein < 50 mg/dL– glucose 50 - 66% serum value– WBC < 10 (all mononuclear)

Typical CSF Findings

< 30-70 mg/dL< 30-70 mg/dL< 1/2 serum1/2-2/3 serumGlucose

≥ 40-15030-15080-500< 50Protein (mg/dL)

> 80% L50% L> 90% PMN> 90% MWBC differential

100-10005-500400-100,000< 10WBC (#/mL)

TubercularViralBacterialNormalComponent

CSF Analysis: Microbiology

• Gram’s stain – 60-90% confirmatory before ABX– 40-60% confirmatory after ABX

• Cultures– CSF– blood

Other CSF Evaluations

• Opening pressure• Latex agglutination • Limulus lysate assay• Polymerase chain reaction (PCR)• Lactate• C-reactive protein• Procalcitonin

Treatment

Causative Bacteria: Children

Newborns (less than 1 month old):

• group B streptococcus (Streptococcus agalactiae)• Escherichia coli• Listeria monocytogenes• Klebsiella spp.

Causative Bacteria: Children, Adults

1 month - ~ 50 years old:

• Streptococcus pneumoniae• Neisseria meningitidis• Haemophilus influenzae• L. monocytogenes• Group B streptococci

Causative Bacteria: Elderly

>50 yrs old:

• Streptococcus pneumoniae• Listeria monocytogenes• Gram - enteric bacilli • P. aeruginosa (less common)• Neisseria meningitidis (rare)

CNS Anatomy

• Cerebrospinal fluid (CSF)– 0.5 mL/min produced – unidirectional flow

Blood-Brain Barrier (BBB)

Blood-Brain Barrier

• Excluded:– proteins, polar molecules

• Move freely:– water, most ions, lipids

• Transported:– amino acids, glucose

Management Principles

• Prompt empiric coverage• Do not delay therapy for lumbar puncture• Base antibacterial coverage on:

– age– risk factors– allergies

Therapy Considerations

• Bactericidal activity in CSF– impaired host defenses– bacteriostatic therapy = poor outcome

• CSF concentration 10-20 x MBC desirable– decreased activity in infected CSF– lower pH– higher protein concentrations

• Consider penetration in both presence and absence of inflammation

• Antimicrobial characteristics favoring penetration:– small molecular weight– high lipophilicity– low ionization – low protein binding

CSF Penetration

Penetration of Selected ABX

fluoroquinolonesrifampin

aztreonamisoniazid

clindamycincarbapenemsmetronidazole

1st gen. cephalosporinsvancomycinchloramphenicol

2nd gen. cephalosporins3rd gen. cephalosporinstrimethoprim

aminoglycosidesmost penicillinssulfonamides

Inadequate concentrationsTherapeutic [ ] with Inflamed Meninges Only

Therapeutic [ ] Regardless of Inflammation

Intrathecal / Intraventricular Therapy

• Avoids issues of CNS penetration• Intrathecal

– may not achieve adequate concentrations– may produce local tissue irritation

• Intraventricular– surgical procedure needed for reservoir placement

• May not offer increased efficacy

Antibiotic Dosing in Meningitis

Cmin = 15-20 mg/LCmin = 5-15 mg/Lvancomycin

24 million U/day6-24 million U/daypenicillin G

2 gm q3-4h0.5-2 gm q4-6hampicillin

2 gm q12h1 gm q24hceftriaxone

2 gm q4h1-2 gm q8hcefotaxime

Dosing in MeningitisStandard DosingAntibiotic

Treatment of Specific Bacteria

Neisseria meningitidis

• Children & young adults• Cases common in winter & spring• Close contacts are at 200-1000x higher risk for

development of meningitis• Unique clinical findings

– petechiae/purpuric rash – 50%– hearing loss – 10%

Wellcome Trust Photographic Library, Synchrotron Radiation Dept., CLRC Daresbury Laboratory.

Neisseria meningitidis

• DOC: ceftriaxone or cefotaxime• Alternatives:

– chloramphenicol– meropenem– fluoroquinolone

Streptococcus pneumoniae

• #1 in adults; 12% incidence in children • Clinical findings:

– predisposing: ear/sinus (50%), pneumonia, endocarditis, head trauma, splenectomy, BMT

– seizures, coma, hearing loss common• Close contacts not at higher risk for development of

meningitis• Penicillin resistance becoming more prevalent

Streptococcus pneumoniae

gatifloxacin or moxifloxacinvancomycin +

ceftriaxone or cefotaxime+ rifampin

ceftriaxone-resistant2

gatifloxacin or moxifloxacinvancomycin +

ceftriaxone or cefotaximeceftriaxone-resistant1

gatifloxacin or moxifloxacinvancomycin +

ceftriaxone or cefotaximePRSP/DRSP

cefepime or meropenemceftriaxone or cefotaximePIRSP

ceftriaxone or chloramphenicolampicillin or penicillin GPSSP

Alternative(s)Drug(s) of ChoiceSusceptibility

Haemophilus influenzae

• Majority of cases begin as primary infection of a parameningeal focus or lung infection

• Decreasing incidence (vaccine)• Close contacts are at high risk for development of

secondary infection• β-lactamase production is common

Haemophilus influenzae

• 30-40% ampicillin-resistant (β-lactamase)• DOC: ceftriaxone or cefotaxime• Alternatives:

– chloramphenicol– meropenem– fluoroquinolone

Listeria monocytogenes

• GI tract is usual route of invasion• Incidence peaks in summer and fall• May present atypically

– often subtle signs/symptoms• Associated with high mortality (22-29%)• DOC: ampicillin ± aminoglycoside• Alternatives:

– TMP/SMX– meropenem

Empiric Therapy by Age

ampicillin + 3rd gen. cephalosporin + vancomycin

S. pneumoniaeN. meningitidis

L. monocytogenes> 50 years

3rd gen. cephalosporin ± vancomycin

H. influenzaeN. meningitidisS. pneumoniae

1-23 months

3rd gen. cephalosporin ± vancomycin

S. pneumoniaeN. meningitidis

2-50 years

3rd gen. cephalosporin +vancomycin ± ampicillin

S. agalactiaeGram - enterics

L. monocytogenes< 1 month

AntibioticsOrganismsAge

Empiric Therapy based on Gram’s Stain

H. influenzae, enterics,

? P. aeruginosa

N. meningitidis

L. monocytogenes

S. pneumoniae

Organism (s)

ceftazidime or cefepime + aminoglycosidebacilli

3rd gen. cephalosporincocci/coccobacilli

Gram negative:

ampicillin ± aminoglycosidebacilli/coccobacilli

3rd gen. cephalosporin ± vancomycincocci

Gram positive:

Suggested Empiric RegimenGram’s Stain Result

Monitoring CNS Infections

• Signs and symptoms:– frequent monitoring (q4h x 3 days)– fever, HA, VS, meningeal signs (nuchal rigidity, etc.)

• CSF: – no repeat LP unless no improvement occurs– improvement generally in 12-24h

Use of Corticosteroids

Rationale for Use

• Used since the 1950’s• Rationale: attenuation of inflammatory response

inflicted by bacterial death• Effects:

– ↓ cerebral edema, ICP– ↓ inflammation– ↓ CSF outflow resistance– ↓ neurologic/audiologic sequelae

Controversies

• Conflicting results in terms of efficacy• Potential adverse effects on antibiotic penetration• Does the organism matter?

– children: H. influenzae– adults: S. pneumoniae, N. meningitidis

• Use in adults versus children

Corticosteroid Usage

• Use in patients > 1 mo. old– insufficient data in neonates

• Administer prior to or with the first dose of ABX• Dexamethasone 0.15 mg/kg q6h x 2-4 days

Prevention

Prophylaxis

“Close contacts” – who are they?

1. within 5-7 days of onset, for ≥ 4 hours2. household members3. shared sleeping quarters4. day care attendees5. nursing homes 6. crowded/confined populations (prisons, etc.)

Prophylaxis Regimens

• N. meningitidis:– rifampin (5-10 mg/kg q12h x 4 doses)– alternatives: ceftriaxone, azithromycin, ciprofloxacin

• H. influenzae:– rifampin (20 mg/kg q24h x 4 doses)

Vaccines: H. influenzae

• Hib capsular polysaccharide• Part of usual childhood vaccine schedule• Start at 2 months of age:

– 1 dose q 2 mo. x 3 doses– 1 dose at 12 mo.

Vaccines: N. meningitidis

• Quadrivalent vaccines: serogroups A,C,Y,W-135– MenomuneR

– MenactraR

• Vaccinate high-risk patients:– splenectomy– sickle cell disease– complement deficiency– outbreaks

Vaccines: S. pneumoniae

• Antigens of 23 serotypes• 80-85% effective, 40,000 deaths/year preventable• Vaccinate:

– all > 65 y.o.– lung/heart disease, diabetes– chronic renal failure– s/p organ transplant– chemotherapy recipients– HIV