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Update and advances in community acquired bacterial meningitis

Hasbun, Rodrigo

Current Opinion in Infectious Diseases: June 2019 - Volume 32 - Issue 3 - p 233–238
doi: 10.1097/QCO.0000000000000543
CNS INFECTIONS: Edited by Adarsh Bhimraj
Free
SDC

Purpose of review Community-acquired bacterial meningitis continues to occur and be associated with significant morbidity and mortality despite the availability of effective conjugate vaccines for the three most important meningeal pathogens.

Recent findings Indications for cranial imaging in suspected bacterial meningitis varies significantly between guidelines. Cranial imaging is of no clinical utility in those patients without indications and fosters delays in performing a lumbar puncture. Delaying lumbar puncture is associated with increased costs in both adults and children with meningitis and previous antibiotic therapy impacts the yield of microbiological results. Delaying antibiotic therapy is associated with worse clinical outcomes. Adjunctive steroids have reduced the mortality of adults with pneumococcal meningitis but have been associated with increased adverse outcomes in Listeria monocytogenes and Cryptococcus neoformans.

Summary Community-acquired bacterial meningitis remains a global health concern with high morbidity and mortality especially in low-income countries. Cranial imaging should be done only in patients with an indication with an attempt to do a prompt lumbar puncture and to initiate antibiotic therapy and adjunctive steroids as soon as possible to improve clinical outcomes.

Section of Infectious Diseases, UT Health McGovern Medical School, Houston, Texas, USA

Correspondence to Rodrigo Hasbun, MD, MPH, Professor of Medicine, Section of Infectious Diseases, UT Health McGovern Medical School, 6431 Fannin St., 2.112 MSB, Houston, TX 77030, USA. Tel: +1 713 500 7140; fax: +1 713 500 5495; e-mail: Rodrigo.Hasbun@uth.tmc.edu

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INTRODUCTION

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 [5].

Box 1

Box 1

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EPIDEMIOLOGY

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[6]. 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 [9]. 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 [8]. 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 [12]. 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 [12]. 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 [14].

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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 [3]. 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 [3]. 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 [18] 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 [16].

Table 1

Table 1

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DIAGNOSIS

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%) [20], but can account for almost 10% of all cases of meningococcal meningitis [21]. 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 [22]. 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) [23]. 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 [24]. The score was also validated with 100% sensitivity in 214 patients with culture-proven bacterial meningitis that had a negative Gram stain [24]. 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) [31].

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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 [32]. 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).

Table 2

Table 2

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OUTCOMES

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 [39]. 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 [40], 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%) [40]. 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▪▪].

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ADJUNCTIVE STEROIDS

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 [3]. 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 [42]. 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.

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CONCLUSION

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.

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Acknowledgements

None.

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Financial support and sponsorship

The study is funded by Grant A Starr Foundation.

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Conflicts of interest

Biofire (speaker, research grant), Merck (speaker), Gilead Sciences (advisory board).

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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
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REFERENCES

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Keywords:

adjunctive steroids; antibiotic therapy; bacterial meningitis; epidemiology; outcomes

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