OVERVIEW: What every practitioner needs to know
Are you sure your patient has bacterial meningitis? What should you expect to find?
Patients usually present with fever (which may be absent in patients receiving immunosuppressive agents) accompanied by meningeal symptoms and the physical findings indicative of meningitis.
Headache. A generalized headache is the rule. A more localized headache should make you worry about brain abscess or brain tumor. Because meningitis is accompanied by severe inflammation, headache should be severe and you would not expect it to be relieved by over-the-counter medications. Little difference in the character of headache has been reported between patients with bacterial versus viral versus fungal meningitis.
Stiff neck. Rigidity of neck muscles (i.e., inability to touch chin to chest) is the rule. Neck stiffness may not be seen in patients receiving corticosteroids or other immunosuppressive agents. Classically, this sign is absent in patients with cryptococcal meningitis. Neck stiffness is often surprisingly severe in patients with viral meningitis. Textbooks often emphasized Kernig’s (i.e., bend knee up to chest and then straighten the leg) and Brudzinski’s signs (i.e., flex neck and the patient draws up knees).
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However, the signs were more useful in the preantibiotic era. In modern medicine, these findings are most commonly encountered in patients with chronic forms of meningitis (e.g., fungal and tuberculous). Their sensitivity is extremely low (5-9%) in bacterial meningitis. Nuchal rigidity only has a sensitivity of 30% and a positive predictive value of 26%.
Vomiting. Vomiting may accompany headache and probably reflects brainstem irritation. The prognostic importance of vomiting and its frequency have not been fully explored in the literature.
Depressed mental status is the single most important characteristic to evaluate in your initial physical exam. To objectively assess mental status, the Glasgow Coma Score should be applied. Mental status most closely correlates with outcome, and is used to determine whether or not to administer corticosteroids.
No focal neurological deficits. A careful neurological exam is critical. Careful examination of the cranial nerves should be performed. Specific cranial nerve findings may suggest localized infections or increased cranial pressure.
Papilledema should not be seen in acute bacterial meningitis because edema of the retinal area takes 48-72 hours to develop and bacterial meningitis usually develops over 12-24 hours. In early meningitis, elevated cerebrospinal fluid (CSF) pressure is rare and usually develops in the later stages of the illness when inflammation is extreme. The findings of any focal neurological deficits or papilledema raise the possibility of a space occupying lesion and represent a contraindication for lumbar puncture.
How did the patient develop bacterial meningitis? What was the primary source from which the infection spread?
Remember, bacterial meningitis usually arises as a consequence of bacteremia, and bacteremia arises as a consequence of a primary infection at one of six sites (this is sometimes termed portal of entry, because this is the site from which bacteria gain entry into the bloodstream). Therefore, each site needs to be evaluated by physical exam, and if symptoms and signs are suggestive of involvement of any of these sites, imaging studies may be indicated:
Pharyngitis. For patients with erythema of the posterior pharynx and possibly symptoms of sore throat and who subsequently develop signs and symptoms of meningitis, you need to keep in mind the possibility of meningococcal diseases. This infection can be spread from person to person by droplets, and Neisseria meningitidis can be carried asymptomatically by healthy individuals. In early studies in military recruits, those who lacked specific protective antibodies against N. meningitidis had a 33% risk over 3 weeks of developing N. meningitidis bacteremia and/or meningitis. Always worry about this organism in crowded environments, such as dormitories.
Otitis media. In children, otitis media is the leading primary infection associated with bacterial meningitis. Prior to the use of Haemophilus influenzae vaccine, H. influenzae was the most common bacterial cause of pediatric meningitis. Now it is rare. Otitis media is also caused by Streptococcus pneumoniae, and this is now the most common pathogen to result in otitis media associated bacterial meningitis.
Sinusitis. This form of infection less commonly leads to bacteremia and only rarely spreads directly to the meninges. The most feared form of bacterial sinusitis is sphenoid sinusitis and, if the bacteria spread beyond the walls of this sinus, bacterial infection of the large complex of veins called the cavernous sinus can result in their thrombosis. Spread to the cavernous sinuses has also been associated with bacterial meningitis. The most common bacteria to result in sinusitis-associated meningitis are S. pneumoniae and H. influenzae.
Pulmonary infection. Lobar pneumonia due to S. pneumoniae is associated with bacteremia in a significant percentage of cases (10-16%, approximately), and bacteremia can result in meningitis. A depressed mental status in a patient with pneumonia should always raise concerns about the possibility of bacterial meningitis.
Endocarditis. Bacterial endocarditis results in persistent bacteremia. Most pathogens associated with this infection rarely cause bacterial meningitis. One exception is Staphylococcus aureus and this invasive pathogen often results in cerebritis, which results in a para-meningeal CSF formula, but rarely actually infects the meninges. Another exception is S. pneumoniae. This rare infection mostly occurs in patients with liver disease or immunosuppression, and in nearly half of cases is complicated by meningitis.
Gastroenteritis. Listerie monocytogenes is a foodborne pathogen commonly contracted by eating foods refrigerated for prolonged periods (Listeria can grow on foods at 4°C), such as deli meats, soft cheeses, and a variety of other foods. On ingesting Listeria-contaminated food, patients with defects in cell-mediated immunity develop bacteremia. Listeria has a unique propensity to infect the meninges and can also invade the brain stem, causing rhombencephalitis. Less commonly, this pathogen can invade the cerebral cortex.
Which individuals are of greater risk of developing bacterial meningitis?
There are specific conditions that predispose patients to bacterial meningitis, and these conditions need to be explored by history and laboratory examination:
Immunoglobulin deficiency. Specific antibodies are capable of binding to encapsulated organisms such as S. pneumoniae through their variable region and then attaching to the immunoglobulin Fc receptors on neutrophils and macrophages to stimulate phagocytosis (or ingestion) of bacteria; stimuli that induce phagocytosis are termed opsonins. Patients with deficiencies in immunoglobulins or an inability to generate specific antibodies against encapsulated organisms are at risk for developing bacteremia and meningitis from these pathogens.
Splenectomy. The spleen filters 10% of the blood flow and allows the blood to pass by resident macrophages and lymphocytes. Foreign objects such as bacteria, particularly when bound with immunoglobulin, are readily phagocytosed and cleared from the blood stream. Patients without spleens are at higher risk for the development of overwhelming S. pneumoniae, H. influenzae, and N. meningitidis sepsis.
Terminal complement deficiency. The terminal complement components are responsible for forming what is sometimes termed an attack complex capable of lysing the lipid laden outer cell wall of Neisseria species, and patients deficient in the production of these products are at increased risk for systemic N. meningitidis infection. It is estimated that 33% of sporadic cases of meningococcal meningitis have a defect in the production of these terminal complement pathway products.
Head trauma with dural leak. Remember, patients who have had significant head trauma, particularly in association with motor vehicle accidents, are at increased risk for CSF leaks in the area of the cribriform plate, as well as at the base of the skull near the middle ear. Patients with cribriform plate defects may have a history of unexplained clear fluid drainage from the nose. Usually, when meningitis occurs, the inflammation temporarily closes the CSF leak. Any patient who suffers more than one episode of S. pneumoniae should undergo studies to exclude a CSF leak.
Immunocompromised patients. Patients receiving immunosuppressants to prevent solid organ rejection or patients who have undergone hematopoietic cell transplant, as well as patients receiving high-dose corticosteroids and patients with AIDS, have depressed cell-mediated immunity and are at increased risk for L. monocytogenes.
Elderly (older than 55 years of age). These individuals also have reduced cell-mediated immunity and are at increased risk for L. monocytogenes.
Post neurosurgery. Following neurosurgery, patients are at risk for meningitis due to nosocomial pathogens, predominantly Gram-negative bacilli, S. aureus and Enterococcus.
Beware: there are other diseases that can mimic bacterial meningitis
Cerebrovascular accident. In particular, subarachnoid hemorrhage can result in headache and depressed mental status. Fever is uncommon initially, and the headache comes on with extreme suddenness.
Brain abscess. Patients suffering with brain abscess may complain of headaches; however, headache is often localized to the side where the brain abscess is located. These patients can develop a depressed mental status and can also present with seizures. Avoid lumbar puncture in these patients because of the danger of herniation.
Brain tumor. Patients with brain tumors can present identically to brain abscess, and, when their mental status is depressed or they develop seizures, the problem can be mistaken for meningitis. Avoid lumbar puncture in these patients as well because of the risk of herniation.
Drug overdose. Depressed sensorium accompanied by fever can also be the result of a drug overdose combined with an aspiration pneumonia. These patients’ symptoms can be difficult to differentiate from bacterial meningitis, and such patients often require lumbar puncture to exclude this diagnosis.
“Chemical” meningitis. Following epidural anesthesia, anesthetics and contaminants can result in an increase in CSF neutrophils and a low CSF glucose. Similar findings can accompany epidermoid tumors or craniopharyngiomas that leak material into the subarachnoid space. Additionally, hypersensitivity reactions to some drugs, especially NSAIDs, several antibiotics and IV immunoglobulin preparations can result in symptoms indistinguishable from those seen with bacterial meningitis.
Elderly patient with fever and confusion. Elderly patients who have had any prior CNS problems may become confused as a consequence of fever or a metabolic imbalance. Because under these circumstances there may be no focal neurological deficits and because many elderly patients may have stiff neck muscles under normal circumstances, it is clinically impossible to differentiate toxic metabolic encephalopathy from meningitis. Therefore, in elderly patients with confusion accompanied by fever, clinicians should have a low threshold to perform a lumbar puncture.
What laboratory studies should you order and what should you expect to find?
Peripheral white blood cell (WBC) with differential. In acute bacterial meningitis, expect an elevated peripheral WBC with increased percentage of bands and polymorphonuclear leukocytes (PMNs). In tuberculous meningitis, rarely there can be a leukemoid reaction (WBC >30,000), but more commonly the percentage of peripheral monocytes is increased. In patients with cryptococcal meningitis, the peripheral lymphocyte count may be decreased, reflecting previously undiagnosed HIV infection that has progressed to AIDS.
Results that confirm the diagnosis
Blood cultures. Blood cultures are very helpful and may be positive, particularly in Listeria, pneumococcal and meningococcal meningitis. Serum cryptococcal antigen is positive in almost all HIV-infected patients with cryptococcal meningitis.
Lumbar puncture. Lumbar puncture (LP) is the critical test for making the diagnosis of meningitis. There is no other diagnostic study capable of diagnosing or ruling out infection of the meninges. If meningitis is part of your differential diagnosis, a lumbar puncture should always be performed if there are no focal neurologic deficits or papilledema to suggest an intracranial mass lesion. The IDSA guidelines have recommended CT scan for all patients with depressed sensorium. A recent review of the Swedish quality registry has revealed that CT significantly delays antibiotic administration, and based on this analysis impaired mental status should no longer be considered a contraindication for lumbar puncture. However, in patients with focal neurological deficits or papilledema, a CT scan with contrast should be performed before lumbar puncture, and, if a space-occupying lesion is found, the lumbar puncture is contraindicated because of an approximately 30% risk of herniation.
CSF profile interpretation (Table I). The cellular response seen in the CSF is very helpful for narrowing the possible etiology. The usual bacterial pathogens induce an acute inflammatory response consisting of neutrophils, although intracellular pathogens, particularly tuberculosis, fungi and to some extent Listeria induce lymphocytic response. A decrease in CSF glucose is thought to be the consequence of impaired blood-brain barrier glucose transport as a consequence of severe inflammation and damage. A normal CSF glucose should be two-thirds the serum glucose. In many patients, a simultaneous blood sugar is not drawn at the time of the lumbar puncture, making interpretation of this value problematic. However, severe cases of bacterial meningitis with markedly depressed mental status are usually accompanied by a very low CSF glucose levels (<25 mg/dL). The elevation in protein is thought to be due to damage to the blood-brain barrier and leakage of serum proteins into the CSF. CSF proteins are usually highest in bacterial meningitis and can reach 1,000 mg/dL.
Table I.
| Type of Infections | WBC | Glucose (nl 2/3 serum) | Protein |
|---|---|---|---|
| > 90% PMN | |||
| Untreated Bacterial | Low (can be < 25 m/dl) | High (150-1000 mg%) | |
| (except Listeria) | |||
| Partially Treated | Lymphs | Low | Moderately high (80-500 mg%) |
| TB | Lymphs | Normal | Slight elevation (60-150 mg%) |
| Parameningeal (brain abscess) | Lymphs or PMN | Normal | Normal or slightly elevated |
Untreated bacterial. A predominance of neutrophils (usually >90% PMN), a markedly low CSF glucose (also termed hypoglycorrhachia), and an elevated CSF protein are seen almost exclusively in bacterial meningitis. The CSF formula always warrants empiric antibiotic coverage. In patients with greater than 90% PMN and the appropriate risk factors, Listeria meningitis should be suspected and empiric coverage for this pathogen should be added (ampicillin or bactrim if PCN allergic).
Tuberculous, fungal, treated bacterial. A predominance of lymphocytes, a moderately low CSF glucose and a moderately elevated CSF protein are the most common findings. This profile is found in patients with tuberculous meningitis (although PMNs may be seen early), fungal meningitis (Cryptococcus the most common form, particularly in patients with AIDS and solid organ transplant patients), and in patients who have partially treated bacterial meningitis (i.e., have received antibiotics more than 24 hours prior to lumbar puncture). The CSF cryptococcal antigen test is very specific and sensitive. If this test is negative, cryptococcal meningitis is essentially excluded.
Viral. A predominance of lymphocytes, a normal CSF glucose, and a modestly elevated CSF protein (usually not > 200 mg/ml) represent the most typical findings. This profile strongly suggests a viral meningitis. Occasionally, viral meningitis, particularly in children, may fluctuate between 100% lymphocytes and 60-70% lymphocytes with 30-40% PMNs. In these patients, the wisest course of action is to cover with antibiotics for 24-48 hours awaiting the CSF culture results to exclude bacterial meningitis, particularly Listeria. When a patient has both a depressed mental status and a viral CSF profile, viral encephalitis needs to be considered.
Parameningeal. A few PMNs and/or lymphocytes with a normal CSF glucose and a normal or slightly elevated protein are typical. This CSF profile is seen when an infection lies near the meninges (parameningeal) but does not directly involve this area. Examples include brain abscess, otitis media, sphenoid and/or frontal bacterial sinusitis. When this CSF profile is observed, CNS imaging should be performed.
If the CSF profile shows a predominance of PMN, what other CSF tests should be ordered?
CSF Gram Stain. In approximately 80% of bacterial meningitis cases, CSF Gram stain is positive and reveals the pathogen. Because Listeria is an intracellular pathogen, CSF Gram stain reveals this organism in approximately 30% of cases.
Latex agglutination for bacteria has no greater sensitivity or specificity than Gram stain and is generally not recommended.
If the CSF profile shows a lymphocytes and a low glucose, what other CSF tests be ordered?
CSF cryptococcal antigen latex agglutination.
CSF acid fast stain and polymerase chain reaction (PCR) for TB.
Mycobacterial and fungal culture.
Peripheral and CSF Venereal Disease Related Laboratory (VDRL) test, as well as a peripheral FTA-ABS or other specific treponema test (MHA-TP, TP-PA). In some cases of syphilitic meningitis, the peripheral VDRL can be negative; however, the peripheral specific treponemal test should always be positive.
If the CSF profile shows lymphocytes and a normal CSF, are other CSF tests indicated?
Generally, not, but the exception is that recurrent bouts of viral meningitis raise the possibility of herpes simplex type 2 viral meningitis (Mollaret’s meningitis). A CSF PCR for herpes simplex should be performed, and if positive, acyclovir treatment should be considered.
What imaging studies will be helpful in making or excluding the diagnosis of bacterial meningitis?
CXR. Particularly in patients with pneumococcal meningitis, CXR may reveal a lobar infiltrate. Other forms of pneumonia are rarely accompanied by meningitis. However, if the individual’s sensorium is markedly depressed or he/she has suffered seizure radiologic changes consistent with aspiration, pneumonia may also be observed.
CT scan with contrast or MRI with contrast. This should be performed if there are physical findings or history suggesting the possibility of brain abscess or brain tumor. In these patients, lesions are generally enhanced by contrast. In patients with meningitis, increased contrast uptake may be seen throughout the meninges. However, this finding is nonspecific. If CNS imaging is to be performed, empiric antibiotics should be initiated after blood cultures have been drawn and before the imaging study. The average time required to complete a CT scan is more than 45 minutes, and in cases of bacterial meningitis, this delay in the initiation of antibiotics can result in increased mortality and morbidity.
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What consult service or services would be helpful for making the diagnosis and assisting with treatment?
Neurology consult. This assists in determining the level of coma and finding if there are focal neurological deficits.
Infectious disease consult. This assists in managing many nuances with regard to empiric antibiotic coverage, as well as for the antibiotic treatment of pneumococcal meningitis.
If you decide the patient has bacterial meningitis, what therapies should you initiate immediately?
Antibiotics should be initiated within 30 minutes. Administer the highest dose of each antibiotic allowable. The blood-brain barrier reduces antibiotic penetration into the central nervous system; therefore, to achieve therapeutic levels in the CSF, maximal doses are required and should be administered intravenously (sometimes referred to as meningeal doses).
The duration of therapy depends on the organism and the response to therapy. For most cases, 10-14 days of antibiotics are sufficient for bacterial meningitis. The one exception to this rule is L. monocytogenes, because relapse is common if the duration of therapy is not extended to 3 weeks. Fungal and tuberculous meningitis require months of therapy while viral meningitis is a self-limited infection that generally does not require therapy. The one exception to this rule is meningitis due to herpes simplex. Intravenous acyclovir or valacyclovir is recommended for these cases.
1. Antibacterial agents
If I am not sure what bacteria is causing the infection what antibiotics should I order?
The empiric regimens depend on the patient’s age, underlying diseases and whether or not the patient has recently been hospitalized or undergone neurosurgery (Table II).
- Neonates require Gram-negative and Group B streptococcal coverage: Cefepime and ampicillin.
- Older children require coverage for S. pneumoniae, N. meningitidis, and H. infuenzae (rare in children who have received the H. influenzae B vaccine): ceftriaxone and vancomycin (until PCN-resistant S. pneumoniae excluded).
- Otherwise healthy adults younger than 55 years of age require coverage for S. pneumoniae, N. meningitides, and H. influenzae (rare in adults): Ceftriaxone and Vancomycin (until PCN-resistant S. pneumoniae excluded).
- Immunocompromised patients (on corticosteroids or other immunosuppressive drugs) should be treated for L. monocytogenes in addition to S. pneumoniae, N. meningitidis, and H. influenzae: ampicillin, ceftriaxone, and vancomycin (until PCN-resistant S. pneumonia excluded).
- Adults older than 55 years of age should also be empirically covered for L. monocytogenes in addition to S. pneumoniae, N. meningitidis, and H. influenzae: ampicillin, ceftriaxone, and vancomycin (until PCN-resistant S. pneumoniae excluded).
- Post neurosurgery needs to cover for Gram-negative bacilli, S. aureus, including MRSA and Enterococcus: cefepime and vancomycin.
2. Other key therapeutic modalities
Corticosteroids. In adult bacterial meningitis, the beneficial effects of corticosteroids are seen in those with a specific level of mental status depression (Glasgow Coma Scale score 8-11). Although no benefit has been documented for more severe coma scores, many clinicians administer dexamethasone (10 mg Q6H IV x 4 day) in all patients with Glasgow Coma Scale scores of 11 or less.
In developing countries, studies have failed to reveal any benefit from dexamethasone. However, in industrialized countries where patients seek medical attention more promptly, studies do suggest some benefit. No harmful side effects have been documented as a consequence of short course dexamethasone; however, CSF penetration of vancomycin may be impaired as a consequence of improved integrity of the blood-brain barrier, and, in patients with PCN-resistant S. pneumoniae, rifampin should be added to the antibiotic regimen to assure cidal CSF activity.
The major complications associated with meningitis arise as a consequence of excessive inflammation. Multiple studies have demonstrated a reduced incidence of deafness, particularly in children, and improved overall outcome if this inflammatory response in bacterial meningitis can be blunted by the administration of high-dose corticosteroids. The benefits of dexamethasone in adults has been demonstrated for S. pneumoniae, but not for N. meningitidis.
Because the cell walls of the bacteria often break down quickly in response to cidal antibiotics, such as cephalosporin, penicillin and vancomycin, and the release of cell wall products can induce a cascade of inflammatory stimuli, corticosteroids should be given before or simultaneously with anti-infective therapy.
Hydration with normal saline. Because of the association of cerebral edema with bacterial and fungal meningitis, administration of free water should be avoided. To maintain fluid and electrolyte balance, normal saline should always be administered. D5W or D5½ normal saline are contraindicated. Hypertonic saline has been shown to reduce cerebral edema, and may be considered in severely ill patients.
Positioning of the head. The head should be positioned at a 30° angle. This will maximize cerebral venous drainage while not significantly compromising cerebral blood flow. This helps reduce CSF pressure.
Intubation and ventilatory support to reduce PaCO2 to 27-30 mmHg are often required. Reductions in PaCO2 result in cerebral vessel constriction that reduce intracerebral blood volume and reduce CSF pressure.
Mannitol or glycerol. If lumbar puncture reveals a CSF pressure greater than 300 mm H2O, the administration of hypertonic solutions that can draw free water from the central nervous system should be considered, and these products can at least temporarily reduce cerebral edema and elevated CSF pressure. If a high CSF pressure is noted at the time of lumbar puncture (LP), immediately replace the stylet and only use the fluid in the manometer for culture, cell count and Gram stain.
Do not immediately remove the LP needle, because the needle leaves a tear in the dura and will allow CSF to leak from this site. This condition can lead to brain stem herniation. Initiation of intravenous mannitol (20% solution administered at a rate of 200 cc/h) should reduce CSF pressure within 30-45 minutes, and the LP needle can be removed at that time
In pediatric cases, oral glycerol has been shown to reduce deafness, as well as other neurological sequelae; however, in adults, their use is of questionable benefit. The role of hypertonic solutions with regards to improving mortality remains controversial.
Antiseizure medications. Preventive administration of seizure medications is not recommended by most experts because less than one-third of cases of bacterial meningitis develop seizures during their acute illness. Standard grand-mal antiseizure medical regimens are recommended.
What complications could arise as a consequence of bacterial meningitis? What should you tell the family about the patient’s prognosis?
- Persistent sensorineural hearing loss occurs in 10% of children but is rare in adults. It is most commonly associated with S. pneumoniae and H. influenzae.
- Seizures (focal or generalized) occur in 20-30% of patients, usually because of cerebral infarction resulting from cerebral arteritis or cortical vein thrombosis. Alcohol withdrawal can be a confounding factor in some cases.
- Elevated CSF pressure due to cerebral edema and/or hydrocephalus can occur and lead to temporal lobe herniation (found in one-fourth of fatal cases).
- Focal neurological deficits, including hemiparesis, dysphasia, and visual field defects caused by arterial or cortical vein occlusions can occur.
- Bacterial meningitis is a very serious infection. If treatment is prompt a rapid recovery can be expected.
- Delays in therapy increase the likelihood of complications and/or death.
- A poor outcome is more likely in patients who are obtunded, elderly, have seizures within the first 24 hours, develop focal neurological deficits, or have an underlying disease (e.g., leukemia, liver disease, alcoholism).
- Overall mortality for bacterial meningitis depends on the organism: 5% for H. influenzae; 10% for N. meningitides; 20% for S. pneumoniae; 20-30% for L. monocytogenes; 20-30% for gram-negative bacillary meningitis (but may be improving with more rapid diagnosis and more effective treatment).
- After recovery, 10-20% of patients have residual neurological deficits. Twenty-five percent of adults who “fully” recovered were subsequently found to have cognitive slowing or other neuropsychological deficits 6-24 months after discharge from the hospital.
- Deafness occurs uncommonly in children.
How do you contract bacterial meningitis and how frequent is the disease?
The World Health Organization (WHO) estimates that there are 1.2 million cases of bacterial meningitis per year worldwide. The incidence of bacterial meningitis in the U.S. has been declining: in 1998-1999 it was 2.00 cases per 100,000, which decreased to 1.38 cases per 100,000 population in 2006-2007.
The epidemiology of bacterial meningitis depends on the etiologic agent:
S. pneumoniae is the most common cause of community acquired bacterial meningitis. It colonizes the nasopharynx of 20% of healthy adults. Colonization is higher during the late fall, winter and early spring. The capsular serotypes that are most likely to cause disease are types 3, 4, 6, 7, 9, 12, 14, 18, 19, and 23. It is spread from person to person by close personal contact. Native Americans and Australian Aboriginal populations are at higher risk of disease, as are patients with immunoglobulin deficiencies or splenectomy.
N. meningitidis is second in prevalence, and is a major problem in developing countries. Rates of meningococcal disease are as high as 5-10 per 100,000 in sub-Saharan Africa. Epidemics in this region are cyclic, occurring every 8-10 years, and can be associated with incidences as high as 1/1000. Local outbreaks also occur in the U.S., Canada, Europe, Japan, Australia and other industrialized countries; however, the overall incidence is lower (0.3-2 per 100,000). The organism colonizes the nasopharynx and is spread from person to person by respiratory droplets. It has an 8-25% colonization rate in adults (highest in adolescents and closed populations (military recruits); higher rates are associated with intimate personal contact and crowding (e.g., dormitories, bars, social events). Infection usually develops within 1-14 days of acquiring the organism. Six serogroups cause disease: A, B, C, W-135, X and Y.
L. monocytogenes is the third to fourth most common cause of community acquired bacterial meningitis. The incidence of listeriosis is only 0.7 cases per 100,000 but is higher in those older than 70 years of age (2.1/100,000), pregnant women (12/100,000), and transplant and HIV patients (100/100,000). It is foodborne (raw milk and cheeses, raw vegetables and fruits, undercooked chicken, hot dogs, and virtually any other processed food product). Prolonged refrigeration is a risk, because the organism is able to grow at 4°C (39°F). Bermudez A, Delicatessen foods are a danger. Microwave reheating usually does not kill this pathogen (>74°C or >165°F required for sterilization).
H. Influenzae is now a rare cause of bacterial meningitis because of widespread H. influenzae B (HIB) vaccination. Adult infections are now 1.7/100,000. H. Influenzae is carried in the nasopharynx 3-5% of children if not vaccinated (much lower following vaccination) and as a consequence a nonimmune household contact of an infected patient is at 600 times higher risk of infection. Patients with HIV are at greater risk (15-79/100,000). Patients with immunoglobulin deficiencies, sickle cell disease, splenectomy, history of recurrent otitis media, Native Americans and attendees of daycare centers are at higher risk.
What pathogens are responsible for this disease?
Table III. Pathogens
Table III.
| Organism | Community-acquired(%) | Nosocomial % |
|---|---|---|
| S. pneumoniae | 40-70 | 5 |
| N. meningitidis | 12-37 | 1 |
| Group B Streptococci | 4-7 | 9 |
| Listeria monocytogenes | 4-11 | 3 |
| H. Influenzae | 4-5 | 4 |
| Staphylococcocus aureus | 2-5 | 9 |
| Gram-negative Bacilli | 3 | 38 |
How do these pathogens cause bacterial meningitis?
During bacterial meningitis, bacteria generally gain access to the subarachnoid space as a consequence of bacteremia (Table III). Less frequently, bacteria can spread to this space by direct spread as a consequence of a CSF leak following head trauma that damages the cribriform plate or results in a basilar skull fracture. Once bacteria gain entry into the sterile subarachnoid space that lacks complement and immunoglobulins, bacteria can grow rapidly. Because of the rapid progression of this infection, emergent treatment is indicated to prevent irreversible neurological damage.
When bactericidal antibiotics are administered, components of the bacterial cell wall are released, stimulating toll-like receptors that in turn stimulate the release of acute inflammatory cytokines. These bacterial products also serve to attract and activate neutrophils that release toxic proteases and oxygen byproducts. These acute inflammatory responses result in cerebral edema, as well as arterial and venous thrombosis. As a consequence of these events, arterial circulation to the cerebral cortex is impaired, leading to cerebral infarction.
What other clinical manifestations may help me to diagnose and manage bacterial meningitis?
Changes in mental status usually include a loss of orientation and lethargy. Less commonly, patients become manic and their symptoms can mimic a psychiatric illness. Bacterial meningitis needs excluded for any patient with sudden behavioral changes that are accompanied by fever.
What other additional laboratory findings may be ordered?
CSF lactate levels are high in bacterial meningitis and can be helpful in differentiating bacterial from viral meningitis. The cut-off level varies from laboratory to laboratory. A CSF level above 2.1-4.44 strongly suggests bacterial meningitis.
How can bacterial meningitis be prevented?
Vaccination
Conjugate vaccines have proven highly effective for preventing bacterial meningitis. H. influenzae type B conjugate vaccine has virtually eliminated H. influenzae bacterial meningitis in the pediatric population. Recent studies have also demonstrated the efficacy of the meningococcal vaccine in young children and adolescents. A conjugate vaccine directed against meningococcal serotypes A, C, W135, and Y polysaccharides is recommended for all persons 11-18 years of age. More recently, recombinant vaccines against serotype B have become available, however routine administration is not presently recommended, being left up to the discretion of the physician and the family. The recommended age for administration is 16-18 years.
The 23-valent pneumococcal capsular antigen vaccine has been shown to reduce invasive pneumococcal disease in many patient populations, including those over age 65. More recently, a 13-valent conjugate pneumococcal vaccine has become available, and should be administered in addition to the older 23-valent vaccine. The incidence of pneumococcal meningitis has decreased with the increased use of the vaccine; however, disease caused by serotypes not found in the vaccine has been observed. It is hoped that the 13-valent conjugated vaccine will lead to even greater reductions in invasive pneumococcal disease, including meningitis.
Chemoprophylaxis
H. influenzae. Rifampin 20 mg/kg daily x 4 days is recommended for household or possibly for daycare center contacts younger than 2 years of age. Prophylaxis should be instituted quickly, because secondary cases usually develop within 6 days of the index case.
WHAT’S THE EVIDENCE for specific management and treatment recommendations?
General reviews
Kim, KS.. “Acute bacterial meningitis in infants and children”. Lancet Infect Dis. vol. 10. 2010. pp. 32-42. (Emphasizes the importance of rapid institution of antibiotics and coverage for potential antibiotic resistant S. pneumoniae.)
Lin, AL, Safdieh, JE.. “The evaluation and management of bacterial meningitis: current practice and emerging developments”. Neurologist. vol. 16. 2010. pp. 143-51. (Emphasizes the poor sensitivity of the classic triad of fever, neck stiffness and altered mental status. Recommends adding headache to this triad to improve sensitivity.)
Large clinical series
van de Beek, D, de Gans, J, Spanjaard, L, Weisfelt, M, Reitsma, JB, Vermeulen, M.. “Clinical features and prognostic factors in adults with bacterial meningitis”. N Engl J Med. vol. 351. 2004. pp. 1849-59.
Thomas, KE, Hasbun, R, Jekel, J, Quagliarello, VJ.. “The diagnostic accuracy of Kernig’s sign, Brudzinski’s sign, and nuchal rigidity in adults with suspected meningitis”. Clin Infect Dis. vol. 35. 2002. pp. 46-52.
Durand, ML, Calderwood, SB, Weber, DJ. “Acute bacterial meningitis in adults. A review of 493 episodes”. N Engl J Med. vol. 328. 1993. pp. 21-8.
Epidemiology
Thigpen, MC, Whitney, CG, Messonnier, NE. “Bacterial meningitis in the United States, 1998-2007”. N Engl J Med. vol. 364. 2011. pp. 2016-25.
Huang, CR, Chen, SF, Lu, CH. “Clinical characteristics and therapeutic outcomes of nosocomial super-infection in adult bacterial meningitis”. BMC Infect Dis. vol. 11. 2011. pp. 133
Moon, SY, Chung, DR, Kim, SW. “Changing etiology of community-acquired bacterial meningitis in adults: a nationwide multicenter study in Korea”. Eur J Clin Microbiol Infect Dis. vol. 29. 2010. pp. 793-800.
Georges, H, Chiche, A, Alfandari, S, Devos, P, Boussekey, N, Leroy, O.. “Adult community-acquired bacterial meningitis requiring ICU admission: epidemiological data, prognosis factors and adherence to IDSA guidelines”. Eur J Clin Microbiol Infect Dis. vol. 28. 2009. pp. 1317-25.
Prognosis
Barahona-Garrido, J, Hernandez-Calleros, J, Tellez-Avila, FI, Chavez-Tapia, NC, Remes-Troche, JM, Torre, A.. “Bacterial meningitis in cirrhotic patients: case series and description of the prognostic role of acute renal failure”. J Clin Gastroenterol. vol. 44. 2010. pp. e218-23.
Vibha, D, Bhatia, R, Prasad, K, Srivastava, MV, Tripathi, M, Singh, MB.. “Clinical features and independent prognostic factors for acute bacterial meningitis in adults”. Neurocrit Care. vol. 13. 2010. pp. 199-204.
Weisfelt, M, de Gans, J, van der Ende, A, van de Beek, D.. “Community-acquired bacterial meningitis in alcoholic patients”. PLoS One. vol. 5. 2010. pp. e9102
Complications
Kasanmoentalib, ES, Brouwer, MC, van der Ende, A, van de Beek, D.. “Hydrocephalus in adults with community-acquired bacterial meningitis”. Neurology. vol. 75. 2010. pp. 918-23.
Pathogenesis
Gerber, J, Nau, R.. “Mechanisms of injury in bacterial meningitis”. Curr Opin Neurol. vol. 23. 2010. pp. 312-8.
Koedel, U, Klein, M, Pfister, HW.. “New understandings on the pathophysiology of bacterial meningitis”. Curr Opin Infect Dis. vol. 23. 2010. pp. 217-23.
Kim, BJ, Hancock, BM, Bermudez, A, Del Cid, N. “Bacterial induction of Snail1 contributes to blood-brain barrier disruption”. J Clin Invest. vol. 125. 2015. pp. 2473-83. (Bacteria stimulate the induction of Snail1 causing a breakdown in the tight junctions of the blood-brain barrier and prevention of upregulation of Snail 1 prevents this effect.)
Lumbar puncture
Michael, B, Menezes, BF, Cunniffe, J. “Effect of delayed lumbar punctures on the diagnosis of acute bacterial meningitis in adults”. Emerg Med J. vol. 27. 2010. pp. 433-8.
Huy, NT, Thao, NT, Diep, DT, Kikuchi, M, Zamora, J, Hirayama, K.. “Cerebrospinal fluid lactate concentration to distinguish bacterial from aseptic meningitis: a systemic review and meta-analysis”. Crit Care. vol. 14. 2010. pp. R240
Sakushima, K, Hayashino, Y, Kawaguchi, T, Jackson, JL, Fukuhara, S.. “Diagnostic accuracy of cerebrospinal fluid lactate for differentiating bacterial meningitis from aseptic meningitis: a meta-analysis”. J Infect. vol. 62. 2011. pp. 255-62.
Rafi, W, Chandramuki, A, Mani, R, Satishchandra, P, Shankar, SK.. “Rapid diagnosis of acute bacterial meningitis: role of a broad range 16S rRNA polymerase chain reaction”. J Emerg Med. vol. 38. 2010. pp. 225-30.
Glimåker, M, Johansson, B, Grindborg, Ö, Bottai, M. “Adult bacterial meningitis: earlier treatment and improved outcome following guideline revision promoting prompt lumbar puncture”. Clin Infect. Dis. vol. 60. 2015. pp. 1162-9. (Depressed mental status should not be considered a contraindication for LP.)
Imaging
Hughes, DC, Raghavan, A, Mordekar, SR, Griffiths, PD, Connolly, DJ.. “Role of imaging in the diagnosis of acute bacterial meningitis and its complications”. Postgrad Med J. vol. 86. 2010. pp. 478-85.
Overall guidelines for treatment
Tunkel, AR, Hartman, BJ, Kaplan, SL. “Practice guidelines for the management of bacterial meningitis”. Clin Infect Dis. vol. 39. 2004. pp. 1267-84.
Beckham, JD, Tyler, KL.. “Initial management of acute bacterial meningitis in adults: summary of IDSA guidelines”. Rev Neurol Dis. vol. 3. 2006. pp. 57-60.
Antibiotic treatment
van de Beek, D, Brouwer, MC.. “No difference between short-course and long-course antibiotics for bacterial meningitis in children, but available evidence limited”. Evid Based Med. vol. 15. 2010. pp. 6-7.
Molyneux, E, Nizami, SQ, Saha, S. “5 versus 10 days of treatment with ceftriaxone for bacterial meningitis in children: a double-blind randomised equivalence study”. Lancet. vol. 377. 2011. pp. 1837-45.
Laxmi, S, Tunkel, AR.. “Healthcare-Associated Bacterial Meningitis”. Curr Infect Dis Rep. 2011.
Sakata, H, Sato, Y, Nonoyama, M. “Results of a multicenter survey of diagnosis and treatment for bacterial meningitis in Japan”. J Infect Chemother. vol. 16. 2010. pp. 396-406.
Sakoulas, G, Nonejuie, P, Kullar, R, Pogliano, J. “Examining the use of ceftaroline in the treatment of Streptococcus pneumoniae meningitis with reference to human cathelicidin LL-37”. Antimicrob Agents Chemother. vol. 59. 2015. pp. 2428-2431. (When dosed at 600 mg, Q8H IV ceftaroline proved to be effective in the treatment of S. pneumonia and promises to be a helpful alternative to vancomycin when intermediate or high penicillin resistance is a concern.)
Adjunctive therapy
Ajdukiewicz, KM, Cartwright, KE, Scarborough, M. “Glycerol adjuvant therapy in adults with bacterial meningitis in a high HIV seroprevalence setting in Malawi: a double-blind, randomised controlled trial”. Lancet Infect Dis. vol. 11. 2011. pp. 293-300.
Liu, S, Li, L, Luo, Z. “Superior effect of hypertonic saline over mannitol to attenuate cerebral edema in a rabbit bacterial meningitis model”. Crit Care Med. vol. 39. 2011. pp. 1467-73.
Peterkovic, V, Trkulja, V, Kutlesa, M, Krajinovic, V, Lepur, D.. “Dexamethasone for adult community-acquired bacterial meningitis: 20 years of experience in daily practice”. J Neurol. 2011.
Brouwer, MC, McIntyre, P, de Gans, J, Prasad, K, van de Beek, D.. “Corticosteroids for acute bacterial meningitis”. Cochrane Database Syst Rev. 2010. pp. CD004405
Quagliarello, V, Scheld, WM.. “Infectious disease: do steroids benefit patients with bacterial meningitis?”. Nat Rev Neurol. vol. 6. 2010. pp. 529-30. (Written by 2 renowned experts on bacterial meningitis. Reviews all the current data and concludes that in industrialized countries corticosteroids should be used. However, they recognize that the world-wide impact of such adjunctive therapy will be minimal. Universal vaccination will be the critical intervention.)
van de Beek, D, Farrar, JJ, de Gans, J. “Adjunctive dexamethasone in bacterial meningitis: a meta-analysis of individual patient data”. Lancet Neurol. vol. 9. 2010. pp. 254-63.
Glimåker, M, Johansson, B, Halldorsdottir, H, Wanecek, M. “Neuro-intensive treatment targeting intracranial hypertension improves outcome in severe bacterial meningitis: an intervention-control study”. Plos 1. vol. 9. 2014: Mar 25. pp. e91976(ICU care with close monitoring of CSF pressure, administration of corticosteroids, osmotherapy, CSF drainage, and cooling reduced mortality by 68%.)
Prevention
Riordan, A.. “The implications of vaccines for prevention of bacterial meningitis”. Curr Opin Neurol. vol. 23. 2010. pp. 319-24.
Leventer-Roberts, M, Feldman, BS, Brufman, I, Cohen-Stavi, CJ. “Effectiveness of 23-valent pneumococcal polysaccharide vaccine against invasive disease and hospital-treated pneumonia among people aged ≥65 years: a retrospective case-control study”. Clin Infect Dis. vol. 60. 2015. pp. 1472-80. (A significant reduction in invasive disease was demonstrated, but not a reduction in pneumonia.)
Ratilal, BO, Costa, J, Pappamikail, L, Sampaio, C.. “Antibiotic prophylaxis for preventing meningitis in patients with basilar skull fractures”. Cochrane Database Syst Rev. 2015. (Antibiotic prophylaxis is not of proven benefit for preventing meningitis. The effectiveness of antibiotics in patients with basilar skull fractures cannot be determined because studies published to date are flawed by biases.)
Outcome
Schmand, B, de Bruin, E, de Gans, J, van de Beek, D.. “Cognitive functioning and quality of life nine years after bacterial meningitis”. J Infect. vol. 61. 2010. pp. 330-4.
DRG CODES and expected length of stay
DRG 094, 095, 096, A390, G001-3, G008, G009, G01, G042.
The overall length of stay is typically 11-12 days. For staphylococcus meningitis the average length of stay is 21 days, and for Meningococcal meningitis 8 days.
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