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Bacillus cereus bacteraemia: comparison between haematologic and nonhaematologic patients
Accepted Manuscript Bacillus cereus bacteraemia: A Comparison between haematological and nonhaematological patients S. Tusgul, G. Prod’hom, L. Senn, R. Meuli, P.-Y. Bochud, S.G. Giulieri PII:
S2052-2975(16)30123-8
DOI:
10.1016/j.nmni.2016.11.011
Reference:
NMNI 254
To appear in:
New Microbes and New Infections
Received Date: 2 August 2016 Accepted Date: 4 November 2016
Please cite this article as: Tusgul S, Prod’hom G, Senn L, Meuli R, Bochud P-Y, Giulieri SG, Bacillus cereus bacteraemia: A Comparison between haematological and non-haematological patients, New Microbes and New Infections (2016), doi: 10.1016/j.nmni.2016.11.011. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
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Bacillus cereus bacteraemia: a comparison between haematological and non-haematological patients 1,2
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S. Tusgul , G. Prod’hom , L. Senn , R. Meuli , P-Y. Bochud , S. G. Giulieri . 1
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Service of Infectious Diseases and Service of Internal Medicine, Department of Medicine,
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Institute of Microbiology, Department of Laboratories, Service of Hospital Preventive
Medicine, Department of Radiology, Lausanne University Hospital, Lausanne, Switzerland.
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Running title: B. cereus bacteraemia in haematological patients
Keywords: Bacillus cereus; bacteraemia; intravascular catheter; central nervous system;
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neutropenia
Abstract: 228 words Main text: 2473 words
Figures: 3 References: 31
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Correspondence:
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Tables: 2
Stefano Giulieri, MD
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Infectious Diseases Service Department of Medicine
Lausanne University Hospital Rue du Bugnon 46
CH-1011 Lausanne
[email protected]
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ABSTRACT
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Bacillus cereus bacteraemia can be severe, especially among patients with haematological
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malignancy. We retrospectively reviewed first episodes of true B. cereus bacteraemia (> 1
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positive bottle plus signs of infection) at our institution between 1997 and 2013 with the aim to
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compare haematological versus non-haematological patients and analyse episodes with
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complicated outcome. Among 56 episodes of positive blood cultures for B. cereus, 21 were
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considered significant. Median age was 54 years (range 23-82). Ten patients (48%) had a
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haematological malignancy; all were neutropenic at the time of B. cereus bacteraemia. Non-
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haematological patients were either intravenous drug users (IVDU) (N=3, 14%), polytraumatized
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(N=3, 14%) or had multiple chronic comorbidities (N=5, 24%). Most episodes were hospital-
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acquired (15, 71%). Sources of bacteraemia were intravascular catheter (11 cases, 52%),
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digestive tract (6, 29%), drug injection (3, 14%) and wound (1, 5%). Adequate antibiotic therapy
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was given to 18 (86%) patients during a median of 17 days (range 2-253). The intravascular
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catheter was removed in 8 cases (42%). Three haematological patients had a complicated
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course with neurological complications (meningoencephalitis and cerebral abscesses).
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Complications appeared to be associated with catheter infection (100% of complicated cases vs.
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29% of non complicated cases). In conclusion, B. cereus bacteraemia can have a complicated
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course in a subset of patients, mainly those with haematological malignancy. Catheter infection
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may be associated with a worse outcome with frequent neurological complications.
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Introduction
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Bacillus cereus is a spore-building Gram-positive rod, that can survive in extreme environmental
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conditions and persist in the hospital (1, 2). While B. cereus is often considered as a
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contaminant, it can also cause significant disease, which manifest in three distinct syndromes:
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food intoxication, localized infection and bacteraemia, the latest being sometimes associated
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with haematogenous complications (e.g. endophtalmitis, cerebral abscesses) (3). Certain clinical
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manifestations like necrotizing infections (e.g. endophtalmitis, fasciitis) might be caused by the
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release of to exotoxins such as proteases, phospholipases and hemolysins (2, 4, 5).
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It is widely recognised that haematological patients have a higher risk for invasive B. cereus
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infection (5-8), but limited data are available on other risk factors for complications of B. cereus
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bacteraemia (such as mortality and metastatic infections). The aims of the present study were to
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compare episodes between haematological and non-haematological patients and to identify
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possible risk factors that may predispose to a complicated course of B. cereus bacteraemia.
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Patients and methods.
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Definition of cases. Cases with > 1 positive blood culture bottle for B. cereus occurring at our
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institution (a 1500-bed university hospital) between January 1997 and April 2013 were identified
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through the microbiological database. We included all patients presenting with a first episodes of
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true B. cereus bacteraemia, defined as > 1 positive blood culture bottles and signs of sepsis (9)
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or localized infection.
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Data collection. The following data were extracted from patients charts: demographic
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characteristics, site of hospitalization, underlying disease, presence of neutropenia (neutrophil
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count < 0.5 x 109/L), previous chemotherapy, treatment with corticoids or other
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immunosuppressive drugs, source of bacteraemia, presence of a central venous catheter (CVC)
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and its management, symptoms and signs of sepsis and localized infection and antibiotic
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treatment. Outcome criteria were mortality at 30 days, presence of haematogenous
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complications (meningitis, cerebral abscesses, infective endocarditis or endophtalmitis), and
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relapse of B. cereus bacteraemia.
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The study was approved by the local Institutional Review Board of the University of Lausanne,
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Switzerland.
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Laboratory methods/Identification and antibiotic susceptibility. B. cereus was identified
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from blood cultures through Gram stain appearance, colony morphology and hemolysis on blood
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agar, positive lecithinase on egg yolk agar or Matrix-Assisted Laser Desorption/Ionization
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(MALDI-TOF). Antimicrobial susceptibility testing was performed using disk diffusion and
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interpreted according to Clinical and Laboratory Standards Institute (CLSI) criteria used for
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staphylococci (due to the absence of criteria for Bacillus species other than B. anthracis) until
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2010 and E-test interpreted with non specific European Committee for Antimicrobial
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Susceptibility Testing (EUCAST) criteria for Gram-positive bacteria was used thereafter.
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Definitions of source of bacteraemia, adequate antibiotic treatment and complicated
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bacteraemia. Bacteraemia was categorised as hospital-onset if it occurred > 48 h after
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admission. Source of B. cereus bacteraemia was ascertained by using the following criteria.
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Catheter-related bloodstream infection (CRBSI): no apparent source for the blood stream
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infection except the catheter or positive catheter tip culture for B. cereus (> 15 cfu). Digestive
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tract: significant abdominal disease confirmed by imaging (e.g. ileus, perforation) or neutropenic
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enterocolitis (clinical or radiological signs). Drug injection: active intravenous drug use and
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temporal association between B. cereus bacteraemia and drug injection. Open fracture/wound:
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sign of infection or wound culture positive for B. cereus.
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Antibiotic treatment was considered adequate if the B. cereus isolate was susceptible to the
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antimicrobial prescribed (or there was a high likelihood of susceptibility based on published data
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(10)) and dosed in accordance with current recommendation. Antibiotic treatment was
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categorized as empirical if administered within 24 hours of collection of the blood culture, and
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before susceptibility was known. Targeted antibiotic treatment referred to the
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treatment continued or initiated on the day that antibiogram results were reported.
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Hematogenous complications were defined by using following criteria. Meningitis: at least one
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clinical sign (headache, neck stiffness, impaired level of consciousness) associated with
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pleocytosis (> 4 white blood cells/mm3). Brain abscess: at least one clinical sign (headache,
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focal neurological deficit, impaired level of consciousness) and radiological evidence. Infective
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endocarditis: definite diagnosis according to the Duke criteria (11). Endophtalmitis: clinical signs
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and positive ophthalmologic examination.
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Statistical analysis. For comparison between groups we used the Fisher’s exact test for
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categorical variables, and the Mann-Whitney test for continuous variables. Calculations were
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performed with Stata, version 12.0 (StataCorp, College Station, TX, USA) and GraphPad Prism,
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version 6.00 (GraphPad Software, Inc., San Diego, CA, USA).
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Results
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Clinical characteristics. During the study period, we identified 56 episodes of positive blood
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cultures for B. cereus, among which 33 were excluded due to contamination (N=31), relapse
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(N=1) and missing clinical data (N=1) and 21 retained as true bacteraemia. Among those,
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median patient age was 54 years (range 23-82) and the majority were men (N=14, 67%).
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Underlying haematological malignancy was observed in 10 patients (48%), chronic disease
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associated with some form of immunosuppression (autoimmune hepatitis, solid tumour, end-
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stage renal disease, diabetes mellitus) in 5 (24%), intravenous drug use (IVDU) in 3 (14%) and
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polytrauma in 3 (14%). Six patients (29%) presented a breakthrough bacteraemia while on
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antibiotic treatment with cephalosporins or penicillins. The annual incidence of B. cereus
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bacteraemia stratified according to underlying condition is shown in Figure 1. Of note, three
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cases among haematological patients clustered in the first months of 2013. However, no common source of infection was identified.
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Most episodes were hospital-onset (71%). Community-onset episodes were either associated
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with IVDU or end-stage renal disease. Fever was present in 18 patients (86%), abdominal
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symptoms (i.e. abdominal pain, vomiting, diarrhea) in 6 (29%), neurological symptoms (including
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confusion, lethargy, generalized headache, blurred vision, photopsia, dysarthria,
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dysdiadochokinesia, hemiparesis, hemineglect) in 4 (19%).
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Source of B. cereus bacteraemia. The source of bacteraemia was CRBSI in eleven cases
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(52%): short-term CVC (5), port (3), tunnelled hemodialysis catheter (2), arterial catheter (1). In
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six cases (29%) bacteraemia originated from the digestive tract: all patients with an abdominal
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source had either abdominal symptoms (4) or a pathological CT (4: bowel wall thickening, ileus).
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Finally source of infection was drug use in three (14%) and wound infection (confirmed by
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multiple positive wound swab cultures) in one (5%).
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Microbiology. Concomitant pathogens were identified in 7 episodes of B. cereus bacteraemia.
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The frequency of polymicrobial infections was similar between haematological and non-
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haematological patients. Cerebrospinal fluid (CSF) was collected in 2 cases (IVDU-associated
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bacteraemia and meningoencephalitis) and was sterile. Results of susceptibility testing are
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shown in figure 2. All tested isolates were susceptible to vancomycin (20/20), fluoroquinolones
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(16/16), gentamicin (9/9) and co-trimoxazole (8/8), while they were resistant to penicillin (18/18)
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and ceftriaxone (16/16). Imipenem susceptibility was assessed in 9 cases. One isolate had a
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minimal inhibitory concentration (MIC) of 3 mg/l. Only 3 of 7 tested isolates were susceptible to
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clindamycin.
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Treatment characteristics. Empirical treatment (including vancomycin or carbapenems) was
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adequate in six cases (26%), while adequate targeted treatment was administered in 18 cases
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(86%). Two immunocompetent patients (one IVDU and one polytraumatized) were treated with
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amoxicillin/clavulanic acid and a haematological patient was treated with imipenem despite an
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MIC of 3 mg/l. Of note, no complication was observed among these patients treated with
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inadequate antibiotics.
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Median duration of adequate antibiotic treatment was 16.5 days (range: 2-253). Nineteen
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patients (91%) had a CVC at time of B. cereus bacteraemia. The CVC was removed in 8 cases
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(42%), including 3 cases of CRBSI. Median delay to device removal was 1.5 days (range 0-16).
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Haematological patients. All but one patient with haematological diseases had nosocomial
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bacteremia and were neutropenic at time of bacteraemia. Median duration of neutropenia was
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11 days (range 5-180). Eight patients had either induction or consolidation chemotherapy for
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acute leukaemia (cytarabine was administered in seven patients). Source of bacteraemia were
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the intestinal tract (5 patients, 50%), and the CVC (5, 50%).
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In this group, median delay to adequate antibiotic treatment was 1 day (range 0-7). The CVC
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was removed in 42% of cases after a median delay of 4.5 days. No significant difference in
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clinical and treatment characteristics was found between haematological and non-
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haematological patients (table 1).
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Complications of B. cereus bacteraemia. Three patients (14%) had central nervous system
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(CNS) complications: one had meningoencephalitis (impaired mental status, CSF pleocytosis)
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and two had cerebral abscesses. An illustrative case of CNS abscess is depicted in figure 3. In
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the other case, B. cereus bacteraemia and cerebral abscesses appeared one month after
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stopping antibiotic treatment for the first episode, which was managed with port retention and
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vancomycin lock. All 3 patients with neurological complications had a haematological
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malignancy. No other hematogenous complications, such as infective endocarditis
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(echocardiography was performed in 9 cases, two of whom had transoesophageal
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echocardiography) or endophtalmitis, were identified.
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Two patients died during the 30 days following B. cereus bacteraemia (10%): one death in a
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patient with autoimmune hepatitis was possibly related to B. cereus bacteraemia, while the other
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patient died of invasive aspergillosis.
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Since features of the group of patients with non-haematological diseases were very
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heterogeneous, we limited the analysis of complications to haematological patients (table 2).
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While demographics and underlying disease did not differ between the two groups, CRBSI was
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the source of bacteraemia in all complicated cases as compared to 29% of uncomplicated
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cases. Overall catheter management was similar between the two groups. Of note, the only
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recurrence was related to catheter retention.
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Discussion
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In this series of 21 patients with B. cereus bacteraemia, we identified four distinct groups of
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patients according to their underlying condition: haematological malignancies, chronic diseases
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(e.g. solid tumour, end-stage renal disease), typically associated with a lower degree of
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immunosuppression compared to haematological malignancies, polytrauma and intravenous
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drug use.
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Haematological patients are a well-known risk group for B. cereus bacteraemia, due to
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neutropenia and a break in the mucosal barrier following high-dose chemotherapy (12) and the
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skin barrier due to CVCs. B. cereus colonizes not only the environment and skin but also the
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intestinal tract, as shown in stool studies of healthy subjects and hospitalized patients (13).
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Autopsies of patients with fatal B. cereus bacteraemia reveal necrotizing intestinal lesions,
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highlighting the association between mucositis / neutropenic enterocolitis and B. cereus
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bacteraemia (14, 15). Our series highlights the important role of neutropenia (90% of patients),
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cytarabine chemotherapy (70%) and enterocolitis (50%) in the pathogenesis of invasive B.
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cereus disease. The median delay of 11 days between onset of neutropenia and B. cereus
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bacteraemia suggests that B. cereus infection is a late event in the course of neutropenia, unlike
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other bacterial infections (e.g. gram negative or streptococcal bacteraemia). This is most likely
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explained by resistance to betalactams commonly used for the initial treatment of febrile
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neutropenia. Intravascular catheters are an important risk factor for B. cereus bacteraemia in this
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population of patients. B. cereus is able to produce biofilms and adhere to foreign bodies (2, 17),
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thus preventing eradication of infection. Guidelines for the management of CRBSI recommend
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removing the CVC within 72 hours of onset of B. cereus bacteraemia (18), as studies indicate
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that the risk of recurrence is higher if the catheter is retained (19-21). Our own case of
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recurrence confirms this risk.
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A striking feature of B. cereus among haematological patients is the ability to invade the CNS
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and produce meningitis, abscesses or haemorrhage (14, 22-25). The pathogenesis of CNS
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invasion is unknown. Intrathecal chemotherapy has been discussed by some authors (7), but it
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is unlikely to explain most of the cases, since the association with bacteraemia points to a
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haematogenous route of infection. In our series, neurological complications were found in 3/10
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haematological patients. The outcome was favourable with long-term antibiotic treatment and no
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drainage of cerebral abscesses was necessary.
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We tried to identify risk factors for CNS involvement in haematological patients by comparing
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episodes complicated by CNS disease with uncomplicated episodes. The only possible predictor
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was catheter-related infection: all three patients with CNS complications had CRBSI, while
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among patients with uncomplicated course the digestive tract was the most common source.
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Although the small sample size prevents a definitive conclusion, we believe that this is an
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interesting observation. Two previous studies have addressed risk factors for complications of B.
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cereus bacteraemia in haematological patients. In a review of 46 published episodes, possible
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predictors of poor outcome were neutropenia, presence of a CVC and neurological symptoms
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(5). A paediatric study with 12 patients identified corticosteroid and cephalosporin exposure,
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neutropenia and intrathecal therapy as possible risk factors for CNS complications (7). Some
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authors have described an association with intestinal mucositis (7, 8). None of our patients with
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CNS complications presented abdominal symptoms.
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Previous studies have highlighted the presence of a CVC as a risk factor for poor outcome (5,
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22) and recurrence (6, 19, 20). To our knowledge this is the first description of a possible
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association between catheter infection and complicated B. cereus bacteraemia.
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Invasive B. cereus infections among non-haematological patients are usually localized
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infections. By contrast, B. cereus bacteraemia is rarely reported, with the notable exception of
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IVDU, where infections are related to heroin contamination (26, 27). Bacteraemia is often
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transient, however complications such as endocarditis and endophtalmitis may occur (3). In our
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series, B. cereus bacteraemia among IVDU had a very benign course, even without adequate
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antibiotic treatment, questioning the role of antibiotic treatment of B. cereus bacteraemia with
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spontaneous resolution.
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B. cereus is usually resistant to all betalactams except carbapenems via a broad-spectrum
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betalactamase (10). As shown in our series, resistance to carbapenems may occur, as already
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described in studies from Japan (22, 28-30). Resistance to clindamycin and fluoroquinolones
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has also been reported (22, 31). Antibiotic treatment should be tailored according to
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susceptibility testing; no data are available to recommend specific regimens.
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Our study has limitations. First, due to small sample size, it was underpowered to compare
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clinical characteristics of patients according to underlying conditions or identify further risk
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factors for complicated B. cereus bacteraemia. Second, when dealing with B. cereus,
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contamination is always an issue. We made every effort to exclude blood culture contaminations
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by selecting only cases with at least two positive blood culture bottles and associated compatible
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symptoms. Third, in the absence of positive cultures of the affected site, both the source
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attribution of B. cereus bacteraemia and the definition of CNS involvement may be arbitrary.
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Definition of CRBSI is particularly difficult, because the CVC was removed in less than half of the
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case. Therefore, like others (19), we relied on the indirect criteria of absence of alternative
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source. Finally, management of patients has changed during the 16-year long study period. This
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may in turn have affected ability to compare the episodes.
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In conclusion, while B. cereus bacteraemia is mostly benign, its clinical course can be severe in
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a subset of patients. Haematological disease and catheter-related infection appear to be risk
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factors for a complicated course. Optimal management in this patient group includes adequate
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antibiotic therapy and catheter removal unless an alternative source is apparent (e.g. intestinal
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mucositis). Future studies should further characterize predictors of a complicated course among
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both haematological and non-haematological patients.
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Acknowledgments. We thank Heba Alwan MD for the English revision of the manuscript.
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References
237 238
1.
239
Bacillus cereus infections in Traumatology-Orthopaedics Department: retrospective investigation
240
and improvement of healthcare practices. J Infect. 2005;50(1):22-30.
241
2.
242
cereus infections. Microbes Infect. 2000;2(2):189-98.
243
3.
244
from Bacillus sp. JAMA. 1979;241(11):1137-40.
245
4.
246
2010;23(2):382-98.
247
5.
248
caused by Bacillus cereus in patients with hematologic malignancies: analysis of its prognosis
249
and risk factors. Leuk Lymphoma. 2010;51(5):860-9.
250
6.
251
therapeutic interventions in 17 cases of Bacillus bacteremia in an immunosuppressed patient
252
population. J Clin Microbiol. 1987;25(4):672-4.
TE D
Dubouix A, Bonnet E, Alvarez M, Bensafi H, Archambaud M, Chaminade B, et al.
Kotiranta A, Lounatmaa K, Haapasalo M. Epidemiology and pathogenesis of Bacillus
EP
Tuazon CU, Murray HW, Levy C, Solny MN, Curtin JA, Sheagren JN. Serious infections
AC C
Bottone EJ. Bacillus cereus, a volatile human pathogen. Clin Microbiol Rev.
Inoue D, Nagai Y, Mori M, Nagano S, Takiuchi Y, Arima H, et al. Fulminant sepsis
Cotton DJ, Gill VJ, Marshall DJ, Gress J, Thaler M, Pizzo PA. Clinical features and
10
ACCEPTED MANUSCRIPT
253
7.
254
cereus bacteremia and meningitis in immunocompromised children. Clin Infect Dis.
255
2001;32(10):1456-62.
256
8.
257
Investigation of a Cluster of Neuroinvasive Bacillus cereus Infections in 5 Patients With Acute
258
Myelogenous Leukemia. Open Forum Infect Dis. 2015;2(3):ofv096.
259
9.
260
Medicine Consensus Conference: definitions for sepsis and organ failure and guidelines for the
261
use of innovative therapies in sepsis. Crit Care Med. 1992;20(6):864-74.
262
10.
263
selected antibiotics for Bacillus anthracis, Bacillus cereus, Bacillus thuringiensis, and Bacillus
264
mycoides from a range of clinical and environmental sources as determined by the Etest. J Clin
265
Microbiol. 2004;42(8):3626-34.
266
11.
267
modifications to the Duke criteria for the diagnosis of infective endocarditis. Clin Infect Dis.
268
2000;30(4):633-8.
269
12.
270
colitis after treatment of acute myelogenous leukemia with idarubicin and cytosine arabinoside.
271
Mayo Clin Proc. 2002;77(8):760-2.
272
13.
273
al. An outbreak of Bacillus species in a cancer hospital. Infect Control Hosp Epidemiol.
274
1998;19(11):856-8.
275
14.
276
septicemic syndrome of Bacillus cereus in a leukemic patient. Intern Med. 1997;36(3):221-6.
277
15.
278
gastritis due to Bacillus cereus in an immunocompromised patient. Infection. 2006;34(2):98-9.
Gaur AH, Patrick CC, McCullers JA, Flynn PM, Pearson TA, Razzouk BI, et al. Bacillus
RI PT
Rhee C, Klompas M, Tamburini FB, Fremin BJ, Chea N, Epstein L, et al. Epidemiologic
M AN U
SC
Medicine ACoCPSoCC. American College of Chest Physicians/Society of Critical Care
Turnbull PC, Sirianni NM, LeBron CI, Samaan MN, Sutton FN, Reyes AE, et al. MICs of
TE D
Li JS, Sexton DJ, Mick N, Nettles R, Fowler VG, Jr., Ryan T, et al. Proposed
AC C
EP
Hogan WJ, Letendre L, Litzow MR, Tefferi A, Hoagland HC, Pruthi RK, et al. Neutropenic
Thuler LC, Velasco E, de Souza Martins CA, de Faria LM, da Fonseca NP, Dias LM, et
Akiyama N, Mitani K, Tanaka Y, Hanazono Y, Motoi N, Zarkovic M, et al. Fulminant
Le Scanff J, Mohammedi I, Thiebaut A, Martin O, Argaud L, Robert D. Necrotizing
11
ACCEPTED MANUSCRIPT
279
16.
280
leukaemia. BMJ Case Rep. 2013;2013.
281
17.
282
surface properties among pathogenic and nonpathogenic strains of the Bacillus cereus group.
283
Appl Environ Microbiol. 2009;75(20):6616-8.
284
18.
285
guidelines for the diagnosis and management of intravascular catheter-related infection: 2009
286
Update by the Infectious Diseases Society of America. Clin Infect Dis. 2009;49(1):1-45.
287
19.
288
the need for catheter removal. Medicine (Baltimore). 2009;88(5):279-83.
289
20.
290
bacteremia. Medicine (Baltimore). 2010;89(5):346; author reply 7.
291
21.
292
infection in an immunocompetent child with hemophilia. J Pediatr Hematol Oncol.
293
2004;26(3):194-6.
294
22.
295
of Bacillus cereus septicemia in patients with hematological disease. Intern Med.
296
2012;51(19):2733-8.
297
23.
298
Bacteremia and Multiple Brain Abscesses During Acute Lymphoblastic Leukemia Induction
299
Therapy. J Pediatr Hematol Oncol. 2013.
300
24.
301
Brain abscesses resulting from Bacillus cereus and an Aspergillus-like mold. J Pediatr Hematol
302
Oncol. 2002;24(7):569-71.
Ammannagari N, Kaewpoowat Q, Ratanapo S, Patel A. Florid skin rash in acute myeloid
RI PT
Auger S, Ramarao N, Faille C, Fouet A, Aymerich S, Gohar M. Biofilm formation and cell
SC
Mermel LA, Allon M, Bouza E, Craven DE, Flynn P, O'Grady NP, et al. Clinical practice
M AN U
Kassar R, Hachem R, Jiang Y, Chaftari AM, Raad I. Management of Bacillus bacteremia:
Park HG, Choi SH. Long-term central venous catheter salvage in patients with Bacillus
TE D
Srivaths PR, Rozans MK, Kelly E, Jr., Venkateswaran L. Bacillus cereus central line
EP
Uchino Y, Iriyama N, Matsumoto K, Hirabayashi Y, Miura K, Kurita D, et al. A case series
AC C
Hansford JR, Phillips M, Cole C, Francis J, Blyth CC, Gottardo NG. Bacillus Cereus
Psiachou-Leonard E, Sidi V, Tsivitanidou M, Gompakis N, Koliouskas D, Roilides E.
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25.
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of CNS Infections Due to B. cereus in the Setting of Acute Myeloid Leukemia: Neuropathology in
305
5 Patients. J Neuropathol Exp Neurol. 2015;74(10):1000-11.
306
26.
307
into the microflora of heroin. J Med Microbiol. 2002;51(11):1001-8.
308
27.
309
paraphernalia. J Infect Dis. 1974;129(3):327-9.
310
28.
311
with acute myeloid leukemia who developed fatal pneumonia caused by carbapenem-resistant
312
Bacillus cereus. J Infect Chemother. 2009;15(1):39-41.
313
29.
314
septicemia of Bacillus cereus resistant to carbapenem in a patient with biphenotypic acute
315
leukemia. J Infect Chemother. 2008;14(5):361-7.
316
30.
317
in a severely neutropenic patient: successful treatment with antimicrobial agents, granulocyte
318
colony-stimulating factor and surgical drainage. Intern Med. 2001;40(7):654-7.
319
31.
320
septicemia caused by Bacillus cereus following reduced-intensity umbilical cord blood
321
transplantation. Haematologica. 2005;90(1):ECR06.
323 324
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McLauchlin J, Mithani V, Bolton FJ, Nichols GL, Bellis MA, Syed Q, et al. An investigation
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Tuazon CU, Hill R, Sheagren JN. Microbiologic study of street heroin and injection
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Katsuya H, Takata T, Ishikawa T, Sasaki H, Ishitsuka K, Takamatsu Y, et al. A patient
Kiyomizu K, Yagi T, Yoshida H, Minami R, Tanimura A, Karasuno T, et al. Fulminant
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Sakai C, Iuchi T, Ishii A, Kumagai K, Takagi T. Bacillus cereus brain abscesses occurring
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Kobayashi K, Kami M, Ikeda M, Kishi Y, Murashige N, Tanosaki R, et al. Fulminant
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Vodopivec I, Rinehart EM, Griffin GK, Johncilla ME, Pecora N, Yokoe DS, et al. A Cluster
325 326
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Figure 1. Timing of infection and underlying diseases.
328
Haematological disease (N=10): acute myeloid leukemia (N=5), myelodysplastic syndrome
329
(N=3), acute lymphatic leukemia (N=2). Chronic disease (N=4): end stage renal disease (N=2),
330
autoimmune hepatitis (N=1), diabetes mellitus (N=1), pseudomyxoma peritonei (N=1).
331
Polytrauma (N=3). Intravenous drug use (IVDU, N=3).
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Figure 2. Antibiotic susceptibility of 21 B. cereus strains.
333
S: susceptible. R: resistant. I: intermediate.
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Figure 3. Brain imaging of haematogenous cerebral abscesses complicating B. cereus
335
bacteraemia in a 63-year old man with relapsing acute myeloid leukemia. At day thirteen after
336
induction chemotherapy the patient presented with neutropenic fever, headache, photopsia and
337
left leg paresis. Magnetic resonance at the first neurological symptoms showed a focal lesion in
338
the paracentral lobule with focal edema and contrast enhancement on T2 and T1 weighted
339
images (arrows) (A). The same day, B. cereus was grown from blood cultures. Contrast
340
enhanced CT performed because of the neurological deterioration (progression of the paresis,
341
lethargy and hemineglect), showed a large increase of the perilesional edema and multiplicity of
342
abscesses (arrowhead) (B). Antibiotic therapy (imipenem switched to oral levofloxacin at
343
discharge), initially associated with high-dose corticoids, was carried on for a total of eight and a
344
half months. Neurological deficits regressed completely. Last follow-up MRI T2 and T1 weighted
345
images showed an inactive lesion with minimal gliosis and no contrast enhancement
346
(arrowhead) (C).
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Non haematological
(N=10)
(N=11)
Age (y)
55.5 (27-78)
44 (23-82)
Men (%)
6 (60)
8 (73)
Nosocomial acquisition (%)
9 (90)
CRBSI
5 (50)
-
Digestive tract
5 (50)
-
IVDU
0
-
Open fracture/wound
Polymicrobial infection (%) Neutropenia duration before
Mucositis (%) Fever (%)
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Adequate antibiotic treatment (%)
1 (9)
3 (27)
0 (0)
1 (9)
4 (40)
3 (27)
11 (5-180)
NR
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bacteraemia (d)
6 (55)
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6 (55)
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Source of infection (%)
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Characteristic
5 (50)
NR
10 (100)
8 (73)
9 (90)
9 (82)
Vancomycin
2 (22)
4 (44)
-
Imipenem
5 (56)
4 (44)
2 (22)
1 (12)
18 (13-253)
14 (2-84)
10 (100)
9 (82)
Catheter removal (%)
4 (40)
4 (44)
Delay until catheter removal (d)
4.5 (1-16)
1 (0-2)
Hospitalization in the ICU (%)
4 (40)
4 (36)
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-
-
Other
Duration of adequate treatment (d) Presence of catheter at time of bacteraemia (%)
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1 (10)
0
Death at 30 days (%)
1 (10)
1 (9)
Values are median (range), unless specified otherwise. CRBSI: catheter-related bloodstream infection. IVDU: intravenous drug use. ICU: intensive care unit. y: years;
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d: days. No significant difference was found between haematological and non haematological
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patients.
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Not complicated
(N=3)
(N=7)
Age (y)
57 (46-64)
54 (27-78)
Male (%)
2 (33)
Active haematological diseases (%)
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Complicated
4 (57)
Myelodysplastic syndrome
1 (33)
2 (29)
-
AML
2 (66)
3 (43)
-
ALL
0 (0)
2 (29)
Cytarabine chemotherapy (%)
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-
2 (66)
5 (71)
3 (100)
2 (29)
0 (0)
5 (71)
Intestinal mucositis (%)
0 (0)
4 (57)
Skin rash (%)
1 (33)
3 (43)
Polymicrobial infection (%)
1 (33)
3 (43)
Adequate antibiotic treatment (d)
3 (100)
6 (86)
Source of infection (%) -
Catheter-related bloodstream infection
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Digestive tract
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-
-
Duration
21 (15-253)
17.5 (13-20)
-
Delay until adequate antibiotic
1 (1)
4 (0-7)
3 (100)
7 (100)
Presence of catheter at time of bacteraemia (%) -
No catheter removal (%)
1 (33)
5 (71)
-
Delay until removal (d)
3 (1-5)
10 (4-16)
2 (66)
2 (29)
Hospitalization in the ICU (%)
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8.5 (4-13)
10.5 (4-17)
Death at 30 days (%)
0 (0)
1 (14)
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Values are median (range), unless specified otherwise; CRBSI: catheter-related bloodstream infection. AML: acute myeloid leukaemia. ALL: acute lymphoblastic leukaemia. y: years; d: days. ICU: intensive care unit.
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No of episodes
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0 1999 2000 2001 2002 2003 2004 2005 2006 2007 2008 2009 2010 2011 2012 2013
Haematological disease
Chronic disease
Polytrauma
IVDU
Pe ni ci lli C n ef (n tr =1 ia 8) xo ne C (n lin =1 da 6) m yc in (n Im =7 ip ) en Va em nc (n om =9 ) y ci C n ip (n ro =2 flo 0) xa c Le in vo (n =1 flo 5) xa ci n G (n en =1 ta 6) m ic C oin tr (n im =9 ox ) az ol (n =8 )
Susceptibility (%) 60
40
20
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80
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100
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S2052-2975(16)30123-8
DOI:
10.1016/j.nmni.2016.11.011
Reference:
NMNI 254
To appear in:
New Microbes and New Infections
Received Date: 2 August 2016 Accepted Date: 4 November 2016
Please cite this article as: Tusgul S, Prod’hom G, Senn L, Meuli R, Bochud P-Y, Giulieri SG, Bacillus cereus bacteraemia: A Comparison between haematological and non-haematological patients, New Microbes and New Infections (2016), doi: 10.1016/j.nmni.2016.11.011. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
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Bacillus cereus bacteraemia: a comparison between haematological and non-haematological patients 1,2
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1,4
5
1
1
S. Tusgul , G. Prod’hom , L. Senn , R. Meuli , P-Y. Bochud , S. G. Giulieri . 1
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Service of Infectious Diseases and Service of Internal Medicine, Department of Medicine,
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Institute of Microbiology, Department of Laboratories, Service of Hospital Preventive
Medicine, Department of Radiology, Lausanne University Hospital, Lausanne, Switzerland.
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Running title: B. cereus bacteraemia in haematological patients
Keywords: Bacillus cereus; bacteraemia; intravascular catheter; central nervous system;
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neutropenia
Abstract: 228 words Main text: 2473 words
Figures: 3 References: 31
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Correspondence:
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Stefano Giulieri, MD
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Infectious Diseases Service Department of Medicine
Lausanne University Hospital Rue du Bugnon 46
CH-1011 Lausanne
[email protected]
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ABSTRACT
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Bacillus cereus bacteraemia can be severe, especially among patients with haematological
3
malignancy. We retrospectively reviewed first episodes of true B. cereus bacteraemia (> 1
4
positive bottle plus signs of infection) at our institution between 1997 and 2013 with the aim to
5
compare haematological versus non-haematological patients and analyse episodes with
6
complicated outcome. Among 56 episodes of positive blood cultures for B. cereus, 21 were
7
considered significant. Median age was 54 years (range 23-82). Ten patients (48%) had a
8
haematological malignancy; all were neutropenic at the time of B. cereus bacteraemia. Non-
9
haematological patients were either intravenous drug users (IVDU) (N=3, 14%), polytraumatized
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(N=3, 14%) or had multiple chronic comorbidities (N=5, 24%). Most episodes were hospital-
11
acquired (15, 71%). Sources of bacteraemia were intravascular catheter (11 cases, 52%),
12
digestive tract (6, 29%), drug injection (3, 14%) and wound (1, 5%). Adequate antibiotic therapy
13
was given to 18 (86%) patients during a median of 17 days (range 2-253). The intravascular
14
catheter was removed in 8 cases (42%). Three haematological patients had a complicated
15
course with neurological complications (meningoencephalitis and cerebral abscesses).
16
Complications appeared to be associated with catheter infection (100% of complicated cases vs.
17
29% of non complicated cases). In conclusion, B. cereus bacteraemia can have a complicated
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course in a subset of patients, mainly those with haematological malignancy. Catheter infection
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may be associated with a worse outcome with frequent neurological complications.
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Introduction
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Bacillus cereus is a spore-building Gram-positive rod, that can survive in extreme environmental
26
conditions and persist in the hospital (1, 2). While B. cereus is often considered as a
27
contaminant, it can also cause significant disease, which manifest in three distinct syndromes:
28
food intoxication, localized infection and bacteraemia, the latest being sometimes associated
29
with haematogenous complications (e.g. endophtalmitis, cerebral abscesses) (3). Certain clinical
30
manifestations like necrotizing infections (e.g. endophtalmitis, fasciitis) might be caused by the
31
release of to exotoxins such as proteases, phospholipases and hemolysins (2, 4, 5).
32
It is widely recognised that haematological patients have a higher risk for invasive B. cereus
33
infection (5-8), but limited data are available on other risk factors for complications of B. cereus
34
bacteraemia (such as mortality and metastatic infections). The aims of the present study were to
35
compare episodes between haematological and non-haematological patients and to identify
36
possible risk factors that may predispose to a complicated course of B. cereus bacteraemia.
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Patients and methods.
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Definition of cases. Cases with > 1 positive blood culture bottle for B. cereus occurring at our
40
institution (a 1500-bed university hospital) between January 1997 and April 2013 were identified
41
through the microbiological database. We included all patients presenting with a first episodes of
42
true B. cereus bacteraemia, defined as > 1 positive blood culture bottles and signs of sepsis (9)
43
or localized infection.
44
Data collection. The following data were extracted from patients charts: demographic
45
characteristics, site of hospitalization, underlying disease, presence of neutropenia (neutrophil
46
count < 0.5 x 109/L), previous chemotherapy, treatment with corticoids or other
47
immunosuppressive drugs, source of bacteraemia, presence of a central venous catheter (CVC)
48
and its management, symptoms and signs of sepsis and localized infection and antibiotic
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treatment. Outcome criteria were mortality at 30 days, presence of haematogenous
50
complications (meningitis, cerebral abscesses, infective endocarditis or endophtalmitis), and
51
relapse of B. cereus bacteraemia.
52
The study was approved by the local Institutional Review Board of the University of Lausanne,
53
Switzerland.
54
Laboratory methods/Identification and antibiotic susceptibility. B. cereus was identified
55
from blood cultures through Gram stain appearance, colony morphology and hemolysis on blood
56
agar, positive lecithinase on egg yolk agar or Matrix-Assisted Laser Desorption/Ionization
57
(MALDI-TOF). Antimicrobial susceptibility testing was performed using disk diffusion and
58
interpreted according to Clinical and Laboratory Standards Institute (CLSI) criteria used for
59
staphylococci (due to the absence of criteria for Bacillus species other than B. anthracis) until
60
2010 and E-test interpreted with non specific European Committee for Antimicrobial
61
Susceptibility Testing (EUCAST) criteria for Gram-positive bacteria was used thereafter.
62
Definitions of source of bacteraemia, adequate antibiotic treatment and complicated
63
bacteraemia. Bacteraemia was categorised as hospital-onset if it occurred > 48 h after
64
admission. Source of B. cereus bacteraemia was ascertained by using the following criteria.
65
Catheter-related bloodstream infection (CRBSI): no apparent source for the blood stream
66
infection except the catheter or positive catheter tip culture for B. cereus (> 15 cfu). Digestive
67
tract: significant abdominal disease confirmed by imaging (e.g. ileus, perforation) or neutropenic
68
enterocolitis (clinical or radiological signs). Drug injection: active intravenous drug use and
69
temporal association between B. cereus bacteraemia and drug injection. Open fracture/wound:
70
sign of infection or wound culture positive for B. cereus.
71
Antibiotic treatment was considered adequate if the B. cereus isolate was susceptible to the
72
antimicrobial prescribed (or there was a high likelihood of susceptibility based on published data
73
(10)) and dosed in accordance with current recommendation. Antibiotic treatment was
74
categorized as empirical if administered within 24 hours of collection of the blood culture, and
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before susceptibility was known. Targeted antibiotic treatment referred to the
76
treatment continued or initiated on the day that antibiogram results were reported.
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Hematogenous complications were defined by using following criteria. Meningitis: at least one
78
clinical sign (headache, neck stiffness, impaired level of consciousness) associated with
79
pleocytosis (> 4 white blood cells/mm3). Brain abscess: at least one clinical sign (headache,
80
focal neurological deficit, impaired level of consciousness) and radiological evidence. Infective
81
endocarditis: definite diagnosis according to the Duke criteria (11). Endophtalmitis: clinical signs
82
and positive ophthalmologic examination.
83
Statistical analysis. For comparison between groups we used the Fisher’s exact test for
84
categorical variables, and the Mann-Whitney test for continuous variables. Calculations were
85
performed with Stata, version 12.0 (StataCorp, College Station, TX, USA) and GraphPad Prism,
86
version 6.00 (GraphPad Software, Inc., San Diego, CA, USA).
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Results
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Clinical characteristics. During the study period, we identified 56 episodes of positive blood
90
cultures for B. cereus, among which 33 were excluded due to contamination (N=31), relapse
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(N=1) and missing clinical data (N=1) and 21 retained as true bacteraemia. Among those,
92
median patient age was 54 years (range 23-82) and the majority were men (N=14, 67%).
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Underlying haematological malignancy was observed in 10 patients (48%), chronic disease
94
associated with some form of immunosuppression (autoimmune hepatitis, solid tumour, end-
95
stage renal disease, diabetes mellitus) in 5 (24%), intravenous drug use (IVDU) in 3 (14%) and
96
polytrauma in 3 (14%). Six patients (29%) presented a breakthrough bacteraemia while on
97
antibiotic treatment with cephalosporins or penicillins. The annual incidence of B. cereus
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bacteraemia stratified according to underlying condition is shown in Figure 1. Of note, three
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cases among haematological patients clustered in the first months of 2013. However, no common source of infection was identified.
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Most episodes were hospital-onset (71%). Community-onset episodes were either associated
102
with IVDU or end-stage renal disease. Fever was present in 18 patients (86%), abdominal
103
symptoms (i.e. abdominal pain, vomiting, diarrhea) in 6 (29%), neurological symptoms (including
104
confusion, lethargy, generalized headache, blurred vision, photopsia, dysarthria,
105
dysdiadochokinesia, hemiparesis, hemineglect) in 4 (19%).
106
Source of B. cereus bacteraemia. The source of bacteraemia was CRBSI in eleven cases
107
(52%): short-term CVC (5), port (3), tunnelled hemodialysis catheter (2), arterial catheter (1). In
108
six cases (29%) bacteraemia originated from the digestive tract: all patients with an abdominal
109
source had either abdominal symptoms (4) or a pathological CT (4: bowel wall thickening, ileus).
110
Finally source of infection was drug use in three (14%) and wound infection (confirmed by
111
multiple positive wound swab cultures) in one (5%).
112
Microbiology. Concomitant pathogens were identified in 7 episodes of B. cereus bacteraemia.
113
The frequency of polymicrobial infections was similar between haematological and non-
114
haematological patients. Cerebrospinal fluid (CSF) was collected in 2 cases (IVDU-associated
115
bacteraemia and meningoencephalitis) and was sterile. Results of susceptibility testing are
116
shown in figure 2. All tested isolates were susceptible to vancomycin (20/20), fluoroquinolones
117
(16/16), gentamicin (9/9) and co-trimoxazole (8/8), while they were resistant to penicillin (18/18)
118
and ceftriaxone (16/16). Imipenem susceptibility was assessed in 9 cases. One isolate had a
119
minimal inhibitory concentration (MIC) of 3 mg/l. Only 3 of 7 tested isolates were susceptible to
120
clindamycin.
121
Treatment characteristics. Empirical treatment (including vancomycin or carbapenems) was
122
adequate in six cases (26%), while adequate targeted treatment was administered in 18 cases
123
(86%). Two immunocompetent patients (one IVDU and one polytraumatized) were treated with
124
amoxicillin/clavulanic acid and a haematological patient was treated with imipenem despite an
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MIC of 3 mg/l. Of note, no complication was observed among these patients treated with
126
inadequate antibiotics.
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Median duration of adequate antibiotic treatment was 16.5 days (range: 2-253). Nineteen
128
patients (91%) had a CVC at time of B. cereus bacteraemia. The CVC was removed in 8 cases
129
(42%), including 3 cases of CRBSI. Median delay to device removal was 1.5 days (range 0-16).
130
Haematological patients. All but one patient with haematological diseases had nosocomial
131
bacteremia and were neutropenic at time of bacteraemia. Median duration of neutropenia was
132
11 days (range 5-180). Eight patients had either induction or consolidation chemotherapy for
133
acute leukaemia (cytarabine was administered in seven patients). Source of bacteraemia were
134
the intestinal tract (5 patients, 50%), and the CVC (5, 50%).
135
In this group, median delay to adequate antibiotic treatment was 1 day (range 0-7). The CVC
136
was removed in 42% of cases after a median delay of 4.5 days. No significant difference in
137
clinical and treatment characteristics was found between haematological and non-
138
haematological patients (table 1).
139
Complications of B. cereus bacteraemia. Three patients (14%) had central nervous system
140
(CNS) complications: one had meningoencephalitis (impaired mental status, CSF pleocytosis)
141
and two had cerebral abscesses. An illustrative case of CNS abscess is depicted in figure 3. In
142
the other case, B. cereus bacteraemia and cerebral abscesses appeared one month after
143
stopping antibiotic treatment for the first episode, which was managed with port retention and
144
vancomycin lock. All 3 patients with neurological complications had a haematological
145
malignancy. No other hematogenous complications, such as infective endocarditis
146
(echocardiography was performed in 9 cases, two of whom had transoesophageal
147
echocardiography) or endophtalmitis, were identified.
148
Two patients died during the 30 days following B. cereus bacteraemia (10%): one death in a
149
patient with autoimmune hepatitis was possibly related to B. cereus bacteraemia, while the other
150
patient died of invasive aspergillosis.
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Since features of the group of patients with non-haematological diseases were very
152
heterogeneous, we limited the analysis of complications to haematological patients (table 2).
153
While demographics and underlying disease did not differ between the two groups, CRBSI was
154
the source of bacteraemia in all complicated cases as compared to 29% of uncomplicated
155
cases. Overall catheter management was similar between the two groups. Of note, the only
156
recurrence was related to catheter retention.
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Discussion
159
In this series of 21 patients with B. cereus bacteraemia, we identified four distinct groups of
160
patients according to their underlying condition: haematological malignancies, chronic diseases
161
(e.g. solid tumour, end-stage renal disease), typically associated with a lower degree of
162
immunosuppression compared to haematological malignancies, polytrauma and intravenous
163
drug use.
164
Haematological patients are a well-known risk group for B. cereus bacteraemia, due to
165
neutropenia and a break in the mucosal barrier following high-dose chemotherapy (12) and the
166
skin barrier due to CVCs. B. cereus colonizes not only the environment and skin but also the
167
intestinal tract, as shown in stool studies of healthy subjects and hospitalized patients (13).
168
Autopsies of patients with fatal B. cereus bacteraemia reveal necrotizing intestinal lesions,
169
highlighting the association between mucositis / neutropenic enterocolitis and B. cereus
170
bacteraemia (14, 15). Our series highlights the important role of neutropenia (90% of patients),
171
cytarabine chemotherapy (70%) and enterocolitis (50%) in the pathogenesis of invasive B.
172
cereus disease. The median delay of 11 days between onset of neutropenia and B. cereus
173
bacteraemia suggests that B. cereus infection is a late event in the course of neutropenia, unlike
174
other bacterial infections (e.g. gram negative or streptococcal bacteraemia). This is most likely
175
explained by resistance to betalactams commonly used for the initial treatment of febrile
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neutropenia. Intravascular catheters are an important risk factor for B. cereus bacteraemia in this
177
population of patients. B. cereus is able to produce biofilms and adhere to foreign bodies (2, 17),
178
thus preventing eradication of infection. Guidelines for the management of CRBSI recommend
179
removing the CVC within 72 hours of onset of B. cereus bacteraemia (18), as studies indicate
180
that the risk of recurrence is higher if the catheter is retained (19-21). Our own case of
181
recurrence confirms this risk.
182
A striking feature of B. cereus among haematological patients is the ability to invade the CNS
183
and produce meningitis, abscesses or haemorrhage (14, 22-25). The pathogenesis of CNS
184
invasion is unknown. Intrathecal chemotherapy has been discussed by some authors (7), but it
185
is unlikely to explain most of the cases, since the association with bacteraemia points to a
186
haematogenous route of infection. In our series, neurological complications were found in 3/10
187
haematological patients. The outcome was favourable with long-term antibiotic treatment and no
188
drainage of cerebral abscesses was necessary.
189
We tried to identify risk factors for CNS involvement in haematological patients by comparing
190
episodes complicated by CNS disease with uncomplicated episodes. The only possible predictor
191
was catheter-related infection: all three patients with CNS complications had CRBSI, while
192
among patients with uncomplicated course the digestive tract was the most common source.
193
Although the small sample size prevents a definitive conclusion, we believe that this is an
194
interesting observation. Two previous studies have addressed risk factors for complications of B.
195
cereus bacteraemia in haematological patients. In a review of 46 published episodes, possible
196
predictors of poor outcome were neutropenia, presence of a CVC and neurological symptoms
197
(5). A paediatric study with 12 patients identified corticosteroid and cephalosporin exposure,
198
neutropenia and intrathecal therapy as possible risk factors for CNS complications (7). Some
199
authors have described an association with intestinal mucositis (7, 8). None of our patients with
200
CNS complications presented abdominal symptoms.
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Previous studies have highlighted the presence of a CVC as a risk factor for poor outcome (5,
202
22) and recurrence (6, 19, 20). To our knowledge this is the first description of a possible
203
association between catheter infection and complicated B. cereus bacteraemia.
204
Invasive B. cereus infections among non-haematological patients are usually localized
205
infections. By contrast, B. cereus bacteraemia is rarely reported, with the notable exception of
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IVDU, where infections are related to heroin contamination (26, 27). Bacteraemia is often
207
transient, however complications such as endocarditis and endophtalmitis may occur (3). In our
208
series, B. cereus bacteraemia among IVDU had a very benign course, even without adequate
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antibiotic treatment, questioning the role of antibiotic treatment of B. cereus bacteraemia with
210
spontaneous resolution.
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B. cereus is usually resistant to all betalactams except carbapenems via a broad-spectrum
212
betalactamase (10). As shown in our series, resistance to carbapenems may occur, as already
213
described in studies from Japan (22, 28-30). Resistance to clindamycin and fluoroquinolones
214
has also been reported (22, 31). Antibiotic treatment should be tailored according to
215
susceptibility testing; no data are available to recommend specific regimens.
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Our study has limitations. First, due to small sample size, it was underpowered to compare
217
clinical characteristics of patients according to underlying conditions or identify further risk
218
factors for complicated B. cereus bacteraemia. Second, when dealing with B. cereus,
219
contamination is always an issue. We made every effort to exclude blood culture contaminations
220
by selecting only cases with at least two positive blood culture bottles and associated compatible
221
symptoms. Third, in the absence of positive cultures of the affected site, both the source
222
attribution of B. cereus bacteraemia and the definition of CNS involvement may be arbitrary.
223
Definition of CRBSI is particularly difficult, because the CVC was removed in less than half of the
224
case. Therefore, like others (19), we relied on the indirect criteria of absence of alternative
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source. Finally, management of patients has changed during the 16-year long study period. This
226
may in turn have affected ability to compare the episodes.
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In conclusion, while B. cereus bacteraemia is mostly benign, its clinical course can be severe in
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a subset of patients. Haematological disease and catheter-related infection appear to be risk
229
factors for a complicated course. Optimal management in this patient group includes adequate
230
antibiotic therapy and catheter removal unless an alternative source is apparent (e.g. intestinal
231
mucositis). Future studies should further characterize predictors of a complicated course among
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both haematological and non-haematological patients.
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Acknowledgments. We thank Heba Alwan MD for the English revision of the manuscript.
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References
237 238
1.
239
Bacillus cereus infections in Traumatology-Orthopaedics Department: retrospective investigation
240
and improvement of healthcare practices. J Infect. 2005;50(1):22-30.
241
2.
242
cereus infections. Microbes Infect. 2000;2(2):189-98.
243
3.
244
from Bacillus sp. JAMA. 1979;241(11):1137-40.
245
4.
246
2010;23(2):382-98.
247
5.
248
caused by Bacillus cereus in patients with hematologic malignancies: analysis of its prognosis
249
and risk factors. Leuk Lymphoma. 2010;51(5):860-9.
250
6.
251
therapeutic interventions in 17 cases of Bacillus bacteremia in an immunosuppressed patient
252
population. J Clin Microbiol. 1987;25(4):672-4.
TE D
Dubouix A, Bonnet E, Alvarez M, Bensafi H, Archambaud M, Chaminade B, et al.
Kotiranta A, Lounatmaa K, Haapasalo M. Epidemiology and pathogenesis of Bacillus
EP
Tuazon CU, Murray HW, Levy C, Solny MN, Curtin JA, Sheagren JN. Serious infections
AC C
Bottone EJ. Bacillus cereus, a volatile human pathogen. Clin Microbiol Rev.
Inoue D, Nagai Y, Mori M, Nagano S, Takiuchi Y, Arima H, et al. Fulminant sepsis
Cotton DJ, Gill VJ, Marshall DJ, Gress J, Thaler M, Pizzo PA. Clinical features and
10
ACCEPTED MANUSCRIPT
253
7.
254
cereus bacteremia and meningitis in immunocompromised children. Clin Infect Dis.
255
2001;32(10):1456-62.
256
8.
257
Investigation of a Cluster of Neuroinvasive Bacillus cereus Infections in 5 Patients With Acute
258
Myelogenous Leukemia. Open Forum Infect Dis. 2015;2(3):ofv096.
259
9.
260
Medicine Consensus Conference: definitions for sepsis and organ failure and guidelines for the
261
use of innovative therapies in sepsis. Crit Care Med. 1992;20(6):864-74.
262
10.
263
selected antibiotics for Bacillus anthracis, Bacillus cereus, Bacillus thuringiensis, and Bacillus
264
mycoides from a range of clinical and environmental sources as determined by the Etest. J Clin
265
Microbiol. 2004;42(8):3626-34.
266
11.
267
modifications to the Duke criteria for the diagnosis of infective endocarditis. Clin Infect Dis.
268
2000;30(4):633-8.
269
12.
270
colitis after treatment of acute myelogenous leukemia with idarubicin and cytosine arabinoside.
271
Mayo Clin Proc. 2002;77(8):760-2.
272
13.
273
al. An outbreak of Bacillus species in a cancer hospital. Infect Control Hosp Epidemiol.
274
1998;19(11):856-8.
275
14.
276
septicemic syndrome of Bacillus cereus in a leukemic patient. Intern Med. 1997;36(3):221-6.
277
15.
278
gastritis due to Bacillus cereus in an immunocompromised patient. Infection. 2006;34(2):98-9.
Gaur AH, Patrick CC, McCullers JA, Flynn PM, Pearson TA, Razzouk BI, et al. Bacillus
RI PT
Rhee C, Klompas M, Tamburini FB, Fremin BJ, Chea N, Epstein L, et al. Epidemiologic
M AN U
SC
Medicine ACoCPSoCC. American College of Chest Physicians/Society of Critical Care
Turnbull PC, Sirianni NM, LeBron CI, Samaan MN, Sutton FN, Reyes AE, et al. MICs of
TE D
Li JS, Sexton DJ, Mick N, Nettles R, Fowler VG, Jr., Ryan T, et al. Proposed
AC C
EP
Hogan WJ, Letendre L, Litzow MR, Tefferi A, Hoagland HC, Pruthi RK, et al. Neutropenic
Thuler LC, Velasco E, de Souza Martins CA, de Faria LM, da Fonseca NP, Dias LM, et
Akiyama N, Mitani K, Tanaka Y, Hanazono Y, Motoi N, Zarkovic M, et al. Fulminant
Le Scanff J, Mohammedi I, Thiebaut A, Martin O, Argaud L, Robert D. Necrotizing
11
ACCEPTED MANUSCRIPT
279
16.
280
leukaemia. BMJ Case Rep. 2013;2013.
281
17.
282
surface properties among pathogenic and nonpathogenic strains of the Bacillus cereus group.
283
Appl Environ Microbiol. 2009;75(20):6616-8.
284
18.
285
guidelines for the diagnosis and management of intravascular catheter-related infection: 2009
286
Update by the Infectious Diseases Society of America. Clin Infect Dis. 2009;49(1):1-45.
287
19.
288
the need for catheter removal. Medicine (Baltimore). 2009;88(5):279-83.
289
20.
290
bacteremia. Medicine (Baltimore). 2010;89(5):346; author reply 7.
291
21.
292
infection in an immunocompetent child with hemophilia. J Pediatr Hematol Oncol.
293
2004;26(3):194-6.
294
22.
295
of Bacillus cereus septicemia in patients with hematological disease. Intern Med.
296
2012;51(19):2733-8.
297
23.
298
Bacteremia and Multiple Brain Abscesses During Acute Lymphoblastic Leukemia Induction
299
Therapy. J Pediatr Hematol Oncol. 2013.
300
24.
301
Brain abscesses resulting from Bacillus cereus and an Aspergillus-like mold. J Pediatr Hematol
302
Oncol. 2002;24(7):569-71.
Ammannagari N, Kaewpoowat Q, Ratanapo S, Patel A. Florid skin rash in acute myeloid
RI PT
Auger S, Ramarao N, Faille C, Fouet A, Aymerich S, Gohar M. Biofilm formation and cell
SC
Mermel LA, Allon M, Bouza E, Craven DE, Flynn P, O'Grady NP, et al. Clinical practice
M AN U
Kassar R, Hachem R, Jiang Y, Chaftari AM, Raad I. Management of Bacillus bacteremia:
Park HG, Choi SH. Long-term central venous catheter salvage in patients with Bacillus
TE D
Srivaths PR, Rozans MK, Kelly E, Jr., Venkateswaran L. Bacillus cereus central line
EP
Uchino Y, Iriyama N, Matsumoto K, Hirabayashi Y, Miura K, Kurita D, et al. A case series
AC C
Hansford JR, Phillips M, Cole C, Francis J, Blyth CC, Gottardo NG. Bacillus Cereus
Psiachou-Leonard E, Sidi V, Tsivitanidou M, Gompakis N, Koliouskas D, Roilides E.
12
ACCEPTED MANUSCRIPT
303
25.
304
of CNS Infections Due to B. cereus in the Setting of Acute Myeloid Leukemia: Neuropathology in
305
5 Patients. J Neuropathol Exp Neurol. 2015;74(10):1000-11.
306
26.
307
into the microflora of heroin. J Med Microbiol. 2002;51(11):1001-8.
308
27.
309
paraphernalia. J Infect Dis. 1974;129(3):327-9.
310
28.
311
with acute myeloid leukemia who developed fatal pneumonia caused by carbapenem-resistant
312
Bacillus cereus. J Infect Chemother. 2009;15(1):39-41.
313
29.
314
septicemia of Bacillus cereus resistant to carbapenem in a patient with biphenotypic acute
315
leukemia. J Infect Chemother. 2008;14(5):361-7.
316
30.
317
in a severely neutropenic patient: successful treatment with antimicrobial agents, granulocyte
318
colony-stimulating factor and surgical drainage. Intern Med. 2001;40(7):654-7.
319
31.
320
septicemia caused by Bacillus cereus following reduced-intensity umbilical cord blood
321
transplantation. Haematologica. 2005;90(1):ECR06.
323 324
RI PT
McLauchlin J, Mithani V, Bolton FJ, Nichols GL, Bellis MA, Syed Q, et al. An investigation
SC
Tuazon CU, Hill R, Sheagren JN. Microbiologic study of street heroin and injection
M AN U
Katsuya H, Takata T, Ishikawa T, Sasaki H, Ishitsuka K, Takamatsu Y, et al. A patient
Kiyomizu K, Yagi T, Yoshida H, Minami R, Tanimura A, Karasuno T, et al. Fulminant
TE D
Sakai C, Iuchi T, Ishii A, Kumagai K, Takagi T. Bacillus cereus brain abscesses occurring
EP
Kobayashi K, Kami M, Ikeda M, Kishi Y, Murashige N, Tanosaki R, et al. Fulminant
AC C
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Vodopivec I, Rinehart EM, Griffin GK, Johncilla ME, Pecora N, Yokoe DS, et al. A Cluster
325 326
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Figure 1. Timing of infection and underlying diseases.
328
Haematological disease (N=10): acute myeloid leukemia (N=5), myelodysplastic syndrome
329
(N=3), acute lymphatic leukemia (N=2). Chronic disease (N=4): end stage renal disease (N=2),
330
autoimmune hepatitis (N=1), diabetes mellitus (N=1), pseudomyxoma peritonei (N=1).
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Polytrauma (N=3). Intravenous drug use (IVDU, N=3).
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Figure 2. Antibiotic susceptibility of 21 B. cereus strains.
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S: susceptible. R: resistant. I: intermediate.
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Figure 3. Brain imaging of haematogenous cerebral abscesses complicating B. cereus
335
bacteraemia in a 63-year old man with relapsing acute myeloid leukemia. At day thirteen after
336
induction chemotherapy the patient presented with neutropenic fever, headache, photopsia and
337
left leg paresis. Magnetic resonance at the first neurological symptoms showed a focal lesion in
338
the paracentral lobule with focal edema and contrast enhancement on T2 and T1 weighted
339
images (arrows) (A). The same day, B. cereus was grown from blood cultures. Contrast
340
enhanced CT performed because of the neurological deterioration (progression of the paresis,
341
lethargy and hemineglect), showed a large increase of the perilesional edema and multiplicity of
342
abscesses (arrowhead) (B). Antibiotic therapy (imipenem switched to oral levofloxacin at
343
discharge), initially associated with high-dose corticoids, was carried on for a total of eight and a
344
half months. Neurological deficits regressed completely. Last follow-up MRI T2 and T1 weighted
345
images showed an inactive lesion with minimal gliosis and no contrast enhancement
346
(arrowhead) (C).
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ACCEPTED MANUSCRIPT Table 1. Patients characteristics. Haematological
Non haematological
(N=10)
(N=11)
Age (y)
55.5 (27-78)
44 (23-82)
Men (%)
6 (60)
8 (73)
Nosocomial acquisition (%)
9 (90)
CRBSI
5 (50)
-
Digestive tract
5 (50)
-
IVDU
0
-
Open fracture/wound
Polymicrobial infection (%) Neutropenia duration before
Mucositis (%) Fever (%)
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Adequate antibiotic treatment (%)
1 (9)
3 (27)
0 (0)
1 (9)
4 (40)
3 (27)
11 (5-180)
NR
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bacteraemia (d)
6 (55)
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Source of infection (%)
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Characteristic
5 (50)
NR
10 (100)
8 (73)
9 (90)
9 (82)
Vancomycin
2 (22)
4 (44)
-
Imipenem
5 (56)
4 (44)
2 (22)
1 (12)
18 (13-253)
14 (2-84)
10 (100)
9 (82)
Catheter removal (%)
4 (40)
4 (44)
Delay until catheter removal (d)
4.5 (1-16)
1 (0-2)
Hospitalization in the ICU (%)
4 (40)
4 (36)
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-
Other
Duration of adequate treatment (d) Presence of catheter at time of bacteraemia (%)
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1 (10)
0
Death at 30 days (%)
1 (10)
1 (9)
Values are median (range), unless specified otherwise. CRBSI: catheter-related bloodstream infection. IVDU: intravenous drug use. ICU: intensive care unit. y: years;
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d: days. No significant difference was found between haematological and non haematological
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Not complicated
(N=3)
(N=7)
Age (y)
57 (46-64)
54 (27-78)
Male (%)
2 (33)
Active haematological diseases (%)
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Complicated
4 (57)
Myelodysplastic syndrome
1 (33)
2 (29)
-
AML
2 (66)
3 (43)
-
ALL
0 (0)
2 (29)
Cytarabine chemotherapy (%)
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2 (66)
5 (71)
3 (100)
2 (29)
0 (0)
5 (71)
Intestinal mucositis (%)
0 (0)
4 (57)
Skin rash (%)
1 (33)
3 (43)
Polymicrobial infection (%)
1 (33)
3 (43)
Adequate antibiotic treatment (d)
3 (100)
6 (86)
Source of infection (%) -
Catheter-related bloodstream infection
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Digestive tract
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-
Duration
21 (15-253)
17.5 (13-20)
-
Delay until adequate antibiotic
1 (1)
4 (0-7)
3 (100)
7 (100)
Presence of catheter at time of bacteraemia (%) -
No catheter removal (%)
1 (33)
5 (71)
-
Delay until removal (d)
3 (1-5)
10 (4-16)
2 (66)
2 (29)
Hospitalization in the ICU (%)
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8.5 (4-13)
10.5 (4-17)
Death at 30 days (%)
0 (0)
1 (14)
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Values are median (range), unless specified otherwise; CRBSI: catheter-related bloodstream infection. AML: acute myeloid leukaemia. ALL: acute lymphoblastic leukaemia. y: years; d: days. ICU: intensive care unit.
2
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No of episodes
3
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0 1999 2000 2001 2002 2003 2004 2005 2006 2007 2008 2009 2010 2011 2012 2013
Haematological disease
Chronic disease
Polytrauma
IVDU
Pe ni ci lli C n ef (n tr =1 ia 8) xo ne C (n lin =1 da 6) m yc in (n Im =7 ip ) en Va em nc (n om =9 ) y ci C n ip (n ro =2 flo 0) xa c Le in vo (n =1 flo 5) xa ci n G (n en =1 ta 6) m ic C oin tr (n im =9 ox ) az ol (n =8 )
Susceptibility (%) 60
40
20
EP
80
AC C
100
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0
R
I
S
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