Brain Abscess

Table II.

Organism	Antibiotic	Dose	Alternative
Streptococci	Penicillin GCeftriaxoneCefotaxime	20-24 mil. units/d (divided Q4H)2-4 g/d (divided Q12H)12 g/d (divided Q6H)	Vancomycin 15-20 mg/kg (divided Q12H)
Staphylococcus auerusMethicillin sensitive (MSSA)Methicillin resistant (MRSA)	Nafcillin or oxacillinVancomycin	Nafcillin 9-12 g/d (divided Q12H)Vancomycin 15-20 mg/kg (divided Q12H)	Vancomycin 15-20 mg/kg (divided Q12H)Trimethoprim-sulfa (if sensitive); 15-20 mg/kg(trimethroprim)(divided Q6H)
Fusobacterium spp.	Penicillin G	20-24 mil. units/d (divided Q4H)	Clindamycin 2.4-4.8g/d (divided Q6H)
Prevotella spp.	Metronidazole	30 mg/kg (divided Q6H)	Clindamycin 2.4-4.8g/d (divided Q6H)
L. monocytogenes	Ampicillin	2 g/d (divided Q4H)	Trimethoprim-sulfa 15-20 mg/kg (trimethroprim) (divided Q6H)
H. influenzae	CeftriaxoneCefotaxime	2-4 g/d (divided Q12H)12 g/d (divided Q6H)	Aztreonam 6-8g/d (divided Q6-8H)Trimethoprim-sulfa 15-20 mg/d (trimethroprim) (divided Q6H)
Enterobacteriaceae	CeftriaxoneCefotaxime	2-4 g/d (divided Q12H)12 g/d (divided Q6H)	Aztreonam 6-8g/d (divided Q6-8H)Trimethoprim-sulfa 15-20 mg/kg (trimethroprim) (divided Q6H)
P. aeruginosa	CeftazadimeCefepime	6g/d (divided Q8H)6g/d (divided Q8H)	Meropenem 6g/d (divided Q8H)Aztreonam 6-8g/d (divided Q6-8H)
Actinomyces spp.	Penicillin G	20-24 mil. units/d (divided Q4H)	Clindamycin 2.4-4.8g/d (divided Q6H)
Nocardia spp.	Trimethoprim-sulfa	15-20 mg/kg (trimethroprim) (divided Q6H)	Meropenem 6g/d (divided Q8H) or ImipenemAmikacin 15 mg/kg (divided Q8H)Ceftriaxone or CefotaximeMinocycline
M. tuberculosis	Isoniazid + Rifampin + Pyrazinamide + Ethambutol	300 mg (Q24) + 600-900 mg (Q24) + 15-30 mg/kg (Q24) + 15 mg/kg (Q24)	—-
Candida spp.	Amphotericin B deoxycholateLiposomal amphotericin B	0.6-1.0 mg/kg (Q24H)5 mg/kg (Q24H)	Fluconazole 800 mg (Q24H)
Aspergillus spp.	Voriconazole	8 mg/kg (divided Q12H)	Amphotericin B deoxycholate 1.0 mg/kg (Q24H)Liposomal amphotericin B 5 mg/kg (Q24H)Posaconazole 800 mg (divided Q6-8H)
Mucorales (Zygomycetes) spp.	Amphotericin B deoxycholateLiposomal amphotericin B	1.0 mg/kg (Q24H)5 mg/kg (Q24H)	Posaconazole 800 mg (divided Q6-8H)1
Scedosporium spp.	Voriconazole	8 mg/kg (divided Q12H)	Posaconazole 800 mg (divided Q6-8H)
Cryptococcus neoformans	Amphotericin B deoxycholateLiposomal amphotericin B+ Flucytosine 2	0.6-1.0 mg/kg (Q24H)5 mg/kg (Q24H)100 mg/kg flucytosine (divided Q6H)	Fluconazole 800 mg (Q24H)
Toxoplasma gondii	Pyramethamine + sulfadiazine	25-75 g (Q24H) + 4-6 g (divided Q6H)	Pyramethamine 25-75 g (Q24H) + Clindamycin 2.4-4.8g/d (divided Q6H)Pyramethamine 25-75 g (Q24H) + AtovoquoneDapsoneTrimethoprim-sulfa 15-20 mg/d (trimethroprim) (divided Q6H)

• Post sinusitis/otitis: Otogenic brain abscesses usually occur in a bimodal distribution in patients younger than 10 years of age and patients older than 40 years of age, whereas paranasal abscesses occur more commonly from adolescence to early adulthood. Streptococci, anaerobes less commonly enterobacteriaceae, are causative.
• Post dental infection: This is enriched for streptococci and anaerobes as causative pathogens.
• HIV/decreased cell mediated immunity: This is less common bacteria, such as Listeria monocytogenes, and non-bacterial abscesses from protozoa (e.g., Toxoplasma gondii), fungi (e.g., Cryptococcus neoformans), or mycobacteria (e.g., Mycobacterium tuberculosis).
• Post neurosurgery or penetrating trauma: This is enriched for staphylococci, enterobacteriaceae, and Pseudmonas aeruginosa.
• Neutropenia: This is enriched for Candida species, but also other invasive fungal pathogens.
• Diabetic ketoacidosis: This is associated with invasive fungal pathogens, including the Mucorales, Aspergillus species, and Scedosporium species.

Beware: there are other diseases that can mimic a brain abscess:

• Subdural empyema
• Cranial epidural abscess
• Suppurative dural venous thrombophlebitis
• Intracranial bleed
• Ischemic stroke
• Non-infectious space occupying lesion (e.g., tumor, particularly in immunocompromised host)

What laboratory studies should you order and what should you expect to find?

Results consistent with the diagnosis

Unfortunately laboratory tests are non-specific. Lumbar puncture is contraindicated in those with suspected or confirmed brain abscess because of risk of brain herniation.

• White blood cell (WBC): Only 10% of patients with brain abscess have a leukocytosis greater than 20,000, and in 40% the WBC is normal.
• ESR and C-reactive protein: These may be moderately increased.
• Blood cultures: In all patients suspected of brain abscess, blood cultures should be obtained prior to antibiotic therapy, and, in those with possible hematogenous source, such as lung abscess, blood cultures may be diagnostic.
• Anti-Toxoplasma IgG antibody: This should be checked in patients suspected of central nervous system (CNS) toxoplasmosis, as more than 95% of patients with AIDS and CNS toxoplasmosis have titers ranging from 1:8 to greater than 1:1024. The rare patient with CNS toxoplasmosis will have an undetectable IgG. However, a positive titer in the presence of a radiographically compatible lesion should prompt an empiric trial of antibiotic therapy for Toxoplasma.
• Serum cryptococcal antigen: In the HIV infected patient in whom C. neoformans is suspected and lumbar puncture is contraindicated in the setting of possible cryptococcoma, a serum antigen testing may be diagnostic.

Results that confirm the diagnosis

• Abscess culture: Purulent drainage from the abscess at the time of surgical drainage should be sent for culture for aerobic and anaerobic bacteria, fungi, and mycobacteria and is diagnostic. Histopathologic staining of infected brain tissue may be confirmatory.

What imaging studies will be helpful in making or excluding the diagnosis of brain abscess?

Contrast-enhanced CT scan or MRI are the standard of care for brain abscess diagnosis:

• Computed tomography (CT): The advent of rapid neuroimaging has improved both the diagnosis and the treatment outcome in patients suspected of brain abscess. CT allows imaging of intracranial structures, as well as the paranasal sinuses, mastoids, and middle ear. CT must be performed with contrast, and, when contraindicated, MRI is preferred. Contrast allows visualization of the characteristic abscess appearance of a hypodense center with peripheral ring enhancement. Adjacent to the enhancement is a variable amount of hypodense edema. In the later stages of infection with more intact encapsulation, contrast does not penetrate as well and may not differentiate a hypodense center. After surgical aspiration of an abscess, CT appearance of improvement may lag by several weeks. CT $$$
• Magnetic resonance imaging (MRI): MRI is the preferred diagnostic procedure when available. More sensitive than CT in visualizing the early edema pattern of new abscess formation, MRI also better differentiates the central necrosis of brain abscess from other non-infected fluid accumulations. MRI can best distinguish spread of infection to the ventricles and subarachnoid space as well. Gadolinium enhancement offers capsular enhancement on T1-weighted images, whereas T2-weighted images highlight the surrounding edema with high intensity signal. Additional patterns on imaging that may provide pathogen-specific clues include: multiple lesions with marked edema and mass effect in HIV-infected patients with toxoplasmosis cerebral infarct with minimal contrast enhancement in immunosuppressed patients with aspergillosis sinus opacification, erosion of bone or fascial planes, or cavernous sinus involvement in rhinocerebral mucormycosis. MRI $$$$
• CT scan of the brain $1000-2000, $$$; MRI $2000-3000, $$$$; costs will vary by institution

What consult service or services would be helpful for making the diagnosis and assisting with treatment?

If you decide the patient has a brain abscess, what therapies should you initiate immediately?

• Management of brain abscess is a best approached in multidisciplinary coordination involving neuroradiologists, neurosurgeons, and infectious disease and critical care specialists.
• General treatment approach: All patients presenting with seizure, focal neurologic deficit, or altered level of consciousness should prompt concern for brain abscess and, thus, trigger evaluation with contrast-enhanced CT scan or MRI. Lumbar puncture should be delayed until a space-occupying lesion is excluded. If neuroimaging is delayed and clinical symptoms progress, then blood cultures for bacteria and fungi should be obtained and empiric antibacterial therapy begun. Once a possible brain abscess is identified by neuroimaging, neurosurgical evaluation should be obtained. If an additional focus is found within the paranasal sinus or middle ear, consultation with an otolaryngologist is recommended.
• Principles of anti-infective therapy: Once an abscess has been aspirated or blood cultures have been drawn in the setting of clinical deterioration, empiric antibiotic therapy should cover pathogens of the patient’s predisposing condition. Only after culture and susceptibilities are known is antibiotic therapy able to be narrowed.
• Given the frequency of streptococci in community acquired brain abscess, an empiric regimen should always include high-dose penicillin-G or a third-generation cephalosporin. A third-generation cephalosporin is preferred given the additional broad gram-negative coverage.
• In almost every setting with suspicion of bacterial abscess, metronidazole or equivalent anaerobic coverage should be added to the regimen given the relatively high percentage of Bacteriodes fragilis isolated and the delayed growth on culture. Metronidazole also targets Prevotella species, attains high intracerebral concentrations, and is not affected by concomitant corticosteroids.
• Other predisposing conditions require more tailored therapy.
• Duration of parenteral antibiotic therapy is 6-8 weeks but should be managed in consultation with an infectious disease specialist. Antibiotic duration cannot be determined based on contrast-enhanced CT scan resolution alone, as nodular lesions may persist 4-6 weeks after successful completion of therapy.

1. Anti-infective agents

If I am not sure what pathogen is causing the infection what anti-infective should I order?

• Community acquired, HIV negative, no prior neurosurgical procedure: Recommend a third-generation cephalosporin, such as cefotaxime 3-4 grams every 8 hours or ceftriaxone 2 gram every 12 hours plus metronidazole at 7.5 mg/kg (usually 500 mg) every 6 hours. If a dental infection is the confirmed source, then high dose penicillin G (24 million units daily) can be substituted for the cephalosporin.
• Post-neurosurgery or penetrating trauma: Recommend an anti-pseudomonal cephalosporin, such as cefepime at 2 grams every 8 hours or ceftazadime at 2 grams every 8 hours plus metronidazole at 7.5 mg/kg (usually 500 mg) every 6 hours. Additionally, vancomycin should be added at 15-20 mg/kg every 12 hours given the prevalence of methicillin-resistant Staphylococcus aureus (MRSA) and Staphylococcus epidermidis. Alternatively, a carbapenem, such as meropenem at 2 grams every 8 hours can be substituted for the anti-pseudomonal cephalosporin and metronidazole. Meropenem may be preferred, depending on the local resistance patterns of multidrug-resistant Enterobacteriaceae. Imipenem, although used successfully in the treatment of abscesses, including those from Nocardia species, is associated with an increased risk of seizures.
• HIV positive, neuroimaging suspicious for CNS toxoplasmosis, anti-Toxoplasma IgG antibody positive or pending: Recommend additional empiric therapy with pyrimethamine, given as single loading dose of 75-100 mg followed by 25-50 mg daily dose, plus sulfadiazine at 1 gram every 6 hours. Folinic acid is also given at 10 mg daily to prevent pyrimethamine induced bone marrow suppression. Clindamycin can be substituted for sulfadiazine and given at 600 mg (intravenous) every 6 hours. In patients with a single enhancing lesion in whom primary CNS lymphoma is a strong consideration or in those with an undetectable anti-Toxoplasma IgG, brain biopsy is recommended. Single-photon emission computed tomography (SPECT) has been used to differentiate CNS lymphoma in this situation but can be confounded by tumor age and presence of a necrotic central focus of some lymphoma lesions. In the case of more characteristic multiple enhancing lesions in an HIV-positive patient with an undetectable anti-Toxoplasma IgG, an empiric trial of 2 weeks of anti-Toxoplasma therapy prior to brain biopsy has been advocated.
• Lung abscess and/or suspicion of Nocardia species: Recommend, in addition to treatment for community acquired brain abscess, vancomycin at 15-20 mg/kg every 12 hours given the slight enrichment for certain strains of community-acquired MRSA to form lung abscess and trimethoprim-sulfamethoxazole at 5 mg/kg every 6 hours. Alternatives to trimethoprim-sulfamethoxazole for the treatment of confirmed CNS nocardiosis include imipenem, amikacin, minocycline, or linezolid. Successful combination regimens for immunocompromised hosts with Nocardia brain abscess have included imipenem and a sulfonamide or amikacin. Species identification of Nocardia is important, as antimicrobial susceptibility will vary. In contrast to other bacterial brain abscesses, if Nocardia is confirmed in an immunocompromised host, antibiotic duration should be continued for up to 12 months.
• Neutropenia and fungal brain abscess suspected: A low threshold for empiric antifungal therapy must be maintained in certain clinical scenarios in the immunocompromised host, but, in confirmed fungal brain abscess, surgical excision is paramount. An amphotericin B preparation, such as amphotericin B deoxycholate at 0.6-1.0 mg/kg daily or liposomal amphotericin B at 5 mg/kg daily, will adequately cover brain abscesses from Candida species and most endemic fungi. If Aspergillus is suspected, voriconazole at 4 mg/kg every 12 hours is preferred and successful combination therapy of voriconazole with an amphotericin B preparation or an echinocandin has been demonstrated. Thus, a reasonable empiric strategy if Aspergillus is suspected would be a combination of an amphotericin B preparation and voriconazole pending surgical excision, histopathology, and culture. Although an amphotericin B preparation is the drug of most activity against mucormycosis, aggressive surgical excision and debridement is most curative when the Mucorales are suspected given the ability to invade blood vessels leading to local tissue infarction and impenetrability of medication. Scedosporium species demonstrate in vitro resistance to amphotericin, and voriconazole has been reported to be beneficial, especially when combined with prompt and complete surgical drainage.
• The majority of patients require surgery. Consensus exists that all lesions greater than 2.5 cm should be excised or stereotactically aspirated. Specimens should be sent for culture and histopathology.
• Craniotomy: Open craniotomy is often not necessary but is more commonly employed in cases of traumatic abscess to assure removal of all foreign material or to debride bone fragments. Posterior fossa abscesses also likely require an open approach because of greater risk of herniation with evolving mass effect. Ventriculostomy is occasionally required if evidence exists for marked increased intracranial pressure due to obstructive hydrocephalus, ventricular rupture, or other uncontrolled mass effect.
• Aspiration: Indications for closed drainage are more controversial. If a patient is stable with an accessible abscess, then prompt aspiration prior to antibiotic therapy may allow specific bacteriologic diagnosis and, therefore, the narrowest of spectrum of long-term antibiotic exposure. However, aspiration during an early cerebritis stage may risk hemorrhage.

2. Next list other therapeutic modalities.

• Corticosteroids: Dexamethasone has a limited role in prevention of impending cerebral herniation in an abscess causing significant mass effect prior to surgical evacuation. Corticosteroids may delay entry of antibiotics into the CNS, slow capsule formation and clearance of bacteria, and alter appearance of follow-up neuroimaging. Thus, prolonged use of corticosteroids beyond surgical drainage should be avoided.
• Anticonvulsants: Although seizures do not affect the overall mortality rate, they may occur in 10-25% of cases of brain abscess, and an anticonvulsant is recommended in the early course of therapy.
• Post-surgical/intensive care monitoring: It is recommended that all patients undergoing non-operative management and those in the early post-operative period following aspiration or excision be observed in a neuro-intensive care setting. Potential for rapid changes in intracranial pressure warrant scheduled neurologic examination and vital sign measurement, usually every hour in the early post-operative period. Antibiotic administration may need to be dose adjusted for change in kidney function. Fever or leukocytosis should not only prompt consideration of the brain abscess, but also hospital acquired infections, including Clostridium difficile, which has led to poor outcome in otherwise successfully treated brain abscesses.

What complications could arise as a consequence of a brain abscess?

What should you tell the family about the patient’s prognosis?

• Case fatality rates have dropped to 0-25% in the era of improved neuroimaging, more effective antibiotic therapy, and new surgical techniques.
• Predictors of poor response include delay in diagnosis, multiple abscesses or localization to the posterior fossa, a fungal pathogen, ventricular rupture (80-100% mortality), and Glasgow Coma Scale less than 12 on presentation.
• Long-term neurologic sequelae develop in 30-50%.

What pathogens are responsible for this disease?

Brain abscess is usually a monomicrobial process, although 30% may have a mixed bacterial infection. Although bacteria predominate, less commonly fungal or protozoal species may cause brain abscess, but the pathogens are highly dependent on the predisposing infection or host immunodeficiency.

Streptococci are the most common of bacterial species, are found in the presence of other bacteria when mixed, and are commonly oropharyngeal in origin. The milleri group of Streptococci, including anginosus, constellatus, and intermedius, have a particular predisposition for deep abscess formation, the brain being no exception (see Table I). Enterobacteriaciae and anaerobes are also prevalent, found in 40% of cases. The anaerobes, such as Prevotella and Bacteroides species, arise in the presence of contiguous dental abscess or more distant lung abscess or empyema. Staphylococcus aureus is found in 10-15% of isolates, is usually of pure culture, and is additionally notable for association with penetrating trauma or infective endocarditis.

With proliferation of broad-spectrum antimicrobial use, immunosuppressive therapy for malignancy or organ transplantation, and hyperalimentation, fungal brain abscesses have become more prevalent. Candida species are more prevalent and can cause micro-abscesses and even a diffuse nodular gliosis pattern of disease. Cerebral aspergillosis warrants mention in discussion of the neutropenic host, and brain involvement may occur in up to 20% of invasive disease. Mucormycosis is observed in patients with diabetes and ketoacidosis, hematologic malignancy, or corticosteroid use and usually cause brain abscess as an extension of destructive rhinocerebral disease.

In contrast, brain abscess with Scedosporium apiospermum may be observed in immunocompetent hosts, usually after exposure to contaminated water, as reported following near-drowning episodes, but has also been associated with pulmonary or intravenous catheter infection.

How do these pathogens cause disease?

Pathogenic stages of brain abscess have been divided into histologic categories depending on the stage of infection:

• early cerebritis (1-3 days)
• late cerebritis (4-9 days)
• early capsule formation (10-13) days
• late capsule formation (14 days onward)

Early cerebritis is marked by bacteria visible on Gram stain, acute inflammation, and marked edema. As macrophages and fibroblasts surround the lesion, the center becomes necrotic in the late cerebritis stage. A thickened collagen capsule begins to form as the necrotic center regresses in the early capsule stage. Edema has usually regressed by the late capsular stage. In animal models of brain abscess, certain pathogens are observed to be more virulent. For example, Staphylococcus aureus develops a greater degree of necrosis, and the time to capsule formation is extended, likely because of α-toxin formation.

WHAT’S THE EVIDENCE: Diagnosis and management of brain abscess is based largely on case series and expert opinion

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