# 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, Oguz Reşat Sipahi, Rafael Sanjuán, et al.

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## To cite this version:

Jacob Bodilsen, Quintino Giorgio D'alessandris, Hilary Humphreys, Mildred A Iro, Matthias Klein, et al. ESCMID guidelines on diagnosis and treatment of brain abscess in children and adults. Clinical Microbiology and Infection, 2024, 30 (1), pp.66-89. 10.1016/j.cmi.2023.08.016. hal-04196689

HAL Id: hal-04196689

https://hal.science/hal-04196689v1

Submitted on 4 Oct 2024

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## Guidelines

# European society of Clinical Microbiology and Infectious Diseases guidelines on diagnosis and treatment of brain abscess in children and adults

Jacob Bodilsen<sup>1, 2, 3, *</sup>, Quintino Giorgio D'Alessandris<sup>4, 5</sup>, Hilary Humphreys<sup>6</sup>, Mildred A. Iro<sup>7</sup>, Matthias Klein<sup>3, 8, 9</sup>, Katharina Last<sup>3, 10</sup>, Inmaculada López Montesinos<sup>11, 12</sup>, Pasquale Pagliano<sup>3, 13, 14</sup>, Oğuz Reşat Sipahi<sup>3, 15, 16</sup>, Rafael San-Juan<sup>12, 17, 18</sup>, Pierre Tattevin<sup>3, 19</sup>, Majda Thurnher<sup>20</sup>, Rogelio de J. Treviño-Rangel<sup>21, 22, 23, 24</sup>, Matthijs C. Brouwer<sup>3, 25</sup>, for the ESCMID Study Group for Infections of the Brain (ESGIB)

## ARTICLE INFO

**Article history:**
Received 23 May 2023
Received in revised form
16 August 2023
Accepted 17 August 2023
Available online 29 August 2023

Editor: L. Leibovici

**Keywords:**
Antibiotic
Antimicrobial

## ABSTRACT

**Scope:** These European Society of Clinical Microbiology and Infectious Diseases 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 1 January 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 29 September 2022. Exclusion criteria were a sample size <10 patients or publication in non-English language. Extracted data was summarized as narrative reviews and tables. Meta-analysis was carried out using a random effects model and heterogeneity was examined by I<fnref n="2" /> tests as well as funnel and Galbraith plots. Risk of bias was assessed using Risk Of Bias in Non-randomised Studies - of Interventions (ROBINS-I) (observational studies) and Quality Assessment of Diagnostic Accuracy Studies 2 (QUADAS-2) (diagnostic studies). The Grading of

<footnote n="1">1) Department of Infectious Diseases, Aalborg University Hospital, Aalborg, Denmark</footnote>

<footnote n="2">2) Department of Clinical Medicine, Aalborg University Hospital, Aalborg, Denmark</footnote>

<footnote n="3">3) European Society of Clinical Microbiology and Infectious Diseases, Study Group for Infections of the Brain (ESGIB), Basel, Switzerland</footnote>

<footnote n="4">4) Department of Neurosurgery, Fondazione Policlinico Universitario "A. Gemelli" IRCCS, Rome, Italy</footnote>

<footnote n="5">5) Department of Neuroscience, Università Cattolica del Sacro Cuore, Rome, Italy</footnote>

<footnote n="6">6) Department of Clinical Microbiology, Royal College of Surgeons in Ireland University of Medicine and Health Sciences, Dublin, Ireland</footnote>

<footnote n="7">7) Department of Paediatric Infectious diseases and Immunology, The Royal London Children's Hospital, Barts Health NHS Trust, London, UK</footnote>

<footnote n="8">8) Department of Neurology, Hospital of the Ludwig-Maximilians University, Munich, Germany</footnote>

<footnote n="9">9) Emergency Department, Hospital of the Ludwig-Maximilians University, Munich, Germany</footnote>

<footnote n="10">10) Institute for Hygiene and Public Health, University Hospital Bonn, Bonn, Germany</footnote>

<footnote n="11">11) Infectious Disease Service, Hospital del Mar, Institut Hospital del Mar d'Investigacions Médiques (IMIM), Barcelona, Spain</footnote>

<footnote n="12">12) CIBERINFEC ISCIII, CIBER de Enfermedades Infecciosas, Instituto de Salud Carlos III, Madrid, Spain</footnote>

<footnote n="13">13) Department of Medicine, Surgery and Dentistry, Scuola Medica Salernitana, Unit of Infectious Diseases, University of Salerno, Baronissi, Italy</footnote>

<footnote n="14">14) UOC Clinica Infettivologica AOU San Giovanni di Dio e Ruggi d'Aragona, Salerno, Italy</footnote>

<footnote n="15">15) Faculty of Medicine, Department of Infectious Diseases and Clinical Microbiology, Ege University, Bornova, Izmir, Turkey</footnote>

<footnote n="16">16) Infectious Diseases Department, Bahrain Oncology Center, King Hamad University Hospital, Muharraq, Bahrain</footnote>

<footnote n="17">17) Unit of Infectious Diseases, 12 de Octubre University Hospital, Madrid, Spain</footnote>

<footnote n="18">18) European Society of Clinical Microbiology and Infectious Diseases, Study Group for Infections in Compromised Hosts (ESGICH), Basel, Switzerland</footnote>

<footnote n="19">19) Department of Infectious Diseases and Intensive Care Unit, Pontchaillou University Hospital, Rennes, France</footnote>

<footnote n="20">20) Department of Biomedical Imaging and Image-Guided Therapy, Medical University of Vienna, Vienna, Austria</footnote>

<footnote n="21">21) Faculty of Medicine, Department of Microbiology, Universidad Autónoma de Nuevo León, Monterrey, Nuevo León, Mexico</footnote>

<footnote n="22">22) European Society of Clinical Microbiology and Infectious Diseases, Fungal Infection Study Group (EFISG), Basel, Switzerland</footnote>

<footnote n="23">23) European Society of Clinical Microbiology and Infectious Diseases, Study Group for Antimicrobial Stewardship (ESGAP), Basel, Switzerland</footnote>

<footnote n="24">24) European Society of Clinical Microbiology and Infectious Diseases, Study Group for Genomic and Molecular Diagnostics (ESGMD), Basel, Switzerland</footnote>

<footnote n="25">25) Department of Neurology, Amsterdam Neuroscience, Amsterdam UMC, University of Amsterdam, Amsterdam, The Netherlands</footnote>

<footnote>* Corresponding author. Jacob Bodilsen, Department of Infectious Diseases, Aalborg University Hospital, Aalborg. Denmark.
E-mail address: Jacob.bodilsen@rn.dk (J. Bodilsen).</footnote>
Brain abscess

Cerebral abscess

Diagnosis

Guideline

Intracranial abscess

Meta-analysis

Review

Treatment

Recommendations Assessment, Development and Evaluation approach was applied to classify strength of recommendations (strong or conditional) and quality of evidence (high, moderate, low, or very low).

**Questions addressed by the guidelines and recommendations:** Magnetic resonance imaging is recommended for diagnosis of brain abscess (strong and high). Antimicrobials may be 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 (conditional and low). Molecular-based diagnostics are recommended, if available, in patients with negative cultures (conditional and moderate). Aspiration or excision of brain abscess is recommended whenever feasible, except for cases with toxoplasmosis (strong and low). Recommended empirical antimicrobial treatment for community-acquired brain abscess in immuno-competent individuals is a 3rd-generation cephalosporin and metronidazole (strong and moderate) with the addition of trimethoprim-sulfamethoxazole and voriconazole in patients with severe immuno-compromise (conditional and low). Recommended empirical treatment of post-neurosurgical brain abscess is a carbapenem combined with vancomycin or linezolid (conditional and low). The recommended duration of antimicrobial treatment is 6–8 weeks (conditional and low). No recommendation is offered for early transition to oral antimicrobials because of a lack of data, and oral consolidation treatment after ≥6 weeks of intravenous antimicrobials is not routinely recommended (conditional and very low). Adjunctive glucocorticoid treatment is recommended for treatment of severe symptoms because of perifocal oedema or impending herniation (strong and low). Primary prophylaxis with antiepileptics is not recommended (conditional and very low). Research needs are addressed. **Jacob Bodilsen, Clin Microbiol Infect 2024;30:66**

© 2023 The Author(s). Published by Elsevier Ltd on behalf of European Society of Clinical Microbiology and Infectious Diseases. This is an open access article under the CC BY license ([http://creativecommons.org/licenses/by/4.0/](http://creativecommons.org/licenses/by/4.0/)).

## 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 6700 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 aetiologies include *Staphylococcus aureus* and Gram-negative bacilli in post-neurosurgical brain abscess, *Mycobacterium tuberculosis* in endemic areas, and *Nocardia* spp., fungi, and parasites in the severely immune-compromised. Historically, predominant risk factors were head trauma, cyanotic congenital heart disease, and chronic ear infections but in recent decades dental infections and immuno-compromise have also become important predisposing conditions [8,23–29]. Methods for diagnosis of brain abscess have improved considerably after pivotal medical advances of computed tomography (CT) and magnetic resonance imaging (MRI) combined with stereotactic and minimally invasive neurosurgical techniques [30–33]. Moreover, targeted microbiological cultures for anaerobic bacteria and the development of molecular diagnosis may provide important clues for antimicrobial therapy [16,34–37].

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 because of 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.

## 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 ten 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.

## Composition of the guideline committee

The ESGIB executive committee appointed six guideline panel members from the study group including the chair (JB). The ESCMID executive committee assigned another seven members. Priority was given to a balance in country representation, gender, and medical specialties. After the first online meeting, the guideline panel was expanded with a paediatrician and a neuroradiologist. All guideline panelists were required to be free from conflicts of interests. The guideline committee is unaware of patient organizations for survivors of brain abscess. Thus, a patient treated by the chair volunteered to join the committee and provided valuable input from inception to publication of the guideline (Supplementary Material).

## Methods

### Evidence collection

In preparation for the project, we examined existing guidelines and systematic reviews by searches at PubMed, the Cochrane Library, SUMsearch, [www.guideine.gov](http://www.guideine.gov), [www.nice.org.uk](http://www.nice.org.uk), and [www.sign.ac.uk](http://www.sign.ac.uk).
<table><caption>**Table 1**
Summary of recommendations</caption><thead><tr><th>Key question</th><th>Recommendation</th><th>Strength of recommendation</th><th>Quality of evidence</th></tr></thead><tbody><tr><td><strong>Diagnosis</strong><br>#1 What is the preferred brain imaging modality in patients with suspected brain abscess?</td><td>We strongly recommend brain MRI including DWI/ADC and T1 weighted imaging with and without gadolinium for patients with suspected brain abscess.<br>If MRI is not available, contrast-enhanced CT is recommended.</td><td>Strong</td><td>High</td></tr><tr><td>#2 Should antimicrobials be withheld until aspiration or excision in patients with suspected brain abscess?</td><td>We conditionally recommend that antimicrobials are withheld until aspiration or excision of brain abscess in patients without severe disease (e.g. sepsis, imminent rupture, or impending herniation) if neurosurgery can be carried out within reasonable time, preferably within 24 h of radiological diagnosis.</td><td>Conditional</td><td>Low</td></tr><tr><td>#3 Should molecular-based diagnostics be used in patients with brain abscess?</td><td>We conditionally recommend the use of molecular-based diagnostics, if available, in patients with negative cultures.</td><td>Conditional</td><td>Moderate</td></tr><tr><td><strong>Treatment</strong><br>#4 Should neurosurgical aspiration or excision be used in patients with brain abscess?</td><td>We strongly recommend neurosurgical aspiration or excision of brain abscess as soon as possible in all patients whenever feasible (excl. toxoplasmosis).</td><td>Strong</td><td>Low</td></tr><tr><td>#5 What is the optimal empirical antimicrobial therapy for brain abscess?</td><td>We strongly recommend a 3rd-generation cephalosporin combined with metronidazole for empirical treatment of community-acquired brain abscess.<br>For severely immuno-compromised patients equivalent to organ transplant recipients, active chemotherapy or biological treatment, or haematological malignancies, we conditionally recommend:<br>A 3rd-generation cephalosporin and metronidazole combined with voriconazole and TMP-SMX.</td><td>Strong</td><td>Moderate</td></tr><tr><td></td><td>We conditionally recommend meropenem combined with vancomycin or linezolid for empirical treatment of post-neurosurgical brain abscess.</td><td>Conditional</td><td>Low</td></tr><tr><td></td><td>We strongly recommend targeted treatment according to antimicrobial susceptibility. On the basis of expert opinion, we consider it good clinical practice to continue coverage for anaerobic bacteria if oral cavity bacteria are identified.</td><td>Strong</td><td>Low<br>Very low</td></tr><tr><td>#6 What is the appropriate duration of antimicrobial therapy for bacterial brain abscess?</td><td>We conditionally recommend a total duration of 6–8 wk of intravenous antimicrobials for aspirated or conservatively treated brain abscesses.<br>On the basis of expert opinion, a shorter duration (e.g. 4 wk) may be considered in patients treated with excision of brain abscess.</td><td>Conditional</td><td>Low<br>Very low</td></tr><tr><td>#7 Should early transition to oral antimicrobials be used in treatment of patients with bacterial brain abscess?</td><td>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.</td><td>—</td><td>—</td></tr><tr><td>#8 Should consolidation therapy with oral antimicrobials after ≥6 wk of IV antimicrobials be used to reduce risks of relapse or recurrence?</td><td>On the basis of expert opinion, we conditionally do not recommend oral consolidation treatment after ≥6 wk of IV antimicrobials for brain abscess (excl. permanent neuroanatomical defects, tuberculosis, nocardiosis, toxoplasmosis, and fungal brain abscess).</td><td>Conditional</td><td>Very low</td></tr><tr><td>#9 Should dexamethasone be used to treat severe symptoms because of perifocal oedema in patients with brain abscess?</td><td>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 because of perifocal oedema or impending herniation in patients with brain abscess.</td><td>Strong</td><td>Low</td></tr><tr><td>#10 Should primary prophylaxis with antiepileptic treatment be used to reduce risks of seizures during admission and subsequent epilepsy?</td><td>On the basis of expert opinion, we conditionally recommend against primary prophylaxis with antiepileptics in patients with brain abscess.</td><td>Conditional</td><td>Very low</td></tr></tbody></table>

ADC, apparent diffusion coefficient; CT, computed tomography; DWI, diffusion-weighted images; MRI, magnetic resonance imaging; TMP-SMX, trimethoprim-sulfamethoxazole.
## Literature search, data synthesis, and risk of bias

Key questions were agreed by the guideline panel during initial meetings and were 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 17 September 2021 and updated on 29 September 2022 (Full search strategy is available in Supplementary Material). Studies were required to be published in the English language within the last 25 years and to have more than ten children or adults included, i.e. case reports were omitted. After automated removal of duplicates, 2887 studies were screened independently by two panel members (MCB and JB) and 460 were selected for full-text review (Fig. 1). Because 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 three to five 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 were 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 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 scientific evidence was summarised as narrative reviews with key references and 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 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 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 systematic review but ineligible for meta-analyses because of a lack of pre-specified raw data for a given PECO were occasionally discussed separately in the narrative summary post hoc if the studies provided other helpful guidance for the key question.

## Grading of evidence and strength of recommendations

In accordance with the Grading of Recommendations Assessment, Development and Evaluation system, the quality of evidence for each key question was categorized as high, moderate, low, or very low (Fig. 2) [52,53]. Recommendations were classified as strong or conditional (weak). Disagreements in recommendations were resolved by discussion within subgroups for each key

<figure><img src="image_4.png" /><figcaption>Fig. 1. Study flowchart.</figcaption></figure>
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 Grading of Recommendations Assessment, Development and Evaluation.

## Recommendations

### 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 post-contrast T1-scan and central hyperintensity on diffusion-weighted imaging (DWI) with corresponding low apparent diffusion coefficient (ADC) 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 abscess, i.e. ability to differentiate brain abscess from tumour, using final clinical diagnosis or neurosurgical confirmation as reference needs further clarification.

A total of 143 studies were examined in full length for this key question of which 115 were excluded because of other imaging modalities (e.g. MR spectroscopy) or inappropriate study populations (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 which 21 had a cross-sectional design, four were case-control studies, and three were cohort studies (Tables S1 and S2) [32,33,54–79]. None were multi-centre studies.

<figure><img src="image_5.png" /><figcaption>**Fig. 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. \*Unrestricted use of the figure granted by the USA GRADE Network.</figcaption></figure>
**Contrast-enhanced CT.** There were no studies assessing the diagnostic accuracy of CT 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 1970s [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.** Meta-analysis of the 28 studies with an accumulated 2128 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) (Figs. 3 and 4) [32,33,54–78]. The corresponding positive predictive value was 88% and the negative predictive value was 90%.

On the basis of 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].

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,

<figure><img src="image_6.png" /><figcaption>**Fig. 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. ADC, apparent diffusion coefficient; DWI, diffusion-weighted imaging; MRI, magnetic resonance imaging.</figcaption></figure>

<figure><img src="image_7.png" /><figcaption>**Fig. 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. ADC, apparent diffusion coefficient; DWI, diffusion-weighted imaging; MRI, magnetic resonance imaging.</figcaption></figure>
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?

**Population:** Patients with suspected brain abscess

**Exposure:** Antimicrobials are withheld until aspiration or excision

**Comparator:** Antimicrobials are not withheld until aspiration or excision

**Outcome:** Microbiological diagnosis of abscess and case-fatality rate

A microbiological diagnosis is crucial for the successful treatment of brain abscess and allows for determination of antimicrobial susceptibility of the causative organism and informs targeted therapy. Yet, whether antimicrobials can be safely withheld until neurosurgical aspiration or excision to improve the probability of establishing a 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 of 6 (67%) included children, and one was a multi-centre study (Table S3).

**Microbiological diagnosis.** In meta-analysis, a microbiological diagnosis was achieved in 123 of 153 (80%) of patients in whom antimicrobials were withheld compared with 41 of 126 (33%) in those who had antimicrobials initiated before neurosurgical aspiration or excision (p < 0.001) (Table S4) [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% (Figs. 5, S1, and S2). However, data on additional diagnostic procedures (e.g. CT scans, blood cultures, and 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 meta-analysis. 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].

**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 of 3 (0%) patients when antimicrobials were withheld compared with 0 of 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 meta-analysis 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 (relative risk (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 recent Canadian study of 139 patients observed an unfavourable outcome in 33 of 123 (27%) if antimicrobials were initiated before aspiration or excision of brain abscess compared with 2 of 16 (13%) if antimicrobial treatment was deferred until neurosurgery (p 0.25) [18].

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 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 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 intended interventions (Appendix 3).

**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

## Microbiological diagnosis

<figure><img src="image_8.png" /><figcaption>**Fig. 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.</figcaption></figure>
Comparator test: Culture

Reference standard: None (concordance between tests was examined)

Molecular-based diagnostics, i.e. nucleic acid amplification tests 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 diagnostics were examined.

A total of 16 studies were initially assessed for relevance for this key question of which nine were included in the final analysis (Table S5) [16,36,37,96–101]. Of these, five were prospective cohorts and three were multi-centre studies. The pooled analysis showed that molecular diagnostics were concordant positive with culture results in 187 of 280 (67%), concordant negative in 22 of 280 (8%), only culture positive in 24 of 280 (9%), only molecular

diagnostics positive in 36 of 280 (13%), and discordant positive (i.e. both tests positive but with different pathogens) in 13 of 280 (5%) (Table 2).

Molecular diagnostics expanded the number of identified pathogens (especially anaerobic bacteria) in 115 of 173 (66%) cases with brain abscess caused by oral cavity 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 meta-analysis 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.

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

<table><caption>**Table 2**
Correlation between culture and molecular diagnostics of specimens from brain abscesses</caption><thead><tr><th rowspan="2">First author</th><th rowspan="2">No.</th><th colspan="2">Culture positive (%)</th><th colspan="2">Molecular detection (%)</th><th rowspan="2">Correlation (%)<sup>a</sup></th><th rowspan="2">Comments</th><th rowspan="2"></th></tr><tr><th>Total</th><th>Only</th><th>Total</th><th>Only</th></tr></thead><tbody><tr><td>Al Masalma, 2009</td><td>20</td><td>17 (85)</td><td>1 (5)</td><td>19 (95)</td><td>3 (15)</td><td>15 (75)</td><td>Increased no. of bacterial species identified by molecular-based diagnostics in cases with brain abscess caused by oral cavity bacteria 8/12 (75)</td><td>Culture positive only in one case of <i>Nocardia</i> spp.</td></tr><tr><td>Al Masalma, 2012</td><td>51</td><td>30 (59)</td><td>0</td><td>39 (76)</td><td>9 (18)</td><td>37 (73)</td><td>14/20 (70)</td><td>Molecular detection only in three cases of <i>T. gondii</i>, one case of <i>Scedosporium apiospermium</i>, and one case of N. carnea.</td></tr><tr><td>Andersen, 2022</td><td>41</td><td>37 (90)</td><td>2 (5)</td><td>37 (90)</td><td>1 (2)</td><td>35 (85)</td><td>16/28 (57)</td><td>Culture positive only in two cases of <i>A. fumigatus</i>, molecular detection positive only in one case of <i>T. gondii</i></td></tr><tr><td>de Lastours, 2008</td><td>24</td><td>21 (88)</td><td>19 (79)</td><td>5<sup>b</sup> (21)</td><td>3 (13)</td><td>2 (8)</td><td>2/5 (40)</td><td>Molecular detection only in one case each of <i>Actinomyces israeli</i>, <i>Streptococcus constellatus</i>, and <i>Fusobacterium nucleatum</i></td></tr><tr><td>Hartung, 2021</td><td>36</td><td>26 (72)</td><td>0</td><td>28 (78)</td><td>7 (19)</td><td>28 (78)</td><td>17/22 (77)</td><td>Molecular detection positive only in seven cases of <i>Nocardia</i> spp. and oral cavity bacteria (e.g. <i>Streptococcus anginosus</i> group and anaerobes)</td></tr><tr><td>Kommedal, 2014</td><td>37</td><td>34 (92)</td><td>1 (3)</td><td>36 (97)</td><td>3 (8)</td><td>33 (89)</td><td>24/32 (75)</td><td>Culture positive only in one case of <i>M. tuberculosis</i></td></tr><tr><td>Kupila, 2003</td><td>12</td><td>7 (58)</td><td>1 (8)</td><td>8 (67)</td><td>2 (17)</td><td>5 (42)</td><td>0/5 (0)</td><td>Culture positive only in one case of <i>Fusobacterium</i> spp.</td></tr><tr><td>Stebner, 2021<sup>c</sup></td><td>46</td><td>42 (91)</td><td>0</td><td>46 (100)</td><td>8 (17)</td><td>19 (41)</td><td>33/42 (79)</td><td>Molecular detection only in one case each of <i>Staphylococcus aureus</i> and <i>Mycoplasma hominis</i></td></tr><tr><td>Tsai, 2004</td><td>13</td><td>10 (77)</td><td>0</td><td>10 (77)</td><td>0</td><td>13 (100)</td><td>1/7 (14)</td><td></td></tr><tr><td>Total</td><td>280</td><td>224 (80)</td><td>24 (9)</td><td>228 (81)</td><td>36 (13)</td><td>187 (67)</td><td>115/173 (66)</td><td></td></tr></tbody></table>

T. gondii, *Toxoplasma gondii*.

<footnote>a Correlations imply that molecular diagnostics detected at least one of those pathogens identified by culture.</footnote>

<footnote>b Molecular diagnostics were used if cultures remained negative after 48 h.</footnote>

<footnote>c Only data on 46 patients with brain abscess and results available for both culture and molecular-based diagnostics were included.</footnote>
## Treatment

### Key question 4

Should neurosurgical aspiration or excision be used in patients with brain abscess?

**Population:** Patients with brain abscess

**Exposure:** No aspiration or excision

**Comparator:** Aspiration or excision

**Outcome:** Microbiological diagnosis, rupture of brain abscess, case-fatality rate, and neurological sequelae

Neurosurgery was the only available therapy for brain abscess before the introduction of antibiotics into hospital care in the 1940s and is considered a crucial 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 the intra-cavitary bacterial load to obtain local source control. Neurosurgical procedures have since been refined by age- or stereotactic guided minimally invasive techniques, which allow aspiration of small brain abscesses located deep within the brain [31,106–108]. Similar to brain biopsy, risks of haemorrhage 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) [22,109–117].

Occasionally, some patients with small brain abscesses and/or an already known pathogen are managed conservatively, i.e. without aspiration or excision. However, the positive predictive value and negative predictive value 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 tumours 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 risks of an adverse outcome [118]. Thus, the safety of a conservative approach remains unclear [119–121].

We evaluated 41 studies for this key question of which 21 provided enough detailed information to be included in the analyses (Table S6) [17,20,39,84,89,94,122–136]. They were all retrospective cohort studies, 18 included children, and three were multi-centre.

**Microbiological diagnosis.** Meta-analysis of four studies eligible for this part of the key question showed that a microbiological diagnosis was established in 26 of 55 (47%) of patients managed conservatively versus 60 of 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 (Figs. 6, S3, and S4, Table S7) [84,123,128,136].

Among studies not included for meta-analysis in this key question because of a lack of data on conservatively treated patients [17,20,83,89,92,94,125,130,135,137,138], the pathogen was identified in a total of 605 of 750 (81%) patients undergoing aspiration or excision with rates as high as 89–99% in several recent studies [17,20,135]. In contrast, a study restricted to conservatively managed individuals with brain abscess from Taiwan reported that the causative pathogen was determined in 23 of 31 (74%) of patients [121]. The causative pathogens were identified by cerebrospinal fluid (CSF) cultures in 10 of 23 (43%), blood cultures in 5 of 23 (22%), both CSF and blood cultures in 4 of 23 (17%), and samples from ear or sinuses in 4 of 23 (17%).

Of note, neurosurgical aspiration or excision is usually not required before initiation 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 [113,139,140].

**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 [18,22,141–144]. Still, risk factors for rupture remain poorly defined although a close proximity to the ventricles has been suggested [142,144]. Of relevance also for this part of the key question, a study of conservatively treated patients observed that rupture occurred among 9 of 31 (29%) [121].

**Case-fatality rate.** A total of 17 studies provided data for this meta-analysis with an overall case-fatality rate of 172 of 704 (24%) in conservatively treated patients compared with 140 of 1484 (9%) in those who had their brain abscess aspirated or excised (p < 0.001) [17,20,39,84,89,94,123–129,131–133,135]. 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 (Fig. 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

Microbiological diagnosis

<figure><img src="image_9.png" /><figcaption>**Fig. 6.** Odds ratios of establishing a microbiological diagnosis according to aspiration or excision of brain abscess or not.</figcaption></figure>
Case-fatality

<figure><img src="image_10.png" /><figcaption>Fig. 7. Risk of death according to aspiration or excision of brain abscess or not.</figcaption></figure>

treated patients (Figs S5 and S6). A large study used national healthcare registries in Denmark from 1982 through 2016 and showed a 1-year mortality of 96 of 405 (24%) in patients treated without aspiration or excision of brain abscess compared with 71 of 525 (14%) in those treated with neurosurgery (p < 0.001) [39]. After adjustment for age, sex, Charlson comorbidity index score, and calendar year, the 1-year mortality rate ratio was 0.78 (95% CI 0.62–0.97) in patients managed by aspiration versus conservative treatment.

Although not included in meta-analysis because of a lack of all pre-specified data, another 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 6-month mortality in adjusted analysis [22]. On the other hand, a single-centre retrospective cohort study of conservatively treated patients with brain abscess observed a high case-fatality rate of 15 of 31 (48%) [121].

*Neurological sequelae.* Neurological sequelae were rarely specified, especially according to neurosurgical intervention or not, and risks of ‘unfavourable/poor 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 of 148 (26%) of conservatively treated patients compared with 192 of 684 (28%) of those treated with aspiration or excision (p 0.75) [94,122,130,133–135]. The corresponding OR of neurological sequelae was 1.1 (95% CI 0.7–1.6) in meta-analysis using neurosurgical aspiration or excision as reference (Figs. 8, S7, and S8).

Other studies that could not be included in this part of the meta-analysis 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 6 months, among 106 patients with early neurosurgery ≤7 days of admission compared with the remaining 118 patients among whom 18 required subsequent aspiration or excision [118]. 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 also comprise severely ill patients who die early during admission or are not considered suitable for neurosurgery. Unfortunately, details on reasons for conservative treatment were rarely available. In addition, a conservative strategy may be revised during treatment because of disease progression, which may skew results in favour of not carrying out aspiration or excision of brain abscess.
Neurological sequelae

<figure><img src="image_11.png" /><figcaption>**Fig. 8.** Risk of neurological sequelae according to aspiration or excision of brain abscess or not.</figcaption></figure>

**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).

Key question 5

What is the optimal empirical antimicrobial therapy for brain abscess?

**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).

We evaluated 26 studies of which 16 were included in meta-analysis for this key question (Table S8) [21,83,85,86,93,94,132,145–153]. They were all retrospective observational cohort studies, 12 included children, and one was multi-centre. Patients with brain abscess were categorized as community-acquired in 367 of 565 (65%), nosocomial in 71 of 565 (13%), immuno-compromised in 36 of 565 (6%), or not reported in 91 of 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

Case-fatality

<figure><img src="image_12.png" /><figcaption>**Fig. 9.** Risk of death in patients treated with penicillin and metronidazole compared with 3rd-generation cephalosporins and metronidazole.</figcaption></figure>
Case-fatality

<figure><img src="image_13.png" /><figcaption>**Fig. 10.** Risk of death in patients treated with penicillin and metronidazole compared with carbapenems.</figcaption></figure>

Case-fatality

<figure><img src="image_14.png" /><figcaption>**Fig. 11.** Risk of death in patients treated with 3rd-generation cephalosporins and metronidazole compared with carbapenems.</figcaption></figure>

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 empirical antimicrobial regimens in meta-analysis (Figs. 9–11 and S9–S14 and Table S9). In one retrospective single-centre study of 59 immuno-competent patients with brain abscess, comparison was made between 3rd-generation cephalosporin and carbapenem-based regimens [132]. The authors found that carbapenems were associated with decreased mortality after adjustment for Glasgow Coma Scale score, intracranial hypertension, and surgical treatment. Notably, the groups were not well balanced in terms of age, calendar year, or 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 and observed no differences in survival according to antimicrobial regimens [153]. Moreover, case-fatality rates did not differ substantially between different antimicrobial treatments in several other smaller studies examining brain abscesses caused by certain groups of pathogens such as *Streptococcus milleri*, *Streptococcus* spp., Gram-negative bacilli, and anaerobic bacteria [85,146,147,152]. 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 of 485 (59%) of cases (Fig. 12) [22]. This was followed by *S. aureus* in 27 of 485 (6%), whereas the remaining cases were either unknown in 71 of 485 (15%) or caused by a large variety of pathogens with frequencies ranging from 1% to 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 [12,16–21,129,136,154,155]. Importantly, a recent Dutch study reported decreased susceptibility of *Streptococcus mitis* group to penicillin [156] 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 [8,28,73,157–159]. For severely immune-compromised individuals such as those with haematological malignancies, organ transplant recipients, or AIDS patients, physicians
<figure><img src="image_15.png" /><figcaption>**Fig. 12.** Causative pathogens among 485 adults hospitalised with brain abscess in Denmark from 2007 through 2020. *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., [22].</figcaption></figure>

need to consider rare pathogens such as nocardiosis, fungal infections including aspergillosis, listeriosis, and toxoplasmosis (Table 3, Fig. 12) [160–168].

Data on intra-cavitary concentration of antimicrobials in patients with brain abscess are scarce and restricted to case reports or small case series [169]. Besides a limited number of observations, almost all the published papers had incomplete information on the timing of drug administration, sampling, and analysis. However, the intra-cavitary concentration of cefotaxime was studied in 15 consecutive adults with brain abscess and found to be sufficiently high early during treatment [170,171]. This was supported by a prospective single-centre cohort study of 66 patients successfully 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 clinical experience of the guideline committee, and more data are needed to examine this aspect [22,172].

Vancomycin, a bactericidal glycopeptide, has been the preferred treatment of brain abscess and other central nervous system infections caused by methicillin-resistant *S. aureus*. However,

linezolid has more favourable pharmaco-kinetic properties and experience with this bacteriostatic drug for brain abscess is increasing [173–180].

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 [181]. 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

<table><caption>**Table 4**
Recommendations for empirical antimicrobial treatment of brain abscess</caption><thead><tr><th rowspan="2">Case characteristic</th><th colspan="2">Empirical treatment</th></tr><tr><th>Standard</th><th>Alternatives</th></tr></thead><tbody><tr><td>Community-acquired</td><td>3rd-generation cephalosporin<sup>a</sup> and metronidazole</td><td>Meropenem</td></tr><tr><td>Severe immuno-compromise (i.e. haematological malignancies, organ transplant recipients)</td><td>3rd-generation cephalosporin<sup>a</sup> and metronidazole combined with voriconazole and TMP-SMX</td><td>Meropenem combined with voriconazole and TMP-SMX</td></tr><tr><td>Post-neurosurgical</td><td>Meropenem and vancomycin or linezolid</td><td>Ceftazidime and linezolid, cefepime and linezolid</td></tr></tbody></table>

TMP-SMX, trimethoprim-sulfamethoxazole.

<table><caption>**Table 3**
Common pathogens in brain abscess in patients with selected severe immuno-compromising conditions</caption><thead><tr><th>Selected immuno-compromising conditions</th><th>Common causes of brain abscess</th></tr></thead><tbody><tr><td>Haematopoietic stem cell transplant recipients</td><td>Fungi, nocardiosis, toxoplasmosis</td></tr><tr><td>Solid organ transplant recipient</td><td>Fungi, nocardiosis, toxoplasmosis</td></tr><tr><td>Patients with AIDS</td><td>Toxoplasmosis</td></tr></tbody></table>

<footnote><sup>a</sup> Consider ceftazidime in cases at increased risk of pseudomonal brain abscess (e.g. chronic suppurative otitis media).</footnote>
treatment of community-acquired brain abscess in children and adults (Table 4) (strong recommendation and low certainty of evidence). Dosages should be tailored toward adequate abscess and central nervous system penetration (Table S10).

Recommendation: We conditionally recommend a 3rd-generation cephalosporin and metronidazole combined with trimethoprim-sulfamethoxazole and voriconazole for empirical treatment of brain abscess in children and adults with severe immunocompromise equivalent to organ transplant recipients, active chemotherapy or biological treatment, or haematological malignancies (Table 4) (conditional recommendation and very low certainty of evidence). An alternative regimen may be meropenem combined with trimethoprim-sulfamethoxazole and voriconazole.

Recommendation: We conditionally recommend meropenem combined with vancomycin or linezolid for empirical treatment of post-neurosurgical brain abscess (Table 4) (conditional recommendation and very low certainty of evidence).

Recommendation: We strongly recommend targeted treatment according to pathogen and antimicrobial susceptibility (Table S11) (strong recommendation and low certainty of evidence). On the basis of expert opinion, we consider it good clinical practice to continue coverage for anaerobic bacteria if oral cavity bacteria are identified.

### Key question 6

What is the appropriate duration of antimicrobial therapy for bacterial brain abscess?

**Population:** Patients with bacterial brain abscess alive at end of treatment (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 meta-analysis (Table S12) [38,83,182,183]. They were all single-centre retrospective cohort studies and two included children.

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 of 90 (0%) for treatment duration <6 weeks compared with 6 of 117 (5%) for treatment durations of ≥6 weeks (p 0.04) (Table S13) [38,83,182]. Meta-analysis showed a corresponding OR of relapse or recurrence of 3.4 (95% CI 0.3–34.2) for treatment duration >6 weeks (Figs. 13, S15, and S16). The aggregated case-fatality rate was 5 of 92 (5%) in patients treated for <6 weeks compared with 1 of 79 (1%) in those with treatment duration ≥6 weeks in three studies included in meta-analysis (p 0.21) [83,182,183]. This yielded a pooled OR of fatal outcome of 0.3 (95% CI 0.0–3.6) in favour of ≥6 weeks treatment duration (Figs. 14, S17, and S18).

One study examined shortened treatment duration for 21–28 days (mean 26) after neurosurgery along with different combinations of abscess irrigation, drainage, and intra-cavitary antimicrobial instillation [182]. They observed no recurrences during a 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) without intra-cavitary antimicrobials.

Because of the scarcity of available data, the guideline group also considered other studies with more indirect evidence on adequate treatment duration. Overall, relapse or recurrence is very rare

### Relapse or recurrence

<figure><img src="image_16.png" /><figcaption>**Fig. 13.** Risk of relapse or recurrence according to treatment duration.</figcaption></figure>

### Case-fatality

<figure><img src="image_17.png" /><figcaption>**Fig. 14.** Risk of death according to treatment duration.</figcaption></figure>
during current clinical practice of 6–8 weeks of intravenous (IV) antimicrobial therapy after aspiration or excision of brain abscess [22,38]. A recent population-based study with virtually complete follow-up observed multiple episodes of brain abscess in only 5 of 480 (1%) of individuals during the study period from 2007 through 2020 [22]. In that study, patients were treated with IV antimicrobials for a median of 44 days (interquartile range (IQR) 41–56). Oral consolidation therapy was used in 119 of 485 (25%) cases and extended the overall median duration of treatment 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 two (4%) cases of relapse or recurrence were observed during a mean follow-up of 3 years. In contrast, a study of 47 patients from England reported that 5 of 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, 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 and low certainty of evidence). On the basis of expert opinion, a shorter duration of 4 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 patients with bacterial brain abscess?

**Population:** Patients with bacterial brain abscess (not nocardiosis or tuberculosis)

**Exposure:** Transition to oral antimicrobials within <6 weeks of treatment

**Comparator:** IV antimicrobials throughout treatment

**Outcome:** Relapse/recurrence, case-fatality rate

<table><caption>**Table 5**
Recommendations for duration of antimicrobial treatment for brain abscess</caption><thead><tr><td>Case characteristic</td><td>Duration of IV treatment<sup>a</sup></td></tr></thead><tbody><tr><td>Aspirated brain abscess</td><td>6–8 wk</td></tr><tr><td>Excised brain abscess</td><td>4 wk<sup>b</sup></td></tr><tr><td>Conservatively treated brain abscess</td><td>6–8 wk</td></tr></tbody></table>

Extended IV treatment has been considered essential for management of patients with brain abscess since the introduction of antimicrobials into hospital care [4–6,104,184]. 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 clinical response [185]. This is also consistent with general treatment principles of cerebral nocardiosis, toxoplasmosis, and tuberculosis. Potential advantages include 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.

After 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 meta-analysis (Table S14) [186,187]. 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 of 24 (4%) in patients switched to early oral antimicrobials (i.e. ≤6 weeks of treatment) and 4 of 77 (5%) in those treated with IV throughout (p 0.84) (Table S15) [187]. Both studies provided data on fatal outcome and this was observed in 0 of 21 (0%) and 1 of 24 (4%) of patients switched to early oral antimicrobials compared with 5 of 28 (18%, p 0.06) and 12 of 77 (16%, p 0.18) of patients treated with prolonged IV treatment [186,187]. The corresponding OR was 5.7 (95% CI 1.0–31.3) in favour of early transition to oral antimicrobials (Figs. 15, S19, and S20). 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 meta-analyses 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 3 months after diagnosis among 108 patients of whom 48 (44%) had been switched to oral antimicrobials [188]. Using continued IV antimicrobials as reference, they observed 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 of early oral antimicrobials guided by normalization of plasma C-reactive protein [145], because of patient request [189], or as part of standard treatment in developing countries [190–193] with an aggregated case-fatality rate of 8 of 200 (4%). Still, a single-centre study from England reported that 5 of 8 (63%) cases with recurrence of brain abscess had been treated with <3 weeks of IV antimicrobials before transition to oral 1st- or 2nd-generation cephalosporin [91].

Risk of bias was assessed to be serious and critical with special emphasis on inadequate confounder control because of the limited sample sizes and likely selection of patients with mild disease to early oral antimicrobial treatment (Appendix 8).

**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.

<footnote><sup>a</sup> Certain difficult-to-treat pathogens such as nocardiosis, toxoplasmosis, tuberculosis, and fungi should follow principles of treatment already established elsewhere.</footnote>

<footnote><sup>b</sup> Expert opinion.</footnote>
Case-fatality

<figure><img src="image_18.png" /><figcaption>Fig. 15. Risk of death according to early switch to oral antimicrobials or not.</figcaption></figure>

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

Oral consolidation therapy after ≥6 weeks of IV antimicrobial treatment is frequently used [8,17,22,38,133,186], and has been recommended by some experts to prevent relapse and recurrence of brain abscess [194]. Indeed, a survey among infectious diseases specialists in Australia, Denmark, France, and Sweden disclosed that oral consolidation therapy was used by 126 of 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 recurrence according to oral consolidation therapy or not.

Among studies that could not be included in meta-analysis for this key question, an Italian multi-centre study of 79 children found that oral consolidation was frequently added to standard 6 weeks of IV treatment [133]. However, the mean duration of antimicrobial therapy did not differ significantly between patients with and without new abscess formation (64.1 days compared with 59.1 days, p 0.78) suggesting, 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 with oral consolidation therapy or not [195].

**Recommendation:** On the basis of expert opinion, we conditionally do not recommend 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 and very low certainty of evidence).

Management of complications

Key question 9

Should dexamethasone be used to treat severe symptoms because of 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

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 because of 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 [196–200]. Others have reported conflicting results regarding intra-cavitary penetration of antibiotics in animal models of brain abscess treated with or without adjunctive corticosteroids [201–205]. 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.

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 data available for the meta-analyses (Table S16) [18,20,38,84,89,122,125,129,141]. They were all retrospective cohort studies, eight included children, one was multi centre, and one was population based.

No studies quantified symptom relief from corticosteroid therapy in patients with brain abscess and perifocal oedema. Risk of neurological deficits was examined in seven studies and was found to be 90 of 303 (30%) in patients treated with corticosteroids compared with 80 of 383 (21%) among those not treated with corticosteroids (p 0.01) (Table S17) [18,20,38,89,122,129,141]. This yielded an OR for neurological deficits of 0.7 (95% CI 0.5–1.0) in favour of no adjunctive corticosteroid treatment (Figs. 16, S20, and S21). Of note, information on type of corticosteroids, dosage, and duration was rarely provided and considerable variations in treatment regimens were likely within and between studies. One study
Neurological deficits

<figure><img src="image_19.png" /><figcaption>**Fig. 16.** Risk of neurological deficits according to adjunctive dexamethasone treatment or not.</figcaption></figure>

Case-fatality

<figure><img src="image_20.png" /><figcaption>**Fig. 17.** Risk of death according to adjunctive dexamethasone treatment or not.</figcaption></figure>

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 [84,125,129]. The pooled risk of death was 20 of 91 (22%) and 24 of 124 (19%) according to adjunctive corticosteroid treatment or not (p 0.76). Consistently, adjunctive corticosteroids treatment was not significantly associated with increased case-failure with an OR of 0.6 (95% CI 0.3–1.4) in meta-analysis (Figs. 17, S22, and S23). 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) [122].

Among studies initially tagged but not included in meta-analysis because of 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 outcome at 6 months after admission [22], or of late seizures and seizure-free survival compared with no corticosteroids [144].

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. On the basis of expert opinion, corticosteroids are helpful for treatment of severe symptoms because of 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 because of perifocal oedema or impending herniation in patients with brain abscess (strong recommendation and low certainty of evidence).

Key question 10

Should primary prophylaxis with antiepileptic treatment be used to reduce risks of seizures during admission and subsequent epilepsy?

Population: Patients with brain abscess without seizures

Exposure: Antiepileptic treatment during admission or at discharge

Comparator: No antiepileptic treatment

Outcome: Seizures during admission and subsequent epilepsy

Seizures are a frequent complication in patients with brain abscess and new-onset 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 and epilepsy is associated with increased long-term mortality among survivors [206–208]. Seizures in patients with previous brain abscess are categorised as epilepsy and should be treated accordingly with antiepileptics [209]. Yet, primary prophylaxis with antiepileptics in patients with brain abscess is controversial but has been
recommended by a few experts [194,210] and adopted into clinical practice as reported in some studies [122,153,207,208,211]. 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 [212,213]. Because 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.

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 meta-analysis [207]. In that study, 10 of 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 of 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 excision of brain abscess, large abscesses, other previous neurosurgical procedures, and stroke [206–208,214–216]. In contrast, occipital lobe abscess has been associated with a decreased risk of epilepsy [206].

**Recommendation:** On the basis of expert opinion, we conditionally recommend against primary prophylaxis with antiepileptics in patients with brain abscess (conditional recommendation and very low certainty of evidence).

## General practice recommendations on management of patients with brain abscess

Neurosurgery is pivotal to obtain source control in patients with brain abscess [3,39,118,217]. However, there is no clear evidence to favour aspiration over excision of brain abscess in terms of mortality (Supplementary Material) [3,218]. 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 [1,219–221].

Samples of pus from the brain abscess should be sent for aerobic and anaerobic cultures as well as histopathological analyses (good clinical practice statement). In endemic areas or according to clinical presentation and exposure, samples may also be sent for Ziehl–Nielsen stain and culture and PCR for tuberculosis. Blood cultures are positive in 28% of patients [2] and should be obtained in all patients, whereas additional microbiological samples may be tailored towards concomitant foci of infection depending on the clinical presentation (good clinical practice statement). It is advised to store microbiological samples for additional analyses in case the aetiology remains unknown after preliminary investigations (good

clinical practice 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 [12,22,38,222], although 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 statement). In contrast, lumbar puncture is relatively contraindicated and the diagnostic yield is usually low [8,38,86,92,125,130,136,222–231]. 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 positron emission tomography (PET)-CT compared with standard diagnostic work-up is unclear and cannot be recommended as a routine examination for now [232–234].

Consultations by ear-nose-throat specialists and maxilla-facial surgeons should be carried out in cases with suspected or evident ear-nose-throat 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 [8,16,21,22,91,130,153] 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. 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 [160,161,164,235,236]. Because 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 2 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 brain imaging by 2 weeks after aspiration, whereas lack of regression by 4 weeks is unusual [80,94,171,217,237–240]. Repeated neurosurgical aspiration, or in selected cases excision, should be carried out in case of clinical deterioration or enlargement of brain abscess, and is almost always required in those without any reduction in brain abscess volume by 4 weeks after first aspiration (good clinical practice statement) [119,217,239]. On the other hand, it may take 3–6 months before residual contrast enhancement resolves on brain imaging and it is often inappropriate to prolong antimicrobial treatment based solely on such radiological findings (good clinical practice statement).

Rupture of brain abscess causes fulminant meningitis with associated substantially increased case-fatality rates of 27–50% and may occur into the subarachnoid space around or between the hemispheres or into the ventricles [22,142–144]. The reported incidence varies from 10% to 35% of which approximately half are diagnosed immediately at admission [22,142–142]. Suggested risk factors include proximity to the ventricles and multiloculated brain abscesses [142–144]. 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 central nervous system (CNS) [38,122,186,227,241].
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 [13,25,137,141,183,242–247]. For patients without vascular right-to-left shunts, antibiotic prophylaxis during dental visits is not indicated (good clinical practice statement) [248].

Long-term sequelae have been observed in about 45% of patients at 6 months after discharge and usually comprise focal neurological deficits corresponding to the 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 5 years after diagnosis compared with matched population controls [12,249]. 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 statement) [250].

Compared with matched population controls, brain abscess has been associated with an increased risk of cancer (adjusted hazard rate ratio 2.09, 95% CI 1.79–2.45) for unclear reasons as well as substantially increased 1-year mortality (adjusted mortality rate ratio 17.5, 95% CI 13–22) [251]. Thus, careful management of comorbidities and maintaining a low threshold for diagnostic work-up for cancer remain important in these patients (good clinical practice statement).

The patient representative underlined that counselling about returning to work and ability to maintain family-life and other social relations should be prioritized in conversations with patients and relatives (good clinical practice statement). In addition, the general very low risk of recurrence should also be discussed with patients (good clinical practice statement).

## 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.

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 disease severity and who were alive around time of early transition to oral antimicrobials. A survey among infectious diseases specialists suggested that trials on early transition to oral antimicrobials and duration of therapy had the highest priority among respondents [42]. Currently, a non-inferiority trial on early transition to oral antimicrobials compared with continued IV treatment is active and recruiting patients [252].

## Author contributions

Conceptualization: MK, PP, ORS, PT, MCB, JB, and 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.

## Transparency declaration

The authors declare that they have no conflicts of interest. The guideline was funded by the European Society of Clinical Microbiology and Infectious Diseases (ESCMID).

## 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 2 years at the ESGIB annual business meeting during ECCMID. Substantial and clinically relevant updates to guideline will be submitted for publication in CMI.

## Acknowledgements

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.

## Appendix A. Supplementary data

Supplementary data to this article can be found online at https://doi.org/10.1016/j.cmi.2023.08.016.

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## Update

# Clinical Microbiology and Infection

Volume 30, Issue 5, May 2024, Page 698

DOI: https://doi.org/10.1016/j.cmi.2024.01.026
<figure><img src="image_21.png" /></figure>

ELSEVIER

Contents lists available at ScienceDirect

Clinical Microbiology and Infection

journal homepage: www.clinicalmicrobiologyandinfection.com

CMI
CLINICAL
MICROBIOLOGY
AND INFECTION

<figure><img src="image_22.png" /></figure>

ESCMID
EUROPEAN SOCIETY OF
CLINICAL MICROBIOLOGY
AND INFECTION

Corrigendum to "European society of clinical microbiology and infectious diseases guidelines on diagnosis and treatment of brain abscess in children and adults" [Clin Microbiol and Infect 30(1) (2024 Jan) 66-89 Doi: 10.1016/j.cmi.2023.08.016]

Jacob Bodilsen <fnref n="1" />,<fnref n="2" />,<fnref n="3" />,*, Quintino Giorgio D'Alessandris <fnref n="4" />,<fnref n="5" />, Hilary Humphreys <fnref n="6" />,
Mildred A. Iro <fnref n="7" />, Matthias Klein <fnref n="3" />,<fnref n="8" />, Katharina Last <fnref n="3" />,<fnref n="9" />, Inmaculada López Montesinos <fnref n="10" />,<fnref n="11" />,
Pasquale Pagliano <fnref n="3" />,<fnref n="12" />,<fnref n="13" />, Oğuz Reşat Sipahi <fnref n="3" />,<fnref n="14" />,<fnref n="15" />, Rafael San-Juan <fnref n="11" />,<fnref n="16" />,<fnref n="17" />,
Pierre Tattevin <fnref n="3" />,<fnref n="18" />, Majda Thurnher <fnref n="19" />, Rogelio de J. Treviño-Rangel <fnref n="20" />,<fnref n="21" />,<fnref n="22" />,<fnref n="23" />,
Matthijs C. Brouwer <fnref n="3" />,<fnref n="24" />, ESCMID Study Group for Infections of the Brain (ESGIB)

The authors regret an inconsistency in the reported quality of evidence for Key Question 4 concerning whether neurosurgical aspiration or excision should be used in patients with brain abscess. The reported quality of evidence was described as "low" in the abstract and Table 1 and should instead be "moderate" as stated in the main text.

The authors would like to apologise for any inconvenience caused.

<footnote n="1">1) Department of Infectious Diseases, Aalborg University Hospital, Aalborg, Denmark</footnote>

<footnote n="2">2) Department of Clinical Medicine, Aalborg University Hospital, Aalborg, Denmark</footnote>

<footnote n="3">3) ESCMID Study Group for Infections of the Brain (ESGIB), Basel, Switzerland</footnote>

<footnote n="4">4) Department of Neurosurgery, Fondazione Policlinico Universitario "A. Gemelli" IRCCS, Rome, Italy</footnote>

<footnote n="5">5) Department of Neuroscience, Università Cattolica del Sacro Cuore, Rome, Italy</footnote>

<footnote n="6">6) Department of Clinical Microbiology, Royal College of Surgeons in Ireland University of Medicine and Health Sciences, Dublin, Ireland</footnote>

<footnote n="7">7) Department of Paediatric Infectious diseases and Immunology, The Royal London Children's Hospital, Barts Health NHS Trust, London, UK</footnote>

<footnote n="8">8) Department of Neurology, Hospital of the Ludwig-Maximilians University, Munich, Germany, Emergency Department, Hospital of the Ludwig-Maximilians University, Munich, Germany</footnote>

<footnote n="9">9) Institute for Hygiene and Public Health, University Hospital Bonn, Bonn, Germany</footnote>

<footnote n="10">10) Infectious Disease Service. Hospital del Mar. Institut Hospital del Mar d'Investigacions Mediques (IMIM), Barcelona, Spain</footnote>

<footnote n="11">11) CIBERINFEC ISCII, CIBER de Enfermedades Infecciosas, Instituto de Salud Carlos III, Madrid, Spain</footnote>

<footnote n="12">12) Department of Medicine, Surgery and Dentistry, Scuola Medica Salernitana, Unit of Infectious Diseases, University of Salerno, Baronissi, Italy</footnote>

<footnote n="13">13) UOC Clinica Infettivologica AOU San Giovanni di Dio e Ruggi d'Aragona, Salerno, Italy</footnote>

<footnote n="14">14) Ege University, Faculty of Medicine, Department of Infectious Diseases and Clinical Microbiology, Bornova, Izmir, Turkey</footnote>

<footnote n="15">15) Bahrain Oncology Center, King Hamad University Hospital, Infectious Diseases Department, Muharraq, Bahrain</footnote>

<footnote n="16">16) Unit of Infectious Diseases, 12 de Octubre University Hospital, Madrid, Spain</footnote>

<footnote n="17">17) ESCMID Study Group for Infections in Compromised Hosts (ESGICH)</footnote>

<footnote n="18">18) Department of Infectious Diseases and Intensive Care Unit, Pontchaillou University Hospital, Rennes, France</footnote>

<footnote n="19">19) Department of Biomedical Imaging and Image-guided Therapy, Medical University of Vienna, Vienna, Austria</footnote>

<footnote n="20">20) Universidad Autónoma de Nuevo León, Faculty of Medicine, Department of Microbiology. Monterrey, Nuevo León, Mexico</footnote>

<footnote n="21">21) ESCMID Fungal Infection Study Group (EFISG), Spain</footnote>

<footnote n="22">22) ESCMID Study Group for Antimicrobial Stewardship (ESGAP), Spain</footnote>

<footnote n="23">23) ESCMID Study Group for Genomic and Molecular Diagnostics (ESGMD), Spain</footnote>

<footnote n="24">24) Department of Neurology, Amsterdam Neuroscience, Amsterdam UMC, University of Amsterdam, Amsterdam, The Netherlands</footnote>

<footnote>DOI of original article: https://doi.org/10.1016/j.cmi.2023.08.016.</footnote>

<footnote>* Corresponding author. Jacob Bodilsen, Department of Infectious Diseases, Aalborg University Hospital, Mølleparkvej 4, 9000 Aalborg, Denmark.
E-mail address: Jacob.bodilsen@rn.dk (J. Bodilsen).</footnote>