Infectious Disorders
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Gram-negative bacillary meningitis …
- Updated 09.13.2024
- Released 03.06.1997
- Expires For CME 09.13.2027
Gram-negative bacillary meningitis
Introduction
Overview
Gram-negative meningitis in the infants and adults is a severe, life-threatening infection. It requires prompt diagnosis and treatment due to high morbidity and mortality rates in these vulnerable populations.
Neonatal meningitis. Neonatal infections, especially in resource-limited settings, are commonly caused by bacteria such as Escherichia coli, Klebsiella, and Pseudomonas species. Escherichia coli, particularly those with the K1 capsular antigen, is a leading cause of gram-negative meningitis in newborns. Beta-hemolytic streptococci are also significant contributors to neonatal sepsis and meningitis worldwide (32). HIV infection predisposes spontaneous Gram-negative bacillary meningitis in neonates. The mortality and morbidity associated with Gram-negative meningitis remain significant despite advances in antimicrobial chemotherapy. Neonates frequently lack many of the classic features of bacillary meningitis, posing a diagnostic challenge.
Meningitis in older children and adults. Gram-negative bacilli are common organisms in nosocomial meningitis in adults. 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 various 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 treating chronic back pain was reported in Germany. Gram-negative meningitis may occur following endoscopic endonasal transsphenoidal surgery, but the frequency is quite low. 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.
Key points
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• Gram-negative bacilli are major causative agents of meningitis in the neonatal period. | |
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• Escherichia coli carrying the K1 capsular antigen is the most common Gram-negative bacillary organism causing neonatal meningitis. | |
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• Nosocomial Gram-negative bacterial meningitis may occur as a complication of neurosurgical procedures, head injury, or secondary to metastatic systemic infection. | |
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• Gram-negative bacilli can be rare causes of spontaneous meningitis in adults, including individuals without risk factors. | |
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• Gram-negative meningitis in neonates and in the elderly may present without typical signs of meningitis. | |
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• Third-generation cephalosporins are highly active against most Gram-negative bacilli and have excellent CSF penetration. | |
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• 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. | |
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• Mortality and long-term sequelae rates are high among adults and children with Gram-negative bacterial meningitis. |
Historical note and terminology
"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 (04). The first large series of adults with Gram-negative meningitis was described in soldiers who suffered head injuries during World War II (37). Subsequent reports largely characterized Gram-negative meningitis as a nosocomial infection in adults who had undergone neurosurgical procedures (19; 41).
Clinical manifestations
Presentation and course
Neonatal Gram-negative meningitis is often diagnosed after the third postnatal day and is associated with higher white blood cell and red blood cell counts in cerebrospinal fluid, whereas adult Gram-negative meningitis typically presents with common meningeal symptoms such as fever, headache, photophobia, and altered mentation, but elderly patients may lack these classic features.
Neonatal meningitis. Neonatal Gram-negative meningitis may present without fever or nuchal rigidity, with atypical seizures, abrupt failure to thrive, bulging fontanelles, necessitating a low threshold for CSF examination. 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 3 days of life was associated with antepartum antibiotic exposure. No difference was noted in either cerebrospinal fluid protein or glucose levels. Additionally, there were no differences in gestational age, birth weight, infant sex, race, or rate of caesarean section (57).
Adult meningitis. Clinical features of Gram-negative meningitis, in adults, 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 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 (43). Focal neurologic deficits may occur through various mechanisms, including cortical vein or sagittal sinus thrombosis, cerebral artery spasm, subdural empyema, hydrocephalus, septic arteritis or endarteritis obliterans, abscess, or focal cerebral edema (66).
Elderly patients, especially those with underlying medical illnesses like diabetes mellitus and cardiac disease, may lack many of the classic features of bacillary meningitis. Confusional state may be the only presenting feature in these patients (20).
Spontaneously arising Gram-negative meningitis more commonly occurs abruptly with a relatively fulminant course, whereas post-neurosurgical infection is frequently more insidious with a protracted illness (05).
Prognosis and complications
Prior to the introduction of third-generation cephalosporins, mortality from Gram-negative bacillary meningitis was high, with Pseudomonas meningitis having an 84% mortality rate (15). Mortality rates fell from 34% (pre-1979) to 13% (1980-1988) (16).
Complications occur in up to 64% of patients, including cerebral edema, hydrocephalus, cranial nerve palsies, epidural abscess, subdural empyema, and brain abscess (41).
Factors associated with 30-day mortality or neurologic deterioration include decreased consciousness, blood glucose greater than 180 mg/dL, higher creatinine, and cerebrospinal fluid glucose less than 50 mg/dL (45).
High body temperature, a low CSF glucose, and meropenem-resistant Acinetobacter baumannii infections contribute to poor prognosis in multidrug-resistant cases (13). Advanced cases may involve cerebral edema, hydrocephalus, cranial nerve palsies, and brain abscess (41). Infant survivors of Gram-negative bacillary meningitis frequently experience developmental disabilities and neurologic sequelae, with 61% affected (64).
Biological basis
Etiology and pathogenesis
Meningitis caused by Gram-negative bacilli commonly occurs in newborns, post-neurosurgical patients, and those with Gram-negative bacteremia. Beyond the first month, Klebsiella species (40%), E coli (15% to 30%), and Pseudomonas aeruginosa (10% to 12%) are frequent causes. Nosocomial infections are increasing, especially in patients over 15 years old.
Gram-negative bacillary meningitis is most common in three settings: newborns, post-head injury, or neurosurgical procedures, and in patients with Gram-negative bacteremia. The causative organisms differ slightly according to the type of patient. In adults 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 incidence of nosocomial Gram-negative meningitis is increasing. In a retrospective survey from a developing country, 59% of episodes of acute bacterial meningitis in patients aged 15 years or older were due to nosocomial infections, with Gram-negative bacilli being common (pathogens in 32.1%) of cases (30). Predisposing factors for nosocomial meningitis include previous treatment with broad-spectrum antibiotics, prematurity with low birthweight, and total parenteral nutrition.
Community-acquired Gram-negative bacillary meningitis, often caused by Klebsiella pneumonia, is seen in elderly persons and those who are debilitated, immunosuppressed, or who have alcoholism or diabetes (39; 12). HIV infection is another predisposing factor, with common organisms including Escherichia coli, Klebsiella pneumonia, and non-typhoidal Salmonella in HIV-positive patients (62).
Polymicrobial meningitis, though unusual, appears most commonly due to mixed Gram-negative infection. The frequency of nosocomial Gram-negative meningitis is also increasing, with Acinetobacter baumannii emerging as an important causative agent (52; 13). Gram-negative meningitis in post-neurosurgical patients is most often due to Klebsiella pneumonia, Acinetobacter calcoaceticus var anitratus, E coli, and P aeruginosa (41; 08; 05; 29).
Factors responsible for spontaneous Gram-negative bacilli meningitis include advanced age, presence of cancer, nosocomial exposure, and urinary tract infection (50). A retrospective review of adult patients who had Gram-negative bacilli cultured from CSF following neurosurgical procedures or traumatic head and spinal injury revealed Klebsiella pneumonia, Enterobacter cloacae, and E coli as the most frequent bacterial isolates (07). Acinetobacter meningitis is becoming increasingly common in the post-neurosurgical setting, with mortality exceeding 15% (31). Changes in the epidemiologic trend of acute bacillary meningitis include an increase in patients with a post-neurosurgical state and a rising incidence of Acinetobacter and staphylococcal infections (11).
With the disruption of the dura-arachnoid barrier due to trauma or surgery, for instance, in trauma cases, depressed skull fractures can allow entry of skin flora into epidural or subdural spaces, especially if the fracture is lacerated enhances the risk of Gram-negative bacilli meningitis. High-speed missile injuries like gunshot wounds generally do not produce significant contamination, but the risk of infection increases with delays in debridement. Furthermore, CSF rhinorrhea or otorrhea is associated with a higher incidence of infection, although pneumococcal infections are more common than those caused by Gram-negative bacilli (10). Congenital or anatomical defects, especially related to the neural tube or urogenital system and disseminated strongyloidiasis, can also predispose patients to Gram-negative meningitis.
Pathophysiology involves bacterial penetration of the blood-brain barrier and replication within the CSF, leading to host inflammatory responses triggered by lipopolysaccharides and cell wall components. These responses involve cytokines, chemokines, and immune cells such as granulocytes, macrophages, and microglia, which contribute to neuronal injury and cerebral edema. Meningeal inflammation, as observed in experimental studies with purified lipopolysaccharide and cell wall products from H influenzae, leads to permeability changes in the blood-brain barrier and increased intracranial pressure. The development of cerebral edema is multifactorial, involving vasogenic, cytotoxic, and interstitial mechanisms.
Meningitis causes purulent exudate, mainly composed of neutrophils and bacteria, which can lead to necrosis due to obstruction of meningeal arteries or veins. As the infection progresses, subarachnoid space exudate accumulates, causing noncommunicating hydrocephalus, interstitial cerebral edema, and potential herniation or infarction. Focal neurologic deficits may result from cranial or spinal nerve injury due to exudates, or from cortical and subcortical ischemia and infarction due to inflammation and thrombosis.
In neonates, certain E coli strains with the K1 polysaccharide capsule, which typically inhabit the large intestine of newborns, are the causative agents. The pathogenesis entails the migration of bacteria from the gastrointestinal tract to the bloodstream and subsequently to the central nervous system. The invasion of the central nervous system by E coli begins with the bacteria binding to and penetrating human brain microvascular endothelial cells. For E coli to effectively cross the blood-brain barrier., a significant level of bacteremia is necessary. The outer membrane protein A of E coli K1, which causes meningitis, aids in the invasion of brain microvascular endothelial cells by serving as an adhesion molecule for attachment (55). The penetration of the blood-brain barrier and subsequent CSF infection are facilitated by E coli factors, such as the K1 capsule, flagella, and type S fimbriae through the binding to and invasion of brain microvascular endothelial cells. Host inflammatory responses are crucial in the pathophysiology; these are triggered by bacterial lipopolysaccharides and cell wall components, leading to the release of cytokines and chemokines, activation of immune cells, and neuronal damage. Experimental studies have demonstrated meningeal inflammation and changes in blood-brain barrier permeability following the administration of purified lipopolysaccharide or cell wall products in animal models (60; 68; 09).
Once in the CSF, the low complement and immunoglobulin environment favors bacterial replication. The host inflammatory response to bacterial components, such as lipopolysaccharides, induces cytokine and chemokine release, leading to immune cell activation and neuronal injury. Neuronal damage is caused by hypoxic insult, neurotoxic bacterial products, and immune mediators, resulting in excitatory amino acid production, free oxygen radicals, nitric oxide, and peroxynitrite. This neuronal loss may lead to permanent neurologic sequelae or death.
In severe cases, meningitis leads to the development of a purulent exudate that covers brain surfaces, particularly the cisterns at the base. This exudate composed mainly of neutrophils and bacteria may cause necrosis due to obstruction of meningeal arteries or veins. Subarachnoid space exudate accumulation leads to noncommunicating hydrocephalus interstitial cerebral edema, and potential herniation or infarction. Focal neurologic deficits are often due to exudates injuring cranial or spinal nerves or from cortical and subcortical ischemia and infarction caused by inflammation and thrombosis.
Epidemiology
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 (67). 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 (16). 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 (34).
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 (47). 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 (23).
A 6-year retrospective study at a Saudi Arabian tertiary hospital analyzed 222 cases of bacterial meningitis, revealing Pseudomonas aeruginosa as the predominant pathogen (43%) (01). Neonates and children were most affected, with nosocomial infections comprising 92% of cases, primarily in intensive care units. Extended-spectrum beta-lactamase resistance was common (12.2%). The findings underscore the burden of bacterial meningitis and the growing issue of antimicrobial resistance.
Prevention
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 (22). 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 (08). However, others have failed to identify antibiotic usage as a risk factor (41). A meta-analysis showed that prophylactic antibiotic use significantly decreased postoperative meningitis infections after craniotomy (02). The measures to prevent neonatal Gram-negative meningitis include early diagnosis and treatment of maternal infections, appropriate use of antibiotics during labor, aseptic techniques during delivery, and improving neonatal care, especially in preterm infants and those in NICUs.
Differential diagnosis
Confusing conditions
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 (48).
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 (58).
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 (66). 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.
Diagnostic workup
Lumbar puncture is crucial for diagnosing bacterial meningitis, often indicating elevated opening pressures (above 180 mm H2O), CSF pleocytosis, and a predominance of neutrophils. Gram staining can detect Gram-negative bacilli in half of the cases, and CSF culture is vital for definitive confirmation. In cases of bacterial meningitis, CSF analysis typically shows reduced glucose levels (commonly below 40 mg/dL or less than 40% of serum glucose) and increased protein concentrations (exceeding 100 mg/dL). These findings, combined with clinical symptoms and other CSF anomalies, are key to confirming the diagnosis.
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 (63). 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 (63).
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 (21). 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 (51). 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 (40).
Management
Third-generation cephalosporins, such as cefotaxime, ceftriaxone, and ceftazidime, are preferred for treating Gram-negative meningitis due to their excellent CSF penetration and efficacy. In cases of multidrug-resistant infections, intravenous colistin or intrathecal/intraventricular antibiotics may be necessary.
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 (14; Kaplan and Patrick 1990). Ceftazidime in particular has become the standard therapy for Pseudomonas meningitis because of its superior activity and rates of cure (18). 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 (65). 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 (46). Intravenous or intrathecal colistin has been demonstrated as an effective and safe treatment option for severe infections caused by multidrug-resistant Gram-negative bacteria (49). Karaiskos and colleagues reported that intraventricular or intrathecal administration of colistin serves as a last-resort therapy for multidrug-resistant and extensively drug-resistant Acinetobacter baumannii ventriculitis or meningitis (27). In a review of 83 cases, an 89% success rate was observed, with cerebrospinal fluid sterilization typically achieved within 4 days and reversible toxicity occurring in 11% of cases. 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 (42). 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 (17). 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 (35; 25).
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 (36; 69). 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 (33; 06). 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 (54). 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 (61; 53). 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) (56). 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 (28).
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 (24). They further suggested that whenever possible, intraventricular administration of antibiotics should be used in patients with ventricular drains.
Extensively-drug-resistant Gram-negative bacteria-related post-neurosurgical infections pose a significant mortality risk, necessitating effective treatment methods. A metaanalysis of 18 studies involving 602 patients compared intravenous treatment alone with a combination of intravenous and intrathecal or intraventricular treatments (38). The combination therapy significantly reduced mortality, particularly in patients with extensively-drug-resistant Gram-negative bacteria, and improved microbiological clearance, clinical symptoms, and cerebrospinal fluid indicators. Importantly, the combined treatment did not increase adverse events at the recommended dose. This suggests that additional intrathecal or intraventricular treatment can enhance bacterial clearance and improve patient outcomes in post-neurosurgical infections (38).
The recent NICE guidelines reviewed the evidence on treating Gram-negative meningitis, particularly caused by Enterobacterales (coliforms), and emphasized critical outcomes like all-cause mortality and long-term neurologic impairments due to the severe impact of the disease. Despite low-quality evidence, no significant difference was noted in mortality or CSF sterilization when comparing third-generation cephalosporin treatment alone to a combination with ciprofloxacin, although the latter showed a higher rate of short-term neurologic complications. Given these findings and the limitations of the evidence, recommendations were based on current clinical practice and expert opinion, advocating for the use of ceftriaxone, aligned with British National Formulary (BNF) guidelines. The choice of ceftriaxone was also supported by its practical benefits, such as once-daily dosing. Further research was recommended to explore the effectiveness of different antibiotic durations (44).
Dexamethasone is not currently recommended for the treatment of Gram-negative bacillary meningitis and neonatal meningitis (12). 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; 66). 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).
Media
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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
-
Ravindra Kumar Garg DM FRCP
Dr. Garg of King George's Medical University in Lucknow, India, has no relevant financial relationships to disclose.
See Profile
Editor
-
John E Greenlee MD
Dr. Greenlee of the University of Utah School of Medicine has no relevant financial relationships to disclose.
See Profile
Former Authors
- Paul G Auwaerter MD MBA
Patient Profile
- Age range of presentation
-
- 1 month to 65+ years
- Sex preponderance
-
- male=female
- Heredity
-
- none
- Population groups selectively affected
-
- none selectively affected
- Occupation groups selectively affected
-
- none selectively affected
ICD & OMIM codes
- ICD-10
-
- Bacterial meningitis, unspecified: G00.9
- Other bacterial meningitis: G00.8
- ICD-11
-
- Bacterial meningitis, unspecified: 1D01.0Z
- Other specified bacterial meningitis: 1D01.0Y
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