Staphylococcal infections: neurologic manifestations …

Shelia Dunaway MD

Infectious Disorders

Updated 07.11.2025
Released 10.19.2006
Expires For CME 07.11.2028

Staphylococcal infections: neurologic manifestations

Author: Shelia Dunaway MD

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Editor: Christina M Marra MD

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Staphylococcal infections: neurologic manifestations

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Introduction

Overview

Staphylococci are one of the leading infectious causes of mortality worldwide, second only to Mycobacterium tuberculosis (48). Neurologic complications occur with both nosocomial and community-acquired staphylococcal infections. Specifically, staphylococcal meningitis is increasingly common and accounts for significant morbidity and mortality in all age groups (145). Prompt recognition and treatment can improve outcomes. Clinical manifestations of staphylococcal infections, with an emphasis on neurologic symptoms and key features that can help with diagnosis, management, and treatment, are reviewed.

Key points

	• Community-acquired staphylococcal infections account for significant morbidity and mortality in all age groups.
	• Staphylococcal infections are among the leading causes of bacterial meningitis in patients following neurosurgical procedures or neurologic trauma.
	• Neurologic complications of staphylococcal infections may occur due to hematogenous (thromboembolic, disseminated) spread or may arise contiguously from adjacent infections.

Historical note and terminology

Staphylococci were first identified and cultured by Pasteur and Koch in the late 1800s (91). Ogston identified Staph as the cause of abscesses in 1881 and coined the name “Staphylococcus” from the Greek “staphyle” due to the appearance of grape-like clusters when viewed with a microscope. In 1884, Rosenbach added the term “aureus” to the pathogenic species due to its gold color in colonies. Staphylococci were initially grouped together with micrococci but now belong to the family Staphyloccaceae (104).

The genus Staphylococcus includes several species pathogenic to humans. Staphylococcus aureus belongs to a subgroup of coagulase-positive staphylococci. Coagulase-negative staphylococci (CoNS) are generally less pathogenic but are also frequently associated with nosocomial or hardware-associated infections. Commonly isolated CoNS include Staphylococcus epidermidis, Staphylococcus lugdunensis, and Staphylococcus haemolyticus. Staphylococcus lugdenensis is more pathogenic than other CoNS and often presents similarly to Staph aureus clinically.

Clinical manifestations

Presentation and course

	• Common neurologic manifestations of staphylococcal infections include meningitis, septic thromboemboli with or without brain abscess, and epidural abscesses.
	• Patients with Staphylococcus aureus meningitis attributed to hematogenous dissemination may present with concomitant endocarditis, bacteremia, and/or osteomyelitis.

The clinical manifestations of Staphylococcus aureus are broad, ranging from skin and soft tissue infection to bacteremia, endocarditis, pneumonia, osteomyelitis, and meningitis. The most common neurologic S aureus infections include meningitis, septic thromboemboli, and epidural abscesses. Staphylococcus aureus is typically more virulent, but coagulase-negative staphylococci are one of the most frequent pathogens associated with post-neurosurgical infections or neurologic trauma (119).

Staphylococci are part of the normal flora of the human skin, upper respiratory system, and gastrointestinal tract. Up to one third of adults are colonized with Staph aureus, and colonization increases risk of infection, including skin abscesses (149). Such lesions usually heal with drainage, with or without antimicrobials. More serious staphylococcal infections can occur spontaneously or as complications of wounds, due to trauma, or postoperatively. When staphylococcal bacteremia occurs, dissemination of the infection can involve numerous organ systems with complications, including endocarditis, osteomyelitis, meningitis, epidural abscess, and septic emboli to the lungs, extremities, and brain.

Meningitis. Staphylococcus aureus is one of the most common causes of bacterial meningitis after penetrating head injuries (106). In addition to S aureus, coagulase-negative staphylococci are also common causes of bacterial meningitis following neurosurgical procedures or CSF shunt placement (70). Neurologic staphylococcal infections can also occur as complications of bacteremia or endocarditis, resulting in secondary infections, including meningitis and septic emboli to the brain.

Staphylococcal meningitis presents similarly to other bacterial meningitides. Meningitis symptoms typically include fever, headache, nausea, vomiting, irritability, and lethargy, proceeding to further altered mental status and then progressing to obtundation, and ultimately, death (142). The classic triad of fever, nuchal rigidity, and altered mental status was noted to be more common in patients 60 years of age or older in one study (148). However, other reviews have noted that elderly patients are less likely to report fever, headaches, nausea and vomiting, or nuchal rigidity and may present with subtle neurologic symptoms, such as disorientation, fatigue, drowsiness, or sensitivity to light (27). Overall, headaches are the most common presenting symptom. Fever may be 103° F or higher. Clinical signs include evidence of meningeal irritation with neck stiffness and pain on flexion, though this finding may be absent in immunocompromised or comatose patients. Patients may rarely present with seizures. Focal signs, such as aphasia, localized weakness and paresis, cranial nerve palsy, or papilledema, may also appear due to abscess formation or septic emboli (104).

Hematogenous. When attributed to hematogenous dissemination, 21% of patients with Staphylococcus aureus meningitis have concomitant endocarditis, and 12% have osteomyelitis. Compared to other etiologies, hematogenous S aureus meningitis is a more severe disease, with a higher mortality, and requires evaluation for other sources or foci of infection (60). Secondary sites of infection should be sought, particularly in patients with implanted prosthesis, cardiac valvular disease, or persistent fever or bacteremia (57).

Patients with S aureus bacteremia and endocarditis often present with fever, tachycardia, and hypotension (“sepsis”). Patients may 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 and even the need for mechanical ventilation and vasopressors. Assessment should include evaluation for cardiac murmur and for petechiae, Roth spots, and Janeway lesions indicative of septic emboli. However, these lesions may not be seen with S aureus endocarditis because the presentation is often too fulminant.

Secondary to trauma, surgery, or contiguous source of infection. Staphylococcus aureus is one of the most common causes of bacterial meningitis after penetrating head injuries. Postoperative meningitis is usually localized and is often associated with surgically implanted hardware. In addition to S aureus, coagulase-negative staphylococci are also common causes of bacterial meningitis following neurosurgical procedures or CSF shunt placement (70).

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. Patients with recent neurosurgery or neurotrauma or who have a CNS shunt should have a thorough evaluation for CNS infection with any worsening of mental status or neurologic exam, fever, or new leukocytosis. The course of nosocomial meningitis is frequently fulminant, with rapid neurologic deterioration leading to respiratory arrest and death. Therefore, initiation of appropriate antibiotic treatment must not be delayed (151).

Diagnostic evaluations for meningitis include CSF gram stain and culture, CSF glucose and protein, CSF opening pressure, and, if indicated, CSF imaging with computed tomography. CSF cell count and protein levels may be elevated due to the underlying condition but typically increase over baseline and decrease with appropriate antimicrobial therapy (79). With external ventricular drains, even gram stains and cultures can be subject to contamination (115). Thus, close monitoring and a low threshold for treatment of bacterial infections are required.

Contiguous sources of meningitis include otitis, sinusitis, and mastoiditis, and the presence of these underlying illnesses should be evaluated.

Septic emboli and mycotic aneurysm. Symptomatic neurologic events may occur in as high as 80% of patients with infective endocarditis (55). All patients with S aureus bacteremia or endocarditis should be evaluated for meningitis and septic emboli because the presence of metastatic infection may impact surgical management and may warrant longer duration of treatment (35). In addition to meningitis, other neurologic complications of staphylococcal endocarditis or bacteremia include cerebral infarction, parenchymal and subarachnoid hemorrhages, and mycotic aneurysms (55). These complications occur in about 40% of cases; however, this figure may be underestimated because patients with staphylococcal endocarditis may not have a complete neurologic evaluation given the urgent nature of their non-neurologic issues (83). Although cerebral infarctions can arise from septic thromboemboli, studies suggest that small-vessel vasculitis secondary to systemic bacteremia-mediated inflammation also plays a role (28). Up to an additional 30% of patients may have silent cerebral septic emboli (123).

The risk of embolization is proportional to the size of the valvular vegetation and decreases rapidly within the first few days of effective antimicrobial therapy (131). Patients with cerebral septic emboli will typically present with multiple cerebral infarctions in various vascular distributions, and they may also have intraparenchymal hemorrhages. Patients with mycotic aneurysms may suffer from subarachnoid hemorrhage (104).

Brain abscess and subdural empyema. Brain abscesses arise from contiguous infection (otitis, sinusitis, or mastoiditis), hematogenously, or secondary to trauma and surgical intervention. Hematogenous brain abscesses are typically located in the distribution of the middle cerebral artery at the junction of gray and white matter. There are often multiple abscesses, and they may be multiloculated (17). These arise from the distal site of infection, including pneumonia and lung abscess, and endocarditis. Right-to-left shunts (patent foramen ovale, congenital cyanotic heart disease) increase the risk (18). Patients typically present with headaches and focal neurologic signs. Abscesses larger than 2.5 cm with mass effect typically require neurosurgical intervention in addition to prolonged antimicrobial therapy.

Subdural empyema, an abscess occurring between the dura and arachnoid, is usually related to sinusitis, otitis media, or mastoiditis. It typically presents as an acute illness with fever and has rapid neurologic deterioration that requires urgent neurosurgical intervention and antibiotics (02).

Epidural abscess. Epidural abscesses can arise hematogenously or contiguously from an infected focus. These are usually located in the spine but may also occur intracranially (140). Spinal epidural abscesses present with localized back pain that may progress to radiculopathy and even paresis, and they are more common in the thoracolumbar region (39). Patients may have fever and leukocytosis, but this is not consistent and may lead to missed diagnosis (32).

Intracranial epidural abscesses are less common and can be a consequence of sinusitis, mastoiditis, or otitis but are more commonly secondary to neurosurgical procedures. Clinical symptoms and signs relate to the expanding mass effect on the brain and may manifest with focal signs, seizures, or signs of elevated intracranial pressure (124).

In patients with staphylococcal meningitis and bacteremia, a low index of suspicion should be maintained for osteomyelitis. Symptoms of osteomyelitis include pain and swelling at the distal ends of long bones in children and pain arising from the vertebral bodies in adults (104). Chronic infection can persist for an extended period, so this should be considered in any patient with a history of staphylococcal bacteremia and appropriate symptoms. Vertebral osteomyelitis can progress to inflammation with phlegmon and epidural abscess, resulting in neurologic compromise with spinal cord compression and potential irreversible paresis (116).

Other. Staphylococcus aureus infection can affect any organ system. Septic arthritis, including prosthetic joint infection, is often seen with Staphylococcus aureus bacteremia (144). Patients with new onset of pain, erythema, warmth, tenderness, or edema of a joint in the setting of Staph aureus bacteremia should have a thorough evaluation for septic arthritis, including an arthrocentesis with cell count, gram stain, and cultures. Staphylococcus aureus pneumonia can occur after viral infections as nosocomial pneumonia or secondary to hematogenous spread, leading to septic emboli, lung abscess, and empyema. Other staphylococcal infections include pyomyositis, sinusitis, septic bursitis, pericarditis, and endophthalmitis (84).

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; thus, both mortality and morbidity are worse in hematogenous cases versus postoperative cases (60). Mortality in hematogenous cases has been reported to be as high as 56% (96), and mortality is higher with S aureus meningitis compared to meningitis caused by other staphylococcal species (29). Independent factors associated with mortality from S aureus meningitis include septic shock, methicillin-resistant S aureus (MRSA) infection, non-postoperative infection, and coma (100). Not surprisingly, post-craniotomy patients who develop bacterial meningitis have a significantly higher mortality than those who do not develop meningitis (67), with the mortality reported between 5% and 19% (31; 121). MRSA infection after major surgical procedures is associated with higher morbidity, including higher rates of in-hospital deaths and longer length of stay compared to patients without MRSA (06).

Administering appropriate antibiotic therapy early is associated with decreased mortality from bacterial meningitis. Morbidity remains high even with the optimal treatment. Worse outcomes are associated with age under 2 years, leukocytosis, and CSF glucose under 45 mg/dL (21). Neurologic complications of acute bacterial meningitis include hydrocephalus (23.1%), subdural effusion (19.4%), and epilepsy (12%). Other complications include subdural empyema, ischemic or hemorrhagic stroke, cerebritis, ventriculitis, and abscesses. In a study of nosocomial ventriculitis and meningitis, adverse outcomes occurred in 78%. Mortality occurred in 9% of patients, but poor functional outcome, including persistent vegetative state (14%), severe disability (36%), and moderate disability (18%) contributed to most poor outcomes (126). Furthermore, advanced age, abnormal neurologic examination, and mechanical ventilation increase the risk of adverse outcomes in nosocomial meningitis, with Staph being the most common pathogen isolated (126).

The prognosis for intracranial epidural abscesses is better than for subdural empyema, especially when surgical drainage is undertaken (87). Complications of spinal epidural abscess include neurologic deficit that may progress to paresis, indicating the need for urgent intervention (154).

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, 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, the patient was started on intravenous vancomycin and ceftriaxone, and an urgent lumbar puncture was performed to evaluate for possible CNS infection. CSF examination revealed 558 white cells, with 88% polymorphonuclear cells. CSF gram stain was positive for gram-positive cocci in clusters. CSF culture grew methicillin-sensitive Staphylococcus aureus (MSSA), and treatment was changed to 2 grams of nafcillin intravenously every 4 hours.

Further work-up with an echocardiogram revealed a hypermobile mass oscillating through the pulmonic valve and a lesion on the mitral valve. He had ischemic lower extremities and septic pulmonary emboli.

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

An intraventricular catheter was placed for ongoing intracranial pressure management. He had multiple septic emboli to lower extremities, kidneys, brain, liver, and lungs and developed cardiac, renal, and liver failure. He was treated with antibiotics and hemodialysis.

Despite these efforts, the patient failed to improve neurologically and remained in a vegetative state. Ultimately, his family decided to withdraw supportive measures, and the patient expired.

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 extracellular matrix disruption.
	• S aureus pathogenicity within the central nervous system is likely attributed to host inflammatory responses.

Etiology and pathogenesis

The genus Staphylococcus consists of over 40 different species of gram-positive spherical bacteria. On Gram stain, they are usually found in irregular clusters but can occur as single cells, pairs, or chains. They grow well on many types of media, under aerobic conditions, and at body temperature. Staph bacteria are part of human skin and nasopharyngeal flora, with up to one third of the population colonized with Staphylococcus aureus (104). Staphylococcus aureus can lead to infection throughout the upper and lower respiratory tracts and cause infection in other regions of the body, including the central nervous system, via hematogenous or direct spread. Strains of Staphylococcus aureus with antimicrobial resistance and virulence factors are associated with more severe infections (03), and the incidence of MRSA colonization is increasing (69).

Key bacterial factors that enable Staphylococcus to cause disease are cell surface and secreted proteins (61). The surface factors allow the organism to colonize the respiratory tracts and skin and adhere to other cells. Secreted proteins include proteases or host protease modulators that promote invasion, host immune evasion, and extracellular matrix disruption (120). Surface adhesins allow staphylococcus to adhere to a variety of host proteins, and more than 20 of these proteins exist in S aureus (95). Those encoded by the sasG and sasH genes are associated with invasive staphylococcal disease, including bacteremia and meningitis (109).

Key surface factors involved in staphylococcal pathogenesis include biofilm, capsule, and adhesins. A biofilm is a matrix of polysaccharides produced and inhabited by bacteria that enable them to adhere to inert surfaces, such as catheters or indwelling hardware. 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 (104). The genes ica and aap are important for biofilm production and may be important determinants of Staphylococcus epidermidis device-related meningitis (128). There are multiple serotypes of polysaccharide capsules in Staphylococcus aureus. Capsule types 5 and 8 are antiphagocytic with an increased virulence in animal models (130) and are responsible for up to 85% of clinical staphylococcal infections (49; 104).

S aureus responds to host-derived and environmental stimuli by adapting expression of various metabolic and virulence genes (61). Virulence gene regulation in staphylococci is exemplified by the accessory gene regulator (agr), which senses bacterial density and responds by modulating toxin production (26). 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. Other regulatory genes respond to various environmental stimuli, such as salt, pH, glucose, oxygen, and antibiotics (104). Many of these genes respond to external stimuli so that one disrupted pathway may be compensated by another one, giving staphylococcus a survival advantage (104; 38). This adaptive ability contributes to the prevalence of antibiotic resistance among staphylococcal species.

Various bacterial and host factors contribute to pathogenicity within the CNS. The host inflammatory response 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 (41). 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 (77). The combination of both lipoteichoic acids and peptidoglycan can cause synergistic host recognition and inflammation, leading to elimination of bacteria (41). The bacterial capsule and protein A of S aureus hide these structures from host recognition (97; 130). Studies show that staphylococci may activate proinflammatory mechanisms within the microvascular brain endothelium causing increased blood-brain barrier permeability, dose-dependent release of cytokines and chemokines, reduced expression of junction proteins, and activation of NF-κB pathways (81), resulting in inflammation and toxicity.

Epidemiology

	• Patients with chronic diseases are at increased risk for staphylococcal infections.
	• Staphylococcus is the most common pathogen in patients after neurosurgical procedures or neurologic trauma, or in those who have indwelling CSF shunts.
	• Patients may present with community-acquired Staphylococcal infections, including meningitis or epidural abscesses.

Patients with many underlying conditions, such as alcoholism, cancer, chronic renal failure with hemodialysis, diabetes mellitus, injection drug use, and immunosuppression are at increased risk for staphylococcal infections (125). Specifically, diabetes mellitus, cirrhosis, native valve endocarditis, hydrocephalus, alcoholism, and brain tumors are risk factors for staphylococcal meningitis (11).

S aureus meningitis is more common with bacteremia (147) and is associated with endocarditis or paraspinal infection in up to 20% of cases. Other infectious sources include skin and soft tissue, sinuses, bones, joints, and lungs (137). S aureus accounts for up to 9% of cases of bacterial meningitis (100).

Staphylococcus is the most common pathogen to cause neurologic complications in patients who have had neurosurgical procedures, neurologic trauma, or who have indwelling CSF shunts, accounting for about 40% of nosocomial meningitis overall (31; 121). Risk factors for postcraniotomy meningitis include higher age, emergency procedures, CSF leak, external ventricular drain, ICU admission, duration of drain placement for over 72 hours, longer duration of surgery, repeat operations, and neurologic trauma (31). 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 (65; 110; 34). With improved infection control procedures, post-neurosurgical MRSA infections have declined (122). Nevertheless, MRSA is an important nosocomial pathogen to consider after neurosurgical procedures, with mortality as high as 45% (100).

S aureus is frequently the 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 (82). Resistance (MRSA) is associated with worse outcomes and accounts for 6.5% of prosthetic valve endocarditis (146). S aureus meningitis incidence follows the bacteremia and endocarditis trends. Encephalopathy and meningitis are seen in 25% of patients with left-sided infective endocarditis (47), and S aureus is the most commonly isolated organism.

Patients with a history of intravenous drug use have increased rates of S aureus colonization and subsequent bacteremia compared to the general population (103). Intravenous drug use is also associated with a greater than 16-fold risk of developing an invasive MRSA infection (59).

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 techniques to avoid CSF leaks and appropriate perioperative antibiotics.
	• Extraventricular drains increase the risk of ventriculomeningitis, but antibiotic and silver-impregnated catheters may reduce risk.

Despite years of research, an effective, safe vaccine against staphylococcus is not available. Some vaccines seemed to ameliorate clinical disease, but none have prevented new infection (102). Antibodies against polysaccharide capsular types of Staphylococcus aureus are protective in animal models, and a conjugate vaccine directed against the most common types to cause disease (type 5 and 8 capsules) demonstrated efficacy in hemodialysis patients (117). However, subsequent studies found it to be ineffective, and development was halted (111). A 4-antigen Staphylococcal aureus vaccine was administered to patients undergoing spinal surgery, and despite eliciting antibody response, it was not efficacious at preventing S aureus infection (56). A phase 1 study of a recombinant 5-antigen S aureus vaccine was evaluated and appeared safe and elicited antigen-specific and functional antibodies (152). Numerous other 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 (114).

CSF leakage is a significant risk factor for nosocomial bacterial meningitis after craniotomy (67). Peri-surgical antibiotic prophylaxis does not prevent the development of bacterial meningitis, though prophylaxis prevents infection of the surgical incision (68). Therefore, prevention of postoperative meningitis relies on careful surgical techniques to avoid CSF leaks. If a CSF leak occurs, surgical repair decreases the incidence of recurrent bacterial meningitis (14).

External ventricular drains increase the risk of infection. Prophylactic catheter exchange actually increases the incidence of ventriculomeningitis (25; 64). Insertion of antimicrobial impregnated ventriculostomy catheters has shown mixed results in the reduction of ventriculomeningitis and is recommended for use by the Infectious Disease Society of America; however, increased antimicrobial resistance is a concern (115; 43). Silver-impregnated catheters have shown mixed results in decreasing catheter-related CSF infection, but no adverse side effects have been noted (43).

Infection is preceded by colonization (132). S aureus colonization increases the risk of skin and soft tissue infection (SSTI), bacteremia, and prosthetic joint infection (40). There are limited data regarding decolonization regimens for craniotomy. One study showed a decreased risk of bacterial meningitis with chlorhexidine showers (54). The European Society of Clinical Microbiology and Infectious Disease recommends decolonization with intranasal mupirocin with or without a chlorhexidine bath for patients colonized with S aureus before cardiothoracic, orthopedic, and other surgeries. Vancomycin should be used for surgical prophylaxis for MRSA carriers in cardiothoracic, orthopedic, and neurosurgical procedures (108).

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 staphylococci (60), 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 (66), because all are part of “normal” skin and nasopharyngeal colonization.

Streptococcus pneumoniae and Neisseria meningitidis are the most common etiologic agents of bacterial meningitis after the neonatal period. In children under the age of 1, Group B streptococci and gram-negative enteric bacilli, particularly Escherichia coli, are the leading etiologic agents.

In patients over 50 years of age, the most common causes of bacterial meningitis include S pneumoniae, N meningitidis, and gram-negative bacilli (53; 105). H influenzae is included in the gram-negative group, along with E coli and Enterobacter. Listeria monocytogenes meningitis is more common in the immunosuppressed, young, pregnant, 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, 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 (85).

The differential diagnosis for spinal epidural abscesses includes disc and degenerative bone disease, metastatic tumors, herpes zoster, transverse myelitis, and vertebral osteomyelitis and/or discitis.

Associated or underlying disorders

Patients with underlying conditions, such as alcoholism, cancer, chronic renal failure with hemodialysis, diabetes mellitus, injection drug use, cerebrovascular or cardiovascular disease, malignancy, and immunodeficiency are at increased risk for staphylococcal infections (125; 11). Risk factors for developing meningitis include previous MRSA infection, presence of implanted devices, prior antimicrobial therapy, diabetes mellitus, cirrhosis, native valve endocarditis, hydrocephalus, alcoholism, and brain tumors. Most patients with S aureus meningitis have other sites of infection, including a surgical site or soft tissue infection, pneumonia, or endocarditis (100).

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.
	• Imaging of the spine is indicated for suspected epidural abscess.

Bacterial meningitis should be considered and promptly treated in any patient with signs of fever, headache, nuchal rigidity, altered mental status, or a clinically compatible picture. The initial presentation may be atypical in some patients, especially young children and the elderly, so a lumbar puncture should be performed with any concern for meningitis. CSF examination showing a predominantly neutrophilic pleocytosis (WBC count above 1000/microL – with neutrophil predominance), with decreased glucose (< 40 mg/dL – a serum glucose ratio of < 0.4) and increased protein concentrations (> 200 mg/dL), is strongly suggestive of bacterial meningitis and should prompt continuation of broad antibiotic coverage; however, importantly, treatment should not be delayed in order to obtain CSF. Opening pressure should be obtained with lumbar puncture. Additional testing, including meningitis/encephalitis PCR panel can be obtained, especially if the patient has received antimicrobials prior to CSF testing (23). Of note, these panels test for common community-acquired meningitis pathogens but do not test for Staph. Request additional CSF to be frozen/stored by the lab, so it can be used for potential future testing if initial testing is not diagnostic.

Brain imaging should be considered prior to CSF examination because bacterial meningitis can cause sufficient brain edema to make a lumbar puncture hazardous (50; 37). Indications for brain imaging before lumbar puncture include altered mental status, new-onset seizure, papilledema, focal neurologic deficit, immunocompromised, or history of CNS disease (135). However, removing altered mental status as an indication for imaging in patients with acute bacterial meningitis led to significantly decreased mortality, from 11.7% to 6.9% (51).

With staphylococcal meningitis, as well as most other etiologic agents, both blood and CSF cultures are often positive. In Staphylococcus aureus bacteremia, the first two blood cultures are positive in more than 90% of cases (104). Even a single positive blood culture is considered clinically significant and should be treated (52). Cultures should be drawn using careful sterile techniques. Treatment should be initiated without delay and should not be delayed if blood culture samples cannot be easily obtained.

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 (25). CSF pleocytosis may not be able to distinguish meningitis from the underlying disorder, and the CSF white blood cell count may differ in CSF compartments, especially in the setting of hydrocephalus (34). CSF protein is usually high but is not a good predictor in the setting of other acute neurologic problems. Glucose is typically low with meningitis, and CSF/blood ratios less than 50% are not typically seen after neurosurgical procedures (71).

A positive gram stain supports the diagnosis in patients with clinical signs and symptoms of infection. CSF cultures, the gold standard of diagnosis, are positive in 70% to 85% of cases before antibiotic administration (126). Cultures should be held for 10 days to identify slowly growing organisms. In a series of nosocomial meningitis, fever was present in 82%, high serum C-reactive protein in 86%, and positive CSF cultures in 79% (121).

For intracranial abscesses, CT-guided needle aspiration or open abscess drainage may assist in diagnosis in addition to MRI or CT imaging. Lumbar puncture is generally contraindicated in individuals with suspected brain abscess.

Echocardiography should be performed in all cases of suspected infective endocarditis, particularly in the setting of staphylococcus bacteremia. Although transesophageal echocardiography (TEE) will provide better diagnostic visualization, transthoracic echocardiography (TTE) is often performed initially; if endocarditis is noted with TTE, TEE may not be required. TEE also may not be immediately available or feasible (12).

Bone biopsy and culture are the gold standard for osteomyelitis diagnosis. However, this may not be feasible. Standard radiological examination may be negative in the first 2 weeks of acute osteomyelitis, but it can rule out other bone pathologies, such as malignancy (113; 139). MRI and CT imaging have a much higher sensitivity at 80% and may detect osteomyelitis as early as 3 days after disease onset (19; 98). MRI is the best modality for the diagnosis of osteomyelitis; however, CT may be useful if MRI is contraindicated. Imaging should also be performed with suspicion of epidural abscess.

Management

Meningitis. When bacterial meningitis is suspected, antibiotic treatment must be initiated immediately, even before lumbar puncture, as delays are associated with increased mortality (08; 16). In adults, 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 50 years of age is ceftriaxone 2 g intravenously every 12 hours or cefotaxime 2 g intravenously every 6 hours. Vancomycin 15 to 20 mg/kg intravenously every 8 to 12 hours should be added if penicillin-resistant pneumococcus is suspected.

For patients 50 years or older, ampicillin 2 g intravenously every 4 hours should be added to the antibiotic regimen to cover Listeria monocytogenes (135; 80; 141). Dexamethasone should be administered to adults with community-acquired bacterial meningitis in resource abundant settings. 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, dexamethasone can be given up to 4 to 12 hours after the first dose of antibiotics (80; 141). If pneumococcus is identified, dexamethasone should be continued for 4 days. For other identified pathogens, adverse outcomes are reduced with steroids for Listeria meningitis (24) and non-pneumococcal, non-H flu meningitis. However, there is insufficient evidence to support the use of dexamethasone with staphylococcal meningitis in healthcare-associated meningitis or with CSF shunts (30; 135).

Antimicrobial treatment can be tailored once culture and sensitivity results are available (09; 10). For MSSA infections, treatment can be narrowed to nafcillin or oxacillin 2 g intravenously every 4 hours. Cefazolin achieves adequate concentrations in the CNS, and there are some limited data that support its use in the treatment of bacterial meningitis (72; 07; 134). For infections with MRSA or CoNS, treatment with vancomycin dosed with trough-guided serum concentration monitoring or area under the curve (AUC)-guided therapy should be administered. AUC dosing reduces the risk of acute kidney injury (01). Teicoplanin has a similar spectrum of coverage as vancomycin and can be administered once daily with less risk of infusion reactions and nephrotoxicity; teicoplanin is not available in the United States.

In cases with resistance (MIC ≥ 2) or clinical failure of vancomycin, linezolid, ceftaroline, or trimethoprim-sulfamethoxazole have been utilized (90; 74; 99; 138). Daptomycin has poor CSF penetration and is discouraged for the treatment of bacterial meningitis. Dalbavancin, telavancin, ortivancin, tedizolid, and eravacycline are newer medications utilized for the treatment of staphylococcus, but CSF penetration does not appear high enough for meningitis treatment (101; 88).

Duration of treatment for S aureus meningitis should be 14 days, but the duration of therapy is based more on general consensus than rigorous trials. Many factors may impact treatment duration. Brain abscess, empyema, epidural abscess, or disseminated infections require extended therapy: 4 to 6 weeks or longer based on clinical response and imaging. A brain abscess over 2.5 cm will also likely require surgical drainage.

Healthcare-associated meningitis and ventriculitis. For healthcare-associated ventriculitis and meningitis, treatment should be initiated urgently. Empiric treatment to treat Staphylococcus species and gram-negative bacteria includes vancomycin (dosed with AUC-guided therapy) plus cefepime 2 g intravenously every 8 hours, or ceftazidime 2 g intravenously every 8 hours, or meropenem 2 g intravenously every 8 hours (136). The gram-negative coverage should be directed by local susceptibility patterns.

Once CSF parameter and culture data are available, treatment can be targeted. A meningitis/encephalitis panel (PCR panel) tests for many pathogens associated with community-acquired meningitis but does not detect Staph nor most gram-negative bacteria; thus, it is often not useful in nosocomial infections. If the clinical suspicion for bacterial infection remains high despite negative CSF cultures, the empiric regimen should be continued provided the patient is clinically improving. Antimicrobial therapy for patients with CoNS with no or minimal CSF pleocytosis, normal CSF glucose, and minimal clinical symptoms is continued for 10 days. The duration is extended to 14 days with CSF pleocytosis, hypoglycorrhachia, and significant clinical symptoms. Patients with S aureus or gram-negative bacilli should be treated for 10 to 14 days. Some recommendations would extend the treatment to 21 days for gram-negative bacilli. For patients with meningitis or brain abscess secondary to otitis or sinusitis, anaerobic coverage should be added to metronidazole 500 mg intravenously every 6 to 8 hours. Metronidazole can be transitioned to oral therapy once the patient is stable.

Patients already receiving antibiotics who develop nosocomial infections or patients with devices and recurrent infections may be at increased risk of 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 (136). 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 (127). Antibiotics used intrathecally include vancomycin, gentamicin, and daptomycin (42). Intrathecal treatment may result in aseptic meningitis and seizures (63), but overall, vancomycin is well tolerated. A randomized controlled trial of combination intravenous and intrathecal vancomycin versus intravenous vancomycin alone showed improved outcomes, and there were no significant adverse events with intrathecal vancomycin (62). In meningitis associated with a CSF shunt or foreign material, the infectious source should be removed, if feasible (136).

Epidural abscess. Spinal epidural abscesses typically require a combination of surgical drainage and antibiotic therapy. Surgery is indicated in patients with neurologic deficits secondary to compression of the spinal cord, vertebral instability, or disease progression despite appropriate antibiotic therapy (133). Medical therapy alone may be indicated if there is no neurologic deficit, the patient is unstable or has unacceptable surgical risk, or the patient has complete paralysis for longer than 48 to 96 hours without progression of neurologic deficit (112). Antimicrobial therapy should begin immediately after collecting two sets of blood cultures. Recommended antibiotics include vancomycin intravenously with a loading dose and ceftriaxone 2 g intravenously every 12 hours. Cefepime, ceftazidime, or meropenem should be substituted for ceftriaxone if there is concern for possible Pseudomonas or other resistant gram-negative bacilli. Spinal epidural abscesses often involve vertebral osteomyelitis or discitis, which is treated with appropriate antibiotics. Repeat imaging is utilized to determine the final duration of antimicrobials as durations longer than 6 weeks may be required.

Intracranial epidural abscesses in adults usually require a combination of surgical drainage and antimicrobial therapy. Antimicrobial therapy may be delayed until surgery is complete to allow for the collection of specimens off antibiotics to improve the yield of culture data. However, if the patient is immunocompromised, has neurologic deficits, or if surgery will be delayed, antibiotics should begin immediately. For contiguous sources of infection, such as sinuses or ear, recommended therapy includes ceftriaxone and metronidazole intravenously. Other sources of infections should be treated with vancomycin, an anti-pseudomonal cephalosporin (ceftazidime or cefepime), if indicated, or ceftriaxone plus metronidazole. Once culture results are available, the antibiotic regimen can be tailored accordingly (136).

Brain abscess, septic cerebral emboli, and mycotic aneurysm. Brain abscesses, septic emboli, and mycotic aneurysms arise from hematogenous spread. Brain abscesses may also be due to a surgical procedure or contiguous infection, including dental, sinus, or chronic ear and mastoiditis infections. In these infections, Staph is second only to Strep as the identified pathogen causing brain abscesses (22). Most patients with brain abscesses require surgical drainage for therapeutic and diagnostic purposes. Surgical drainage may not be indicated if the abscess is in vital regions or inaccessible areas, there is cerebritis without necrosis, the lesion is under 2.5 cm without significant neurologic deficit, or blood culture identifies the pathogen. For bacterial abscesses, initial antimicrobial therapy is targeted to the source once an aspirate or biopsy is obtained. If surgical intervention is delayed or not feasible, antimicrobials should be administered. For oral, ear, or sinus sources, ceftriaxone 2 g intravenously every 12 hours, metronidazole 500 mg intravenously every 6 to 8 hours, and vancomycin (dosed with AUC-guided therapy) should be administered. If Pseudomonas is suspected, ceftazidime, cefepime, or meropenem should be given in lieu of ceftriaxone. Antibiotics can be narrowed based on culture data and continued for 6 to 8 weeks with extension as indicated based on imaging and resolution of infection (36). Dexamethasone 10 mg intravenously once, then 4 mg intravenously every 6 hours, should be administered if mass effect is present (118).

Disseminated Staph infection and other sites of infection. When staphylococcal meningitis occurs with other foci of infection, such as osteomyelitis, septic arthritis, or endocarditis, antibiotic treatment must often continue for 6 weeks and may require surgical debridement of extra CNS sites of infection (104). With endocarditis, the need for cardiothoracic surgery should be assessed on a case-by-case basis, but indications for surgery with left-sided endocarditis include heart failure, difficult to treat pathogen (fungi or multi-drug-resistant organisms), cardiac abscess or heart block, and persistence of bacteremia despite appropriate treatment. Large vegetations (> 10 mm) may increase the risk of embolism and are considered when assessing the need for early surgery. Additional indications for surgery with right-sided endocarditis include very large vegetation (> 20 mm) and recurrent septic pulmonary emboli (94).

The decision to perform heart valve surgery can be complicated in the setting of cerebral emboli and should be guided by a multidisciplinary approach. Previously, anticoagulation associated with cardiopulmonary bypass and after valve replacement was thought to increase risk in patients with cerebral septic emboli (104). However, studies suggest that most patients with septic embolic stroke have improved outcomes with early surgery (150). Patients with severe neurologic deficits or hemorrhagic stroke have an increased risk of neurologic deterioration or death, and delaying cardiac surgery by at least 4 weeks is generally recommended.

Novel new therapies are needed to treat staphylococcal infections. A 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 (45). A phase 3 trial for S aureus bacteremia/endocarditis failed to show improved response in patients treated with a lysin plus a standard of care antibiotic (46).

Antimicrobials developed with activity against MRSA include tedizolid, ceftaroline, delafloxacin, dalbavancin, telavancin, ortivancin, and omadacycline, which have not been approved for use in neurologic infections (13; 89). Ceftobiprole and iclaprim are not available in the United States (153).

Outcomes

Bacterial meningitis is a medical emergency, with a mortality rate approaching 100% without treatment. Urgent treatment is required to improve outcomes (129). Studies have shown a marked increase in mortality if antibiotics are administered at more than 2 hours, and significant neurologic impairment if antibiotics are administered at more than 3 hours, after presentation (44).

The overall mortality rate for Staphylococcus aureus meningitis is 27% to 36%, with a community-acquired mortality rate as high as 50%. Mortality with postoperative infection is lower at 14%; however, these outcomes are much worse with retention of cerebrospinal devices. Increased age, altered mental status, the presence of underlying disease, bacteremia, septic shock, and resistance are all associated with increased mortality (100).

Spinal epidural abscesses require medical and surgical management. The overall mortality rate for epidural abscesses has been reported to be around 2%, but the morbidity rate is as high as 22%, with 76% of patients reported to have improvement after surgery (Hugues et al 2024).

Special consideration must be taken regarding the use of vancomycin in high doses or for prolonged periods of time. Higher doses or higher trough levels can result in nephrotoxicity and high-frequency hearing loss in neonates and the elderly, especially when used concomitantly with aminoglycosides (74; 75). Therapeutic drug monitoring utilizing area under the curve dosing improves outcomes (73).

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. Vertical transmission of MRSA at delivery has been reported in 13% of babies born to women colonized with MRSA, rising to 44% with MRSA vaginal colonization. Neonates born to women colonized with MRSA have a higher rate of skin and soft tissue infection (92), and infants with neurosurgical devices have an increased incidence of staphylococcal meningitis (93). Rarely, cases of staphylococcal meningitis in the mother have been attributed to postpartum endometritis (04; 05).

Penicillins, cephalosporins, and vancomycin are considered safe and effective in pregnancy (86). As with any such decision during pregnancy, the possible risk to the fetus must be weighed against the potential benefit to the mother (20).

Anesthesia

Epidemiological studies suggest that postoperative Staphylococcus aureus infection is predominantly due to transmission from patient skin colonization rather than healthcare provider contact. This emphasizes the importance of proper decolonization and sanitization techniques undertaken by both patient and provider (76). 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. Intravenous preoperative antibiotics should be administered so that the concentration is effective at the time of incision. Patients with normal pulmonary function undergoing general anesthesia with endotracheal intubation should receive an increased fraction of inspired oxygen intraoperatively and in the immediate postoperative period after extubation to decrease surgical site infections. Patients should also be normothermic and euglycemic (15).

Spinal epidural abscess, usually caused by staphylococcus, can rarely be seen after epidural anesthesia (33; 107). 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 (78).

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Contributors

All contributors' financial relationships have been reviewed and mitigated to ensure that this and every other article is free from commercial bias.

Author

Shelia Dunaway MD

Dr. Dunaway of Vanderbilt University Medical Center has no relevant financial relationships to disclose.
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Editor

Christina M Marra MD

Dr. Marra of the University of Washington School of Medicine has no relevant financial relationships to disclose.
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Former Authors

Katharina M Busl MD MS
Maegan Lu MD
Shuhan Zhu MD

Patient Profile

Age range of presentation: 1 month to 65+ years
Sex preponderance: male=female
Heredity: Inborn errors of immunity: chronic granulomatous disease, varies
Population groups selectively affected: none selectively affected
Occupation groups selectively affected: none selectively affected

ICD & OMIM codes

ICD-10: Intracranial abscess and granuloma: G06.0

Staphylococcal arthritis and polyarthritis: M00.0

Staphylococcal infection, unspecified: A49.0

Staphylococcal meningitis: G00.3

Epidural abscess: G06.2

Subdural empyema: J86.9

Vertebral osteomyelitis: M46.2

Discitis: M46.4

CSF shunt infection: T85.730A
ICD-11: Other specified staphylococcal or streptococcal diseases: 1B5Y

Other specified pyogenic bacterial infection of skin or subcutaneous tissue: 1B7Y

Bacterial infection of unspecified site: 1C41

Bacterial infection of joint: FA10.0

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Staphylococcal infections: neurologic manifestations

Associated Disorders

alcoholism
cancer
chronic renal failure with hemodialysis
diabetes mellitus
injection drug use
- cerebrovascular or cardiovascular disease
- malignancy
- immunodeficiency
- previous MRSA infection
- presence of implanted devices
- prior antimicrobial therapy
- diabetes mellitus
- cirrhosis
- native valve endocarditis
- hydrocephalus
- brain tumors
- surgical site or soft tissue infection
- pneumonia
- endocarditis

Differential Diagnosis

encephalitis
systemic infection
sepsis
viral encephalitis
viral meningitis
- fungal meningitis
- tuberculous meningitis
- trauma
- closed head injury
- child abuse
- hypoglycemia
- ketoacidosis
- electrolyte imbalance
- uremia
- toxic exposure
- seizure
- brain tumor
- subarachnoid hemorrhage
- intracranial hemorrhage
- epidural abscess
- Haemophilus influenzae
- Neisseria meningitidis
- Group B streptococci
- gram-negative enteric bacilli
- Escherichia coli
- Enterobacter
- Pseudomonas
- Listeria monocytogenes
- Streptococcus pneumoniae
- systemic lupus erythematosus
- Behçet syndrome
- benign recurrent lymphocytic meningitis
- leptomeningeal carcinomatosis
- HIV
- neurosarcoidosis
- neurosyphilis
- drug-induced meningitis
- toxoplasmosis
- cryptococcal meningitis
- Nocardia
- disc and degenerative bone disease
- metastatic tumors
- herpes zoster
- transverse myelitis
- vertebral osteomyelitis
- discitis

Also Relevant

Brain abscess
Intracranial subdural empyema
Meningococcal meningitis
Pneumococcal meningitis
Recurrent meningitis

Staphylococcal infections: neurologic manifestations

Cite this article

Introduction

Overview

Key points

Historical note and terminology

Clinical manifestations

Presentation and course

Prognosis and complications

Clinical vignette

Biological basis

Etiology and pathogenesis

Epidemiology

Prevention

Differential diagnosis

Confusing conditions

Associated or underlying disorders

Diagnostic workup

Management

Outcomes

Special considerations

Pregnancy

Anesthesia

References

Contributors

Author

Editor

Former Authors

Patient Profile

ICD & OMIM codes

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Questions or Comment?

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