Epstein-Barr virus infections of the nervous system
Nov. 11, 2023
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Gram-negative bacilli are common organisms in nosocomial meningitis in adults. Escherichia coli containing the K1 capsule is the leading cause of Gram-negative meningitis in neonates. In patients with Gram-negative bacterial meningitis, Acinetobacter baumannii is emerging as an important causative agent. Nosocomial Gram-negative bacterial meningitis is a complication of a variety of surgical procedures, such as craniotomy, placement of internal or external ventricular catheters, lumbar puncture, intrathecal infusions, or spinal anesthesia; head injury; or at times secondary to metastatic infection in patients with hospital-acquired bacteremia. An outbreak of meningitis and spinal infections with Gram-negative bacteria following local injections for the treatment of chronic back pain was reported in Germany. Gram-negative meningitis may occur following endoscopic endonasal transsphenoidal surgery, but the frequency is quite low. HIV infection predisposes spontaneous Gram-negative bacillary meningitis. Escherichia coli, Klebsiella, and Pseudomonas species cause 20% to 28% of early-onset infant bacteremia and 14% cases of infant meningitis globally, particularly in low- and middle-income countries. The mortality and morbidity associated with Gram-negative meningitis have remained significant despite advances in antimicrobial chemotherapy. Some patients lack many of the classic features of bacillary meningitis, especially the elderly, and pose a diagnostic challenge. CSF culture is the most important test to establish the diagnosis of Gram-negative meningitis. Metagenomic next-generation sequencing is now a widely used molecular technology that rapidly detects Gram-negative bacteria in CSF specimens of patients with nosocomial meningitis. The exact pathogenesis of Gram-negative meningitis is not completely understood. A meta-analysis showed that combined intraventricular antibiotic plus intravenous treatment was not superior to standard intravenous-only treatment in nosocomial ventriculitis/meningitis. In this article, the author reviews the latest information on the clinical features, etiology, pathogenesis, treatment, and outcome of Gram-negative bacillary meningitis.
• Gram-negative bacilli are major causative agents of meningitis in the neonatal period.
• Escherichia coli carrying the K1 capsular antigen is the most common Gram-negative bacillary organism causing neonatal meningitis.
• Nosocomial Gram-negative bacterial meningitis may occur as a complication of neurosurgical procedures, head injury, or secondary to metastatic systemic infection.
• Gram-negative bacilli can be rare causes of spontaneous meningitis in adults, including individuals without risk factors.
• Third-generation cephalosporins are highly active against most Gram-negative bacilli and have excellent CSF penetration.
• Although effective against Gram-negative infections outside the central nervous system, systemically administered aminoglycosides, such as gentamicin, have very poor penetration across the meninges, even in the presence of meningitis.
• Mortality and long-term sequelae rates are high among adults and children with Gram-negative bacterial meningitis.
"Gram-negative meningitis" is a term generally used to encompass those infections of the CSF and meninges due to bacteria such as Enterobacteriaceae and Pseudomonas aeruginosa occurring beyond the neonatal period, exclusive of Neisseria meningitis and Haemophilus influenzae, although some authors use the term to include all of the above. Occasional reports of Gram-negative bacillary meningitis date from as early as the 19th century. Case descriptions of Gram-negative meningitis following abortions, genitourinary procedures, and spinal anesthesia began to appear with some frequency in the 1930s and 1940s. An early literature review of 100 cases of Gram-negative meningitis found that most infections occurred in the neonatal period (05). The first large series of adults with Gram-negative meningitis was described in soldiers who suffered head injuries during World War II (41). Subsequent reports largely characterized Gram-negative meningitis as a nosocomial infection in adults who had undergone neurosurgical procedures (23; 45).
Clinical features of Gram-negative meningitis often include typical signs and symptoms of any meningitis such as fever, headache, photophobia, neck stiffness, and altered mentation (including signs of cerebral dysfunction such as lethargy, delirium, confusion, or coma), but there is little to distinguish it specifically from other meningeal infections. In situations of severe meningeal inflammation, signs of meningeal irritation may be present. Seizures and focal signs such as cranial nerve palsies may occur in up to 40% of patients. Focal neurologic deficits may occur through a wide variety of mechanisms, including cortical vein or sagittal sinus thrombosis, cerebral artery spasm, subdural empyema, hydrocephalus, septic arteritis or endarteritis obliterans, abscess, or focal cerebral edema (73).
Some patients may lack many of the classic features of bacillary meningitis, especially the elderly, who are predisposed to Gram-negative infection. In a large series of 696 meningitis episodes, the classic triad of fever, neck stiffness, and mental status changes occurred in only 44% of the cases, but 95% had at least two of the four symptoms of headache, fever, neck stiffness, and altered mental status (72). Confusional state may be the only presenting feature in elderly patients with underlying medical illness such as diabetes mellitus and cardiac disease (24). Fever is usually present in this group, but headache and meningeal signs may be absent.
Spontaneously arising Gram-negative meningitis more commonly occurs abruptly with a relatively fulminant course, whereas postneurosurgical infection is frequently more insidious with a protracted illness (06). Neurosurgical patients usually display headache, fever, and altered mentation that may be a normal postoperative consequence and otherwise self-limited or may herald an infectious meningitis. Elderly patients can lack many typical clinical features that would otherwise direct the clinician to suspect CNS infection. Regardless, clinical presentation may be variable over hours or days, and a high index of suspicion must be maintained.
Among neonates, some differences have been noted between Gram-positive meningitis and Gram-negative meningitis. Gram-negative meningitis was more often diagnosed after the third postnatal day and was associated with higher white blood cell and red blood cell counts. Gram-negative meningitis diagnosed in the first three days of life was associated with antepartum antibiotic exposure. No difference was noted in either cerebrospinal fluid protein or glucose levels. There were no differences in gestational age, birth weight, infant sex, race, or rate of Caesarean section (63).
Before the introduction of the third-generation cephalosporins, mortality from Gram-negative bacillary meningitis was high. Pseudomonas meningitis had a mortality rate of 84% in a series of patients seen between 1972 and 1979 (16). A decreased rate of mortality was reported in one series. In a study, overall mortality has been shown to fall from 34% (prior to 1979) to 13% (1980 to 1988) (19).
Complications may arise in up to 64% of patients presenting with Gram-negative meningitis (45). Advanced bacterial meningitis may be accompanied by cerebral edema and hydrocephalus, cranial nerve palsies, epidural abscess, subdural empyema, and brain abscess. In a study, 61% of infants who survived Gram-negative bacillary meningitis had developmental disabilities and neurologic sequelae (70).
In a study, factors associated with 30-day mortality or neurologic deterioration in Gram-negative postneurosurgical meningitis were decreased level of consciousness, blood glucose level greater than 180 mg/dL, higher creatinine level, and cerebrospinal fluid glucose less than 50 mg/dL (48).
In patients with multidrug-resistant Gram-negative bacterial meningitis, a high body temperature, a low CSF glucose content, and an infection caused by meropenem resistant Acinetobacter baumannii were common reasons for failed treatment and poor prognosis (14).
Meningitis caused by Gram-negative bacilli is most common in three settings: in newborn children, after head injury or neurosurgical procedures, and in patients with Gram-negative bacteremia. The specific organisms causing Gram-negative meningitides differ slightly in their frequency according to the type of patient. Beyond the first month of life, the most common causes include Klebsiella species (about 40%), E coli (15% to 30%), and Pseudomonas aeruginosa (10% to 12%). The frequency of nosocomial Gram-negative meningitis is also increasing. A retrospective survey from a developing country revealed that in patients 15 years or older with acute bacterial meningitis, among 180 episodes of acute bacterial meningitis in 161 cases, 59% of episodes were because of some nosocomial infection. Gram-negative bacilli were common pathogenic organisms in patients with nosocomial meningitis (32.1%) (34). Nosocomial meningitis is uncommon in younger children. Predisposing factors for nosocomial meningitis in children were previous treatment with broad-spectrum antibiotics, prematurity with low birthweight, and total parenteral nutrition. Neurosurgery was not found to be a significant risk factor for the development of nosocomial meningitis in children (42).
In spontaneously arising cases, E coli and P aeruginosa account for most infections, with fewer cases due to other Gram-negative species such as Serratia, Enterobacter, Proteus, and Klebsiella (45; 06; 16; 70). Anaerobic bacterial causes of meningitis are rare, except in cases following intraventricular rupture of a brain abscess but may infrequently complicate chronic otitis media or sinusitis or follow neurosurgical procedures. Bacteroides fragilis is the most commonly identified anaerobic, Gram-negative organism (21). In a study, the characteristics of spontaneous aerobic Gram-negative bacillary meningitis were determined in 40 adults requiring admission to an intensive care unit. Eight infections were hospital-acquired, and most patients had predisposing factors, mainly chronic alcoholism and an immunocompromised status. Three immunosuppressed patients had disseminated strongyloidiasis. E coli (57%) and Klebsiella pneumoniae (17%) were the most frequent pathogens. Community acquired Gram-negative bacillary meningitis (frequently caused by Klebsiella pneumoniae) is seen in elderly persons and in those who are debilitated, immunosuppressed, or who have alcoholism or diabetes (43; 13). HIV infection can also predispose spontaneous Gram-negative bacillary meningitis. In a cohort of 26 patients with Gram-negative bacillary meningitis, a predisposing condition was found in 24 patients (68). Nineteen patients were HIV-infected and had a median CD4 count of 24/mm3. Chronic renal disease, diabetes mellitus, myeloma, and alcoholism were other underlying conditions. Common organisms were Escherichia coli, Klebsiella pneumoniae, and non-typhoidal Salmonella in HIV-positive patients and Klebsiella pneumoniae in the HIV-negative group. In many studies, among prevalent Gram-negative organisms for hospital-acquired bacterial meningitis, Acinetobacter baumannii is emerging as an important causative agent (57; 14).
Gram-negative meningitis in postneurosurgical patients has been reported most often due to Klebsiella pneumonia, Acinetobacter calcoaceticus var anitratus, E coli, and P aeruginosa (45; 09; 06; 33). Polymicrobial meningitis, though unusual, appears to be most commonly due to mixed Gram-negative infection. The causative pathogens of meningitis among patients in hospital settings vary according to the status of the immune system and underlying diseases. The most frequent bacteria causing meningitis in these persons are Gram-negative bacilli (Pseudomonas spp., Acinetobacter baumannii, Escherichia coli, and Klebsiella pneumoniae) and Gram-positive cocci (Staphylococcus aureus and coagulase-negative staphylococci) (04). A review of meningitis following endoscopic endonasal transsphenoidal surgery noted that eight patients (of 1450 patients) had meningitis. In four patients, CSF culture revealed Gram-negative bacteria (Klebsiella pneumoniae, Escherichia coli, Alcaligenes spp., and Haemophilus influenzae) (50). A retrospective observational study was conducted in a tertiary care center in Northern India to evaluate 96 post-neurosurgery patients with CSF leaks managed with external ventricular drain or ventriculoperitoneal shunt (31). The study found that multidrug-resistant Gram-negative bacteria, particularly ESBL-producing Acinetobacter baumannii, were isolated in most cases of bacterial meningitis.
In a study, Gram-negative bacilli caused approximately 9% of spontaneous bacterial meningitis in adults. Factors that were responsible for spontaneous Gram-negative bacilli included advanced age, presence of cancer, nosocomial exposure, and urinary tract infection, as distant foci of infection (55). A retrospective review of adult patients who had Gram-negative bacilli cultured from CSF following a neurosurgical procedure or traumatic head and spinal injury revealed that Klebsiella pneumoniae, Enterobacter cloacae, and E coli were the most frequent bacterial isolates (08). Acinetobacter meningitis is becoming an increasingly common cause of meningitis in the postneurosurgical setting, with mortality exceeding 15% (35). A study revealed a change in the epidemiologic trend of acute bacillary meningitis, with an increase in the number of patients with a postneurosurgical state and a rising incidence of Acinetobacter and staphylococcal infections (12). Craniotomy for head trauma or tumor is the most common procedure performed in patients who develop Gram-negative bacillary meningitis. CSF shunts may also be associated with Gram-negative meningitis, although they more commonly engender infection by Staphylococci. Patients who develop Gram-negative meningitis postoperatively often have one or more of the following predispositions to this infection. Most appear to be over the age of 50 and may be immunocompromised either iatrogenically or due to underlying disease such as malignancy. Other associated conditions include alcoholism, diabetes mellitus, Gram-negative pneumonia or septicemia, sinusitis, and urinary tract infection. Gram-negative microorganisms were the most frequent causal agents identified in patients with external ventricular drain-related infections (meningitis or ventriculitis). The length of time that the catheter is in place contributes to the infection rate (11). Congenital or anatomical defects, especially related to the neural tube or urogenital system, may also predispose Gram-negative meningitis. Rarely, disseminated strongyloidiasis may be the underlying basis, as the hyperinfection causes intense parasitic migration across bowel lumen that is thought to be responsible for frequent bouts of Gram-negative bacteremia.
The specifics regarding the pathophysiology of Gram-negative bacillary meningitis are little studied beyond clinical description. Partial understanding of the general mechanisms of any infectious bacterial meningitis has been gleaned mainly through the study of human clinical specimens and experimental animal models of meningitis (59). Most studies have restricted their focus to infection with E coli (neonatal associated strains), Haemophilus influenzae, and Streptococcus pneumoniae and, therefore, may not be directly applicable to cases of non-neonatal, Gram-negative meningitis.
Strains of E coli expressing the K1 polysaccharide capsule normally colonize the large intestine of newborn infants; bacterial meningitis is the result of bacterial migration from the gastrointestinal tract to the blood circulation and from blood to the central nervous system. The involvement of central nervous system by E coli begins with bacterial binding to and invasion of human brain microvascular endothelial cells, which are the main cellular components of the blood-brain barrier. Successful penetration across the blood-brain barrier by E coli requires a high degree of bacteremia. Several E coli factors like K1 capsule contribute to invasion of brain microvascular endothelial cells (78). Flagella are locomotive organelles of bacteria, enabling the organisms to reach tissues, obtain nourishment, and colonize. Microarray experiments have demonstrated that bacterial flagella play a role in the E coli K1 association with and invasion of human brain microvascular endothelial cells. Researchers in this study compared the gene expression profile of E coli K1 associated with human brain microvascular endothelial cells to the gene expression profile of E coli K1 not associated with human brain microvascular endothelial cells. The study revealed that there was a 3-fold increase in the expression of the flagellum-I gene (encoding an ATP synthase involved in flagellar synthesis and motility) in human brain microvascular endothelial cells associated with E coli (51).
Bacterial meningitis ensues when pathogenic virulence factors overcome host defense mechanisms. Unlike spontaneous pneumococcal or meningococcal meningitis, Gram-negative meningitis in adults is commonly a disease of the debilitated or postsurgical patient. Therefore, specific virulence factors of these bacteria may be less important in their neurotropic potential than the overall state of the host. Regardless, there are two likely routes by which a Gram-negative bacillus can cause meningitis.
The first relies on a path similar to the most common bacterial causes of meningitis (S pneumoniae, H influenzae, Neisseria meningitidis, and E coli), whereby the pathogen must first colonize the host mucosal epithelium, invade, survive within the intravascular space before crossing the blood-brain barrier, and subsequently replicate within the CSF. Numerous potential factors such as urinary tract infection, nosocomial pneumonia, or skewed nasopharyngeal flora because of illness or prior antibiotic administration may allow the host to acquire Gram-negative bacteria on a mucosal or epithelial surface. Specific host defenses may include secretory IgA, mucosal ciliary activity, as well as the epithelial surface itself. However, some bacteria produce IgA proteases or ciliastatic factors, impairing these defenses, aiding in mucosal invasion and allowing for hematogenous spread. Deficiency in the C5 component of complement, a recessive autosomal defect, is frequently associated with recurrent infectious episodes including meningitis caused by Gram-negative microorganisms (18).
Binding patterns of most Gram-negative organisms depend on fingerlike projections from their cell surface, called pili, which usually attach to nonciliated epithelial cells; however, they are not essential as in the case of H influenzae. Subsequent intravascular survival is in part dependent on avoiding the bactericidal effects of complement activity that foster neutrophilic phagocytosis. This is particularly important for E coli-causing neonatal meningitis because the presence of a K1 capsule makes these organisms particularly resistant to phagocytosis (17). Entry into the CSF is not well understood, but penetration of the blood-brain barrier for many strains of E coli causing neonatal meningitis is dependent on specific pili, called S fimbriae, that bind to sialyl galactoside moieties of cell surface glycoproteins (37). The outer membrane protein A of meningitis-causing E coli K1 is shown to contribute to invasion of the human brain microvascular endothelial cells. The outer membrane protein-A acts as an adhesion molecule for attachment with brain microvascular endothelial cells (61).
Gram-negative meningitis has been documented following disruption of the dura-arachnoid barrier secondary to trauma or surgery. In the case of trauma, depressed skull fractures allow entry of skin flora into epidural, or if lacerated, subdural spaces, whereas high-speed missile injuries such as gunshot wounds usually do not produce significant exogenous or endogenous contamination. The likelihood of infection increases with the length of time to debridement. Additionally, CSF rhinorrhea or otorrhea is associated with a higher incidence of infection, although more commonly causing pneumococcal than Gram-negative bacillary infection.
By any route, once entry has been gained to the CSF, the poor opsonic activity of the CSF due to the low complement and the low immunoglobulin environment makes conditions favorable for bacterial replication.
Most of the clinical consequences of bacterial meningitis are due to the host inflammatory responses engendered by subcapsular components such as lipopolysaccharide and cell wall determinants like peptidoglycan. The lipopolysaccharide constituents of the Gram-negative bacterial wall are among the most potent activators of inflammation. These activate granulocytes via specific CD14 and toll-like receptor-4 surface receptors and coreceptors. Toll-like receptors of the endothelial cells after activation of a chain of reactions induce the release of tumor necrosis factor-alpha, interleukins, nitric oxide, and matrix metalloproteinases (47; 13). Cytokines and chemokines are also released by macrophages, microglia, astrocytes, ependyma, and CSF leukocytes.
In experimental studies, meningeal inflammation has been observed when purified lipopolysaccharide as well as cell wall products from H influenzae have been inoculated intracisternally into rats and was shown to produce inflammation and permeability changes in the blood-brain barrier (66; 76; 10). Importantly, an increased total quantity of lipopolysaccharide in CSF is directly related to morbidity and mortality in experimental and human meningitis and is one reason why suppressors of inflammation, such as corticosteroids, are often proposed as adjunctive therapy with antibiotics. In experimental models, cytokines, tumor necrosis factor-alpha, and interleukin-1 stimulate leukocyte activation and migration. The cytokine response leads to an immediate increase in CSF protein concentration and leucocytosis. The endothelium expresses multiple leukocyte adhesion molecules and presents chemotactic factors such as interleukin-8 when activated by inflammatory mediators. These changes further promote neutrophil adherence and transendothelial migration. Interleukin-6 is the prime mediator of the systemic inflammatory response to meningeal infection and increases the permeability of the endothelial cells (75; 13). Hypoxic insult, neurotoxic bacterial products, and host’s immune mediators combine to cause neuronal injury by inducing the production of excitatory amino acids, free oxygen radicals, nitric oxide, and peroxynitrite. Activation of apoptotic cascade and necrotic cell death pathways cause neuronal loss that may result in permanent neurologic sequelae or even death (75; 13).
The development of cerebral edema is likely multifactorial due to the contributions of vasogenic edema of the altered blood-brain barrier, cytotoxins from bacteria or neutrophils, and interstitial from impaired CSF outflow. Ultimately, after initial increases in cerebral blood flow, increased intracranial pressure may decrease blood flow, and loss of cerebrovascular autoregulation subjects the brain to the potential hypoperfusion. In severe cases of meningitis, the inflammation produces a purulent exudate that may cover most surfaces of the brain, but especially the cisterns at the base (01). This exudate is composed mainly of large numbers of neutrophils and bacteria, with evidence of inflammation within small and medium-sized subarachnoid arteries. Necrosis may occur because of obstruction of either meningeal arteries or veins. As the infection progresses subarachnoid space exudate accumulates, leading to obstruction of CSF flow. When cerebrospinal fluid (which normally exits by the foramina of Magendie and Luschka) is blocked by excessive exudate, noncommunicating hydrocephalus results, leading to interstitial cerebral edema and potential herniation or infarction due to impaired cerebral blood flow. Focal neurologic defects are often the result of exudates injuring cranial or spinal nerves. Other focal defects or seizures may be the result of cortical and subcortical ischemia and infarction due to inflammation and thrombosis of veins and arteries.
There is no precise epidemiological information regarding Gram-negative meningitis. The overall annual attack rate of bacterial meningitis is roughly 3.0 cases per 100,000 population, although this varies according to age, race, and gender. Gram-negative bacilli account for 1% to 2% of bacterial meningitis in children (ages older than 1 month to 15 years) and approximately 1% to 10% of bacterial meningitis in adults (older than 15 years), although some information suggests the percentage may be as high as 11% to 17% in centers with active neurosurgical services.
Gram-negative meningitis is most often a nosocomial infection. Nosocomial Gram-negative bacterial meningitis is a complication variety of surgical procedures, such as craniotomy, placement of internal or external ventricular catheters, lumbar puncture, intrathecal infusions, or spinal anesthesia; head injury; or at times secondary to metastatic infection in patients with hospital-acquired bacteremia (74). An estimated 50% of nosocomial bacterial meningitis cases occur following neurosurgical procedures and 30% occur after head trauma, especially when CSF rhinorrhea or otorrhea is present. The remaining 20% usually occur in a host of other predisposing conditions that are often found in debilitated patients who would be frequently infected or colonized with Gram-negative bacteria.
A series describing acute bacterial meningitis in 445 adults admitted to the Massachusetts General Hospital (1962 to 1988) identified 40% of the cases as nosocomial, with Gram-negative bacilli as a group accounting for 33% of nosocomial infections but only 3% of community-acquired episodes (19). In this study during the period 1971 to 1988, Gram-negative bacilli were the most common cause (surpassing S pneumoniae), suggesting that for at least some tertiary care centers, this category is now the most common cause of bacterial meningitis.
Communication between the CSF and the environment, CSF leak, and perioperative steroid use are risk factors for postcraniotomy meningitis. In a cohort of 324 patients who underwent craniotomy, almost 40% of the patients developed at least one infection. Meningitis was encountered in 16 procedures (4.8%), and CSF cultures were positive in all. Gram-negative pathogens (Acinetobacter spp., Klebsiella spp., Pseudomonas aeruginosa, Enterobacter cloaceae, Proteus mirabilis) represented 88% of the pathogens responsible for infections in patients undergoing craniotomy (38).
Paul and colleagues reported patients who developed meningitis and spinal infections with Gram-negative bacteria following local injections for the treatment of chronic back pain (52). They reported that 28 of 297 patients who received CT-guided spinal injections developed meningitis or spinal infections. Pseudomonas aeruginosa was responsible for iatrogenic meningitis or spinal infection following therapeutic spinal injections.
A metaanalysis revealed that Escherichia coli, Klebsiella, and Pseudomonas spp cause 20% to 28% of early-onset infant bacteremia and 14% cases of infant meningitis globally, particularly in low- and middle-income countries (27).
Given the limited and sporadic nature of most spontaneously arising Gram-negative meningitis, there are no specific preventive measures. However, there remains controversy whether the use of prophylactic antibiotics prior to neurosurgical procedures predisposes to Gram-negative infection. Most practitioners appear to use antibiotics, even in clean neurosurgical procedures, based on numerous controlled and uncontrolled trials showing fewer postoperative infectious complications in those who received antibiotics (26). Some authors suggest that because most spontaneously arising, community-acquired posttraumatic meningitis is due to either S pneumoniae or H influenzae, perioperative antibiotics are, therefore, a risk for Gram-negative infection (09). However, others have failed to identify antibiotic usage as a risk factor (45). A meta-analysis showed that prophylactic antibiotic use significantly decreased postoperative meningitis infections after craniotomy (02).
Gram-negative meningitis often cannot be distinguished on clinical grounds from other bacterial presentations of meningitis, although it should be suspected, especially in the hospitalized neurosurgical patient. The diagnosis of meningitis must be considered in any febrile patient with headache and lethargy and not attributed to other processes such as delirium tremens or hepatic encephalopathy unless ruled out by lumbar puncture (53).
Bacterial meningitis, in general, may produce signs and symptoms similar to brain abscess, subdural empyema, and epidural abscess, although these processes more frequently cause focal headache, pain, and neurologic deficits. Once lumbar puncture has been performed, and pleocytosis of the CSF established, the initial differential diagnosis must be broad if the answer is not apparent on Gram stain. Other considerations include viral meningitis, which often causes severe headache, but otherwise, patients are usually alert and awake. Serum C-reactive protein is capable of distinguishing Gram stain-negative bacterial meningitis from viral meningitis on admission with high sensitivity and high specificity (64).
Patients with space occupying lesions (eg, subdural empyema, brain abscess, or necrotic temporal lobe in herpes simplex encephalitis) may present with symptoms that appear to be similar with those of bacterial meningitis. In these patients, lumbar puncture may be complicated by brain herniation (73). Leptospiral, rickettsial, borrelial, and syphilitic infections may mimic an acute bacterial cause. Noninfectious etiologies such as sarcoid, rheumatologic illnesses such as Behçet disease, and malignancies such as lymphoma or metastatic carcinoma must be included, although there may be extra neurologic signs of illness to suggest these diagnoses.
Once meningitis is suspected, lumbar puncture provides the necessary confirming diagnostic information. Opening pressures are almost always elevated in cases of bacterial meningitis (higher than 180 mm H20). A Gram stain demonstrating Gram-negative bacilli can be found in up to 48% of patients, which is a significantly lower percentage than for the more common meningeal pathogens S pneumoniae (90%), H influenzae (85%), and N meningitidis (75%). Typical CSF leukocyte counts may range from 10 to 10,000, but 1000 to 5000 is the norm, with a neutrophilic predominance in most patients. Hypoglycorrhachia (lower than 50 mg/dL) may be present in up to 60% of patients, and CSF protein concentrations are often elevated due to disruption of the blood-brain barrier; however, the latter is not as specific for bacterial meningitis, and both measurements may be nearly normal in the immunocompromised patient. CSF culture is the most important test to establish the diagnosis of Gram-negative meningitis (69). Community-acquired Gram-negative meningitis is rare in patients without predisposing factors. Genitourinary, gastrointestinal, oral, and sinus sources of meningitis are common and should be looked for in patients with Gram-negative meningitis.
Initial diagnosis is often difficult in the postoperative neurosurgical patient with a fever and CSF pleocytosis, which may be ascribed to either early bacterial infection or to the normal consequence of postsurgical aseptic inflammation. Headache, fever, signs of meningeal irritation, seizures, and abnormal mental status in the setting of recent trauma or neurosurgery are suggestive of central nervous system bacterial infection (69).
There are few rapid diagnostic tests, other than the Gram stain, for identifying the subset of patients with Gram-negative infection. The Limulus lysate assay, prepared from amebocytes of the horseshoe crab Limulus polyphemus, can detect endotoxin present from Gram-negative pathogens (25). This assay can detect Gram-negative bacteria when present in quantities of >103 CFU/mL, with a sensitivity ranging from 71% to 97%. Because of its limited sensitivity and its inability to discriminate amongst the many types of Gram-negative bacteria, this test has not found widespread use as a diagnostic tool.
Metagenomic next-generation sequencing is now an increasingly available molecular diagnostic method that rapidly detects individual pathogens in biological specimens. In a series, metagenomic next-generation sequencing helped in identifying culprit microorganism in CSF specimens in neurosurgical patients with external ventricular and lumbar drainage-associated ventriculitis and meningitis (56). Earlier, in many of these patients, conventional tests had failed to detect any organism in the CSF.
Radiographic procedures have a limited role in the diagnosis of acute bacterial meningitis. Brain imaging (CT or MRI) should precede lumbar puncture if there is clinical evidence of focal neurologic deficit, moderate-to-severe impairment of consciousness, raised intracranial pressure (papilledema), where an intracranial mass lesion is suspected, and in cases with a major convulsive episode. CT scanning may be useful in the subset of patients with basilar skull fractures, as it may detect intracranial air or localize the site of fracture. Site of leaks may also be localized by radionuclide cisternography or by the use of water-soluble contrast dye injected intrathecally prior to CT scanning. Ventriculitis manifests with either intraventricular abscess, ependymal enhancement, or intraventricular loculations on neuroimaging (44).
Systemically administered aminoglycosides, although effective against Gram-negative infections outside the central nervous system, have poor penetration across the blood-brain barrier and do not provide effective therapy for meningitis. In contrast, as a class, third-generation cephalosporins are highly active against most Gram-negative bacilli and are also favored for their excellent CSF penetration. Antibiotics such as cefotaxime, ceftriaxone, and ceftazidime have largely replaced older therapies using intrathecal aminoglycosides (15; Kaplan and Patrick 1990). Ceftazidime in particular has become the standard therapy for Pseudomonas meningitis because of its superior activity and rates of cure (22). Mortality rates of 40% to 90% using standard regimens consisting of an aminoglycoside often in combination with chloramphenicol dropped to 6% to 22% using cephalosporin-based regimens. Currently, the emergence of multidrug-resistant Gram-negative bacilli is a major concern, especially in patients with nosocomial bacterial meningitis. Resistance to the third- and fourth-generation cephalosporins and carbapenems has reduced the antibiotic options available (71). At least 21 days of therapy is recommended because high rates of relapse are likely in patients treated with shorter courses.
The treatment of meningitis caused by Gram-negative bacilli in neurosurgical patients is a major challenge because of the complexity of these patients and the emergence of antibiotic resistance in many of the causative organisms. In a series, 25% of isolates were resistant to third-generation cephalosporins (49). Colistin has been reported an effective and safe drug for therapy of severe infections due to multidrug-resistant Gram-negative bacteria (54). Studies have demonstrated acceptable effectiveness and considerably less toxicity than reported in older studies of polymyxins. These older antibiotics may be used for the treatment of intensive care unit-acquired infections of various types, including meningitis (46). The limited available evidence suggests that therapy with intraventricular and intrathecal polymyxins alone or in combination with systemic antimicrobial agents is also effective against Gram-negative meningitis (20). With the emergence of resistant Gram-negative bacilli (especially Acinetobacter baumannii) that may cause meningitis, empiric therapy with a carbapenem, with or without an aminoglycoside administered by the intraventricular or intrathecal route, is recommended; colistin (given intravenously or intraventricularly) can be used if the organism is subsequently found to be resistant to carbapenems (39; 29).
Other drugs may be useful in the treatment of Gram-negative meningitis in certain situations. Aztreonam achieves good CSF concentrations and has been used with success; imipenem has similar profiles but has an increased risk of seizures in this setting (40; 77). Fluoroquinolones and trimethoprim and sulfamethoxazole have excellent profiles for treatment of Gram-negative meningitis, but published data regarding their use are even more limited. Meropenem, a carbapenem antibiotic, shows promising activity against many Gram-negative organisms, including P aeruginosa, for meningitis treatment (36; 07). Its advantages over imipenem include greater activity against Gram-negative bacteria and lack of association with seizures. Any of these drugs are only used when antimicrobial sensitivities dictate a choice other than a third-generation cephalosporin or if beta-lactam allergies preclude their use.
In pediatric patients, intraventricular administration of antibiotics has no proven value in the management of Gram-negative meningitis. In fact, the use of intraventricular antibiotics, in addition to intravenous antibiotics, resulted in a 3-fold increased relative risk for mortality compared to standard treatment with intravenous antibiotics alone (60). However, intraventricular and lumbar administration of antibiotics in adults can lead to a quick CSF sterilization in postneurosurgical patients with meningitis and ventriculitis. The relapse rate of meningitis or ventriculitis is also very low among patients treated by intraventricular and lumbar antibiotics. Intraventricular and lumbar intrathecal antibiotics appear to be an effective and safe treatment for meningeal infections caused by multidrug-resistant organisms (67; 58). Mortality was significantly lower in patients with Gram-negative postoperative meningitis due to carbapenem-resistant bacteria that received intrathecal or intraventricular antibiotic therapy (2 of 23 vs. 9 of 27) (62). A systematic review and metaanalysis showed that a combined intraventricular antibiotic plus intravenous treatment was not superior to standard intravenous-only treatment in nosocomial ventriculitis/meningitis (32).
In a review, Heffernan and Roberts raised concern that currently used intravenous antibiotic regimens in patients with Gram-negative bacterial meningitis or ventriculitis may fail to produce optimum therapeutic concentrations in CSF and suggested that therapeutic drug monitoring, where available, should be performed to achieve appropriate drug dosing (28). They further suggested that whenever possible, intraventricular administration of antibiotics should be used in patients with ventricular drains.
Dexamethasone is not currently recommended for the treatment of Gram-negative bacillary meningitis and neonatal meningitis (13). There are no controlled studies of the effects of corticosteroid therapy even in patients with both meningitis and septic shock; therefore, corticosteroid therapy cannot be unequivocally recommended for such patients (03; 73). Adjunctive treatment with dexamethasone in animal models of Gram-positive and Gram-negative meningitis has been shown to have detrimental effects on hippocampal function (Spreer at al 2006).
All contributors' financial relationships have been reviewed and mitigated to ensure that this and every other article is free from commercial bias.
Ravindra Kumar Garg MD
Dr. Garg of King George's Medical University in Lucknow, India, has no relevant financial relationships to disclose.See Profile
John E Greenlee MD
Dr. Greenlee of the University of Utah School of Medicine has no relevant financial relationships to disclose.See Profile
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