Keywords
bacterial meningitis, brain abscess, subdural empyema, epidural abscess, spinal epidural abscess, septic intracranial thrombophlebitis, venous sinus thrombosis
Acute bacterial infections of the central nervous system (CNS) include meningitis, brain abscess, subdural empyema, epidural abscess, and septic intracranial thrombophlebitis. The etiology, clinical presentation, diagnosis, and treatment of each of these bacterial infections are discussed in this chapter.
Acute Bacterial Meningitis
Bacterial meningitis is an acute purulent infection in the subarachnoid space, associated with an inflammatory reaction in the brain parenchyma and cerebral vasculature. During its treatment, not only must the meningeal pathogen be eradicated, but also the neurologic complications resulting from an often robust inflammatory reaction must be anticipated and managed. The most common causative organisms of bacterial meningitis are Streptococcus pneumoniae , Neisseria meningitidis , Listeria monocytogenes , group B streptococci, and gram-negative bacilli. The current epidemiology of acute bacterial meningitis, the best diagnostic tests to perform on cerebrospinal fluid (CSF), the use of dexamethasone as adjunctive therapy, and the present recommendations for the use of chemoprophylaxis and vaccination are discussed here.
Etiology
The most common etiologic organisms of acute bacterial meningitis in children and adults are S. pneumoniae and N. meningitidis. Prior to the routine use of the Haemophilus influenzae type b conjugate vaccine, H. influenzae type b was the most common cause of bacterial meningitis in children in the United States. This vaccine has dramatically reduced the incidence of meningitis in infants and children. H. influenzae type b remains an important cause of bacterial meningitis in older adults, immunocompromised patients, and patients with chronic lung disease, splenectomy, leukemia, or sickle cell anemia. Children too young to have completed a primary H. influenzae type b vaccination course are also at risk.
S. pneumoniae is the most common cause of meningitis in adults older than 18 years. A number of predisposing conditions increase the risk of pneumococcal meningitis, the most common of which is pneumonia. Acute and chronic otitis media, alcoholism, diabetes mellitus, splenectomy, hypogammaglobulinemia, and head trauma with basilar skull fracture and CSF rhinorrhea are also important risk factors. Approximately 44 percent of clinical isolates of S. pneumoniae in the United States have either intermediate or high levels of resistance to penicillin, and an increasing incidence of isolates are resistant to the third-generation cephalosporins, including cefotaxime and ceftriaxone. It is therefore imperative that all isolates of S. pneumoniae be tested for penicillin and cephalosporin susceptibility and that a repeat lumbar puncture, if safe, be performed 48 hours into antimicrobial therapy in cases of penicillin-resistant pneumococcal meningitis to document microbiologic cure.
N. meningitidis is the second most common cause of meningitis in adults, but has a predilection for those younger than age 60. The quadrivalent (serogroups A, C, W-135, and Y) meningococcal glycoconjugate vaccine is recommended for all 11- to 18-year olds. The vaccine does not provide immunity to N. meningitidis serogroup B, which is of concern as serogroups B and C cause the majority of cases of meningococcal meningitis in the United States and Europe.
The Enterobacteriaceae ( Proteus species, Escherichia coli , Klebsiella species, Serratia species, and Enterobacter species) cause meningitis in older adults; in adults with underlying diseases such as cancer, diabetes, alcoholism, congestive heart failure, chronic lung disease, and hepatic or renal dysfunction; and in neurosurgical patients.
L. monocytogenes is a cause of meningitis in individuals with impaired cell-mediated immunity from older age (adults greater than 60 years), organ transplantation, pregnancy, malignancy, chronic illness, or immunosuppressive therapy. The routine use of trimethoprim-sulfamethoxazole as a prophylactic agent for the prevention of Pneumocystis carinii pneumonia in patients with the acquired immunodeficiency syndrome (AIDS) has the added benefit of reducing the risk of L. monocytogenes infection including meningitis.
Staphylococcus aureus and coagulase-negative staphylococci are the predominant organisms causing meningitis as a complication of invasive neurosurgical procedures, particularly shunting procedures for hydrocephalus and with subcutaneous Ommaya reservoirs or following lumbar puncture for the administration of intrathecal chemotherapy.
Streptococcus agalactiae , or group B streptococcus, is a leading cause of bacterial meningitis and sepsis in neonates and is increasingly recognized in two groups of adults: puerperal women and patients with serious underlying diseases.
Clinical Presentation
Fever, headache, and stiff neck constitute the classic triad of symptoms and signs of bacterial meningitis. Patients are also typically lethargic or stuporous, and the level of consciousness may deteriorate rapidly. Nausea, vomiting, and photophobia are common complaints which often reflect elevated intracranial pressure (ICP). Seizure activity occurs in approximately 40 percent of patients, typically either at the onset or within the first few days of the illness.
A stiff neck, or meningismus, is the pathognomonic sign of meningeal irritation. Meningismus is present when the neck resists passive flexion. The Kernig and Brudzinski signs are classic signs of meningeal irritation, although their sensitivity is relatively low. Kernig sign is elicited with the patient in the supine position; the thigh is flexed on the abdomen, with the knee flexed. Attempts to passively extend the leg elicit pain when meningeal irritation is present. The Brudzinski sign is elicited with the patient in a supine position and is positive when passive flexion of the neck results in spontaneous flexion of the hips and knees.
Increased ICP is an expected complication of bacterial meningitis and is the major cause of obtundation and coma. The most common signs of increased ICP in bacterial meningitis are an altered level of consciousness and papilledema. Cerebral arteritis and septic venous thrombosis of the cerebral dural sinuses and cortical veins are also complications of bacterial meningitis and present as focal neurologic deficits or with new-onset seizure activity.
The rash of meningococcemia begins as a diffuse erythematous maculopapular rash resembling a viral exanthem, but the lesions rapidly become petechial. This rash can be differentiated from the rash of a viremia in that petechiae are found on the trunk and lower extremities in meningococcemia. Petechiae may also be found in the mucous membranes and conjunctiva and occasionally on the palms and soles. Other infectious diseases that may manifest with a petechial, purpuric, or erythematous maculopapular rash resembling that of meningococcemia include enteroviral meningitis, Rocky Mountain spotted fever, West Nile virus encephalitis, bacterial endocarditis, echovirus type 9 viremia, and, more rarely, pneumococcal or H. influenzae meningitis.
Diagnosis
The diagnosis of bacterial meningitis is made by examination of the CSF. The necessity of neuroimaging prior to lumbar puncture has been debated for years. Neuroimaging prior to lumbar puncture should be performed in any patient with an altered level of consciousness, papilledema, focal neurologic deficit, an immunocompromised state, or new-onset seizure activity. When the clinical presentation is suggestive of bacterial meningitis, blood cultures should be obtained and dexamethasone and empiric antimicrobial therapy initiated immediately. If the patient is being treated with antibiotics, there is no risk in delaying lumbar puncture until after neuroimaging has been performed. Antibiotic therapy for several hours prior to lumbar puncture does not alter the CSF white blood cell (WBC) count or glucose concentration enough to obscure the diagnosis of bacterial meningitis, and it is not likely to sterilize the CSF enough to prevent the isolation of a microorganism on Gram stain or in culture.
The classic CSF abnormalities in bacterial meningitis are: (1) an increased opening pressure, (2) a pleocytosis of polymorphonuclear leukocytes (10 to 10,000 WBCs/mm 3 ), (3) a decreased glucose concentration (<45 mg/dl or CSF/serum glucose ratio of<0.31), and (4) an increased protein concentration. A CSF sample should be analyzed, using Gram stain and bacterial culture. The Gram stain is positive in 70 to 90 percent of untreated cases. Cerebrospinal fluid PCR assays have been developed to detect bacterial nucleic acid in CSF. A 16S rRNA conserved sequence broad-based bacterial PCR can detect small numbers of viable and nonviable organisms in the CSF. When the broad-range PCR is positive, a PCR that uses specific bacterial primers to detect the nucleic acid of S. pneumoniae , N. meningitidis , E. coli , L. monocytogenes , H. influenzae , and S. agalactiae can be performed to identify the responsible organism. It is anticipated that this broad-range PCR may eventually be used more commonly to exclude the diagnosis of bacterial meningitis. The latex particle agglutination (LA) test for the detection of bacterial antigens of S. pneumoniae , N. meningitidis , H. influenzae type b, group B streptococcus, and E. coli K1 strains in CSF is useful for making a diagnosis of bacterial meningitis in patients who have been pretreated with oral or parenteral antibiotics and in whom Gram stain and CSF culture are negative; it is being replaced by PCR-based assays. The LA test has a specificity of 96 percent for S. pneumoniae and 100 percent for N. meningitidis. It has a sensitivity of 69 to 100 percent for the detection of S. pneumoniae in CSF and a sensitivity of 33 to 70 percent for the detection of bacterial antigens of N. meningitidis in CSF. A negative LA test for bacterial antigens does not exclude bacterial meningitis, and this test is therefore not recommended for deciding whether to continue or discontinue empiric antibiotic therapy. The Limulus amebocyte lysate assay is a rapid diagnostic test for the detection of gram-negative endotoxin in CSF to make a diagnosis of gram-negative bacterial meningitis. This test is reported to have a sensitivity of 99.5 percent and a specificity of 86 to 99.8 percent, but it is not routinely available. In clinical practice, when bacterial meningitis is a possibility, most physicians treat with empiric therapy until the results of bacterial cultures are negative.
If there are petechial skin lesions, biopsies should be performed. The rash of meningococcemia results from the dermal seeding of organisms with vascular endothelial damage, and biopsy may reveal the organism on Gram stain.
Lumbar puncture should be performed with a 22- or 25-gauge needle, and a minimal amount of CSF removed for analysis. Approximately 6 ml of CSF is typically sufficient to obtain a cell count, determine glucose and protein concentrations, and analyze the sample using Gram stain, culture, and PCR or LA methods. An additional 1 ml of CSF can be sent for herpes simplex virus (HSV) DNA since HSV-1 encephalitis is the leading disease in the differential diagnosis of bacterial meningitis. The result of CSF RT-PCR for enteroviruses is often available within hours and, as enteroviruses are the most common viral cause of meningitis, a CSF RT-PCR should usually be sent in patients suspected of having meningitis.
Differential Diagnosis
HSV encephalitis is an important consideration in the differential diagnosis of bacterial meningitis, and arthropod-borne viral encephalitis should be considered during the summer and early fall months while mosquitoes are biting. Focal intracranial mass lesions and subarachnoid hemorrhage also need to be included in the differential diagnosis when approaching patients with suspected meningitis.
Herpes Simplex Virus Encephalitis
The clinical presentation of HSV encephalitis (discussed in detail in Chapter 43 ) often includes hemicranial headache, fever, behavioral abnormalities, focal or generalized seizure activity, and focal neurologic deficits (e.g., dysphasia, hemiparesis with greater involvement of the face and arm, and superior field defects). The symptoms of HSV encephalitis typically evolve over several days, and the presentation is often less acute than bacterial meningitis. In patients with HSV encephalitis, fluid-attenuated inversion recovery (FLAIR), T2-, and diffusion-weighted magnetic resonance imaging (MRI) sequences demonstrate lesions in the medial and inferior temporal lobe extending into the insula. The absence of an abnormality on MRI 48 hours after symptom onset should prompt consideration of another diagnosis. There is a distinctive electroencephalographic (EEG) pattern in HSV encephalitis, consisting of periodic, stereotyped complexes from one or both temporal areas that occur at regular intervals of 1 to 2 seconds and are typically observed between day 2 and day 15 of the illness. Examination of the CSF reveals an increased opening pressure, a lymphocytic pleocytosis of 5 to 500 cells/mm 3 , a mild to moderate elevation in the protein concentration, and a normal or mildly decreased glucose concentration. There may be red blood cells or xanthochromia, findings that reflect the hemorrhagic nature of the encephalitis but are neither sensitive nor specific markers of the disorder. Results of CSF viral cultures for HSV-1 are almost always negative. The PCR is typically positive within 72 hours of symptom onset and then declines in sensitivity after the first week. If an initial CSF HSV PCR is negative within the first 72 hours of symptoms and HSV remains a major diagnostic consideration, the CSF should be resampled as the initial result may be a false negative. Cerebrospinal fluid and serum samples can also be sent for HSV IgG antibody titers; antibodies to HSV appear in the CSF approximately 8 to 12 days after the onset of symptoms and can be detected for at least 30 days. A serum to CSF HSV-1 antibody ratio of less than 20 to 1 is considered diagnostic of intrathecal synthesis of antibodies and HSV encephalitis in the appropriate clinical context.
Arthropod-Borne Virus Encephalitis
During the summer and early fall months when mosquitoes are active, arthropod-borne viral encephalitis (see Chapter 43 ) should be included in the differential diagnosis of patients with meningitis. In the United States, the La Crosse virus, the St. Louis encephalitis virus, and the West Nile virus are the most common causes of arthropod-borne viral encephalitis. Eastern equine encephalitis virus causes the most severe arthropod-borne viral encephalitis, and the fatality rate is high. Japanese encephalitis virus is the most common cause of arthropod-borne human encephalitis worldwide. Venezuelan equine encephalitis virus is endemic in South America and is a rare cause of encephalitis in Central America and the southwestern United States, particularly in Texas.
The clinical presentation of arthropod-borne viral encephalitis, regardless of the specific virus, is fairly characteristic. The onset of encephalitic symptoms may be preceded by an influenza-like prodrome of fever, malaise, myalgias, nausea, and vomiting followed by headache, confusion, stupor, and occasionally convulsions. Focal neurologic deficits and focal seizure activity have been reported in cases of encephalitis caused by eastern equine encephalitis virus and La Crosse virus. Patients with West Nile virus encephalitis may have conjunctivitis or a maculopapular or roseolar rash. Patients with West Nile virus or St. Louis virus encephalitis may present with a polio-like acute asymmetric flaccid weakness or tremors, myoclonus, or parkinsonian features. Japanese encephalitis virus tends to infect the basal ganglia and the thalamus, leading to tremors during the acute disease and a parkinsonian-like syndrome in survivors.
Either neuroimaging is normal or there are nonspecific abnormalities. Focal abnormalities in the basal ganglia and the thalamus have been reported in eastern equine, Japanese, and West Nile virus encephalitis.
Examination of the CSF demonstrates a polymorphonuclear leukocytic pleocytosis or a lymphocytic pleocytosis. The CSF glucose concentration is usually normal. Based on criteria established by the US Centers for Disease Control and Prevention, a confirmed case of arboviral encephalitis is defined as a febrile illness with encephalitis during a period when arboviral transmission is likely to occur, plus at least one of the following: (1) fourfold or greater rise in serum antibody titer between the time of acute illness and 4 weeks later; (2) isolation of virus from tissue, blood, or CSF; or (3) a specific immunoglobulin M (IgM) antibody identified in the CSF. However, La Crosse virus has not been isolated from CSF and St. Louis encephalitis virus, eastern equine encephalitis virus, and western equine encephalitis virus are rarely isolated from CSF; therefore antibody titers are typically the diagnostic test of choice. A CSF PCR assay is available for the detection of West Nile virus nucleic acid; however, it has a low sensitivity so a negative test does not exclude the disorder. The detection of West Nile virus IgM in CSF is considered the most sensitive diagnostic test for West Nile virus encephalitis. West Nile virus IgM antibodies may persist in serum (not the CSF) for a year or more after exposure to the virus and therefore cannot be used for definitive diagnosis of recent infection.
Rocky Mountain Spotted Fever
Rocky Mountain spotted fever is caused by the bacterium Rickettsia rickettsii. The disease begins with high fever, prostration, myalgias, headache, nausea, and vomiting. The rash is characteristic and presents initially as a diffuse erythematous maculopapular rash appearing 2 to 4 days after the onset of symptoms, usually beginning at the wrist and ankles and then spreading distally, including to the palms and soles, and proximally within a matter of a few hours. Diagnosis is made by immunofluorescent staining of skin biopsy specimens or by the detection of IgM and IgG antibodies.
Focal Infectious Intracranial Mass Lesions
Focal infectious intracranial mass lesions, including brain abscess, subdural empyema, and epidural abscess, are discussed later in this chapter but should be included in the differential diagnosis of bacterial meningitis. The presence of a focal infectious intracranial mass lesion is suggested by focal or generalized seizure activity or focal neurologic deficits on examination and is ruled out by neuroimaging.
Subarachnoid Hemorrhage
The possibility of a subarachnoid hemorrhage should also be included in the differential diagnosis of acute bacterial meningitis. Clinical presentation is characterized by the explosive onset of a severe headache or a sudden transient loss of consciousness followed by a severe headache. Because of the presence of blood in the subarachnoid space, nuchal rigidity is frequently present, leading to diagnostic confusion with infectious meningitis. A dilated nonreactive pupil is suggestive of a subarachnoid hemorrhage from an aneurysm of the posterior communicating artery. Computed tomography (CT) of the brain may demonstrate blood in the basal cisterns. If the CT scan is normal, the spinal fluid should be examined for red blood cells and xanthochromia. Red blood cells are present in the CSF within minutes of the rupture of an intracranial aneurysm and usually fail to clear in successive tubes of CSF. A sample of the blood-tinged CSF should be centrifuged; a yellow or xanthochromic color in the supernatant is present 6 to 12 hours following subarachnoid hemorrhage and lasts for 2 to 3 weeks. Xanthochromic spinal fluid may also be seen when the CSF protein concentration is elevated (above 150 to 200 mg/dl), and therefore it can be seen in bacterial meningitis.
Treatment
Empiric Antimicrobial Therapy
When bacterial meningitis is suspected, antimicrobial therapy is initiated immediately after blood cultures are obtained and before the results of CSF Gram stain, culture, and antimicrobial susceptibility tests are known. Empiric therapy should be based on the possibility that the patient has penicillin- and cephalosporin-resistant pneumococcal meningitis and should include a combination of a third- (ceftriaxone or cefotaxime) or fourth-generation cephalosporin (cefepime) plus vancomycin. Acyclovir is added to the empiric regimen to cover HSV ( Table 39-1 ). Ampicillin should be added to cover L. monocytogenes if the patient is over the age of 60 years or is immunosuppressed. When the patient has been treated with trimethoprim-sulfamethoxazole for prophylaxis of toxoplasmosis or P. carinii pneumonia, it is less likely that the meningitis is due to L. monocytogenes. Meningitis that complicates a neurosurgical procedure, epidural anesthesia, or intrathecal chemotherapy should be treated empirically with a combination of vancomycin plus ceftazidime, cefepime, or meropenem. Vancomycin is used to cover staphylococci and ceftazidime, cefepime, or meropenem to cover gram-negative bacilli, specifically Pseudomonas aeruginosa. The doses of each of the antimicrobial agents are provided in Table 39-2 , which shows both pediatric and adult dosing ranges.
| Community-acquired (immunocompetent child or adult) | Cefotaxime or ceftriaxone or cefepime plus Vancomycin plus |
| Acyclovir | |
| Community-acquired (immunosuppressed individual) | Cefotaxime or ceftriaxone or cefepime plus Vancomycin plus |
| Acyclovir plus | |
| Ampicillin | |
| Iatrogenic (associated with neurosurgery, epidural anesthesia, intrathecal chemotherapy) | Vancomycin plus Ceftazidime or meropenem |
| Antimicrobial Agent | Total Daily Pediatric Dose (Dosing Interval) | Total Daily Adult Dose (Dosing Interval) |
|---|---|---|
| Acyclovir | 30 mg/kg daily (every 8 h) | 30 mg/kg daily (every 8 h) |
| Ampicillin | 300 mg/kg daily (every 6 h) | 12 g/day (every 4 h) |
| Cefepime | 150 mg/kg daily (every 8 h) | 6 g/day (every 8 h) |
| Cefotaxime | 225–300 mg/kg daily (every 6–8 h) | 12 g/day (every 4–6 h) |
| Ceftazidime | 150–200 mg/kg daily (every 8 h) | 8 g/day (every 8 h) |
| Ceftriaxone | 100 mg/kg daily (every 12 h) | 4 g/day (every 12 h) |
| Meropenem | 120 mg/kg daily (every 8 h) | 6 g/day (every 8 h) |
| Metronidazole | 30 mg/kg daily (every 6 h) | 1.5–2 g/day (every 6 h) |
| Nafcillin | 150–200 mg/kg daily (every 6 h) | 12 g/day (every 4 h) |
| Penicillin G | 0.3 million U/kg/d (every 4 h) | 24 million U/day (every 4 h) |
| Vancomycin | 45–60 mg/kg daily (every 6 h) | 45–60 mg/kg daily (every 6 h) |
| Intrathecal vancomycin | 10 mg/day | 20 mg/day |
Specific Antimicrobial Therapy
All CSF bacterial isolates should be tested for antimicrobial susceptibility. In experimental models of bacterial meningitis, the maximal bactericidal activity occurs when the antibiotic concentration is 10 to 30 times greater than the minimal bactericidal concentration of the microorganism in vitro.
Pneumococcal Meningitis
Antimicrobial therapy for pneumococcal meningitis is initiated with a third- or fourth-generation cephalosporin and vancomycin. Some strains of pneumococci are sensitive to penicillin. Once the results of antimicrobial susceptibility tests are known, therapy can be modified accordingly ( Table 39-3 ). According to the guidelines of the National Committee for Laboratory Standards, an isolate of S. pneumoniae is considered to be highly resistant to penicillin with a minimal inhibitory concentration (MIC) of at least 2 µg/ml. An isolate of S. pneumoniae is considered to have intermediate resistance to penicillin with an MIC of 0.1 to 1 µg/ml and to be susceptible to penicillin with an MIC of less than 0.1 µg/ml. Penicillin G can be used to treat susceptible strains of S. pneumoniae in various clinical situations. For S. pneumoniae meningitis, however, more rigid guidelines are applied. An isolate in this situation is defined as penicillin-susceptible when the MIC is 0.06 µg/ml or less, to have intermediate resistance when the MIC is 0.1 to 1.0 µg/ml, and to be highly resistant when the MIC is greater than 1.0 µg/ml. Isolates of S. pneumoniae that have MICs of 0.5 µg/ml or less are defined as susceptible to the cephalosporins (cefotaxime, ceftriaxone, cefepime). Those with MICs of 1 µg/ml are considered to have intermediate resistance, and those with MICs of 2 µg/ml or more are considered resistant. For meningitis due to pneumococci, when the MICs of cefotaxime or ceftriaxone are 0.5 µg/ml or less, treatment with cefotaxime or ceftriaxone is probably adequate. If the MICs are 1 µg/ml or more, vancomycin is the antibiotic of choice. Rifampin can be added to vancomycin for its synergistic effect because it is highly active against most penicillin-resistant pneumococci, but rifampin is inadequate as monotherapy because resistance develops rapidly.
| Organism | Antibiotic |
|---|---|
| Streptococcus pneumoniae | |
| Sensitive to penicillin | Penicillin G or ceftriaxone or cefotaxime |
| Relatively resistant to penicillin | Ceftriaxone or cefotaxime |
| Resistant to penicillin | Vancomycin plus |
| Cefotaxime or ceftriaxone+/−intraventricular vancomycin | |
| Neisseria meningitidis | Ceftriaxone or penicillin G or ampicillin |
| Staphylococci | |
| Methicillin-sensitive | Nafcillin |
| Methicillin-resistant | Vancomycin |
| Listeria monocytogenes | Ampicillin |
| Enterobacteriaceae | Cefotaxime or ceftriaxone or cefepime |
| Pseudomonas aeruginosa | Ceftazidime or cefepime or meropenem |
| Haemophilus influenzae | Ceftriaxone |
| Streptococcus agalactiae | Ampicillin or penicillin G |
| Anaerobes | Metronidazole |
| Nocardia asteroides | Trimethoprim-sulfamethoxazole |
| Bacteroides species | Metronidazole |
For pneumococcal meningitis, a repeat lumbar puncture should be performed 24 to 48 hours after the initiation of antimicrobial therapy to document eradication of the pathogen, if possible. Consideration should be given to using intraventricular vancomycin in patients not responding to parenteral vancomycin. The intraventricular route of administration is preferred over the intrathecal route because adequate concentrations of vancomycin in the cerebral ventricles are not always achieved with intrathecal administration. Intraventricular and intrathecal vancomycin is safe and is not associated with a risk of seizure activity.
A 2-week course of intravenous antimicrobial therapy is recommended for pneumococcal meningitis.
Meningococcal Meningitis
Penicillin G or a third-generation cephalosporin ( Table 39-3 ) remains the antibiotic of choice for meningococcal meningitis. Isolates of N. meningitidis with moderate or relative resistance to penicillin (defined as a penicillin MIC of 0.1 to 1.0 µg/ml) and decreased susceptibility to ampicillin have been reported from a wide variety of geographic locations. All CSF isolates of N. meningitidis should be tested for penicillin and ampicillin susceptibility. If antimicrobial susceptibility testing demonstrates that the isolate is a relatively penicillin-resistant strain, or in areas with a high prevalence of meningococci with decreased susceptibility to penicillin, cefotaxime or ceftriaxone should be used. A 7-day course of intravenous antibiotic therapy is adequate for most uncomplicated cases of meningococcal meningitis. The index case and all close contacts should receive chemoprophylaxis with a 2-day regimen of rifampin (600 mg every 12 hours for 2 days in adults and 10 mg/kg every 12 hours for 2 days in children older than 2 years of age). Rifampin should not be used in pregnant women. Pregnant and lactating women and children less than 2 years of age may be given intravenous or intramuscular ceftriaxone, in a single injection of 250 mg for adults and 125 mg for children. Close contacts are defined as individuals who have had contact with nasopharyngeal secretions either through kissing or sharing toys, beverages, or cigarettes.
Staphylococcal Meningitis
Meningitis caused by S. aureus or coagulase-negative staphylococci is treated with nafcillin or oxacillin. Vancomycin is the drug of choice for methicillin-resistant staphylococci and for patients allergic to penicillin. The CSF should be monitored during therapy, and if the spinal fluid continues to yield viable organisms after 48 hours of intravenous therapy, intraventricular vancomycin, 10 mg once daily for children or 20 mg once daily for adults, should be added.
Listeria monocytogenes Meningitis
Meningitis due to L. monocytogenes is treated with ampicillin for at least 3 weeks. Gentamicin should be added to ampicillin in critically ill patients. Meningitis caused by this organism is seen less often today in immunosuppressed patients than in the past because of trimethoprim-sulfamethoxazole administration in these patients as prophylaxis against P. carinii pneumonia and toxoplasmosis .
Enterobacteriaceae Meningitis
Meningitis caused by the Enterobacteriaceae, including Proteus species, E. coli , Klebsiella species, Serratia species, and Enterobacter species, is treated with a third- or fourth-generation cephalosporin, either cefotaxime, ceftriaxone or cefepime, for 3 weeks.
Pseudomonas aeruginosa Meningitis
The third-generation cephalosporins cefotaxime, ceftriaxone, and ceftazidime are equally efficacious for the treatment of gram-negative bacillary meningitis, with the exception of meningitis caused by P. aeruginosa. Meningitis resulting from infection with this organism is treated with ceftazidime, cefepime, or meropenem intravenously for 3 weeks.
Newer Antimicrobial Agents
Meropenem is a carbapenem antibiotic structurally related to imipenem, but reportedly with less seizure proclivity. In experimental models, meropenem has bactericidal activity similar to that of the combination of ceftriaxone and vancomycin against penicillin-resistant S. pneumoniae. The safety and efficacy of meropenem were compared with those of cefotaxime in a prospective randomized trial of 190 children with bacterial meningitis (caused by H. influenzae , S. pneumoniae , and E. coli ). Seizures occurred within 24 hours before antibiotic therapy in 16 of 98 patients (16%) randomized to receive meropenem, and in 6 of 92 patients (7%) randomized to receive cefotaxime. In patients without seizures before therapy, seizures occurred during treatment in 5 of 82 patients (6%) receiving meropenem and in 1 of 86 patients (1%) receiving cefotaxime. Meropenem is highly active in vitro against L. monocytogenes as well as against multidrug- resistant gram-negative bacteria and P. aeruginosa. The dose of meropenem is 2 g intravenously every 8 hours for adults; the pediatric dose is 40 mg/kg every 8 hours. The number of patients enrolled in clinical trials of meropenem for bacterial meningitis has not been sufficient to date to correctly assess its efficacy or epileptogenic potential.
Cefepime is a broad-spectrum fourth-generation cephalosporin with in vitro activity similar to that of cefotaxime or ceftriaxone against the common meningeal pathogens H. influenzae , S. pneumoniae , and N. meningitidis , and greater activity against Enterobacter species and P. aeruginosa. The dose of cefepime is 3 g intravenously every 8 hours in adults. In clinical trials, cefepime has been demonstrated to be equivalent to cefotaxime in the treatment of pneumococcal and meningococcal meningitis, but its efficacy in bacterial meningitis caused by penicillin- and cephalosporin-resistant pneumococcal organisms has not been established.
Dexamethasone Therapy
The use of dexamethasone as adjunctive therapy in bacterial meningitis comes from present understanding of the pathophysiology of the neurologic complications of bacterial meningitis. The critical event in pathogenesis is the inflammatory reaction in the subarachnoid space to the invading meningeal pathogen. The pathogen itself is not responsible for most neurologic complications. In bacterial meningitis, damage to the CNS progresses long after the CSF has been sterilized by antibiotic therapy. Lysis of bacteria and release of bacterial cell wall components in the subarachnoid space are the initial steps in the induction of the inflammatory process and formation of a purulent exudate in the subarachnoid space ( Fig. 39-1 ). Components of bacterial cell walls, such as lipopolysaccharide molecules (endotoxin), a cell wall component of gram-negative bacteria, and teichoic acid and peptidoglycan, cell wall components of the pneumococcal species, induce meningeal inflammation by stimulating the production of inflammatory cytokines and chemokines by microglia (CNS macrophage-equivalent cells), astrocytes, monocytes, microvascular endothelial cells, and white blood cells in the CSF space. There are a number of consequences that result from the presence of inflammatory cytokines in CSF. Tumor necrosis factor (TNF) and interleukin-1 (IL-1) act synergistically to alter the permeability of the blood–brain barrier, allowing for the leakage of serum proteins and other molecules into the CSF and contributing to the formation of a purulent exudate. The purulent exudate may obstruct the flow of CSF through the ventricular system and diminish the resorptive capacity of the arachnoid granulations in the dural sinuses, leading to obstructive and communicating hydrocephalus and to interstitial edema. The exudate also surrounds and narrows the diameter of the lumen of the large arteries at the base of the brain with infiltration of inflammatory cells in the arterial walls (vasculitis). These inflammatory cytokines also recruit polymorphonuclear leukocytes from the bloodstream and upregulate the expression of selectins on cerebral capillary endothelial cells and leukocytes, which allow for migration of leukocytes into the CSF. Experimental models of meningitis suggest that bacterial eradication is not a leukocyte-dependent phenomenon. Neutrophils degranulate and release toxic metabolites that contribute to cytotoxic edema, cell injury, and death. The adherence of leukocytes to cerebral capillary endothelial cells increases the permeability of blood vessels, allowing for the leakage of plasma proteins into the CSF and further contributing to the inflammatory exudate in the subarachnoid space.
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