COMMUNITY ACQUIRED COMMUNITY ACQUIRED BACTERIAL BACTERIAL MENINGITIS IN ADULTSMENINGITIS IN ADULTS

Julie Hoffman, M.D.Julie Hoffman, M.D. Department of IDDepartment of ID Jacobi Medical CenterJacobi Medical Center

Acute MeningitisAcute Meningitis

Meningitis-inflammation of the meninges, Meningitis-inflammation of the meninges, identified by abnormal WBCs in CSFidentified by abnormal WBCs in CSF

Clinically defined as syndrome characterized Clinically defined as syndrome characterized the onset of meningeal symptoms over the the onset of meningeal symptoms over the course of hours to up to several days .HA is a course of hours to up to several days .HA is a prominent early symptom followed by prominent early symptom followed by confusion and coma. confusion and coma.

Blurs into chronic meningitis( onset weeks to Blurs into chronic meningitis( onset weeks to months) and encephalitis which is months) and encephalitis which is distinguished by decreased mentation with distinguished by decreased mentation with minimal meningeal signs. minimal meningeal signs.

Differential Diagnosis of Differential Diagnosis of Acute MeningitisAcute Meningitis

InfectiousInfectious Virus-nonpolio enterovirus,arbovirus,herpesvirus, Virus-nonpolio enterovirus,arbovirus,herpesvirus,

LCM virus, HIV, adenovirus, influenzaLCM virus, HIV, adenovirus, influenza RichettsiaRichettsia Bacteria-H influ, N mening, S pneum, Listeria, E coli, Bacteria-H influ, N mening, S pneum, Listeria, E coli,

Strep agal, propionobacteria,staph, enterococcus, Strep agal, propionobacteria,staph, enterococcus, Klebs, Salmonella, Norcardia, Strep pyogenes, MTB,Klebs, Salmonella, Norcardia, Strep pyogenes, MTB,

SpirochetesSpirochetes Protozoa/helminths-naegleria/angiotrongylus/Protozoa/helminths-naegleria/angiotrongylus/

strongyloides/baylisascarisstrongyloides/baylisascaris Other infectious syndromes-parameningeal Other infectious syndromes-parameningeal

focus/IE/postinfectious/postvaccinationfocus/IE/postinfectious/postvaccination Noninfectious-tumors/medications/SLE/seizures/Noninfectious-tumors/medications/SLE/seizures/

migrainemigraine

CHANGING CHANGING EPIDEMIOLOGYEPIDEMIOLOGY

Since the introduction of Since the introduction of H.influenza(1990) and Streptococcus H.influenza(1990) and Streptococcus pneumonia conjugate vaccine (PCV7)pneumonia conjugate vaccine (PCV7)(2000) decreased frequency and peak (2000) decreased frequency and peak incidence has shifted from children<5 incidence has shifted from children<5 to adults median age 39. Highest case to adults median age 39. Highest case fatality rates among ages >65fatality rates among ages >65

90% reduction in incidence of 90% reduction in incidence of invasive H influenza infection.invasive H influenza infection.

icaac/idsa 2008 abstact g-761

Impact of PCV7Impact of PCV7 CDC study- compared rates of IPD(invasive pneumococcal CDC study- compared rates of IPD(invasive pneumococcal

disease) reported to 8 US sites participating in Active disease) reported to 8 US sites participating in Active BacterialCore Surveillance from 1998-1999 and 2006BacterialCore Surveillance from 1998-1999 and 2006

Decreased incidence from 24.4 to 13.5/ Decreased incidence from 24.4 to 13.5/ 100,000(45%)100,000(45%)

IPD due to vaccine serotypes declined 15.5 to IPD due to vaccine serotypes declined 15.5 to 1.3/1000001.3/100000

Nonvaccine serotypes increased 6.1to Nonvaccine serotypes increased 6.1to 7.7/100,000.Serotype 19A form .8-2.77.7/100,000.Serotype 19A form .8-2.7

11-15,000 cases of IPD annually in <5 and 9-18,000fewer 11-15,000 cases of IPD annually in <5 and 9-18,000fewer annually >5. annually >5.

10,000 fewer deaths, .170,000 cases of IPD prevented with 10,000 fewer deaths, .170,000 cases of IPD prevented with vaccine since introductionvaccine since introduction

Increase in antibiotic nonsusceptible strains in 2006Increase in antibiotic nonsusceptible strains in 2006 75% of strains serotype 19A75% of strains serotype 19A

ICAAC/IDSA 2008 ABSTRACT G-2075

SEROTYPES CAUSING IPD SEROTYPES CAUSING IPD IN HIGH HIV PREVALENCE IN HIGH HIV PREVALENCE

POPPOP IPD SURVEILLANCE IN 3 NEWARK IPD SURVEILLANCE IN 3 NEWARK

HOSPITALS(HIV PREV 2%)-BLOOD/CSF HOSPITALS(HIV PREV 2%)-BLOOD/CSF CULTURES 12/07-4/30/08CULTURES 12/07-4/30/08

41/48 ANALYZED FOR SEROTYPE41/48 ANALYZED FOR SEROTYPE 37 ADULTS(MEDIAN age 37 ADULTS(MEDIAN age

52)AA76%,HISP24%,HIV32%52)AA76%,HISP24%,HIV32% 31(94%) NONVACCINE SEROTYPE(NVT)-19A 31(94%) NONVACCINE SEROTYPE(NVT)-19A

(39%)(39%) 9(22%)PCN RESISTANT-19A 7/99(22%)PCN RESISTANT-19A 7/9

Emergence of serotype 19a Emergence of serotype 19a in childrenin children

Texas Childrens HospitalTexas Childrens Hospital 1/07-7/08 248 sinus cultures via nasal 1/07-7/08 248 sinus cultures via nasal

endoscopy in recurrent or chronic endoscopy in recurrent or chronic sinusitissinusitis

24 pneumococcal isolates- 21 24 pneumococcal isolates- 21 nonvaccine serotypesnonvaccine serotypes

12 serotype 19A-4 mdr( res 12 serotype 19A-4 mdr( res pcn/cef/erythro/clinda/bactrim) 7 pcn/cef/erythro/clinda/bactrim) 7 resistant to PCNresistant to PCN

Pediatric Infectious Journal Pediatric Infectious Journal Sept 2009Sept 2009

Serotype 19A in FranceSerotype 19A in France

35% of penumococcus isolated 35% of penumococcus isolated from two hospitals in France from two hospitals in France during 2007- serotype 19A during 2007- serotype 19A

13% of all IPD was due to 13% of all IPD was due to serotype 19Aserotype 19A

96% resistant to PCN, 95% to 96% resistant to PCN, 95% to erythromycinerythromycin

Specific OrganismsSpecific Organisms

Multicenter study in US in 1995 (after Multicenter study in US in 1995 (after H influ vaccine) frequency of pathogen H influ vaccine) frequency of pathogen varied with age. Reduction of 55% varied with age. Reduction of 55% compared with 1985compared with 1985

Adults less than 60, S pneu. -60%, Adults less than 60, S pneu. -60%, N.mening- 20%, H influenza -N.mening- 20%, H influenza -10%,Listeria-6%, GBS -4%10%,Listeria-6%, GBS -4%

Over 60, S pneum-70%, Listeria 20%, Over 60, S pneum-70%, Listeria 20%, GBS/N.meningitis/H influenz-3-4%GBS/N.meningitis/H influenz-3-4%

Meningitis Mortality by Meningitis Mortality by PathogenPathogen

ListeriaListeria Leading predisposing factors: hematologic malignancy, Leading predisposing factors: hematologic malignancy,

solid tumors, kidney transplant, also hemochromatosis; solid tumors, kidney transplant, also hemochromatosis; in recent series 31% had no underlying disease.in recent series 31% had no underlying disease.

Intracellular pathogen; macrophage dysfunction Intracellular pathogen; macrophage dysfunction predisposes.predisposes.

Occurs more often in age <3 or >45 yearsOccurs more often in age <3 or >45 years Pts. with Listeria have fewer meningeal signs, less likely Pts. with Listeria have fewer meningeal signs, less likely

to have high CSF white count and protein than other to have high CSF white count and protein than other pathogens.pathogens.

Gram stain of CSF negative in 2/3rds of patientsGram stain of CSF negative in 2/3rds of patientsCan overdecolorize—so difficult to identify!Can overdecolorize—so difficult to identify!

CSF may be normal early in infection; with suggestive CSF may be normal early in infection; with suggestive signs/symptoms repeat LP in 12-24 hours.signs/symptoms repeat LP in 12-24 hours.

Can have localized brain abscess and Can have localized brain abscess and meningoencephalitismeningoencephalitis

Outbreaks are usually foodborne: cheese, coleslaw, Outbreaks are usually foodborne: cheese, coleslaw, meat products; 5% of people are asymptomatic carriersmeat products; 5% of people are asymptomatic carriers

Pneumococcal meningitis Pneumococcal meningitis mortality by agemortality by age

Mortality and Mortality and developmentdevelopment

PATHOGENSISPATHOGENSIS

TREATMENT GUIDELINESTREATMENT GUIDELINES

NEJM 12/31/01 345:24:1727

Head CT prior to LPHead CT prior to LP Risk of herniation after LP varies among studiesRisk of herniation after LP varies among studies Study from 1959-129 patients with increased ICP- Study from 1959-129 patients with increased ICP-

1.2% with papilledema/12% without herniated after 1.2% with papilledema/12% without herniated after LPLP

LP results in small transient decreases in CSF LP results in small transient decreases in CSF pressure throught subarachnoid space as a result pressure throught subarachnoid space as a result of removal of fluid and continued leakage.of removal of fluid and continued leakage.

Herniation may occur in space occupying Herniation may occur in space occupying inflammatory inflammatory lesions(empyema/abscess/toxo),tumor, hemorrage lesions(empyema/abscess/toxo),tumor, hemorrage esp rapidly expanding. Also with meningitis with esp rapidly expanding. Also with meningitis with inc ICP with cerebral edema, thrombosis of sagital inc ICP with cerebral edema, thrombosis of sagital sinus, occlusion of villi. Herniation may also occur sinus, occlusion of villi. Herniation may also occur without LP without LP

1995-1999, 301 adults (>16)with clinically 1995-1999, 301 adults (>16)with clinically suspected meningitis presenting to Yale ED suspected meningitis presenting to Yale ED prospectively evaluated to identify clinical and lab prospectively evaluated to identify clinical and lab features that would predict CT abnormalities.features that would predict CT abnormalities.

235(78%) had CT before LP235(78%) had CT before LP

CT before LPCT before LP 96/235 had none of these risks96/235 had none of these risks 3/96 had abnormal CT findings but no 3/96 had abnormal CT findings but no

herniation. herniation. 4/235 had mass effect and no LP 4/235 had mass effect and no LP

performedperformed LP delayed average of two hours in group LP delayed average of two hours in group

undergoing CTundergoing CT Even with normal CT, clinical signs Even with normal CT, clinical signs

suggestive of high ICP should caution suggestive of high ICP should caution against LPagainst LP

Neurologic OutcomesNeurologic Outcomes

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

Dexamethsone in adults with Dexamethsone in adults with meningitismeningitis Radomized placebo controlled double blind Radomized placebo controlled double blind

multicenter study with 301 patients from multicenter study with 301 patients from Netherlands,Austria,Germany,Belgium,DenmarkNetherlands,Austria,Germany,Belgium,Denmark

Patients> 17 with suspected meningitis randomized to Patients> 17 with suspected meningitis randomized to receive dexa 10 mg q 6 x4 days or placebo given 15-20 receive dexa 10 mg q 6 x4 days or placebo given 15-20 minutes before antibioticsminutes before antibiotics

8 weeks after enrollment, percentage of patients with 8 weeks after enrollment, percentage of patients with unfavorable outcome(15%vs 25%)and death(7%and unfavorable outcome(15%vs 25%)and death(7%and 15%) was significantly lower in the dexa group.15%) was significantly lower in the dexa group.

Patients with pneumococcal meningitis had Patients with pneumococcal meningitis had significantly less unfavorable outcomes (26%vs52%) significantly less unfavorable outcomes (26%vs52%) and death (14%vs 34%) with dexamethasoneand death (14%vs 34%) with dexamethasone

No benefit with other pathogensNo benefit with other pathogens Greatest benefit with moderate to severe GCS scoreGreatest benefit with moderate to severe GCS score All pneumococcal isolates susceptible to PenAll pneumococcal isolates susceptible to Pen

IDSA recommendationsIDSA recommendations Dexamethasone >15mg/kg q6h for 2-4 days Dexamethasone >15mg/kg q6h for 2-4 days

with the first dose 10-20 minutes before or with the first dose 10-20 minutes before or with the first dose of anibioticswith the first dose of anibiotics

Continue if csf gram stain with gram pos Continue if csf gram stain with gram pos diplococci or cultures positive for diplococci or cultures positive for pneumococcuspneumococcus

Do not use in patients who have already Do not use in patients who have already received antibioticsreceived antibiotics

Unknown benefit with resistant pneumococcus.Unknown benefit with resistant pneumococcus. Dexa decreases vanco penetration Dexa decreases vanco penetration

Csf diagnostic tests Csf diagnostic tests Opening pressure->200mmOpening pressure->200mm Pleocytosis-.1000 ( range Pleocytosis-.1000 ( range

<100,>10,000)<100,>10,000) Neutraphilic predominance(10% Neutraphilic predominance(10%

lymphocytic)lymphocytic) Serum glucose/csf glucose <.4Serum glucose/csf glucose <.4 Elevated proteinElevated protein Csf culture positive 70-85% without Csf culture positive 70-85% without

antibioticsantibiotics

Csf diagnostic testsCsf diagnostic testsGram StainGram Stain

Gram stain-accurate id of Gram stain-accurate id of organism-60-90%organism-60-90%

Dependent on concentration of Dependent on concentration of bacteria and organism-S pneum-bacteria and organism-S pneum-90% cases, h.infl-86%, n mening- 90% cases, h.infl-86%, n mening- 75%,gram neg-50%,listeria-30%75%,gram neg-50%,listeria-30%

20% lower with prior antibiotics20% lower with prior antibiotics False positive-contaminated with False positive-contaminated with

skin fragmentskin fragment

Csf diagnostic testsCsf diagnostic testslatex agglutinationlatex agglutination

Most useful in patients treated with Most useful in patients treated with antibiotics and whose gram stain antibiotics and whose gram stain and culture are negativeand culture are negative

901 csf bacterial antigen tests 901 csf bacterial antigen tests performed over 37 months-no performed over 37 months-no modification of therapy in 22/26 modification of therapy in 22/26 positivespositives

344 csf specimens-10 true pos( pos 344 csf specimens-10 true pos( pos culture)-3 false neg/2 false pos. no culture)-3 false neg/2 false pos. no change in managementchange in management

Lab testing to distinguish Lab testing to distinguish viral from bacterial etiologyviral from bacterial etiology PCR more sensitive than viral PCR more sensitive than viral

culture-sens 86-100%,specificity 92-culture-sens 86-100%,specificity 92-100%100%

CRP- high negative predictive value CRP- high negative predictive value – normal without meningitis– normal without meningitis

TreatmentTreatment

Antibiotics and release of Antibiotics and release of LTA and TALTA and TA

Rifampin and treatment of Rifampin and treatment of pneumococcal meningitispneumococcal meningitis

AAC 2003-Gerber et alAAC 2003-Gerber et al Rabbits with pneumococcal Rabbits with pneumococcal

experimental meningitis treated with experimental meningitis treated with rifampin followed by ceftriaxone. rifampin followed by ceftriaxone.

Significant decrease in LTA and Significant decrease in LTA and neuronal apoptosis on autopsy.neuronal apoptosis on autopsy.

Duration of treatmentDuration of treatment

Synergy of Vancomycin and Synergy of Vancomycin and Ceftriaxome in Ceftriaxome in

experimental meningitisexperimental meningitis