Meningitis due to Staphylococcus aureus accounts for 1–9% of cases of bacterial meningitis and is associated with mortality rates of 14–77%. It usually is associated with neurosurgical interventions (eg, cerebrospinal fluid [CSF] shunts), trauma, or underlying conditions, such as the following:
See Meningitis for a complete discussion of treatment strategies.
In one study, 38 of 154 (25%) cases of bacterial meningitis during a 7-year period were nonpneumococcal, gram-positive coccal infections. Most cases were due to S aureus and S epidermidis.[1] In another clinical case series of 33 patients with meningitis, spanning a decade, at a single urban teaching hospital, S aureus was found to be the causative agent in 12 (36%) of the cases by using CSF cultures, PCR, and accessory gene regulator typing.[2]
In yet another clinical series, coagulase-negative staphylococcus (CoNS) was reported to make up 52.8% of pathogens of ventriculoperitoneal shunt infections in pediatric patients younger than 8 years. Data on adult CoNS meningitis were not given, because these had not been specifically examined in the literature.
Once bacteria enter and replicate in the CSF, inflammation of the subarachnoid space ensues because of bacterial (eg, cell wall components) and host factors (eg, prostaglandins, tumor necrosis factor alpha). Alteration of blood-brain barrier permeability leads to cerebral edema and increased intracranial pressure. Meningitis also modifies blood flow throughout the subarachnoid space, resulting in vasculitis and ischemia. Oxygen radicals may contribute to the increased water content, increased intracranial pressure, and changes in blood flow seen in meningitis.
Neonates are colonized by S aureus soon after birth; major niches include umbilical stump, perineal area, skin, and gastrointestinal tract. Later in life, major niches include anterior nares, and about 25% of children and adults become carriers. Carriers experience more postsurgical infections than do noncarriers.
The next step after colonization is penetration through the epithelial or mucosal surface. The mechanisms underlying penetration are not completely understood, but trauma, surgery, immunosuppression, and other infections are predisposing conditions. After penetration and complement activation, S aureus is coated by C3b, immunoglobulin G (IgG), or both (opsonization).
Staphylococci are then ingested and killed by polymorphonuclear cells and monocytes. Failure of these defense mechanisms can lead to recurrent or chronic infection. Inherited or acquired defects of chemotaxis, opsonization, or polymorphonuclear leukocyte function (eg, due to severe bacterial infections, rheumatoid arthritis, decompensated diabetes mellitus) predispose patients to continuation of the infection process.
Foreign body infection leads to an acquired phagocytic defect. After hours or days of contact with the foreign body, S aureus produces a polysaccharide/adhesin substance that causes it to adhere to the foreign body and protects it from the environment. Attachment of S aureus to foreign surfaces involves interaction with proteins of the extracellular matrix, including fibrinogen, fibronectin, laminin, thrombospondin, vitronectin, elastin, bone sialoprotein, and collagen. The resident phagocytic population close to the foreign body is not able to kill the invading strain. Moreover, anchoring of S aureus to foreign substances modifies its susceptibility to antimicrobial agents. These factors explain the inability of antibiotics alone to eradicate foreign body infection.
The site of central nervous system (CNS) invasion during septicemia is still not clear. It may involve the dural venous system or choroid plexus, where receptors for pathogens have been found. Transcytosis through microvascular endothelial cells is another possible mechanism of meningeal invasion during meningitis. Once bacteria are in the subarachnoid space, host mechanisms are inadequate to control the infection. Meningeal inflammation increases CSF complement concentrations. However, complement concentration is still insufficient and, despite the increased number of leukocytes, opsonic and bactericidal activities are suboptimal, leading to multiplication of bacteria in the CSF.
In IV drug users, S aureus from bacterial vegetations on cardiac valves is most commonly the starting point for systemic involvement and meningitis.
Patients with S aureus bacteremia can be characterized as belonging to 1 of 2 groups. In the first group, the bacterium is introduced during surgery, through trauma, or via local spreading (especially coagulase-negative staphylococci) from contiguous infection.
In the second group of patients, composed of individuals with hematogenous or spontaneous meningitis, S aureus is disseminated systemically. Infection is more often community acquired in these patients, and the incidence of positive blood culture results is higher, as is mortality rate.
Hospitals with active neurosurgical services generate more cases of staphylococcal meningitis (eg, infection of CSF shunts) than do other clinical facilities.
A particularly high rate of S aureus carriers is found in the following groups:
Staphylococcal meningitis is uncommon in immunocompetent individuals in the absence of focal infection (eg, pneumonia, osteomyelitis, endocarditis, parameningeal infection, psoas[3] or epidural abscess, sinusitis, tropical pyomyositis[4] ), neurosurgical interventions, or congenital dermal sinus.
The development of nosocomial staphylococcal meningitis is subsequent to central nervous system conditions and interventions, which include hematoma, ventriculo-peritoneal shunts and other embedded devices, tumors, and spinal anesthesia. In a recent case series, out of 62 patients, 37 cases were due to Staphylococcal aureus and 25 cases due to coagulase-negative Staphylococci.[5]
Higher mortality (36% in one clinical series) has a higher association with community-acquired staphylococcal meningitis. S aureus hematogenous meningitis has devastating clinical consequences and elevated mortality rates, especially if it is community acquired.[6]
In the United States, S aureus meningitis accounts for 1-6% of cases of meningitis.[7, 8]
Worldwide, S aureus meningitis constitutes 0.3-8.8% of all cases of bacterial meningitis. Hospitals with active neurosurgical services generate more cases of staphylococcal meningitis (eg, infection of CSF shunts). S aureus is the second most common cause of CSF shunt infections, outnumbered only by S epidermidis.
Newborn nurseries seem to experience waves of staphylococcal epidemics that occur in cycles (ie, epidemics occurred in the 1900s, late 1920s, early 1950s, early 1970s, late 1980s, and early 1990s). S aureus was the most common staphylococcal pathogen in the nursery from the 1950s to the 1970s.
Staphylococcal meningitis is associated with a high mortality rate (about 50% in adults), particularly hematogenous S aureus meningitis (mortality rate, 18-56%). The prognosis for CSF shunt infections is more favorable, probably because of earlier recognition. (Shunt infections can be insidious, although a fulminant postoperative course can be seen with S aureus infection.)
Patients in whom the bacteria is introduced during surgery or by trauma or local spreading (especially coagulase-negative staphylococci) from contiguous infection have a lower mortality rate than do patients with hematogenous meningitis; this may be explained by early recognition and less systemic involvement in the nonhematogenous meningitis patients.
Any localized S aureus infection can lead to bacteremia. In the pre-antibiotic era, the mortality rate was 82%. Studies have since reported mortality rates of 30-40% in non–drug-using patients with S aureus septicemia.
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Untreated bacterial meningitis is usually fatal. A disproportionate number of deaths occur in infants and elderly persons, with the mortality rate being highest in neonates. However, the prognosis for patients with CSF shunt infections is more favorable.
The presence of bacteremia, coma, seizures, or various underlying diseases (eg, alcoholism, diabetes mellitus, multiple myeloma, head trauma) significantly worsens the prognosis; therefore, an aggressive approach should be used in these settings.
The likelihood of either disability in or complete recovery of the patient, as well as of future employability, depends on the underlying condition and the severity of the meningitis.
Classic signs of staphylococcal meningitis include the following:
In immunosuppressed patients, the classic meningeal signs may be absent.
In S aureus septicemia, look for signs of systemic embolization/seeding, including the following:
With a high index of suspicion, making the diagnosis of bacterial meningitis is, in general, not difficult. All febrile patients with lethargy, headache, or confusion of sudden onset, even if fever is only low grade or the patient is a confused alcoholic, should undergo an urgent lumbar puncture, since a definitive diagnosis of meningitis can be made only by examination of CSF.
In patients who have not undergone a neurosurgical procedure, presentation of S aureus meningitis may be similar to that of other types of bacterial meningitis. Patients with septicemia have additional systemic signs and symptoms, including septic shock.
Common presentations of CoNS meningitis include low-grade fever (in 14-92% of cases), malaise, poor feeding, and irritability. Signs of meningeal irritation are not usually present, since no functional communication exists between the infected ventricles and CSF spaces in most cases.
Redness of the skin overlying a shunt, if it occurs, is a highly specific sign. Infections with symptoms referable to the distal portion of the shunt are more specific; shunts that end in a vessel lead to bacteremia, while shunts that end in the pleural or peritoneal space cause peritonitis or pleuritis.
CoNS is a normal inhabitant of the human skin and mucous membranes. Patients most at risk for CoNS infection frequently have a disruption in their host defense mechanisms due to surgery, foreign body placement, or immunosuppression. Because CoNS is a common contaminant of cultures, the diagnostic definition of adult CoNS meningitis is different from that of meningitis caused by other common pathogens and is therefore defined by a more strict criteria.
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Complete blood cell (CBC) count with differential demonstrates polymorphonuclear leukocytosis with left shift.
CSF analysis is the diagnostic test of choice for suspected meningitis. CSF lactate dehydrogenase (LDH) appears to be diagnostic and has a prognostic value in bacterial meningitis. Increase in total LDH is observed consistently in bacterial meningitis, mostly due to increases in fractions 4 and 5, which are derived from granulocytes. LDH fractions 1 and 2, derived presumably from brain tissue, are elevated only slightly in bacterial meningitis but rise sharply in patients who develop neurologic sequelae.
Leukocyte count in the CSF ranges from 250-100,000/µL. Counts above 50,000 raise the possibility of a brain abscess having ruptured into a ventricle. Neutrophils predominate early in infection, but mononuclear cells (lymphocytes, plasma cells, histiocytes) steadily increase as the infection continues.
Protein content is higher than 45 mg/dL in greater than 90% of cases. In most cases, the protein ranges from 100 to 500 mg/dL. Glucose content is usually diminished to below 40 mg/dL or to less than 40% of blood glucose level. Gram stain of CSF sediment permits identification of the causative agent in most cases.
Blood cultures should always be obtained. They are positive in 40-60% of patients with Haemophilus influenzae, meningococcal, or pneumococcal meningitis, but data are scarce for staphylococcal meningitis. Blood cultures may provide the only definite clue as to the causative agent if CSF cultures are negative and if more sophisticated diagnostic identification procedures are not readily available.
Because of earlier antibiotic intervention in patients presenting with signs suggestive of bacterial meningitis, a noted rise occurs in culture-negative CSF and blood cultures in some laboratories. This makes the use of a non–culture-based system to detect and identify the causal agents increasingly important. It is here that the 16S rRNA polymerase chain reaction (PCR) becomes a valuable molecular tool to aid in the detection on nonculturable etiologic agents of meningitis.
With the advent of polyacrylamide gel electrophoresis (PAGE) to separate mixed 16S rRNA amplicons prior to sequencing without the need of cloning, the PCR technique is increasingly being used to augment staphylococci identification.
16S rRNA genes exist in all bacteria and accumulate mutations at a slow constant rate over time; therefore, they may be used as "molecular clocks." Highly variable portions of the 16S rRNA sequence provide unique signatures to any bacterium and useful information about relationships between them. These properties provide important aids in microbiologic diagnostics, especially in equivocal cases.
Complement levels and immunoglobulin levels should be part of the evaluation of every patient with bacterial meningitis.
Antibody levels should be monitored and pneumococcal and meningococcal vaccines should be given to patients with recurrent bacterial meningitis, because this is common in persons with previous head trauma, skull fracture, or dural CSF leak, as well as in patients with deficiencies of any of the complement components or hypogammaglobulinemia.
Other laboratory methods for identification of causative organisms include counterimmunoelectrophoresis (CIE), radioimmunoassay (RIA), latex particle agglutination (LPA), and enzyme-linked immunosorbent assay (ELISA).
Chest radiographs are important because they may show an abscess or pneumonitis, an important consideration for infants and immunocompromised patients. Sinus and skull radiographs may show the presence of cranial osteomyelitis, paranasal sinusitis, or mastoiditis.
Computed tomography (CT) scans of the head are usually normal but may reveal nonspecific cerebral edema or show previous neurosurgical interventions. CT scans reveal eroding skull lesions and routes for bacterial invasion (eg, mastoiditis, sinusitis, tumors, sinus wall defects, brain abscess, subdural empyema).
In patients with immunosuppression or with focal findings, papilledema, or other signs of increased intracranial pressure, a CT scan of the head must be done before the spinal tap to detect mass lesions that could result in herniation. Patients with space-occupying lesions do not undergo lumbar puncture because the withdrawal of CSF removes counterpressure from below, thus increasing the effect of compression from above and exacerbating the brain shift already present. A CT scan should be preceded by blood cultures and the initiation of antibiotic therapy.
Magnetic resonance imaging (MRI) with contrast enhancement may demonstrate cortical reactions, including infarctions, hydrocephalus, and meningeal exudates. The role of MRI with contrast T1 and T2 sequences is not well established.
Transthoracic and transesophageal echocardiograms are helpful for the evaluation of endocarditis. Negative tests do not rule out endocarditis, since neither technique is sensitive enough to detect small vegetations, which may require more than 10 days to develop. (Blood cultures and peripheral manifestations also help to point to staphylococcal endocarditis as the source of meningitis.)
CSF pressure is elevated consistently (>180 mm H2 O), but pressures greater than 400 mm H2 O suggest the potential for herniation.
YKL-40, putative biomarker of neuroinflammation, a member of the family 18 glycosyl hydrolases, is secreted by activated neutrophils and macrophages and may function in tissue inflammation and remodeling. This is a useful adjunct, since CNS infections are characterized by an inflammatory response within the subarachnoidal space or brain parenchyma. However, preliminary research findings to date do not show a definite positive correlation with levels of CSF YKL-40 levels as they have shown with other forms of purulent meningitis. As easily assayable biomarker research for different subsets of meningitis continue, YKL-40 could play a vital role, but further research is needed.
Pia-arachnoiditis with edema and microinfarcts is observed. Polymorphonuclear leukocytes fill the subarachnoid space in severely affected areas and are found predominantly around the leptomeningeal blood vessels in less severe cases. In fulminant meningitis, the inflammatory cells infiltrate the walls of the leptomeningeal veins and produce a venulitis that can lead to venous occlusion and subsequent hemorrhagic infarction of the underlying brain.
Bacterial meningitis is a medical emergency. Once purulent meningitis is confirmed by CSF analysis, initial treatment measures include administration of antibiotics with effective CNS penetration and maintenance of adequate blood pressure. Initial antibiotic selection should be based on Gram stain or rapid bacterial antigen tests. If the spinal tap is delayed or the organism cannot be rapidly identified, empiric selection of an antibiotic with effective CNS penetration should be based on age and underlying disease status, since delay in treatment is associated with adverse clinical outcome.
See Meningitis for complete information on the condition and general treatment strategies.
Standard empirical therapy varies according to age. In infants younger than age 4 weeks, such therapy employs ampicillin plus cefotaxime or an aminoglycoside.
Infants aged 4-12 weeks should be treated with ampicillin plus a third-generation cephalosporin.
In children aged 12 weeks to 18 years, a third-generation cephalosporin or ampicillin plus chloramphenicol is an appropriate combination.
Adults aged 18-50 years and individuals with basilar skull fracture should be treated with a third-generation cephalosporin, while individuals older than age 50 should be treated with ampicillin plus a third-generation cephalosporin.
The following newer antibiotics have helped broaden therapeutic options for staphylococcal meningitis.
As clinical experience increases with these newer antibiotics, they certainly have the potential to replace the older antibiotics.
Immunocompromised patients should receive the combination of vancomycin, ampicillin, and ceftazidime. Patients who have experienced head trauma, have a CSF shunt or who have undergone a neurosurgical procedure should be treated with vancomycin and ceftazidime.
Vancomycin should be added to empirical regimens when highly penicillin- or cephalosporin-resistant strains of Streptococcus pneumoniae are suspected. Ampicillin should be added to empirical treatment at any age if Listeria monocytogenes is a consideration.
If allergy to penicillins and cephalosporins precludes the use of these agents, chloramphenicol is a reasonable alternative.
Dose calculations are based not only on a patient’s age, as discussed above, but also on his/her renal and hepatic functions.
Once S aureus meningitis is confirmed and sensitivity determined, therapy may be altered or simplified by using vancomycin, oxacillin, or nafcillin alone. For methicillin-sensitive S aureus, nafcillin or oxacillin is standard therapy. If the infective organism is methicillin-resistant S aureus (MRSA) or S epidermidis, vancomycin is the drug of choice.
Most experts recommend addition of rifampin if the patient shows no clinical improvement 72 hours after initial treatment of S aureus meningitis.[17, 18, 19]
Most cases of bacterial meningitis are treated for a period of 10-14 days, except when a parameningeal focus of infection persists (as in most cases of staphylococcal meningitis). In such cases, treatment should be continued for a longer period. Effects of therapy should be tagged to clinical improvement.
Use of steroids in S aureus meningitis is controversial. While adjunctive dexamethasone is beneficial for H influenzae type B and pneumococcal meningitis, and although some authors favor its use in all types of bacterial meningitis, at present the routine use of dexamethasone is not recommended.
Shunt removal is often necessary to optimize therapy. If infection is suspected, CSF should be removed from the shunt and sent for studies. Treatment should be started if initial results point to meningeal inflammation and should be modified according to culture results. If infections are difficult to eradicate or if the shunt cannot be removed, direct instillation of the antimicrobial agent is warranted. Daily intraventricular vancomycin doses range from 4-10 mg. Gentamicin doses are 1-2 mg/day for children and 4-8 mg/day for adults. Combination with an IV agent is always required. Intraventricular teicoplanin also has been employed successfully. Since the entire shunt has a propensity to be contaminated once one section is infected, partial shunt revision is not recommended.
In cases of S aureus meningitis due to septicemia, once the source of infection is identified, surgical debridement or excision may be indicated.
Obstructive or normal pressure hydrocephalus may complicate the clinical picture, leading to further obtundation. When either of these is present, neurosurgical consultation for shunting should be considered.
Bed rest and general supportive measures are needed by the patient until the acute illness phase has passed; thereafter, physical activity may be increased gradually as tolerated.
Monitoring all aspects of recovery, including those related to cognitive sequelae, normal pressure hydrocephalus, and seizures, is important.
Seizures are more frequent after H influenzae meningitis than after S aureus meningitis. In fulminant meningitis, incidence of strokes is increased because of venulitis, which leads to microinfarcts.
The most effective way to protect patients against Staphylococcal meningitis is vaccination. However, due to S aureus' high adaptability, remarkable epidemiologic transition, its poorly understood pathomechanism and immunity against pathogens—critical requirements for induction of cellular immunity and effective vaccine development—it is challenging to develop a potent anti-S aureus vaccine that is both safe and efficacious. Protective immunity against S aureus is incompletely understood.[20] Animal models, especially murine models, despite multiple trials have not predicted vaccine success in humans. Further, S aureus is much more complex with multiple, extensive array of virulence factors, including hemolysins, toxins, and superantigens that manifest as a very broad range of diseases in infected patients. These effectively neutralize the host's immune responses far more effectively than most bacterial pathogens making vaccine development very difficult.[21] Despite a few vaccine clinical trials that showed lack of efficacy, intensive research continues unabated in the attempt to find either an effective universal Staphylococcus aureus vaccine or a narrowly focused S aureus vaccine.