Accepted Manuscript

An update on bacterial brain abscess in immunocompetent patients

R. Sonneville, R. Ruimy, N. Benzonana, L. Riffaud, A. Carsin, J.-M. Tadié, C. Piau, M.

Revest, P. Tattevin

PII: S1198-743X(17)30259-8
DOI: 10.1016/j.cmi.2017.05.004
Reference: CMI 943

To appear in: Clinical Microbiology and Infection

Received Date: 24 March 2017

Revised Date: 29 April 2017
Accepted Date: 1 May 2017

Please cite this article as: Sonneville R, Ruimy R, Benzonana N, Riffaud L, Carsin A, Tadié J-M, Piau
C, Revest M, Tattevin P, An update on bacterial brain abscess in immunocompetent patients, Clinical
Microbiology and Infection (2017), doi: 10.1016/j.cmi.2017.05.004.

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 ACCEPTED MANUSCRIPT
1 Narrative review

2 An update on bacterial brain abscess in immunocompetent patients

3 Running title: Brain abscess in immunocompetent

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5 R. Sonneville ¹, R. Ruimy 2, N. Benzonana 3, L. Riffaud 4, A. Carsin 5, J-M

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6 Tadié 6, C. Piau 7, M. Revest 6, P. Tattevin 6,8*

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7 1) Intensive Care Medicine and Infectious Diseases, AP-HP, Bichat Hospital, and UMR1148,

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8 LVTS, Sorbonne Paris Cité, INSERM/Paris Diderot University, Paris, France
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9 2) Microbiology, Archet Hospital, Nice Côte d’Azur University, Nice, France
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10 3) Clinical Microbiology, Dr. Lütfi Kırdar Kartal Training and Research Hospital, Istanbul,

11 Turkey
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12 4) Neurosurgery, Pontchaillou University Hospital, Rennes, France

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13 5) Radiology, Maison Blanche University Hospital, Reims, France

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14 6) Infectious Diseases and Intensive Care Unit, Pontchaillou University Hospital, Rennes,
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15 France
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16 7) Microbiology, Pontchaillou University Hospital, Rennes, France

17 8) ESCMID Study Group for Infectious Diseases of the Brain

18 * Corresponding Author: P. Tattevin, Infectious Diseases and Intensive Care Unit,

19 Pontchaillou University Hospital, 2, rue Henri Le Guilloux, 35033 Rennes Cedex, France.

20 Tel +33 299289564. Fax +33 299282452 E-mail address: pierre.tattevin@chu-rennes.fr

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21 ABSTRACT

22 Background. Brain abscess is a focal infection of the brain, that begins as a localized area of

23 cerebritis. In immunocompetent patients, bacteria are responsible for >95% of brain abscess,

24 and enter the brain either through contiguous spread following otitis, sinusitis, neurosurgery,

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25 or cranial trauma, or through hematogenous dissemination. Aims. To identify recent advents

26 in the field. Sources We searched Medline and Embase for articles published during years

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27 2012-2016, with the keywords ‘brain’, and ‘abscess’. Content. The triad of headache, fever,

28 and focal neurologic deficit, is complete in ~20% of patients on admission. Brain imaging

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29 with contrast – preferentially magnetic resonance imaging – is the gold standard for

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30 diagnosis, and should be followed by stereotactic aspiration of at least one lesion, before the
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31 start of any antimicrobials. Efforts should be made for optimal management of brain abscess

32 samples, for reliable microbiological documentation. Empirical treatment should cover oral
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33 streptococci (including milleri group), meticillin-susceptible staphylococci, anaerobes, and

34 Enterobacteriaceae. As brain abscess are frequently polymicrobial, de-escalation based on

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35 microbiological results is safe only when aspiration samples have been processed optimally,
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36 or when primary diagnosis is endocarditis. Otherwise, many experts advocate for anaerobes
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37 coverage even with no documentation, given the sub-optimal sensitivity of current

38 techniques. A 6-week combination of third-generation cephalosporin and metronidazole will

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39 cure most cases of community-acquired brain abscess in immunocompetent patients.

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40 Implications. significant advent in brain imaging, minimally invasive neurosurgery,

41 molecular biology, and antibacterial agents, has dramatically improved the prognosis of brain

42 abscess in immunocompetent patients over the last decades.

43 Keywords: Brain; abscess; neurosurgery; Streptococcus milleri; stereotactic aspiration;

44 review; third-generation cephalosporin; metronidazole

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45 Introduction

46 Among the ‘big three’ central nervous system (CNS) infections, brain abscess has

47 always been the last in terms of research priority. Indeed, an unlimited ‘pubmed search’

48 performed in March 2017 retrieved 68,710 papers with the keyword ‘meningitis’, 58,880

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49 with ‘encephalitis’, and only 10,548 with ‘brain abscess’. However, brain abscess is a

50 fascinating disease, with complex diagnostic challenges, and potentially severe consequences

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51 (1-3). Due to significant progress in imaging studies, surgical techniques, microbiological

52 tests, and antimicrobial agents use, based on pharmacokinetic/pharmacokinetic (PK/PD)

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53 principles, prognosis has improved over the last decades (4). Although brain abscess has been

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54 the subject of a few recent reviews and meta-analysis elsewhere (1-3), none took into account
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55 the multidisciplinary nature of this disease. As a group of authors, with a combination of

56 expertise in infectious diseases, intensive care, microbiology, neurosurgery, and imaging, we

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57 reviewed the state-of-the art for brain abscess, in 2017, focusing on immunocompetent

58 patients, with special emphasis on recent papers: We searched Medline and Embase for
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59 articles published during years 2012-2016, with the keywords ‘brain’, and ‘abscess’. Papers
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60 that specifically addressed immunocompromised patients, and case reports, were excluded.
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61 Although we applied no age restriction, our research retrieved no paper specifically dealing

62 with brain abscess in children.

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63
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64 Pathogenesis

65 Brain abscess is a focal infection of the brain, that begins as a localized area of

66 cerebritis, and develops into a collection of pus surrounded by a well-vascularized capsule

67 (5). A landmark experimental model with systematic histological and computed tomography

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68 (CT) studies in dogs estimated the time course of untreated streptococcal brain abscesses as

69 follows: early cerebritis (days 1-3), late cerebritis (days 4-9), early capsule formation (days

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70 10-13), and late capsule formation (after day 14) (6). In lesions that were well encapsulated

71 (14 days and older), five distinct histological zones were apparent: i) a well formed necrotic

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72 center; ii) a peripheral zone of inflammatory cells, macrophages, and fibroblasts; iii) the

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73 dense collagenous capsule; iv) a layer of neovascularization associated with continuing
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74 cerebritis; and v) astrogliosis, and cerebral edema external to the capsule. Other seminal

75 studies in animals have brought upon valuable concepts for pathogenesis. First, the brain is
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76 highly susceptible to bacterial infections once the blood-brain barrier has been crossed:

77 Indeed, injections of 104 colony-forming units (CFUs) of Staphylococcus aureus, or 106

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78 CFUs of Escherichia coli, had no consequence in skin tissues, while 102 CFUs of the same
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79 organisms were sufficient to establish abscess in brain tissues (7). Second, although strict
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80 anaerobes or microaerophilic bacteria were unable to establish brain abscess in a rat model,

81 synergistic infectivity between strict anaerobes and other bacteria is a key factor in
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82 pathogenesis (8). Third, capsule tends to be less robust on the ventricular surface, as
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83 compared to the cortical surface of brain abscess. This may be due to differences in

84 vascularization between grey and white matter, and may explain why rupture of brain abscess

85 mostly occurs into the ventricular system - with severe consequences - rather than in the

86 subarachnoid space.

87 In immunocompetent patients, bacteria are responsible for >95% of brain abscess (2).

88 They enter the brain either through contiguous spread (e.g. following otitis, mastoiditis,

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89 sinusitis, neurosurgical procedures, or cranial trauma) in 40-50% of cases, or through

90 hematogenous dissemination in 30-40% of cases, especially in case of infective endocarditis,

91 in patients with predisposing conditions associated with pulmonary circulation shunt (e.g.

92 congenital heart disease, pulmonary arterio-venous fistulas, as in hereditary hemorrhagic

93 telangiectasia), or as a consequence of distant infectious foci (e.g. dental infection, pulmonary

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94 abscess) (1, 9). For the management of an individual patient with brain abscess, the clinician

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95 should aim to identify the pathogenesis, as this has consequences regarding the main bacteria

96 to be suspected, the investigations to be performed (e.g. echocardiography when endocarditis

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97 is suspected), the therapeutic strategy (e.g. source control, in selected cases, for otitis or

98 mastoiditis), and secondary prevention (e.g. reinforced dental hygiene). Table 1 depicts the

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major points to be considered during this important step.
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100
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101 Epidemiology
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102 Limited data are currently available on the epidemiology of brain abscess (9). The
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103 incidence has been estimated at 0.3 to 0.9 per 100,000 inhabitants per year in developed

104 countries (10-12), with a male-to-female sex ratio of 2:1 to 3:1, and a median age of 30-40
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105 years. Of note, a meta-analysis of literature data found that the distribution of bacterial
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106 pathogens was not significantly different from one continent to another, and has been stable
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107 over the last 60 years (2). However, a study from Finland suggested that the proportion of

108 brain abscess due to dental infections might be on the rise (10). On the other hand, the

109 incidence of brain abscess may decrease when the general health of the population improves,

110 according to studies performed in the USA during years 1935-1981 (12), and in South Africa

111 during years 1983-2002 (13).

112 A systematic review of 9,699 cases of brain abscess reported between 1935 and 2012

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113 found that most common predisposing conditions were contiguous foci of infection: otitis or

114 mastoiditis (33%), sinusitis (10%), and meningitis (6%) (2). Brain abscess was related to

115 hematogenous spread in 33% of cases, mostly with endocarditis (13%), pulmonary infection

116 (8%) or dental infection (5%). Others were attributed to recent neurosurgery (9%), or cranial

117 trauma (14%), while the source could not be identified in 19% of cases, so-called

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118 ‘cryptogenic brain abscess’.

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119 The risk of brain abscess is estimated at 5-9% in patients with hereditary hemorrhagic

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120 telangiectasia (14), <5% in patients with infective endocarditis overall (7% in critically ill

121 patients) (15), and 0.2% after cranial surgery (16). Brain abscess was encountered in only

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122 0.5% (14/950) of patients with bacterial meningitis in the 2006-2011 nationwide prospective
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123 cohort from the Netherlands (17), and in 2% (6/252) of patients with neurolisteriosis in the

124 2009-2013 nationwide prospective cohort from France (18), much below the 10% proportion
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125 of brain abscess among patients with neurolisteriosis previously estimated, based on literature

126 review (19).

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127

128 Diagnosis
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129 The classical triad of headache, fever, and focal neurologic deficit, is present in only
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130 ~20% of patients with brain abscess on admission. Headache is reported in 69% of patients,
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131 fever in 53%, and focal neurologic deficit in 48% (1, 2, 4, 5, 13, 20-23). Other common

132 neurologic symptoms include seizures (25%), and altered consciousness (43%). The mean

133 duration of symptoms before diagnosis is 8.3 days (2). The location of brain abscess impacts

134 the neurologic presentation, and may be estimated from a careful clinical examination,

135 although major discrepancies between clinical findings, and imaging studies, are not rare. In a

136 patient with brain abscess, the abrupt onset of meningeal signs, associated with worsening of

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137 headache and neurological status, should prompt clinicians to order urgent brain imaging, to

138 rule out rupture of an abscess into the ventricular space with ventriculitis, carrying a high risk

139 of obstructive hydrocephalus, and letality of 50-85% (11, 24).

140 Brain imaging is the cornerstone for the diagnosis of brain abscess (Fig. 1). CT with

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141 contrast-enhancement typically shows, at capsule stage, a peripheral rim-enhanced lesion

142 including a hypodense center (central necrosis), surrounded by a variable hypodense area

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143 (edema). Brain abscess appears as single in most cases with CT (81% in the meta-analysis),

144 and will be mostly located in frontal (31%) or temporal (28%) lobes (2). Magnetic resonance

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145 imaging (MRI) should be preferred if readily available, as it offers many advantages over

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146 contrast-enhanced CT, including i) better resolution, allowing identification of additional
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147 lesions; ii) earlier detection of lesions at risk of complications; iii) lower toxicity of the

148 contrast-enhancement agent (gadolinium) (1, 9). Lastly, the combined use of morphological
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149 sequences, proton MR spectroscopy, diffusion weighted imaging (DWI), and the calculation

150 of apparent diffusion coefficient (ADC), has significantly improved the performance of MRI,
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151 allowing sensitivity and specificity of 94%, and 95%, respectively, to differentiate abscess
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152 from tumors (25, 26), one of the major challenges with brain imaging until recently. Pyogenic
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153 abscess appears as a mass with a continuous capsule, respectively hyperintense and

154 hypointense in T1- and T2-weighted sequences, with regular rim enhancement after
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155 gadolinium injection (Fig. 2). The necrotic center is hypointense in T1-weighted sequence,
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156 hyperintense in T2-weighted sequence, and hyperintense in DWI. Moreover, it typically

157 presents with low values of ADC, and peaks corresponding to lipids, lactate and amino-acids

158 in MR spectroscopy (25).

159 No biological test has any added value for the diagnostic workout at this stage. Blood

160 leucocytes count, and serum C reactive protein are increased in ~60% of patients, and may be

161 abnormal in most differential diagnosis. Blood cultures (40-60 mL) should be collected

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162 before initiation of antibacterial treatment, as it was found to be positive in 28% of patients

163 with brain abscess (135/484) in a recent meta-analysis (2). HIV testing should be proposed to

164 all patients with brain abscess, as cerebral toxoplasmosis may be the first opportunistic

165 infection in patients with previously undiagnosed HIV infection. Both tests are especially

166 relevant in patients with bilateral brain abscess (Fig. 3).

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167

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168 Neurosurgery

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169 Progress in neurosurgical techniques is one of the key factor behind improved

170 prognosis over last decades. Stereotactic surgery - a minimally invasive form of surgical

171
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intervention which makes use of a three-dimensional coordinate system to locate small
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172 targets inside the body – allows the aspiration of any brain abscess >1 cm with good
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173 tolerability, regardless of its location (27). Development of neuronavigation assistance in

174 routine neurosurgical practice allowed the planning of the optimal trajectory from the point of
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175 brain entry to the abscess, with the aim of avoiding any areas critical for neurological
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176 functions. As a consequence, neurosurgical approach has dramatically changed for brain

177 abscess: i) total resection through craniotomy is now rarely considered first, except for
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178 patients with large multi-lobulated abscess and severe cranial hypertension; ii) stereotactic
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179 aspiration by neuronavigation, either CT- or MRI-guided, is indicated for all patients with
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180 undocumented brain abscess >1 cm; iii) although not based on robust evidence, an abscess

181 size >2.5 cm is considered as a stand-alone indication for drainage, even in patients with

182 microbiological documentation (e.g. through positive blood cultures) (28); iv) drainage

183 should be discussed in case of periventricular lesions at high risk of intraventricular rupture,

184 and in case of difficult-to-treat bacteria or fungal infections (1, 9).

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185 Other indications for neurosurgery include placement of an external ventricular

186 catheter for drainage and monitoring of intracranial pressure, in all cases of abscess rupture

187 into the ventricular system, and in selected cases of large abscess with hydrocephalus

188 (personal opinion). The importance of adequate sampling of brain abscess tissues and fluids

189 cannot be overstated: these are among the most precious surgical samples, with high risk of

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190 opportunity loss in case of sub-optimal sampling and processing, given the importance of

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191 accurate identification of bacteria involved, the polymicrobial context, the fragility of some

192 pathogens (e.g. strict anaerobes when exposed to room air) (29), and the broad spectrum of

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193 differential diagnosis. Fast processing of surgical specimen, good anaerobic culture

194 conditions, and the use of blood culture bottles and molecular biology techniques when

195
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appropriate, improve the yield of microbiological diagnosis from brain abscess samples (30).
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196 In our institution, we build a specific protocol for brain abscess sampling in the operating
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197 room, with a check list to ensure that the risk of non-contributive samples due to pre-

198 analytical adverse events will be kept to a minimum (Table 2).

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199
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200 Microbiology
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201 Although significant progress has already been achieved, this field will most likely
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202 improve dramatically during the next few years (personal opinion). According to a recent
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203 systematic review and meta-analysis, of the 6,663 patients with brain abscess who had

204 samples submitted for cultures during years 1935-2012, 4,543 (68%) yielded at least one

205 potential pathogen, of whom 902 (23%) were polymicrobial. Streptococci predominated

206 (n=2,000; 34%), mostly oral streptococci, including the milleri group, while Streptococcus

207 pneumoniae was isolated from only 2.4% of patients. Staphylococci were second (n=1,076;

208 18%), of whom 84% were S. aureus. Gram-negative bacilli came third (n=861; 15%), mostly

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209 Enterobacteriaceae. However, these figures are probably not representative of the actual

210 distribution of pathogens involved in brain abscess, for the following reasons: i) a substantial

211 proportion of these samples have been obtained while patients were already on antibacterial

212 treatment, which dramatically decreases the sensitivity of cultures, especially for the most

213 susceptible bacteria; ii) limited information is available on samples processing and culture

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214 techniques in these series, although it has a huge impact on cultures yield, especially for strict

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215 anaerobes such as Prevotella sp., Bacteroides sp., and Fusobacterium sp. (31-33).

216 The advent of molecular biology, and metagenome sequencing have demonstrated the

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217 gap between bacterial species identified through conventional cultures, and bacterial genetic

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218 material that can be amplified from brain abscess samples. 16S rRNA-based amplification,
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219 cloning, and high-throughput sequencing have dramatically increased the number of

220 identified agents of brain abscesses (29). The systematic use of multiple 16S ribosomal DNA
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221 sequencing on samples obtained from 71 patients with brain abscess increased the proportion

222 of patients with documentation (from 66% to 83%), with the identification of 186 strains, as
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223 compared to only 58 with conventional cultures (34, 35). However, the clinical significance
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224 of these large numbers of bacteria (as much as 16 distinct species in a single brain abscess),
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225 identified only through metagenomics analysis, but not by conventional cultures, remains to

226 be proven. For example, Mycoplasma sp. were among the most common bacterial species
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227 identified through molecular biology. Still, >90% of brain abscess resolve with a 6 week-
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228 course of third-generation cephalosporin combined with metronidazole (4), although this

229 regimen has no activity on Mycoplasma sp.

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231 Antibacterial treatment

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232 Although the level of evidence supporting the choice of antibacterial regimens is

233 limited, in the absence of randomized trial, there is a global consensus for the following

234 points: i) antibacterial treatment should be initiated as soon as possible, immediately after

235 stereotactic aspiration of one abscess has been performed, and blood cultures sampled; ii)

236 empirical treatment should cover streptococci, staphylococci, strict anaerobes, and

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237 Enterobacteriaceae, pending results of aspiration samples and blood cultures; iii) for

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238 community-acquired brain abscess, a combination of third generation cephalosporin (for

239 adults, i.v. cefotaxime 8-12 g/day or ceftriaxone, 4g/day), and metronidazole (1.5 g/day),

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240 would be recommended in most settings (personal opinion, and (1, 9)). One of the major

241 controversies in this field is the opportunity for de-escalation once microbiological results are

242
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available. Indeed, given the large proportion of polymicrobial brain abscess (at least >30%),
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243 and the high risk of missing a co-pathogen in this context, many experts would advocate that,
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244 except for brain abscess associated with endocarditis, it is reasonable to keep an adequate

245 coverage for anaerobes throughout the duration of treatment, even when stereotactic
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246 aspiration found no anaerobes. Given this concern that microbiological results might not
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247 identify all pathogens involved, any additional suspicion that samples were sub-optimal (e.g.

248 limited volume, samples obtained while antibacterial treatment was already initiated, long
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249 delay between sampling and analysis), should prompt clinician to continue empirical
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250 treatment for the whole six-week duration (personal opinion). However, the potential
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251 neurotoxicity of six-week metronidazole should not be underestimated. Hence, when

252 anaerobic infections have been reliably ruled out, metronidazole may be discontinued.

253 Most experts recommend six-week duration for bacterial brain abscess in

254 immunocompetent patients, based on their clinical experience, and practices in other location

255 of bacterial brain abscess, but no clinical study specifically addressed treatment duration for

256 brain abscess. Likewise, indications for follow-up imaging studies still mostly rely on experts

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257 opinion, although a recent study found that bacterial brain abscesses with favourable outcome

258 decrease by 10% per week on MRI follow-up imaging studies (36). In the absence of any

259 systematic study in the field, it seems reasonable to perform systematic brain imaging study

260 at week 6 in patients with no clinical complication. Some experts would continue

261 antibacterial treatment in patients with residual abscess cavity at six weeks, but we are not

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262 aware of any study supporting these practices. Additional imaging studies will be performed

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263 in case of brain lesions at risk of complications (e.g. periventricular location, size > 2.5 cm),

264 or in patients with persistent fever, or any neurological event (personal opinion).

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265 When antibacterial treatment can be safely targeted to the pathogen(s) identified

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266 through cultures, basic principles of PK/PD apply, including i) use drugs with significant
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267 diffusion through the blood-brain barrier, although brain diffusion cannot be directly

268 extrapolated from concentrations measured in cerebrospinal fluid (37); ii) a preferential use
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269 of agents that remain active in acid environments, which is the rule for bacterial abscess. For

270 example, aminoglycosides will be avoided, as probably not effective within abscess fluid and
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271 tissues, while metronidazole (not affected by low pH) will be the preferential drug for
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272 anaerobes (personal opinion). Another controversy relies in the preferential use of parenteral
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273 drugs. We routinely switch to oral drugs, even early in the process, provided the bacteria

274 targeted are susceptible to an effective oral drug, well absorbed, and that adherence is not an
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275 issue. Table 3 depicts first-line antibacterial treatment for the main pathogens isolated from
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276 brain abscess in immunocompetent patients.

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278 Symptomatic measures

279 Simple measures may be of importance in patients with intracranial hypertension

280 and/or altered mental status. Although not based on robust evidence, early ICU admission

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281 should be considered in patients with comorbidities, severe neurological presentation (i.e.,

282 GCS <13 and/or seizures), and/or cerebral lesion(s) with edema and significant mass effect.

283 A short course of adjunctive steroids may be proposed in case of warning signs of brain

284 herniation. Primary seizure prophylaxis is not recommended (personal opinion).

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285

286 Unmet needs and perspectives

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287 Clinical research on brain abscess remains limited, in 2017, so that unmet needs are

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288 quite large. In our opinion, the priorities would be: i) to gather a multidisciplinary,

289 international group of experts with the aim of designing practical guidelines for the

290
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management of patients suspected of brain abscess; ii) to initiate international prospective
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291 cohort studies with standardized collection of data, including one-year follow-up, to better
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292 characterize clinical presentations, microbiology, medical and surgical treatment approaches,

293 prognostic factors, and sequelae. These necessary first steps would pave the way for
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294 interventional studies, including randomized trials, to better define optimal surgical and
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295 medical treatment, both poorly evidence-based, in 2017.

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296

297 In conclusion, brain abscess is a fascinating disease, with a prognosis that

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298 dramatically improved over the last decades due to advent in brain imaging, minimally
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299 invasive neurosurgery, and better use of old and more recent antibacterial agents. In 2017,

300 when diagnosis is made ‘in time’, and basic rules of management are applied, the rate of cure

301 should be >90%.

302

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303 Table 1. Pathogenesis of brain abscess and its consequences for patients management

Predisposing condition Bacteria Comments

Hematogenous (30-40% of brain abscess in immunocompetent patients)

Infective endocarditis Staphylococcus aureus, Even with no previously known

oral streptococci, HACEK underlying condition,
bacteria echocardiography must be
performed in all patients with

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bilateral or cryptogenic brain
abscess
Pulmonary circulation Polymicrobial, including Careful skin examination to detect

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shunts (congenital heart streptococci, anaerobes skin lesions related to hereditary
disease, arterio-venous (Actinomyces sp., hemorrhagic telangiectasia (Rendu-
fistulas) Prevotella sp., Bacteroides Osler-Weber syndrome)

sp., Fusobacterium sp.)
Dental infection Polymicrobial, mainly
Streptococcus milleri group
(S. anginosus, S.
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Preferentially affect frontal lobes
Orthopantogram and dentist

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constellatus, S. consultation to be performed
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intermedius), anaerobes
(Actinomyces sp., May require dental extraction
Prevotella sp., Bacteroides
sp., Fusobacterium sp.) Secondary prevention is key
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(reinforced dental hygiene)

Contiguous spread from local infection (40-50% of brain abscess in immunocompetent)
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Otitis, mastoiditis, Polymicrobial, mainly Preferentially affect temporal lobes

sinusitis streptococci, (otitis, mastoiditis, sphenoid
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Enterobacteriaceae, sinusitis), or frontal lobes (other

Streptococcus pneumoniae, sinusitis)
anaerobes (Prevotella sp., Systematic ENT examination for
Bacteroides sp.), S. aureus patients with unilateral brain
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(sinusitis) abscess
Selected cases may require surgery
for source control
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Cranial traumatism Polymicrobial, mainly S. Risk factors: open wound

aureus, Streptococcus contaminated with environmental
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pyogenes, anaerobes flora (telluric bacteria), sub-optimal

(Clostridium sp., or delayed wound care
Actinomyces sp.)
Neurosurgery Polymicrobial, mainly S. Risk factors: foreign devices,
aureus, coagulase-negative including ventricular derivation,
staphylococci, bone graft, etc.
Enterobacteriaceae
Cryptogenic brain abscess (10-20% of brain abscess in immunocompetent)
304 HACEK, Haemophilus spp., Aggregatibacter spp., Cardiobacterium spp., Eikenella

305 corrodens, and Kingella spp.; ENT, ear, nose and throat

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306 Table 2. Suggested protocol for the processing of surgical samples (stereotactic aspiration or
307 craniotomy), based on authors’ opinion

Laboratory Samples Targets, comments

Streptococci, staphylococci, anaerobes

10 mL to be directly inoculated on
(blood culture bottles increases the
blood culture bottles
yield, especially if previous use of
(aerobic/anaerobic)
antibacterials)

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- Gram staining
Bacteriology *

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- Cultures on routine media
Two separate dry tubes
- Molecular biology to be performed if

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At least 5 mL in each tube cultures sterile after 48 h

- Tests for mycobacteria if risk factors

for tuberculosis

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One dry tube for fluid sample
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Histology Differential diagnosis (cancer)
If tissue, to be sent in sterile water
Only if immunocompromised (HIV,
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immunuppressive agents, organ

Mycology, transplant, malignant hemopathy)
Dry tube
parasitology
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Specific tests for Toxoplasma, invasive

mycosis (Aspergillus spp.)
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Basic rules
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To be sent within one hour to the microbiology laboratory, for immediate processing, 24/24

Two sets of blood cultures should be obtained, before and just after surgery, optimally prior to
antibiotic administration.
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Patients characteristics and clinical suspicion to be communicated to the microbiologist.

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308 * The volume of samples to be inoculated on blood culture bottles depends on the volume

309 that can be obtained, hence on abscess size

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310 Table 3. First line antibacterial treatment for main pathogens isolated from brain abscess in

311 immunocompetent patients

Bacteria Antibacterial treatment Comments

Staphylococcus aureus High doses i.v. oxacillin Brain diffusion of cloxacillin

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(150 mg/kg/d) and cefazolin probably lower

Streptococcus sp. High doses i.v. amoxicillin or To be adjusted based on MIC

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ampicillin (200 mg/kg/d), or

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penicillin G (300-400 000

UI/kg/d), or ceftriaxone (2 g

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b.i.d.) or cefotaxime (200
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mg/kg/d)

Strict anaerobes Metronidazole, 500 mg/kg t.i.d. i.v. or oral theoretically

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(Prevotella sp., similar, in terms of brain and

Bacteroides sp., blood concentrations

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Fusobacterium sp.)
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Actinomyces spp. High doses i.v. amoxicillin or

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ampicillin (200 mg/kg/d), or

penicillin G (300-400 000

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UI/kg/d)
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Enterobacteriaceae Ceftriaxone (2 g b.i.d.) or

cefotaxime (200 mg/kg/d)

HACEK bacteria Ceftriaxone (2 g b.i.d.) or Drug susceptibility testing

cefotaxime (200 mg/kg/d) poorly reliable

312 i.v., intravenous; HACEK, Haemophilus parainfluenzae, Aggregatibacter spp., Cardiobacterium

313 spp., Eikenella corrodens, and Kingella spp.

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314 Figure legends

315

316 Figure 1. Algorithm for the management of patients suspected of brain abscess

317

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318 Figure 2. Typical brain abscess on magnetic resonance imaging. a: axial T1-weighted image:

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319 abscess with a thin hyperintense capsule (white arrow), hypointense central necrosis, and a

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320 mass effect in the adjacent structures; b: axial T2-weighted image: the same abscess with a

321 thin hypointense capsule (white arrow), hyperintense central necrosis, and a peripheral

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322 hyperintense edema; c: axial diffusion-weighted image: the center of the abscess is
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323 hyperintense; d: axial image, cartography of apparent diffusion coefficient (ADC): the central

324 component appears hypointense on ADC map; e: axial T1-weighted image after gadolinium
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325 injection: the peripheral capsule (right arrow) is enhanced.

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326
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327 Figure 3. Contrast-enhanced computed tomography: bilateral brain abscesses with hypodense

328 center (central necrosis), limited by a ring-shaped, contrast-enhanced capsule, surrounded by

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329 a variable hypodense area (edema).

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330
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331 Transparency declaration

332 Conflicts of interest: All authors, none.

333 No external funding was received for this work.

334

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Clinical suspicion of brain abscess
Headache, fever, focal neurologic deficit, seizures, mental status changes, etc.

Search for predisposing conditions

Contiguous spread of local infection
- Otitis, sinusitis
- Recent neurosurgery

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- Recent cranial trauma

Conditions at risk of hematogenous spread

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- Hereditary hemorrhagic telangiectasia
- Endocarditis
- Pulmonary infection

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- Dental infection Brain MRI readily available (<24 h)

YES NO
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Urgent CT + contrast-enhancement
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NO Brain imaging compatible with brain abscess

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If first imaging was CT, order Brain MRI

YES
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If brain MRI not suggestive, look for other diagnosis

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Collect 40-60 mL of blood cultures before initiation of antibacterial treatment

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HIV test
Stereotactic aspiration
- All abscess > 2.5 cm
- If no abscess > 2.5 cm, at least one of those > 1 cm (the most accessible)
- Microbiology tests: routine (aero + anaerobes) +/- molecular biology (PCR 16S
rDNA, if negative) + others if risk factors (tuberculosis, fungal, etc.)

Empirical antibacterial treatment

Third generation cephalosporin (cefotaxime or ceftriaxone) + metronidazole
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