1. COMMUNITY ACQUIRED BACTERIAL MENINGITIS IN ADULTS Julie Hoffman, M.D. Julie Hoffman, M.D. Department of ID Department of ID Jacobi Medical Center Jacobi Medical Center

2. Acute Meningitis Meningitis-inflammation of the meninges, identified by abnormal WBCs in CSF Meningitis-inflammation of the meninges, identified by abnormal WBCs in CSF Clinically defined as syndrome characterized the onset of meningeal symptoms over the course of hours to up to several days.HA is a prominent early symptom followed by confusion and coma. Clinically defined as syndrome characterized the onset of meningeal symptoms over the course of hours to up to several days.HA is a prominent early symptom followed by confusion and coma. Blurs into chronic meningitis( onset weeks to months) and encephalitis which is distinguished by decreased mentation with minimal meningeal signs. Blurs into chronic meningitis( onset weeks to months) and encephalitis which is distinguished by decreased mentation with minimal meningeal signs.

3. Differential Diagnosis of Acute Meningitis Infectious Infectious Virus-nonpolio enterovirus,arbovirus,herpesvirus, LCM virus, HIV, adenovirus, influenza Virus-nonpolio enterovirus,arbovirus,herpesvirus, LCM virus, HIV, adenovirus, influenza Richettsia Richettsia Bacteria-H influ, N mening, S pneum, Listeria, E coli, Strep agal, propionobacteria,staph, enterococcus, Klebs, Salmonella, Norcardia, Strep pyogenes, MTB, Bacteria-H influ, N mening, S pneum, Listeria, E coli, Strep agal, propionobacteria,staph, enterococcus, Klebs, Salmonella, Norcardia, Strep pyogenes, MTB, Spirochetes Spirochetes Protozoa/helminths- naegleria/angiotrongylus/strongyloides/baylisascaris Protozoa/helminths- naegleria/angiotrongylus/strongyloides/baylisascaris Other infectious syndromes-parameningeal focus/IE/postinfectious/postvaccination Other infectious syndromes-parameningeal focus/IE/postinfectious/postvaccination Noninfectious-tumors/medications/SLE/seizures/migraine Noninfectious-tumors/medications/SLE/seizures/migraine

4. CHANGING EPIDEMIOLOGY Since the introduction of H.influenza(1990) and Streptococcus pneumonia conjugate vaccine (PCV7)(2000) decreased frequency and peak incidence has shifted from children 65 Since the introduction of H.influenza(1990) and Streptococcus pneumonia conjugate vaccine (PCV7)(2000) decreased frequency and peak incidence has shifted from children 65 90% reduction in incidence of invasive H influenza infection. 90% reduction in incidence of invasive H influenza infection.

5. icaac/idsa 2008 abstact g-761 Impact of PCV7 CDC study- compared rates of IPD(invasive pneumococcal disease) reported to 8 US sites participating in Active BacterialCore Surveillance from 1998- 1999 and 2006 CDC study- compared rates of IPD(invasive pneumococcal disease) reported to 8 US sites participating in Active BacterialCore Surveillance from 1998- 1999 and 2006 Decreased incidence from 24.4 to 13.5/ 100,000(45%) Decreased incidence from 24.4 to 13.5/ 100,000(45%) IPD due to vaccine serotypes declined 15.5 to 1.3/100000 IPD due to vaccine serotypes declined 15.5 to 1.3/100000 Nonvaccine serotypes increased 6.1to 7.7/100,000.Serotype 19A form.8-2.7 Nonvaccine serotypes increased 6.1to 7.7/100,000.Serotype 19A form.8-2.7 11-15,000 cases of IPD annually in 5. 11-15,000 cases of IPD annually in 5. 10,000 fewer deaths,.170,000 cases of IPD prevented with vaccine since introduction 10,000 fewer deaths,.170,000 cases of IPD prevented with vaccine since introduction Increase in antibiotic nonsusceptible strains in 2006 Increase in antibiotic nonsusceptible strains in 2006 75% of strains serotype 19A 75% of strains serotype 19A

9. CDC PNEUMOCOCCAL serotype 19 A SURVEILLANCE Absolute rate increase in children <5 2006 compared to 2000 -12% Absolute rate increase in children <5 2006 compared to 2000 -12% In adults-over 65-5% In adults-over 65-5%

10. ICAAC/IDSA 2008 ABSTRACT G-2075 SEROTYPES CAUSING IPD IN HIGH HIV PREVALENCE POP IPD SURVEILLANCE IN 3 NEWARK HOSPITALS(hiv PREV 2%)-BLOOD/CSF CULTURES 12/07-4/30/08 IPD SURVEILLANCE IN 3 NEWARK HOSPITALS(hiv PREV 2%)-BLOOD/CSF CULTURES 12/07-4/30/08 41/48 ANALYZED FOR SEROTYPE 41/48 ANALYZED FOR SEROTYPE 37 ADULTS(MEDIAN AGE 52)AA76%,HISP24%,HIV32% 37 ADULTS(MEDIAN AGE 52)AA76%,HISP24%,HIV32% 31(94%) NONVACCINE SEROTYPE(NVT)-19A (39%) 31(94%) NONVACCINE SEROTYPE(NVT)-19A (39%) 9(22%)PCN RESISTANT-19A 7/9 9(22%)PCN RESISTANT-19A 7/9

11. Specific Organisms Multicenter study in US in 1995 (after H influ vaccine) frequency of pathogen varied with age. Reduction of 55% compared with 1985 Multicenter study in US in 1995 (after H influ vaccine) frequency of pathogen varied with age. Reduction of 55% compared with 1985 Adults less than 60, S pneu. -60%, N.mening- 20%, H influenza -10%,Listeria-6%, GBS -4% Adults less than 60, S pneu. -60%, N.mening- 20%, H influenza -10%,Listeria-6%, GBS -4% Over 60, S pneum-70%, Listeria 20%, GBS/N.meningitis/H influenz-3-4% Over 60, S pneum-70%, Listeria 20%, GBS/N.meningitis/H influenz-3-4%

12. Meningitis Mortality by Pathogen

13. Pneumococcal meningitis mortality by age

15. Mortality and development

17. PATHOGENSIS

22. TREATMENT GUIDELINES

23. NEJM 12/31/01 345:24:1727

25. Head CT prior to LP Risk of herniation after LP varies among studies Risk of herniation after LP varies among studies Study from 1959-129 patients with increased ICP- 1.2% with papilledema/12% without herniated after LP Study from 1959-129 patients with increased ICP- 1.2% with papilledema/12% without herniated after LP LP results in small transient decreases in CSF pressure throught subarachnoid space as a result of removal of fluid and continued leakage. LP results in small transient decreases in CSF pressure throught subarachnoid space as a result of removal of fluid and continued leakage. Herniation may occur in space occupying inflammatory lesions(empyema/abscess/toxo),tumor, hemorrage esp rapidly expanding. Also with meningitis with inc ICP with cerebral edema, thrombosis of sagital sinus, occlusion of villi. Herniation may also occur without LP Herniation may occur in space occupying inflammatory lesions(empyema/abscess/toxo),tumor, hemorrage esp rapidly expanding. Also with meningitis with inc ICP with cerebral edema, thrombosis of sagital sinus, occlusion of villi. Herniation may also occur without LP 1995-1999, 301 adults (>16)with clinically suspected meningitis presenting to Yale ED prospectively evaluated to identify clinical and lab features that would predict CT abnormalities. 1995-1999, 301 adults (>16)with clinically suspected meningitis presenting to Yale ED prospectively evaluated to identify clinical and lab features that would predict CT abnormalities. 235(78%) had CT before LP 235(78%) had CT before LP

26. CT before LP 96/235 had none of these risks 96/235 had none of these risks 3/96 had abnormal CT findings but no herniation. 3/96 had abnormal CT findings but no herniation. 4/235 had mass effect and no LP performed 4/235 had mass effect and no LP performed LP delayed average of two hours in group undergoing CT LP delayed average of two hours in group undergoing CT Even with normal CT, clinical signs suggestive of high ICP should caution against LP Even with normal CT, clinical signs suggestive of high ICP should caution against LP

31. Introduction Unfavorable neurological outcomes not completely the result of inadequate treatment with antibiotics. CSF cultures are sterile within 24-48 hours after starting antibiotics. In animal studies, pneumococcal and gram negative(meningococcus/H flu) induce meningitis and death. Steroids reduce both csf inflammation and neurologic sequelae in some infections. Unfavorable neurological outcomes not completely the result of inadequate treatment with antibiotics. CSF cultures are sterile within 24-48 hours after starting antibiotics. In animal studies, pneumococcal and gram negative(meningococcus/H flu) induce meningitis and death. Steroids reduce both csf inflammation and neurologic sequelae in some infections.

32. Dexamethsone in adults with meningitis Radomized placebo controlled double blind multicenter study with 301 patients from Netherlands,Austria,Germany,Belgium,Denmark Radomized placebo controlled double blind multicenter study with 301 patients from Netherlands,Austria,Germany,Belgium,Denmark Patients> 17 with suspected meningitis randomized to receive dexa 10 mg q 6 x4 days or placebo given 15-20 minutes before antibiotics Patients> 17 with suspected meningitis randomized to receive dexa 10 mg q 6 x4 days or placebo given 15-20 minutes before antibiotics 8 weeks after enrollment, percentage of patients with unfavorable outcome(15%vs 25%)and death(7%and 15%) was significantly lower in the dexa group. 8 weeks after enrollment, percentage of patients with unfavorable outcome(15%vs 25%)and death(7%and 15%) was significantly lower in the dexa group. Patients with pneumococcal meningitis, more significant benefit with unfavorable outcome (26%vs52%) and death (14%vs 34%) Patients with pneumococcal meningitis, more significant benefit with unfavorable outcome (26%vs52%) and death (14%vs 34%) No benefit with other pathogens No benefit with other pathogens Greatest benefit with moderate to severe GCS score Greatest benefit with moderate to severe GCS score All pneumococcal isolates susceptible to Pen All pneumococcal isolates susceptible to Pen

35. IDSA recommendations Dexamethasone >15mg/kg q6h fpr 2-4 days with the first dose 10-20 minutes before or with the first dose of anibiotics Dexamethasone >15mg/kg q6h fpr 2-4 days with the first dose 10-20 minutes before or with the first dose of anibiotics Continue if csf gram stain with gram pos diplococci or cultures positive for pneumococcus Continue if csf gram stain with gram pos diplococci or cultures positive for pneumococcus Do not use in patients who have already received antibiotics Do not use in patients who have already received antibiotics Unknown benefit with resistant pneumococcus. Unknown benefit with resistant pneumococcus. Dexa decreases vanco penetration Dexa decreases vanco penetration

36. Csf diagnostic tests Opening pressure->200mm Opening pressure->200mm Pleocytosis-.1000 ( range 10,000) Pleocytosis-.1000 ( range 10,000) Nuetraphilic predominance(10% lymphocytic) Nuetraphilic predominance(10% lymphocytic) Serum glucose/csf glucose <.4 Serum glucose/csf glucose <.4 Elevated protein Elevated protein Csf culture positive 70-85% without antibiotics\ Csf culture positive 70-85% without antibiotics\

37. Csf diagnostic tests Gram Stain Gram stain-accurate id of organism-60-90% Gram stain-accurate id of organism-60-90% Dependent on concentration of bacteria and organism-S pneum-90% cases, h.infl-86%, n mening- 75%,gram neg-50%,listeria-30% Dependent on concentration of bacteria and organism-S pneum-90% cases, h.infl-86%, n mening- 75%,gram neg-50%,listeria-30% 20% lower with prior antibiotics 20% lower with prior antibiotics False positive-contaminated with skin fragment False positive-contaminated with skin fragment

38. Csf diagnostic tests latex agglutination Most useful in patients treated with antibiotics and whose gram stain and culture are negative Most useful in patients treated with antibiotics and whose gram stain and culture are negative 901 csf bacterial antigen tests performed over 37 months-no modification of therapy in 22/26 positives 901 csf bacterial antigen tests performed over 37 months-no modification of therapy in 22/26 positives 344 csf specimens-10 true pos( pos culture)-3 false neg/2 false pos. no change in management 344 csf specimens-10 true pos( pos culture)-3 false neg/2 false pos. no change in management

39. Lab testing to distinguish viral from bacterial etiology PCR more sensitive than viral culture-sens 86- 100%,specificity 92-100% PCR more sensitive than viral culture-sens 86- 100%,specificity 92-100% CRP- high negative predictive value – normal without meningitis CRP- high negative predictive value – normal without meningitis

40. Treatment

42. Synergy of Vancomycin and Ceftriaxome in experimental meningitis

43. Antibiotics and release of LTA and TA

44. Rifampin and treatment of pneumococcal meningitis AAC 2003-Gerber et al AAC 2003-Gerber et al Rabbits with pneumococcal experimental meningitis treated with rifampin followed by ceftriaxone. Rabbits with pneumococcal experimental meningitis treated with rifampin followed by ceftriaxone. Significant decrease in LTA and neuronal apoptosis on autopsy. Significant decrease in LTA and neuronal apoptosis on autopsy.

45. Duration of treatment