Journal Pre-proof

ESCMID guidelines on diagnosis and treatment of brain abscess in children and

adults

Jacob Bodilsen, Quintino Giorgio D’Alessandris, Hilary Humphreys, Mildred A. Iro,

Matthias Klein, Katharina Last, Inmaculada López Montesinos, Pasquale Pagliano,
Oğuz Reşat Sipahi, Rafael San-Juan, Pierre Tattevin, Majda Thurnher, Rogelio de J.
Treviño-Rangel, Matthijs C. Brouwer, for the ESCMID Study Group for Infections of
the Brain (ESGIB)

PII: S1198-743X(23)00399-3
DOI: https://doi.org/10.1016/j.cmi.2023.08.016
Reference: CMI 3398

To appear in: Clinical Microbiology and Infection

Received Date: 23 May 2023

Revised Date: 16 August 2023
Accepted Date: 17 August 2023

Please cite this article as: Bodilsen J, D’Alessandris QG, Humphreys H, Iro MA, Klein M, Last K,
Montesinos IL, Pagliano P, Sipahi OR, San-Juan R, Tattevin P, Thurnher M, de J. Treviño-Rangel R,
Brouwer MC, for the ESCMID Study Group for Infections of the Brain (ESGIB), ESCMID guidelines on
diagnosis and treatment of brain abscess in children and adults, Clinical Microbiology and Infection,
https://doi.org/10.1016/j.cmi.2023.08.016.

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© 2023 The Author(s). Published by Elsevier Ltd on behalf of European Society of Clinical Microbiology
and Infectious Diseases.
 ESCMID guidelines on diagnosis and treatment of brain abscess in
children and adults

Jacob Bodilsen1,2,3, Quintino Giorgio D’Alessandris4,5, Hilary Humphreys6, Mildred A.

Iro7, Matthias Klein3,8, Katharina Last3,9, Inmaculada López Montesinos10,11, Pasquale
Pagliano3,12,13, Oğuz Reşat Sipahi3,14,15, Rafael San-Juan11,16,17, Pierre Tattevin3,18,
Majda Thurnher19, Rogelio de J. Treviño-Rangel,20,21,22,23, and Matthijs C. Brouwer3,24
for the ESCMID Study Group for Infections of the Brain (ESGIB)

1) Department of Infectious Diseases, Aalborg University Hospital, Aalborg, Denmark

2) Department of Clinical Medicine, Aalborg University Hospital, Aalborg, Denmark
3) ESCMID Study Group for Infections of the Brain (ESGIB), Basel, Switzerland
4) Department of Neurosurgery, Fondazione Policlinico Universitario “A. Gemelli” IRCCS, Rome, Italy
5) Department of Neuroscience, Università Cattolica del Sacro Cuore, Rome, Italy

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6) Department of Clinical Microbiology, Royal College of Surgeons in Ireland University of Medicine

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and Health Sciences, Dublin, Ireland
7) Department of Paediatric infectious diseases and immunology, The Royal London Children’s
Hospital, Barts Health NHS Trust, London, UK

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8) Department of Neurology, Hospital of the Ludwig-Maximilians University, Munich, Germany
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Emergency Department, Hospital of the Ludwig-Maximilians University, Munich, Germany
9) Institute for Hygiene and Public Health, University Hospital Bonn, Bonn, Germany
10) Infectious Disease Service. Hospital del Mar. Institut Hospital del Mar d'Investigacions Mèdiques
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(IMIM), Barcelona, Spain
11) CIBERINFEC ISCIII, CIBER de Enfermedades Infecciosas, Instituto de Salud Carlos III, Madrid, Spain
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12) Department of Medicine, Surgery and Dentistry, Scuola Medica Salernitana, Unit of Infectious
Diseases, University of Salerno, Baronissi, Italy
13) UOC Clinica Infettivologica AOU San Giovanni di Dio e Ruggi d’Aragona – Salerno – Italy
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14) Ege University, Faculty of Medicine, Department of Infectious Diseases and Clinical Microbiology,
Bornova, Izmir, Turkey
15) Bahrain Oncology Center, King Hamad University Hospital, Infectious Disesases Department,
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Muharraq, Bahrain
16) Unit of Infectious Diseases, 12 de Octubre Universitary Hospital, Madrid, Spain.
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17) ESCMID Study Group for Infections in Compromised Hosts (ESGICH)

18) Department of Infectious Diseases and Intensive Care Unit, Pontchaillou University Hospital,
Rennes, France
19) Department of Biomedical Imaging and Image-guided Therapy, Medical University of Vienna,
Vienna, Austria
20) Universidad Autónoma de Nuevo León, Faculty of Medicine, Department of Microbiology.
Monterrey, Nuevo León, Mexico
21) ESCMID Fungal Infection Study Group (EFISG)
22) ESCMID Study Group for Antimicrobial Stewardship (ESGAP)
23) ESCMID Study Group for Genomic and Molecular Diagnostics (ESGMD)
24) Department of Neurology, Amsterdam Neuroscience, Amsterdam UMC, University of Amsterdam,
Amsterdam, The Netherlands

Corresponding author:
Jacob Bodilsen, MD PhD Associate Professor
Department of Infectious Diseases, Aalborg University Hospital, Aalborg, Denmark.
[email protected]

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Abstract (of no more than 400 words):
Scope
These ESCMID guidelines are intended for clinicians involved in diagnosis and treatment of
brain abscess in children and adults.

Methods
Key questions were developed, and a systematic review was carried out of all studies
published since January 1st, 1996, using the search terms “brain abscess” OR “cerebral
abscess” as Mesh terms or text in electronic databases of PubMed, Embase, and the
Cochrane registry. The search was updated on September 29th, 2022. Exclusion criteria were
a sample size <10 patients or publication in non-English language. Extracted data was
summarized as narrative reviews and tables. Metanalysis was carried out using a random
effects model and heterogeneity was examined by I2 tests as well as funnel and Galbraith

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plots. Risk of bias was assessed using ROBINS-I (observational studies) and QUADAS-2

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(diagnostic studies). The GRADE approach was applied to classify strength of
recommendations (strong or conditional) and quality of evidence (high, moderate, low, or

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very low).
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Questions addressed by the guideline and Recommendations
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MRI is recommended for diagnosis of brain abscess (strong, high). Antimicrobials may be
withheld until aspiration or excision of brain abscess in patients without severe disease if
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neurosurgery can be carried out within reasonable time, preferably within 24 hours
(conditional, low). Molecular-based diagnostics are recommended, if available, in patients
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with negative cultures (conditional, moderate). Aspiration or excision of brain abscess is

recommended whenever feasible, except for cases with toxoplasmosis (strong, low).
Recommended empirical antimicrobial treatment for community-acquired brain abscess in
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immuno-competent individuals is a 3rd generation cephalosporin and metronidazole (strong,

moderate) with the addition of trimethoprim-sulfamethoxazole and voriconazole in patients
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with severe immuno-compromise (conditional, low). Recommended empirical treatment of

post-neurosurgical brain abscess is a carbapenem combined with vancomycin or linezolid
(conditional, low). The recommended duration of antimicrobial treatment is 6-8 weeks
(conditional, low). No recommendation is offered for early transition to oral antimicrobials
due to a lack of data, and oral consolidation treatment after ≥6 weeks of intravenous
antimicrobials is not routinely recommended (conditional, very low). Adjunctive
glucocorticoid treatment is recommended for treatment of severe symptoms due to
perifocal oedema or impending herniation (strong, low). Primary prophylaxis with
antiepileptics is not recommended (conditional, very low). Research needs are addressed.

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Full document (of no more than 4500 words;).
Scope and context

Brain abscess is defined as an encapsulated area of pus within the brain parenchyma
and is a life-threatening infection with a high risk of neurological deficits among
survivors.[1,2] The epidemiology and treatment of brain abscess has changed
significantly during the last century and may vary depending on socio-economic
factors and overall health status of populations.[2–9]. The annual incidence has been
estimated at 0.4-1.3 per 100,000 inhabitants which corresponds to approximately
6,700 cases per year in Europe.[10–15] The most frequent causative pathogens in
community-acquired brain abscess are oral cavity bacteria such as Streptococcus
anginosus group, Fusobacterium spp., and Aggregatibacter spp., which are often
associated with dental and chronic ear infections.[2,16–22] Other less common

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aetiologies include Staphylococcus aureus and Gram-negative bacilli in post-
neurosurgical brain abscess, Mycobacterium tuberculosis in endemic areas, and

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Nocardia spp., fungi, and parasites in the severely immune-compromised. Historically,
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predominant risk factors were head trauma, cyanotic congenital heart disease, and
chronic ear infections but in recent decades dental infections and immuno-
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compromise have also become important predisposing conditions.[8,23–29] Methods
for diagnosis of brain abscess have improved considerably following pivotal medical
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advances of computed tomography (CT) and magnetic resonance imaging (MRI)

combined with stereotactic and minimally invasive neurosurgical techniques.[30–33]
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Moreover, targeted microbiological cultures for anaerobic bacteria and the

development of molecular diagnosis may provide important clues for antimicrobial
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therapy.[16,34–37]
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Brain abscess remains a challenging disease to manage with neurosurgical drainage

and high-dose antibiotics as cornerstones of treatment. This may be complicated by
regional differences in pathogens and antimicrobial susceptibility as well as risk of
drug toxicity during the prolonged treatment. Brain abscess also carries a high risk of
death with 30-, 90-day, and 1-year mortality rates of 7%, 13%, and 20%
respectively.[12,14,38] Sequelae occur in approximately 70% of survivors, primarily as
neurological deficits and epilepsy.[2,22,39–41]

There is considerable practice variation in the diagnostic approach and treatment due
to a lack of randomized clinical trials and clinical guidelines summarizing the available
evidence for management of patients with brain abscess.[42] Under the auspices of
the European Society of Clinical Microbiology and Infectious Diseases (ESCMID), the
ESCMID Study Group for Infections of the Brain (ESGIB) initiated the current guideline
to provide such guidance.

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Aim of guideline

The aim of this guideline is to provide recommendations on diagnosis and treatment

of brain abscess for clinicians providing care for children and adults with brain abscess.
The conclusions rely upon updated scientific evidence, clinical experience, and expert
opinion of the guideline committee to inform best medical practice.

To this end, the guideline committee developed 10 key questions on clinical

controversies in the diagnosis and treatment of brain abscess (Table 1). Several other
important aspects were addressed as background questions by literature review and
expert consensus.

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Composition of the guideline committee

The ESGIB executive committee appointed six guideline panel members from the

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study group including the chair (JB). The ESCMID executive committee assigned
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another seven members. Priority was given to a balance in country representation,
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gender, and medical specialties. After the first online meeting, the guideline panel was
expanded with a paediatrician and a neuroradiologist. All guideline panellists were
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required to be free from conflicts of interests. The guideline committee is unaware of

patient organisations for survivors of brain abscess. Thus, a patient treated by the
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chair volunteered to join the committee and provided valuable input from inception
to publication of the guideline (Suppl. Material).
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Methods

Evidence collection. In preparation for the project, we examined existing guidelines

and systematic reviews by searches at Pubmed, the Cochrane Library, SUMsearch,
www.guideline.gov, www.nice.org.uk, and www.sign.ac.uk.

Literature search, data synthesis, and risk of bias.

In the absence of randomised controlled trials, key questions were agreed by the
guideline panel during initial meetings. The key questions were then formulated as
Population, Exposure, Comparator, and Outcome (i.e. PECOs) for observational
studies on management, and as Participants, Index test, Comparator test, and
Reference standard for diagnostic studies. A broad literature search of scientific
studies of ‘brain abscess’ or ‘cerebral abscess’ as text or MESH terms was carried out
by a medical librarian in the electronic databases of PubMed, EMBASE, and the
Cochrane Library on September 17, 2021 and updated on September 29, 2022 (Full
search strategy is available in Suppl. Material). Studies were required to be published
in the English language within the last 25 years and to have more than 10 children or

4
adults included, i.e. case reports were omitted. After automated removal of
duplicates, 2,887 studies were screened independently by two panel members (MCB
and JB) and 460 were selected for full text review (Figure 1). Since five studies could
not be retrieved, a total of 455 studies were reviewed in full-length and tagged for
potential relevance for each key question by the chair (Appendix 1).

Groups of 3-5 panel members were assigned to each key question and separate data
extraction tables were designed, piloted, and revised based on preliminary
experiences. Next, raw data was obtained as relevant for individual PECOs including
crude and adjusted measures of relative risk whenever available. Data extraction was
carried out by the chair except for key question #3 in which all three group members
participated in this task. Risk of bias of individual studies for each key question was
assessed independently by all members of the subgroup using ROBINS-I for

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observational studies and QUADAS-2 for studies on diagnostic accuracy (Appendices
2-9).[43,44] Any discrepancies in these assessments were resolved by discussion. The

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scientific evidence was summarised as narrative reviews with key references and
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summary tables by the chair and discussed within subgroups. Aggregated data was
analysed using a random effects model and heterogeneity was examined by the I2
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test.[45–47] Funnel and Galbraith plots were also created to assess true
heterogeneity, selection (e.g. publication) and other biases, or chance according to
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study size.[48–51] Of note, tests for heterogeneity and publication bias based on <10
studies may have limited sensitivity and specificity.[51] Studies included in the
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systematic review but ineligible for metanalyses due to lack of pre-specified raw data
for a given PECO were occasionally discussed separately in the narrative summary post
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hoc if the studies provided other helpful guidance for the key question.
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Grading of evidence and strength of recommendations. In accordance with the

Grading of Recommendations Assessment, Development and Evaluation (GRADE)
system, the quality of evidence for each key question was categorised as high,
moderate, low, or very low (Figure 2).[52,53] Recommendations were classified as
strong or conditional (weak). Disagreements in recommendations were resolved by
discussion within subgroups for each key question (assisted by the chair) and finally
approved by the entire guideline committee at meetings under the supervision of an
ESCMID methodologist (MP).

Background questions. Other aspects of management were addressed by literature

review and expert opinion, and guidance was provided as “Good clinical practice”
statements, i.e. without undergoing GRADE evaluation.

Recommendations

5
Diagnosis
Key question 1: What is the preferred brain imaging modality in patients with
suspected brain abscess?

Participants: Patients with suspected brain abscess

Index test: Brain CT or MRI +/-contrast material
Comparator test: No comparator or the alternative test
Reference standard: Diagnosis of brain abscess confirmed by aspiration/excision of
pus, culture of abscess material, or final clinical diagnosis

A diagnosis of brain abscess usually begins with CT or MRI of the head and subsequent
confirmation by neurosurgical aspiration or excision. MRI typically shows a ring-
enhancing lesion on postcontrast T1-scan and central hyperintensity on diffusion-
weighted imaging (DWI) with corresponding low apparent diffusion coefficient (ADC)

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values.[32,33,54,55] The higher resolution in MRI likely infers improved sensitivity
compared with contrast enhanced CT in patients ultimately diagnosed with brain
abscess. Yet, the diagnostic accuracy of CT or MRI in patients with suspected brain

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abscess, i.e. ability to differentiate brain abscess from tumour, using final clinical
diagnosis or neurosurgical confirmation as reference needs further clarification.
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A total of 143 studies were examined in full length for this key question of which 115
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were excluded due to other imaging modality (e.g. MR spectroscopy) or inappropriate

study population (i.e. restricted to patients with confirmed brain abscess and not all
patients with suspected brain abscess). This left 28 studies for further analyses of
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which 21 had a cross-sectional design, four were case-control studies, and three were
cohort studies (Suppl. Tables 1 and 2).[32,33,54–79] None were multi-centre studies.
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Contrast enhanced CT. There were no studies assessing the diagnostic accuracy of CT
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of the head in patients with suspected brain abscess during the study period. Although
CT greatly improved the diagnosis of brain abscess after the introduction in the
1970’s,[30,80,81] it is widely accepted to have lower sensitivity and specificity
compared with brain MRI.[82] Still, contrast enhanced CT may be used in settings
where MRI is not available.

MRI including DWI and ADC sequences and contrast enhancement. Metanalysis of the
28 studies with an accumulated 2,128 number of patients/lesions suspected of brain
abscess showed a sensitivity of 92% (95% CI 88-95) and a specificity of 91% (95% CI
86-94) (Figures 3 and 4).[32,33,54–78] The corresponding positive predictive value
(PPV) was 88% and the negative predictive value (NPV) was 90%.

Based on the literature review, it appears that MRI may be less sensitive in case
patients have been treated with antibiotics for several weeks, in patients with
toxoplasmosis, and in post-neurosurgical brain abscess.[56,63,68,73,76]

6
Common limitations of the examined studies were unclear methods of identification
of selected patients with confirmed and disproven brain abscess, single-centre study
designs, and heterogeneity in MRI protocols between studies (Appendix 2).

Recommendation: We strongly recommend brain MRI including DWI/ADC and T1

weighted imaging with and without gadolinium for patients with suspected brain
abscess (strong recommendation, high quality of evidence). If MRI is not available,
contrast-enhanced CT is recommended.

Key question 2. Should antimicrobials be withheld until aspiration or excision in

patients with suspected brain abscess?

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Population: Patients with suspected brain abscess
Exposure: Antimicrobials are withheld until aspiration or excision
Comparator: Antimicrobials are not withheld until aspiration or excision

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Outcome: -p
Microbiological diagnosis of abscess and case-fatality rate
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A microbiological diagnosis is crucial for the successful treatment of brain abscess and
allows for determination of antimicrobial susceptibility of the causative organism and
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informs targeted therapy. Yet, whether antimicrobials can be safely withheld until
neurosurgical aspiration or excision to improve the probability of establishing a
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microbiological diagnosis remains uncertain. For this key question, a total of 17 studies
were considered of relevance of which six provided data that could be readily
extracted.[83–88] All six studies were retrospective cohort studies, 4/6 (67%) included
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children, and one was a multi-centre study (Suppl. Table 3).

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Microbiological diagnosis. In metanalysis, a microbiological diagnosis was achieved in

123/153 (80%) of patients in whom antimicrobials were withheld compared with
41/126 (33%) in those who had antimicrobials initiated before neurosurgical
aspiration or excision (p<0.001) (Suppl. Table 4).[83–88] The corresponding odds ratio
was 10.5 (95% CI 2.9-38.3) in favour of withholding antimicrobials with moderate
heterogeneity reflected by an I2 of 49% (Figure 5, Suppl. Figures 1 and 2). However,
data on additional diagnostic procedures (e.g. CT scans, blood cultures, serological
tests) and time from initiation of antimicrobial therapy until neurosurgical aspiration
or excision were either not reported or varied considerably.

Indirect support for withholding empirical antimicrobials was also offered by other
studies in the systematic review that could not be included in the metanalysis. They
showed high proportions of patients with a microbiological diagnosis if antimicrobials
were deferred until neurosurgery[89–92] or with shorter duration of preceding
antibiotics.[86,92–95]

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Case fatality rate. Only one study with 20 patients provided data for this part of the
key question in which a fatal outcome was observed in 0/3 (0%) patients when
antimicrobials were withheld compared with 0/17 (0%) when they were not withheld
(p=1.0).[83]

However, other studies without all the required pre-specified raw data available for
inclusion in the metanalysis also provided additional clues to this part of the key
question. A nationwide and population-based cohort study of 485 Danish adults with
brain abscess found that deferral of antibiotics until aspiration or excision was not
associated with increased 6-month risks of mortality (RR 0.79 [95% CI 0.42-1.52]) or
unfavourable outcome (RR 1.15 [95% CI 0.87-1.52]) in adjusted analyses.[22] Another

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recent Canadian study of 139 patients observed an unfavourable outcome in 33/123

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(27%) if antimicrobials were initiated before aspiration or excision of brain abscess
compared with 2/16 (13%) if antimicrobial treatment was deferred until neurosurgery

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(p=0.25).[18]
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Important caveats in these analyses were low sample sizes in most studies and risks
of confounding by indication, i.e. antimicrobials were more likely to be initiated
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immediately in patients with severe disease, and immortal time bias, i.e. patients with
deferred initiation of antimicrobials were by definition alive until neurosurgery was
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carried out yielding a survival advantage compared with other patients. The
corresponding risk of bias assessment was considered critical for the key question,
especially in domains of confounding, selection of patients, and deviations from
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intended interventions (Appendix 3).

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Recommendation: We conditionally recommend that antimicrobials are withheld

until aspiration or excision of brain abscess in patients without severe disease if
neurosurgery can be carried out within reasonable time, preferably within 24 hours
of radiological diagnosis (conditional recommendation, low certainty of evidence).

Key question 3. Should molecular-based diagnostics be used in patients with brain

abscess?

Participants: Patients with brain abscess

Index test: Molecular-based testing
Comparator test: Culture
Reference standard: None (concordance between tests was examined)

8
Molecular-based diagnostics, i.e. nucleic acid amplification tests (NAAT) or genomic
sequencing, have been applied in recent years to increase the diagnostic yield of
brain abscess material and potentially shorten time to microbiological diagnosis from
days to hours. This may guide choice of antimicrobials at both early and later stages
in case of e.g. treatment failure or other reasons for changes in therapy.

Few studies provided control groups without brain abscess which precluded use of
‘final clinical diagnosis of brain abscess’ as reference standard to obtain sensitivity
and specificity of cultures of brain abscess material compared with molecular-based
diagnostics. In addition, sensitivity of cultures may be limited for some fastidious
microorganisms or in case of preceding antimicrobial treatment. Lacking a true
reference standard, only concordance between cultures and molecular-based

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diagnostics were examined.

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A total of 16 studies were initially assessed for relevance for this key question of

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which nine were included in the final analysis (Suppl. Table 5).[16,36,37,96–101] Of
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these, five were prospective cohorts and three were multi-centre studies. The
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pooled analysis showed that molecular diagnostics were concordant positive with
culture results in 187/280 (67%), concordant negative in 22/280 (8%), only culture
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positive in 24/280 (9%), only molecular diagnostics positive in 36/280 (13%), and
discordant positive (i.e. both tests positive but with different pathogens) in 13/280
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(5%) (Table 2).

Molecular diagnostics expanded the number of identified pathogens (especially

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anaerobic bacteria) in 115/173 (66%) cases with brain abscess caused by oral cavity
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bacteria compared with culture and a few additional cases of Nocardia spp.[96–98]
Support for the clinical relevance of these findings was offered by one retrospective
study using meticulous culturing techniques to grow the previously identified
bacteria by molecular-based diagnostics on stored samples of brain abscess
material.[37]

Another study not included in the metanalysis also detected the presence of
archaeal methanogens in some patients with brain abscess, but the clinical relevance
needs to be confirmed in other studies.[102]

Importantly, inclusion criteria varied substantially between studies and the

molecular methodologies ranged from in-house testing to use of commercially
available kits (Appendix 4). Detailed information on previous antimicrobial treatment
and routine microbiological methods were usually not reported. Moreover, most
studies assessed only one specimen per patient even though multiple specimens
may have been taken, and few evaluated the impact of molecular diagnosis on
choice or duration of antimicrobial therapy.

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Recommendation: We conditionally recommend use of molecular-based diagnostics,
if available, in culture-negative cases (conditional recommendation, moderate
certainty of evidence).

Treatment

Key question 4. Should neurosurgical aspiration or excision be used in patients with

brain abscess?

Population: Patients with brain abscess

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Exposure: No aspiration or excision

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Comparator: Aspiration or excision
Outcome: Microbiological diagnosis, rupture of brain abscess, case-

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fatality rate, and neurological sequelae
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Neurosurgery was the only available therapy for brain abscess before the
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introduction of antibiotics into hospital care in the 1940’s and is considered a crucial
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component of management of this life-threatening infection.[3,4,6,103–105] The

procedure may confirm the diagnosis by aspiration or excision of pus from the
lesion, identify the pathogen and test for antimicrobial susceptibility, and decrease
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the intracavitary bacterial load to obtain local source control. Neurosurgical

procedures have since been refined by image- or stereotactic guided minimally
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invasive techniques which allow aspiration of small brain abscesses located deep
within the brain.[31,106–108] Similar to brain biopsy, risks of haemorrhage
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associated with aspiration or excision of brain abscess range 0-3%, whereas repeated
procedures to treat the brain abscess are required in 21% and 6% of cases,
respectively (Supplementary Material).[109–118]

Occasionally, some patients with small brain abscesses and/or an already known
pathogen are managed conservatively, i.e. without aspiration or excision. However,
the PPV and NPV of MRI with DWI/ADC for differentiating brain abscess from tumour
are 88% and 90%, respectively, as shown in Key Question 1. This means that MRI
would get the tentative diagnosis wrong in ≈1 out of 10 cases compared with an
immediate and definite diagnosis by neurosurgery (i.e. aspiration of pus or
obtainment of tumorous material for further examinations). A conservative
approach may therefore result in a potential diagnostic delay of 2-8 weeks in
patients with brain tumour while awaiting radiological response to empiric
antimicrobials. Other patients with brain abscess may deteriorate during
conservative treatment and require subsequent aspiration or excision with increased

10
risks of an adverse outcome.[119] Thus, the safety of a conservative approach
remains unclear.[120–122]

We evaluated 41 studies for this key question of which 21 provided enough detailed
information to be included in the analyses (Suppl. Table 6).[17,20,39,84,89,94,123–
137] They were all retrospective cohort studies, 18 included children, and three were
multi-centre.

Microbiological diagnosis: Metanalysis of four studies eligible for this part of the key
question showed that a microbiological diagnosis was established in 26/55 (47%) of
patients managed conservatively versus 60/91 (66%) of those treated with aspiration
or excision of brain abscess (p=0.04) yielding an odds ratio of 2.3 (95% CI 1.0-5.0) in
favour of neurosurgery (Figure 6, Suppl. Table 7, Suppl. Figures 3 and

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4).[84,124,129,137]

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Among studies not included for metanalysis in this key question due to a lack of data
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on conservatively treated patients,[17,20,83,89,92,94,126,131,136,138,139] the
pathogen was identified in a total of 605/750 (81%) patients undergoing aspiration
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or excision with rates as high as 89-99% in several recent studies.[17,20,136] In
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contrast, a study restricted to conservatively managed individuals with brain abscess

from Taiwan reported that the causative pathogen was determined in 23/31 (74%)
of patients.[122] The causative pathogens were identified by CSF cultures in 10/23
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(43%), blood cultures in 5/23 (22%), both CSF and blood cultures in 4/23 (17%), and
samples from ear or sinuses in 4/23 (17%).
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Of note, neurosurgical aspiration or excision is usually not required before initiation

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of empirical treatment for toxoplasmosis in sero-positive patients with HIV and ring-
enhancing brain lesions, whereas e.g. central nervous system lymphoma should be
ruled out in HIV patients who are sero-negative for toxoplasmosis.[114,140,141]

Rupture of brain abscess: No studies compared risks of rupture of brain abscess

among conservatively treated patients with those treated by aspiration or excision.
In general, rupture of brain abscess has been described to occur in 10-35% of
patients with brain abscess and is associated with substantially increased risks of
death and unfavourable outcome.[18,22,142–145] Still, risk factors for rupture
remain poorly defined although a close proximity to the ventricles has been
suggested.[143,145] Of relevance also for this part of the key question, a study of
conservatively treated patients observed that rupture occurred among 9/31
(29%).[122]

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Case-fatality rate: A total of 17 studies provided data for this metanalysis with an
overall case-fatality rate of 172/704 (24%) in conservatively treated patients
compared with 140/1,484 (9%) in those who had their brain abscess aspirated or
excised (p<0.001).[17,20,39,84,89,94,124–130,132–134,136] The corresponding OR
for fatal outcome was 0.5 (95% CI 0.3-0.6) in favour of neurosurgical aspiration or
excision of brain abscess (Figure 7). Statistical heterogeneity between studies was
assessed to be low with an I2 of 11%, whereas funnel and Galbraith plots suggested
an association between large study size and increased mortality in conservatively
treated patients (Suppl. Figures 5 and 6). A large study used national healthcare
registries in Denmark from 1982 through 2016 and showed a 1-year mortality of
96/405 (24%) in patients treated without aspiration or excision of brain abscess
compared with 71/525 (14%) in those treated with neurosurgery (p<0.001).[39]

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After adjustment for age, sex, Charlson comorbidity index score, and calendar year,

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the 1-year mortality rate ratio was 0.78 (95% CI 0.62-0.97) in patients managed by
aspiration versus conservative treatment.

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Although not included in metanalysis due to lack of all pre-specified data, another
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Danish study based on medical record review of 485 adults from 2007 through 2020
found that aspiration or excision of brain abscess was not associated with improved
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6-month mortality in adjusted analysis.[22] On the other hand, a single-centre

retrospective cohort study of conservatively treated patients with brain abscess
na

observed a high case-fatality rate of 15/31 (48%).[122]

Neurological sequelae: Neurological sequelae were rarely specified, especially

ur

according to neurosurgical intervention or not, and risks of “unfavourable/poor

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outcome” (e.g. Glasgow Outcome Score of 1-3) were accepted as proxies. Thus, six
studies were identified for this key question and neurological sequelae occurred in
39/148 (26%) of conservatively treated patients compared with 192/684 (28%) of
those treated with aspiration or excision (p=0.75).[94,123,131,134–136] The
corresponding OR of neurological sequelae was 1.1 (95% CI 0.7-1.6) in metanalysis
using neurosurgical aspiration or excision as reference (Figure 8, Suppl. Figures 7 and
8).

Other studies that could not be included in this part of the metanalysis showed
diverging results. A Danish nationwide and population-based cohort study of 485
adults with brain abscess found that neurosurgical aspiration or excision of brain
abscess was not an independent prognostic factor for unfavourable outcome defined
as a Glasgow Outcome Score of 1-4 at discharge (RR 1.00 [95% CI 0.88-1.14]) or 6
months thereafter (RR 1.07 (95% CI 0.77-1.47]).[22] In contrast, a single-centre study
from the United States observed a decreased risk of treatment failure, i.e.
progression of abscess size or development of new abscesses within six months,

12
among 106 patients with early neurosurgery ≤7 days of admission compared with
the remaining 118 patients among whom 18 required subsequent aspiration or
excision.[119] Propensity score adjusted analysis showed a hazard rate ratio for
treatment failure of 0.55 (95% CI 0.31-0.98) in favour of early neurosurgery.
Moreover, the adjusted hazard rate ratio for treatment failure was 0.59 (95% CI
0.34-1.01) using time to neurosurgery as a time-dependent variable.

Risk of bias was critical in all studies examined for this key question with inadequate
confounder adjustment and selection bias between the analysed groups as
important limitations (Appendix 5). This may substantially affect the results in an
unpredictable manner. As an example, conservative treatment is likely assigned to
individuals with mild disease or an already determined pathogen, but the group may

f
also comprise severely ill patients who die early during admission or are not

oo
considered suitable for neurosurgery. Unfortunately, details on reasons for
conservative treatment were rarely available. In addition, a conservative strategy

r
may be revised during treatment due to disease progression which may skew results
-p
in favour of not carrying out aspiration or excision of brain abscess.
re
lP

Recommendation: We strongly recommend neurosurgical aspiration or excision of

brain abscess as soon as possible in all patients whenever feasible (excl.
toxoplasmosis) (strong recommendation, moderate certainty of evidence).
na
ur

Key question 5. What is the optimal empirical antimicrobial therapy for brain
abscess?
Jo

Population: Patients with brain abscess

Exposure: Cephalosporin and metronidazole-based regimen,
carbapenem-based regimen, add-on vancomycin
Comparator: Penicillin and metronidazole-based regimen
Outcome: Case-fatality rate

Optimal empirical and targeted antimicrobial treatment is a key component in

management of patients with brain abscess. Yet, such antimicrobial regimens remain
poorly defined and have thus far relied on pharmacokinetic aspects, pathogen
distributions according to patient type (e.g. immuno-competent, immuno-
compromised, or nosocomial brain abscess), burden of antimicrobial resistance
patterns, and predisposing condition (e.g. dental infections, chronic otitis media,
congenital cyanotic heart disease, or head trauma).

13
We evaluated 26 studies of which 16 were included in metanalysis for this key
question (Suppl. Table 8).[83,85,86,93,94,133,146–155] They were all retrospective
observational cohort studies, 12 included children, and one was multi-centre.
Patients with brain abscess were categorised as community-acquired in 367/565
(65%), nosocomial in 71/565 (13%), immuno-compromised in 36/565 (6%), or not
reported in 91/565 (16%). Few studies provided individual or group level data on
specific antimicrobials and associated outcomes, or it was unclear if the described
treatment was empirical or targeted. In consequence, all studies reporting such
detailed information were included into the analysis for guidance on choice of
empirical antimicrobial treatment of brain abscess.

There were no substantial differences in case-fatality rates between the examined

f
empirical antimicrobial regimens in metanalysis (Figures 9-11, Suppl. Table 9, Suppl.

oo
Figures 9-14). In one retrospective single centre study of 59 immuno-competent
patients with brain abscess, comparison was made between 3rd generation

r
cephalosporin and carbapenem-based regimens.[133] The authors found that
-p
carbapenems were associated with decreased mortality after adjustment for
Glasgow Coma Scale score, intracranial hypertension, and surgical treatment.
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Notably, the groups were not well balanced in terms of age, calendar year, or
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number of patients with multiple brain abscesses, and residual confounding remains
likely. Another study from Turkey provided detailed data on empirical and targeted
antimicrobial treatment among 51 neurosurgically treated patients at a single centre
na

and observed no differences in survival according to antimicrobial regimens.[155]

Moreover, case-fatality rates did not differ substantially between different
ur

antimicrobial treatments in several other smaller studies examining brain abscesses

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caused by certain groups of pathogens such as Streptococcus milleri, Streptococcus

spp., Gram-negative bacilli, and anaerobic bacteria.[85,147,148,154] Risk of bias was
assessed to be critical for this key question in almost all the examined studies
(Appendix 6)

The guideline panel therefore relied on distributions of causative pathogens, their

antimicrobial susceptibilities, and pharmacokinetic considerations for
recommendations on optimal empirical antimicrobial treatment. A recent Danish
cohort study of all adults hospitalized for brain abscess in Denmark from 2007
through 2020 confirmed previous observations that oral cavity bacteria were the
predominant aetiology and accounted for 287/485 (59%) of cases (Figure 12).[22]
This was followed by S. aureus in 27/485 (6%), whereas the remaining cases were
either unknown in 71/485 (15%) or caused by a large variety of pathogens with
frequencies ranging from 1-3%. There was no clear pattern between anatomic
location of brain abscess and pathogens. Other studies of adults and children are
consistent with this distribution of pathogens.[12,16–21,130,137,156,157]

14
Importantly, a recent Dutch study reported decreased susceptibility of Streptococcus
mitis group to penicillin[158] and brain abscesses caused by oral cavity bacteria are
often polymicrobial and may include Haemophilus spp.[16,36,37,98] Thus, whether a
combination of high-dose benzylpenicillin and metronidazole is adequate as targeted
treatment in these patients is uncertain. Other studies have shown that S. aureus
may be relatively more prevalent in low-resource settings or where penetrating head
trauma is more frequent but also following neurosurgical procedures.[8,28,73,159–
161] For severely immune-compromised individuals such as those with
haematological malignancies, organ transplant recipients, or AIDS patients,
physicians need to consider rare pathogens such as nocardiosis, fungal infections
including aspergillosis, listeriosis, and toxoplasmosis (Table 3, Figure 12).[162–170]

f
Data on intra-cavitary concentration of antimicrobials in patients with brain abscess

oo
are scarce and restricted to case-reports or small case series.[171] Besides a limited
number of observations, almost all the published papers had incomplete information

r
on the timing of drug administration, sampling, and analysis. However, the intra-
-p
cavitary concentration of cefotaxime was studied in 15 consecutive adults with brain
re
abscess and found to be sufficiently high early during treatment.[172,173] This was
supported by a prospective single-centre cohort study of 66 patients successfully
lP

treated with cefotaxime and metronidazole.[94] Although toxicity issues related to

bone-marrow suppression of cefotaxime was frequent in that study, this is not the
na

clinical experience of the guideline committee, and more data are needed to
examine this aspect.[22,174]
Vancomycin, a bactericidal glycopeptide, has been the preferred treatment of brain
ur

abscess and other central nervous system infections caused by methicillin-resistant

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S. aureus (MRSA). However, linezolid has more favourable pharmaco-kinetic

properties and experience with this bacteriostatic drug for brain abscess is
increasing.[175–182]

Indirect clues to appropriateness of antimicrobials for brain abscess may also be

derived from treatment experiences of bacterial meningitis as well as cerebral
toxoplasmosis and nocardiosis.[183] Important characteristics to be considered for
choice of antimicrobials include lipophilicity, molecular size, stability in the acidic
environment within an abscess, risk of development of resistance, affinity to efflux
pumps in the blood-brain-barrier, polarity, and risk of drug toxicity.

Recommendation: We strongly recommend 3rd generation cephalosporin combined

with metronidazole for empirical treatment of community-acquired brain abscess in
children and adults (Table 4) (strong recommendation, low certainty of evidence).

15
Dosages should be tailored toward adequate abscess and central nervous system
penetration (Suppl. Table 10).

Recommendation: We conditionally recommend a 3rd generation cephalosporin and

metronidazole combined with trimethoprim-sulfamethoxazole (TMP-SMX) and
voriconazole for empirical treatment of brain abscess in children and adults with
severe immuno-compromise equivalent to organ transplant recipients, active
chemotherapy or biological treatment, or haematological malignancies (Table 4)
(conditional recommendation, very low certainty of evidence). An alternative
regimen may be meropenem combined with TMP-SMX and voriconazole.

Recommendation: We conditionally recommend meropenem combined with

f
vancomycin or linezolid for empirical treatment of post-neurosurgical brain abscess

oo
(Table 4) (conditional recommendation, very low certainty of evidence).

r
Recommendation: We strongly recommend targeted treatment according to
-p
pathogen and antimicrobial susceptibility (Suppl. Table 11) (strong recommendation,
re
low certainty of evidence). Based on expert opinion, we consider it good clinical
practice to continue coverage for anaerobic bacteria if oral cavity bacteria are
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identified.
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Key question 6. What is the appropriate duration of antimicrobial therapy for

bacterial brain abscess?
ur

Population: Patients with bacterial brain abscess alive at end of treatment

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(not nocardiosis or tuberculosis)

Exposure: Antimicrobial treatment <6 weeks
Comparator: Antimicrobial treatment ≥6 weeks
Outcome: Relapse/recurrence, case-fatality rate

An optimal duration of antimicrobial therapy needs to balance risks of relapse and

recurrence with development of drug toxicity, antimicrobial stewardship principles,
patient convenience, and healthcare costs. Currently, guidance on duration of
treatment is based on clinical experience and expert opinion.

A total of nine studies were examined for this key question of which four were of
sufficient detail to be included in metanalysis (Suppl. Table 12).[38,83,184,185] They
were all single-centre retrospective cohort studies and two included children.

16
Risks of relapse and recurrence among patients presumed to be alive at end of
antimicrobial therapy for brain abscess was assessed in three studies and was 0/90
(0%) for treatment duration <6 weeks compared with 6/117 (5%) for treatment
durations of ≥6 weeks (p=0.04) (Suppl. Table 13).[38,83,184] Metanalysis showed a
corresponding OR of relapse or recurrence of 3.4 (95% CI 0.3-34.2) for treatment
duration >6 weeks (Figure 13, Suppl. Figures 15 and 16). The aggregated case-fatality
rate was 5/92 (5%) in patients treated for <6 weeks compared with 1/79 (1%) in
those with treatment duration ≥6 weeks in three studies included in metanalysis
(p=0.21).[83,184,185] This yielded a pooled OR of fatal outcome of 0.3 (95% CI 0.0-
3.6) in favour of ≥6 weeks treatment duration (Figure 14, Suppl. Figures 17 and 18).

One study examined shortened treatment duration for 21-28 days (mean 26) after
neurosurgery along with different combinations of abscess irrigation, drainage, and

f
intracavitary antimicrobial instillation.[184] They observed no recurrences during a

oo
mean follow-up of 26 months (range 6-72) and there was no substantial difference in
case-fatality compared with historic controls treated for 28-47 days (mean 36)

r
without intracavitary antimicrobials.
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Due to the scarcity of available data, the guideline group also considered other
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studies with more indirect evidence on adequate treatment duration. Overall,
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relapse or recurrence is very rare during current clinical practice of 6-8 weeks of IV
antimicrobial therapy following aspiration or excision of brain abscess.[22,38] A
recent population-based study with virtually complete follow-up observed multiple
na

episodes of brain abscess in only 5/480 (1%) of individuals during the study period
from 2007 through 2020.[22] In that study, patients were treated with IV
ur

antimicrobials for a median of 44 days (IQR 41-56). Oral consolidation therapy was
used in 119/485 (25%) cases and extended the overall median duration of treatment
Jo

to 84 days (IQR 59-128). Of note, predisposing conditions for recurrence of brain

abscess were rare including neuroanatomic defects or vascular right-to-left shunts
such as congenital cyanotic heart disease or pulmonary arteriovenous
malformations. Another study used absence of fever for 10-14 days combined with
resolution of abscess on brain imaging to guide treatment in 55 neurosurgically
treated patients.[87] The mean duration of antimicrobial therapy was 22 days (range
10-66) and just 2 (4%) cases of relapse or recurrence were observed during a mean
follow-up of three years. In contrast, a study of 47 patients from England reported
that 5/8 patients with recurrence had been treated with <3 weeks of IV
antimicrobials before transition to 1st or 2nd generation oral cephalosporins.[91]

Risk of bias was considered critical in all studies included in this key question,
particularly for domains of confounding and classification of interventions (Appendix
7). Consistently, associations between treatment duration and outcome may be
biased by potential selection of patients with severe and complicated disease to
longer treatment duration. On the other hand, patients with longer treatment
duration also have a survival advantage compared with shorter treatment duration,

17
i.e. immortal time bias. Most studies also failed to exclude patients who died before
antimicrobial treatment was completed, lacked proper comparison groups, and
information on duration of treatment and follow-up was often missing.

Recommendation: We conditionally recommend a total duration of 6-8 weeks of

intravenous antimicrobials for aspirated or conservatively treated brain abscesses
(Table 5) (conditional recommendation, low certainty of evidence). Based on expert
opinion, a shorter duration of four weeks may be considered in patients treated with
excision of brain abscess.

Key question 7. Should early transition to oral antimicrobials be used in treatment of

f
patients with bacterial brain abscess?

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Population: Patients with bacterial brain abscess (not nocardiosis or

r
tuberculosis)
Exposure:
-p
Transition to oral antimicrobials within <6 weeks of treatment
Comparator: IV antimicrobials throughout treatment
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Outcome: Relapse/recurrence, case-fatality rate
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Extended IV treatment has been considered essential for management of patients

with brain abscess since the introduction of antimicrobials into hospital care.[4–
na

6,104,186] In year 2000, however, some experts recommended early transition to an

appropriate oral regimen after 1-2 weeks of IV treatment in patients with a good
ur

clinical response.[187] This is also consistent with general treatment principles of

cerebral nocardiosis, toxoplasmosis, and tuberculosis. Potential advantages include
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convenience of treatment and improvement in quality of life, decreased risks of line

complications and nosocomial infections, and reductions in healthcare costs.
Although early transition to oral antimicrobials has since been adopted as a
treatment option in some countries, effectiveness and safety remain uncertain. The
patient representative highlighted the convenience and possibility of early discharge
and rehabilitation with early transition to oral antimicrobials.

Following the preliminary full-text review, 17 studies were tagged to be of potential

relevance for this key question. However, only two studies provided sufficiently
detailed data to be included in the pre-specified metanalysis (Suppl. Table
14).[188,189] They were both retrospective multi-centre cohort studies and almost
all patients were treated with aspiration or excision of brain abscess. Children were
included in one of the studies.

Risks of recurrence or relapse was assessed in just one study and was reported to be
1/24 (4%) in patients switched to early oral antimicrobials (i.e. ≤6 weeks of
treatment) and 4/77 (5%) in those treated with IV throughout (p=0.84) (Suppl. Table

18
15).[189] Both studies provided data on fatal outcome and this was observed in 0/21
(0%) and 1/24 (4%) of patients switched to early oral antimicrobials compared with
5/28 (18%, p=0.06) and 12/77 (16%, p=0.18) of patients treated with prolonged IV
treatment. [188,189] The corresponding OR was 5.7 (95% CI 1.0-31.3) in favour of
early transition to oral antimicrobials (Figure 15, Suppl. Figures 19 and 20). However,
selection of patients with mild and uncomplicated disease to early transition to oral
antimicrobials was not sufficiently accounted for and likely explains the observed
survival advantage.

A few studies that could not be included in the metanalyses also provided support
for the feasibility of early oral antimicrobial treatment for brain abscess. A French
single-centre study examined risks of unfavourable outcome at three months after
diagnosis among 108 patients of whom 48 (44%) had been switched to oral

f
antimicrobials.[190] Using continued IV antimicrobials as reference, they observed

oo
an adjusted odds ratio for unfavourable outcome of 0.2 (95% CI 0.0-0.6) in patients
who were switched to orals early during management. Other studies described use

r
of early oral antimicrobials guided by normalisation of plasma C-reactive
-p
protein,[146] due to patient request,[191] or as part of standard treatment in
developing countries[192–195] with an aggregated case-fatality rate of 8/200 (4%).
re
Still, a single-centre study from England reported that 5/8 (63%) cases with
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recurrence of brain abscess had been treated with <3 weeks of IV antimicrobials
before transition to oral 1st or 2nd generation cephalosporin.[91]
na

Risk of bias was assessed to be serious and critical with special emphasis on
inadequate confounder control due to the limited sample sizes and likely selection of
ur

patients with mild disease to early oral antimicrobial treatment (Appendix 8).
Jo

Recommendation: No recommendation. For early transition to oral antimicrobials in

patients with brain abscess, there is insufficient evidence at the time of writing to
provide a recommendation.

Key question 8. Should consolidation therapy with oral antimicrobials after ≥6 weeks
of IV antimicrobials be used to reduce risks of relapse or recurrence?

Population: Patients with bacterial brain abscess (excl. permanent

neuroanatomic defects, tuberculosis, nocardiosis,
toxoplasmosis, and fungal brain abscess)
Exposure: Oral consolidation therapy after ≥6 weeks of IV treatment
Comparator: No oral consolidation therapy and alive at end of IV treatment
Outcome: Relapse or recurrence of brain abscess within one year after
end of treatment

19
Oral consolidation therapy after ≥6 weeks of IV antimicrobial treatment is frequently
used,[8,17,22,38,134,188] and has been recommended by some experts to prevent
relapse and recurrence of brain abscess.[196] Indeed, a survey among infectious
diseases specialists in Australia, Denmark, France, and Sweden disclosed that oral
consolidation therapy was used by 126/264 (47%) of respondents.[42] Consistent
with reflections on overall duration of treatment, potential decreased risks of
relapse and recurrence with oral consolidation therapy should be weighed against
increased risks of drug reactions, antimicrobial stewardship considerations, and
healthcare costs.

A total of eight studies were tagged for relevance for this key question during initial
full-text review of all studies on brain abscess. Yet, none reported risks of relapse or

f
oo
recurrence according to oral consolidation therapy or not.
Among studies that could not be included in metanalysis for this key question, an

r
Italian multi-centre study of 79 children found that oral consolidation was frequently
-p
added to standard six weeks of IV treatment.[134] However, the mean duration of
antimicrobial therapy did not differ significantly between patients with and without
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new abscess formation (64.1 days compared with 59.1 days, p=0.78) suggesting,
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indirectly, a lack of benefit of oral consolidation therapy for risk of recurrence.

Consistent with this result, another study of 40 children in England also showed
comparable short- and long-term risks of neurological sequelae in patients treated
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with oral consolidation therapy or not.[197]

ur

Recommendation: Based on expert opinion, we conditionally do not recommend

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oral consolidation treatment after ≥6 weeks of IV antimicrobials for brain abscess

(excl. permanent neuroanatomical defects, tuberculosis, nocardiosis, toxoplasmosis,
and fungal brain abscess) (conditional recommendation, very low certainty of
evidence).

Management of complications

Key question 9. Should dexamethasone be used to treat severe symptoms due to

perifocal oedema in patients with brain abscess?

Population: Patients with brain abscess and perifocal oedema

Exposure: Dexamethasone
Comparator: No dexamethasone
Outcome: Case-fatality rate and neurological deficits

20
Corticosteroids, usually in the form of dexamethasone, are effective in attenuating
oedema around brain abscesses and are frequently used on an individual basis as
adjunctive treatment in patients with brain abscess.[2,22] They are considered
especially helpful in patients with impending herniation or severe symptoms due to
perifocal oedema. However, corticosteroids may also decrease or weaken collagen
deposition and thereby lead to impaired capsule formation with associated risks of
rupture of brain abscess although this was not confirmed in animal studies.[198–
202] Others have reported conflicting results regarding intracavitary penetration of
antibiotics in animal models of brain abscess treated with or without adjunctive
corticosteroids.[203–207] This may introduce uncertainty in the safety of
corticosteroids for symptomatic treatment of patients with brain abscess. The
importance of symptom relief with adjunctive corticosteroids, if considered safe, was
highlighted by the patient representative.

f
oo
A total of 13 studies were considered of relevance for this key question.
Unfavourable outcome according to different outcome scale scores was accepted as
proxies for neurological deficits in four reports yielding a total of nine studies with

r
-p
data available for the metanalyses (Suppl. Table
16).[18,20,38,84,89,123,126,130,142] They were all retrospective cohort studies,
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eight included children, one was multi-centre, and one was population-based.
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No studies quantified symptom relief from corticosteroid therapy in patients with

brain abscess and perifocal oedema. Risk of neurological deficits was examined in
na

seven studies and was found to be 90/303 (30%) in patients treated with
corticosteroids compared with 80/383 (21%) among those not treated with
corticosteroids (p=0.01) (Suppl. Table 17). [18,20,38,89,123,130,142] This yielded an
ur

OR for neurological deficits of 0.7 (95% CI 0.5-1.0) in favour of no adjunctive

corticosteroid treatment (Figure 16, Suppl. Figures 20 and 21). Of note, information
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on type of corticosteroids, dosage, and duration was rarely provided and

considerable variations in treatment regimens was likely within and between
studies. One study detailed risks of unfavourable outcome if corticosteroids were
administered before or after neurosurgical procedures for brain abscess and
observed no substantial differences compared with no corticosteroid treatment.[38]
Fatal outcome according to adjunctive corticosteroid treatment or not was
accounted for in three studies.[84,126,130] The pooled risk of death was 20/91
(22%) and 24/124 (19%) according to adjunctive corticosteroid treatment or not
(p=0.76). Consistently, adjunctive corticosteroids treatment was not significantly
associated with increased case-fatality with an OR of 0.6 (95% CI 0.3-1.4) in
metanalysis (Figure 17, Suppl. Figures 22 and 23). In addition, use of corticosteroids
was not associated with increased risk of rupture in univariate analysis in one study
of 113 patients with brain abscess (5/24 [21%] vs. 26/89 (29%), p=0.41).[123]
Among studies initially tagged but not included in metanalysis due to lack of all pre-
specified raw data for this key question, adjusted analyses of adjunctive
corticosteroid treatment did not show increased risks of death or unfavourable

21
outcome at six months after admission,[22] or of late seizures and seizure-free
survival compared with no corticosteroids.[145]
Risk of bias related to this key question was critical or serious in the included studies,
particularly for lack of confounder adjustment, selection bias of corticosteroid
treatment primarily used in patients with severe disease, and missing data (Appendix
9).

Recommendation. Based on expert opinion, corticosteroids are helpful for treatment

of severe symptoms due to perifocal oedema in patients with brain abscess. In the
absence of convincing clinical data of harm related to adjunctive corticosteroid
treatment, we strongly recommend use of corticosteroids for management of severe
symptoms due to perifocal oedema or impending herniation in patients with brain

f
abscess (strong recommendation, low certainty of evidence).

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Key question 10. Should primary prophylaxis with antiepileptic treatment be used to

r
-p
reduce risks of seizures during admission and subsequent epilepsy?
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Population: Patients with brain abscess without seizures
Exposure: Antiepileptic treatment during admission or at discharge
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Comparator: No antiepileptic treatment

Outcome: Seizures during admission and subsequent epilepsy
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Seizures are a frequent complication in patients with brain abscess and new-onset
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epilepsy is diagnosed in up to one third of survivors.[39,40] Patients with brain

abscess and seizures are more likely to have an unfavourable outcome at discharge
Jo

and epilepsy is associated with increased long-term mortality among survivors.[208–

210] Seizures in patients with previous brain abscess are categorised as epilepsy and
should be treated accordingly with antiepileptics.[211] Yet, primary prophylaxis with
antiepileptics in patients with brain abscess is controversial but has been
recommended by a few experts[196,212] and adopted into clinical practice as
reported in some studies.[123,155,209,210,213] Infectious diseases specialists are
often involved in such decisions as part of multidisciplinary management together
with neurologists and neurosurgeons. However, experiences from randomised
controlled trials in patients with brain tumours and severe head trauma are
discouraging.[214,215] Since primary prophylaxis concerns individuals free from the
disease of consideration at time of initiation, a clear benefit is required, i.e.
prevention of first seizure episode needs be balanced against unnecessary treatment
in a substantial proportion of patients. The patient representative indicated that
risks of side-effects associated with potentially unnecessary antiepileptics for
primary prophylaxis should be emphasized.

22
A total of 14 studies were tagged to be of interest for this key question, but only one
single-centre retrospective cohort study met the pre-specified requirements for
metanalysis.[209] In that study, 10/103 (9%) of survivors with aspirated or excised
supratentorial brain abscesses developed subsequent epilepsy despite post-
discharge treatment with antiepileptics for a mean duration of 15 days (standard
deviation 26) compared with 0/6 of untreated patients (p=0.03). The median follow-
up time was 15 months (range 0.5-122) from diagnosis of brain abscess. The overall
relative short mean duration of antiepileptic treatment and lack of confounder
adjustment likely explain the contradictory finding of increased risk of epilepsy
among those treated with antiepileptics after admission.

Other studies suggested that risk factors for epilepsy in patients with brain abscess
comprised seizures early during admission, frontal lobe brain abscess, aspiration or

f
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excision of brain abscess, large abscesses, other previous neurosurgical procedures,
and stroke.[208–210,216–218] In contrast, occipital lobe abscess has been

r
associated with a decreased risk of epilepsy.[208]
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re
Recommendation: Based on expert opinion, we conditionally recommend against
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primary prophylaxis with antiepileptics in patients with brain abscess (conditional

recommendation, very low certainty of evidence).
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ur
Jo

23
General practice recommendations on management of patients with brain abscess

Neurosurgery is pivotal to obtain source control in patients with brain

abscess.[3,39,120,219] However, there is no clear evidence to favour aspiration over
excision of brain abscess in terms of mortality (Suppl. material).[3,220] Aspiration is
associated with approximately 20% risk of re-aspiration or secondary excision,
whereas primary excision is more invasive and not always feasible.[2,22] Aspiration
has been the preferred neurosurgical procedure throughout the recent decades and
is recommended in most cases of brain abscess. Still, excision may be considered in
abscesses caused by certain difficult-to-treat pathogens such as fungi or Nocardia
spp., and in superficial brain abscesses located in non-eloquent areas or the
posterior fossa.[1,221–223]

f
Samples of pus from the brain abscess should be sent for aerobic and anaerobic

oo
cultures as well as histopathological analyses (good clinical practice statement). In
endemic areas or according to clinical presentation and exposure, samples may also

r
be sent for Ziehl-Nielsen stain and culture and PCR for tuberculosis. Blood cultures
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are positive in 28% of patients[2] and should be obtained in all patients, whereas
re
additional microbiological samples may be tailored towards concomitant foci of
infection depending on the clinical presentation (good clinical practice statement). It
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is advised to store microbiological samples for additional analyses in case the

aetiology remains unknown after preliminary investigations (good clinical practice
na

statement). Blood tests such as C-reactive protein, procalcitonin, and white blood
cell count are not useful to rule in or rule out brain abscess,[12,22,38,224] although
ur

they may indicate severe disease/rupture if elevated. HIV test should also be
considered in all patients with non-traumatic brain abscess (good clinical practice
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statement). In contrast, lumbar puncture is relatively contraindicated and the

diagnostic yield is usually low.[8,38,86,92,126,131,137,224–233] Relevant imaging
may include chest x-ray or CT of the thorax-abdomen-pelvis for patients with an
unclear source of infection (good clinical practice statement), and CT pulmonary
angiogram should be considered to rule out pulmonary arteriovenous malformations
in patients with recurrent brain abscess for unknown reasons. The role of PET-CT
compared with standard diagnostic work-up is unclear and cannot be recommended
as a routine examination for now.[234–236]

Consultations by ear-nose-throat (ENT) specialists and maxilla-facial surgeons should

be carried out in cases with suspected or evident ENT or dental infections and in
those with brain abscess caused by oral cavity bacteria (good clinical practice
statement). Endocarditis is diagnosed in ≤5% of patients with brain
abscess[8,16,21,22,91,131,155] and transoesophageal echocardiography should be
reserved for bacteraemic patients with monomicrobial brain abscess caused by
streptococci or staphylococci without other obvious predisposing conditions, e.g.

24
neurosurgery or open head trauma (good clinical practice statement). Some patients
with brain abscess may be diagnosed secondarily to infections with high risks of
dissemination to the brain such as pulmonary aspergillosis or
nocardiosis.[162,163,166,237,238] Since co-infections do occur and local source
control in the brain is important, shared decision-making is required to decide
between neurosurgical abscess aspiration and conservative treatment in a case-by-
case evaluation (good clinical practice statement).

Brain imaging should be carried out immediately in all patients with clinical
deterioration. Otherwise, imaging needs only to be done in regular intervals (e.g.
every two weeks) after aspiration or excision until clinical cure is evident (good
clinical practice statement). Although the radiological evolution of brain abscess
varies considerably, abscess volume is often stationary or only slightly diminished on

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brain imaging by two weeks after aspiration, whereas lack of regression by four
weeks is unusual.[80,94,173,219,239–242] Repeated neurosurgical aspiration, or in

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selected cases excision, should be carried out in case of clinical deterioration or
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enlargement of brain abscess, and is almost always required in those without any
reduction in brain abscess volume by four weeks after first aspiration (good clinical
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practice statement).[120,219,241] On the other hand, it may take 3-6 months before
residual contrast enhancement resolves on brain imaging and it is often
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inappropriate to prolong antimicrobial treatment based solely on such radiological

findings (good clinical practice statement).
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Rupture of brain abscess causes fulminant meningitis with associated substantially

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increased case-fatality rates of 27-50% and may occur into the subarachnoid space
around or between the hemispheres or into the ventricles.[22,143–145] The
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reported incidence varies from 10-35% of which approximately half are diagnosed
immediately at admission.[22,143–145] Suggested risk factors include proximity to
the ventricles and multiloculated brain abscesses. [143–145] Treatment frequently
entails external ventricular drainage for obstructive hydrocephalus, whereas
addition of intraventricular antibiotics is without proven effect and has been
reserved for multidrug resistant pathogens with presumed poor penetration of
available drugs into the CNS.[38,123,188,229,243]

Recurrence of brain abscess is very rare except in patients with neuroanatomical

defects or vascular right-to-left shunts, e.g. congenital cyanotic heart disease and
pulmonary arteriovenous malformations, that are not amenable for corrective
measures.[13,25,138,142,185,244–249] For patients without vascular right-to-left
shunts, antibiotic prophylaxis during dental visits is not indicated (good clinical
practice statement).[250]

Long-term sequelae have been observed in about 45% of patients at six months after
discharge and usually comprise focal neurological deficits corresponding to the
25
anatomic location of the brain abscess and neurocognitive impairment, especially in
those with rupture of brain abscess.[2,22] This may lead to lower employment rates
(risk difference 26%, 95% CI 17-36) and higher risks of disability pension (risk
difference 29%, 95% CI 20-38) among patients with brain abscess at five years after
diagnosis compared with matched population-controls.[12,251] Thus, referral to
specialised neurorehabilitation is vital for managing long-term sequelae and for
helping patients to exploit their full potential for regaining functional capacity (good
clinical practice statement). This may include physical and occupational therapy as
well as patient education and coping strategies. Patients with brain abscess have also
been shown to have an increased use of anxiolytics (from 4% to 17%) and
antidepressants (from 2% to 11%) in the first year after diagnosis and physicians
need to be attentive towards signs of affective disorders (good clinical practice

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statement).[252]

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Compared with matched population controls, brain abscess has been associated with

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an increased risk of cancer (adjusted hazard rate ratio 2.09, 95% CI 1.79-2.45) for
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unclear reasons as well as substantially increased 1-year mortality (adjusted
mortality rate ratio 17.5, 95% CI 13.-22.0).[253] Thus, careful management of
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comorbidities and maintaining a low threshold for diagnostic work-up for cancer
remain important in these patients (good clinical practice statement).
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The patient representative underlined that counselling about returning to work and
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ability to maintain family-life and other social relations should be prioritised in

conversations with patients and relatives (good clinical practice statement). In
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addition, the general very low risk of recurrence should also be discussed with
patients (good clinical practice statement).
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Future directions
Future research needs were not a formal part of development of this guideline and
recommendations are therefore guided by areas with no or very low certainty of
evidence as well as discussions within the panel.

Over the coming years, molecular methods will become more common and
accessible through reductions in costs of available commercial products. This might
extend the findings from culture, which will remain important for susceptibility
testing and occasionally additional isolates for further identification. However, a
minimum standard for aerobic and anaerobic cultures should be agreed and some
specifications for molecular tests to provide consistency between centres is
warranted. There is also a need to determine whether more rapid results and an
expanded array of identified pathogens detected using molecular diagnostics have a
positive impact on patient management and outcome.

26
Improved study designs among observational studies may be helpful and should
incorporate proper control groups. Common areas to address are confounding in
adequately powered sample sizes and immortal time bias in comparisons between
treatments. Specifically, future studies may consider comparison of patients
originally planned for conservative treatment (irrespective of later neurosurgical
procedures) with early aspiration or excision and use time to neurosurgery as a time-
dependent variable in addition to adjustment for disease severity at time of
diagnosis. Improved predictors of treatment failure including death, rupture of brain
abscess, and disease progression among conservatively treated patients are also
needed. Analysis of early transition to oral antimicrobials should include a
comparison group (IV throughout) that is balanced in terms of comorbidities and

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disease severity and who were alive around time of early transition to oral

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antimicrobials. A survey among infectious diseases specialists suggested that trials
on early transition to oral antimicrobials and duration of therapy had the highest

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priority among respondents.[42] Currently, a non-inferiority trial on early transition
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to oral antimicrobials compared with continued IV treatment is active and recruiting
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patients.[254]
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Conflict of interest
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All authors report no conflicts of interests relevant to this guideline.

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Funding sources
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The guideline was funded by the European Society of Clinical Microbiology and
Infectious Diseases, (ESCMID).

Author contributions
Contribution Author(s)
Conceptualization MK, PP, ORS, PT, MCB, JB, ESGIB
Methodology All authors
Formal analysis JB
Data curation All authors
Writing original draft JB
Review and editing All authors
Project administration JB
Funding acquisition JB

27
Acknowledgments
We thank Cecilia Ramlau-Hansen, a survivor of brain abscess, for her kind and
helpful input from a patient’s perspective throughout the development of this
guideline. We also thank Professor Jean-Paul Stahl for overseeing the project and
Professor Mical Paul for methodological assistance on behalf of the ESCMID
Guideline Subcommittee.

Updating
Two members of the guideline committee (the chair plus one other) will summarize
recent developments within the field of brain abscess and assess the need for
update every two years at the ESGIB annual business meeting during ECCMID.

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Substantial and clinically relevant updates to guideline will be submitted for

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publication in CMI.

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Jo

28
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based matched cohort study. Clin Microbiol Infec 2020;26:1093.e1-1093.e3.
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[246] Kjeldsen AD, Tørring PM, Nissen H, Andersen PE. Cerebral abscesses among
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51
Table 1: Summary of recommendations

Key question Recommendation Strength of Quality of

recommendation evidence

Diagnosis

#1 What is the preferred We strongly recommend brain MRI including Strong High
brain imaging modality in DWI/ADC and T1 weighted imaging with and
patients with suspected without gadolinium for patients with suspected
brain abscess? brain abscess.

If MRI is not available, contrast-enhanced CT is

recommended.

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#2 Should antimicrobials We conditionally recommend that antimicrobials Conditional Low

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be withheld until are withheld until aspiration or excision of brain
aspiration or excision in abscess in patients without severe disease (e.g.
patients with suspected sepsis, imminent rupture, or impending

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brain abscess? -p
herniation) if neurosurgery can be carried out
within reasonable time, preferably within 24 hours
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of radiological diagnosis.

#3 Should molecular- We conditionally recommend the use of Conditional Moderate

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based diagnostics be used molecular-based diagnostics, if available, in

in patients with brain patients with negative cultures.
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abscess

Treatment
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#4 Should neurosurgical We strongly recommend neurosurgical aspiration Strong Low

aspiration or excision be or excision of brain abscess as soon as possible in
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used in patients with brain all patients whenever feasible (excl.

abscess? toxoplasmosis).

#5 What is the optimal We strongly recommend a 3rd generation Strong Moderate

empirical antimicrobial cephalosporin combined with metronidazole for
therapy for brain abscess? empirical treatment of community-acquired brain
abscess.
For severely immuno-compromised patients Conditional Low
equivalent to organ transplant recipients, active
chemotherapy or biological treatment, or
haematological malignancies, we conditionally
recommend:

A 3rd generation cephalosporin and metronidazole

combined with voriconazole and TMP-SMX.

We conditionally recommend meropenem Conditional Low

combined with vancomycin or linezolid for
 empirical treatment of post-neurosurgical brain
abscess.
We strongly recommend targeted treatment Strong Low
according to antimicrobial susceptibility testing.

Based on expert opinion, we consider it good Very low

clinical practice to continue coverage for
anaerobic bacteria if oral cavity bacteria are
identified.
#6 What is the appropriate We conditionally recommend a total duration of Conditional Low
duration of antimicrobial 6-8 weeks of intravenous antimicrobials for
therapy for bacterial brain aspirated or conservatively treated brain
abscess? abscesses.

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Based on expert opinion, a shorter duration (e.g. 4 Very low
weeks) may be considered in patients treated with
excision of brain abscess.

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#7 Should early transition No recommendation. For early transition to oral - -
to oral antimicrobials be
used in treatment of
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antimicrobials in patients with brain abscess,
there is insufficient evidence at the time of writing
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patients with bacterial to provide a recommendation.
brain abscess?
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#8 Should consolidation Based on expert opinion, we conditionally do not Conditional Very low
therapy with oral recommend oral consolidation treatment after ≥6
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antimicrobials after ≥6 weeks of IV antimicrobials for brain abscess (excl.

weeks of IV antimicrobials permanent neuroanatomical defects, tuberculosis,
be used to reduce risks of nocardiosis, toxoplasmosis, and fungal brain
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relapse or recurrence? abscess).

#9 Should dexamethasone In the absence of convincing clinical data of harm Strong Low
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be used to treat severe related to adjunctive corticosteroid treatment, we

symptoms due to perifocal strongly recommend use of corticosteroids for
oedema in patients with management of severe symptoms due to perifocal
brain abscess? oedema or impending herniation in patients with
brain abscess.
#10 Should primary Based on expert opinion, we conditionally Conditional Very low
prophylaxis with recommend against primary prophylaxis with
antiepileptic treatment be antiepileptics in patients with brain abscess.
used to reduce risks of
seizures during admission
and subsequent epilepsy?

ADC, apparent diffusion coefficient; DWI, diffusion weighted images; MRSA, methicillin-resistant Staphylococcus
aureus; TMP-SMX, trimethoprim-sulfamethoxazole
Table 2: Correlation between culture and molecular diagnostics of specimens from brain abscesses.
Culture positive Molecular
Comments
(%) detection (%)
Increased no. of bacterial
species identified by
First author No. Total Only Total Only Correlation (%)* molecular-based General
diagnostics in brain abscess
due to oral cavity bacteria
Al Masalma,
20 17 (85) 1 (5) 19 (95) 3 (15) 15 (75) 8/12 (75) Culture positive only in 1 case of Nocardia spp.
2009

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Al Masalma, Molecular detection only in 3 cases of T. gondii, 1 case of

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51 30 (59) 0 39 (76) 9 (18) 37 (73) 14/20 (70)
2012 Scedosporium apiospermium, and 1 case of N. carnea.
Andersen, Culture positive only in 2 cases of A. fumigatus, molecular

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41 37 (90) 2 (5) 37 (90) 1 (2) 35 (85) 16/28 (57)

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2022 detection positive only in 1 case of T. gondii
Molecular detection only in 1 case each of Actinomyces

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de Lastours, 19 5**
24 21 (88) 3 (13) 2 (8) 2/5 (40) israeli, Streptococcus constellatus, and Fusobacterium
2008 (79) (21)
nucleatum

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Molecular detection positive only in 7 cases of Nocardia
Hartung,
36 26 (72) 0 28 (78) 7 (19) 28 (78) 17/22 (77) spp. and oral cavity bacteria (e.g Streptococcus anginosus

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2021
group and anaerobes)
Kommedal, 33 (89)

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37 34 (92) 1 (3) 36 (97) 3 (8) 24/32 (75) Culture positive only in 1 case of M. tuberculosis
2014
Culture positive only in 1 case of Fusobacterium spp.
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Kupila, 2003 12 7 (58) 1 (8) 8 (67) 2 (17) 5 (42) 0/5 (0) Molecular detection only in 1 case each of Staphylococcus
aureus and Mycoplasma hominis
Stebner, 46
46 42 (91) 0 8 (17) 19 (41) 33/42 (79)
2021*** (100)
Tsai, 2004 13 10 (77) 0 10 (77) 0 13 (100) 1/7 (14)
224 228 36
Total 280 24 (9) 187 (67) 115/173 (66)
(80) (81) (13)
T. gondii: Toxoplasma gondii.
*Correlations imply that molecular diagnostics detected at least one of those pathogens identified by culture.
**Molecular diagnostics were used if cultures remained negative after 48 hours.
***Only data on 46 patients with brain abscess and results available for both culture and molecular-based diagnostics were included.
Table 3: Common pathogens in brain abscess in patients with selected severe
immuno-compromising conditions.

Selected immuno-compromising conditions Common causes of brain abscess

Haematopoietic stem cell transplant recipients Fungi, nocardiosis, toxoplasmosis
Solid organ transplant recipient Fungi, nocardiosis, toxoplasmosis
AIDS patients Toxoplasmosis

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Table 4: Recommendations for empirical antimicrobial treatment of brain abscess.

Empirical treatment
Case characteristic Standard Alternatives
Community-acquired 3rd generation cephalosporin* and Meropenem
metronidazole.
Severe immuno-compromise (i.e. 3rd generation cephalosporin* and Meropenem combined with
haematological malignancies, organ metronidazole combined with voriconazole and TMP-SMX.
transplant recipients) voriconazole and TMP-SMX.
Post-neurosurgical Meropenem and vancomycin or Ceftazidime and linezolid,
linezolid cefepime and linezolid
*Consider ceftazidime in cases at increased risk of pseudomonal brain abscess (e.g. chronic suppurative otitis media).

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Table 5: Recommendations for duration of antimicrobial treatment for brain
abscess.

Case characteristic Duration of IV treatment*

Aspirated brain abscess 6-8 weeks

Excised brain abscess 4 weeks**

Conservatively treated brain abscess 6-8 weeks

*Certain difficult-to-treat pathogens such as nocardiosis, toxoplasmosis, tuberculosis, and fungi should follow
principles of treatment already established elsewhere. **Expert opinion.

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Figure 1: Study flow chart

Identification of studies via databases and registers

Records identified from:

Identification

PubMed: 2,308
Embase: 1,752 Records removed before screening:
Cochrane registry: 89 Duplicate records removed, n = 1,262

Total: 4,149

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Records screened Records excluded by manual review of title
n = 2,887
-p and/or abstract, n = 2,427
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Screening

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Reports sought for retrieval Reports not retrieved

n = 460 n=5
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Full-text articles assessed for

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eligibility Reports excluded:0

n = 455
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Included

Studies included in qualitative

synthesis, n = 455
Figure 2: Approach and implications to rating the quality of evidence and strength of
recommendations using the Grading of Recommendations Assessment,
Development and Evaluation (GRADE) methodology.

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*Unrestricted use of the figure granted by the USA GRADE Network

Figure 3: Forest plot of sensitivity and specificity of MRI with DWI and ADC
sequences for diagnosis of brain abscess among patients with focal ring-enhancing
lesions.

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ADC: Apparent diffusion coefficient. CI: Confidence interval. DWI: Diffusion-weighted imaging. MRI: Magnetic
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resonance imaging.
Figure 4: Summary receiver operating curve (SROC) of false positive rate and
sensitivity of MRI with DWI and ADC sequences for diagnosis of brain abscess among
patients with focal ring-enhancing lesions.

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ADC: Apparent diffusion coefficient. DWI: Diffusion-weighted imaging. MRI: Magnetic resonance imaging.
Figure 5: Odds ratios of establishing a microbiological diagnosis according to
whether antimicrobial treatment was withheld or not until neurosurgical aspiration
or excision of brain abscess.

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CI: Confidence interval
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Figure 6: Odds ratios of establishing a microbiological diagnosis according to
aspiration or excision of brain abscess or not.

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CI: Confidence interval.

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Figure 7: Risk of death according to aspiration or excision of brain abscess or not.
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CI: Confidence interval.

Figure 8: Risk of neurological sequelae according to aspiration or excision of brain
abscess or not.

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Figure 9: Risk of death in patients treated with penicillin and metronidazole
compared with 3rd generation cephalosporins and metronidazole.

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CI: Confidence interval.

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Figure 10: Risk of death in patients treated with penicillin and metronidazole
compared with carbapenems.
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CI: Confidence interval.

Figure 11: Risk of death in patients treated with 3rd generation cephalosporins and
metronidazole compared with carbapanems.

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CI: Confidence interval.
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Figure 12: Causative pathogens among 485 adults hospitalised with brain abscess in
Denmark from 2007 through 2020.

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*Severe immune-compromise was defined as solid organ transplant recipients, haematological malignancies, or
immune-suppressive treatment. Please note differences in y-axis. Adopted with permission from Bodilsen et al, Brain,
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2020, https://doi.org/10.1093/brain/awac312.
Figure 13: Risk of relapse or recurrence according to treatment duration.

CI: Confidence interval.

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Figure 14: Risk of death according to treatment duration
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CI: Confidence interval.

Figure 15: Risk of death according to early switch to oral antimicrobials or not.

CI: Confidence interval.

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Figure 16: Risk of neurological deficits according to adjunctive dexamethasone
treatment or not.

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CI: Confidence interval.
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Figure 17: Risk of death according to adjunctive dexamethasone treatment or not.

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CI: Confidence interval.