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Eggerthella lenta bacteremia: clinical and microbiological characteristics 1

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Gardiner BJ1, Tai AY1, Kotsanas D1, Francis M2, Roberts SA3, Ballard SA4, Junckerstorff RK1, 3

Korman TM1,2,5 4

5

Affiliations 6

1Monash Infectious Diseases, 2Microbiology, Monash Health, Clayton, Victoria, Australia 7

3Department of Microbiology, Auckland Hospital, Auckland, New Zealand 8

4Department of Infectious Diseases, Austin Health, Heidelberg, Victoria, Australia 9

5Department of Medicine, Monash University, Clayton, Victoria, Australia 10

11

Address for correspondence: 12

Dr Brad Gardiner 13

Monash Infectious Diseases 14

Monash Medical Centre 15

246 Clayton Road 16

Clayton VIC 3168 17

+613 9594 4564 (ph) 18

+613 9594 4533 (fax) 19

[email protected] 20

21

Keywords: Eggerthella lenta, anaerobe, antimicrobial susceptibility testing, antimicrobial 22

resistance 23

Running title: Eggerthella lenta bacteremia 24

JCM Accepts, published online ahead of print on 17 December 2014J. Clin. Microbiol. doi:10.1128/JCM.02926-14Copyright © 2014, American Society for Microbiology. All Rights Reserved.

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Conflicts of interest: none to declare 25

26

Financial support: none 27

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Words: 2750 29

Abstract: 174 30

Tables: 5 31

Figures: 0 32


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Abstract 33

34

Eggerthella lenta is an emerging pathogen that has been under-recognised due to historical 35

difficulties with phenotypic identification. Until now, its pathogenicity, antimicrobial 36

susceptibility profile and optimal treatment have been poorly characterised. In this study we 37

report the largest cohort of patients with E. lenta bacteremia to date and describe in detail 38

their clinical features, microbiologic characteristics, treatment and outcomes. We identified 39

33 patients; median age was 68 years and there was no gender predominance. 27/33 (82%) 40

of patients had serious intra-abdominal pathology, often requiring a procedure. Of those 41

who received antibiotics (28/33, 85%), median duration was 21.5 days. All-cause mortality 42

was 6% at 7 days, 12% at 30 days and 33% at 1 year. Of 26 isolates available for further 43

testing, all were identified as E. lenta by both commercially available MALDI-TOF MS 44

systems, and none were found to harbour a vanA or vanB gene. Of 23 which underwent 45

susceptibility testing, all were susceptible to amoxicillin-clavulanate, cefoxitin, 46

metronidazole, piperacillin-tazobactam, ertapenem and meropenem, 91% were susceptible 47

to clindamycin, 74% to moxifloxacin and 39% to penicillin. 48

49


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Background 50

51

Eggerthella lenta is an anaerobic, non-sporulating, gram-positive bacillus in the 52

Coriobacteriaceae family that was first described in 1935 by Arnold Eggerth [1]. It has since 53

been characterised in more detail [2] and was called Eubacterium lentum until genetic 54

analysis in 1999 placed it in its own distinct genus [3,4]. Two closely related species, 55

Paraeggerthella hongkongensis and Eggerthella senensis have also been described recently 56

[5-7]. The complete genomic sequence was first published in 2009 [8,9]. 57

58

Due to historical difficulties with laboratory identification, there is a paucity of published 59

data on the spectrum of disease that E. lenta causes and its optimal treatment. E. lenta is 60

part of the normal human intestinal microbiome [10] and has been most commonly 61

associated with infections from a gastrointestinal tract (GIT) source, which are often 62

polymicrobial [11]. Severe, disseminated disease has been described [12], and overall 63

mortality is significant, ranging from 36-43% [13,14]. 64

65

E. lenta is being increasingly recognised in the modern clinical microbiology laboratory due 66

to the widespread uptake of new technologies such as automated phenotypic identification 67

systems and molecular sequencing techniques. More recently, it has been demonstrated 68

that matrix assisted laser desorption ionization time of flight mass spectrometry (MALDI-69

TOF MS) is capable of rapidly identifying E. lenta [15-17]. 70

71

Antimicrobial susceptibility testing (AST) for anaerobes remains restricted to specialised 72

reference laboratories, so antimicrobial therapy for patients with infections due to 73


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anaerobic bacteria is often empiric. However given that resistance among anaerobic 74

organisms is increasing, susceptibility data is important to guide therapy [18-20]. There is 75

limited published data on the susceptibility profile of E. lenta, and breakpoints are 76

extrapolated from other species. In 2001, Stinear et al. were developing a rapid PCR based 77

screening method for detection of faecal carriers of vancomycin-resistant Enterococci (VRE) 78

when they identified the vanB locus in Eggerthella lenta, hypothesizing that anaerobic 79

bowel flora may represent the origin of VRE, and demonstrating that E. lenta is capable of 80

acquiring vancomycin resistance [21-23]. 81

82

In this study we have retrospectively reviewed 33 patients with E. lenta bacteremia, which 83

represents the largest published series to date. We describe their clinical features, 84

laboratory identification by both phenotypic and genotypic methods, and AST results. 85

86

Methods 87

88

Case Ascertainment & Clinical Data Collection 89

This study was conducted at Monash Health, a large healthcare network encompassing 5 90

campuses and over 2200 beds in Melbourne, Australia. Cases were identified by searching 91

our Microbiology database from January 2000 to September 2013 for all positive blood 92

cultures with Eubacterium lentum or Eggerthella lenta. Clinical data were collected from 93

medical records. Cases were classified as community onset if the positive blood culture was 94

collected within 72 hours of admission to hospital and there was no identifiable prior 95

health-care contact, health-care associated if within 72 hours and contact with the hospital 96

system within one month (eg. dialysis, admissions, procedures etc), and nosocomial if 97


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beyond 72 hours after admission. Measures of illness severity (Simplified Acute Physiology 98

Score, SAPS II [24] and Pitt Bacteremia Score [25]) as well as comorbidity (Charlson Index) 99

[26,27] were calculated. The study was approved by our Human Research Ethics Committee. 100

101

Blood Cultures 102

E. lenta was isolated from BacT/ALERT anaerobic blood culture bottles using the BacT/ALERT 103

3D automated microbial detection system (bioMerieux, Marcy, l’Etoile, France). The 104

number of hours (or days if hours not available) to detection of growth was recorded for 105

each case. 106

107

Isolate Identification 108

Available isolates were retrieved from storage and purity plated on Oxoid ANAERO plates 109

(Thermo Fisher Scientific, Basingstoke, United Kingdom). After 48 hours incubation, they 110

were identified via multiple methods. Phenotypic identification was performed based on 111

Gram stain, colony morphology and Vitek-2 ANC card (bioMerieux, Marcy, l’Etoile, France). 112

MALDI-TOF identification was performed using both available commercial systems Bruker 113

MS (Bruker Daltonics, Bremen, Germany) and Vitek MS (bioMerieux, Marcy l’Etoile, France; 114

formerly known as Axima@SARAMIS, Shimadzu). For isolates that could not be retrieved 115

from storage, original phenotypic identification was with RapID-ANA II System (Innovative 116

Diagnostic Systems, Inc, Atlanta, Ga.). 117

118

Bruker MS analysis was performed as previously described [28,29]. Each isolate was grown 119

on a chocolate agar plate for 72 hours anaerobically. The extended direct transfer method 120

was used whereby a single colony was touched and applied as a thin film directly onto a 121


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spot on a MALDI target plate, overlayed with 1 µL of 70% formic acid and allowed to dry at 122

room temperature. 1 µL of HCCA matrix solution (α-cyano-4hydroxy-cinnamic acid in 50% 123

acetonitrile, 47.5% water, 2.5% trifluoroacetic acid) (Sigma Aldrich) was added to each spot 124

and allowed to dry. E. coli (strain MB11464_1) was used as a calibration standard. 125

Spectrometric measurements were performed using the Microflex LT mass spectrometer 126

(Bruker Daltonik), and analyzed using the MALDI Biotyper software (version 3.1). As per 127

manufacturer instructions, the log score value of ≥2.0 met the criteria for species. A score of 128

1.700- 1.999 allowed identification correct to the level of genus, whilst a score <1.7 was 129

interpreted as showing no identity. 130

131

Vitek MS (bioMérieux) analysis was also performed as previously described [28,30]. Single 132

colonies from a 72-hour brain heart infusion agar plate were directly smeared onto wells of 133

the target plate; 0.5 µL of ready-to-use 40% formic acid (bioMérieux, Marcy l'Etoile, France) 134

was added to each sample and allowed to air dry at room temperature. 1 µL of ready-to-use 135

HCCA matrix solution (bioMérieux, Marcy l'Etoile, France) was added to each spot and 136

allowed to dry. E. coli ATCC 8739 strain was used as a calibration standard. To generate 137

protein mass fingerprints, the FlexiMass-DS target was loaded onto an adapter, prior to 138

insertion into the Vitek MS instrument. Raw spectra were generated with the Launchpad v. 139

2.8 software (Shimadzu-Biotech) and protein mass spectra fingerprints were then directed 140

to SARAMISTM (AnagnosTec GmbH) for analysis. Isolates were identified by comparison with 141

spectra in the reference MS database (containing 3178 Superspectrum). Identification at 142

genus or species level was considered reliable if the score was above the 75% confidence 143

level when matched to the superspectrum (SuperS), a consensus spectrum for that 144

Genus/Species compiled from reference spectra of that organism in the database. A result is 145


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also acceptable if a ‘comparison’ result is obtained indicating good match to one or more 146

reference spectra, but not the SuperS. 147

148

Bacterial DNA was extracted, amplified, and sequenced using the MicroSEQ 16S rRNA 149

Bacterial Identification Kit (Perkin Elmer Applied Biosystems Inc., Foster City, CA, USA). The 150

resulting 16S rRNA gene sequences were then analyzed with MicroSeq 500 software 151

(version 2.2.1). If the sequences were 99.0% compatible with the database, the identity 152

was acceptable to the level of species. 153

154

Antimicrobial susceptibility testing (AST) 155

AST was performed for E. lenta clinical isolates and E. lenta ATCC 43055 strain [31] using the 156

reference agar dilution procedure (Wadsworth method) on Brucella agar supplemented 157

with 5 g/mL haemin + 1 g/mL vitamin K + 5% (v/v) laked sheep blood, with a final volume 158

of 20 mL/plate (18 mL agar + 2 mL antibiotic). The ‘direct colony suspension’ method was 159

used [32,33]. Plates were incubated in an anaerobic chamber for 48 hours in an atmosphere 160

of 4-7% CO2. An inoculum of 105 cfu/spot was used. Antibiotic powders were supplied by 161

Sigma-Aldrich (penicillin, cefoxitin, ceftriaxone, vancomycin, piperacillin-tazobactam, 162

metronidazole, clindamycin), GlaxoSmithKline (amoxicillin-clavulanate), Merck (ertapenem), 163

Pfizer (tazobactam, tigecycline), Bayer (moxifloxacin) and AstraZeneca (meropenem). 164

165

Testing for teicoplanin was performed using the Etest method (bioMérieux), lot number 166

1002276240 according to the manufacturer’s recommended guidelines [34]. 167

168

Interpretative criteria 169


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Minimum inhibitory concentrations (MICs) were compared to standard Clinical & Laboratory 170

Standards Institute (CLSI) and European Committee on Antimicrobial Susceptibility Testing 171

(EUCAST) breakpoints (available only for Gram-positive anaerobes) and reported as 172

susceptible, intermediate, or resistant. 173

174

van gene PCR 175

After incubation for 48 hours, the ANAERO (Oxoid) plates were swabbed with a dry sterile 176

cotton swab and the organism was placed into sterile saline. Bacteria were pelleted at 177

10,000g for 10 minutes and the supernatant discarded. DNA was extracted from pellets of 178

bacteria using the PureLink DNA mini prep kit with the Gram-positive modification protocol 179

(Invitrogen). DNA was eluted using 200 L 10mM Tris pH 8.5. DNA concentrations were 180

determined by Qubit assay. Real-time PCR for vanA and vanB was performed using the 181

Roche LightCycler FastStart DNA Master HybProbe kit as described by Palladino et al [35]. 182

Control isolates were MLG043 (E. lenta containing vanB [23]) and clinical isolates of 183

Enterococcus faecium containing vanA and E. faecium containing vanB [22]. 184

185

Statistical analysis 186

Categorical data are presented as total numbers and percentages. Continuous data are 187

expressed as mean and standard deviation with median and range as required. 188

189

Results 190

191

Clinical data 192


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The clinical characteristics of 33 patients with E. lenta bacteremia are summarized in tables 193

1 & 2. Median age was 68 years (mean 62.4 23.9, range 11-95), and 17/33 (52%) were 194

male. Median length of stay was 11 days (24 ± 26, 1-94), and 10/33 (30%) patients were 195

admitted to the intensive care unit (ICU). The majority of patients (64%) had community-196

onset disease, and 39% had polymicrobial bacteremia, with a variety of enteric organisms 197

isolated. Blood cultures flagged positive after a median of 3 days incubation (2.85 ± 1.09, 1-198

5). Time-to-positivity could be determined for 30 patients; median time was 65.5 hours 199

(72.5 ± 25.2, 40.1-122.6). The most common presenting symptoms were fever (82%) and 200

abdominal pain (64%). 82% of patients had the GIT identified as the likely source. Median 201

SAPS-II score was 25 (27 ± 12.2, 6-64), Charlson Comorbidity score 2 (2.45 ± 2.25, 0-7) and 202

Pitt Bacteremia score 2 (2.15 ± 1.9, 0-8). 67% of patients had an abnormal white cell count 203

at the time of bacteremia (WCC, <4 or >11x109/L) and C-reactive protein (CRP) was elevated 204

in all 31 patients in whom it was measured. 205

206

Abdominal imaging was performed in more than half of patients, and in three-quarters an 207

abnormality was found. Treatment was dependent on the underlying pathology, with 21/33 208

patients undergoing at least one procedure. 12 patients underwent surgery, 3 had 209

radiologic-guided procedures (eg. drainage of abscess) and 11 proceeded to diagnostic 210

and/or therapeutic endoscopy. Antibiotic treatment was variable. 5 patients received no 211

antibiotic therapy, and all were alive at 1 year. These were generally patients with self-212

limiting illnesses who had clinically improved by the time their blood cultures had flagged 213

positive, so their treating clinicians had decided that antibiotic therapy was not indicated. Of 214

those treated with antibiotics, median duration was 21.5 days (36.7 ± 56.2, 2-301). A wide 215

range of antibiotics were used, most often metronidazole-containing regimens (8 patients) 216


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or amoxicillin-clavulanate (6 patients). 1-year follow-up was available for all patients. All-217

cause mortality was 6% at 7 days, 12% at 30 days, and 33% at 1 year. 218

219

Isolate identification 220

28 isolates were available for comprehensive testing. All were confirmed as E. lenta using 221

the Vitek-2 ANC card and 16S rRNA gene sequencing. 5 older isolates originally identified by 222

Rapid-ANA could not be revived. 26 isolates were available for testing in the Bruker MS 223

system, which accurately identified all 26 to the genus level (>1.7), including 19/26 as E. 224

lenta (>2.0). 23 isolates were tested in the Biomerieux MALDI system; all were identified as 225

E. lenta with a 99.9% confidence value. 226

227

Antimicrobial susceptibility testing (AST) 228

Table 3 shows the AST results for 23 E. lenta isolates. Applying CLSI interpretative criteria 229

[32], all isolates were susceptible to amoxicillin-clavulanate, cefoxitin, metronidazole, 230

ertapenem, piperacillin-tazobactam, and meropenem. Susceptibility to clindamycin was 231

91%, moxifloxacin 74% and penicillin 39%; all were resistant to ceftriaxone. No CLSI 232

breakpoints are available for tigecycline, vancomycin or teicoplanin however all isolates had 233

an MIC 1mg/L. Using EUCAST breakpoints, interpretations were similar except for penicillin 234

and piperacillin-tazobactam, to which no isolates were susceptible [36]. 235

236

Van gene PCR 237

23 E. lenta isolates were tested; all were negative for vanA and vanB genes. All positive 238

controls tested positive. 239

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Discussion 241

242

Our study represents the largest, most comprehensive study of patients with E. lenta 243

bacteremia described in the literature to date. Our findings suggest that E. lenta bacteremia 244

is associated with a spectrum of disease, ranging from asymptomatic bacteremia (generally 245

seen in the setting of a transient gastrointestinal illness), to part of polymicrobial 246

bacteremia from an intra-abdominal source (eg. perforated viscus), to severe 247

monomicrobial disseminated disease. A significant proportion of our cohort had serious GIT 248

pathology, often requiring surgical or radiologic intervention and ICU admission to achieve 249

cure. This suggests that when identified in blood cultures, E. lenta should not necessarily be 250

dismissed as a contaminant but rather represent a trigger for more detailed evaluation of 251

the patient and appropriate abdominal diagnostic imaging. 252

253

Published reports of E. lenta bacteremia are outlined in Table 4. Our cohort has some 254

differences compared to previous case series. Venugopal et al [14] provided detailed clinical 255

information on 25 cases, but no microbiological data. They reported a higher proportion of 256

healthcare onset bacteremias (50%). Only 44% of their patients had an abdominal source, 257

and 40% had a skin or soft tissue source, most often infected decubitus ulcers, associated 258

with high rates of hospitalized, bedridden patients (44%). They identified ICU admission and 259

absence of fever on day of admission as risk factors for increased 30-day mortality, which 260

was much higher than in our series (36% vs. 12%). Interestingly of our 10 patients admitted 261

to ICU, all were alive at 30 days, and of the 4 patients dead at 30 days, two were febrile on 262

admission. Lee et al [13] describe 7 patients with E. lenta bacteremia. They had a 263

comparatively lower median age of 56, 71% were community onset, and 43% of patients 264


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had an underlying malignancy. They did not identify the source of infections, although 30% 265

had ‘abdominal symptoms’. Lau et al [5,6] described 5 cases of E. lenta bacteremia, 3 of 266

which were polymicrobial, and 2 of which occurred in patients with infected decubitus 267

ulcers. 268

269

In addition to these series, there are 6 published case reports of patients with E. lenta 270

bacteremia. Two describe severe, disseminated disease with multifocal abscesses requiring 271

extended courses of intravenous antibiotics and/or surgical drainage to cure [12,37]. There 272

are other published cases of severe E. lenta infection without definite bacteremia, including 273

reports of frontal sinusitis [38], pyomyositis [39], cutaneous abscesses [40], spondylodiscitis 274

[41], and liver abscess [42]. E. lenta has also been implicated in the pathogenesis of bacterial 275

vaginosis [43-45] and linked to appendicitis in children [46]. 276

277

Identification of E. lenta by MALDI-TOF was initially not reliable due to the limited number 278

of anaerobic bacteria included in earlier versions of the databases [28,47]. In 2011 Justesen 279

et al. [30] reported that one E. lenta isolate was identified by the Bruker MS using an 280

updated database, but not the Shimadzu MALDI-TOF MS. In more recent studies, E. lenta 281

has been correctly identified using the Bruker MS: 2/2 isolates to species level [15], 8/8 282

isolates to genus and 6/8 isolates to species level [16], and 8/10 isolates to genus and 2/10 283

isolates to species level [17]. Our study shows that E. lenta can be reliably identified using 284

both available commercial MALDI-TOF MS platforms. 285

286

Access to anaerobic AST is problematic however, and lack of available data has led to 287

breakpoint extrapolation from other anaerobic species to E. lenta. Our antimicrobial 288


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susceptibility results are consistent with previous studies (table 5), which have shown that 289

isolates are frequently resistant to penicillin, have variable susceptibility to clindamycin and 290

moxifloxacin, but remain susceptible to amoxicillin-clavulanate, cefoxitin, metronidazole 291

and carbapenems. The difference between the EUCAST (S≤8/4, R>16/4 mg/L) and CLSI 292

(S≤32/4, I=64/4, R≥128/4 mg/L) breakpoints for piperacillin-tazobactam are significant, and 293

given the high piperacillin-tazobactam MICs of our isolates has resulted in significant 294

differences in the interpretations of our susceptibility results. Neither criterion is supported 295

by clinical outcome studies, and it may well be that piperacillin-tazobactam has activity 296

against E. lenta. Although vanB has been detected previously in E. lenta in our laboratory 297

[21-23] and high vancomycin MICs have been reported in the literature [48], we did not 298

detect the vancomycin resistance genes vanA or vanB or phenotypic resistance in any of the 299

isolates that were tested. 300

301

In summary, Eggerthella lenta appears to be a significant human pathogen that is often 302

associated with serious GIT pathology. If the diagnosis is not apparent at the time of 303

isolation of this organism in blood cultures, detailed investigation of the abdomen should be 304

undertaken. E. lenta is likely to be increasingly identified given the ease and rapidity of 305

MALDI-TOF MS and the uptake of this technology into many clinical microbiology 306

laboratories worldwide. The most reliable antibiotic treatment options appear to be 307

cefoxitin, metronidazole, amoxicillin-clavulanate and the carbapenems, with the role of 308

piperacillin-tazobactam currently unclear. However with rising rates of resistance in 309

anaerobes increasingly reported, AST should be considered to guide therapy particularly in 310

serious infections. 311

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Acknowledgements 313

314

We would like to thank the Microbiology Departments at Monash Health (particularly 315

Richard Streitberg and Megan Wieringa) and Auckland Hospital (Patricia Dove, Audrey Tiong 316

and Nadia Al Anbuky). 317

318

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507


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Table 1: E. lenta bacteremia patient characteristics and clinical features (n=33).

Clinical characteristic Details

Demographics Age (Mean ± standard deviation) Male sex Length of stay (days) Admission to intensive care Admitting unit Medical Surgical Other

62.4 ± 23.9 (median 68, range 11-95) 17 (52%) 23.6 ± 26.3 (11, 1-94) 10 (30.3%) 16 (48.5%) 13 (39.4%) 4 (12.1%)

Onset Community Healthcare-associated Nosocomial

21 (63.6%) 2 (6.1%) 10 (30.3%)

Microbiological characteristics Anaerobic bottle only Day blood culture flagged positive Time-to-positivity (hours) Polymicrobial bacteraemia

33 (100%) 2.85 ± 1.09 (3, 1-5) 72.5 ± 25.2 (65.6, 40.1-122.6) 13 (39.4%)

Symptoms Fever Abdominal pain Vomiting Diarrhoea

27 (81.8%) 21 (63.6%) 12 (36.4%) 8 (24.2%)

Severity scores Simplified Acute Physiology Score (SAPS-II) Pitt bacteraemia score

27 ± 12.2 (25, 6-64) 2.15 ± 1.9 (2, 0-8)

Medical comorbidities Diverticular disease Colonic polyps Gastrointestinal malignancy Inflammatory bowel disease Chronic liver disease Gastrointestinal instrumentation or surgery within 30d Any chronic gastrointestinal pathology Immunosuppression Diabetes Renal failure Non-gastrointestinal malignancy No significant comorbidities Charlson comorbidity score

8 (24.2%) 5 (15.2%) 4 (12.1%) 1 (3%) 1 (3%) 5 (15.2%) 19 (57.6%) 5 (15.2%) 9 (27.3%%) 12 (36.4%) including 3 (9.1%) dialysis 4 (12.1%) 5 (15.1%) 2.45 ± 2.25 (2, 0-7)

Likely source Hepatobiliary (liver, pancreas, gallbladder, biliary) Upper gastrointestinal tract Colon Bowel (unable to localize) Appendix Skin or soft tissue Other

3 (9.1%) 5 (15.2%) 10 (30.3%) 5 (15.2%) 4 (12.1%) 3 (9.1%) 3 (9.1%)

Investigations Haemoglobin (RR: 119-160g/L) White cell count (RR: 4.0-11.0x10

9/L)

Albumin (RR: 35-45g/L) C-reactive protein (RR: 0-5mg/L) Abdominal CT (done/abnormal) Abdominal ultrasound (done/abnormal)

112 ± 24 (112, 77-167) 14.9 ± 8.7 (3.2-39) 27 ± 6.8 (26, 14-39) 138.5 ± 107.1 (26, 14-39) 17 (51.5%) / 13 (39.4%) 9 (27.3%) / 6 (18.2%)

Treatment No directed treatment Antibiotic therapy Duration of antibiotics if treated (days) Surgical procedure Radiologic procedure Endoscopy performed (diagnostic and/or therapeutic)

5 (15.2%) 28 (84.8%) 36.7 ± 56.2 (21.5, 2-301) 12 (36.4%) 3 (9.1%) 11 (33.3%)

Outcome 7-day mortality 30-day mortality 1-year mortality

2 (6.1%) 4 (12.1%) 11 (33.3%)

Readmission Within 3 months Within 12 months

11 (33.3%) 16 (48.5%)


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Table 2: Individual patient diagnosis and treatment information.

Case Age/Sex Diagnosis

Treatment details

Outcome Procedure Antibiotic ^

Duration (days)

1 57/F Viral gastroenteritis None Metronidazole 10 Alive at 12 months

2 75/F Metastatic gastric cancer Distal gastrectomy & roux-en-y reconstruction Trimethoprim 16 Death at 9 months

3 44/F Chronic cholelithiasis Cholecystectomy None 0 Alive at 12 months

4 68/F Urinary tract sepsis Sigmoidoscopy Amoxycillin & metronidazole 12 Alive at 12 months

5 85/F Sepsis of unknown source None Ceftriaxone 8 Alive at 12 months

6 87/M Diabetic foot infection None Ticarcilllin-clavulanate 12 Death on day 6

7 17/F Faecal peritonitis secondary to anastomotic leak Laparotomy, washout, end-ileostomy Meropenem 71 Alive at 12 months

8 68/M Perforated gangrenous appendicitis Open appendectomy Ceftriaxone & metronidazole 8 Alive at 12 months

9 57/F Perforated sigmoid diverticulum Pelvic washout + Hartmann’s Amoxycillin-clavulanate 48 Alive at 12 months

10 81/M Diverticulitis Colonoscopy Ciprofloxacin & metronidazole 19 Death at 8 months

11 81/M Prosthetic hip joint infection None Ticarcillin-clavulanate 2 Death on day 17

12 12/M Gastroenteritis None None 0 Alive at 12 months

13 45/F Diverticulitis Colonoscopy Cephalexin & metronidazole 21 Alive at 12 months

14 94/M Ischial osteomyelitis Debridement Cotrimoxazole & ciprofloxacin 301 Alive at 12 months

15 81/M Acute appendicitis Laparoscopic appendectomy Metronidazole 3 Alive at 12 months

16 37/M Diverticular abscess with colo-vesical fistula Gastroscopy Meropenem 32 Death on day 24

17 11/M Portal vein thrombophlebitis None Clindamycin & ciprofloxacin 43 Alive at 12 months

18 95/F Myocardial infarction Gastroscopy Ceftriaxone & azithromycin 4 Death on day 4

19 29/F Labour None None 0 Alive at 12 months

20 77/M Colitis Colonoscopy Amoxicillin-clavulanate 42 Alive at 12 months

21 70/M L1-2 discitis, osteomyelitis, paravertebral abscess, psoas abscess & meningitis*

CT-guided drainage Meropenem & linezolid 90 Alive at 12 months

22 47/M Perforated appendix Laparoscopic appendectomy Amoxycillin-clavulanate 18 Alive at 12 months

23 78/F Viral gastroenteritis None None 0 Alive at 12 months

24 66/M Stroke Colonoscopy Ceftriaxone & metronidazole 44 Alive at 12 months

25 87/F Exacerbation of COPD None Amoxycillin & doxycycline 6 Death at 11 months

26 88/F Colonic arterio-venous malformations, diverticular disease

Colonoscopy Amoxicillin-clavulanate 7 Death at 7 months

27 66/M Infected femoral artery puncture site, ischemic gut

Debridement & femoral arterial repair; gastroscopy, colonoscopy & push enteroscopy

Meropenem 43 Death at 3 months

28 72/M Biliary sepsis, pancreatic cancer Percutaneous transhepatic cholangiogram Amoxycillin-clavulanate & metronidazole

46 Death at 4 months

29 30/M Gastroenteritis None None 0 Alive at 12 months

30 87/M Sigmoid diverticulitis; C. difficile colitis None Metronidazole 23 Death at 3 months

31 45/F Left thigh abscess Debridement & washout of abscess Amoxycillin-clavulanate 23 Alive at 12 months

32 65/F Non small cell lung cancer Right upper/middle lobectomy; sigmoidoscopy Piperacillin-tazobactam 54 Alive at 12 months

33 57/F Entero-cutaneous fistula Laparotomy, mesh removal, fistula repair, cholecystectomy Piperacillin-tazobactam 22 Alive at 12 months

^as most patients received multiple antibiotics, those displayed are the ones used for the longest time; *previous described case report [12]


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Table 3: Antimicrobial susceptibility testing results for 23 isolates plus control strain.

Patient isolate

Minimum inhibitory concentration, mg/L (interpretive criteria)

PEN FOX* CRO AMC TZP CLI MOX* MET ERT MEM TGC VAN^ TEC

ATCC43055 0.5 (S/I) 8 (S) >128 (R) 1 (S) 16 (S/I) 0.25 (S) 0.25 (S) 2 (S) 1 (S) 0.5 (S) 0.5 1 (S) 0.12 3 1 (I/R) 8 (S) >128 (R) 1 (S) 16 (S/I) 1 (S) 0.5 (S) 2 (S) 1 (S) 0.5 (S) 0.5 1 (S) 0.12 6 1 (I/R) 8 (S) >128 (R) 1 (S) 16 (S/I) 0.25 (S) 4 (I) 2 (S) 1 (S) 0.5 (S) 0.5 1 (S) 0.12 8 0.5 (S/I) 4 (S) 128 (R) 1 (S) 16 (S/I) 0.25 (S) 4 (I) 2 (S) 1 (S) 0.25 (S) 0.5 1 (S) 0.12 9 1 (I/R) 8 (S) 128 (R) 1 (S) 16 (S/I) 0.5 (S) 8 (R) 2 (S) 1 (S) 0.5 (S) 0.5 1 (S) 0.12

10 0.5 (S/I) 8 (S) 128 (R) 1 (S) 16 (S/I) 0.25 (S) 4 (I) 2 (S) 1 (S) 0.25 (S) 1 1 (S) 0.12 11 1 (I/R) 16 (S) >128 (R) 1 (S) 32 (S/R) 0.5 (S) 0.25 (S) 2 (S) 1 (S) 0.5 (S) 0.5 1 (S) 0.12 12 0.5 (S/I) 8 (S) >128 (R) 1 (S) 16 (S/I) 0.25 (S) 0.5 (S) 2 (S) 1 (S) 0.5 (S) 0.5 1 (S) 0.12 13 1 (I/R) 8 (S) >128 (R) 1 (S) 16 (S/I) 0.25 (S) 0.25 (S) 2 (S) 1 (S) 0.5 (S) 0.5 1 (S) 0.12 14 1 (I/R) 8 (S) >128 (R) 1 (S) 16 (S/I) 0.12 (S) 0.25 (S) 2 (S) 1 (S) 0.5 (S) 1 1 (S) 0.25 16 0.5 (S/I) 8 (S) >128 (R) 1 (S) 16 (S/I) 2 (S) 0.25 (S) 2 (S) 1 (S) 0.5 (S) 0.5 0.5 (S) 0.12 17 1 (I/R) 16 (S) >128 (R) 1 (S) 32 (S/R) 0.5 (S) 0.25 (S) 2 (S) 1 (S) 0.5 (S) 0.5 1 (S) 0.12 18 0.5 (S/I) 8 (S) >128 (R) 1 (S) 16 (S/I) 0.25 (S) 1 (S) 2 (S) 1 (S) 0.5 (S) 1 1 (S) 0.12 19 0.5 (S/I) 8 (S) >128 (R) 1 (S) 16 (S/I) 32 (R) 0.25 (S) 2 (S) 1 (S) 0.25 (S) 0.5 1 (S) 0.12 21 1 (I/R) 8 (S) >128 (R) 1 (S) 16 (S/I) 8 (R) 64 (R) 2 (S) 1 (S) 0.5 (S) 0.5 1 (S) 0.12 22 0.5 (S/I) 8 (S) >128 (R) 1 (S) 16 (S/I) 0.25 (S) 0.25 (S) 2 (S) 1 (S) 0.5 (S) 1 1 (S) 0.25 23 0.5 (S/I) 8 (S) >128 (R) 1 (S) 16 (S/I) 0.25 (S) 0.25 (S) 2 (S) 1 (S) 0.5 (S) 0.5 1 (S) 0.25 24 1 (I/R) 8 (S) >128 (R) 1 (S) 16 (S/I) 0.25 (S) 4 (I) 2 (S) 1 (S) 0.5 (S) 1 1 (S) 0.25 25 1 (I/R) 16 (S) >128 (R) 1 (S) 16 (S/I) 0.25 (S) 0.25 (S) 2 (S) 1 (S) 0.5 (S) 0.5 1 (S) 0.12 26 1 (I/R) 8 (S) >128 (R) 1 (S) 16 (S/I) 0.12 (S) 2 (S) 2 (S) 1 (S) 0.25 (S) 0.5 1 (S) 0.25 27 1 (I/R) 8 (S) >128 (R) 1 (S) 16 (S/I) 1 (S) 0.25 (S) 2 (S) 1 (S) 0.5 (S) 0.5 1 (S) 0.25 28 1 (I/R) 8 (S) >128 (R) 1 (S) 32 (S/R) 0.5 (S) 0.25 (S) 2 (S) 1 (S) 0.5 (S) 0.5 1 (S) 0.12 29 1 (I/R) 8 (S) >128 (R) 1 (S) 32 (S/R) 0.5 (S) 0.25 (S) 2 (S) 1 (S) 0.5 (S) 0.5 1 (S) 0.12 30 0.5 (S/I) 8 (S) >128 (R) 1 (S) 16 (S/I) 0.25 (S) 0.25 (S) 2 (S) 1 (S) 0.5 (S) 0.5 1 (S) 0.12

(n=23) No. (%)

susceptible 9 (39%) 23 (100%) 0 23 (100%) 23 (100%) 21 (91%) 17 (74%) 23(100%) 23(100%) 23(100%) NB 23(100%) NB

PEN, penicillin; FOX, cefoxitin; CRO, ceftriaxone; AMC, amoxicillin-clavulanate; TZP, piperacillin-tazobactam; CLI, clindamycin; MOX, moxifloxacin; MET, metronidazole; ERT, ertapenem; MEM, meropenem; TGC, tigecycline; VAN, vancomycin; TEC, teicoplanin. S, susceptible; I, intermediate; R, resistant ; CLSI / EUCAST (where interpretations are discordant) *CLSI breakpoint only, ^EUCAST breakpoint only, NB: no breakpoints available


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Table 4: Previously reported case series and case reports of E. lenta bacteremia.

Ref. Age/Sex Diagnosis Treatment details

Outcome Procedure Antibiotic Duration

Case series

14 (n=25)

36-90/ 5 M

Decubitus ulcer (8 patients)

NS

4 piperacillin/tazobactam, 1 metronidazole & ciprofloxacin, 1 ampicillin/sulbactam – amoxicillin/clavulanate, 1 vancomycin, ceftazidime & metronidazole, 1 ceftriaxone & metronidazole

NS

50% survival

36-83/ 4 M

Intra-abdominal sepsis (10 patients)

Different regimens including piperacillin/tazobactam, amoxicillin/clavulanate, ciprofloxacin or ceftriaxone & metronidazole, imipenem/cilastatin

80% survival

72,78/F Urinary source (2 patients) Ceftriaxone-ciprofloxacin; vancomycin & metronidazole 50% survival

51/M Gluteal abscess & left hip osteomyelitis Piperacillin/tazobactam Survived

81/M, 72/F

Not stated (2 patients) Metronidazole & ciprofloxacin; none 50% survival

71/F Gastrointestinal bleed None Death

79/F Percutaneous endoscopy gastrostomy site infection Clindamycin Survival

13 (n=7)

Median 56 (51-93)

Two patients had ‘abdominal symptoms’ NS

2 received penicillins, 4 cephalosporins, 1 metronidazole NS

3 deaths within 60 days

5,6 (n=5)

69/F Lung cancer, intestinal obstruction

NS

Metronidazole

NS

Cured

74/M Alcoholic cirrhosis, gastrointestinal bleeding Ticarcillin/clavulanate Died

75/F Pelvic inflammatory disease Cefuroxime + metronidazole Cured

87/F Infected decubitus ulcer Cefuroxime + cloxacillin Died

84/F Infected decubitus ulcer Cefuroxime + metronidazole + netilmicin Cured

49 (n=2)

82/M Intestinal perforation Colostomy Piperacillin/tazobactam & ciprofloxacin, imipenem 1 month Favourable

33/M Acute appendicitis & parietal abscess Appendicectomy Amoxicillin/clavulanate Unclear Favourable*

Case reports

12 70/M Spondylodiscitis, osteomyelitis, meningitis, and multiple abscesses

Drainage of subdiaphragmatic and right psoas collections

Meropenem & linezolid 3 months Favourable

37 19/M Multifocal abscesses – brain, liver, spleen, lung Laparoscopic cholecystectomy iv penicillin G & oral metronidazole 5 months Favourable

50 53/M Metastatic rectal cancer None iv cefotaxime and amikacin – oral antibiotics >4 days Favourable*

51 21/F Crohn’s disease; small bowel obstruction Ileo-caecal resection & repair of anastomotic leak

Vancomycin & piperacillin/tazobactam – vancomycin, meropenem & metronidazole – meropenem

3 weeks Favourable*

52 86/F Infected decubitus ulcer None Cefuroxime – amoxicillin >2 days Favourable*

53 68/F Tubo-ovarian abscess; post-operative bowel leak Hysterectomy, salpingo-oophrectomy; sigmoid resection & Hartmann’s, drainage of perisplenic collection

Ampicillin, gentamicin, metronidazole – vancomycin, ticarcillin/clavulanate, metronidazole

>1 month Favourable*

*Alive and well at hospital discharge; long-term follow-up not reported; ^two publications describing the same patient cohort NS, not stated


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Table 5: E. lenta minimum inhibitory concentration (MIC) ranges and susceptibility rates reported in the literature. All studies utilized CLSI agar dilution methodology and CLSI breakpoints.

Reference

(year) Number of

isolates

Minimum inhibitory concentration range (mg/L), % susceptible

PEN FOX CRO AMC TZP CLI MOX MET ERT MEM TGC VAN

48 (2013) 20 0.125-0.5 1-8

54 (2013) 10 8-16, 100 16-64, 90 0.25-0.5, 100 0.5-1, 100 1-2, 100 0.5

13 (2012) 8 1-4, 0 32-64, 87.5 0.5->32, 37.5 0.25->32, 75 1-2, 100 0.5, 100 0.12-0.25 0.5-2

55 (2009) 17 0.5-1 8-16 0->32 0.25-0.5

33 (2006) 10 ≤0.06-4, 10 0.5-8, 100 ≤0.12-256, 30 ≤0.06-1, 100 ≤0.12-32, 100 ≤0.06-1, 100 0.12-1, 100 ≤0.06-0.5, 100

56 (2005) 9 0.12-0.5* 0.12-0.5 0.5-1

57 (2005) 14 ≤0.12-32 ≤0.06-1 0.25-2

58 (2004) 10 ≤0.03-0.5* ≤0.03-32 0.5-1

59 (2004) 20 0.25-32

95 0.12-8

90 0.03-1

100 0.06-4

100

60 (2003) 8 1* 1 0.06-0.25 0.25-0.5 ≤0.125-0.5 1-2

61 (2003) 12 ≤0.06-1* ≤0.06-2 ≤0.06-0.5 ≤0.06-1 ≤0.06->64

62 (2003) 17 0.25-2* 1-16 ≤0.03-1 0.125-1 0.5-2

63 (2002) 16 0.25->64 ≤0.125-32 0.03->32 0.25->16 0.06-2 0.06-4

64 (1998)

Group A, 25 2*, 0 32-128, 0 0.5-4, 88 1-2, 100

Group B, 6 0.5*, 100 1, 100 ≤0.06, 100 1-2, 100

PEN, penicillin (*ampicillin); FOX, cefoxitin; CRO, ceftriaxone; AMC, amoxicillin-clavulanate; TZP, piperacillin-tazobactam; CLI, clindamycin; MOX, moxifloxacin; MET, metronidazole; ERT, ertapenem; MEM, meropenem; TGC, tigecycline; VAN, vancomycin


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