Clinical manifestations

Presentation and course

	• Common neurologic manifestations of Staphylococcus aureus infection include meningitis, septic thromboemboli, and epidural abscesses.
	• Patients with Staphylococcus aureus meningitis attributed to hematogenous dissemination may present with concomitant endocarditis and/or osteomyelitis.

The clinical manifestations of Staphylococcus aureus are broad, ranging from soft tissue infection to bacteremia, endocarditis, and meningitis. In this article, the most common neurologic manifestations of S aureus infection are discussed, including meningitis, septic thromboemboli, and epidural abscesses, as well as commonly associated S aureus infections affecting other organ systems.

Meningitis. Staphylococci are part of the normal flora of the human skin, respiratory system including the upper airways, and gastrointestinal tract. They typically cause localized infections, such as skin pustules or abscesses or sinusitis. Such lesions usually heal quickly when the pus is drained. More serious staphylococcal infections are usually seen as complications of wounds, such as from trauma or postoperatively. For example, Staphylococcus aureus is one of the most common causes of bacterial meningitis as a complication after penetrating head injury. In addition to S aureus, coagulase-negative staphylococci are also common causes of bacterial meningitis following neurosurgical procedures or CSF shunt placement (54). When staphylococcal bacteremia occurs, numerous organ systems can be affected by secondary infections, including endocarditis, osteomyelitis, meningitis, and septic emboli to the lungs, extremities, and brain.

Staphylococcal meningitis presents similarly to other bacterial meningitides. Meningitis symptoms typically include fever, headache, nausea, vomiting, irritability, and lethargy, proceeding to further clouding of consciousness and, ultimately, death. Fever may be 103 degrees Fahrenheit or higher. Clinical signs include evidence of meningeal irritation with neck stiffness on flexion, though this finding may be absent in immunocompromised or comatose patients. Focal signs may also appear due to abscess formation or septic emboli.

In nosocomial meningitis and ventriculitis, the presentation may be difficult to discern from the underlying process, such as a posttraumatic or postsurgical condition, and a high degree of suspicion must be held. The course is frequently fulminant, with rapid neurologic deterioration leading to respiratory arrest and death. Therefore, initiation of appropriate antibiotic treatment must not be delayed.

Up to 79% of staphylococcal meningitis cases follow neurologic surgeries, and up to half occur in the setting of a widely disseminated infection (77). Postoperative meningitis is usually localized and is associated with surgically implanted hardware. When attributed to hematogenous dissemination, 21% of patients with Staphylococcus aureus meningitis had concomitant endocarditis, and 12% had osteomyelitis. Compared to other etiologies, hematogenous S aureus meningitis is generally a more severe disease, with much higher mortality, and requires evaluation for other sources or foci of infection (38). Secondary sites of infection should be sought, particularly in patients with implanted prosthesis or persistent fever or bacteremia (40).

Patients with S aureus bacteremia and endocarditis will usually present with a septic syndrome including fever, tachycardia, and hypotension. Patients will often have congestive heart failure or septic pulmonary emboli secondary to right-sided infective endocarditis. Clinically, they may initially present with dyspnea that progresses to subsequent worsening respiratory and cardiac status. Assessment should include evaluation for cardiac murmur, indicative of valvular regurgitation, and for petechiae, Janeway lesions, and Osler nodes, indicative of septic emboli to the extremities. However, these skin lesions may not be seen with S aureus endocarditis because the presentation is often too fulminant, and these lesions are a delayed sign of a more subacute endocarditis. In all cases of suspected infective endocarditis, particularly in the setting of staphylococcus bacteremia, echocardiography should be performed without delay. Although transesophageal echocardiography is preferred, transthoracic echocardiography may be performed if transesophageal echocardiography is not immediately available or feasible (09).

Septic emboli. Symptomatic neurologic events may occur in as high as 80% of patients with infective endocarditis (39). All patients with S aureus bacteremia or endocarditis should be evaluated for meningitis as the presence of metastatic infection may warrant longer duration of treatment (24). In addition to meningitis, other neurologic complications of staphylococcal endocarditis or bacteremia include cerebral infarction, parenchymal and subarachnoid hemorrhages, and mycotic aneurysms (39). These complications occur in about 40% of cases; however, this figure may be underestimated because patients with staphylococcal endocarditis may not have complete neurologic evaluation, given the urgent nature of their nonneurologic issues (65). Although cerebral infarctions can arise from septic thromboemboli, a study suggests that small-vessel vasculitis secondary to systemic bacteremia-mediated inflammation also plays a role (19). There may be up to an additional 30% of patients who have silent cerebral septic emboli (95). The risk of embolization is roughly proportional to the size of the valvular vegetation and decreases rapidly within the first few days of effective therapy. Patients with cerebral septic emboli will typically present with multiple cerebral infarctions in various vascular distributions, and they may also have intraparenchymal hemorrhages. Anticoagulation is strongly contraindicated in patients with infective endocarditis because of the risk of hemorrhagic conversion of cerebral septic emboli. Also, patients with mycotic aneurysms may suffer from subarachnoid hemorrhage. Mycotic aneurysms arise from direct invasion of the arterial wall by the infecting organisms, from septic embolization of the vasa vasorum, or from the deposition of immune complexes that trigger local inflammation and weakening of the arterial wall (65).

Epidural abscess. Epidural abscesses are rare neurologic complications of S aureus infection and can arise hematogenously or contiguously from an infected focus. They are more often located in the spinal cord but may also occur intracranially (109). Furthermore, intracranial epidural abscesses are less common than parenchymal or subdural brain abscesses. Intracranial abscesses can be a consequence of sinusitis, mastoiditis, or otitis, but are more commonly an iatrogenic sequela from neurosurgical procedures. For this reason, the most likely organisms are staphylococcus species or gram-negative bacteria (51). Clinical symptoms and signs relate to the expanding mass effect of the epidural abscess on the brain parenchyma. Manifestations include local compression with focal signs or seizures or signs of globally elevated intracranial pressure (96).

Pyomyositis. Another neurologic condition caused by Staphylococcus is pyomyositis (65). It is a rare subacute infection of skeletal muscles, likely of hematogenous origin but also associated with muscle trauma. The rarity of the disease is attributed to the resistance of muscles to infection. It is much more commonly seen in Africa and the South Pacific than in North America, although its incidence is rising in the United States and Europe, likely due to the increase in community-acquired methicillin-resistant Staphylococcus aureus (MRSA) (89). Any muscle may be involved, but the quadriceps and iliopsoas are most commonly involved. Symptoms start with insidious, dull, cramping pain; low-grade fever; and muscle aches that evolve over 1 to 2 weeks into severe muscle pain, swelling, and tenderness. Up to 31% of patients with pyomyositis may have concomitant septicemia or bacteremia. Untreated disease continues to evolve into muscle destruction, osteomyelitis or osteoarthritis, distant dissemination, and death (60).

Osteomyelitis. In patients with staphylococcal meningitis and bacteremia, a low index of suspicion must also be maintained for osteomyelitis. The suggestive symptoms include pain and swelling, usually at the distal ends of long bones in children and in the vertebral bodies in adults (65). Chronic infection can continue for months or even years, so this diagnosis must always be considered in any patient with a history of staphylococcal bacteremia and appropriate symptoms. The mainstay of diagnosis is bone biopsy and culture. However, several imaging modalities may be useful in ruling out other diagnoses. For example, although standard radiological examination may be negative in the first 2 weeks of an acute osteomyelitis process, it should be the first imaging modality ordered to rule out other bone pathologies, such as malignancy (87; 108). Other modalities such as bone scans and MRI have a much higher sensitivity at 80% and may detect osteomyelitis as early as 3 days after disease onset (14; 76).

Other. Staphylococcus aureus infections also affect other organ systems. Pneumonia often occurs from hematogenous spread during bacteremia, and especially with right-sided endocarditis, leading to abscesses and empyema. Other associated conditions include sinusitis, septic arthritis, septic bursitis, pericarditis, and in rare cases, endophthalmitis (91).

Prognosis and complications

The prognosis of staphylococcal meningitis, as with most bacterial meningitis, relates directly to early diagnosis and initiation of appropriate antibiotic therapy. Prognosis is also significantly affected by the presence of other infectious foci, particularly endocarditis. Not surprisingly, therefore, both mortality and morbidity are lower in postoperative cases than in hematogenous cases (38). In 96 consecutive cases of nonsurgical hematogenous S aureus meningitis that occurred between 1991 and 2000, mortality was 56%, and this mortality was steady throughout the 10-year study period (74). In a study of Danish patients with bacterial meningitis, S aureus infection was associated with a higher incidence of death from systemic complications, such as septic shock, respiratory failure, and other organ failure (88). Mortality is higher with S aureus meningitis compared to meningitis caused by other staphylococcal species (20). Postcraniotomy patients who develop bacterial meningitis have a significantly higher mortality than those who do not develop meningitis (48). Methicillin-resistant Staphylococcus aureus (MRSA) is one of the leading gram-positive organisms that cause infection after neurosurgical procedures (81). MRSA septicemia after major surgical procedures is associated with higher morbidity, including higher rates of in-hospital deaths and longer length of stay (03). For nosocomial meningitis caused by staphylococcus, series indicate mortality between 5% and 19% (21; 93).

Appropriate therapy instituted early is associated with decreased mortality from bacterial meningitis. Morbidity, however, is high, even with the optimal treatment. Neurologic complications of acute bacterial meningitis in a study included hydrocephalus (23.1%), subdural effusion (19.4%), and epilepsy (12%). Worse outcomes were associated with age under 2 years, leukocytosis, and CSF glucose level less than 45 mg/dL (15). Other complications during acute illness are similar to that seen with meningitides of any etiology and include empyema, ischemic or hemorrhagic stroke, cerebritis, ventriculitis, and abscesses. In a study of nosocomial ventriculitis and meningitis, adverse outcomes occurred in 78%, with mortality in 9%, but poor functional outcome, including persistent vegetative state (14%), severe disability (36%), and moderate disability (18%) contributed to the majority of outcomes (98). Furthermore, risk for adverse outcome of meningitis and ventriculitis include higher age, abnormal neurologic examination, and mechanical ventilation (98).

In particular, 30-day mortality from S aureus meningitis ranges between 20% and 30%. Independent factors associated with mortality from S aureus meningitis include sepsis or septic shock, MRSA infection, nonpostoperative infection, and coma (77). Staphylococci species account for up to 15% of intracranial infections, including subdural empyemas and intracranial abscesses (50). The prognosis for intracranial epidural abscesses is better than for subdural empyema, especially when surgical drainage is undertaken (68).

Clinical vignette

A 32-year-old man with tetralogy of Fallot status post-bovine pulmonic valve replacement 1 month earlier was admitted with a sudden onset of high fevers, nausea, vomiting, diarrhea, and headache after being found on the floor by his family.

On admission, the patient was alert but confused, with neck pain on flexion. Initial head CT was unremarkable. Due to the fevers, neck pain, and altered mental status, an urgent lumbar puncture was performed to evaluate for possible CNS infection. Spinal fluid examination revealed 558 white cells, with 88% polymorphonuclear cells. Spinal fluid gram stain showed gram-positive cocci in clusters, and the patient was started on intravenous vancomycin and ceftriaxone. Spinal fluid culture grew methicillin-sensitive Staphylococcus aureus (MSSA), and treatment was changed to 2 grams of nafcillin intravenously every 4 hours.

Further work-up with echocardiogram revealed a thin hypermobile mass oscillating through the pulmonic valve. He had ischemic lower extremities and septic pulmonary emboli, as well as anemia and thrombocytopenia (15,000).

Repeat head CT showed a small amount of blood in the occipital horns and a communicating hydrocephalus. He was sedated and intubated, with coarse bronchial breath sounds bilaterally, tachycardia, and ashen lower extremities. On neurologic exam, his cranial nerves were intact. He moved all 4 extremities spontaneously and in response to pain, with no clear asymmetry.

Platelets were infused to relieve the intracranial pressure, and an intraventricular catheter was placed for ongoing intracranial pressure management. He had multiple septic emboli to feet, kidneys, brain, liver, and lungs and developed cardiac, renal, and liver failure. He was treated with antibiotics and renal dialysis. He developed a deep venous thrombosis, and an inferior vena cava filter was placed.

Despite these efforts, the patient failed to improve neurologically and remained in a vegetative state. Ultimately, his family indicated that he would not wish to remain in this state, supportive measures were withdrawn, and he died.

Biological basis

	• Key bacterial factors that enable Staphylococcus to cause disease are surface and secreted proteins.
	• Surface factors involved in staphylococcal pathogenesis include its biofilm-forming capacity, capsule, and adhesins.
	• Secreted proteins include proteases or host protease modulators promoting invasion, host immune evasion, and extracelluar matrix disruption.
	• S aureus pathogenicity within the central nervous system is likely attributed to host inflammatory response.

Etiology and pathogenesis

The genus Staphylococcus consists of at least 20 different species of gram-positive spherical bacteria. They are usually found in irregular clusters but can occur as single cells, pairs, or chains. They are nonmotile and do not form spores. They grow well on many types of media, under aerobic conditions, and at body temperature. At room temperature, they ferment carbohydrates to produce lactic acid and pigments with colors ranging from white to orange to yellow. Some species are a normal part of human skin flora, whereas others are serious pathogens, particularly causing surgical infections. The pathogenic species typically hemolyze blood, produce toxins, and are coagulase- and catalase-positive. Antibiotic-resistant forms of the organism are a major clinical problem (16).

Staphylococcus aureus causes infection throughout the upper and lower respiratory tracts by direct spread from nasopharyngeal colonization. It causes infection in other regions of the body, including the central nervous system, via hematogenous or direct spread.

The importance of various bacterial factors in promoting virulence is typically demonstrated in 2 ways. One approach is to generate mutants that lack a particular protein and demonstrate reduced virulence. Another is to show that immunization with a purified component produces antibodies that confer protection in animal models.

Key bacterial factors that enable Staphylococcus to cause disease are cell surface and secreted proteins (43). The surface factors allow the organisms to colonize the respiratory tracts, skin, or other surfaces and also to attach to organs where they cause disease. Secreted proteins include proteases or host protease modulators that promote invasion, host immune evasion, and extracellular matrix disruption (92). The secreted proteins are toxins that can cause severe disease, including toxic shock syndrome, scalded skin syndrome, and food poisoning, but are not as critical in the development of neurologic disease. S aureus also has factors that allow it to respond to host-derived and environmental stimuli by adapting expression of various metabolic and virulence genes (43). This adaptive ability contributes to the prevalence of antibiotic resistance among staphylococcal species.

Virulence gene regulation in staphylococci is exemplified by the accessory gene regulator (agr), which senses bacterial density and responds by modulating toxin production (18). During times of low cell density, agr increases expression of surface adhesins to facilitate colony growth. During times of high cell density, agr switches expression to favor secreted proteins. There are other regulatory genes that respond to various environmental stimuli, such as salt, pH, glucose, oxygen, and antibiotics (65). Many of these genes are controlled by 2-component systems involving membrane-bound histidine kinases that autophosphorylate in response to external stimuli. Examples of 2-component systems include agr, ArIRS, SaeRS, and SrrAB (26). The complexities of this network make understanding staphylococcal regulation a difficult task. One disrupted pathway may be compensated by another pathway, so that an observed phenotype is not truly reflective of the function of the disrupted pathway. Such redundancy obviously gives Staphylococcus a survival advantage. However, agr appears to be a central hub on which other regulatory pathways converge (65).

Key surface factors involved in staphylococcal pathogenesis include biofilm, capsule, and adhesins. Biofilm is a matrix of polysaccharides produced and inhabited by bacteria that enables them to adhere to inert surfaces, such as catheter tips in the blood or CSF or indwelling hardware. Biofilms are common to many bacteria, including coagulase-negative staphylococcal species. Colonization of inert surfaces is a 2-step process involving nonspecific adherence of individual cells to the inert surface followed by biofilm formation, and recruitment and growth of additional bacteria (65). The genes ica and aap are important for biofilm production and may be important determinants of Staphylococcus epidermidis device-related meningitis (101). Although S aureus isolates from indwelling medical devices have greater biofilm-forming capacity than isolates from endocarditis or osteomyelitis, no differences in clinical outcomes based on biofilm formation have been demonstrated (52).

At least 11 serotypes of polysaccharide capsule have been reported in Staphylococcus aureus (44). Organisms with capsule types 5 and 8 are antiphagocytic, have increased virulence in animal models (104), and are responsible for up to 85% of clinical staphylococcal infections (65; 34).

Surface adhesins allow staphylococcus to adhere to a variety of host proteins. More than 20 of these proteins exist in S aureus (73). Those encoded by the sasG and sasH genes are associated with invasive staphylococcal disease, including bacteremia and meningitis (84).

Various bacterial and host factors contribute to pathogenicity of the organism within the central nervous system. In its attempt to mitigate infection, the host inflammatory response likely causes much of the pathological damage. Lipoteichoic acids are cell wall components that are implicated in inflammation by triggering the innate immune system and release of cytokines by macrophages (28). Peptidoglycan is the major scaffold for anchoring surface adhesins to the cell wall but is also recognized by the innate immune system to trigger cytokine release and inflammation (58). In fact, the combination of both lipoteichoic acids and peptidoglycan can cause synergistic host recognition and inflammation, leading to elimination of bacteria (28). The bacterial capsule and protein A of S aureus hide these structures from host recognition (75; 104).

In vitro studies show that staphylococcal infection may activate proinflammatory mechanisms within the microvascular endothelium in the brain causing increased blood-brain barrier permeability, dose-dependent release of cytokines and chemokines, reduced expression of interendothelial junction proteins (VE-Cadherin, claudin-5, and ZO-1), and activation of both canonical and noncanonical NF-κB pathways (62).

Epidemiology

	• Patients with chronic diseases are at increased risk for staphylococcal infections.
	• Staphylococcus is the most common pathogen to cause neurologic complications in patients who have had neurosurgical procedures or trauma, or who have indwelling CSF shunts.

Patients with various underlying conditions, such as alcoholism, cancer, chronic renal failure with hemodialysis, diabetes mellitus, injection drug use, and other chronic diseases are at increased risk for staphylococcal infections (97). In one study, Staphylococcus aureus bacteremia in patients with no underlying medical condition was always associated with a detectable infectious focus (66). Up to 20% of staphylococcal meningitis occur in the setting of endocarditis or paraspinal infection; other infectious sources include skin and soft tissue, sinuses, bones, joints, and lungs (107).

S aureus accounts for up to 9% of cases of bacterial meningitis (77). However, staphylococcus is the most common pathogen to cause neurologic complications in patients who have had neurosurgical procedures or trauma or who have indwelling CSF shunts, overall constituting about 40% of nosocomial meningitis (21; 93). Risk factors for postcraniotomy meningitis include higher age, emergency procedures, CSF leak, external ventricular drain, ICU admission, duration of drain placement for > 72 hours, longer duration of surgery, repeat operations, and trauma (21).

Staphylococcus epidermidis and S aureus are the most common causes of meningitis in patients with CSF shunts and are associated with direct contamination of the CSF, such as in the postoperative or posttraumatic period (46; 86; 23). S aureus meningitis is more common in patients with an associated bacteremia, and the incidence of S aureus bacteremia has been increasing over the past 20 years or so (113). In fact, in one study, S aureus was the most frequent cause of community-onset bacteremia at 18%, Escherichia coli was second at 15%, coagulase-negative staphylococci was third at 12%, and pneumococci was fourth at 7% (53). S aureus is also a leading cause of nosocomial bacteremia, particularly in association with intravascular and urinary catheters (113). In a series of postneurosurgical infections, the incidence of invasive MRSA infections significantly declined between 2006 and 2015, likely an effect of improved infection control protocols (94). Nevertheless, MRSA is an important nosocomial pathogen to consider after neurosurgical procedures as its mortality is as high as 45% (77).

S aureus is also becoming an increasingly frequent etiology for infectious endocarditis, accounting for about 30% of native valve endocarditis, 70% of endocarditis in intravenous drug users, and 20% of prosthetic valve endocarditis (64). In a study, MRSA accounted for 6.5% of prosthetic valve endocarditis (112). S aureus meningitis incidence presumably follows these bacteremia and endocarditis trends. In a study of patients with left-sided infective endocarditis, 25% experienced encephalopathy and meningitis (33). Cultures taken from those who developed neurologic sequelae revealed that S aureus was the most commonly isolated organism.

Staphylococcal pyomyositis is more common in Africa and the South Pacific than in North America, for unknown reasons. However, its incidence is rising in the United States and Europe, probably due to the increase in community-acquired MRSA (89). It occurs in all age groups but is significantly more frequent in those under 30 years old and in men (12). Pyomyositis is associated with various disease states, including human immunodeficiency virus (HIV), diabetes mellitus, organ transplant, and chronic kidney disease. In a study of pyomyositis patients in the United States between 2002 and 2014, 46% were positive for MSSA and 20% were positive for MRSA (60).

It is important to note that patients with a history of intravenous drug use have increased rates of S aureus colonization and subsequent bacteremia compared to the general population (79). Intravenous drug use is also associated with a greater than 16-fold risk of developing invasive MRSA infection, the prevalence of which has grown from 4.1% to 9.2% between 2011 and 2016 within this population (42).

Prevention

	• Current vaccine candidates directed against S aureus toxins, secretory proteins, surface proteins, or cell wall components have not demonstrated protection against bacteremia in humans.
	• Prevention of postoperative meningitis relies on careful surgical technique to avoid CSF leak.

An effective, safe vaccine against infection from Staphylococcus is not available, despite years of research. Some vaccines have seemed to ameliorate clinical disease, but none have prevented new infection (63). Antibodies against various polysaccharide capsular types of Staphylococcus aureus are protective in animal models of sepsis, and a conjugate vaccine directed against type 5 and type 8 capsules demonstrated some efficacy in hemodialysis patients (90). However, protection waned over 40 weeks as antibody levels decreased. Subsequent studies demonstrated the effectiveness of a booster immunization to maintain protective antibody levels for an extended time period (30; 83). Despite these seemingly promising results, the manufacturer announced in early 2005 that it would not continue development of the vaccine. Current vaccine candidates directed against toxins, secretory proteins, surface proteins, or cell wall components are in the preclinical or early clinical phase, but none have demonstrated protection against bacteremia in humans to date (05). However, a vaccine candidate involving the use of bacterial outer membrane vesicles as a vehicle for lipidated S aureus antigens has demonstrated a robust antibody response in mouse models (41).

One study showed that CSF leakage is by far the strongest predictor of nosocomial bacterial meningitis after craniotomy (48). Perisurgical antibiotic prophylaxis did not prevent development of bacterial meningitis, though such prophylaxis did prevent infection of the surgical incision (49). Prevention of postoperative meningitis therefore relies mostly on careful surgical technique to avoid CSF leak.

Prophylactic catheter exchange does not significantly reduce the incidence of ventriculostomy-related ventriculomeningitis (17). Routine ventriculostomy catheter changes are associated with increased catheter-related infections and increased median hospital and neurosurgical intensive care unit stays compared to catheter changes only when clinically indicated (45). Insertion of antimicrobial impregnated ventriculostomy catheters is proposed to prevent bacterial colonization along the catheter surface, thereby reducing the risk of device-related ventriculomeningitis; however, the possible induction of antimicrobial resistance, leading to major health care problems, remains a significant concern. Silver-impregnated catheters may decrease rates of catheter-related CSF infection without inducing antimicrobial resistance (31). However, no significant difference in CSF infection rates have been found between antimicrobial or silver-impregnated catheters compared to conventional catheters (114).

As hematogenous seeding plays a significant role in the development of S aureus meningitis (01), adequate management of extra-CNS infection may prevent CNS infection.

Differential diagnosis

Confusing conditions

The etiology of bacterial meningitis encompasses a broad differential of causative organisms. Suspected pathogens are largely based on patient age and various environmental risk factors.

Following neurologic surgeries or trauma, meningitis or brain abscess is frequently due to Staphylococcus (38), along with pneumococcus and nontypeable Haemophilus influenzae. In the setting of a preceding sinusitis, otitis media, head trauma, neurosurgical procedure, or CSF leak, Streptococcus pneumoniae, nontypeable H influenzae, and Staphylococcus epidermidis are common etiologic agents of meningitis (47), because all are a common part of “normal” skin and nasopharyngeal colonization. Surgical repair of CSF leaks of various origins effectively prevents recurrent bacterial meningitis (10).

S pneumoniae and Neisseria meningitidis are the most common etiologic agents of bacterial meningitis at all ages after the neonatal period. In children less than one year of age, Group B streptococci and gram-negative enteric bacilli, particularly Escherichia coli, are the leading etiologic agents, presumably because of exposure to these agents during birth. Due to passive transfer of maternal antibodies, these neonates do not typically develop H influenzae infection or pneumococcal or meningococcal meningitis.

In patients over 50 years of age, the most common causes of bacterial meningitis include S pneumoniae, N meningitidis, and gram-negative bacilli (37; 80). H influenzae is included in the gram-negative group, along with E coli, Enterobacter, and Pseudomonas. S pneumoniae is more likely to cause meningitis in association with pneumonia. Pseudomonas meningitis is more common in those with chronic lung disease. E coli or Enterobacter meningitis is more common in the setting of chronic urinary tract infection, and Staphylococcus aureus is more common in the setting of endocarditis. Listeria monocytogenes meningitis is more common in the immunosuppressed and elderly.

The signs and symptoms frequently seen with acute bacterial meningitis, including fever, behavioral or personality changes, and mental status changes, can be nonspecific and suggest other diagnoses, including systemic infection or sepsis, viral encephalitis or meningitis, fungal or tuberculous meningitis, trauma or closed head injury or child abuse, multiple metabolic abnormalities (hypoglycemia, ketoacidosis, electrolyte imbalance, uremia, toxic exposure), seizure, and brain tumor. Even meningismus does not exclude alternative diagnoses, such as subarachnoid hemorrhage, intracranial hemorrhage, and epidural abscess. Less common differential diagnoses include systemic lupus erythematosus, Behçet syndrome, benign recurrent lymphocytic meningitis, leptomeningeal carcinomatosis, HIV, neurosarcoidosis, neurosyphilis, or drug-induced meningitis (67). In order to prevent morbidity and mortality from missed diagnoses, it is important to keep a low index of suspicion for acute bacterial meningitis and err on the side of starting treatment early.

Associated or underlying disorders

In a study of 350 Spanish patients with Staphylococcus aureus meningitis between 1981 and 2015, 60% of patients had severe underlying comorbidities, including diabetes, cerebrovascular or cardiovascular disease, malignancy, and immunodeficiency. The most common risk factors for developing meningitis included previous MRSA infection, presence of implanted devices, and antimicrobial therapy. Of note, 47% of patients had an associated S aureus infection elsewhere in the body, including a surgical site or soft tissue infection, pneumonia, or endocarditis (77).

Diagnostic workup

	• CSF cultures are the gold standard for diagnosing staphylococcal meningitis.
	• CT imaging of the brain should be considered prior to CSF examination to assess the risk of brain herniation in suspected bacterial meningitis.

Bacterial meningitis, including that caused by Staphylococcus, should be considered and promptly treated in any patient with signs of fever, nuchal rigidity, altered mental status, and a clinically compatible picture. The initial presentation may be atypical in some patients, especially young children and the elderly. CSF examination showing a predominantly neutrophilic pleocytosis with decreased glucose and increased protein concentrations is strongly suggestive of bacterial meningitis and should prompt broad antibiotic coverage, although, importantly, treatment should not be delayed in order to obtain CSF. Brain imaging should also be considered prior to CSF examination because bacterial meningitis can cause sufficient brain edema to make a lumbar puncture hazardous. Data on risk of herniation and findings of CT scans have been added to guidelines (35; 25). Indications for brain imaging before lumbar puncture include altered mental status, new-onset seizure or focal neurologic deficit, immunocompromise, or history of CNS disease (105). However, it should be noted that one study found that removing altered mental status as an indication for imaging in patients with acute bacterial meningitis led to significantly decreased mortality, from 11.7% versus 6.9% (36). No tests are currently available that are rapid enough to confirm Staphylococcus as the causative organism in time to base initial treatment on that finding.

With staphylococcal meningitis, as well as most other etiologic agents, both blood and CSF cultures will usually be positive. However, again, treatment should be initiated without delay, even prior to obtaining culture samples. In Staphylococcus aureus bacteremia, the first two blood cultures are positive in more than 90% of cases (65). When endocarditis is the source of the bacteremia, as it often is with S aureus, the volume of blood cultures is critical because there may be as few as 1 to 100 bacteria per milliliter of blood (65). Therefore, 8 to 12 mL of blood should be drawn for each culture, using careful sterile technique. In the unusual case in which cultures may be sterilized by antibiotic administration prior to sample procurement, several immunological and PCR-based methods are available for detecting bacterial antigen or nucleic acid.

Diagnosis of nosocomial bacterial meningitis and ventriculitis is not as straightforward as diagnosis of community-acquired bacterial meningitis. Clinical signs and symptoms and CSF pleocytosis are often unreliable or nonspecific in the presence of underlying neurologic disease or prior neurosurgical procedure. No single CSF parameter can reliably diagnose ventriculostomy-related ventriculitis or meningitis (17). CSF cultures, still regarded as the gold standard of diagnosis, are positive in 70% to 85% of cases before antibiotic administration. In a series of nosocomial meningitis, fever was present in 82%, high serum CRP in 86%, and CSF cultures were positive in 79% (93).

For intracranial abscesses, in addition to MRI or CT imaging, CT-guided needle aspiration or open abscess drainage and evacuation may assist in determination of the exact pathogen. Lumbar puncture is generally contraindicated in individuals with suspected brain abscess.

Management

	• Prompt initiation of empiric antibiotic therapy is the mainstay of treatment in suspected bacterial meningitis.
	• Targeted antibiotic therapy can be established after speciation of cultures and identifying the extent of extra-CNS infection.

When bacterial meningitis is suspected, emergent antibiotic treatment must be initiated, even before lumbar puncture, as delays are associated with increased mortality (06; 13). In persons older than the neonatal period, empiric treatment for community-acquired bacterial meningitis is directed primarily against Streptococcus pneumoniae and Neisseria meningitidis. The current recommendation for the treatment of community-acquired meningitis for adults younger than 60 years of age is cefotaxime 2 g every 6 hours or ceftriaxone 2 g every 12 hours. For patients 60 years or older, amoxicillin 2 g every 4 hours should be added to the antibiotic regimen. Vancomycin 15 to 20 mg/kg intravenously every 12 hours or rifampin 600 mg every 12 hours may be added if a penicillin-resistant organism (eg, pneumococcus) is suspected. European and UK guidelines for the treatment of bacterial meningitis were published in 2016 (61; 110). The latest U.S. guidelines for community-acquired bacterial meningitis were published in 2004 (105).

If the setting is for healthcare-associated meningitis, practice guidelines published in 2017 offer specific antibiotic regimen recommendations (106). In these settings, empiric treatment is directed primarily against cutaneous staphylococcus species and, due to increasing incidence, gram-negative bacteria (106). If the meningitis is associated with a CSF shunt or other foreign or surgical object, the infectious source should be removed (106).

If final speciation is pending and Streptococcus pneumoniae meningitis is suspected, dexamethasone may be used as adjunctive therapy to prevent hearing loss and other associated neurologic complications. The recommended dosage of dexamethasone is 0.15 mg/kg every 6 hours given with, or 15 to 20 minutes prior to, antibiotics for the first 4 days of therapy. If antibiotics have already been initiated, European and UK guidelines recommend dexamethasone can be given up to 4 and 12 hours after the first dose of antibiotics, respectively (61; 110). Debate about this recommendation is still ongoing (27; 111) because speciation is rarely known at the time of treatment initiation, and the benefit for other forms of community-acquired bacterial meningitis is not as well established (105). However, it is part of the current guidelines for the treatment of bacterial meningitis (105; 110). Dexamethasone 0.15 mg/kg every 6 hours initiated prior to the first dose of antibiotic and continued for the first 2 to 4 days of treatment decreases the risk of neurologic sequelae from community-acquired bacterial meningitis in children (55; 70; 102). Overall, these results suggest that dexamethasone should be strongly considered in any patient with suspected community-acquired bacterial meningitis and especially in all children and in adults at risk for S pneumoniae meningitis. Dexamethasone therapy should ideally only be continued if the diagnosis of S pneumoniae meningitis is confirmed. Additionally, there is insufficient evidence to support the use of dexamethasone for bacterial meningitis in neonates (105).

After speciation of Staphylococcus, therapy can be tailored based on antibiotic sensitivity (07; 08). For MSSA infection, treatment can be switched to nafcillin or oxacillin 2 g intravenously every 4 hours. For infection from MRSA, treatment should be continued with vancomycin 15 mg/kg intravenously every 8 to 12 hours, dosed to maintain serum trough concentrations of 15 to 20 ug/ml. A loading dose of 20 to 35 mg/kg may be considered for seriously ill patients with suspected MRSA infection (56). For Staphylococcus epidermidis infection, treatment should be continued with vancomycin. In cases with vancomycin resistance or clinical failure of vancomycin, linezolid is often effective (69). The total duration of treatment should be 10 to 21 days, but if infection is associated with a brain abscess, treatment will need to be longer. An abscess may also require surgical drainage.

For nosocomial ventriculitis and meningitis, treatment should similarly be initiated promptly and continued for 10 to 14 days. However, rigorous data are absent regarding the duration of treatment for nosocomial infections, particularly if the culture is negative. Patients already receiving antibiotics who develop nosocomial infections or patients with devices and recurrent infections often pose a specific challenge due to antibiotic resistance. No antibiotics are currently approved for intrathecal use by the U.S. Food and Drug Administration, and no strong data exist on indications for intrathecal treatment (106). However, intrathecal therapy may be considered for severe ventriculitis, persistently positive CSF cultures despite appropriate intravenous dosing, multidrug-resistant pathogens, intolerance of systemic antibiotic administration, or when device removal is not feasible (99). Antibiotics used intrathecally include vancomycin, gentamicin, and daptomycin (29). Vancomycin is well tolerated when administered intrathecally.

When staphylococcal meningitis and bacteremia occur with other foci of infection, such as osteomyelitis or endocarditis, antibiotic treatment must often continue for at least 4 to 6 weeks and may require surgical debridement of extra-CNS sites of infection (65). Indications for heart valve replacement include heart failure and recurrent septic embolization after effective antibiotic therapy has been established. The decision to perform heart valve surgery can be especially difficult in the setting of cerebral emboli because anticoagulation during extracorporeal circulation and after valve replacement (if indicated) puts the patient at significant risk for hemorrhagic conversion of septic infarctions (65). However, one study showed that patients with infective endocarditis and septic cerebral infarction who have valve replacement within the first 72 hours after stroke have significantly better outcomes compared to those treated with medical management alone or to those treated with surgery more than 8 days after stroke (78; 85). Although there was previously concern regarding early surgery exacerbating neurologic injury, such as reperfusion hemorrhage, studies suggest that most patients with septic embolic stroke have improved neurologic outcomes and mortality rates with early surgery (115).

For intracranial epidural abscesses, an empiric regimen of antibiotics should be chosen that takes into account the site of origin, and hence, most likely pathogens. To date, no randomized controlled trials have assessed the efficacy of different antibiotic regimens for the treatment of intracranial epidural abscesses. In instances where staphylococcal infection is suspected, a regimen covering staphylococcal, streptococcal, and gram-negative bacilli should be chosen. These regimens largely include intravenous vancomycin plus metronidazole plus a cephalosporin. Once a specimen has been obtained that reliably allows for speciation, the antibiotic regimen can be tailored accordingly. This might not be the case for nosocomial meningitis, where cultures often remain negative or may only be partially growing due to prior antibiotic exposure (106)

In addition to antibiotics, it is imperative that appropriate supportive care be instituted. Advancements in intensive care techniques offer significant benefit for patients with bacterial meningitis, including staphylococcal meningitis (103).

Guidelines for the treatment of pyomyositis are similar to the staphylococcal-specific regimens for meningitis, with duration of parenteral treatment of 2 to 3 weeks (100). If there is evidence of abscess formation, it should usually be drained (72).

A new and novel class of anti-infectives are lysins, which are derived from bacteriophages. They represent highly evolved enzymes that cleave essential bonds in the bacterial cell wall peptidoglycan for phage progeny release. Lysins can eliminate bacteria both systemically and topically and can act synergistically with antibiotics by resensitizing bacteria to nonsusceptible antibiotics. The advantages over antibiotics are their specificity for the pathogen without disturbing the normal flora, the low chance of bacterial resistance, and their ability to kill colonizing pathogens on mucosal surfaces, a capacity previously unavailable. Lysins, therefore, may be a much-needed antimicrobial in an age of mounting antibiotic resistance (32).

Outcomes

In a study of 350 Spanish patients with Staphylococcus aureus meningitis between 1981 and 2015, the overall 30-day mortality rate was 23%. In particular, patients with nosocomial infections in the setting of CSF devices had an overall 30-day mortality of 18%. Neither empiric antibiotic therapy nor the use of multiple antimicrobials targeted against culture isolates was associated with decreased mortality (77).

Special consideration must be taken with regards to the use of vancomycin in high doses or for prolonged periods of time, particularly in the setting of suspected staphylococcus infection. Higher doses or higher trough levels can result in nephrotoxicity and high-frequency hearing loss in the elderly, especially when used concomitantly with aminoglycosides (56). Although future studies are indicated to further delineate this association, it is important to avoid vancomycin toxicity by maintaining appropriate trough levels.

Special considerations

Pregnancy

Little is known about the neurologic complications of staphylococcal infection in pregnancy, but they are presumably similar to the complications seen in nonpregnant individuals. Little is known about the possibility of vertical transmission of Staphylococcus from mother to fetus, but it does not seem to be a significant issue (04). Rarely, cases of staphylococcal meningitis have been attributed to postpartum endometritis (02).

The penicillins and the cephalosporins are likely safe in pregnancy. The risk of vancomycin in pregnancy is unknown. As with any such decision during pregnancy, the possible risk to the fetus must be weighed against the potential benefit to the mother.

Anesthesia

Epidemiological studies suggest that postoperative Staphylococcus aureus infection is predominantly due to transmission from patient skin colonization rather than healthcare provider contact. Both the patient and subsequent patients in the same operating room are at risk of infection. This emphasizes the importance of proper decolonization and sanitization techniques undertaken by both patient and provider (57). The 2017 Centers for Disease Control guidelines for the prevention of surgical site infection recommend that patients bathe or shower with soap or an antiseptic agent on the night prior to surgery, at the least. Patients with normal pulmonary function undergoing general anesthesia with endotracheal intubation should be given an increased fraction of inspired oxygen both intraoperatively and in the immediate postoperative period after extubation to prevent the incidence of surgical site infections (11).

Spinal epidural abscess, usually caused by staphylococcus, can rarely be seen after epidural anesthesia (22; 82). To prevent such complications, anesthesia providers must ensure implementation of standard precautions before, during, and after neuraxial anesthesia procedures. Precautions include proper hand hygiene and the use of sterilized facemasks, gowns, gloves, and drapes (59).