Acute bacterial meningitis

Acute bacterial meningitis is a fulminant, often fatal purulent infection of the membranes of the brain.

The main symptoms of the disease are headache, fever, and stiff neck. Without emergency treatment, stupor and coma develop. Diagnosis is based on CSF analysis. Antibiotic therapy with 3rd and 4th generation cephalosporins, vancomycin, and ampicillin is usually empirical at the onset of the disease; glucocorticoids are also prescribed. Mortality rates remain high.

[ 1 ], [ 2 ], [ 3 ], [ 4 ], [ 5 ], [ 6 ]

What causes acute bacterial meningitis?

Many bacteria can cause meningitis, but the leading pathogens during the first two months of life are group B streptococci, followed by Neisseria meningitidis (meningococci) and Streptococcus pneumoniae (pneumococci). Meningococci are found in the nasopharynx of about 5% of people; they are spread by airborne droplets and contact. For unclear reasons, only a small proportion of carriers develop meningitis.

Meningococcal meningitis most often affects children in their first year of life. The disease also tends to develop into an epidemic in closed communities (in army barracks, student dormitories, boarding schools).

In adults, the most common causative agent of meningitis is pneumococcus. Those at increased risk include those with chronic otitis, sinusitis, mastoiditis, recurrent meningitis, pneumococcal pneumonia, sickle cell anemia, asplenia [splenic aplasia] and cerebrospinal fluid leakage, and those who abuse alcohol. The incidence of pneumococcal meningitis is decreasing due to the introduction of vaccination.

Meningitis of gram-negative etiology (mainly Escherichia coli, Klebsiella spp. and Enterobacter spp.) is most likely in individuals with immunodeficiency states, after operations on the central nervous system and traumatic brain injury, with bacteremia (for example, after manipulations on the genitourinary tract) or with infection with a nosocomial infection. In individuals with immunodeficiency states and in certain communities, the causative agent of meningitis may be representatives of the genus Pseudomonas. Haemophilus influenzae type B as a causative agent of bacterial meningitis is currently rare due to widespread vaccination, but is sometimes isolated from individuals with immunodeficiency, after traumatic brain injury and in unvaccinated individuals.

Staphylococcal meningitis may develop after penetrating head wounds, neurosurgical interventions (often as a combined infection) or with bacteremia (in patients with endocarditis). Listeria meningitis may develop at any age, more often in individuals with immunosuppression due to chronic renal infection, liver dysfunction or treatment with glucocorticoids or cytostatics after organ transplantation.

Bacteria usually reach the meninges by hematogenous route from colonization sites in the nasopharynx or other foci of infection (e.g. pneumonia). The affinity of bacteria for cerebrospinal fluid is not fully understood, but the ability of bacteria to encapsulate and the presence of fixing cilia play a certain role in the colonization process. The presence of receptors for cilia and other bacterial surface structures in the choroid plexus facilitates the penetration of bacteria into cerebrospinal fluid-containing spaces.

Bacteria can enter the CSF through contact, spreading from a nearby source of infection (for example, with sinusitis, mastoiditis), or in cases of contact between CSF and the external environment (for example, with penetrating skull injuries, neurosurgical interventions, meningomyelocoele, the presence of a fistula).

Pathophysiology of acute bacterial meningitis

Under the influence of bacterial cell surface components, complement, and proinflammatory cytokines (tumor necrosis factor, IL-1), neutrophils rush into the cerebrospinal fluid-containing spaces. Neutrophils produce membrane-toxic metabolites that damage the vascular endothelium, resulting in vasculitis and thrombophlebitis, leading to focal ischemia or infarction and cerebral edema. As a result of vasculitis, the integrity of the blood-brain barrier is disrupted, which contributes to further growth of cerebral edema. Purulent exudate in the cerebrospinal fluid blocks the processes of cerebrospinal fluid circulation and reabsorption, resulting in hydrocephalus. Increasing cerebral edema and hydrocephalus further increase intracranial pressure, and systemic complications develop, including hyponatremia due to the syndrome of insufficient synthesis of antidiuretic hormone (SIADH), disseminated intravascular coagulation (DIC), and septic shock, which often leads to bilateral hemorrhagic infarction of the adrenal glands (Waterhouse-Friderichsen syndrome).

Symptoms of acute bacterial meningitis

The onset of fever, headache, stiff neck, and vomiting characteristic of meningitis is often preceded by respiratory symptoms. An extremely severe condition may develop within 24 hours in adults and even more rapidly in children. Kernig's and Brudzinski's signs occur in approximately 1/2 of patients, 30% of patients develop epileptic seizures, 10-20% have symptoms of cranial nerve damage [for example, III (oculomotor nerve), VII (facial nerve), or VIII pair of cranial nerves] and other types of focal neurological symptoms. In children over 2 years of age and adults, disturbances of consciousness develop in the following sequence: excitement - confusion - drowsiness - stupor - coma. Opisthotonus may develop.

Dehydration is common, with vascular collapse occurring and possibly progressing to shock. Infection, particularly meningococcal, is characterized by dissemination throughout the body, with involvement of the joints, lungs, sinuses, and other organs. The appearance of a petechial (hemorrhagic) or purple rash indicates generalized septicemia and meningococcal meningitis. Careful examination of the head, ears, spine, and skin may reveal the source or portal of entry of infection. Indentations in the spine, fistulas, nevi, or tufts of hair may indicate the presence of a meningomyelocele.

In children under 2 years of age, meningeal signs may be absent. In children of the first two months of life, clinical symptoms of meningitis are nonspecific, especially in the early stages of the disease. Fever, hypothermia, dystrophy, drowsiness, vomiting, and irritability are often observed. Later, epileptic seizures, shrill cry, bulging and tension of the large fontanelle may join in. A few days later, young children may develop subdural effusion, manifested by epileptic seizures, persistent fever, and hydrocephalus.

In elderly people, symptoms may also be non-specific (e.g. lethargy with or without fever), meningeal signs may be absent or insignificant. In this case, limitation of movement in the neck (in all directions) may be due to arthritis, which should not be mistaken for manifestations of meningism.

Partially treated meningitis. When otitis media or sinusitis is detected in a patient at an early stage of the disease, even before the typical signs of meningitis appear, antibiotic therapy is usually prescribed. Some drugs can partially (but temporarily) suppress the infectious process, which will manifest itself as a slowdown in the progression of the disease, weakening of meningeal symptoms. Such a situation significantly complicates the diagnosis of meningitis.

Diagnosis of acute bacterial meningitis

Fever, lethargy or irritability, high-pitched cry, bulging parietal fontanelle, meningeal signs, or hypothermia in children younger than 2 years of age should prompt suspicion of acute bacterial meningitis. Similarly, in older children and adults, bacterial meningitis should be considered if they have meningeal signs, unexplained altered consciousness, especially if fever and risk factors are present.

Because acute bacterial meningitis, especially meningococcal meningitis, can be fatal within hours, it requires immediate diagnosis and treatment. Urgent lumbar puncture and initiation of antibiotic and glucocorticoid treatment without waiting for laboratory test results are indicated.

CSF pressure may be elevated. Gram-stained smears show CSF organisms in 80% of patients. CSF neutrophil counts are usually greater than 2000/μL. Glucose levels are reduced to less than 40 mg/dL due to impaired glucose transport into the CNS and its uptake by neutrophils and bacteria. Protein levels are usually greater than 100 mg/dL. Cultures are positive in 90% of cases; they may be false-negative in partially treated patients. Latex agglutination assays are used to detect antigens of meningococci, Haemophilus influenzae type B, pneumococci, group B streptococci, and E. coli K1. Horseshoe crab amoebocyte lysate is used to detect endotoxin of gram-negative bacteria in the blood (LAL test). LAL test and latex agglutination reaction help to identify pathogens in cases of partially treated meningitis and meningitis against the background of immunodeficiency, as well as in cases when the pathogen is not isolated from the cerebrospinal fluid. PCR helps to identify the pathogen in similar situations.

CT scan is either normal or shows decreased ventricular size, effacement of sulci, and increased density over the convexital surfaces of the hemispheres. MRI with gadolinium is the best method for diagnosing subarachnoid inflammation. The images obtained should be carefully examined for signs of brain abscess, infection of the paranasal sinuses and mastoid process, skull fractures, and congenital malformations. Later, after several days or weeks, venous infarctions or communicating hydrocephalus may be detected.

A number of infectious and non-infectious diseases may resemble bacterial meningitis, and their differentiation is aided by the clinical picture of the disease in combination with the results of CT and cerebrospinal fluid analysis. Despite fever, headache, and stiff neck, viral meningitis is, however, much milder and has other changes in the cerebrospinal fluid. A violent and sudden onset of the disease, severe headache, and stiff neck are also characteristic of subarachnoid hemorrhage, but there is no fever, CT shows hemorrhage, and the CSF contains a large number of erythrocytes or has a xanthochromic color. A brain abscess is accompanied by fever, headache, and impaired consciousness, but stiff neck is not characteristic unless the abscess contents break through into the cerebrospinal fluid-containing space with the lightning-fast development of secondary meningitis. Severe generalized infectious diseases (eg, sepsis, infective endocarditis) may be accompanied by impaired consciousness, increased body temperature, decreased tissue perfusion, but there is no stiffness of the occipital muscles, and the CSF is either normal or has slight leukocytosis. Cerebellar tonsil wedging may cause secondary impaired consciousness (due to obstructive hydrocephalus) and stiffness of the neck muscles, but there is no fever, and the true cause is easily diagnosed by CT or MRI. Moderate fever and headache, changes in mental status, and inflammation of the meninges are observed in cerebral vasculitis (eg, lupus) and venous thrombosis, but the changes in the CSF in these diseases are similar to those in viral encephalitis.

The acute onset of the disease, fulminant course, clinical manifestations and results of CSF examinations in fungal meningitis or amoebic (Naegleria) meningoencephalitis are virtually indistinguishable from the picture of bacterial meningitis. Gram staining and standard cultures do not detect bacteria. Microscopic examination of cerebrospinal fluid and sowing on selective nutrient media can detect the fungus. Characteristic movements of amoebae can be seen when examining non-centrifuged CSF by the thick drop method; in addition, sowing on selective media is carried out. Tuberculous meningitis is characterized by a subacute or chronic course with rare exceptions; in terms of the nature of changes, CSF in tuberculosis occupies an intermediate place between acute bacterial and aseptic meningitis; special staining methods (for acid-fast bacteria or immunofluorescence) are used to confirm the diagnosis.

Blood tests include culture (positive blood culture is obtained in 50% of cases), general clinical blood test with white blood cell count, biochemical blood test (electrolytes, serum glucose, residual nitrogen and urea), and a coagulogram. Monitoring of the Na content in the blood plasma is carried out to detect SIADH, monitoring of coagulogram parameters allows not to miss the onset of DIC. Cultures of urine, nasopharyngeal secretions, respiratory secretions and discharge from lesions on the skin are carried out.

Waterhouse-Friderichsen syndrome may be suspected when a patient with high fever does not recover from shock despite adequate treatment, or when a patient suddenly develops a hemorrhagic rash and signs of DIC syndrome. Cortisol levels are measured and CT, MRI, or ultrasound of the adrenal glands is performed.

[ 7 ], [ 8 ], [ 9 ], [ 10 ], [ 11 ]

Prognosis and treatment of acute bacterial meningitis

Antibacterial and symptomatic therapy with early recognition of the disease has reduced the mortality rate of acute bacterial meningitis to below 10%. However, with late diagnosis, in newborns, the elderly, and immunocompromised individuals, the mortality rate remains high. The prognosis is unfavorable with persistent leukopenia or the development of Waterhouse-Friderichsen syndrome. Survivors may experience deafness and symptoms of damage to other cranial nerves, cerebral infarction, repeated seizures, and mental disorders.

If acute bacterial meningitis is suspected, antibiotic and glucocorticoid treatment is started immediately after blood and CSF samples have been taken for culture. In less severe cases and when the diagnosis is in doubt, antibiotics may be delayed until CSF results are available. Starting antibiotic therapy before lumbar puncture slightly increases the likelihood of false-negative bacteriological results, especially in cases of pneumococcal infection, but does not affect the results of other tests.

Dexamethasone at a dose of 0.15 mg/kg in children and 10 mg intravenously in adults every 6 hours should be started 15 minutes before the first dose of antibiotics and continued for 4 days. Dexamethasone can prevent hearing loss and other neurologic complications by suppressing the release of proinflammatory cytokines released during lysis of bacteria by antibiotics. Dexamethasone should not be administered to immunocompromised patients to avoid compromising immune defenses in aseptic meningitis. If the pathogen is not isolated from the cerebrospinal fluid, it is advisable to supplement treatment with antituberculosis drugs. If the culture does not grow or is identified after 24-48 hours, glucocorticoid administration should be discontinued; glucocorticoid administration for more than 24 hours without adequate antibiotic coverage may aggravate the infectious process. In addition, glucocorticoids prevent vancomycin from penetrating the blood-brain barrier, therefore the dose of vancomycin must be increased.

If there is any doubt about the accuracy of the CSF results, the lumbar puncture can be repeated after 8-24 hours (or sooner if the patient's condition worsens). If the clinical picture and final CSF results confirm the diagnosis of aseptic meningitis, antibiotics should be discontinued. If the patient's condition remains severe despite antibiotic therapy (possibly causing a false-negative culture result), antibiotics are not stopped.

The choice of antibiotic depends on the type of pathogen and the patient's age. Third-generation cephalosporins (e.g., ceftriaxone, cefotaxime) are generally universally effective against most pathogens isolated from patients of all age groups. Instead of third-generation cephalosporins, children can be prescribed the fourth-generation cephalosporin cefepime; in addition, cefepime is indicated for meningitis of pseudomonas aeruginosa etiology. Currently, due to the spreading resistance of pneumococci to cephalosporins, they are trying to replace them with vancomycin in combination with rifampin (or without). Ampicillin has retained its effectiveness against listeria. Although aminoglycosides poorly penetrate the blood-brain barrier, they are still used for empirical treatment of gram-negative meningitis in newborns. After clarifying the etiology of the disease based on the results of bacteriological testing, antibiotic therapy is adjusted.

After the start of antibiotic therapy, the cerebrospinal fluid is constantly monitored for sterility and cytosis - every 24-48 hours. Antibiotics are continued for at least one week after the body temperature has normalized and the CSF parameters have improved almost to normal (complete normalization may require several weeks). The dosage of antibiotics is not reduced after clinical improvement, since as the inflammatory process in the membranes subsides, their permeability to the drug decreases.

Doses of intravenous antibiotics for bacterial meningitis

	Dosage
Antibiotic	Children	Adults
Ceftriaxone	50 mg/kg every 12 hours	2 g every 12 hours
Cefotaxime	50 mg/kg	2 g every 4-6 hours
Ceftazidime	50 mg/kg every 8 hours	2 g every 8 hours
Cefepime	2g every 12 hours	2g/z8-12 h
Ampicillin	75 mg/kg	2-3 g every 4 hours
Penicillin G	4 million units in 4 hours	4 million units in 4 hours
Nafcillin and oxacillin	50 mg/kg	2 g every 4 hours
Vancomycin	15 mg/kg	500-750 mg every 6 hours
Gentamicin and tobramycin	2.5 mg/kg	2 mg/kg every 8 hours
Amikacin	10 mg/kg	7.5 mg/kg every 12 hours
Rifampin	6.7 mg/kg	600 mg every 24 hours
Chloramphenicol	25 mg/kg	1 g every 6 hours

Renal function should be monitored.

Symptomatic therapy is aimed at normalizing body temperature, stopping edema, correcting electrolyte disturbances, convulsions, and shock. If Waterhouse-Friderichsen syndrome is suspected, high doses of hydrocortisone are prescribed (100 to 200 mg intravenously every 4 hours or as a continuous infusion after an initial bolus); the absence of data on the concentration of the hormone in the blood is not a reason to delay treatment.

In severe cases of cerebral edema, the amount of fluid administered is controlled, and controlled hyperventilation (PaCO2, 25-30 mm Hg), mannitol (0.25-1.0 g/kg IV), and dexamethasone (4 mg IV every 4 hours) are prescribed to prevent central _and transtentorial herniation; intracranial pressure is monitored. If the ventricles increase in size, intracranial pressure monitoring is started and the ventricles are drained to eliminate excess cerebrospinal fluid, but the prognosis is usually unfavorable.

In young children, if there is subdural effusion, it is necessary to remove the fluid by repeated daily subdural punctures through the cranial sutures. The amount of cerebrospinal fluid removed from each side should not exceed 20 ml/day to avoid displacement of the brain substance. If the effusion, despite punctures, persists for 3-4 weeks, surgical intervention with possible excision of the subdural membrane is indicated.

In case of severe meningococcal meningitis, it is advisable to prescribe drotrecogin alfa (activated protein C) to effectively suppress the inflammatory response. When sepsis develops against the background of meningitis, the risk of intracranial hemorrhage increases sharply, regardless of whether the patient receives drotrecogin alfa or not.

Prevention of acute bacterial meningitis

All children are recommended to receive a 7-valent pneumococcal conjugate vaccine covering more than 80% of the microorganisms that cause meningitis. The standard highly effective anti-Haemophilus vaccine is administered at the age of two months. The quadrivalent meningococcal vaccine is administered to children with immunodeficiency or functional asplenia from the age of two years; in addition, travelers to endemic areas and laboratory medical personnel who directly handle meningococcal samples in daily practice are vaccinated. It is advisable to cover students living in dormitories and conscripts to the armed forces with meningococcal vaccine.

To limit airborne transmission, a patient with meningitis is placed in a special box with respiratory isolation for at least the first 24 hours. Gloves, masks and medical gowns are used. Post-exposure prophylaxis should be carried out among family members of the patient, medical personnel and other persons who were in close contact with the patient. In case of meningococcal meningitis, it consists of immunization with a meningococcal vaccine (to prevent spread) and oral rifampicin for 48 hours (adults - 600 mg 2 times a day; children - 10 mg/kg 2 times a day; newborns - 5 mg/kg 2 times a day). Alternatively, a single intramuscular injection of ceftriaxone (adults - 250 mg; children - 125 mg) or a single dose of 500 mg of ciprofloxacin orally (only for adults) is allowed. For the prevention of hemophilic infection, rifampicin is taken orally at a dose of 20 mg/kg once a day (but not more than 600 mg/day) for 4 days. There is no consensus regarding the implementation of post-exposure prophylaxis for young children (under 2 years) in kindergartens and nurseries. After contact with pneumococcal infection, chemoprophylaxis is usually not carried out.