1. M ENINGITIS Bacterial Pathogenesis

2. W HAT IS MENINGITIS ? …… oThe brain and spinal cord are covered by connective tissue layers collectively called the meninges which form the blood-brain barrier. 1-the pia mater (closest to the CNS) 2-the arachnoid mater 3-the dura mater (farthest from the CNS). The meninges contain cerebrospinal fluid (CSF).

4. W HAT IS MENINGITIS ? Meningitis is an inflammation of the meninges, which, if severe, may become encephalitis, an inflammation of the brain. Clinical syndrome involving inflammation of the brain membrane and characterized by headache, nuchal rigidity ( neck stiffness ), photophobia and CSF changes. Depending on the duration of the symptoms, meningitis may be classified as acute or chronic. Acute meningitis denotes the evolution of symptoms within hours to several days, while chronic meningitis has an onset and duration of weeks to months. The duration of symptoms of chronic meningitis is characteristically at least 4 weeks.

7. A CUTE BACTERIAL MENINGITIS CAUSED BY S. PNEUMONIAE Presently the most common cause of meningitis Causes meningitis by escaping the local host defenses and phagocytic mechanisms May be associated with other foci of infection such as pneumonia, sinusitis, or endcarditis

8. A CUTE BACTERIAL MENINGITIS CAUSED BY N. MENINGITIS Initiates invasion by penetrating the airway epithelial surface. Leading cause of bacterial meningitis and meningococcemia in children and young adults. Risk factors: (1) deficiency in terminal complement components (C5-C9), (2) Properdin defects that increase the risk of invasive disease, (3) household crowding, chronic medical illness, use of corticosteroid, smoking, (4) overcrowding e.g. in college dormitories etc.

9. A CUTE BACTERIAL MENINGITIS CAUSED BY H. INFLUENZAE Can spread from one individual to another by airborne droplets or direct contact with secretions. Most serious acute manifestation of systemic infection Primarily affects infants under 2 years. Its isolation in adults suggests presence of underlying medical disorder including sinusitis, alcoholism, etc.

10. A CUTE BACTERIAL MENINGITIS CAUSED BY L ISTERIA MONOCYTOGENES Associated with one of the highest mortality rates. Outbreaks associated with comtaminated milk and cheese. Persons at risk include pregnant women, infants and children, elderly individuals, patients with alcoholism, adults who are immunocompromised, individuals with chronic liver and renal disease, individuals with diabetes, and those with conditions of iron overload

11. A CUTE BACTERIAL MENINGITIS CAUSED BY S. AGALACTIAE Most common agent of neonatal menintigis. Also reported in adults, primarily affecting individuals older than 60 years. Predisposing factors are diabetes mellitus, pregnancy, alcoholism, hepatic failure, renal failure and corticosteroid treatment.

12. A CUTE BACTERIAL MENINGITIS CAUSED BY AEROBIC GRAM - NEGATIVE BACILLI E.g. E. coli, Klebsiella pneumoniae, Serratia marcescens, P. aeruginosa, Salmonella species. E. coli is the common agent of meningitis among neonates. Predisposing factors include (1) neurosurgical procedures or intracranial manipulation; (2) old age ; (3) immunosuppression ; (4) high-grade gram negative bacillary bacteremia ; and (5) disseminated strongyloidiasis.

13. A CUTE BACTERIAL MENINGITIS CAUSED BY S TAPHYLOCOCCUS SPECIES Risk factors: (1) status postneurosurgery and posttrauma, (2) presence of CSF shunts, and (3) infective endocarditis and paraspinal infection. Staphylococcus epidermidis is the most common cause of meningitis in patients with CNS shunts.

14. A CUTE VIRAL MENINGITIS Caused by enteroviruses, Herpesviurs, mumps virus, Adenovirus, etc. Usually spread by fecal-oral or respiratory routes and occurs during summer and fall in temperate climates and year-round in tropical regions. Mostly occurs in individuals younger than 15 years, with highest attack rates in children who are younger than 1 year.

16. C HRONIC BACTERIAL MENINGITIS CAUSED BY M. TUBERCULOSIS Humans are only reservoirs.

17. C HRONIC BACTERIAL MENINGITIS CAUSED BY T. PALLIDUM Usually acquired by sexual contact Other modes of transmission include direct contact with an active lesion, passage through the placenta, and blood transfusion.

18. C HRONIC BACTERIAL MENINGITIS CAUSED BY B. BURGDORFERI Although rare during stage I of lyme disease, CNS involvement may occur, involving meningitis at this time.

19. F UNGAL MENINGITIS Fungal meningitis caused by C. neoformans (fungus), C. immitis, H. capsulatum, Candida species.

20. T REATMENT Bacterial meningitis: Choice of antibiotic depends on the kind of bacteria that cause meningitis. OrganismAntibioticAlternative (eg. allergy) Unknown pyogenic Cefotaxime( 50 g/kg intravenously every 6 hrs) Benzylpenicilin or Chloramphenicol MeningococcusBenzylpenicilinCefotaxime PneumococcusCefotaximePenicillin HaemophilusCefotaximeChloramphenicol

21. T REATMENT ( CONTINUED ) Viral meningitis: requires supportive therapy, most viruses are not amenable to specific treatment. Fungal meningitis: long courses of highly dosed antifungals, such as amphotericin B and flucytosine

22. Neonatal meningitis by Group B Streptococci.

24. P ATHOGENESIS OF N EONATAL D ISEASE Vaginal colonization in pregnant women Adherence to epithelial cells and resisting mucosal immune defenses Fetus aspirates infected fluid as organism ascends into the amniotic cavity by penetration of placental membranes or at time of delivery Bacteria enter the fetal lung through aspiration of infected amniotic fluid.

25. P ATHOGENESIS OF N EONATAL D ISEASE Pneumonia with lung epithelial and endothelial cell injury are characteristic of early disease, cytotoxic properties of ß-hemolysin and the influx of host neutrophils. GBS invade alveolar epithelial and pulmonary endothelial cells within membrane-bound vacuoles Newborn infants, particularly premature infants, have fewer alveolar macrophages than adults and exhibit poor neutrophil chemotaxis. GBS are inefficiently phagocytosed in the absence of opsonization by specific antibody or complement, diminished in neonatal serum.

26. P ATHOGENESIS OF N EONATAL D ISEASE Polysaccharide capsule of GBS has a marked inhibitory effect on phagocytic clearance by preventing complement deposition on the bacterial surface. Components of GBS surface protein C may both retard opsonization and decrease killing of GBS taken up by neutrophils

27. P ATHOGENESIS OF N EONATAL D ISEASE Cell wall-associated components of circulating GBS induce a sepsis syndrome characterized by severe systemic hypotension, pulmonary hypertension, hypoxemia and acidosis. Effects of a host inflammatory response mediated by release of tumor necrosis factor (TNFalpha), interleukins, prostaglandins and thromboxane. Bloodstream dissemination allows GBS to reach multiple body sites, and invasion of brain microvascular endothelial cells may be the first step in production of meningitis.

28. P ATHOGENESIS Doran, Kelly S. & Nizet, Victor. Molecular pathogenesis of neonatal group B streptococcal infection: no longer in its infancy. Molecular Microbiology 2004;54:23-31. Fig. 1. Stages in the molecular and cellular pathogenesis of neonatal group B Streptococcal (GBS) infection.

29. P ATHOGENESIS Maximal cell adherence at acidic pH of vaginal mucosa Selective fibronectin adherence mediated by RogB and FbsA Rib protein expressed by invasive isolates Traverses chorionic (of or relating to the outermost of the two fetal membranes that surrounds the embryo), not amniotic (of or relating to the innermost of the two fetal membranes that surrounds the embryo), cells by generation of oxygen radicals and PGE2 Suspected association with membrane rupture and preterm delivery

30. P ATHOGENESIS Infant lung damage: intracellular invasion, direct cytolytic injury, and damage induced by the inflammatory response Loss of pulmonary and blood-brain barrier integrity due to β-hemolysin/cytolysin promoting IL-8 release Effects can be neutralized by major surfactant phospholipid constituent CAMP factor triggers cell lysis by creating discrete pores Conserved GBS surface proteins (ScpB, Sip, BSP)

31. V IRULENCE F ACTOR GBS S URFACE P OLYSACCHARIDE C APSULE Antiphagocytic properties Capsule-deficient mutants diminished virulence in animal models Sialic acid residues on capsule inhibit the binding of opsonically- active C3 component of complement to the cell surface blocking activation of the alternative pathway http://medicine.ucsd.edu/NizetLab

32. V IRULENCE F ACTOR GBS S URFACE P OLYSACCHARIDE C APSULE ( CONTD.) Transplacental passage of type-specific anticapsular IgG antibody from mother to infant is an important protective factor against invasive disease

33. V IRULENCE F ACTOR GBS Β - HEMOLYSIN Cytotoxic to pulmonary epithelial and endothelial cells Pulmonary injury and alveolar protein exudate in early-onset pneumonia Activity is blocked by surfactant phospholipid Induces cytokine release and nitric oxide production in macrophages Stimulate elements of the sepsis cascade

34. V IRULENCE F ACTOR C5 A - PEPTIDASE Cleaves and inactivates the complement-derived neutrophil chemoattractant C5a C5a-peptidase-deficient mutants are more rapidly cleared from the lungs of infected animals when compared to the isogenic wild-type strain

35. ‘G LASS T EST ’ A rash that does not fade under pressure will still be visible when the side of a clear drinking glass is pressed firmly against the skin. If someone is ill or obviously getting worse, do not wait for a rash. It may appear late or not at all. A fever with a rash that does not fade under pressure is a medical emergency.

36. The End…