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Infectious Disease I: Central Nervous System Infections

Infectious Disease I: Central Nervous System Infections. Courses in Therapeutics and Disease State Management. Learning Objectives (Slide 1 of 3). Define meningitis and  encephalitis

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Infectious Disease I: Central Nervous System Infections

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  1. Infectious Disease I:Central Nervous System Infections Courses in Therapeutics and Disease State Management

  2. Learning Objectives (Slide 1 of 3) • Define meningitis and encephalitis • List, in order of relative incidence, the most common age-dependent bacterial causes of meningitis, and identify the fatality rate associated with each • Analyze laboratory values of CSF components and describe the values as normal or as indicative of a specific infective condition • Identify the common signs and symptoms of bacterial meningitis • Select appropriate empirical therapy directed against suspected bacterial meningitis according to age group

  3. Learning Objectives (Slide 2 of 3) • List the antibiotic of first choice and alternatives to treat meningitis secondary to Streptococcus pneumoniae, Neisseria meningitidis, and Haemophilus influenzae • Identify general principles of chemoprophylaxis after exposure to H. influenzae and N. meningitidis index cases • List the physiochemical properties associated with increased penetration of antibiotics into the CNS • Classify antibiotics according to level of penetration into the CNS • List three reasons why corticosteroid use in bacterial meningitis is controversial

  4. Learning Objectives (Slide 3 of 3) • Assess the value of dexamethasone as adjunctive therapy in meningitis • Discuss the role vaccination plays in the prevention of meningitis and what impact vaccination is having on the epidemiology of meningitis • Select appropriate antifungal therapy to treat Cryptococcus neoformans • List the viruses most commonly associated with encephalitis and meningoencephalitis and provide recommendations for therapy as appropriate

  5. Required Reading • Elshaboury RH, Hermsen ED, Holt JS, Mitropoulos IF, Rotschafer JC. Chapter 84. Central Nervous System Infections In: DiPiro JT, Talbert RL, Yee GC, Matzke GR, Wells BG, Posey L. eds. Pharmacotherapy: A Pathophysiologic Approach, 9e. New York, NY: McGraw-Hill; 2014. • Tunkel AR, Hartman BJ, Kaplan SL, et.al.. 2004. Practice guidelines for the management of bacterial meningitis. Clin. Infect. Dis. 39:1267-1284. • Tunkel AR, Hasbun R, Bhimraj A, et.al.. 2017 Infectious Diseases Society of America’s Clinical Practice Guidelines for Healthcare-Associated Ventriculitis and Meningitis. Clin Infect Dis 2017; 64 (6): e34-e65.

  6. Overview (Slide 1 of 2) • Infections involving the brain, spinal cord, and associated tissues, fluids, and membranes • Meningitis • Encephalitis • Brain Abscess • Shunt infections • Postoperative infections • High rates of mortality and morbidity

  7. Overview (Slide 2 of 2) • Community Acquired Meningitis • Healthcare-associated Ventriculitis and Meningitis • Cerebrospinal fluid (CSF) shunts • CSF drains • Intrathecal infusion pumps  • Deep brain stimulation hardware • Neurosurgery or Head Trauma

  8. Pathophysiology • Blood Brain Barrier • Pathogen gain entry to the CNS • Contiguous spread • Hematogenous seeding • Direct inoculation • Reactivation of a latent infection • Damage occurs due to immune response to bacterial cellular components Schematic representation of a blood–cerebrospinal fluid barrier capillary, brain tissue capillary, and normal tissue capillary.

  9. Acute Bacterial Meningitis: Most Common Pathogens • Community Acquired Meningitis • Streptococcus pneumoniae • Group B Streptococcus • Neisseria meningitidis • H. influenzae • Listeria monocytogenes • Healthcare-associated Ventriculitis and Meningitis • Community Acquired Meningitis pathogens • Gram negative bacilli • Staphylococcus aureus • Coagulase-negative staphylococci • Propionibacterium acnes Hypothetical schema of pathophysiologic events that occur during bacterial meningitis. (IL-1, interleukin 1; TNF, tumor necrosis factor; PAF, platelet-activating factor; CBF, cerebral blood flow; CSF, cerebrospinal fluid; PGE2, prostaglandin E2; ICP, intracranial pressure.)

  10. Clinical Presentation, Signs and Symptoms (Slide 1 of 2) • Headache • Fever • Nuchal rigidity • Altered mental Status • Nausea • Focal neurological deficits • Brudzinski’s sign • Kernig’s sign • Seizures • Photophobia • Skin lesions • Petechial rash • Neonates • Altered feeding/ sleeping • Bulging fontanel • Seizures • Irritability/ lethargy

  11. Clinical Presentation, Signs and Symptoms (Slide 2 of 2) Link: Schematic of Brudzinski’s signs Link: Schematic of Kernig’s sign

  12. Laboratory Tests • Lumbar Puncture • Opening Pressure • CSF composition • CSF gram stain • CSF culture • Blood Cultures • Scraping of skin lesions • WBC • Cranial Imaging • Magnetic resonance imaging (MRI) • Computed tomography (CT) scan

  13. Mean Values of the Components of Normaland Abnormal Cerebrospinal Fluid aInitial cerebrospinal fluid (CSF) and while blood cell (WBC) count may reveal a predominance of polymorphonuclear leukocytes (PMNs).

  14. Goals of Therapy • Prevent Death • Prevent residual neurological deficits • Eradicate or control invading organism by starting appropriate antimicrobial therapy • Ameliorate clinical signs and symptoms • Provide supportive care • Prevent future infections through timely introduction of vaccination and chemoprophylaxis

  15. Nonpharmacological Treatment • Respiratory and Circulatory Support as needed

  16. Pharmacological Treatment • Early administration of appropriate antimicrobial therapy • Antimicrobial agents must have sufficient CNS penetration • Initial empiric antimicrobial therapy based on patient specific factors • Focused and targeted antimicrobial therapy once pathogen identified • Supportive Care • Fluids • Electrolytes • Antipyretics • Analgesics

  17. Antimicrobial Penetration into the CSF (Table 1 of 3)

  18. Antimicrobial Penetration into the CSF(Table 2 of 3) *May not achieve therapeutic levels against organisms with higher MIC, as in P. aeruginosa. Tazobactam does not penetrate blood–brain barrier.

  19. Antimicrobial Penetration into the CSF(Table 3 of 3) ⱡCefuroxime is an exception. ◊Documented effectiveness for Borrelia burgdorferi. □Includes clavulanic acid, sulbactam, and tazobactam. ∆ Achieves therapeutic concentrations for Cryptococcus neoformans therapy.

  20. Empiric Therapy: Most Common Pathogens by Age (Slide 1 of 4) • Less than 1 months old • Pathogens • S. agalactiae • E. coli • Klebsiella pneumoniae • Enterobacter spp. • Listeria monocytogenes • Empiric Antibiotics • Ampicillin IV plus cefotaxime IV or ampicillin IV plus aminoglycoside IV

  21. Empiric Therapy: Most Common Pathogens by Age (Slide 2 of 4) • 1-23 months old • Pathogens • Streptococcus pneumoniae • Neisseria meningitidis • H. influenzae • S. agalactiae • Empiric Antibiotics • Vancomycin IV plus third-generation cephalosporin IV (cefotaxime or ceftriaxone)

  22. Empiric Therapy: Most Common Pathogens by Age (Slide 3 of 4) • 2-50 years • Pathogens • Neisseria meningitidis • Streptococcus pneumoniae • Empiric Antibiotics • Vancomycin IV plus third-generation cephalosporin IV (cefotaxime or ceftriaxone)

  23. Empiric Therapy: Most Common Pathogens by Age (Slide 4 of 4) • > 50 years • Pathogens • Neisseria meningitidis • Streptococcus pneumoniae • Listeria monocytogenes • E. coli • Klebsiella pneumoniae • Enterobacter spp. • Empiric Antibiotics • Ampicillin IV plus third-generation cephalosporin IV (cefotaxime or ceftriaxone) plus vancomycin IV

  24. Empiric Therapy: Most Common Pathogen Healthcare-associated Ventriculitis and Meningitis • Pathogens • Community Acquired Meningitis pathogens • Gram negative bacilli • Staphylococcus aureus • Coagulase-negative staphylococci • Propionibacterium acnes • Empiric Antibiotics • Vancomycin IV or Linezolid IV plus ceftazidime IV or cefepime IV, or meropenem IV

  25. Streptococcus pneumoniae Targeted Therapy(Slide 1 of 3) • Penicillin MIC < 0.1 mg/L • Standard Therapy • Penicillin G 4 million units IV Q4H • Ampicillin 2 gm IV Q4H • Alternate Therapies • Ceftriaxone 2 gm IV Q12H • Cefotaxime 2 gm IV Q4H • True β-lactam Allergy • Chloramphenical 50-100 mg/kg/day in divided doses every 6 hours; max daily dose: 4 g/day • Duration of treatment • 10-14 days

  26. Streptococcus pneumoniae Targeted Therapy (Slide 2 of 3) • Penicillin MIC 0.1-1 mg/L • Standard Therapy • Ceftriaxone 2 gm IV Q12H • Cefotaxime 2 gm IV Q4H • Alternate Therapies • Meropenem 2 gm IV Q8H • Cefepime 2 gm IV Q8H • True β-lactam Allergy • Chloramphenical 50-100 mg/kg/day in divided doses every 6 hours; max daily dose: 4 g/day • Duration of treatment • 10-14 days

  27. Streptococcus pneumoniae Targeted Therapy (Slide 3 of 3) • Penicillin MIC > 2 mg/L or Ceftriaxone MIC ≥ 1 • Standard Therapy • Ceftriaxone 2 gm IV Q12H PLUS Vancomycin • Cefotaxime 2 gm IV Q4H PLUS Vancomycin • Alternate Therapies • Moxifloxacin 400 mg IV q24H • Duration of treatment • 10-14 days

  28. Neisseria meningitidis Targeted Therapy (Slide 1 of 2) • Penicillin MIC < 0.1 mg/L • Standard Therapy • Penicillin G 4 million units IV Q4H • Ampicillin 2 gm IV Q4H • Alternate Therapies • Ceftriaxone 2 gm IV Q12H • Cefotaxime 2 gm IV Q4H • Chloramphenical 50-100 mg/kg/day in divided doses every 6 hours; max daily dose: 4 g/day • Duration of treatment • 7-10 days

  29. Neisseria meningitidis Targeted Therapy (Slide 2 of 2) • Penicillin MIC 0.1-1 mg/L • Standard Therapy • Ceftriaxone 2 gm IV Q12H • Cefotaxime 2 gm IV Q4H • Alternate Therapies • Meropenem 2 gm IV Q8H • Cefepime 2 gm IV Q8H • True β-lactam Allergy • Moxifloxacin 400 IV Q24H • Chloramphenical 50-100 mg/kg/day in divided doses every 6 hours; max daily dose: 4 g/day • Duration of treatment • 7-10 days

  30. H. influenza Targeted Therapy (Slide 1 of 2) • β-lactamase negative • Standard Therapy • Ampicillin 2 gm IV Q4H • Alternate Therapies • Ceftriaxone 2 gm IV Q12H • Cefotaxime 2 gm IV Q4H • Cefepime 2 gm IV Q8H • True β-lactam Allergy • Moxifloxacin 400 IV Q24H • Chloramphenical 50-100 mg/kg/day in divided doses every 6 hours; max daily dose: 4 g/day • Duration of Treatment • 7-10 days

  31. H. influenza Targeted Therapy(Slide 2 of 2) • β-lactamase positive • Standard Therapy • Ceftriaxone 2 gm IV Q12H • Cefotaxime 2 gm IV Q4H • Alternate Therapies • Cefepime 2 gm IV Q8H • True β-lactam Allergy • Moxifloxacin 400 IV Q24H • Chloramphenical 50-100 mg/kg/day in divided doses every 6 hours; max daily dose: 4 g/day • Duration of Treatment • 7-10 days

  32. Listeria monocytogenes Targeted Therapy • Standard Therapy • Ampicillin 2 gm IV Q4H • Alternate Therapies • Meropenem 2 gm IV Q8H • True β-lactam Allergy • Trimethoprim/ Sulfamethoxazole IV • 10-20 mg TMP/kg/day in divided doses every 6-12 hours • Duration of Treatment • 21 days

  33. Methicillin Susceptible Staphylococcus Aureus Targeted Therapy • Standard therapy • Nafcillin or Oxacillin 1.5-3 gm IV Q4H • Alternate Therapy • Meropenem 2 gm IV Q8H • True β-lactam Allergy • Vancomycin • Duration of Treatment • 2-3 weeks • 4-6 weeks if shunt involved

  34. Methicillin Resistant Staphylococcus Aureus Targeted Therapy • Standard Therapy • Vancomycin • Alternate Therapy • Trimethoprim/ Sulfamethoxazole • 10-20 mg TMP/kg/day in divided doses every 6-12 hours • Linezolid 600 mg IV Q12H • Duration of Treatment • 3-4 weeks • 4-6 weeks if shunt involved

  35. Cryptococcus neoformans Targeted Therapy • Standard Therapy • Amphotericin B combined with flucytosine for 2 weeks • Alternate Therapy • Amphotericin B • Amphotericin B plus High dose Fluconazole • Amphotericin B plus Voriconazole or Itraconazole • Duration of Treatment • 2 to 6 weeks of induction therapy • 8 weeks of consolidation therapy

  36. Viral Encephalitis and Meningoencephalitis Targeted Therapy • Common Viruses • Herpes simplex virus • West Nile virus • Enteroviruses • Standard Therapy • Acyclovir 10 mg/kg IV Q8H • Alternate Therapy • Foscarnet 120-200 mg/kg IV per day in divided doses every 8-12 hours • Duration of Treatment • 14-21 days

  37. Dexamethasone • Corticosteroids inhibit the production of pro-inflammatory cytokines • Clinical trial data surrounding the benefits of corticosteroids in meningitis is conflicting • A series trials and systematic review showed steroids may improve neurological and mortality outcomes in adult patients • A larger trial showed conflicting data • Various antimicrobial agents were used • Dexamethasone was administered at different times in relation to the first antimicrobial dose • Patients had varying levels of illness severity • Overall use of corticosteroids in the setting of meningitis is controversial

  38. Dexamethasone Recommendations • Infants and children • H. influenza: Dexamethasone 0.15 mg/kg Q6H for 2-4 days • Administer before or concurrently with the first dose of antibiotics • Pneumococcal: not routinely recommended must weigh risk versus benefit • Adults • Pneumococcal: Dexamethasone 10 mg IV Q6H for 2-4 days • Administer before or concurrently with the first dose of antibiotics • Other bacterial causes of meningitis: not routinely recommended

  39. Evaluation of Outcomes • Monitor the following every 4 hours for 3 days • Fever • Headache • Meningismus • Vital signs • Acute changes in Mental Status/ Glasgow Coma Scale • Adjust antimicrobial therapy based on microbiologic findings

  40. Prophylactic Antibiotics (Slide 1 of 2) • Prophylaxis of close contacts should be started only after consultation with the local health department • Close Contacts • Members of same household • Individuals who share the same sleeping quarters • Day care contacts • Individuals exposed to oral secretions of infected patient

  41. Prophylactic Antibiotics (Slide 2 of 2) • Neisseria meningitidis • Close contacts • Rifampin 600 mg PO BID x 2 days • Ciprofloxacin 500 mg PO x1 dose • Ceftriaxone 250 mg IM x 1 dose • Azithromycin 500 mg PO x 1 dose • H. influenza • Close Contacts • Rifampin 600 mg PO BID x 4 days • Fully vaccinated children do not require prophylactic antibiotics

  42. Vaccination • Neisseria meningitidis • Meningococcal Polysaccharide Vaccine (Groups A / C / Y and W-135) • Meningococcal (Groups A / C / Y and W-135) Diphtheria Conjugate Vaccine • Meningococcal Group B vaccine • Streptococcus pneumoniae • Pneumococcal Conjugate Vaccines • 7-valent • 13-valent • Pneumococcal Polysaccharide Vaccine • 23-valent • H. influenza • Hib Conjugate vaccine

  43. Summary • Meningitis is an infection of the central nervous system with high rates of morbidity and mortality • Early identification of meningitis and early initiations of antibiotics is key to improve outcomes • High doses of antimicrobials that penetrate the CNS are required • Adjust therapy as soon as cultures finalized • Prevention with vaccination and prophylactic antibiotics

  44. References • Elshaboury RH, Hermsen ED, Holt JS, Mitropoulos IF, Rotschafer JC. Chapter 84. Central Nervous System Infections In: DiPiro JT, Talbert RL, Yee GC, Matzke GR, Wells BG, Posey L. eds. Pharmacotherapy: A Pathophysiologic Approach, 9e. New York, NY: McGraw-Hill; 2014. • Tunkel AR, Hartman BJ, Kaplan SL, et.al.. 2004. Practice guidelines for the management of bacterial meningitis. Clin. Infect. Dis. 39:1267-1284. • Tunkel AR, Hasbun R, Bhimraj A, et.al.. 2017 Infectious Diseases Society of America’s Clinical Practice Guidelines for Healthcare-Associated Ventriculitis and Meningitis. Clin Infect Dis 2017; 64 (6): e34-e65.

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