Community-acquired bacterial meningitis remains a global public health concern with significant morbidity and mortality despite the availability of conjugate vaccines [1▪,2]. Even though there are differences in the causes by age and geographic distribution, Streptococcus pneumoniae and Neisseria meningitidis are still the most common causes worldwide in the nonneonatal period [1▪,2,3]. Cranial imaging is over utilized and of limited utility in suspected meningitis and fosters delays in diagnosis and increased costs [1▪]. Early diagnosis, prompt antibiotic therapy and early adjunctive steroids (in adults in high-income or medium-income countries with S. pneumoniae) can reduce morbidity and mortality [1▪,3]. Recently, adjunctive steroids have been associated with an increased mortality in Listeria monocytogenes meningitis [4▪] and possibly with delayed cerebral thrombosis .
The epidemiology of community-acquired bacterial meningitis has dramatically shifted in the last 3 decades since the introduction of the conjugate vaccines for the three most common meningeal pathogens: Haemophilus influenzae type b, N. meningitidis, and S. pneumoniae. Most recently, the introduction of MenAfriVac (Serum Institute of India Ltd, Hadapsur, Pune, India), a conjugate vaccine against serogroup A N. meningitidis, in sub-Saharan Africa has eliminated Group A meningococcal meningitis outbreaks but new epidemics with serogroup W and C are now occurring [7▪▪,8]. S. pneumoniae and N. meningitidis remain the most common pathogens in children beyond the neonatal period and in adults [1▪,2,3]. In neonates, Streptocococcus agalactiae and Escherichia coli are the most common pathogens [1▪,2,3].
Bacterial meningitis is an important disease worldwide [7▪▪,8]. In 2016, the global burden of disease study documented meningitis caused 318 thousands deaths annually in the world resulting in 20 383 thousands years of life lost . The incidence rates varied per country ranging from 0.7 to 0.9 per 100 000 per years in the United States and European countries to incidence rates between 10 and 40 per 100 000 per year in Africa . In the United States, bacterial meningitis continues to cause approximately 13% of all cases of meningitis and encephalitis in adults and children [10,11]. The most recent population-based observational study in the United States done between 1997 and 2010 reported on 50 822 cases for the five most commonly identified bacteria . The two most common identifiable pathogens were S. pneumoniae (21 858 cases) with an incidence of 0.306 cases per 100 000 people, and N. meningitidis (12 833 cases; incidence rate 0.123 per 100 000 people). The incidence of pneumococcal meningitis and meningococcal meningitis significantly decreased during the study period most likely associated with the introduction of the pneumococcal conjugate vaccine in 2000 and by the quadrivalent meningococcal (A, C, Y, and W135) conjugate vaccine in 2005 . In the Netherlands, a large prospective study of 1412 episodes of community-acquired bacterial meningitis from 2006 until 2014, S. pneumoniae was responsible for 51%, N. meningitidis for 37%, and L. monocytogenes for 4% of cases [13▪▪]. There are however geographical differences in the epidemiology of bacterial meningitis. In Southeast Asia, the most common pathogen is Streptococcus suis, accounting for ∼30% of cases and is seen in patients that have close contact with pigs .
CRANIAL IMAGING IN SUSPECTED MENINGITIS
Obtaining a head computed tomography (CT) scan to rule out an intracranial mass before a lumbar puncture has become routine practice . In 2004, the Infectious Diseases Society of America (IDSA) guidelines recommended that the following adult patients should undergo CT prior to lumbar puncture: immunocompromised state, history of central nervous system disease, new-onset seizure, papilledema, abnormal level of consciousness, and focal neurological deficit . Despite the IDSA guidelines, patients with community-acquired meningitis continue to undergo cranial imaging in patients without indications with no clinical utility [15▪] Recently, the United Kingdom, the European and the Swedish guidelines have recommended more strict indications for cranial imaging but compliance with the guidelines remain approximately 50% (Table 1) [16,17▪▪,18,19]. One study of 815 adults with bacterial meningitis in Sweden showed a decrease in mortality if there was adherence to the Swedish guidelines in contrast to the IDSA or European guidelines but this findings has not been validated  The feared complication of cerebral herniation occurred in 47 (3.1%) out of 1533 episodes of bacterial meningitis; 17 out of 47 (40%) of those patients that herniated had normal head CT scans .
Bacterial meningitis is a medical emergency that requires a prompt lumbar puncture for the diagnosis [1▪,3]. The typical findings include an elevated opening pressure, a cerebrospinal fluid (CSF) white blood cell (WBC) count usually more than 1000/μl (range, <100 to >10 000/μl), a neutrophilic pleocytosis, an elevated CSF protein (usually >100 mg/dl) and hypoglycorrachia (<30 mg/dl) [1▪,19]. In adults, the absence of a CSF pleocytosis in pneumococcal meningitis is extremely rare (0.2%) , but can account for almost 10% of all cases of meningococcal meningitis . Therefore, a Gram stain and culture should be done even if the CSF WBC is normal. The CSF Gram stain examination can provide rapid, accurate identification of the causative microorganism with sensitivity ranging from 50 to 90% in patients with community-acquired bacterial meningitis [1▪,5,13▪▪]. Up to 95% of patients that present with acute meningitis have a negative Gram stain prompting empirical antibiotic therapy for the majority of patients even though the minority have bacterial meningitis . In children, the Bacterial Meningitis Score can be used to differentiate bacterial from aseptic meningitis if the patient has low-risk characteristics (negative CSF Gram stain, CSF absolute neutrophil count <1000 cell/μl, CSF protein <80 mg/dl, and peripheral absolute neutrophil count <10 000 cells/μl) . One of the most important predictors for bacterial meningitis in this scoring system is a positive Gram stain where the diagnosis is not a dilemma to clinicians. In adults, a risk score was derived and validated in 960 patients with meningitis and a negative Gram stain identifying a ‘zero risk’ subgroup for any urgent treatable cause (e.g., bacterial meningitis, herpes simplex encephalitis, fungal cause) with 100% sensitivity . The score was also validated with 100% sensitivity in 214 patients with culture-proven bacterial meningitis that had a negative Gram stain . An elevated CSF lactate concentrations may also be useful in differentiating bacterial from nonbacterial meningitis in patients who have not received prior antimicrobial therapy with better diagnostic accuracy than the CSF WBC count, glucose, and protein levels [25,26].
Despite the availability of these clinical models, adults, and children continue to receive empirical antibiotic therapy for the majority of patients [10,11]. Furthermore, the sensitivity of the CSF Gram stain and culture in patients with bacterial meningitis is reduced by prior antimicrobial therapy fostering uncertainty in the etiological diagnosis [27,28], this prompted the UK guidelines to routinely recommend obtaining a PCR for the two most common meningeal pathogens (S. pneumoniae and N. meningitidis) in patients presenting with meningitis [17▪▪]. The impact of antibiotic therapy in the yield of the CSF cultures is a possible explanation for why delaying a lumbar puncture in adults and children with meningitis is associated with increased costs as patients are treated empirically for partially treated bacterial meningitis [29,30]. Clinicians can still rely on the CSF profile (CSF WBC, glucose, protein) to help them differentiate viral from bacterial meningitis as they are not impacted by antibiotic therapy [27,28]. A multiplex PCR is currently available that can aid in rapidly identifying 14 causes of meningitis and encephalitis (E. coli K1, H. influenzae, L. monocytogenes, N. meningitidis, S. agalactiae, S. pneumoniae, cytomegalovirus, enterovirus, herpes simplex virus 1, herpes simplex virus 2, human herpes virus 6, human parechovirus, varicella zoster, Cryptococcus neoformans/Cryptococcus gattii) .
EMPIRICAL ANTIBIOTIC THERAPY
Empirical therapy should be started as soon as possible in patients presenting with suspected bacterial meningitis [1▪,3,17▪▪]. A delay in antibiotic therapy has been associated with an increase in adverse clinical outcomes in several retrospective studies [32–36]. A large study documented that a delay in initiation of antimicrobial therapy after patient arrival in the emergency department was associated with an adverse clinical outcome when the patient's condition advanced to a high stage of prognostic severity . Several other retrospective studies have also shown an increase in adverse outcomes with delays of antibiotic therapy; especially after 6 h [33–36].
In adults, the recommended antibiotic of choice is either cefotaxime 8–12 g/day divided into every 4 or 6-h doses or ceftriaxone 4 g/day divided into doses every 12 h. In countries where the rate of ceftriaxone resistance rate is more than 1% (as defined as a minimum inhibitory concentration ≥2 mg/l) in S. pneumoniae isolates, vancomycin should be added at a dose of 35–45 mg/kg/day divided into doses every 8 or 12 h [1▪]. If L. monocytogenes is a concern in immunosuppressed patients, neonates or over 50 years of age, ampicillin should be added and given as 12 g/day divided into 4-h intervals [1▪,3,17▪▪]. In patients with penicillin allergy, trimethoprim–sulfamethoxazole can be used. Once the pathogen is isolated and susceptibility testing results known, antimicrobial therapy should be modified for optimal treatment (Table 2).
The mortality of patients with bacterial meningitis varies geographically and by pathogen. The mortality in adults varies from 6% in Germany to 54% in Malawi [37,38] and in neonates from 10% in developed countries to 58% in developing countries . Significant neurological sequelae (cognitive deficit, bilateral hearing loss, motor deficit, seizures, visual impairment, hydrocephalus) are seen in survivors that again are highest in low-income countries. In a review of 18 183 survivors of acute bacterial meningitis , the risk for major sequelae was highest in Africa (25.1%) and southeast Asia (21.6%) than in Europe (9.4%); the risk for sequelae was also higher in patients with pneumococcal meningitis (24.7%) than in H. influenzae type b (9.5%) and in N. meningitidis (7.2%) . The largest prospective study of adults with community acquired bacterial meningitis to date done in the Netherlands identified the following risk factors for mortality: older age, absence of otitis or sinusitis, alcoholism, tachycardia, lower score on the Glasgow Coma Scale, cranial nerve palsy, a CSF WBC count of less than 1000 cells/μl, a positive blood culture, and a high serum C-reactive protein concentration [13▪▪].
The only adjunctive therapy that has shown to impact outcomes in patients with bacterial meningitis is adjunctive steroids in high and medium-income countries [1▪,3,17▪▪,41▪▪]. Bacteriolytic antibiotics such as third-generation cephalosporins and vancomycin cause an inflammatory response in the subarachnoid space that leads to neurological morbidity that can be ameliorated with steroids. In adults, adjunctive dexamethasone decreases mortality with pneumococcal meningitis and in children decreases hearing loss with H. influenzae meningitis. The IDSA guidelines recommend that dexamethasone should be given at least 20 min before the first dose of antibiotic beginning with 0.15 mg/kg every 6 h . Once the first dose of antibiotic is given the IDSA guidelines no longer recommends starting dexamethasone but it is recommended up to 4 h after starting antibiotics in the 2016 European guidelines and up to 12 h in the 2016 UK guidelines [17▪▪,41▪▪]. There is only one retrospective study of 80 adults with pneumococcal meningitis in the ICU that showed that steroids if given up to 12 h was associated an impact on mortality . The implementation of adjunctive steroids has been associated with a reduction in mortality in pneumococcal meningitis in high-income countries [10,38,43]. Adjunctive dexamethasone should be discontinued if the meningitis is subsequently found not to be caused by S. pneumoniae[1▪,17▪▪,43], especially in patients with L. monocytogenes or C. neoformans as steroids in these causes are associated with worse outcomes [3,44]. A recent possible association of the use of adjunctive steroids is the development of delayed cerebral injury (DCI) in patients with an initial good clinical recovery followed by sudden deterioration several days after presentation [5,45]. The mechanism accounting for DCI is currently unknown.
Community-acquired bacterial meningitis continues to be associated with significant morbidity and mortality across the world with significant geographical differences. Cranial imaging is over utilized and of no clinical benefit in patients with suspected meningitis without indications. Delaying lumbar puncture is associated with increased cost and delaying antibiotic therapy is associated with worse clinical outcomes. Early adjunctive steroids improve mortality in adults with pneumococcal meningitis but increases adverse outcomes in L. monocytogenes and C. neoformans.
Financial support and sponsorship
The study is funded by Grant A Starr Foundation.
Conflicts of interest
Biofire (speaker, research grant), Merck (speaker), Gilead Sciences (advisory board).
REFERENCES AND RECOMMENDED READING
Papers of particular interest, published within the annual period of review, have been highlighted as:
- ▪ of special interest
- ▪▪ of outstanding interest
1▪. van de Beek D, Brouwer M, Hasbun R, et al. Community-acquired bacterial meningitis
. Nat Rev Dis Primers 2016; 2:16074.
Excellent thorough review of community-acquired bacterial meningitis.
2. Oordt-Speets AM, Bolijn R, van Hoorn RC, et al. Global etiology of bacterial meningitis
: a systematic review and meta-analysis. PLoS One 2018; 13:e0198772.
3. Tunkel AR, Hartmann BJ, Kaplan SL, et al. Practice guidelines for the management of bacterial meningitis
. Clin Infect Dis 2004; 39:1267–1284.
4▪. Charlier C, Perrodeau É, Leclercq A, et al. Clinical features and prognostic factors of listeriosis: the MONALISA national prospective cohort study. Lancet Infect Dis 2017; S1473–S3099:30521–30527.
Large French cohort study of listeriosis describing the clinical epidemiology, outcomes and the deleterious impact of adjunctive steroids.
5. Gallegos C, Tobolowsky F, Nigo M, Hasbun R. Delayed cerebral injury in adults with bacterial meningitis
: a novel complication of adjunctive steroids
? Crit Care Med 2018; 46:e811–e814.
6. Dery M, Hasbun R. Changing epidemiology
of bacterial meningitis
. Curr Infect Dis Rep 2007; 9:301–307.
7▪▪. Trotter CL, Lingani C, Fernandez K, et al. Impact of MenAfriVac in nine countries of the African meningitis belt, 2010–2015: an analysis of surveillance data. Lancet Infect Dis 2017; 17:867–872.
Surveillance study in nine countries in the meningitis belt in sub-Saharan Africa documenting the impressive impact of serogroup A meningococcal vaccine.
8. Brouwer MC, van de Beek D. Epidemiology
of community-acquired bacterial meningitis
. Curr Opin Infect Dis 2018; 31:78–84.
9. GBD 2016 Causes of Death Collaborators. Global, regional, and national age-sex specific mortality for 264 causes of death, 1980–2016: a systematic analysis for the Global Burden of Disease Study 2016. Lancet 2017; 390:1151–1210.
10. Hasbun R, Rosenthal N, Balada-Llasat JM, et al. Epidemiology
of meningitis and encephalitis in the United States, 2011–2014. Clin Infect Dis 2017; 65:359–363.
11. Hasbun R, Wootton SH, Rosenthal N, et al. Epidemiology
of meningitis and encephalitis in infants and children in the United States, 2011–2014. Pediatr Infect Dis J 2019; 38:37–41.
12. Lopez Castelblanco R, Lee M, Hasbun R. Epidemiology
of bacterial meningitis
in the United States from 1997–2010: trends after conjugate vaccination and adjunctive dexamethasone recommendations: a population observational based study. Lancet Infect Dis 2014; 14:813–819.
13▪▪. Bijlsma MW, Brouwer MC, Kasanmoentalib ES, et al. Community-acquired bacterial meningitis
in adults in the Netherlands, 2006–2014: a prospective cohort study. Lancet Infect Dis 2016; 16:339–347.
Largest prospective study documenting the clinical epidemiology, outcomes, and risk factors in adults with community-acquired bacterial meningitis.
14. van Samkar A, Brouwer MC, Schultsz C, et al. Streptococcus suis
meningitis: a systematic review and meta-analysis. PLoS Negl Trop Dis 2015; 9:e0004191.
15▪. Salazar L, Hasbun R. Cranial imaging before lumbar puncture in adults with community-acquired meningitis: clinical utility and adherence to the Infectious Diseases Society of America guidelines. Clin Infect Dis 2017; 64:1657–1662.
Large study evaluating the lack of utility of cranial imaging in adults with community-acquired meningitis that undergo a computed tomography scan without an indication.
16. Costerus JM, Brouwer MC, Sprengers MES, et al. Cranial computed tomography, lumbar puncture, and clinical deterioration in bacterial meningitis
: a nationwide cohort study. Clin Infect Dis 2018; 67:920–926.
17▪▪. McGill F, Heyderman RS, Michael BD, et al. The UK joint specialist societies guideline on the diagnosis and management of acute meningitis and meningococcal sepsis in immunocompetent adults. J Infect 2016; 72:405–438.
UK guidelines that review recommendations to diagnose and manage both viral and bacterial meningitis.
18. Glimaker M, Sjolin J, Akesson S, Naucier P. Lumbar puncture performed promptly or after neuroimaging in acute bacterial meningitis
in adults: a prospective national cohort study evaluating different guidelines. Clin Infect Dis 2018; 66:321–328.
19. Costerus JM, Brouwer MC, Bijlsma MW, et al. Impact of an evidence-based guideline on the management of community-acquired bacterial meningitis
: a prospective cohort study. Clin Microbiol Infect 2016; 22:928–933.
20. Erdem H, Ozturk-Engin D, Cag Y, et al. Central nervous system infections in the absence of cerebrospinal fluid pleocytosis. Int J Infect Dis 2017; 65:107–110.
21. Sivakmaran M. Meningococcal meningitis revisited: normocellular CSF. Clin Pediatr 1997; 36:351–355.
22. Sulaiman T, Salazar L, Hasbun R. Acute versus sub acute community-acquired meningitis in adults: an analysis of 611 patients. Medicine 2017; 96:e7984.
23. Nigrovic LE, Malley R, Kuppermann N. Meta-analysis of bacterial meningitis
score validation studies. Arch Dis Child 2012; 97:799–805.
24. Hasbun R, Bijlsma M, Brouwer MC, et al. Risk score for identifying adults with CSF pleocytosis and negative CSF Gram stain at low risk for an urgent treatable cause. J Infect 2013; 67:102–110.
25. Huy NT, Thao NTH, Diep DTN, et al. Cerebrospinal fluid lactate concentration to distinguish bacterial from aseptic meningitis: a systemic review and meta-analysis. Crit Care 2010; 14:R240.
26. Sakushima K, Hayashino Y, Kawaguchi T, et al. Diagnostic accuracy of cerebrospinal fluid lactate for differentiating bacterial meningitis
from aseptic meningitis: a meta-analysis. J Infect 2011; 62:255–262.
27. Nigrovic LE, Malley R, Macias CG, et al. Effect of antibiotic pretreatment on cerebrospinal fluid profiles of children with bacterial meningitis
. Pediatrics 2008; 122:726–730.
28. Rogers T, Sok K, Erickson T, et al. Impact of antibiotic therapy
in the microbiological yield of healthcare-associated ventriculitis and meningitis. Open Forum Infect Dis 2019; ofz050.
29. Balada-LLasat JM, Rosenthal N, Hasbun R, et al. Cost of managing meningitis and encephalitis among infants and children in the United States. Diagn Microbiol Infect Dis 2019; 93:349–354.
30. Balada-LLasat JM, Rosenthal N, Hasbun R, et al. Cost of managing meningitis and encephalitis among adult patients in the United States of America. Int J Infect Dis 2018; 71:117–121.
31. Leber AL, Everhart K, Ballada-Llasat JM, et al. Multicenter evaluation of the Biofire film array meningitis encephalitis panel for detection of bacteria, viruses, and yeast in cerebrospinal fluid specimens. J Clin Microb 2016; 54:2251–2261.
32. Aronin SI, Peduzzi P, Quagliarello VJ. Community-acquired bacterial meningitis
: risk stratification for adverse clinical outcome and effect of antibiotic timing. Ann Intern Med 1998; 129:862–869.
33. Miner JR, Heegaard W, Mapes A, et al. Presentation, time to antibiotics, and mortality of patients with bacterial meningitis
at an urban county medical center. J Emerg Med 2001; 21:387–392.
34. Proulx N, Fre[Combining Acute Accent]chette D, Toye B, et al. Delays in the administration of antibiotics are associated with mortality from adult acute bacterial meningitis
. QJM 2005; 98:291–298.
35. Køster-Rasmussen R, Korshin A, Meyer CN. Antibiotic treatment delay and outcome in acute bacterial meningitis
. J Infect 2008; 57:449–454.
36. Bodilsen J, Dalager-Pedersen M, Schonheyder HC, Nielsen H. Time to antibiotic therapy
and outcome in bacterial meningitis
: a Danish population-based cohort study. BMC Infect Dis 2016; 16:392.
37. Buchholz G, Koedel U, Pfister HW, et al. Dramatic reduction of mortality in pneumococcal meningitis. Crit Care 2016; 20:312.
38. Wall EC, Cartwright K, Scarborough M, et al. High mortality amongst adolescents and adults with bacterial meningitis
in sub-Saharan Africa: an analysis of 715 cases from Malawi. PLoS One 2013; 8:e69783.
39. Furyk JS, Swann O, Molyneux E. Systematic review: neonatal meningitis in the developing world. Trop Med Int Health 2011; 16:672–679.
40. Edmond K, Clark A, Korczak VS, et al. Global and regional risk of disabling sequelae from bacterial meningitis
: a systematic review and meta-analysis. Lancet Infect Dis 2010; 10:317–328.
41▪▪. van de Beek D, Cabellos C, Dzupova O, et al. ESCMID guideline: diagnosis and treatment of acute bacterial meningitis
. Clin Microbiol Infect 2016; Suppl 3:S37–S62.
European guidelines that does an excellent job in summarizing the diagnostic and management challenges.
42. Auburtin M, Porcher R, Bruneel F, et al. Pneumococcal meningitis in the Intensive Care Unit. Prognostic Factors of Clinical Outcomes
in a series of 80 cases. Am J Respir Crit Care Med 2002; 165:713–717.
43. Brouwer MC, Heckenberg SG, de Gans J, et al. Nationwide implementation of adjunctive dexamethasone therapy for pneumococcal meningitis. Neurology 2010; 75:1533–1539.
44. Beardsley J, Wolbers M, Kibengo FM, et al. Adjunctive dexamethasone in HIV-associated cryptococcal meningitis. N Engl J Med 2016; 374:542–554.
45. Engelen-Lee JY, Brouwer MC, Aronica E, et al. Delayed cerebral thrombosis complicating pneumococcal meningitis: an autopsy study. Ann Intensive Care 2018; 8:20.