Acute Bacterial Meningitis and Infective Endocarditis

Burk Jubelt

Barnett R. Nathan

INTRODUCTION

The parenchyma, coverings, and blood vessels of the nervous system may be invaded by virtually any pathogenic microorganism. It is customary, for convenience of description, to divide the syndromes produced according to the initial site of involvement. This division is arbitrary because the inflammatory process frequently involves more than one of these structures.

Involvement of the meninges by pathogenic microorganisms is known as leptomeningitis when the infection and inflammatory response are confined to the subarachnoid space and the arachnoid and pia. Cases are divided into acute, subacute, and chronic meningitis according to the rapidity with which the inflammatory process develops. This rate of development, in part, is related to the nature of the infecting organism. Chronic meningitis is discussed in Chapter 64. In some cases, acute bacterial meningitis can be complicated by focal purulent abscesses of the central nervous system (CNS) (Fig. 61.1) or its surrounding structures (empyema). These focal bacterial infections are discussed in Chapter 62.

FIGURE 61.1 Epidural abscess. A: Axial, noncontrast CT demonstrates a right posterior temporal lucent epidural collection with prominent white matter edema in the underlying cerebral parenchyma. Calcified choroid in the effaced atrium of the right lateral ventricle is shifted anteromedially. B: Postcontrast scan at this same level demonstrates abnormal dural enhancement and shift of the internal cerebral veins owing to the mass effect. (Courtesy of Drs. J. A. Bello and S. K. Hilal.)

Acute bacterial meningitis presents as a neurologic emergency and often overlaps with sepsis, and the principles of therapy are the same: early initiation of broad-spectrum antibiotics, volume resuscitation and vasopressors in the face of hypotension, and careful attention to airway control and oxygenation.

ACUTE BACTERIAL MENINGITIS

Bacteria may gain access to the ventriculosubarachnoid space by way of the blood, in the course of septicemia, or as a metastasis from infection of the heart, lung, or other viscera. The meninges may also be invaded by direct extension from a septic focus in the skull, spine, or parenchyma of the nervous system (e.g., sinusitis, otitis, osteomyelitis, brain abscess). Organisms may also gain entrance to the subarachnoid space through compound fractures of the skull and fractures through the nasal sinuses or mastoid or after neurosurgical procedures. Pathogen introduction by lumbar puncture is rare. The pathologic background, symptoms, and clinical course of most patients with acute purulent meningitis are similar
regardless of the causative organism. The classic triad of fever, neck stiffness, and altered mental status occurs in less than half of all patients, but 95% have at least two of four symptoms of fever, neck stiffness, altered mental status, and headache. Empiric therapy depends on age, whether the infection is community or nosocomially acquired, and other risk factors (head trauma or surgery, crowded living conditions, and underlying illnesses [e.g., diabetes, alcoholism, hematologic and immunologic disorders]). Diagnosis and therapy depend on the isolation and identification of the organism and determination of the source of the infection (Fig. 61.2).

FIGURE 61.2 Management algorithm for adults with suspected acute bacterial meningitis. CNS, central nervous system; STAT, immediately; CSF, cerebrospinal fluid; CT, computed tomography. (From Tunkel AR, Hartman BJ, Kaplan SJ, et al. Practice guidelines for the management of bacterial meningitis. Clin Infect Dis. 2004;39:1267-1284.)

Acute purulent meningitis may be the result of infection with almost any pathogenic bacteria. Isolated examples of infection by uncommon forms are recorded in the literature. In the United States, Streptococcus pneumoniae now accounts for about one-half of cases when the infecting organism is identified, and Neisseria meningitidis accounts for about one-fourth of the total cases (Table 61.1).

In the neonatal period, group B streptococci and Escherichia coli are the most common causative agents. Approximately 60% of the postneonatal bacterial meningitis of children used to be caused by Haemophilus influenzae. Introduction of the H. influenzae type B vaccine was followed by a 100-fold decrease in incidence. However, the peak incidence still occurs in children younger than 2 months of age. Overall fatality rate from bacterial meningitis is now about 15%. Many deaths occur during the first 48 hours of hospitalization.

TABLE 61.1 Causes of Bacterial Meningitis in the United States

	Adults (18 Yr and Older)		Children (17 Yr and Younger)
Organism	No. of Cases Reported	Percentage of Total	No. of Cases Reported	Percentage of Total
Haemophilus influenzae	65	6%	47	8%
Streptococcus pneumoniae	769	71%	200	34%
Neisseria meningitidis	130	12%	106	18%
Group B Streptococcus	76	7%	223	38%
Listeria monocytogenes	46	4%	12	2%
Total	1,086	100%	588	100%
Data from Thigpen MC, Whitney CG, Messonnier NE, et al. Bacterial meningitis in the United States, 1998-2007. N Engl J Med. 2011;364(21):2016-2025.

MENINGOCOCCAL MENINGITIS

Meningococcal meningitis occurs in sporadic form and at irregular intervals in epidemics. Epidemics are especially likely to occur during large shifts in population, and crowding as in a time of war, and in college dormitories.

Epidemiology

Meningococcus is the causative organism in about 25% of all cases of bacterial meningitis in the United States. Serogroup B is now the most commonly reported serotype (50%). Children and
young adults are predominantly affected. The normal habitat of the meningococcus is the nasopharynx, and the disease is spread by colonized individuals. A polysaccharide vaccine for groups A, C, Y, and W-135 meningococci has reduced the incidence of meningococcal infection among military recruits. The vaccine also has been used for control of serogroup C outbreaks in schools and on college campuses and for children with increased risk of infection (asplenia, HIV infection, complement deficiencies).

Pathobiology

Meningococci (N. meningitidis) may gain access to the meninges directly from the nasopharynx through the cribriform plate. The bacteria, however, are usually recovered from blood before meningitis commences, indicating that colonization of the nasopharynx with subsequent bacteremia and spread to the CNS is more common.

The bacterial polysaccharide capsule seems to be most important in attachment and penetration to gain access to the body. Elements in the bacterial cell wall (pili, fimbria) are critical for penetration into the cerebrospinal fluid (CSF) through the vascular endothelium and in induction of the inflammatory response.

In acute fulminating cases, death may occur before there are any significant pathologic changes in the nervous system. In the usual case, when death does not occur for several days after onset of the disease, an intense inflammatory reaction occurs in the meninges. The inflammatory reaction is especially severe in the subarachnoid space over the convexity of the brain and around the cisterns at the base of the brain. It may extend along the Virchow-Robin perivascular spaces into the brain and spinal cord. Meningococci, both intra- and extracellular, are found in the meninges and CSF. With progression of the infection, the pia-arachnoid becomes thickened and adhesions may form. Inflammatory reaction and fibrosis of the meninges along the roots of the cranial nerves are thought to cause the cranial nerve palsies that are seen occasionally.

Damage to the auditory nerve often occurs suddenly, and the resulting hearing loss is usually permanent. The damage may result from extension of the infection to the inner ear or from thrombosis of the nutrient artery. Signs and symptoms of parenchymal damage (e.g., hemiplegia, aphasia, and cerebellar signs) are caused by infarcts resulting from thrombosis of inflamed arteries or veins.

In the past, the inflammation in meningitis had been attributed mainly to the toxic effects of bacteria. In all types of meningitis, the contribution to the inflammatory process of cytokines released by phagocytic and immunoactive cells, particularly interleukin 1 and tumor necrosis factor, has been recognized. These studies have formed the basis for the use of anti-inflammatory corticosteroids in the treatment of meningitis.

Clinical Manifestations

The onset of meningococcal meningitis is similar to that of other forms of meningitis and is accompanied by chills and fever, headache, nausea and vomiting, pain in the back, stiffness of the neck, and prostration. The occurrence of a petechial or hemorrhagic skin rash is a manifestation of meningococcemia. At the onset of meningitis, the patient is irritable. In children, there is frequently a characteristic sharp, shrill cry (meningeal cry). With progress of the disease, the sensorium becomes clouded and stupor or coma may develop. Occasionally, the onset may be fulminant and accompanied by deep coma. Convulsive seizures are often an early symptom, especially in children, but focal neurologic signs are uncommon in the initial presentation.

The patient appears acutely ill and may be confused, stuporous, or obtunded. The temperature is elevated at 101°F to 103°F, but it may occasionally be normal at the onset. The pulse is usually rapid and the respiratory rate is increased. Blood pressure is normal except in acute fulminating cases when there may be profound hypotension. A petechial rash may be found in the skin, mucous membranes, or conjunctiva in meningococcemia but never in the nail beds. It usually fades in 3 or 4 days. There is rigidity of the neck with Kernig and Brudzinski signs. These signs may be absent in newborn, elderly, or comatose patients. Increased intracranial pressure causes bulging of an unclosed anterior fontanelle and periodic respiration. Cranial nerve palsies and focal neurologic signs are uncommon and usually do not develop until several days after the onset of infection. The optic discs are normal, but papilledema is a sign of increased intracranial pressure.

Complications and sequelae include those commonly associated with any inflammatory process in the meninges and cerebral blood vessels (i.e., convulsions, cranial nerve palsies, focal cerebral lesions, damage to the spinal cord or nerve roots, hydrocephalus) and those that are due to involvement of other portions of the body by meningococci (e.g., panophthalmitis and other types of ocular infection, arthritis, purpura, pericarditis, endocarditis, myocarditis, pleurisy, orchitis, epididymitis, albuminuria or hematuria, adrenal hemorrhage). Disseminated intravascular coagulation may complicate the meningitis. Complications may also arise from intercurrent infection of the upper respiratory tract, middle ear, and lungs. Any of these complications may leave permanent residua, but the most common sequelae are due to injury of the nervous system. These include deafness, ocular palsies, blindness, changes in cognitive functioning, convulsions, and hydrocephalus. With the available methods of treatment, complications and sequelae of meningeal infection are rare, and the complications due to the involvement of other parts of the body by the meningococci or other intercurrent infections are more readily controlled.

Diagnosis

The white blood cell count is increased, usually in the range of 10,000/mm³ to 30,000/mm³, but occasionally may be normal or higher than 40,000/mm³. The urine may contain albumin, casts, and red blood cell (RBC). Meningococci may be cultured from the nasopharynx in most cases, from the blood in more than 50% of the cases in the early stages, and from skin lesions when these are present.

The CSF is under increased pressure, usually between 200 and 500 mm H₂O. The fluid is cloudy (purulent) because it contains a large number of cells, predominantly polymorphonuclear leukocytes. The cell count in the fluid is usually between 2,000/mm³ and 10,000/mm³. Occasionally, it may be less than 100/mm³ and infrequently, more than 20,000/mm³. The protein concentration is increased. The glucose concentration is decreased usually to levels below 20 mg/dL. Gram-negative diplococci may be seen intra- and extracellularly in stained smears of the fluid, and meningococci may be cultured in more than 90% of untreated patients. Meningococcal meningitis may be diagnosed with certainty only by the isolation of the organism from the CSF. The diagnosis may be made, however, with relative certainty before the organisms are isolated in a patient with headache, vomiting, chills and fever, neck stiffness, and a petechial cutaneous rash, especially if there is an epidemic of meningococcal meningitis or if there has been exposure to a known case of meningococcal meningitis.

To establish the diagnosis of meningococcal meningitis, cultures should be made of skin lesions, nasopharyngeal secretions, blood, and CSF. The diagnosis may be established in many cases by examination of smears of the sediment of the CSF after application of the Gram stain.

Treatment

Antibiotic therapy for bacterial meningitis usually commences before the causative organism is confirmed (empiric therapy). Therefore, the initial regimen should be appropriate for most likely organisms, the determination of which depends to some extent on the patient’s age and the predisposing and associated conditions. Third- or fourth-generation cephalosporins, usually ceftriaxone or cefotaxime, in combination with vancomycin have become the first choice of treatment for bacterial meningitis (Table 61.2). Their spectrum is broad, and they have become particularly useful since the occurrence of S. pneumoniae strains that are resistant to penicillin or ampicillin and amoxicillin. Once the result of culture and sensitivities is known, antibiotic therapy is modified accordingly (Table 61.3). Unless a dramatic response to therapy occurs, the CSF should be examined 24 to 48 hours after the initiation of treatment to assess the effectiveness of the antibiotic. Posttreatment examination of the CSF is not a meaningful criterion of recovery, and the CSF does not need to be reexamined if the patient is clinically well. The recommended duration of treatment is 7 days.

Several studies have suggested an improved outcome with the use of corticosteroids particularly if dexamethasone 6 mg every 6 hours is given shortly before the initiation of antibiotic treatment and continued for 4 days [Level 1].1 Corticosteroids are beneficial in treating children with acute bacterial meningitis, especially in preventing hearing loss. Data in adults confirmed meningococcal meningitis favor steroid therapy to prevent hearing loss and decrease morbidity for those living in high-income countries. The lack of benefit in low-income countries may be due to the length of time between symptom onset and medical care, as well as poor nutrition and other comorbidities.

TABLE 61.2 Recommended Empiric Antibiotics for Suspected Bacterial Meningitis according to Age or Predisposing Factors

Age or Predisposing Feature	Antibiotics
Age 0-4 wk	Ampicillin plus either cefotaxime or an aminoglycoside^a
Age 1 mo-50 yr	Vancomycin plus cefotaxime or ceftriaxone^b
Age older than 50 yr	Vancomycin plus ampicillin plus ceftriaxone or cefotaxime plus vancomycin^b
Impaired cellular immunity	Vancomycin plus ampicillin plus either cefepime or meropenem
Recurrent meningitis	Vancomycin plus cefotaxime or ceftriaxone
Basilar skull fracture	Vancomycin plus cefotaxime or ceftriaxone
Head trauma, neurosurgery, or CSF shunt	Vancomycin plus ceftazidime, cefepime, or meropenem
^aUsually gentamycin 50 to 100 mg/kg. ^bAdd ampicillin if Listeria monocytogenes is a suspected pathogen. CSF, cerebrospinal fluid.
From van de Beek D, Brouwer MC, Thwaites GE, et al. Advances in treatment of bacterial meningitis. Lancet. 2012;380(9854):1693-1702.

TABLE 61.3 Dosing of Empiric Antibiotics for Acute Bacterial Meningitis

Medication	Dosing
Pediatric Dosing^a
Cefotaxime	50 mg/kg IV every 6 h up to 12 g/day
Ceftriaxone	75 mg/kg initially, then 50 mg/kg every 12 h, up to 4 g/day
Vancomycin	15 mg/kg IV every 8 h
Ampicillin	50 mg/kg IV every 6 h
Penicillin G	250,000 to 400,000 U/kg/day in four to six divided doses
Gentamycin	2.5 mg/kg IV every 8 h
Adult Dosing
Cefotaxime	2 g IV every 4 h
Ceftriaxone	2 g IV every 12 h
Cefepime	2 g every 8 h
Vancomycin	750-1,000 mg IV every 12 h or 10-15 mg/kg IV every 12 h
Ampicillin	2 g IV every 4-6 h
Penicillin G	4 million units IV every 4 h
Meropenem	2 g IV every 8 h
^aOlder than 1 month of age.
IV, intravenous.