Histoplasmosis of the nervous system
Histoplasmosis is an infection caused by the fungus Histoplasma capsulatum. Infection is endemic to certain areas of the United States, including the
Jun. 09, 2021
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This article includes discussion of Staphylococcal infections: neurologic manifestations, staphylococci, Staphylococcus, Staphylococcus aureus, and Staphylococcus epidermidis. The foregoing terms may include synonyms, similar disorders, variations in usage, and abbreviations.
Staphylococcus is the leading cause of bacterial meningitis in patients with CSF shunts or following neurosurgical procedures or neurologic trauma. Additionally, community-acquired staphylococcal infection, including meningitis, is becoming increasingly common and accounts for significant morbidity and mortality in essentially all age groups. Prompt recognition and treatment can improve outcomes. In this article, the author reviews the clinical manifestations of Staphylococcus infections, with emphasis on neurologic symptoms and key features that can help physicians avoid pitfalls leading to missed or late diagnosis. The most up-to-date treatment recommendations are incorporated into this update.
Staphylococci were first identified and cultured by Pasteur and Koch in the late 1800s, but Ogston, in 1881, was the first to study the organism carefully and coin the name (52). “Staphylococcus” comes from the Greek “staphyle,” meaning “bunch of grapes,” and was introduced because of the grape-like clusters that these organisms form when observed in pus from human abscesses. In 1884, Rosenbach was the first to grow this organism in pure culture and added the term “aureus” to the name because of its yellow-orange color in colonies. Staphylococci were initially grouped together with micrococci but differ in several important aspects, including nucleic acid composition, respiratory chain composition, and cell wall structure. Staphylococci now belong to the broad Bacillus-Lactobacillus-Streptococcus cluster (44).
Staphylococcus species are among the most common pathogens for intracranial epidural abscesses, as many arise as a complication after neurosurgical procedures. 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. 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, though this can be lacking in children, the elderly, and the deeply comatose. Focal signs may also appear. However, especially 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.
Staphylococcal meningitis and brain abscesses are frequently seen following neurologic surgeries or trauma or in the setting of a widely disseminated infection. When attributed to hematogenous dissemination, 21% of patients with Staphylococcus aureus meningitis had concomitant endocarditis and 12% had osteomyelitis. Postoperative meningitis, on the other hand, is usually localized and associated with surgically implanted hardware. Compared to the previous situations, hematogenous S aureus meningitis is generally a more severe disease with much higher mortality and requires evaluation for other sources or foci of infection (28).
Patients with S aureus bacteremia and endocarditis will usually present with a septic syndrome including fever, tachycardia, and hypotension. Any patient with S aureus bacteremia or endocarditis should be evaluated for meningitis based on a low index of suspicion (17). Patients will often have congestive heart failure or septic pulmonary emboli and will be short of breath initially, with 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 addition to meningitis, other neurologic complications of staphylococcal endocarditis or bacteremia include cerebral septic emboli and mycotic aneurysms. 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 (44). There may be up to an additional 30% of patients who have silent cerebral septic emboli (67). 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 (44).
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 (44). 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. Standard radiological examination may be negative, especially within the first 10 days of an acute osteomyelitis process, whereas bone scanning and MRI have a sensitivity of 80% (09). Diagnosis must be confirmed by bone biopsy with culture.
Pneumonia occurs from hematogenous spread during bacteremia and especially with right-sided endocarditis, leading to abscesses and empyema. Other associated conditions include septic arthritis, septic bursitis, and pericarditis.
Largely via contiguous spread from an infected focus, epidural abscesses can arise either as spinal epidural abscess, the much more common variant (see chapter on “Spinal epidural abscess”), or intracranial epidural abscess. Intracranial epidural abscess is less common than parenchymal brain abscess or subdural abscess/empyema. Intracranial abscesses can be a consequence of sinusitis, mastoiditis, or otitis, but more commonly are an iatrogenic sequela from neurosurgical procedures. This is the reason that the most likely organisms are staphylococcus species, or gram-negative bacteria (34). Clinical symptoms and signs relate to the expanding mass effect the epidural abscess creates on to the brain parenchyma, and can either manifest through local compression with focal signs or seizures, or signs of globally elevated intracranial pressure, or focal pertaining to the specific location of the abscess (68).
Another neurologic condition caused by Staphylococcus is pyomyositis (44). It is a rare subacute infection of skeletal muscles believed to be of hematogenous origin though often 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, probably due to the increase in community acquired methicillin-resistant Staphylococcus aureus (63). 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, evolving over one to two weeks into severe muscle pain, swelling, and tenderness, sometimes associated with a septic syndrome. Untreated disease continues to evolve into muscle destruction, osteomyelitis or osteoarthritis, distant dissemination, and death.
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 (28). 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 (54). Mortality is higher with S. aureus meningitis compared to meningitis caused by other staphylococcal species (12). Postcraniotomy patients who develop bacterial meningitis have a significantly higher mortality than those who do not develop meningitis (32). For nosocomial meningitis caused by staphylococcus, recent series indicate mortality between 5% and 19% (13; 65).
With appropriate therapy instituted early, mortality is improved. Morbidity, however, is high, even with the best possible treatment. Complications during acute illness are similar to that seen with meningitides of any etiology and include subdural effusion, empyema, ischemic or hemorrhagic stroke, cerebritis, ventriculitis, abscess, and hydrocephalus. In one study of nosocomial ventriculitis and meningitis, adverse outcomes occurred in 78%, with mortality the outcome in 9%; but poor functional outcome including persistent vegetative state (14%), severe disability (36%), and moderate disability (18%) contributed to the majority of outcomes (69). Furthermore, risk for adverse outcome of meningitis and ventriculitis include higher age, abnormal neurologic examination, and mechanical ventilation (69).
MRSA infections that are a complication of surgical procedures are specifically associated with higher morbidity, including higher in-hospital mortality and longer length of stay (Allareddy et al 2015). However, prognosis for intracranial epidural abscesses are better than for subdural empyema, especially when surgical drainage is undertaken (47).
A 32-year-old male with Tetralogy of Fallot status post-bovine pulmonic valve replacement about a year previously, but healthy and living independently, was admitted with 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 a supple neck. Head CT was unremarkable, and 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 placed on intravenous vancomycin and ceftriaxone. Spinal fluid culture grew methicillin sensitive Staphylococcus aureus and treatment was changed to nafcillin two grams intravenously every four hours. Echocardiogram found a thin hypermobile mass moving back and forth through the pulmonic valve. He was found to have ischemic lower extremities and septic pulmonary emboli. He also had anemia and low platelets (15,000). He declined neurologically and required a ventilator as well as blood pressure support. Repeat head CT showed a small amount of blood in the occipital horns and communicating hydrocephalus. Neurology was consulted. The hydrocephalus was attributed to the meningitis. He was sedated and intubated with coarse bronchial breath sounds bilaterally, tachycardia, and ashen lower extremities. Cranial nerves were intact. He was observed to move all four extremities spontaneously and in response to pain with no clear asymmetry. To relieve the intracranial pressure, platelets were infused and a large volume lumbar puncture was performed. Subsequently, 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 aggressive 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.
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, 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 (10).
Staphylococcus aureus causes infection throughout the upper and lower respiratory tracts by direct spread from the nasopharynx, which is frequently colonized; it causes infection elsewhere, including the central nervous system, via hematogenous spread.
The importance of various bacterial factors in promoting virulence typically has been demonstrated in two ways. One approach is to make 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 surface and secreted proteins (38). 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. 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 environmental stimuli by adapting expression of various metabolic and virulence genes (14; 48). 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 and responds to bacterial density (49). 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. Numerous other regulatory genes that respond to various environmental stimuli, such as salt, pH, glucose, oxygen, and antibiotics, have been described (44). The complexities of this network make understanding of 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 (44).
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 in-dwelling hardware after neurologic surgery. Biofilms are common to many bacteria, including coagulase-negative staphylococcal species. Colonization of inert surfaces is thought to be a 2-step process: nonspecific adherence of individual cells to the inert surface, followed by biofilm formation and recruitment and growth of additional bacteria (44). The genes ica and aap are important for biofilm production and may be important determinants of Staphylococcus epidermidis device-related meningitis (71).
At least 11 serotypes of polysaccharide capsule have been reported in Staphylococcus aureus (29). Organisms with capsule types 5 and 8 are antiphagocytic, have increased virulence in animal models (74), and are responsible for up to 75% of clinical staphylococcal infections (44).
Surface adhesins allow Staphylococcus to adhere to a variety of host proteins. At least 21 of these proteins have been found in S aureus (40; 60), with at least two of them, encoded by the sasG and sasH genes, apparently associated with invasive staphylococcal disease, including bacteremia and meningitis (60).
Various bacterial and host factors contribute to pathogenicity of the organism within the central nervous system. In its attempt to fight the infection, the host inflammatory response probably causes much of the pathological damage. Lipoteichoic acids are plasma membrane components that have been implicated in inflammation by triggering the innate immune system and release of cytokines by macrophages (20). 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 (39). In fact, the combination of both lipoteichoic acids and peptidoglycan can cause synergistic host recognition and inflammation, leading to elimination of bacteria (20). The bacterial capsule and protein A hide these structures from host recognition (55; 74).
Recent in vitro studies have demonstrated how staphylococcal infection may activate proinflammatory mechanisms within the microvascular endothelium in the brain causing increased blood-brain barrier permeability, dose-dependent release of cytokines/chemokines, reduced expression of interendothelial junction proteins (VE-Cadherin, claudin-5, and ZO-1), and activation of both canonical and noncanonical NF-κB pathways (41).
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 (37). In one study, Staphylococcus aureus bacteremia in patients with no underlying medical condition was always associated with a detectable infectious focus (45). Up to 20% of staphylococcal meningitis cases are associated with endocarditis or a paraspinal infection; other infectious sources include skin and soft tissue infection, sinusitis, osteomyelitis, arthritis, and pneumonia (78).
Staphylococcus infection is the most common pathogen to cause neurologic complications in patients who have had neurosurgical procedures or trauma or have in-dwelling CSF shunts, overall constituting about 40% of nosocomial meningitis (13; 65). Risk factors for postcraniotomy meningitis include higher age, emergency procedures, CSF leak, EVD, ICU admission, duration of drain placement for > 72 hours, longer duration of surgery, repeat operations, and trauma (13).
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 (30; 62; 16). 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 (81). 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% (35). S aureus is also a leading cause of nosocomial bacteremia, particularly in association with intravascular and urinary catheters (81). In a series of postneurosurgic infections, the incidence of invasive MRSA infections was found to have significantly declined between 2006 and 2015, likely an effect of improved infection control protocols (66).
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 (43). S aureus meningitis incidence presumably follows these bacteremia and endocarditis trends.
Staphylococcal pyomyositis is much more common in Africa and the South Pacific then 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 methicillin-resistant S. aureus (63). It occurs in all age groups but is significantly more frequent in those under 30 years old and in males (08).
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 (42). 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 (64). 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 (22; 59). Despite these seemingly promising results, the manufacturer announced in early 2005 that it would not continue development of the vaccine. Other vaccine formulations are still in various stages of development.
A study showed that CSF leakage is by far the strongest predictor of nosocomial bacterial meningitis after craniotomy (32). Perisurgical antibiotic prophylaxis did not prevent development of bacterial meningitis, though such prophylaxis did prevent infection of the surgical incision (33). Prevention of postoperative meningitis therefore relies mostly on careful surgical technique to avoid CSF leak.
Prophylactic catheter exchange has not been shown to significantly reduce the incidence of ventriculostomy-related ventriculomeningitis (11). Insertion of antimicrobial impregnated ventriculostomy catheters has been 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 ventriculostomies may provide protection against infection without inducing antimicrobial resistance. Available data suggest that infection rates may be lower with the use of these catheters (23).
Aggressive antibiotic management of staphylococcal infection when clinically evident elsewhere in the body may prevent progression to involvement of the nervous system.
The history and examination data obtained from any given case of acute bacterial meningitis can be variable. 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. 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.
Following neurologic surgeries or trauma, meningitis or brain abscess is frequently due to Staphylococcus (28), 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 provoked meningitis (31), 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 (07).
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 (27; 57). H influenzae is included in the gram-negative group, along with E coli, Enterobacter, and Pseudomonas. S pneumoniae is more likely to be in association with pneumonia, Pseudomonas in association with chronic lung disease, E coli or Enterobacter in the setting of chronic urinary tract infection, and Staphylococcus aureus in the setting of endocarditis. Listeria monocytogenes can also be found, especially in the immunosuppressed and elderly.
Bacterial meningitis, including that caused by Staphylococcus, should be considered and promptly treated in any patient with a compatible presentation, keeping in mind that the presentation may be atypical in some patients, especially young children and the elderly. CSF examination showing a predominantly neutrophilic pleocytosis is strongly suggestive of bacterial meningitis and should prompt broad antibiotic coverage, although, importantly, treatment should not even be delayed in order to obtain CSF. Brain imaging should also be considered prior to CSF examination because bacterial meningitis can cause enough brain edema to make a lumbar puncture hazardous. Data on risk of herniation and findings of CT scans have been added to previous guidelines, and imaging should be obtained when indicated (26; 18). 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 (44). 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 one to 100 bacteria per milliliter of blood (44). Therefore, 8 to 12 mL of blood should be drawn for each culture, using careful sterile technique. In the unusual case wherein 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. Similar techniques are also useful for detecting presence of antibiotic resistance proteins and genes (46; 25).
Diagnosis of nosocomial meningitis and ventriculitis is not as straight forward. 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 has been identified to reliably diagnose ventriculostomy-related ventriculitis or meningitis (11). 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% (65).
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.
When bacterial meningitis is suspected, emergent antibiotic treatment must be initiated without waiting for speciation to be made (04). In persons older than the neonatal period, empiric treatment for community-acquired bacterial meningitis is directed primarily against Staphylococcus pneumoniae and Neisseria meningitidis. Current recommendations for treatment of community-acquired meningitis for ages two to 50 years is vancomycin 15 mg/kg intravenously every 8 to 12 hours up to 2 g/day (maintain serum trough concentration of 15 to 20 ug/ml) plus either cefotaxime 50 mg/kg intravenously every four to six hours (maximum 2 g IV every four hours) or ceftriaxone 50 to 100 mg/kg intravenously every 12 hours (maximum 2 g IV every 12 hours). For patients over age 50 years, addition of ampicillin 2 g intravenously every four hours is recommended. European guidelines for treatment of bacterial meningitis were published in 2016 (79), whereas latest US guidelines were published in 2004 (for community acquired bacterial meningitis) (76).
If the setting is for healthcare-associated meningitis, practice guidelines published in 2017 will offer specific antibiotic regimen recommendations (77). In these settings empiric treatment is directed primarily against cutaneous staphylococcus species and, due to increasing incidence, gram negative bacteria (77). If the meningitis is associated with a CSF shunt or other foreign or surgical object, the infectious source should be removed (77). Similarly, if a meningitis and bacteremia is associated with an intravascular catheter or other foreign body, that object must be removed.
After speciation of Staphylococcus, therapy can be tailored based on antibiotic resistance (05; 06). For methicillin-sensitive Staphylococcus aureus (MSSA) infection, treatment can be switched to nafcillin or oxacillin 2 g intravenously every four hours. For infection from methicillin-resistant S aureus (MRSA), treatment should be continued with vancomycin 15 mg/kg intravenously every 8 to 12 hours, dosed by level with a suggested trough of 20 mg/dL for CNS penetration. For Staphylococcus epidermidis infection, treatment should be continued with vancomycin. In cases with vancomycin resistance or clinical failure of vancomycin, linezolid is often effective (50). Total duration of treatment should be 10 to 21 days, but if infection is associated with a brain abscess, treatment might have to take into account neuroimaging resolution, which may take much 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, even though rigorous data are absent regarding duration of treatment for nosocomial infections, especially if culture is negative. Patients who are already on antibiotics and develop a nosocomial infection, and patients with devices and recurrent infection often pose a specific challenge due to antibiotic resistance. No antibiotics are currently approved for intrathecal use by the US Food and Drug Administration, and no strong data exist on indications for intrathecal treatment (77). 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 (70). Antibiotics used intrathecally include vancomycin, gentamycin, and daptomycin (21). Vancomycin is well tolerated when given by the intrathecal route.
When staphylococcal meningitis and bacteremia are associated with other foci of infection, such as osteomyelitis or endocarditis, antibiotic treatment must often continue for four to six weeks or even longer and may require surgical debridement (44). 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 if indicated, after valve replacement, puts the patient at significant risk for hemorrhagic conversion of the septic infarctions (44). Other studies, however, suggest that patients with infective endocarditis and septic cerebral infarction who have valve replacement within the first 72 hours after stroke have significantly better outcome compared to those treated with medical management only or to those treated with surgery more than eight days after stroke (56; 61). A head CT must be performed prior to surgery, and surgery should be delayed in patients who already have evidence of intracerebral hemorrhage.
Dexamethasone 0.15 mg/kg every six hours given 15 to 20 minutes prior to antibiotics for the first four days of therapy is recommended in cases of S pneumoniae meningitis. Debate about this recommendation is still ongoing (19; 80) 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 (76). However, it is part of the current guidelines for treatment of bacterial meningitis (76; 79). Dexamethasone 0.15 mg/kg every six hours initiated prior to the first dose of antibiotic and continued for the first two to four days of treatment decreases the risk of neurologic sequelae from community-acquired bacterial meningitis in children (36; 51; 72). Overall, these results suggest that dexamethasone should be strongly considered in any patient with suspected community-acquired bacterial meningitis and especially in children and adults at risk for S pneumoniae meningitis.
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. 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 oftentimes remain negative or may only be partially growing due to prior antibiotic exposure (77)
In addition to medication therapies, 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 (73).
Guidelines for treatment of pyomyositis are not clearly defined but should probably be based on the same staphylococcal-specific regimens recommended above for meningitis, with duration of parenteral treatment for seven to 14 days, followed by oral treatment for up to six weeks (44). If there is evidence of abscess formation, it usually should be drained (53).
A new and novel class of antiinfectives are lysins: they are derived from bacteriophages, representing highly evolved enzymes produced to 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 antiinfective in an age of mounting antibiotic resistance (24).
Little is known about the neurologic complications of staphylococcal infection in pregnancy, but they are presumably similar to the complications seen in nonpregnant hosts. 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 (03). Rarely, cases of staphylococcal meningitis have been attributed to postpartum endometritis (01).
The penicillins and the cephalosporins are believed to be 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.
Staphylococcal meningitis is a rare complication of spinal anesthesia. Epidural abscess, usually caused by staphylococcus, can be seen after epidural anesthesia (15; 58).
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