BACTERIAL MENINGITIS. Alan J. Lesse, M.D.

Transcription

1 BACTERIAL MENINGITIS Alan J. Lesse, M.D.

2 Learning Objectives After listening to this lecture, you should be able to: Predict the most likely bacteria causing meningitis based on the patient s age and underlying disease Recommend antibiotic treatment for patients with meningitis based on that epidemiology Understand the major risks of lumbar puncture and the contraindications to performing a lumber puncture Predict the etiologic agent of meningitis based on spinal fluid results for glucose, protein, cell count, and differential. You should be able to predict bacterial, viral, fungal, and tubercular meningitis based on those results.

3 Great Review Community-acquired bacterial meningitis. van de Beek D, Brouwer M, Hasbun R, Koedel U, Whitney CG, Wijdicks E. Nat Rev Dis Primers Nov 3;2: doi: /nrdp Review.

4 Come Back to My Residency With Me Called to the ER. (Profound sense of depression ensues) 21 yo male honor student at college was brought to the ER 2 hours previously for suspected overdose. He was found asleep with his mother s bottle of phenobarbital next to him. Mother didn t know if any pills were missing.

5 Case Routine exam in ER shows somulent male without focal findings on neurologic examination. Routine blood work sent off and shows nothing other than a mildly elevated white blood cell count. Allowed to sleep while labs are sent. When labs return normal it was decided that he could be discharged home with observation. Prior to discharged they aroused the student and took a temperature for discharge vital signs- temperature 103 F.

6 Uh-oh ER physician re-examines patient and finds him barely arousable. His neck is now stiff. He performs a lumbar puncture and calls me down to admit patient. When I arrive in ER there s a tube of spinal fluid, obviously turbid from across the room and he says, See, I did all your work for you! I said Have you given him any antibiotics yet? When the response was, No, I was waiting to see what you wanted to give him. I said:!#@$%#%!%@^%! (Under my breath!). Out loud I said Draw up 4 million units of penicillin while I examine him and start it STAT.

7 Physical examination Comatose male with board-like neck on flexion. These lesions on the fingers.

8 Initial Lesions on Fingers and Toes

9 Went on to

10 Buffy Coat

11 Diagnosis Meningococcemia with menigococcal meningitis and purpura fulminans

12 Lancet 2012; 380:

13 Bacterial Meningitis A life-threatening medical emergency!!! Studies have shown a direct correlation between survival and delay in antibiotic therapy Rapid assessment and therapy are paramount in the treatment of this disease

14 Definition Meningitis Bacterial meningitis is an acute purulent infection within the subarachnoid space. The meninges, the subarachnoid space, and the brain parenchyma are all involved in the inflammatory reaction; as such, meningoencephalitis is the more accurate descriptive term. Harrison s Online Chapter 372: Bacterial Meningitis and Other Suppurative Infections

15 Epidemiology Approximately 2.5 cases/100,000 population Recent change in epidemiology H. influenzae meningitis declined precipitously following the introduction of the H. influenzae type b (Hib) vaccine in 1987 accounts for <10% of bacterial meningitis cases Increasing prevalence of penicillin- and cephalosporin-resistant strains of S. pneumoniae. Meningococcal infections on college campuses Meningococcal disease in North America and Europe due to the emergence of a virulent strain of serogroup C, serotype 2a N. meningitidis. Harrison s Online Chapter 372: Bacterial Meningitis and Other Suppurative Infections

16 Epidemiology Annual meningitis epidemics, caused primarily by the serogroup A meningococcus, continue to occur in the meningitis belt of sub-saharan Africa. Epidemics due to the serogroup B meningococcus continue to occur in Europe, Latin America, and New Zealand.

17 Figure 2 The meningitis belt Adapted from MacNeil, J. R. & Meyer, S. A. Chapter 3: infections related to travel: meningococcal disease. CDC (updated 10 July 2015), which was produced using data from the WHO ( van de Beek, D. et al. (2016) Community-acquired bacterial meningitis Nat. Rev. Dis. Primers doi: /nrdp

18 Epidemiology Group B streptococcus or S. agalactiae was previously responsible for meningitis predominantly in neonates, but it has been reported with increasing frequency in individuals >50 years, particularly those with underlying diseases. L. monocytogenes has emerged as an important cause of bacterial meningitis in the elderly and in individuals with impaired cell-mediated immunity.

19 Success of H. influenzae type b Vaccine N Engl J Med 1997;337:970-6

20 Figure 5 Effect of conjugate vaccines on bacterial meningitis infections van de Beek, D. et al. (2016) Community-acquired bacterial meningitis Nat. Rev. Dis. Primers doi: /nrdp

21 Bacterial Epidemiology Consider the Table to Be RED Age Group Pathogens Neonates (within 72 hrs of birth) Infants less than 6 mo Children from 6 mo- 2yr 2yr-19 yo >60 E. coli Group B Streptococcus Listeria monocytogenes E. coli Group B Streptococcus Streptococcus pneumoniae Streptococcus pneumoniae Neisseria meningitidis Neisseria meningitidis Streptococcus pneumoniae Streptococcus pneumoniae Neisseria meningitidis Streptococcus pneumoniae Group B Streptococcus Listeria monocytogenes

22 Pathophysiology of Meningitis Colonization of the nasopharynx Bacteria are transported across epithelial cells Bloodstream access Intraventricular choroid plexus Entry into CSF Harrison s Online Chapter 372: Bacterial Meningitis and Other Suppurative Infections

23 Figure 1 Anatomical considerations for the diagnosis of bacterial meningitis van de Beek, D. et al. (2016) Community-acquired bacterial meningitis Nat. Rev. Dis. Primers doi: /nrdp

24 Figure 3 Microbial survival in the bloodstream and central nervous system invasion van de Beek, D. et al. (2016) Community-acquired bacterial meningitis Nat. Rev. Dis. Primers doi: /nrdp

25 Figure 4 Host pathogen interactions and immune activation in bacterial meningitis van de Beek, D. et al. (2016) Community-acquired bacterial meningitis Nat. Rev. Dis. Primers doi: /nrdp

26 Pathophysiology Bacteria rapidly multiply within CSF Decreased or absent WBC, complement and immunoglobulins Phagocytosis is impaired Area of impaired host immunity Many neurologic manifestations result from the inflammatory response and not the bacteria. As a result, neurologic injury can progress even after the CSF has been sterilized by antibiotic therapy. The lysis of bacteria lipopolysaccharide (LPS) teichoic acid and peptidoglycans Leukocytes Tumor necrosis factor (TNF) and interleukin (IL) 1 appear in the CSF within 1 to 2 h of intracisternal inoculation of LPS Followed by an increase in CSF protein concentration and leukocytosis. Harrison s Online Chapter 372: Bacterial Meningitis and Other Suppurative Infections

27 Pathogenesis Cytokines and chemokine TNF and IL-1 increase the permeability of the blood-brain barrier Exudate and proteins decrease the resorptive capacity of the arachnoid granulations leading to obstructive and communicating hydrocephalus Increased expression of selectins More leukocytes in CSF Adds to the inflammatory exudate. Neutrophil degranulation results in the release of toxic metabolites that contribute to cytotoxic edema, cell injury, and death. Harrison s Online Chapter 372: Bacterial Meningitis and Other Suppurative Infections

28 N Engl J Med 2006;354:44-53.

29 N Engl J Med 2006;354:44-53.

30 Mortality of bacterial meningitis 1990 s 6%, 10%, 25% 2000 s 6%, 10%, 25%

31 n engl j med 351;18 october 28, 2004

32 Clinical Presentation Classic Tetrad Fever Headache Altered mental status Stiff neck

33 Symptoms of meningitis in elderly

34 Do You Know Your Signs Kernig Kernig's original description, when patients sat on the edge of a bed with their legs dangling, an attempt to extend the knee joint more than 135 degrees, or in severe cases more than 90 degrees, elicited spasm of the extremity that disappeared when the patient lay supine or stood up. Today, the maneuver is most commonly performed with the patient lying supine and the hips and knees flexed at 90 degrees. A positive sign is present when extension of the knee from this position elicits resistance or pain in the lower back or posterior thigh. Attia et al. Does this patient have meningitis. JAMA :

35 Brudzinski Polish physician, described many meningeal signs in children. His best known "nape of the neck" sign (Brudzinski sign) is passive neck flexion in a supine patient results in flexion of the knees and hips. A separate sign, the contralateral reflex, is present if passive flexion of one hip and knee causes flexion of the contralateral leg. Are they sensitive, especially in the adult or elderly Attia et al. Does this patient have meningitis. JAMA :

36 Clinical Accuracy of Exam 696 episodes of menigitis in the Netherlands Only 44% had classic tetrad Van de Beek N Engl J Med 2004;351:

37 Diagnosis Lumbar puncture is required DO NOT TALK YOURSELF OUT OF THE NEED TO DO AN LP!!!!! There are risks to LP Herniation Nerve injury Bleeding Infection

38 When NOT to LP Unilateral findings on PE Papilledema

39 Lancet 2012; 380:

40 Lumbar Puncture Contraindications Lancet Infect Dis 2007; 7:

41 Spinal Fluid Analysis Bacterial Meningitis Low Glucose general less than 40 mg/dl or.5 CSF/serum ratio Elevated Protein generally Neutrophilic pleocytosis >100 wbc/hpf with >90% neutrophils Positive Gram stain

42 Spinal Fluid Formula Leukocytes Protein Glucose Comment Bacterial >100 mainly neutrophils <40 or <.4 ratio Neutrophilic with low glucose and high protein Viral Slightly elevated Normal Lymphocytic normal glucose & slightly raised protein Fungal mainly lymphs Low Lymphocytic lower glucose & raised protein TB mainly lymphs may be much higher Low and very low Lymphocytic with low glu & high protein

43 Differential Diagnosis Bacterial meningitis Viral meningitis/encephalitis Fungal meningitis Brain Abscess Parameningeal Focus Other

44 Therapy Neonates: Ceftriaxone (High dose) + Ampicillin (High Dose) + Vanco (For penicillin-resistant pneumococcus Adults Ceftriaxone (High dose) + Vanco (For penicillin-resistant pneumococcus Elderly or Cell-Mediated Immunodeficiency Ceftriaxone (High dose) + Vanco (For penicillin-resistant pneumococcus + Ampicillin (High Dose)

45 Principals of Therapy for Meningitis Agent MUST enter CNS at high concentrations above the MIC (example: ceftriaxone) Agent MUST be bacteriocidal Agent must be active against the suspected pathogens (adding ampicillin for Listeria or vancomycin for Penicillin-resistant pneumococcus)

46 What if you need a CT? Treat with ATB prior to CT scan Get blood cultures prior to ATB Additional studies on spinal fluid

47 Steroids for Adult Meningitis? (N Engl J Med 2002;347: )

48 Problems with Steroids Concentration of vancomycin in CSF is decreased by dexamethasone therapy Study did not have any cases of penicillin-resistant pneumococcus As rates of PRSP increase, the advantage of steroid may decrease

49 Predictive Factors for Outcome Aronin et al. Ann Intern Med.1998;129: Three baseline clinical features (hypotension, altered mental status, and seizures) were independently associated with adverse clinical outcome Adverse clinical outcome was more common for patients in whom the prognostic stage advanced from low risk (P = 0.008) or intermediate risk (P = 0.003) at arrival in the emergency department to high risk before administration of antibiotics. Delay in therapy after arrival in the emergency department was associated with adverse clinical outcome when the patient's condition advanced to the highest stage of prognostic severity before the initial antibiotic dose was given.

50 Prevention Vaccine Chemoprophylaxis

51 Aerobic Gram Negative Bacteria Cocci Rods Grows on MacConkey Agar Neisseria N. gonorrhoeae N. meningitidis Moraxella Moraxella catarrhalis Kingella Escherichia Enterobacter Klebsiella Slow or variable lactose Citrobacter Serratia Yes Yes Lactose Fermentor No Glucose Fermentor No Non-enteric Growth Requirements Haemophilus Actinobacillus Cardiobacterium Eikenella Bordetella Brucella Francisella Pasteurella Legionella Proteus Providentia Salmonella Shigella Yersinia Vibrio* Aeromonas* Yes No Positive Oxidase Negative Pseudomonas Burkholderia Alcaligenes Stenotrophomonas Acinetobacter

52 Hemolysis classification Aerobic Gram Positive Bacteria Cocci Rods Listeria Corynebacteria Bacillus Erysipelothrix Catalase negative Catalase positive Chains Clusters Streptococcus Enterococcus Staphylococcus Lancefield Grouping Group A S. pyogenes Group B S. agalactiae Groups,C,D,F,G and others Enterococcus faecalis Enterococcus faecium Enterococus durans others Formerly Group D Strep Coagulase positive Staphylococcus aureus Coagulase negative Coagulasenegative staphylococci Non-Lancefield Groupable Viridans Streptococci Streptococcus pneumoniae

53 Meningeal Pathogens Streptococcus pneumoniae Pulmonary Section Haemophilus influenzae Pulmonary Neisseria meningitidis IMC516 and Today Listeria monocytogenes IMC516 and Today E. coli and Group B Streptococcus Renal and Musculoskeletal

54 Neisseria meningitidis Causes sporadic disease in the U.S. (2400/year) Leading cause of meningitis in young adults High case-fatality ratio (50% untreated; 8-10% of treated) Epidemic killer world-wide associated with specific capsular polysaccharide types (A,B,C and Y) Epidemics occur every 8-14 years in the "meningitis belt" (most recently 1996; 250K infected: ~20K deaths)

55 Meningococcal septicemia -results when virulent organisms invade the blood stream -ranges from low-level meningococcemia to fulminating sepsis -high fever, arthralgia and small vessel blockage -rash resulting from pinpoint hemorrhages (petechiae) -in severe infections, dusky red blotches (purpura fulminans) -hemorrhage and necrosis occur -destruction of the adrenal glands (Waterhouse-Friderichsen Syndrome) -death can occur within 12 hours of onset

56 Purpura Fulminans

57 Meningococcal meningitis -begins suddenly with severe headache, high fever -progressive stiffness of the neck, back and shoulders (positive Kernig s sign) -photophobia may be present -petechiae and purpura are sometimes present

58 Meningococcal Virulence Factors LOS Peptidoglycan fragments (PGF) Pili (Fimbriae) Factor H Binding protein IgA protease a secreted enzyme which cleaves human IgA (mucosal immunity) polysaccharide capsule an extracellular covering blocks phagocytosis by macrophages and PMNs important component for serotyping Group B capsule is sialic acid

59 Meningococcemia and Meningococcal Meningitis Medical emergency Treatment with ceftriaxone high dose or penicillin (I favor ceftriaxone until sensitivities and travel history are known) Increased incidence in terminal complement deficiency patients (C6-C9)

60 Neisseria menigitidis Vaccine Polysaccharide developed first Protein conjugated capsular vaccine with Group A, C, Y, and W135 polysaccharide (MCV4) Long lasting immunity compared to the polysaccharide vaccine New Group B meningococcal vaccine Bexsero recombinant proteins Neisserial adhesin A (NadA), Neisserial Heparin Binding Antigen (NHBA), and factor H binding protein (fhbp), 25 micrograms of Outer Membrane Vesicles (OMV), This is the first major use of genomics to produce a multi-component vaccine Trumenba 2 important subfamilies, A and B, of a lipoprotein factor H binding protein (fhbp) which is found in more than 97% of all serogroup B meningococcal disease strains. Initial concern with GBS, no association at present time

61 Target for MCV4 College freshmen living in dormitories Microbiologists who are routinely exposed to meningococcal bacteria U.S. military recruits Anyone traveling to, or living in, a part of the world where meningococcal disease is common, such as parts of Africa Anyone who has a damaged spleen, or whose spleen has been removed Anyone who has terminal complement component deficiency (an immune system disorder) People who might have been exposed to meningitis during an outbreak

62 Listeria monocytogenes Gram positive rod More frequently seen in immunocompromised patients High frequency of disseminated inections in pregnancy Seen in neonates, elderly, and immunocompromised Frequently causes a meningoencephalitis

63 Listeria monocytogenes Microbiology Exhibits tumbling motility Can be mistaken for Gram negative rod Requires thorough pasteurization and the organism can multiply at 4 C Frequently associated with milk products

64 Listeria monocytogenes Consider in the T-cell immune deficiency, especially transplants and lymphomas Pregnancy associated Elderly and liver disease Therapy generally requires addition of ampicillin