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Meningitis is an inflammation of the arachnoid, the pia mater, and the intervening cerebrospinal fluid (CSF). The inflammatory process extends throughout the subarachnoid space about the brain and spinal cord and regularly involves the ventricles. Pyogenic meningitis, considered in this chapter, is usually an acute infection with bacteria that evoke a polymorphonuclear response in the CSF. One of its major forms, that caused by meningococci, is considered in Ch. 281 ; less acute forms of bacterial meningitis, characterized by a mononuclear cell response in the CSF, are discussed in Ch. 311 and Ch. 406 .
In the 1970 s and 1980 s, 20,000 to 25,000 cases of bacterial meningitis occurred annually in the United States. If all cases are included regardless of the age of patients, data from the Centers for Disease Control and Prevention indicate that Haemophilus influenzae type b was the most frequent bacterial cause (45%), followed by Streptococcus pneumoniae (18%) and Neisseria meningitidis (14%). About 70% of all cases occurred in children under age 5. The relative frequencies with which the different bacterial species cause meningitis are age related (Table 280-1) . In the newborn, group B streptococci and gram-negative bacilli (most frequently Escherichia coli, but also other enteric bacilli and Pseudomonas) are the principal causes. Beyond the first month of life and extending through childhood, H. influenzae and N. meningitidis have been the most frequent causes of bacterial meningitis. The pre-eminent position of H. influenzae as a cause of meningitis in infants and young children (and as the leading cause of bacterial meningitis overall) has changed dramatically since immunization with the H. influenzae type b conjugate vaccines was introduced in the late 1980 s. Whereas the rate of H. influenzae meningitis in the United States had been about 40 per 100,000 children under age 5 in the mid-1980 s, it had fallen to about 2 per 100,000 in this age group by 1993. Consequently, the relative frequencies of S. pneumoniae and N. meningitidis have increased among children. In adults, S. pneumoniae, N. meningitidis, and Listeria monocytogenes are responsible for most cases of community-acquired bacterial meningitis. Meningococcal meningitis is the only type that occurs in outbreaks; its relative frequency among the meningitides depends on whether statistics have been gathered in a hyperendemic area or during an epidemic period. In about 10% of patients with pyogenic meningitis, the bacterial cause cannot be defined. Simultaneous mixed meningitis is rare, occurring in the setting of neurosurgical procedures, penetrating head injury, erosion of the skull or vertebrae by adjacent neoplasm, or intraventricular rupture of a cerebral abscess; the isolation of anaerobes should strongly suggest the latter two of these.
Important changes have occurred in the frequencies of several types of bacterial meningitis over the past 25 years. Gram-negative bacillary meningitis has doubled in frequency in adults, reflecting more frequent and extensive neurosurgical procedures as well as other nosocomial factors. L. monocytogenes has increased eight- to tenfold as a cause of bacterial meningitis in urban general hospitals, reflecting the enlarging immunosuppressed population at particular
|
|
Neonates ( |
Children (1 month-15 years) (%) |
Adults
|
|---|---|---|---|
| S. pneumoniae | 0-5 | 10-20 | 40-50 |
| N. meningitidis | 0-1 | 25-40 | 15-30 |
| H. influenzae | 5 | 40-60 ¶ | 2-4 |
| Streptococci |
40-50
|
2-4 | 5-10 |
| Staphylococci | 5 | 1-2 | 5-10 |
| Listeria | 5-10 | 1-2 | 5-10 |
| Gram-negative bacilli | 30-45 § | 1-2 | 5 |
In large urban tertiary-care general hospitals, the distribution of bacterial etiologies of adult meningitis differs from that in smaller community hospitals, where community-acquired disease predominates. For example, at the Massachusetts General Hospital about 40% of cases of bacterial meningitis in adults are of nosocomial origin. In this category, the leading etiologies are gram-negative bacilli (primarily E. coli and Klebsiella), accounting for about 40% of nosocomial episodes, and various streptococci, Staphylococcus aureus, and coagulase-negative staphylococci, each responsible for 10% of nosocomial cases.
The clinical setting in which meningitis develops may provide a clue to the specific bacterial cause. Meningococcal disease, including meningitis, may occur sporadically and in cyclic outbreaks. In the past, military recruits were particularly susceptible, but now meningococcal vaccine (polysaccharides of groups A, C, Y, and W135) is employed for protection. Large urban outbreaks can occur.
Certain predisposing factors are frequently associated with the development of pneumococcal meningitis. Acute otitis media (± mastoiditis) occurs in about 20% of adult patients. Pneumonia is present in about 15% of patients with pneumococcal meningitis, a much higher frequency than in meningitis caused by H. influenzae or N. meningitidis. Acute pneumococcal sinusitis is occasionally the initial focus from which infection spreads to the meninges. A significant head injury (recent or remote) has occurred in about 10% of patients with pneumococcal meningitis. CSF rhinorrhea (usually caused by a defect or fracture in the cribriform plate) is present in about 5% of patients with pneumococcal meningitis. Meningitis occurring in young children with sickle cell anemia is most likely to be caused by S. pneumoniae. A variety of defects in host defenses (primary or acquired immunoglobulin deficiencies, the asplenic state) may predispose to severe pneumococcal disease, particularly bacteremia and meningitis. Alcoholism is an underlying problem in 10 to 25% of adults with pneumococcal meningitis in urban hospitals.
S. aureus meningitis is seen most commonly as a complication of a neurosurgical procedure, following penetrating skull trauma, or occasionally secondary to staphylococcal bacteremia and endocarditis. Meningitis caused by gram-negative bacilli takes one of three forms: neonatal meningitis, meningitis following trauma or neurosurgery, or spontaneous meningitis in adults (e.g., bacteremic Klebsiella meningitis in a patient with diabetes mellitus). The most common causes of gram-negative bacillary meningitis in the adult are E. coli (about 30%) and Klebsiella-Enterobacter (about 40%). The most frequent causes of bacterial meningitis in patients with neoplastic disease are gram-negative bacilli (particularly Pseudomonas aeruginosa and E. coli), L. monocytogenes, S. pneumoniae, and S. aureus. Meningitis caused by group A streptococci is uncommon but occasionally occurs following acute otitis media.
The age-related incidence (children under 5 years) of H. influenzae type b meningitis has been so striking that the occurrence of this disease in an adult should raise the question of the presence of an underlying anatomic or immunologic defect, circumventing the usual barrier interposed by serum bactericidal mechanisms.
The incidence of meningitis is higher in the first month of life than in any other single month. In the newborn, the group B Streptococcus can produce either an "early-onset" (occurring within 8 days of delivery and characterized by a fulminant illness with septicemia, severe respiratory distress, and sometimes meningitis) or a "late-onset" (occurring 10 days to 2 months after delivery and presenting a more insidious, slowly progressive illness which usually includes meningitis) infection. The second leading cause, E. coli strains containing K1 capsular antigen, is usually acquired by the neonates from their mothers, who carry the organism in their stool.
The clinical signs in neonatal meningitis suggest sepsis but not necessarily central nervous system (CNS) involvement: fever (in only 60%), jaundice, diarrhea, lethargy, poor feeding or vomiting, respiratory distress (including apnea), seizures, irritability, bulging fontanel (in only 30%), and nuchal rigidity (15%). Frequently, only by examining the CSF can the presence of meningitis be ruled in or out.
The purulent exudate is distributed widely in the subarachnoid space, most abundant in the basal cisterns and about the cerebellum initially, but also extending into the sulci over the cerebrum. There is no direct invasion of cerebral tissue by the infecting organism or the inflammatory exudate, but the subjacent brain becomes congested and edematous. The effectiveness of the pial barrier accounts for the fact that cerebral abscess does not complicate bacterial meningitis. Indeed, when these two processes coexist, the sequence usually has been that of an initial abscess subsequently leaking its contents into the ventricular system, producing meningitis. There are two possible exceptions to the aforementioned generalization: (1) neonatal meningitis due to Citrobacter, in which the organisms appear to invade the brain after producing a necrotizing vasculitis of small penetrating blood vessels, and (2) Listeria rhombencephalitis, a very rare process in which brain stem infection can occur simultaneously with Listeria meningitis (or alone). Structures adjacent to the meninges may show a variety of pathologic changes secondary to bacterial meningitis. Cortical thrombophlebitis results from venous stasis and adjacent meningeal inflammation. Infarction of cerebral tissue may follow. Involvement of cortical and pial arteries with peripheral aneurysm formation and vascular occlusion occurs occasionally in bacterial meningitis. Rarely, narrowing of the supraclinoid portion of the internal carotid artery at the base of the brain occurs as a result of arteritis and arterial spasm. In fulminating cases (particularly meningococcal meningitis), cerebral edema may be marked even though the pleocytosis is only moderate. Rarely such patients develop temporal lobe and cerebellar herniation, resulting in compression of the midbrain and medulla. Damage to cranial nerves occurs in areas where dense exudate accumulates; the third and sixth cranial nerves are also vulnerable to damage by increased intracranial pressure. Ventriculitis probably occurs in most cases of bacterial meningitis; rarely this progresses to the accumulation of pus, ventricular empyema. Hydrocephalus can develop during meningitis from obstruction to CSF flow within the ventricular system (obstructive hydrocephalus) or extraventricularly (communicating hydrocephalus). Subdural effusions are sterile transudates that develop over the cerebral cortex in about 15% of infants with bacterial meningitis. Rarely such effusions become infected, producing a subdural empyema. In the past the diagnosis was made almost exclusively in infants, in whom abnormal transillumination or increasing head size can be detected. Now, sterile or infected (showing peripheral contrast enhancement) subdural collections can be demonstrated readily by computed tomographic scan as low-density areas about the cerebrum.
Bacteria may reach the meninges by several routes: (1) systemic bacteremia, (2) direct ingress from the upper respiratory tract or skin through an anatomic defect (e.g., skull fracture, eroding sequestrum, meningocele), (3) passage intracranially via venules in the nasopharynx, or (4) spread from a contiguous focus of infection (infection of the paranasal sinuses, leakage of a brain abscess). Bacteremic spread to the meninges is probably the most frequent path of infection. However, not all bacteremic organisms have the same likelihood of causing meningitis. Bacteremia with H. influenzae and N. meningitidis is usually initiated by pharyngeal adhesion and colonization by an infecting strain. Adhesion of such strains, as well as of S. pneumoniae, to mucosal surfaces is abetted by their capacity to produce IgA proteases (cleaving this antibody in the hinge region) and thus inactivating this local antibody defense. N. meningitidis adhesion to nasopharyngeal cells is effected by fimbriae or pili. In an in vitro nasopharyngeal organ culture these organisms injure ciliated epithelial cells and induce ciliostasis, selectively adhering to nonciliated epithelial cells. Meningococci invade the nasopharyngeal mucosal cells via endocytosis and are transported to the abluminal side in membrane-bound vacuoles. H. influenzae, in contrast, invades intercellularly by causing separation of apical tight junctions between columnar epithelial cells. When these meningeal pathogens gain access to the bloodstream,
Following entry into the bloodstream, CNS invasion occurs, but the mechanisms by which and sites at which this occurs are unclear. A high-grade and sustained bacteremia appears necessary. An important role for specific bacterial adhesion to elements of the bloodbrain barrier is likely, as indicated by the preferential binding of fimbriated strains of E. coli to the endothelial cell surface of cerebral capillaries and the epithelial cell surface of the choroid plexus and ventricles. Evidence from animal models suggests that CNS invasion sites following bacteremia may develop at foci of nonspecific sterile inflammation above the cribriform plate and through the choroid plexus.
Most bacterial species causing meningitis (H. influenzae type b, N. meningitidis, S. pneumoniae, E. coli K1, group B Streptococcus) are antiphagocytic. Whether the capsular polysaccharide confers some special meningeal tropism, possibly through surface receptors, is not known. Although the primary focus initiating the bacteremia is usually in the upper respiratory tract or lung (pneumonia), it may be in the heart (endocarditis) or the gastrointestinal or urinary tracts. Once established in any part of the meninges, infection quickly extends throughout the subarachnoid space. Bacterial replication proceeds relatively unhindered, since CSF levels of complement are low early in meningeal inflammation, resulting in minimal opsonic and bactericidal activity (or none), and since surface phagocytosis of unopsonized organisms is meager in such a fluid environment. A secondary bacteremia may follow meningeal infection and itself contribute to continuing further inoculation of the CSF.
Current experimental evidence suggests that meningeal inflammation follows bacterial entry and growth in the CSF and that specific bacterial components (e.g., pneumococcal cell walls or lipoteichoic acid, H. influenzae lipopolysaccharide (LPS)) are major eliciters of this response by causing release into the subarachnoid space of various pro-inflammatory cytokines such as interleukin-1 (IL-1) and tumor necrosis factor (TNF) from endothelial and meningeal cells. These cytokines increase adherence and transendothelial movement of neutrophils, as has been shown in endothelial cell monolayers in culture. Cytokines appear to enhance this passage of leukocytes by inducing several families of adhesion molecules that interact with corresponding receptors on leukocytes. The three likely families mediating endothelial-leukocyte adhesion are the (1) immunoglobulin superfamily, e.g., intercellular adhesion molecules (ICAM) 1 and 2; (2) integrins, e.g., CD11/CD18 subfamily; and (3) selectins, e.g., endothelial-leukocyte adhesion molecule (ELAM-1). Cytokines also can act to increase the binding affinity of a leukocyte selectin, leukocyte-adhesion molecule (LAM-1), for its endothelial cell receptor, contributing further to neutrophil trafficking into the subarachnoid space.
Once within the subarachnoid space, neutrophils are further activated to release products such as prostaglandins and toxic oxygen metabolites that increase local vascular permeability and may cause direct neurotoxicity. Evidence of breaching of the blood-brain barrier is found in animal models of meningitis where endothelial intercellular tight junctions are disrupted, where increased pinocytotic vesicles appear in endothelial cells, and where albumin escapes across postcapillary venules into the subarachnoid space.
The foregoing inflammatory changes can contribute to development of increased intracranial pressure and alterations in cerebral blood flow. Cerebral edema is commonly due to increased permeability of the blood-brain barrier (vasogenic), may be due to cellular
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|
Percentage of Episodes of Meningitis | |||||
|---|---|---|---|---|---|---|
| Time of Onset of Findings | Hemiparesis | Aphasia | Visual-Field Defect | Gaze Preference | Seizures | Other |
|
Early ( |
9 | 6 | 2 | 10 | 15 | 5 |
| Late (> 24 h) | 2 | 1 | 0.3 | 0 | 8 | 1 |
|
Total
|
11 | 7 | 2.3 | 10 | 23 | 6 |
An acute onset of fever, generalized headache, vomiting, and stiff neck are common to many types of meningitis. The majority of patients with pyogenic meningitis of the three common causes have had an antecedent or accompanying upper respiratory tract infection or nonspecific febrile illness, acute otitis (or mastoiditis), or pneumonia. Myalgias (particularly in meningococcal disease), backache, and generalized weakness are common symptoms. The illness usually progresses rapidly, with development of confusion, obtundation, and loss of consciousness. Occasionally the onset may be less acute, with meningeal signs present for several days to a week.
Evidences of meningeal irritation (drowsiness and decreased mentation, stiff neck, Kernig s and Brudzinski s signs) are usually present. In certain patients, the findings of meningitis may be easily overlooked; infants, obtunded patients, or elderly patients with congestive failure or pneumonia may develop meningitis without prominent meningeal signs. Their lethargy should be investigated carefully, and meningeal signs should be sought; if any doubt exists, examination of the CSF is indicated.
The presence of a petechial, purpuric, or ecchymotic rash in a patient with meningeal findings almost always indicates meningococcal infection and requires prompt treatment because of the rapidity with which this infection can progress (see Ch. 281) . Rarely, extensive petechial and purpuric lesions occur in meningitis caused by S. pneumoniae or H. influenzae. Very rarely skin lesions almost indistinguishable from those of meningococcal bacteremia occur in patients with acute S. aureus endocarditis who also have meningeal signs and a pleocytosis (secondary either to staphylococcal meningitis or to embolic cerebral infarction). Usually one or two of the lesions in such a patient are those of purulent purpura; aspiration of material reveals staphylococci on Gram stain. In the summer months, viral aseptic meningitis may produce meningeal signs, macular and petechial skin lesions, and a pleocytosis of several hundred cells, sometimes with neutrophils predominating initially.
Cranial nerve abnormalities, involving principally the third, fourth, sixth, or seventh nerves, occur in 5 to 10% of adults with community-acquired meningitis. These usually disappear shortly after recovery. Persistent sensorineural hearing loss occurs in 10% of children with bacterial meningitis. In another 16% a transient conductive hearing loss develops. The most likely sites of involvement in persistent sensorineural deafness appear to be the inner ear (infection or toxic products possibly spreading from the subarachnoid space along the cochlear aqueduct) and the acoustic nerve. In children, permanent hearing impairment is more common following meningitis due to S. pneumoniae than to H. influenzae or N. meningitidis.
Seizures (focal or generalized) occur in 20 to 30% of patients and may result from readily reversible causes (high fever in infants; penicillin neurotoxicity when large doses are administered intravenously in the presence of renal failure) or, more commonly, from focal cerebral injury. Seizures can occur during the first few days or
Brain swelling and increased CSF pressure are associated with seizures, third nerve dysfunction, abnormal reflexes, coma, hypertension, and bradycardia. In approximately one-quarter of fatal cases of community-acquired meningitis in adults, cerebral edema accompanied by temporal lobe herniation is observed at autopsy.
Papilledema is rare (1%) in bacterial meningitis even with high CSF pressures, probably because the patient is seen early in the process before changes have occurred in the nerve head. Its presence should indicate the possibility of some other associated or independent suppurative intracranial process (subdural empyema, brain abscess). Marked central hyperpnea sometimes occurs in patients with severe bacterial meningitis; CSF acidosis (principally caused by increased lactic acid levels) provides much of the respiratory stimulus.
Focal cerebral signs (principally hemiparesis, dysphasia, visual field defects, and gaze preference) occur in about 25% of adults with community-acquired bacterial meningitis (Table 280-2) . They may develop during early meningitis secondary to occlusive vascular processes or some days later. Also, cerebral blood flow velocity may be decreased in the presence of increased intracranial pressure and lead to temporary or lasting neurologic dysfunction. It is important to distinguish lateralizing findings resulting from postictal changes (Todd s paralysis), which usually persist for no more than several hours.
Prompt treatment of bacterial meningitis usually results in rapid recovery of neurologic function. Persistent or late-onset obtundation and coma without focal findings suggests development of brain swelling, subdural effusion (in the infant), hydrocephalus, loculated ventriculitis, cortical thrombophlebitis, or sagittal sinus thrombosis. The last three are commonly associated with fever and continuing pleocytosis.
Residual neurologic damage remains in 10 to 20% of patients who recover from bacterial meningitis. Developmental delay and speech defects are each observed in about 5% of children. In infants surviving neonatal meningitis, significant sequelae are much more frequent (15 to 50%).
Initial CSF pressure is usually moderately elevated (200 to 300 mm H2 O in the adult). Striking elevations (>450 mm H2 O) occur in occasional patients with acute brain swelling complicating meningitis in the absence of an associated mass lesion.
By the time of hospitalization, most patients with pyogenic meningitis have large numbers (at least 105 per milliliter) of bacteria in the CSF. Careful examination of the Gram-stained smear of the spun sediment of CSF reveals the etiologic agent in 60 to 80% of cases. In most instances when gram-positive diplococci (or short-chaining cocci) are observed on stained CSF smear, they are pneumococci. In certain clinical settings it is important to distinguish this organism from the relatively penicillin-resistant Enterococcus, which would require adding an aminoglycoside to penicillin in treatment. This can be done by identifying pneumococcal polysaccharide in the CSF by latex particle agglutination (or by employing the quellung reaction). Rarely, three species may morphologically mimic Neisseria in the CSF or suggest a mixed infection with short gramnegative rods and meningococci: Acinetobacter calcoaceticus, Moraxella spp., and Pasteurella multocida. Culture of the CSF reveals the etiologic agent in 80 to 90% of patients with bacterial meningitis.
In patients in whom the etiologic agent is not identified on Gram-stained smear of the CSF, rapid diagnosis may often be made by detection of specific bacterial antigens by latex agglutination (LA). This technique has been employed most extensively in the rapid diagnosis of meningitis caused by H. influenzae type b but also has been used in diagnosing meningococcal (groups A, B, C, and Y) and pneumococcal meningitis and meningitis due to group B streptococci. Since E. coli K1 and N. meningitidis serogroup B share a common antigenic determinant, immunologic cross-reactivity may cause a falsepositive reaction with the group B meningococcal reagent. Since the bacterial cause can be found on Gram-stained smear in most cases of bacterial meningitis, the role of LA appears to be as an adjunct in rapid diagnosis when no organisms are observed or in providing a specific rather than a morphologic (Gram stain) diagnosis.
The limulus gelation assay for endotoxin is positive in the CSF of patients with meningitis caused by gram-negative but not by gram-positive bacteria.
The cell count in untreated meningitis usually
ranges between 100 and 10,000 per cubic millimeter, with polymorphonuclear
leukocytes predominating initially (80%) and lymphocytes
appearing subsequently. Extremely high cell counts (>50,000
per cubic millimeter) may occur rarely in primary bacterial meningitis
but also should raise the possibility of intraventricular rupture
of a cerebral abscess. Cell counts as low as 10 to 20 may be observed
early in bacterial meningitis (particularly that caused by N.
meningitidis and H. influenzae). Occasionally, in granulocytopenic
patients or in the elderly with overwhelming pneumococcal meningitis,
the CSF may contain very few leukocytes and yet may appear
grossly turbid because of the presence of myriads of organisms. Meningitis
caused by several bacterial species (Mycobacterium tuberculosis,
Borrelia burgdorferi, Treponema pallidum) characteristically
produces a lymphocytic pleocytosis. L. monocytogenes meningitis
in infants may produce a primarily lymphocytic response in
the CSF; in the adult there is usually a polymorphonuclear response,
but rarely lymphocytes predominate.
The CSF glucose is reduced to values of 40 mg per deciliter or below (or <50% of the simultaneous blood level) in 50% of patients with bacterial meningitis; this finding can be very valuable in distinguishing bacterial meningitis from most viral meningitides or parameningeal infections. A normal CSF glucose does not exclude the diagnosis of bacterial meningitis. The simultaneous blood glucose level should be determined, because patients with diabetes mellitus (or those who are receiving intravenous glucose infusions) have an elevated level of glucose in the CSF, and its significance can be appreciated only on comparison with the simultaneous blood level. However, it may take 90 to 120 minutes for equilibration to occur after major shifts in the level of glucose in the circulation. The hypoglycorrhachia characteristic of pyogenic meningitis appears to be due to interference with normal carrier-facilitated diffusion of glucose and to increased utilization of glucose by host cells.
The level of protein in the CSF is usually elevated above 100 mg per deciliter, and the higher values are more commonly observed in pneumococcal meningitis. Extreme elevations, 1000 mg per deciliter or more, indicate subarachnoid block secondary to the meningitis.
Elevated levels of lactic acid occur in pyogenic meningitis. Although lactic dehydrogenase levels are higher in patients with bacterial meningitis than in those with viral infections of the CNS, these alterations are not of help in determining the specific etiologic agent involved. C-reactive protein is increased in about 95% of patients with bacterial meningitis and is not increased in most patients with viral meningitis. However, it does not seem to provide more information than the CSF cell count, is not helpful in diagnosing bacterial meningitis in newborns, and does not provide clues to the bacterial species involved.
Bacteremia is demonstrable in about 80% of patients with H. influenzae meningitis, 50% of those with pneumococcal meningitis, and 30 to 40% of those with meningococcal meningitis. Cultures of the upper respiratory tract are not helpful in establishing an etiologic diagnosis. Determining serum creatinine and electrolytes is important in view of the gravity of the illness, the occurrence of specific abnormalities secondary to the meningitis (syndrome of inappropriate secretion of antidiuretic hormone), and problems in therapy in the presence of renal dysfunction (seizures and hyperkalemia with high-dose penicillin therapy). In patients with extensive petechial and purpuric skin lesions, evaluation for coagulopathy is indicated.
In view of the frequency with which pyogenic meningitis is associated with primary foci of infection in the chest, nasal sinuses, or mastoid, roentgenograms of these areas should be taken at the appropriate time after antimicrobial therapy begins when clinically indicated. Computed tomographic (CT) scans are not indicated in most patients with bacterial meningitis. If
Diagnosis of bacterial meningitis is not difficult in a febrile patient with meningeal symptoms and signs developing in the setting of a predisposing illness. The diagnosis may be less obvious in the elderly, obtunded patient with pneumonia or the confused alcoholic patient in impending delirium tremens. Examination of the CSF should be carried out promptly whenever there is any question of meningitis.
Headache, fever, vomiting, stiff neck, and pleocytosis are features of meningeal inflammation and are common to many types of meningitis (e.g., bacterial, fungal, viral) and also to some parameningeal processes. The CSF findings are most helpful in distinguishing among these processes (see Ch. 421) . In the patient with meningitis whose CSF does not reveal the etiologic agent on Gram-stained smear, particularly when the CSF glucose is normal and the polymorphonuclear pleocytosis is atypical, certain treatable processes which can mimic bacterial meningitis should be considered in differential diagnosis: (1) Parameningeal infections. The presence of infections (chronic ear or nasal accessory sinus infections, lung abscess) predisposing to brain abscess, epidural (cerebral or spinal) abscess, subdural empyema, or pyogenic venous sinus phlebitis should be sought. Neurologic findings may appear in the course of primary bacterial meningitis, but their presence should alert the physician to the need for close scrutiny for the presence of a space-occupying infectious process in the CNS. Neurologic symptoms or findings antedating the onset of meningeal symptoms should suggest the possibility of a parameningeal infection. The isolation of an anaerobic organism should suggest the possibility of intraventricular leakage of a cerebral abscess. (2) Bacterial endocarditis. Bacterial meningitis may occur during bacterial endocarditis caused by pyogenic organisms such as S. aureus and enterococci. In subacute bacterial endocarditis, sterile embolic infarctions of the brain may occur and produce meningeal signs and a pleocytosis containing several hundred cells, including polymorphonuclear leukocytes. A history of dental manipulation, fever, and anorexia antedating the meningitis should be sought; careful examination for heart murmurs and peripheral stigmata of endocarditis is indicated. (3) "Chemical" meningitis. The clinical and CSF findings (polymorphonuclear pleocytosis and even reduced glucose level) of bacterial meningitis may be produced by chemically induced inflammation. Acute meningitis following a diagnostic lumbar puncture or spinal anesthesia may be due to bacterial or chemical contamination of equipment or anesthetic agent. Chemical meningitis, characterized by a polymorphonuclear pleocytosis, hypoglycorrhachia, and a latent period of 3 to 24 hours, may occur following 1% of metrizamide myelograms. Endogenous chemical meningitis resulting from material from an epidermoid tumor or a craniopharyngioma leaking into the subarachnoid space can produce a polymorphonuclear pleocytosis and hypoglycorrhachia. Birefringent material may be seen on polarizing microscopy of the CSF sediment.
Rarely, a patient develops meningitis characterized by subacute onset and persistent neutrophilic CSF pleocytosis lasting weeks or months without ready bacteriologic diagnosis. The etiologic agent in such cases of chronic neutrophilic meningitis has usually been either a fungus (Aspergillus, Candida, Blastomyces) or a bacterium such as Nocardia or Actinomyces species.
When shock occurs in pyogenic meningitis, it is usually a manifestation of an accompanying intense bacteremia, as in fulminant meningococcemia, rather than of the meningitis itself. Management is guided by the principles of septic shock therapy with appropriate modifications for myocardial failure (see Ch. 281) .
Coagulopathies are frequently associated with the intense bacteremias (usually meningococcal, occasionally pneumococcal) and hypotension which can accompany meningitis. The changes may be mild, such as thrombocytopenia (with or without prolongation of prothrombin and partial thromboplastin times), or more marked, with clinical evidences of disseminated intravascular coagulation (see Ch. 281) .
Previously, 5 to 10% of patients with pneumococcal meningitis, particularly those with bacteremia and pneumonia as well, developed acute endocarditis, most commonly on the aortic valve. The incidence is currently much lower, as a result of earlier treatment of the initiating infection. In such patients, febrile relapse and a new murmur may appear shortly after completion of antimicrobial therapy for meningitis.
Septic arthritis may result from the bacteremia associated with meningitis caused by S. pneumoniae, N. meningitidis, or H. influenzae.
With appropriate antimicrobial treatment of meningitis of the three most common bacterial causes, patients become afebrile within 2 to 5 days. Sometimes fever persists beyond this or recurs after an afebrile period. In the patient with persisting headache, obtundation, and cerebral findings, inadequate drug therapy or neurologic sequelae (cortical venous thrombophlebitis, ventriculitis, subdural collections) are important considerations. Re-evaluation of the CSF, particularly Gram-stained smear and culture, is essential under these circumstances. Drug fever may be responsible in the patient who continues to show clinical improvement in all other respects. Metastatic infection (septic arthritis, purulent pericarditis, thoracic empyema, endocarditis) may be the cause of continuing or recurrent fever.
A syndrome consisting of fever, arthritis, and pericarditis 3 to 6 days after initiation of effective antimicrobial therapy of meningococcal meningitis occurs in about 10% of patients (see Ch. 281) .
Repeated episodes of bacterial meningitis generally indicate a host defect, either in local anatomy or in antibacterial and immunologic defenses (e.g., recurrent N. meningitidis infections in patients with congenital or acquired deficiencies of complement, particularly late-acting components). Eleven percent of adults with pneumococcal meningitis have had more than one episode, whereas 0.5% of patients with meningitis caused by other organisms have had recurrent attacks. S. pneumoniae is the cause of one third of episodes of community-acquired recurrent meningitis; various streptococci, H. influenzae, and N. meningitidis are the causes of another one third of episodes. In contrast, in nosocomial recurrent meningitis, gram-negative bacilli and S. aureus are the causes of about 60% of episodes. A history of head trauma is much more frequent in patients with recurrent meningitis. Organisms may enter the subarachnoid space directly, through a defect in the cribriform plate (the most common site), in association with the empty sella syndrome, via a basilar skull fracture, through an erosive sequestrum of the mastoid, through congenital dermal defects along the craniospinal axis (usually evident before adult life), or as a consequence of penetrating cranial trauma or neurosurgical procedures. The anatomic defect may produce a frank CSF leak (rhinorrhea or, less commonly, otorrhea) or may entrap a vascular cuff of meninges which might subsequently serve as a direct route for organisms to reach the meninges. CSF rhinorrhea may be intermittent, and meningitis may occur months or years after head injury.
Any patient with bacterial meningitis, particularly if meningitis is recurrent, should be evaluated carefully for any congenital or post-traumatic
Recurrent pneumococcal meningitis may occur without apparent predisposing circumstances, and cryptic CSF leaks should be sought actively in such patients by CT scanning of the frontal and mastoid regions and by radioisotope techniques. (Radioiodine-labeled albumin is introduced intrathecally, and pledgets of cotton placed in the nares are subsequently examined for the radionuclide. Radioisotopic cisternography has been used successfully.) Intrathecal introduction of fluorescein as a visual tracer (under ultraviolet light) can be employed similarly to detect active leaks. Surgical closure of CSF fistulas should be carried out to prevent further episodes of meningitis. Newer extracranial approaches via the ethmoid sinuses to repair cribriform plate or sphenoid sinus dural defects are successful and avoid the higher morbidity associated with craniotomy.
In most patients with CSF otorrhea and rhinorrhea following an acute head injury, the leak ceases in 1 or 2 weeks. Persistent rhinorrhea for more than 4 to 6 weeks is an indication for surgical repair. Prolonged administration of penicillin does not prevent pneumococcal meningitis and may encourage infection with more drug-resistant species.
Rarely, recurrent meningitis of nonbacterial etiology may mimic bacterial meningitis. Mollaret s meningitis consists of repeated febrile episodes of mild meningeal symptomatology, usually without neurologic abnormalities. Initially, large "endothelial" cells may be seen in the CSF along with polymorphonuclear leukocytes, which subsequently are replaced by lymphocytes. Behcet s syndrome, characterized by relapsing oral and genital ulcers and ocular lesions (hypopyon), may exhibit a variety of neurologic abnormalities, including recurrent meningitis.
The introduction of antimicrobial agents has converted bacterial meningitis from a disease that was almost always fatal to one that the majority of patients survive without significant neurologic residua. The mortality rate for community-acquired bacterial meningitis varies with the etiologic agent and the clinical circumstances. With current antimicrobial therapy the mortality rate for H. influenzae meningitis is below 5% and that for meningococcal meningitis is about 10%. The highest mortality is with pneumococcal meningitis, in which the rate is about 25%. The mortality rate for gram-negative bacillary meningitis, commonly nosocomial in origin, in adults has been 20 to 30%, but it appears to be decreasing in the past 5 to 10 years. The mortality rate for recurrent community-acquired meningitis in adults (about 5%) is strikingly lower than the 25% rate for nonrecurrent episodes. Poor prognostic factors include advanced age, presence of other foci of infection, underlying diseases (leukemia, alcoholism), obtundation, seizures within the first 24 hours, and delay in instituting appropriate therapy.
Antimicrobial therapy should be begun promptly in this life-threatening emergency. Treatment should be aimed at the most likely causes based on clinical clues (age of the patient, presence of a purpuric rash, a recent neurosurgical procedure, CSF rhinorrhea). If the infecting organism is observed on examination of the Gram-stained smear of the CSF sediment, specific therapy is initiated. If the etiologic agent is not seen on smear (or not detected by LA), treatment for bacterial meningitis of unknown etiology should be carried out (see below).
With the exception of chloramphenicol, the commonly used antimicrobial agents do not readily penetrate the normal blood-brain barrier, but the passage of penicillin and other antimicrobials is enhanced in the presence of meningeal inflammation. Antimicrobial drugs should be administered intravenously throughout the treatment period; reducing dosage as the patient improves should be avoided, because normalization of the blood-brain barrier during recovery reduces the CSF levels of drug that are achievable. Bactericidal drugs (penicillin, ampicillin, third-generation cephalosporins) are preferred whenever possible in the treatment of meningitis caused by susceptible bacteria. In animal models of bacterial meningitis, CSF levels of antibiotics at least 10 to 20 times the minimal bactericidal concentration appear to be needed for optimal therapy. Several antimicrobial drugs (first- or second-generation cephalosporins, clindamycin) do not provide effective levels in the CSF and should not be used.
The treatment of choice for pneumococcal meningitis in the adult has been penicillin (Table 280-3) . For patients allergic to penicillin, chloramphenicol has been a reasonable alternative (see below). However, problems have developed because of the emergence of penicillin resistance in some pneumococcal isolates. Such resistance has arisen as a result of successive stepwise chromosomal mutations in genes for penicillin-binding proteins and is not due to beta-lactamase production. Penicillin-resistant isolates are either relatively resistant (minimum inhibitory concentration (MIC) of 0.1 to 1.0 µg per milliliter) or highly resistant (MIC > 1.0 µg per milliliter). Penicillin-resistant pneumococcal strains have been found worldwide: 44% of isolates in parts of Spain, 45% in regions of South Africa, and almost 60% of isolates in Hungary. In the United States, currently almost 7% (range 0 to 32%) of pneumococcal isolates are penicillin-resistant, with higher percentages being noted in certain geographic areas such as Nashville, Tennessee, and parts of Texas and Kentucky. Cases of pneumococcal meningitis due to moderately and highly penicillin-resistant strains (some multiple antibiotic resistant) have now emerged in this country. Thus antimicrobial susceptibilities should be determined for all pneumococcal isolates from CSF, blood, or sterile body fluids (Table 280-3) . Worrisome has been the recent appearance of cefotaxime resistance in pneumococcal isolates from children in South Africa and Texas. Since commercial MIC panels may not detect resistance to third-generation cephalosporins, it is necessary to determine the MIC to these drugs by means other than using such a panel. If the MIC for cefotaxime or ceftriaxone (<1.0 µg per milliliter) indicates a highly susceptible isolate, cefotaxime or ceftriaxone would be the drug of choice. If the isolate is highly penicillin-resistant or is resistant to 1.0 µg per milliliter of ceftriaxone or cefotaxime, alternative therapy (vancomycin with or without rifampin intravenously) is indicated. If the patient has pneumococcal meningitis and comes from an area where highly resistant strains are known to occur, then initial therapy (pending susceptibility testing) with cefotaxime (or ceftriaxone) plus vancomycin intravenously is reasonable.
Although resistance to chloramphenicol is unusual among pneumococcal isolates from the United States, chloramphenicol has shown poor bactericidal activity against penicillin-resistant isolates from children with meningitis in South Africa. The relative chloramphenicol resistance of such strains may not be discerned on usual laboratory testing but is revealed when the minimum bactericidal concentration is determined. In areas where highly penicillin-resistant or chloramphenicol-resistant pneumococci are found, vancomycin replaces chloramphenicol in initial treatment of pneumococcal meningitis in the highly penicillin-allergic patient.
Penicillin G or ampicillin intravenously, in the dosage used to treat meningitis due to penicillin-susceptible pneumococci, is used to treat N. meningitidis meningitis. Recently, meningococci resistant to penicillin have been isolated occasionally in Spain, South Africa, Canada, and rarely the United States. Most of these isolates have been relatively resistant to penicillin (MIC 0.1 to 1.0 µg per milliliter), although a rare strain has had high-level resistance due to beta-lactamase production. The latter-type strains require the use of third-generation cephalosporins, but "meningitis dosages" of penicillin or ampicillin may provide CSF levels that are sufficient for infections due to some strains of relatively penicillin-resistant N. meningitidis.
At present, 30 to 35% of isolates of H. influenzae type b in the United States are beta-lactamase producers and ampicillin resistant; cefotaxime is the initial therapy of choice (see Table 280-3) . Chloramphenicol combined with ampicillin is an acceptable alternative. If the isolate proves susceptible to ampicillin, the chloramphenicol
|
Therapy of Choice
|
Penicillin Susceptibility |
Alternative Therapy
|
|---|---|---|
| Pneumococcal Meningitis |
|
|
| Penicillin, 24 million units qd in divided doses q2-4h | MIC < 0.1 µg/ml | If penicillin allergic: chloramphenicol, 4-6 grams qd; cefotaxime or ceftriaxone; vancomycin |
| or |
|
|
| Ampicillin, 12 grams qd in divided doses q2-4h |
|
|
| Cefotaxime, 2 grams q4-6h | MIC 0.1-1.0 µg/ml | Vancomycin |
| or |
|
|
| Ceftriaxone, 2 grams q12h |
|
|
|
Vancomycin, 2-3 grams
|
MIC > 1.0 µg/ml |
|
|
|
|
|
| Haemophilus influenzae Meningitis |
|
|
| For child: Cefotaxime, 180 mg/kg qd in divided doses q4-6h |
|
Chloramphenicol, 100 mg/kg qd |
| or |
|
plus |
| Ceftriaxone, loading dose of 100 mg/kg followed by 50 mg/kg q12h (not to exceed 4 grams/d) |
|
Ampicillin, 300-400 mg/kg until beta-lactamase status known |
| For adult: Cefotaxime, 2 grams q4h |
|
Chloramphenicol, 4-6 grams qd |
|
|
|
plus |
|
|
|
Ampicillin, 12 grams qd until beta-lactamase status known |
|
|
|
|
| Staphylococcus aureus Meningitis |
|
|
| Methicillin-susceptible |
|
|
| Nafcillin, 10-12 grams qd in divided doses q4h; in difficult cases may add rifampin, 600 mg qd IV or PO |
|
If penicillin allergic: vancomycin, 2-3 grams qd in divided doses q8-12h |
| Methicillin-resistant |
|
|
|
Vancomycin, 2-3 grams
|
|
|
|
|
|
|
| Listeria monocytogenes Meningitis |
|
|
| Penicillin § , 24 million units qd in divided doses q2-4h |
|
If penicillin allergic: trimethoprim-sulfamethoxazole (20 mg/kg of trimethoprim component qd in divided doses q6-12h) |
| or |
|
|
| Ampicillin, 12 grams qd in divided doses q2-4h |
|
|
|
|
|
|
| Meningitis Due to Susceptible Enterobacteriaceae |
|
|
| Cefotaxime, 12 grams qd in divided doses q4h |
|
Aztreonam; trimethoprim-sulfamethoxazole; ciprofloxacin |
| or (if susceptibilities not known) |
|
|
| Ceftazidime, 6 grams qd in divided doses q8h and an aminoglycoside (e.g., gentamicin, 5 mg/kg qd in divided doses q8h) (if no response to initial therapy, consider adding intrathecal gentamicin, 3-5 mg dose q24h for first few days) |
|
|
|
|
|
|
| Pseudomonas aeruginosa Meningitis |
|
|
| Ceftazidime, 6-8 grams qd in divided doses q6-8h and an aminoglycoside (tobramicin or gentamicin); (if no response to initial therapy, consider adding intrathecal gentamicin) |
|
Antipseudomonal penicillin (piperacillin or azlocillin) plus tobramicin (or gentamicin); ciprofloxacin; aztreonam |
Treatment for adult meningitis caused by methicillin-sensitive S. aureus is listed in Table 280-3 . For the penicillin-allergic, vancomycin is the alternative of choice. Since penetration of vancomycin into the CSF is limited, adjunctive intrathecal (or intraventricular) therapy with vancomycin * (without preservative) has occasionally been resorted to when CSF cultures have remained positive after 48 hours of intravenous therapy alone and where CSF levels can be monitored. For adult meningitis due to methicillin-resistant S. aureus, intravenous vancomycin (with adjunctive intrathecal vancomycin as needed) is the treatment of choice. In refractory cases, adding another drug for systemic therapy (rifampin or gentamicin) may be warranted.
Cefotaxime (see Table 280-3) is used to treat meningitis known to be due to susceptible gram-negative bacilli (E. coli, Klebsiella, Proteus, and so forth). It should not be used to treat meningitis due to less susceptible species such as Pseudomonas aeruginosa and Acinetobacter. Initial treatment (on the basis only of findings on Gram-stained smear of CSF) of adults with gram-negative bacillary meningitis is listed in Table 280-3 . After identifying the specific pathogen and determining its drug susceptibilities, alterations in antimicrobial therapy may be indicated. If the organism is P. aeruginosa, use a third-generation cephalosporin with antipseudomonal activity (see Table 280-3) .
Initial treatment of meningitis when the etiologic agent cannot be identified on Gramstained smear of CSF is based on available clinical clues. In the neonate, a wide range of gram-positive (group B streptococci, Listeria) and gram-negative organisms (E. coli, Klebsiella, H. influenzae) may be the cause, indicating the intravenous use of combined therapy with drugs such as ampicillin with gentamicin (or amikacin), or ampicillin with cefotaxime (the combination favored by most pediatric infectious disease specialists), until results of cultures become available. In children, therapy is directed at the three most frequent pathogens: H. influenzae, S. pneumoniae, and N. meningitidis. The appearance of ampicillin resistance among strains of H. influenzae two decades ago necessitated the shift from single-drug therapy (ampicillin) to a two-drug approach (ampicillin-chloramphenicol) in the treatment of meningitis of unknown cause in
The frequency of CSF examinations depends on the clinical course, but a repeat examination should be done in 24 to 48 hours if there has not been satisfactory improvement. Routine "end-of-treatment" CSF examination is unnecessary in most patients with the common types of community-acquired bacterial meningitis. Meningococci are rapidly eliminated from the circulation and CSF with appropriate antimicrobial therapy, which should be continued for 5 to 7 days after the patient becomes afebrile. If the patient has responded well, a follow-up lumbar puncture is not necessary. H. influenzae meningitis should be treated for 10 days (at least for 7 days after the patient becomes afebrile). Follow-up CSF examination may be omitted in those patients who have responded with rapid clinical resolution of the meningitis. In pneumococcal meningitis, antimicrobial treatment should be continued for 10 to 14 days, and follow-up examination of the CSF should be done. More prolonged therapy is indicated with concomitant parameningeal infection. Treatment of gram-negative bacillary meningitis with parenteral antimicrobials is prolonged, usually for a minimum of 3 weeks (particularly in patients with a recent neurosurgical procedure) in order to prevent relapse. Repeated examinations of the CSF are necessary both during and at the conclusion of treatment to determine whether bacteriologic cure has been achieved.
Occasional patients with acute bacterial meningitis develop marked brain swelling (CSF pressure >450 mm H2 O), which may lead to temporal lobe or cerebellar herniation following lumbar puncture. To decrease the possibility of this complication of increased pressure, only a small amount of CSF should be removed for analysis (the amount present in the manometer) and a 20% solution of mannitol (0.25 to 0.5 gram per kilogram) infused intravenously over 20 to 30 minutes, monitoring (if possible) the decline of CSF pressure to a lower level before the spinal needle is removed. Continued control of increased intracranial pressure, if needed thereafter, may be effected with mannitol, dexamethasone (10 mg intravenously, followed by 4 mg every 6 hours), or both. Brain swelling is about the only current indication for the use of corticosteroids in treating pyogenic meningitis in adults; they should be employed only when the appropriate antimicrobial drugs are administered. In the stuporous patient or one with respiratory insufficiency and markedly increased intracranial pressure, use of a ventilator to reduce the arterial PCO2 to between 25 and 32 mm Hg is reasonable. Intravenous lidocaine can be used to block increased intracranial pressure associated with intubation, and subsequent transient increases associated with hyperactive airway reflexes can be mitigated by intratracheal instillation of lidocaine prior to vigorous suctioning. With continued elevations of intracranial pressure, a continuous intracranial monitoring device may be warranted.
Initial hypotension, if present, should be treated with fluid resuscitation in keeping with shock management principles. Over the next 24 to 48 hours, fluid limitation (1200 to 1500 ml daily in adults) to prevent brain swelling from the effects of inappropriate antidiuretic hormone secretion, sometimes associated with meningitis (particularly in children), is advisable.
Four prospective, controlled trials in children of the routine use of dexamethasone to reduce the pathophysiologic CNS consequences of the inflammatory response during bacterial meningitis have been performed. Dexamethasone was administered intravenously (either 0.15 mg per kilogram every 6 hours for 4 days or 0.4 mg per kilogram every 12 hours for 2 days) either at the time of or 10 to 20 minutes before initiating antimicrobial therapy (third-generation cephalosporin). Corticosteroid use had no effect on mortality but did reduce the incidence of neurologic sequelae (primarily bilateral sensorineural hearing loss). Complicating gastrointestinal bleeding (usually occult) has been observed rarely but merits caution. On the basis of these studies, most pediatric infectious disease programs surveyed in 1992 used dexamethasone in bacterial meningitis of children over 2 months of age. Most of the children in the studies had H. influenzae meningitis, the most common type at the time, and the results reflect primarily the effects of dexamethasone on this form. Currently, H. influenzae meningitis has been sharply reduced in incidence by the use of protein-conjugate vaccines, but whether dexamethasone will have a similar effect in reducing neurologic sequelae of meningitis due to S. pneumoniae and N. meningitidis in children has not yet been established. As of this writing, use of adjunctive dexamethasone in cases of severe H. influenzae meningitis seems indicated, but whether adjunctive corticosteroid use will have a similar salutory effect in reducing the incidence of sensorineural hearing loss or neurologic sequelae in adults is not known and awaits results of a multicenter trial.
Patients with acute bacterial meningitis should receive constant nursing attention to ensure prompt recognition of seizures and to prevent aspiration. If seizures occur, they should be treated acutely with diazepam (Valium) administered slowly intravenously in a dose of 5 to 10 mg in the adult. Maintenance anticonvulsant therapy can be continued thereafter with intravenous phenytoin (Dilantin) until the medication can be administered orally. Sedation should be avoided because of the danger of respiratory depression and aspiration.
Surgical treatment of an accompanying pyogenic focus such as mastoiditis should be carried out when complete recovery from the meningitis has occurred, but under continuing antibiotic administration. Rarely, the mastoid infection (e.g., Bezold abscess) is so hyperacute that early drainage may be required after 48 hours or so of antibiotic therapy when the acute meningeal process has subsided somewhat.
Durand ML, Calderwood SB, Weber DJ, et al.: Acute bacterial meningitis in adults: A review of 493 episodes. N Engl J Med 328:21, 1993. A detailed review of an extensive experience in adults between 1962 and 1988 in a large urban general hospital. Community-acquired, nosocomial, and recurrent forms of bacterial meningitis are categorized; the bacteriologic, clinical, CSF, and neurologic findings are well described.
Feigin RD, McCracken GH Jr, Klein JO: Diagnosis and management of meningitis. Pediatr Infect Dis J 11:785, 1992. A comprehensive review of bacterial meningitis in children (from neonate to adolescent). Epidemiology, bacteriology, pathogenesis and pathophysiology, neurologic features, CNS complications, and current treatment are emphasized.
Odio CM, Faingezicht I, Paris M, et al.: The beneficial effects of early dexamethasone administration in infants and children with bacterial meningitis. N Engl J Med 324:1525, 1991. This study showed that adjuvant dexamethasone treatment resulted at 12 hours in lowered CSF pressures and improved cerebral perfusion pressures and at follow-up, after 15 months, in decreased sensorineural hearing loss or neurologic sequelae.
Pfister H-W, Feiden W, Einhaupl K-M: Spectrum of complications during bacterial meningitis in adults. Arch Neurol 50:575, 1993. In this thorough prospective evaluation of 86 adults with bacterial meningitis, neurologic complications (cerebrovascular injury, brain swelling, cerebral herniation, hydrocephalus) are described. This study describes features helpful for identification of these complications and, particularly, their temporal relationships.
Quagliarello V, Scheld WM: Bacterial meningitis: Pathogenesis, pathophysiology, and progress. N Engl J Med 327:864, 1992. In this insightful and comprehensive review, particular attention is given to the role of bacterial components, cytokines and other mediators, and endothelial and leukocyte adhesins in the generation of the inflammatory response in the subarachnoid space.
Roos KL, Tunkel AR, Scheld WM: Acute bacterial meningitis in children and adults. In Scheld WM, Whitley RJ, Durack DT (eds): Infections of the Central Nervous System. New York, Raven Press, 1991. A thorough, particularly well illustrated consideration of all aspects of bacterial meningitis, including pathology, pathogenesis, clinical features, epidemiology, and treatment. Includes a helpful section on neuroimaging changes.
Swartz MN, Dodge PR: Bacterial meningitis--A review of selected aspects. N Engl J Med 272:725, 1965. Detailed account of Massachusetts General Hospital experience. Particularly good on clinical aspects, neurologic complications, and differential diagnosis.
Meningococcal infections are a major cause of mortality and morbidity in developed and developing nations. Neisseria meningitidis is the causative agent in meningococcal infections. It has become the most common cause of bacterial meningitis in United States children since using the Haemophilus influenzae type b protein-capsular polysaccharide conjugate vaccine in infants has dramatically reduced their incidence of meningitis due to this organism. Considerable progress has been made in managing and preventing infections due to N. meningitidis since the organism was first described in 1887 (Table 281-1) . Because the meningococcal vaccine has limited effectiveness in the group at greatest risk for infection, children younger than age 2, meningococcal infection is still a major worldwide problem. The devastating nature of systemic meningococcal infection makes it imperative that preventive measures be developed to fully control this disease. In addition, an effective vaccine against meningococcal serogroup B infection has not been developed. Until this goal is realized, it is crucial that the clinician recognize and be able to successfully treat the infection as early as possible in its course to ensure an outcome with minimal mortality and morbidity.
N. meningitidis is a gram-negative diplococcus. Meningococci are considered a fastidious species, and media containing appropriate supplementation must be used to ensure reliable growth from clinical samples. Selective media such as Thayer-Martin medium have allowed the organism to be isolated from sites that contain diverse background flora, such as the nasopharynx. The organism grows best between 35 to 37° C in an atmosphere of 5% carbon dioxide. The organism will not grow below 32° C or above 41° C. Laboratory confirmation of the presence of the organism depends on the metabolism of glucose and maltose with the production of acid. Gas is not produced during this metabolic process.
The meningococcus has a very narrow environmental niche. It is a strict human pathogen that has only been isolated from human mucosal surfaces or body fluids. A number of factors contribute to the organism s ability to colonize and cause infection. The meningococcus has a typical gram-negative cell wall containing lipopolysaccharide or endotoxin, which is the primary toxin of the meningococcus. Meningococci express pili (attachment organelles) which they need to adhere to nasopharyngeal epithelial cells. Meningococci can express polysaccharide capsules; this is probably the most important virulence factor associated with this species. Thirteen
| Year | Advance |
|---|---|
| 1805 | Epidemic cerebrospinal fluid fever (meningococcal meningitis) described in Geneva. |
| 1885 | Causative organism identified. |
| 1904 | Distinct serotypes of N. meningitidis described. |
| 1909 | Asymptomatic nasopharyngeal carrier state recognized. |
| 1911 | Use of serotherapy for management of meningococcal infection. |
| 1933 | Use of sulfonamides to treat meningococcal meningitis. |
| 1942 | Sulfonamide prophylaxis used in military camps to prevent epidemics. |
| 1950 | High-dose penicillin used successfully to treat meningococcal meningitis. |
| 1963 | Sulfonamide-resistant meningococci identified at Fort Ord, CA. |
| 1971 | Meningococcal capsular C polysaccharide used to successfully prevent meningococcal disease to prevent disease in U.S. Army recruits. |
| 1989 | N. meningitidis resistant to penicillin C first reported. |
The pathogenesis of meningococcal infection is now beginning to be understood. The factors involved in colonization and invasion of the nasopharyngeal surface are shown in Figure 281-1A . The meningococcus can adhere to and enter the nonciliated cells of the nasopharyngeal mucosa. Organisms are able to transmigrate through these cells to the submucosal space, where they have access to enter capillaries and arterioles. If the organism can invade the vascular system, the capsular polysaccharide (in the absence of specific antibody) provides an antiphagocytic barrier that protects the organism against normal host clearing mechanisms. Figure 281-1B outlines the process by which endotoxin (lipo-oligosaccharide, or LOS), through the release of cytokines, leads to shock and disseminated intravascular coagulation (DIC) in meningococcal sepsis. Endotoxin and cytokine levels in meningococcal sepsis have been measured and high tumor necrosis factor alpha (TNFalpha) and interferon-gamma levels correlate with a poor prognosis.
The propensity of the meningococcus to invade the central nervous system (CNS) and cause meningitis is poorly understood. The organism probably gains entry through the arachnoid villi. The release of endotoxin and peptidoglycan in the cerebrospinal fluid (CSF) evokes inflammatory factors that are chemoattractive for polymorphonuclear leukocytes (PMN s). Enzymes released by PMN s intensify the meningeal inflammation, leading to increased cerebral vascular permeability and brain edema.
N. meningitidis can cause endemic and epidemic infection. At present, meningococcal infection is endemic in the United States, with approximately 2500 cases per year reported to the Centers for Disease Control and Prevention. This gives a case rate of approximately 1 in 105 total population. The fatality rate is approximately 12%. Disease rates in children younger than age 2 are approximately 10 times higher than in the overall population. Seasonal variation occurs, with the highest attack rates in February and March and the lowest in September. The male-to-female patient ratio is approximately equal. The predominate serogroups causing infection in the United States currently are serogroups B and C.
Before World War II, periodic epidemics of meningococcal infection ravaged American cities. These were caused primarily by the serogroup A meningococcus. With increasing standards of living, these epidemics have abated in this country, and infection due to the serogroup A has virtually disappeared in the United States.
Large-scale epidemics still occur with a deadly frequency in Africa, parts of Asia, South America, and the countries of the former Soviet Union. These epidemics are most commonly caused by serogroup A meningococcus and occasionally by the serogroup C meningococcus. In an area appropriately named "the meningitis belt" because it crosses the waist of sub-Saharan Africa, epidemics of meningococcal infection occur every 7 to 10 years. The case rate during these epidemics can be as high as 1 in 1000 total population. Case rates in children younger than 2 can be 1 in 100. In the developed nations of western Europe, epidemics due to serogroup B meningococcus have occurred over the past decade. Norway suffered such an epidemic with case rates of 1 in 10,000; a high attack rate was seen among teenagers.
The reason for the epidemic spread of the meningococcus is not known. The organism is considered a respiratory pathogen, and spread is most likely by the aerosol route. It is clear that the high attack rates seen in developing countries is in part due to poverty and the consequences of crowding, poor sanitation, and malnutrition. Factors such as herd immunity and specific virulence factors associated with "epidemic strains" have been implicated in the rapid spread of infection in these situations. Predisposition to meningococcal infection has been associated with preceding respiratory tract infection, particularly influenza.
Figure 281-1 A, A schematic representation of nasopharyngeal invasion
by the meningococcus. The process involves attachment to surface of
nonciliated
cells by meningococcal pili. Short-range attachment factors
(meningococcal surface components) are probably involved in the endocytotic
engulfment process as microvilli of the nasopharyngeal cell surround
the organism. The nonciliated cells through which the organisms transmigrate
do not appear to sustain damage. By contrast, the ciliated mucosal
cells die and are extruded from the mucosal surface. Meningococcal
lipooligosaccharide,
peptidoglycan, and possibly other toxins are thought to be
responsible for this cytolytic activity. Organisms in the submucosal space
then have access to entry into capillaries and arterioles and can invade the
vascular system.
(Data from Stephens DS: Gonococcal and meningococcal
pathogenesis as defined by human cell, cell culture, and organ culture
assays. Clin
Microbiol Rev 2:S104, 1989.)
B, The rapid doubling time of the
meningococcus and its ability to shed large amounts of endotoxin by a
process called "blebbing" rapidly lead to a high-grade septic state with
shock. Endotoxin (lipo-oligosaccharide, or LOS) interacts with macrophages
to release cytokines, vasoactive lipids (prostaglandins), and free radicals
such as H2
O2
, O-
, and NO. These substances damage
vascular endothelium,
resulting in platelet deposition and vasculitis. This leads to vascular
disruption
and the petechiae and ecchymoses that are frequently seen during
meningococcal infection. Clotting factors are consumed, and DIC ensues,
which is an ominous consequence of delayed treatment. Occasionally, the
intravascular clotting can lead to occlusion of major arterial vessels in the
extremities, requiring amputation. The most dire consequence of all these
vascular effects is Waterhouse-Friderichsen syndrome, which is multiorgan
failure due to shock and hemorrhagic diathesis.
(Data from Brandtzaeg P,
Ovstebo R, Kierulf P: Compartmentalization of lipopolysaccharide production
correlates with clinical presentation in meningococcal disease. J Infect
Dis 166:650, 1992.)
Epidemic infections in American military recruit camps were a major problem before vaccination was introduced. Throughout the nineteenth century, the unique susceptibility of military recruits can be attested to by the clinical descriptions of this infection that can be found in the records of the Crimean and American Civil Wars. Since vaccinating recruits started in 1972 with a tetravalent vaccine containing serogroup A, C, Y, and W-135 polysaccharides, epidemics have not occurred.
Intimate contacts of cases, including family members, college roommates, and nursery school classmates are at 100- to 1000-fold increased risk of acquiring meningococcal infection. Such individuals should be told about the increased risk and monitored closely for emergence of co-primary cases (cases that arise within 48 hours of the primary case) and given chemoprophylaxis (see treatment section below) to prevent secondary cases of infection. Hospital personnel who care for patients with meningococcal disease are not at increased risk of acquiring infection. Exceptions would include individuals who suffer needle sticks contaminated with body fluids from untreated patients and health care personnel who give mouth-to-mouth resuscitation to infected individuals. It may be wise to manage such individuals with parenteral therapy rather than using chemoprophylaxis. Isolating patients in hospitals is a common practice--limited to respiratory isolation and terminated 24 hours after instituting appropriate antibiotic therapy.
There are several different meningococcal infection syndromes. In the early twentieth century, the ability to isolate meningococci from the nasopharynx of otherwise healthy individuals led to the concept of asymptomatic carriage of bacterial pathogens. The observation that increased carriage rates coincided with onset of epidemics among military recruits during World War I first linked the relationship of the carrier state to disease. The nasopharyngeal carrier state is considered an active infection, because some individuals have symptomatic pharynitis and develop rises in serologic titers to the infecting organism. It is considered that all cases of acute systemic meningococcal infection are preceded by recent nasopharyngeal colonization. Studies have shown that the carrier state can persist for long periods, with about 5% of the population carrying the meningococcus in their nasopharynx during endemic periods. The majority of these isolates are unencapsulated. During epidemics, the carrier rate can rise to over 30%, with the majority of individuals carrying the epidemic strains in their nasopharynx. Generally, most individuals who become carriers are asymptomatic. Evidence exists that the systemic immune system is primed during the period of nasopharyngeal carriage, since antibodies to the infecting strains can be shown to evolve concordant with colonization.
In a study of an epidemic among military recruits, it has been shown that nasopharyngeal colonization by the meningococcal strain responsible for the epidemic resulted in a 40% incidence of systemic infection if the person colonized also lacked bactericidal antibodies to the epidemic strain. This study confirmed the role of nasopharyngeal carriage as the source of systemic infection and the importance of the serum antibody in protecting against systemic meningococcal infection.
Acute systemic infection can be manifest clinically by three syndromes: meningitis, meningitis with meningococcemia, and meningococcemia without obvious signs of meningitis. Typically, an otherwise healthy patient develops sudden onset of fever, nausea, vomiting, headache, decreased ability to concentrate, and myalgia. The patient frequently tells the physician that this is the sickest he/she has ever felt. Many have an impending feeling of death. In children, the infection is rarely seen below age 6 months because they are protected by placentally transferred antibodies. Because children younger than age 2 cannot relate many symptoms, sudden onset of fever, leukocytosis, and lethargy become important findings. Initially, the physical examination may be unrevealing, with the exception of an acutely ill patient. The preceding symptoms of pharyngitis which may be associated with nasopharyngeal carriage can lead to a preliminary diagnosis of streptococcal infection. This frequently results in treatment with low-dose penicillin, which has little effect on the emerging meningococcal sepsis. Alternatively, the diagnosis of influenza is assigned to the patient because of complaints of fever, chills, and myalgia. In general, patients with meningococcal infection present considerably sicker than the majority of patients with streptococcal or viral infections. The vital signs will show a low blood pressure with an elevated pulse rate. Diaphoresis is common. In such patients, an intensive search for petechiae should be mounted (see Color Plate 10A) . A complete examination of the skin with the patient completely undressed is essential. The physical examination
The infection can progress rapidly. Depending on the patient s presentation, a critical situation can occur very quickly. Profound shock with DIC is the most ominous development in these patients. Coagulopathy, defined as a partial thromboplastin time of > 50 seconds or a fibrinogen concentration of > 150 µg per deciliter, is an excellent predictor of poor prognosis. A number of studies have demonstrated that myocardial dysfunction can occur in meningococcal sepsis. Signs of heart failure, including gallop rhythms and congestive heart failure with pulmonary edema, are not uncommon. In one large series, 15% of pediatric patients were admitted to intensive care units because of cardiovascular manifestations. Approximately 25% of patients who died of meningococcal sepsis had evidence of myocarditis. In France, a group of severely ill patients with meningococcal sepsis showed low stroke volume indices (29 ml per square meter) and tachycardia (> 135 beats per minute), a profile suggesting a greater myocardial depression than usually observed in gram-negative sepsis. In infection due to meningococcal serogroup C, pericarditis with tamponade can seriously complicate the course of treatment unless recognized and managed. When DIC occurs, persistent bleeding at intravenous sites and sites of arterial punctures can complicate management of the tamponade.
Neurologic complications include signs of meningeal irritation, an encephalopathic state, and coma. Seizures can occur but are less common than in other forms of bacterial meningitis. In general, patients surviving meningococcal CNS infection have remarkably few sequelae (see Ch. 421) , but cerebrovascular accidents secondary to intracranial bleeding can lead to paresis. Cases of posterior pituitary insufficiency have been reported in patients recovering from meningococcal infection.
Prognosis can vary depending on the presentation of the patient, the skill and completeness of the physician, and the nature of the facility. At tertiary care hospitals during endemic periods of infection, mortality rates as low as 8% have been reported. Patients who present with meningococcemia alone tend to have a higher mortality rate (up to 20%). During World War II, meningococcal mortality rates using sulfonamides were as low as 2%. Many of these patients were hospitalized and treated as soon as symptoms began. Recent studies in Norway and Africa have supported the concept that early onset of therapy significantly reduces mortality.
The laboratory diagnosis is based on isolating N. meningitidis from blood cultures or CSF. Blood cultures will be positive in 60 to 80% of untreated patients, while CSF cultures will be positive in 50 to 70%. Gram stain analysis of CSF requires a skilled patient observer but it can provide diagnostic results rapidly. Gram stain of the CSF can be useful as a rapid diagnostic tool, especially in patients with meningococcal meningitis. Approximately 50% of these patients will have a positive Gram stain. In cases of meningococcemia without overt meningitis, the CSF Gram stain will be positive in < 25% of patients. Recent studies have suggested that Gram stain analysis of punch biopsy or needle aspiration of hemorrhagic skin lesions in meningococcal sepsis without clinical evidence of meningitis can lead to rapid diagnosis; approximately 70% of such skin lesions were positive. The tinctorial results for punch biopsy specimens were not affected by antibiotics, because Gram staining gave positive results up to 45 hours after antibiotic therapy was started. Cultures of these biopsies or aspirates also were useful diagnostically for as long as 13 hours after instituting antibiotic therapy. Detecting meningococcal capsular polysaccharide in CSF also can be used for rapid diagnosis; the test is most sensitive for the A and C polysaccharides and considerably less sensitive for serogroup B polysaccharide. In meningococcemia without clinically apparent meningitis, the antigen detection methods can be negative despite profound sepsis. Recently, polymerase chain reaction (PCR) has been demonstrated as a potentially rapid method for diagnosing CSF infection and serum. Further testing must be done to confirm the specificity and sensitivity of this technique.
As soon as the practitioner seriously considers the diagnosis of systemic meningococcal infection, therapy must be instituted within 30 minutes. The case must be considered a medical emergency. In 1933, sulfonamides revolutionized the treatment of meningococcal infection. Before antibiotics, almost all cases resulted in death or profound morbidity with complications. Early administration of appropriate antibiotics is the cornerstone of successful management. Thorough organization and documentation of patient management are crucial. Blood cultures should be drawn immediately, an intravenous line established, and penicillin G (chloramphenicol can be used in penicillin-allergic patients) infused over 15 minutes (Table 281-2) . No evidence exists that release of endotoxin which may occur after administering antibiotics adversely effects outcome; therefore, this should not be a reason to delay onset of therapy. Antibiotics should not be delayed while the spinal tap is done. If the spinal tap is obtained within 45 minutes of the antibiotics, there will be limited reduction in positive CSF cultures and no modification of the CSF cytology or hypoglycoracchia. In two recent studies in Great Britain, high-dose penicillin administered before hospitalization to patients suspected of having meningococcal infection greatly reduced morbidity and mortality.
Patients with meningococcal sepsis frequently have multisystem involvement. If the patient is not at a tertiary care hospital, the stabilized patient possibly should be transferred to such a facility. The patient should be cared for in intensive care with continuous monitoring and careful management of fluids and electrolytes. Because of fluid loss due to fever and the increased vascular permeability, fluids, electrolytes, and colloid should be administered and blood pressure, urine output, and cardiac function monitored. A number of studies indicate that meningococcal sepsis is associated with cardiac failure; thus attention must be paid to cardiac status during the sepsis and shock state. Treatment of heart failure may be indicated. Vasoactive agents such as dopamine may be necessary to maintain blood pressure and tissue perfusion. Because DIC occurs frequently, monitoring clotting parameters such as platelets, fibrin, and fibrin split products is a crucial part of management. Correcting this problem is a key to survival and reduced morbidity and may require the advice of one skilled in managing hemorrhagic disorders. Studies have shown recently that fresh-frozen plasma may negatively influence outcome in systemic meningococcal infections; careful consideration should be given to this conclusion before administration. Recent studies have suggested that exchange transfusion may improve the survival rate among patients with fulminant meningococcal sepsis. The beneficial effect is most likely not based on the elimination of endotoxin. One of the most serious causes of morbidity in fulminant meningococcal sepsis is skin necrosis and loss of distal digits and limbs. It has been suggested that epidural sympathetic blockade may preserve the lower extremities of such patients. Skin necrosis can be managed by debridement, grafting, and nutritional support after the patient has been stabilized.
Penicillin remains the cornerstone of therapy. The meningococcus is sensitive to a wide range of antibiotics, including third-generation cephalosporins and quinolones. Ampicillin is equivalent to penicillin G and can be used if there is uncertainty about the etiologic diagnosis at the time that therapy is instituted. Recent reports from southern Europe (primarily Spain and Greece) of the isolation of penicillin-resistant meningococci could have ominous consequences if epidemics occur due to these organisms. In Spain, the prevalence of N. meningitidis isolates that are moderately susceptible to penicillin and ampicillin has increased to almost 50%. These strains do not produce beta-lactamase. In these strains, the basis of meningococcal resistance to penicillin is alteration in a group of inner membrane enzymes, the penicillin-binding proteins (PBP s), which are
| Antibiotic | Dosage |
|---|---|
| Penicillin G | 300,000 units/kg/d IV, up to 24 million units/day |
| Ampicillin | 150-200 mg/kg/d IV, up to 12 grams/day |
| Ceftriaxone | 2 grams/day IV |
| Chloramphenicol | For use in penicillin-allergic patients, 100 mg/kg/day IV, up to 4 grams/d |
Individuals with deficiencies in complement components appear to be uniquely susceptible to meningococcal infection. In properdin-deficient patients, fulminant meningococcal sepsis is a frequent cause of death. Families of such individuals should be investigated for a history of sudden septic death in relatives. Such families should be managed closely and undergo vaccination with the tetravalent meningococcal vaccine.
In patients with the late complement component deficiencies (LCCD), meningococcal infection occurs in older individuals (mean age 17) and tends to be milder (mortality ~ 2%) and caused by less common serogroups (serogroup Y and W-135) than occurs in the general population. LCCD patients respond normally to meningococcal capsular polysaccharide vaccine with the development of antibodies that are functional in both complement-dependent bactericidal assays and opsonophagocytic assays. These patients have a more rapid decline in capsular antibody than that seen in normal individuals, suggesting that LCCD patients are critically dependent on capsular antibody for protection against meningococcal disease. Vaccination, probably on a recurrent basis, is an important component in preventing meningococcal disease in LCCD patients.
Chronic meningococcal sepsis, which is indistinguishable from the gonococcal dermatitis-arthritis syndrome, can occur. These patients have typical painful skin lesions usually on the extremities with migratory polyarthritis and tenosynovitis (see Ch. 239) . This form of meningococcal sepsis can persist for weeks if untreated. This syndrome responds promptly to antibiotic therapy.
Pneumonia due to N. meningitidis has been reported since the 1930 s. In a recent study of community-acquired infections in Finland, N. meningitidis was implicated as the etiologic agent in 6%. Epidemic pneumonia due to serogroup Y strains has occurred at a military training center. Patients presented with chills, chest pain, and cough; rales and fever occurred in almost all patients, and infections were frequently multilobar (40%). The incidence of sepsis associated with these infections is quite low, and the diagnosis is usually made with transtracheal aspirations. There was no mortality, and all patients responded well to treatment with penicillin.
Pericarditis is usually associated with infections due to N. meningitidis serogroup C. It has been reported associated with meningococcemia and as an isolated syndrome. Patients can present with chest pain and signs of tampanode, but relatively asymptomatic disease can occur with detection made by sonography. Treatment with antibiotics and removal of the pericardial fluid usually results in a successful outcome. Pericarditis can occur in patients convalescing from meningococcal sepsis. It should be considered if fever and shortness of breath on minimal exertion occur when the patient is recovering from meningococcal sepsis. Echocardiogram will result in rapid diagnosis of this complication of infection. In convalescent patients, antibiotic therapy should be continued, and pericardiocentesis may be indicated. There is no evidence that steroids or anti-inflammatory agents have a role in management.
Meningococci have been isolated from the urethra and can cause clinical urethritis. In a recent study of over 5000 urethral cultures from homosexual men, the isolation rate was 0.2%, compared with 4.7% for N. gonorrhoeae among the same population. Eight of these patients had symptomatic urethritis. In the same study, there were no isolates among almost 9000 urethral cultures from heterosexual males or almost 16,000 cervical cultures. This study strongly suggests that there is an association between orogenital sex and urethral acquisition of the meningococcus. Meningococcal urethritis has been managed successfully with penicillin and/or tetracycline.
The observation that sulfonamides could clear the nasopharynx carriage of meningococci for weeks after a single day of therapy led to the concept of chemoprophylaxis for preventing secondary infection in hyperepidemic situations. However, because of the profligate use of sulfonamides for chemoprophylaxis in the 1950 s, the meningococcus developed resistance to these agents, and in 1963 epidemics were occurring on Vietnamese military bases. Military studies to find alternatives to sulfonamides resulted in an effective anticapsular vaccine in 1971 and use of minocycline and rifampin for chemoprophylaxis. Eradication of the carrier state in intimate contacts of index cases with chemoprophylaxis is an effective way to prevent secondary cases. The concept behind successful prophylaxis is the use of short-term antibiotic therapy (one to two doses) to achieve long-term (3- to 4-week) eradication of the meningococcus from the nasopharynx. Although physicians realize that prophylaxis is necessary, they fail to appreciate that specific antibiotics must be used for effective management. Penicillin, penicillin derivatives, and first- and second-generation cephalosporins are not effective for prophylaxis because they do not eradicate the meningococcus during the short courses of therapy. Rifampin and ceftriaxone have been shown to be effective agents for prophylaxis (Table 281-3) . Recently, quinoline derivatives also have been shown to be effective for chemoprophylaxis.
The immunologically different meningococcal serogroups were identified in the early 20th century, which led to the use of capsular-specific serotherapy to manage meningococcal infection before effective chemotherapy was developed. The ability of these polysaccharides to evoke a protective immune response is the basis for the meningococcal vaccines. An effective tetravalent capsular polysaccharide vaccine (containing A, C, Y, and W-135 polysaccharides) is available to prevent meningococcal infections in people older than age 2. Over 100 million doses of this vaccine have been given worldwide, with no serious side effects reported. Tetravalent vaccine should be administered to all intimate contacts of index cases at the start of chemoprophylaxis. This vaccine also has been used effectively in the U.S. military and in aborting epidemics caused by serogroup strains represented in the vaccine. A principal drawback of the vaccine is the lack of immunogenicity in children younger than age 2, limiting widespread application of the current vaccine in countries with recurrent epidemic infections. These children respond poorly to polysaccharides for reasons that are not clearly understood. Recent successes in vaccinating young children with H. influenzae polysaccharide conjugated to proteins suggest that a similar strategy might be useful for meningococcal polysaccharides. Such a vaccine is not currently available.
In addition, the lack of an antigen that can elicit protection against meningococcal serogroup B infection has limited the vaccine s use. The serogroup B polysaccharide is a poor immunogen, even in adults, perhaps because it resembles "self" antigens. Vaccine development in serogroup B strains has focused on other meningococcal subcapsular surface antigens (proteins and possibly lipopolysaccharide). These vaccines are based on serotypic protein antigens, and the vaccine must be tailored to the serotype of the specific meningococcal strain causing the epidemic. A recent noncapsular serogroup B vaccine has been tested in an epidemic in Brazil, and the results indicate that there was vaccine efficacy in children older than age 2.
| Antibiotic | Dosage |
|---|---|
| Rifampin | Adults, 600 mg q12h for 2 days. Children, 10 mg/kg q12h for 2 days. |
| Ceftriaxone | Single 250-mg dose for adults, single 125-mg dose for children. Limited experience and at present should only be used if rifampin is contraindicated. |
| Ofloxacin | 400 mg as a single dose. Limited experience and should be used only if rifampin is contraindicated. No experience in children. |
Apicella MA: Neisseria meningitidis. In Mandell GL, Douglas RG, Bennett JE (eds.): Principles and Practices of Infectious Diseases, New York, Churchill Livingstone, 1990, pp 1600-1612. Complete description of the biology and pathogenesis of N. meningitidis infection.
Cartwright K, Reilly S, White D, et al.: Early treatment with parenteral penicillin in meningococcal disease. Br Med J 305:143, 1992. Description of the improved outcome in meningococcal infection if therapy is instituted early.
Densen P: Complement deficiencies and meningococcal disease. Clin Exp Immunol 86(suppl 1):57, 1991. Review of the role of complement deficiencies and susceptibility to meningococcal infection.
Durand ML, Calderwood SB, Weber DJ, et al.: Acute bacterial meningitis in adults. N Engl J Med 328:21, 1993. Recent review of bacterial meningitis in an American hospital.
Gilja HO, Halstensen A, Digranes A, et al.: Single-dose Ofloxacin to eradicate tonsillopharyngeal carriage of Neisseria meningitidis. Antimicrob Agents Chemother 37:2024, 1993. This article demonstrates the usefulness of quinolones for meningococcal prophylaxis.
McGee ZA, Baringer JR: Acute meningitis. In Mandell GL, Douglas RG, Bennett JE (eds.): Principles and Practices of Infectious Diseases. New York, Churchill Livingstone, 1990, pp 741-761. Detailed discussion of the differential diagnosis and management of bacterial meningitis.
Ni H, Knight AL, Cartwright K, et al.: Polymerase chain reaction for diagnosis of meningococcal meningitis. Lancet 340:1432, 1992. Description of PCR to diagnosis meningococcal infection from clinical materials.
Schwartz B: Chemoprophylaxis for bacterial infections: Principles of and application to meningococcal infection. Rev Infect Dis 13(suppl 2):S170, 1991. Review of the concepts and strategies in chemoprophylaxis of meningococcal infection; studies validating using ceftriaxone.
The name Haemophilus is derived from the Greek nouns haima, meaning "blood," and philos, meaning "lover." Haemophilus species primarily infect the respiratory tract, skin, or mucous membranes of humans. From these sites, organisms can invade to cause bacteremia, meningitis, epiglottitis, endocarditis, septic arthritis, or cellulitis.
The Haemophilus species are small, non-motile, aerobic or facultative anaerobic, pleomorphic, gram-negative bacilli. The prototype of this genus, H. influenzae, was originally recovered from patients with influenza by Richard Pfeiffer in 1893, and it was considered the etiology of that disease for many years. The growth requirements of important Haemophilus species are summarized in Table 282-1 . Primary isolation of Haemophilus species is best accomplished on chocolate agar medium in a CO2 -enriched atmosphere.
H. influenzae is the most important pathogen in this genus. It can be recovered from sites where it colonizes, such as the nasopharynx and upper respiratory tract, and from sites where it causes disease, such as the blood, cerebrospinal fluid (CSF), sputum, pleura, middle ear, and joints (Table 282-2) .
H. influenzae consists of encapsulated (typable) and nonencapsulated (nontypable) strains. The former are responsible for most of
| Species | X | V | CO2 | Hemolysis |
|---|---|---|---|---|
| H. influenzae | + | + | - | - |
| H. influenzae, b. aegyptius | + | + | - | - |
| H. parainfluenzae | - | + | - | - |
| H. aphrophilus | + * | - | + | - |
| H. paraphropilus | - | + | + | - |
| H. haemolyticus | + | + | - | + |
| H. parahaemolyticus | - | + | - | + |
| H. ducreyi | + | - | - |
+
|
| Species | Normal Flora | Associated Disease(s) |
|---|---|---|
| H. influenzae | Nasopharynx | Meningitis |
|
|
Upper respiratory tract | Epiglottitis |
|
|
|
Sinusitis |
|
|
|
Otitis |
|
|
|
Pneumonia |
|
|
|
Cellulitis |
|
|
|
Arthritis |
|
|
|
Osteomyelitis |
|
|
|
Obstetric infections |
|
|
|
Endocarditis |
| H. influenzae b. aegyptius | No | Purulent conjunctivitis |
|
|
|
Brazilian purpuric fever |
The capsules of H. influenzae are important virulence factors that inhibit opsonization, clearance, and intracellular killing of the organisms. H. influenzae type b, the most common cause of meningitis in infancy and childhood worldwide, contains a pentose capsular polysaccharide consisting of polyribosyl-ribitol phosphate (PRP). Other serotypes contain hexose polysaccharides. It is believed that H. influenzae type b is more virulent than other serotypes because it is highly resistant to clearance once bacteremia has been initiated.
Fimbriae are important virulence factors that enhance the adherence of H. influenzae to mucosal surfaces. Both typable and nontypable H. influenzae isolates contain fimbriae. The lipo-oligosaccharides (LOS s) of H. influenzae also contribute to their virulence. LOS s appear to play a crucial role in facilitating the survival of H. influenzae on mucosal surfaces within the nasopharynx and in initiating invasive disease (bloodstream invasion) from these sites.
Outer membrane proteins (OMP s) also serve as virulence factors in H. influenzae disease. At least 15 different H. influenzae OMP s have been identified. One of these OMP s (P2, 39 to 40 kDa) functions as a porin, and others are associated with iron binding. Successful scavenging of iron within the human host is crucial for H. influenzae to multiply.
Antibodies have been recognized for decades as an important part of the host defenses against H. influenzae diseases. The classic studies of Fothergill and Wright (1933) demonstrated that most cases of H. influenzae meningitis occurred in children during the ages between their losing passively acquired maternal antibodies and developing active humoral immunity to the organism. It is now recognized that these protective antibodies function primarily to opsonize and facilitate H. influenzae clearance rather than to directly kill virulent organisms.
Complement is also an essential component of the host defenses against some H. influenzae diseases. Children with congenital deficiencies of C2, C3, and Factor I have an increased incidence of H. influenzae infections. Patients who lack a functional spleen or who have undergone splenectomy also are at risk for developing overwhelming infection with H. influenzae type b.
The precise prevalence and incidence of H. influenzae infections are unknown. This organism can be detected frequently in the nasopharynx of both children and adults. Between 3 and 5% of infants harbor H. influenzae type b in their nasopharynx. Nontypable H. influenzae can be detected in the nasopharyngeal culture of > 70% of young children. Infections, however, occur in only a small fraction of colonized patients. The risk of infection in nonimmune household contacts of a patient with invasive H. influenzae disease is approximately 600-fold greater than the risk in the age-adjusted general population.
H. influenzae type b was the most common cause of meningitis in young children before effective vaccines were introduced in the 1980 s. Vaccination dramatically reduced the incidence of this infection in young children. In a recent population-based study in Atlanta, Ga., over a 1-year period, invasive H. influenzae disease occurred
Patients with human immunodeficiency virus (HIV) infection are at increased risk for H. influenzae infection. Rates of invasive H. influenzae infection among men aged 20 to 49 with HIV infection and the acquired immunodeficiency syndrome (AIDS) were 14.6 and 79.2 per 100,000, respectively. The majority of these infections were caused by nontypable H. influenzae strains, although in a second study, 10 of 15 bacteremic H. influenzae type b infections observed in adults occurred in patients at risk for HIV infection, and AIDS was documented in 7 of these patients.
Other factors also increase the risk of H. influenzae infections. These include globulin deficiencies, sickle cell disease, splenectomy, malignancy, pregnancy, CSF leaks, head trauma, alcoholism, and race. Eskimo, Navajo, and Apache children have H. influenzae type b infection rates which are significantly greater than those in comparable non-native populations. In addition, day care attendance, crowding, presence of siblings, previous hospitalizations, and previous otitis media have been shown to increase the risk H. influenzae type b disease in young children, while breast-feeding decreases this risk.
H. influenzae is spread from person to person. Colonization of an individual depends on the virulence factors described above. When H. influenzae translocates across damaged epithelial cells, it invades the blood stream. Encapsulated organisms, particularly H. influenzae type b, are especially resistant to clearance.
The central nervous system (CNS) is primarily invaded via the choroid plexus. H. influenzae and its LOS s initiate an inflammatory process within the subarachnoid which is typical of pyogenic meningitis. This process can be transiently accelerated by using antibiotics that liberate LOS s from organisms if corticosteroids are not administered simultaneously.
H. influenzae meningitis commonly occurs in children under age 5 and in adults with histories of skull trauma or CSF leaks. H. influenzae type b strains cause the overwhelming majority of these. A review of 493 episodes of acute bacterial meningitis in adults over a 27-year period showed that 19 cases (4%) were due to H. influenzae.
H. influenzae meningitis is clinically indistinguishable from other forms of acute bacterial meningitis. Most patients with H. influenzae meningitis have CSF white blood counts > 1000 per cubic millimeter and hypoglycorrachia. The CSF Gram stain shows pleomorphic gram-negative bacilli in 60 to 70% of untreated cases. In some patients, however, the bipolar staining may result in a mistaken diagnosis of pneumococcal meningitis. Thus Gram stain is neither sensitive nor specific for diagnosing H. influenzae meningitis.
A diagnosis of H. influenzae type b meningitis can be rapidly and reliably established by detecting PRP capsular antigens in CSF. The diagnosis can be established in most cases even when antibiotics have been given before CSF is obtained.
H. influenzae type b is the most common cause of acute epiglottitis in both children and adults. Epiglottitis is a life-threatening infection in children which usually occurs in patients younger than age 5. The symptoms are fever, drooling, dysphagia, and respiratory distress or stridor, which appear over the course of hours. In adults, fever, sore throat, dysphagia, and odynaphagia occur. Cervical tenderness and lymphadenopathy can be found at all ages. Laryngoscopy demonstrates a swollen, cherry-red epiglottis. However, this procedure should be avoided or undertaken only by experts, since it may precipitate an acute airway obstruction and thus make an emergency tracheotomy necessary. The diagnosis of acute epiglottitis is more safely confirmed by a lateral x-ray of the neck. The patient must be maintained in an upright position during this procedure, however, in order to avoid additional compromise of the airway. The etiology is usually established by blood culture. Cultures of the pharynx and other mucosal surfaces are less useful because H. influenzae may be part of the normal flora. A recent review suggests that while vaccination has effectively reduced the incidence of this disease in children, it is increasingly observed in adults.
H. influenzae is a common cause of pneumonia in both children and adults. Nosocomial infections, including ventilator-associated pneumonia, also can be caused by these organisms. The clinical features of H. influenzae pneumonia include fever, cough, and signs and radiographic findings of lobar consolidation. Parapneumonic effusions or empyema occur commonly in patients with H. influenzae pneumonia. Gram-negative bacilli in sputum suggest the diagnosis, but isolation of H. influenzae from sputum culture alone is inadequate to prove an etiology because of the high frequency with which this organism colonizes the respiratory tract. A diagnosis can be established by isolating H. influenzae from either the blood or pleural fluid.
Tracheobronchitis is a condition characterized by fever, cough, and purulent sputum that occurs in the absence of radiographic infiltrates suggestive of pneumonia. It frequently occurs in patients with known chronic lung disease. Blood cultures are rarely positive. A combination of pleomorphic gram-negative bacilli predominating in purulent sputum, antibody titers to H. influenzae that rise following infection, and the response, at least transiently, to treatment for H. influenzae infection strongly suggest this diagnosis.
H. influenzae and Staplylococcus pneumoniae are the most frequent bacterial isolates from antral punctures or surgical specimens of patients with acute purulent sinusitis. Most H. influenzae isolates are nontypable. While patients may respond initially to treatment directed against H. influenzae, the response is transient if sinus obstruction is not relieved. H. influenzae is not an important pathogen in patients with chronic sinusitis.
H. influenzae is the most frequent cause of otitis media in young children. Approximately 90% of the H. influenzae isolates obtained by tympanocentesis are nontypable; H. influenzae type b causes most of the remaining 10% of infections. Patients with otitis media may present with ear pain or irritability. Drainage can be present. An inflamed, opaque, bulging or perforated tympanic membrane is usually demonstrated. The etiology can be proven by Gram stain and culture of purulent fluid obtained by tympanocentesis. Otitis caused by H. influenzae type b may occur in association with bacteremia and meningitis.
H. influenzae type b is the cause of 5 to 15% of the cases of cellulitis in young children. Most of the infections occur on the face or neck. H. influenzae cellulitis is often described as causing a distinctive blue or violaceous discoloration of the skin. However, the fever, erythema, and tenderness observed may not be distinguishable from other causes. Diagnosis is established by culture of blood and/or tissue aspirates from the involved area.
H. influenzae causes primary bacteremia in both children and adults. In infants or children, occult meningitis or epiglottitis can be present. A rigorous clinical and laboratory evaluation is essential to avoid missing diagnoses of life-threatening focal infections in these patients. In adults, primary H. influenzae type b bacteremia often occurs in patients with underlying diseases such as lymphoma, leukemia, or alcoholism.
Pregnancy is associated with a significant risk for H. influenzae infection. In the Atlanta study, 7 of 47 adult H. influenzae invasive infections occurred in pregnant women.
H. influenzae type b is an important cause of primary bacterial pericarditis in children. It rarely causes this infection in adults; however, pericarditis can occur in association with pneumonia, probably as a result of contiguous spread of the infection.
H. influenzae is a very unusual cause of endocarditis, considering the frequency with which invasive disease occurs. Most infections occur in patients with pre-existing valvular heart disease. Because of its slow initial growth in blood culture media, the diagnosis of this infection may be delayed or missed. Patients with H. influenzae endocarditis are at high risk for arterial embolic phenomena.
H. influenzae type b is a common cause of septic arthritis in young children; it is rare in adults. H. influenzae type b arthritis is clinically indistinguishable from other cause of pyogenic arthritis.
Third-generation cephalosporins are currently considered to be the treatment of choice for serious H. influenzae infections, such as meningitis or epiglottitis. Treatment with ceftriaxone (adult dose: 1 gram IV every 12 hours) or cefotaxime (adult dose: 2 grams IV every 8 hours) should be started for patients with proven or suspected H. influenzae infection, and this should be continued at least until the full susceptibility data are available.
Ampicillin was considered to be the treatment of choice for all H. influenzae infections until the mid-1970 s. Since the first reports of ampicillin-resistant H. influenzae isolates in 1972, however, this problem has been increasing. At present, 30% of H. influenzae type b isolates and 15% of nontypable H. influenzae isolates are resistant to ampicillin. The majority contain a plasmid-mediated, R-factor enzyme (TEM-1) beta-lactamase, which can be detected rapidly in the laboratory. A small number of isolates, however, have altered penicillin-binding proteins. These proteins bind penicillin and other beta-lactam antibiotics poorly. As a consequence, the isolates may be resistant to some cephalosporins such as cefaclor, cefamandole, and cefuroxime in addition to ampicillin. Therefore, patients with proven or suspected H. influenzae infections should not be treated with ampicillin or with second-generation cephalosporins until susceptibilities to these antibiotics are proven. Chloramphenicol resistance also occurs in H. influenzae; resistance is caused by an inactivating enzyme, chloramphenical acetyl transferase. A small number of H. influenzae isolates are resistant to both ampicillin and chloramphenicol.
Amoxicillin can be used for otitis media in children because of the lower prevalence of beta-lactamases in nontypable H. influenzae isolates. Bactrim is also effective for most isolates. A combination of erythromycin and sulfisoxazole can be used in patients with documented penicillin allergy.
The first H. influenzae type b vaccines were licensed for use in the United States in 1985. These contained purified PRP antigens. However, postlicensing studies of PRP vaccines in the United States showed variable efficacy. The PRP vaccines elicit a type 2, thymus-independent B-cell response, generate few (if any) memory B cells, and fail to stimulate a response in neonates and infants.
Protein-conjugated PRP vaccines were developed to overcome the problem of the lack of immune response in the most susceptible infants and some young children. Several are now licensed for use in infants. At present, protein-conjugated PRP vaccines are recommended for use in all infants over age 2 months, but not earlier than age 6 weeks. However, all patient populations are not equally protected. Additional studies are necessary to determine the optimal vaccine preparations and dosage schedules for the infants at greatest risk for H. influenzae type b disease.
Antibiotic prophylaxis should be used for unimmunized household or day care contacts of a patient with invasive H. influenzae type b disease. Rifampin is the treatment of choice. It should be given in a dose of 10 mg per kilogram once daily for 4 days to neonates younger than 1 month, 20 mg per kilogram (up to a maximum of 600 mg) once daily for 4 days to older children, and 600 mg daily for 4 days to adults.
H. influenzae, biogroup aegyptius (Koch-Weeks bacillus) causes epidemic purulent conjunctivitis in children. This disease commonly occurs in hot climates or in the summer season. The infection causes conjunctival erythema, edema, mucopurulent exudate, and varying discomfort in the eyes. An unusually virulent clone of H. influenzae, biogroup aegyptius, causes an invasive infection called Brazilian purpuric fever (BPF). BPF is characterized by petechial or purpuric skin lesions and vascular collapse, which occur days to weeks after an initial episode of conjunctivitis in infants and children younger than 10 years. BPF is usually fatal.
H. parainfluenzae can be found as part of the normal flora of the mouth and pharynx (Table 282-3) . It is a rare cause of meningitis in children and an even rarer cause of meningitis in adults. It may cause dental infections or dental abscesses. Cases of brain abscess, epidural abscess, liver abscess, osteomyelitis, pneumonia, empyema, epiglottitis, peritonitis, septic arthritis, and septicemia caused by this organism have been reported. H. parainfluenzae also causes subacute endocarditis, often in young adults. Haemophilus species cause approximately 1% of cases of infective endocarditis in non-drug-abusing patients. H. parainfluenzae and H. aphrophilus (see below) are the species most frequently recovered from these patients. H. parainfluenzae forms
| Species | Normal Flora | Associated Disease(s) |
|---|---|---|
| H. parainfluenzae | Mouth and pharynx | Endocarditis, brain abscess, liver abscess, pneumonia, epiglottitis, arthritis, osteomyelitis |
| H. aphrophilus | Mouth | Endocarditis, brain abscess, periodontal abscess, osteomyelitis |
| H. paraphropilus | Mouth and pharynx | Endocarditis, brain abscess, liver abscess |
| H. haemolyticus | Nasopharynx | ? |
| H. parahaemolyticus | Mouth and pharynx | Endocarditis, empyema of gallbladder, ? pharyngitis |
| H. ducreyi | No | Chancroid |
H. aphrophilus can be found as part of the normal oral flora (see Table 282-3) . Like H. parainfluenzae, H. aphrophilus grows very slowly on primary isolation from blood cultures. It frequently causes bulky vegetations, and arterial emboli are common. H. aphrophilus is also a rare cause of brain abscess, periodontal abscess, meningitis, osteomyelitis, and suppurative pulmonary infections. Ampicillin or ampicillin plus an aminoglycoside should be used to treat infections.
H. paraphrophilus can be found as part of the normal flora of the mouth and pharynx (see Table 282-3) . H. paraphrophilus is a rare cause of endocarditis, and arterial emboli have been observed in 50% of the cases H. paraphrophilus endocarditis. It is also a rare cause of brain abscess and liver abscess. Ampicillin is the treatment of choice for this infection.
H. parahaemolyticus is an important pathogen in domestic animals, causing porcine pleuropneumonia. The organism can be found in the human mouth and pharynx. It is a rare cause of human subacute endocarditis and of empyema of the gallbladder (see Table 282-3) . H. parahaemolyticus has been isolated from throat cultures of patients with pharyngitis. Animal isolates of H. parahaemolyticus are sensitive to tetracycline and sulfa drugs. There is insufficient information about human isolates to permit recommendations for therapy.
Adams WG, Keaver KA, Cochi SL, et al.: Decline of childhood Haemophilus Influenzae type b (Hib) disease in the Hib vaccine era. JAMA 269:221, 1993. Shows that, in children < age 5, there was a 71 to 82% reduction in H. influenzae type b meningitis in the year following licensing of the Hib conjugate vaccines in the U.S.
Centers for Disease Control and Prevention. Recommendations for use of the Haemophilus b conjugate vaccines and a combined diphtheria, tetanus, pertussis, and Haemophilus b vaccine. Recommendations of the Advisory Committee on Immunization Practices (ACIP). MMWR 42 (No.RR-13):1, 1993. Contains recommendations for use of Haemophilus b conjugate vaccines for infants beginning at age 2 months (but not earlier than age 6 weeks); also describes the safety, immunogenicity, efficacy, adverse reactions, contraindications, and precautions for vaccine use.
Durand ML, Calderwood SB, Weber DJ, et al.: Acute bacterial meningitis in adults: A review of 493 episodes. N Engl J Med 328:21, 1993. Summarizes data from a large series of adults with acute bacterial meningitis seen over 27 years. H. influenzae caused acute bacterial meningitis in 19 (4%) of the adults. Thirteen of these patients had community-acquired infections and six developed nosocomial H. influenzae meningitis after neurosurgery.
Farley MM, Stephens DS, Brachman PS, et al.: Invasive Haemophilus influenzae disease in adults. Ann Intern Med 116:806, 1992. A population-based study showing that 47 cases of invasive H. influenzae disease occurred in adults in metropolitan Atlanta from December 1988 through May 1990 (incidence 1.7 per 100,000 adults per year).
Fothergill LD, Wright J: Influenzal meningitis: The relation of age incidence to the bactericidal power of blood against the causal organism. J Immunol 24:273, 1993. The classic study showing that H. influenzae meningitis occurs in children during the ages between the loss of passively acquired maternal antibodies and the development of active immunity to this organism.
Liu VC, Smith A: Molecular mechanisms of Haemophilus influenzae pathogenicity. Antibiot Chemother 45:30, 1992. Reviews the virulence factors that have been associated with invasive H. influenzae infections, including the capsule, outer membrane proteins, fimbria, and lipo-oligosaccharides of the organism.
Moxon ER: Pathogenesis of invasive Haemophilus influenzae disease. Molecular basis of invasive Haemophilus influenzae type b disease. J Infect Dis 165(Suppl 1): S77, 1992. Studies of mutant strains of H. influenzae have clarified the mechanisms of colonization, mucosal damage, translocation, and multiplication of the organism within the vascular system to reach concentrations necessary for CNS invasion.
Steinhart R, Reingold AL, Taylor F, et al.: Invasive Haemophilus influenzae infection in men with HIV infection. JAMA 268:3350, 1992. A population-based study shows that the rates of invasive H. influenzae among men aged 20 to 49 with HIV infection without AIDS and with AIDS were 14.6 and 79.2 in 100,000 respectively.
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