- Email: [email protected]
Monomicrobial vs Polymicrobial Clostridium difficile Bacteremia: A Case Report and Review of the Literature
Accepted Manuscript Monomicrobial vs Polymicrobial Clostridium difficile bacteremia: A Case Report and Review of the Literature Noora Kazanji, DO, Mihajlo Gjeorgjievski, MD, Siddhartha Yadav, MD, Amy N. Mertens, DO, Carl Lauter, MD MACP PII:
S0002-9343(15)00458-1
DOI:
10.1016/j.amjmed.2015.05.014
Reference:
AJM 13011
To appear in:
The American Journal of Medicine
Received Date: 14 April 2015 Revised Date:
16 May 2015
Accepted Date: 18 May 2015
Please cite this article as: Kazanji N, Gjeorgjievski M, Yadav S, Mertens AN, Lauter C, Monomicrobial vs Polymicrobial Clostridium difficile bacteremia: A Case Report and Review of the Literature, The American Journal of Medicine (2015), doi: 10.1016/j.amjmed.2015.05.014. 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.
ACCEPTED MANUSCRIPT
1 2
Title: Monomicrobial vs Polymicrobial Clostridium difficile bacteremia: A Case Report and Review of the Literature
3 4 5
Noora Kazanji DO , Mihajlo Gjeorgjievski MD , Siddhartha Yadav MD , Amy N. Mertens DO , Carl Lauter MD MACP3
1
2
1
11
Corresponding Author:
12
Noora Kazanji, DO
13
Department of Internal Medicine
14
Beaumont Health System
15
3601 W 13 Mile Rd
16
Royal Oak, MI 48073
17
USA
18
Email: [email protected]
19
Phone: 248 551 3000
20
Fax: 248 551 1163
21
SC
RI PT
1. Resident Physician, Department of Internal Medicine, Beaumont Health System 2. Chief Medical Resident, Department of Internal Medicine, Beaumont Health System 3. Director, Division of Allergy and Immunology. Member, Division of Infectious Diseases, Beaumont Health System
M AN U
6 7 8 9 10
1
Funding Source: None
23 24 25 26 27 28 29 30 31
Conflict of Interest Statement: On behalf of all authors, the corresponding author states that there is no conflict of interest.
33 34 35
Note: All authors had access to the data and played a role in writing the manuscript. The results presented in this paper have not been published previously in whole or part, except in abstract form.
EP
Article Type: Clinical Communications to the Editor
Keywords: Clostridium difficile; bacteremia; Anaerobe; Monomicrobial bacteremia; Polymicrobial bacteremia Running Head: C. difficile monomicrobial bacteremia Acknowledgments: None
AC C
32
TE D
22
36 37 38 39 40 1
ACCEPTED MANUSCRIPT
To the editor: Extra-intestinal Clostridium difficle (C. difficile) infections account for less than 0.2% of all C. difficile infections [1]. C. difficile bacteremia is even more unusual and only a handful of cases have been described. When bacteremia occurs, it is commonly polymicrobial and associated with other intestinal flora [1]. We present a unique case of monomicrobial C. difficile bacteremia and compare all reported cases in the literature of monomicrobial C. difficile bacteremia with cases of polymicrobial C. difficile bacteremia.
48 49 50 51 52 53 54 55 56 57 58
A 40 year-old man with a past medical history significant for alcohol abuse presented with a one week history of abdominal pain and vomiting. He denied recent antibiotic use. He had normal vitals, jaundice, abdominal tenderness and distension, gynecomastia, and asterixis. Laboratory results revealed thrombocytopenia, hyponatremia, acute kidney injury, transaminitis, elevated International Normalized Ratio (INR), and lactic acidosis. An abdominal CT scan demonstrated cirrhosis, gastrohepatic varices, and colitis. Two separate blood cultures were drawn on day one and again on day three. Due to clinical deterioration on day three, antibiotic coverage was broadened from ceftriaxone to intravenous vancomycin and piperacillin-tazobactam. The patient expired on day three due to severe hypotension. All four sets of blood cultures returned positive for C. difficile after six days of inoculation. A stool sample collected shortly before his death returned positive for toxigenic C. difficile.
59 60 61 62 63 64 65 66 67 68 69 70 71 72
Although rare, C. difficile can present as monomicrobial bacteremia as was exemplified by our case. In order to better understand the pathogenesis, we reviewed all 44 cases of C. difficile bacteremia reported thus far in the literature and compared several factors between monomicrobial and polymicrobial C. difficile bacteremia. The cases were obtained thorough PubMed with key words: “clostridium”, “difficile”, “bacteremia”, “infection.” There was no temporal limit, beginning from the first case reported in 1962.
73 74 75 76 77 78 79 80 81 82
Several hypotheses have been formulated to understand the etiopathogenesis of C. difficile bacteremia. One familiar mechanism is the direct transfer of polymicrobial gut flora to the bloodstream through a site of injury in the intestinal mucosa [2]. Bacterial translocation is another mechanism; any factor disrupting the normal intestinal mucosal barrier such as inflammation or immunosuppression can promote translocation of bacteria from the intestine to the lymph nodes, peritoneum and blood [3]. Given the polymicrobial nature of the intestinal flora, a different method is needed to explain monomicrobial C. difficile bacteremia. In our review, five cases of the monomicrobial group were noted to have extraintestinal foci compared to only one case in the polymicrobial group [2-6]. This important difference suggests that evaluation for further infective foci should be considered as a mechanism for monomicrobial C. difficile bacteremia.
83 84
References:
85 86 87 88
M AN U
SC
RI PT
41 42 43 44 45 46 47
AC C
EP
TE D
The most common presenting symptoms of C. difficile bacteremia was fever (60%) followed by abdominal pain (43%). There were no significant differences (p>0.05) between monomicrobial and polymicrobial C. difficile bacteremia with regard to recent surgery, presence of bowel perforation, recent antibiotic usage, presence of liver disease, malignancy, or positive stool toxin. The presence of blood in the stool, however, was more common in polymicrobial C. difficile bacteremia (p<0.05). Overall mortality was 39%. Underlying liver disease or malignancy was present in 64% of cases. This suggests that C. difficile bacteremia may simply be a prognostic marker of severe underlying immunodeficiency.
1. Balzan S, Almeida C, Cleva R et aI. Bacterial translocation: overview of mechanisms and clinical impact. J Gastroenterol Hepatol 2007Apr;22(4):464-471. 2. Durojaie O, Gaur S, Alsaffar L. Bacteraemia and breast abscess: unusual extraintestinal manifestations of Clostridium difficile infection. J Med Microbiol. 2011 Mar;60(Pt 3):378-80
2
ACCEPTED MANUSCRIPT
89 90 91 92
3. Mattila E, Arkkila P, Mattila PS et al. Extraintestinal Clostridium difficile infections. Clin Infect Dis 2013 Sep;57(6):e148-53.
93 94 95 96 97 98
5. Duthilly A, Blanckaert K, Thielemans B et. al. Clostridium difficile bacteremia. PresseMed. 2001 Dec 8;30(37):1825-6.
99
Table 1: Summary of all reported cases of monomicrobial and polymicrobial C. difficile bacteremia
4. Kaufman E, Liska D, Rubinshteyn V et al. Clostridium difficile bacteremia. Surg Infect. 2013 Dec;14:559-60.
RI PT
6. Saginur R, Fogel R, Begin L et. al. Splenic abscess due to Clostridium difficile. Infect Dis.1983 Jun;147(6):1105.
100
Table 2: Patient laboratory results
101
Table 3: Patient culture data
SC
Technical Appendix
AC C
EP
TE D
M AN U
102
3
ACCEPTED MANUSCRIPT
RI PT
Technical Appendix
Technical Appendix Table 1: Summary of all reported cases of monomicrobial and polymicrobial Clostridium difficile bacteremia
SC
Reports of Monomicrobial Clostridium difficile bacteremia:
PubMed ID
Age Sex
Presenting signs
Surgery or Perforation
Recent antibiotic use
Other comorbidities
Smith, 1962
13914327
5Mo ,M
Cough, Coryza, Anorexia
Unknown
Unknown
None
Not tested
Byl, 1996
8729213
18, M
Fevers, Chills, Abdominal pain, Vomiting, Diarrhea
No
Yes
None
Byl, 1996
8729213
78, M
Trauma, Aspiration, Fevers, Diarrhea
No
Libby, 2009
19398213
40, F
Fatigue, weight loss
Lee, 2010 Lee, 2010
20678312
69, F 38, M
Dead on arrival
Abdominal pain
Treatment
Outcome
Unknown
Unknown
Positive
No
PO vancoymycin
Recovered
None
Negative
Unknown
IV and PO vancomycin
Survived
Yes
Acute myeloid leukemia
Not tested
No
vancomycin, cefepime, metronidazole
Died
None
Unknown
Positive
No
None
No
Unknown
Liver cirrhosis Wilson disease
Negative
No
cefmetazole
Dead on arrival Died
TE D Yes
EP
AC C
20678312
C. diff recovere d from other sites Unknown
No
Stool toxin
M AN U
Author, Year
ACCEPTED MANUSCRIPT
20678312
65, F
Fevers, Abdominal pain
Perforated peptic ulcer with laporotomy
Unknown
None
Unknown
Lee, 2010
20678312
58, M
Fevers, Abdominal pain
No
Unknown
Liver Cirrhosis
Negative
Lee, 2010
20678312
12, M
Fevers, Dyspnea
No
Unknown
Biliary Atresia
Negative
Lee, 2010
20678312
41, F
Fevers, Dyspnea
No
Unknown
Pulmonary Fibrosis
Negative
Durojaie, 2011
21127155
39, F
Menorrhagia and spontaneous bruising
No
Yes
Chronic hepatitis and alcoholic liver disease
Unknown
Mcgill, 2011
24111758
39, M
Jaundice, vomiting, fecal incontinence
No
No
Alcoholic liver disease
Mcgill, 2011
24111758
20, M
Fevers, tachycardia, acidosis
Elective subtotal colectomy
Kaufman, 2013
24111758
57, M
Abdominal pain
No
metronidazole
Died
No
metronidazole
Recovered
No
piperacillintazobactam and vancomycin ceftazidime, gentamycin, vancomycin
Recovered
Breast abscess
AmoxicillinClavulanate and Metronidazole
Recovered
Not tested
No
cefuroxime, metronidazole
Recovered
Juvenile polyposis syndrome
Positive
No
Recovered
Mantle cell lymphoma
Unknown
Peritonea l fluid
Enteral vancomycin, IV meropenem, IV metronidazole IV vancomycin, metronidazole
SC
M AN U
TE D
AC C
EP
Yes
Unknown
No
RI PT
Lee, 2010
No
Recovered
Hospice
ACCEPTED MANUSCRIPT
23667848
60, M
Fever, rectal stricture, hydronephrosis, metastatic prostate cancer
Loop ileostomy
Yes
Prostate cacner with metastasis to multiple sites
Negative
Matilla E, 2013
23771984
69, M
Abdominal pain, fevers, ischemic colitis, diarrhea
AAA repair
Yes
Unknown
Duthilly, 2001
11776702
66, M
Fever, diarrhea, anal margin abscess
drainage of abscess
unknown
Paraparesis, recurrent UTI, Fulminant colitis 6 months prior to presentation AML
Saginur, 1983
6854068
68, M
ascites, hepatic encephalopathy
No
no
Cid, 1998
9542965
3, M
Fever, odynophagia, acute pericarditis
No
Current, 2014
Current case
40, M
Abdominal pain, Vomiting
Unknown
Hospice
Resected AAA, adjacent lymph node
Unknown
Recovered
Unknown
anal margin abscess
IV metronidazole
Recovered
Cirrhosis, chronic pancreatitis
Unknown
Penicillin G
Died
Thalasemia minor, recurrent tonsilitis
Not tested
Splenic abscess, ascitic fluid No
Recovered
Alcoholic liver disease
Positive
IV vancomycin, amoxicillinclavulanic acid, cefotaxime IV vancomycin, IV piperacillintazobactam
SC
AC C
No
M AN U
TE D
EP
Yes
Yes
Unknown
RI PT
Choi, 2013
No
Died
ACCEPTED MANUSCRIPT
RI PT
Reports of Polymicrobial Clostridium difficile bacteremia:
PubM ed ID
Age Sex
Presenting signs
Surgery or Perforation
Recent abx use
Other comorbidities
Stool toxin
C. diff recovered from other sites
Treatment
Outcome
Other microbes recovered
Spencer, 1984
64321 76
65, M
Claudication, painful and swollen left foot (toe gangrene)
Aorto femoral bypass
No
Not Reported
Negative
Unknown
PO vancomycin, cefuroxime, IV metronidazole
Recovered from current episode and died due to staph aureus septicemia
Bacteroides Fragilis
Rampling, 1985
38572 33
35, F
Abdominal pain, Fever, Diarrhea, Jaundice
No
Yes
Positive
Unknown
PO vancomycin, IV metronidazole
Died
Bacteroides spp,and group D streptococci
Rampling, 1985
38572 33
69, F
Admitted for CNS metastasis of leukemia
No
Positive
No
IV metronidazole, cloxacillin, cotrimoxazole, ampicillin, and gentamicin
Died
Bacteroides spp, Escherichia coli
Gerard, 1989
24970 02
39, M
Fevers, Left mandible radionecrosis
No
Feldman, 1995
75485 12
85, F
Recurrent diarrhea, fever, hypotension
Escherichia coli, Enterococcus fecalis, Bacteroides vulgatos Enterococcus fecalis
M AN U
TE D
Acute myeloid leukemia, neutropenic post cytotoxic therapy, Jaundice Acute lymphoblastic leukemia
AC C
EP
yes
SC
Author, Year
Unknown
Oral cancer
Unknown
Unknown
IV and PO vancomycin, metronidazole, perfloxacin
Recovered
No
Yes
CVA
Positive
Unknown
vancomycin, gentamycin
Recovered
ACCEPTED MANUSCRIPT
97877 41
17, M
Ileus, partial small bowel obstruction
No
Yes
Duchenne musculai dystrophy
Not tested
Unknown
Unknown
Recovered
Candida Parapsilosis
Wolf, 1998
97877 41
33, F
Pelvic abscess and rectovaginal fistula
No
Yes
Metastatic cervical cancer
Not tested
Unknown
Unknown
Died
Wolf, 1998
97877 41
77, M
Perforated sigmoid diverticulum
No
Yes
Severe emphysema on steroids
Unknown
Unknown
Died
Clostridium cadaveris, Bacteroides melaninogenicu s, Fusobacterium spp. Eubacterium lentum
GarciaLechuz, 2001
11591 212
66, M
Pyelonephriti s
No
Unknown
GarciaLechuz, 2001
11591 212
65, M
Ischemic colitis
Cardiac surgery, ischemic colitis
Unknown
Zheng, 2007
17531 516 17531 516 19723 585
40, M
Abdominal Pain, diarrhea, vomiting, fever
Lee, 2010
20678 312
45, M
abdominal pain
No
No
SC
M AN U
Not tested
Bladder cancer with metastasis
Not tested
Unknown
Imipenem
Died
Obesity
Not tested
Unknown
ceftriaxone and ciprofloxacin
Died
Unknown
Unknown
ceftriaxone
Recovered
Staphylococcus epidermidis
Positive
Unknown
ceftriaxone
Died
Coagulasenegative, Staphylococcus spp.
TE D
EP
Eliott, 2009
Yes
AC C
Zheng, 2007
No patient related information reported No patient related information reported
RI PT
Wolf, 1998
Unknown
Liver failure, alcoholism, bone marrow suppresion from alcohlism, pancreatitis Liver cirrhosis
Enterococcus faecium, Bacteroids fragilis Enteroccus faecium, Bacteroides ovatus
ACCEPTED MANUSCRIPT
20678 312
83, M
Fever, Bloody stool
No
Unknown
None
Negative
Unknown
Imipenem
Died
Escherichia coli
Lee, 2010
20678 312
87, F
Bloody stool
No
Unknown
CHF, ESRD
Positive
Unknown
vancomycin and meropenem
Recovered
Lee, 2010
20678 312
80, F
Bloody stool
No
Unknown
Liver cirrhosis
Positive
Unknown
metronidazole
Recovered
Lee, 2010
20678 312
66, F
Fever, abdominal pain, lower GI bleeding
Yes - Hip surgery
Unknown
Pseudomonas aeruginosa, Enterococcus faecium, E. coli, ESBL– Klebsiella oxytoca Coagulasenegative staphylococcus spp. Enterobacter cloacae
Lee, 2010
20678 312
75, F
No
Unknown
Hemminger, 2011
21509 425
83, M
Fever, abdominal pain, vomiting Fever, Abdominal pain, nausea, vomiting, confusion, respiratory distress
Hemminger, 2011
21509 425
39, M
Yes- Cecal Perforation
No
SC
M AN U Femoral neck fracture
Negative
Unknown
cefepime and metronidazole
Recovered
Lymphoma
Unknown
Unknown
cefepime and metronidazole
Recovered
K. pneumoniae, Clostridium perfringens
CAD, ESRD, Right hemicolecto my (10 months prior), malnutrition
Negative
Unknown
IV metronidazole
Recovered
Escherichia coli
Gastric adenocarcino ma s/p tumor resection and chemoradiati on
Not tested
Unknown
Unknown
Recovered but discharged hospice to advanced cancer
Candida glabrata
TE D No
EP
AC C
Abdominal pain, vomiting, obstipation
Yes localized bowel perf
RI PT
Lee, 2010
ACCEPTED MANUSCRIPT
24179 365
50, M
nausea, vomiting from small bowel obstruction
Yes perforation, free bowel abscess, and partial obstruction of jejunum.
No
Crohn's disease on biologics
Negative
Studemeister , 1987
35653 49
62, M
nausea, vomiting fever
No
Unknown
Unknown
Matilla E, 2013
23771 984
72, F
Fevers, diarrhea
Yes Resection of colon
Unknown
HTN, coronary bypass surgery, appendectom y, cholecystecto my, aortofemoral bypass grafting Colon cancer with peritoneal carcinomatos is
Recovered
Escherichia coli, Enterococcus Faecalis, and Klebsiella Oxytoca
Splenic abscess
piperacillin, netilmycin, metronidazole
Recovered
Pseudomonas paucimobilis
Unknown
Unknown
Died
Bacteroides fragilis
SC
M AN U
TE D
ampicillin/ sulbactam, gentamicin, pipercillintazobactam
Unknown
RI PT
Daruwala, 2009
Unknown
AC C
EP
Abbreviations: CHF, Congestive heart failure; ESRD, end-stage renal disease; GI, gastrointestinal; AAA, abdominal aortic aneurysm; UTI, urinary tract infection; PO, oral; IV, intravenous; Mo, month
ACCEPTED MANUSCRIPT
Technical Appendix Table 2: Laboratory Results at admission of our patient Patient's results
Reference range
Leukocyte Count
6.8 billion cells/L
4.00 - 10.00 x billion cells/L
Hemoglobin
13.0 gm/dL
14.3-18.3 g/dL
Platelets
131 billion cells/L
150-400 x 10 /L
Sodium
114 mmol/L
136-145 mmol/L
Potassium
3.7 mmol/L
3.5-5.1 mmol/L
Bicarbonate
16 mmol/L
Urea
8 mmol/L
Creatinine
1.62 mg/dL
Total bilirubin
17.5 mg/dL
Conjugated bilirubin
9.5 mg/dL
0.0-0.3 mg/dL
Total protein
6.4 g/dL
6.4-8.6 g/dL
Albumin
2.3 gm/dL
35–52 g/L
Alkaline phosphatase
234 U/L
40–120 U/L
SC
M AN U
TE D
EP
AC C
Alanine transaminase
9
23-29 mmol/L 8-22 mg/dL
0.6-1.4 mg/dL
0.3-1.2 mg/dL
83 U/L
10–40 U/L
294 U/L
15–40 U/L
65 µmol/L
11-35 µmol/L
Hepatitis A IgM antibody
Negative
Negative
Hepatitis B surface antigen
Negative
Negative
Aspartate transaminase Ammonia
RI PT
Laboratory investigation
ACCEPTED MANUSCRIPT
Negative
Negative
Hepatitis C antibody
Negative
Negative
INR
2.4
1 international units
Lactic acid
8.2 mmol/L
0.5-2.2 mmol/L
Blood ethanol level
59 mg/dL
< 10 mg/dL
AC C
EP
TE D
M AN U
SC
RI PT
Hepatitis B core IgM antibody
ACCEPTED MANUSCRIPT
RI PT
Technical Appendix Table 3: Culture Data
Time Collected
Initial Identification
Final Identification
Time to final positivity
Blood venipuncture
Day 1
Gram-negative bacilli
Clostridium difficile
6 days, 2 hrs
Blood venipuncture
Day 1
Gram-variable bacilli
Blood venipuncture
Day 3
Gram-variable bacilli
Blood venipuncture
Day 3
Gram-variable bacilli
Clostridium difficile
4 days
Urine culture
Day 3
No growth
No growth
1 day
Stool Nucleic Acid Amplification
Day 4
Toxigenic C. difficile
7 hrs
M AN U Clostridium difficile
5 days, 19 hrs
Clostridium difficile
4 days
TE D
EP AC C
SC
Source
S0002-9343(15)00458-1
DOI:
10.1016/j.amjmed.2015.05.014
Reference:
AJM 13011
To appear in:
The American Journal of Medicine
Received Date: 14 April 2015 Revised Date:
16 May 2015
Accepted Date: 18 May 2015
Please cite this article as: Kazanji N, Gjeorgjievski M, Yadav S, Mertens AN, Lauter C, Monomicrobial vs Polymicrobial Clostridium difficile bacteremia: A Case Report and Review of the Literature, The American Journal of Medicine (2015), doi: 10.1016/j.amjmed.2015.05.014. 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.
ACCEPTED MANUSCRIPT
1 2
Title: Monomicrobial vs Polymicrobial Clostridium difficile bacteremia: A Case Report and Review of the Literature
3 4 5
Noora Kazanji DO , Mihajlo Gjeorgjievski MD , Siddhartha Yadav MD , Amy N. Mertens DO , Carl Lauter MD MACP3
1
2
1
11
Corresponding Author:
12
Noora Kazanji, DO
13
Department of Internal Medicine
14
Beaumont Health System
15
3601 W 13 Mile Rd
16
Royal Oak, MI 48073
17
USA
18
Email: [email protected]
19
Phone: 248 551 3000
20
Fax: 248 551 1163
21
SC
RI PT
1. Resident Physician, Department of Internal Medicine, Beaumont Health System 2. Chief Medical Resident, Department of Internal Medicine, Beaumont Health System 3. Director, Division of Allergy and Immunology. Member, Division of Infectious Diseases, Beaumont Health System
M AN U
6 7 8 9 10
1
Funding Source: None
23 24 25 26 27 28 29 30 31
Conflict of Interest Statement: On behalf of all authors, the corresponding author states that there is no conflict of interest.
33 34 35
Note: All authors had access to the data and played a role in writing the manuscript. The results presented in this paper have not been published previously in whole or part, except in abstract form.
EP
Article Type: Clinical Communications to the Editor
Keywords: Clostridium difficile; bacteremia; Anaerobe; Monomicrobial bacteremia; Polymicrobial bacteremia Running Head: C. difficile monomicrobial bacteremia Acknowledgments: None
AC C
32
TE D
22
36 37 38 39 40 1
ACCEPTED MANUSCRIPT
To the editor: Extra-intestinal Clostridium difficle (C. difficile) infections account for less than 0.2% of all C. difficile infections [1]. C. difficile bacteremia is even more unusual and only a handful of cases have been described. When bacteremia occurs, it is commonly polymicrobial and associated with other intestinal flora [1]. We present a unique case of monomicrobial C. difficile bacteremia and compare all reported cases in the literature of monomicrobial C. difficile bacteremia with cases of polymicrobial C. difficile bacteremia.
48 49 50 51 52 53 54 55 56 57 58
A 40 year-old man with a past medical history significant for alcohol abuse presented with a one week history of abdominal pain and vomiting. He denied recent antibiotic use. He had normal vitals, jaundice, abdominal tenderness and distension, gynecomastia, and asterixis. Laboratory results revealed thrombocytopenia, hyponatremia, acute kidney injury, transaminitis, elevated International Normalized Ratio (INR), and lactic acidosis. An abdominal CT scan demonstrated cirrhosis, gastrohepatic varices, and colitis. Two separate blood cultures were drawn on day one and again on day three. Due to clinical deterioration on day three, antibiotic coverage was broadened from ceftriaxone to intravenous vancomycin and piperacillin-tazobactam. The patient expired on day three due to severe hypotension. All four sets of blood cultures returned positive for C. difficile after six days of inoculation. A stool sample collected shortly before his death returned positive for toxigenic C. difficile.
59 60 61 62 63 64 65 66 67 68 69 70 71 72
Although rare, C. difficile can present as monomicrobial bacteremia as was exemplified by our case. In order to better understand the pathogenesis, we reviewed all 44 cases of C. difficile bacteremia reported thus far in the literature and compared several factors between monomicrobial and polymicrobial C. difficile bacteremia. The cases were obtained thorough PubMed with key words: “clostridium”, “difficile”, “bacteremia”, “infection.” There was no temporal limit, beginning from the first case reported in 1962.
73 74 75 76 77 78 79 80 81 82
Several hypotheses have been formulated to understand the etiopathogenesis of C. difficile bacteremia. One familiar mechanism is the direct transfer of polymicrobial gut flora to the bloodstream through a site of injury in the intestinal mucosa [2]. Bacterial translocation is another mechanism; any factor disrupting the normal intestinal mucosal barrier such as inflammation or immunosuppression can promote translocation of bacteria from the intestine to the lymph nodes, peritoneum and blood [3]. Given the polymicrobial nature of the intestinal flora, a different method is needed to explain monomicrobial C. difficile bacteremia. In our review, five cases of the monomicrobial group were noted to have extraintestinal foci compared to only one case in the polymicrobial group [2-6]. This important difference suggests that evaluation for further infective foci should be considered as a mechanism for monomicrobial C. difficile bacteremia.
83 84
References:
85 86 87 88
M AN U
SC
RI PT
41 42 43 44 45 46 47
AC C
EP
TE D
The most common presenting symptoms of C. difficile bacteremia was fever (60%) followed by abdominal pain (43%). There were no significant differences (p>0.05) between monomicrobial and polymicrobial C. difficile bacteremia with regard to recent surgery, presence of bowel perforation, recent antibiotic usage, presence of liver disease, malignancy, or positive stool toxin. The presence of blood in the stool, however, was more common in polymicrobial C. difficile bacteremia (p<0.05). Overall mortality was 39%. Underlying liver disease or malignancy was present in 64% of cases. This suggests that C. difficile bacteremia may simply be a prognostic marker of severe underlying immunodeficiency.
1. Balzan S, Almeida C, Cleva R et aI. Bacterial translocation: overview of mechanisms and clinical impact. J Gastroenterol Hepatol 2007Apr;22(4):464-471. 2. Durojaie O, Gaur S, Alsaffar L. Bacteraemia and breast abscess: unusual extraintestinal manifestations of Clostridium difficile infection. J Med Microbiol. 2011 Mar;60(Pt 3):378-80
2
ACCEPTED MANUSCRIPT
89 90 91 92
3. Mattila E, Arkkila P, Mattila PS et al. Extraintestinal Clostridium difficile infections. Clin Infect Dis 2013 Sep;57(6):e148-53.
93 94 95 96 97 98
5. Duthilly A, Blanckaert K, Thielemans B et. al. Clostridium difficile bacteremia. PresseMed. 2001 Dec 8;30(37):1825-6.
99
Table 1: Summary of all reported cases of monomicrobial and polymicrobial C. difficile bacteremia
4. Kaufman E, Liska D, Rubinshteyn V et al. Clostridium difficile bacteremia. Surg Infect. 2013 Dec;14:559-60.
RI PT
6. Saginur R, Fogel R, Begin L et. al. Splenic abscess due to Clostridium difficile. Infect Dis.1983 Jun;147(6):1105.
100
Table 2: Patient laboratory results
101
Table 3: Patient culture data
SC
Technical Appendix
AC C
EP
TE D
M AN U
102
3
ACCEPTED MANUSCRIPT
RI PT
Technical Appendix
Technical Appendix Table 1: Summary of all reported cases of monomicrobial and polymicrobial Clostridium difficile bacteremia
SC
Reports of Monomicrobial Clostridium difficile bacteremia:
PubMed ID
Age Sex
Presenting signs
Surgery or Perforation
Recent antibiotic use
Other comorbidities
Smith, 1962
13914327
5Mo ,M
Cough, Coryza, Anorexia
Unknown
Unknown
None
Not tested
Byl, 1996
8729213
18, M
Fevers, Chills, Abdominal pain, Vomiting, Diarrhea
No
Yes
None
Byl, 1996
8729213
78, M
Trauma, Aspiration, Fevers, Diarrhea
No
Libby, 2009
19398213
40, F
Fatigue, weight loss
Lee, 2010 Lee, 2010
20678312
69, F 38, M
Dead on arrival
Abdominal pain
Treatment
Outcome
Unknown
Unknown
Positive
No
PO vancoymycin
Recovered
None
Negative
Unknown
IV and PO vancomycin
Survived
Yes
Acute myeloid leukemia
Not tested
No
vancomycin, cefepime, metronidazole
Died
None
Unknown
Positive
No
None
No
Unknown
Liver cirrhosis Wilson disease
Negative
No
cefmetazole
Dead on arrival Died
TE D Yes
EP
AC C
20678312
C. diff recovere d from other sites Unknown
No
Stool toxin
M AN U
Author, Year
ACCEPTED MANUSCRIPT
20678312
65, F
Fevers, Abdominal pain
Perforated peptic ulcer with laporotomy
Unknown
None
Unknown
Lee, 2010
20678312
58, M
Fevers, Abdominal pain
No
Unknown
Liver Cirrhosis
Negative
Lee, 2010
20678312
12, M
Fevers, Dyspnea
No
Unknown
Biliary Atresia
Negative
Lee, 2010
20678312
41, F
Fevers, Dyspnea
No
Unknown
Pulmonary Fibrosis
Negative
Durojaie, 2011
21127155
39, F
Menorrhagia and spontaneous bruising
No
Yes
Chronic hepatitis and alcoholic liver disease
Unknown
Mcgill, 2011
24111758
39, M
Jaundice, vomiting, fecal incontinence
No
No
Alcoholic liver disease
Mcgill, 2011
24111758
20, M
Fevers, tachycardia, acidosis
Elective subtotal colectomy
Kaufman, 2013
24111758
57, M
Abdominal pain
No
metronidazole
Died
No
metronidazole
Recovered
No
piperacillintazobactam and vancomycin ceftazidime, gentamycin, vancomycin
Recovered
Breast abscess
AmoxicillinClavulanate and Metronidazole
Recovered
Not tested
No
cefuroxime, metronidazole
Recovered
Juvenile polyposis syndrome
Positive
No
Recovered
Mantle cell lymphoma
Unknown
Peritonea l fluid
Enteral vancomycin, IV meropenem, IV metronidazole IV vancomycin, metronidazole
SC
M AN U
TE D
AC C
EP
Yes
Unknown
No
RI PT
Lee, 2010
No
Recovered
Hospice
ACCEPTED MANUSCRIPT
23667848
60, M
Fever, rectal stricture, hydronephrosis, metastatic prostate cancer
Loop ileostomy
Yes
Prostate cacner with metastasis to multiple sites
Negative
Matilla E, 2013
23771984
69, M
Abdominal pain, fevers, ischemic colitis, diarrhea
AAA repair
Yes
Unknown
Duthilly, 2001
11776702
66, M
Fever, diarrhea, anal margin abscess
drainage of abscess
unknown
Paraparesis, recurrent UTI, Fulminant colitis 6 months prior to presentation AML
Saginur, 1983
6854068
68, M
ascites, hepatic encephalopathy
No
no
Cid, 1998
9542965
3, M
Fever, odynophagia, acute pericarditis
No
Current, 2014
Current case
40, M
Abdominal pain, Vomiting
Unknown
Hospice
Resected AAA, adjacent lymph node
Unknown
Recovered
Unknown
anal margin abscess
IV metronidazole
Recovered
Cirrhosis, chronic pancreatitis
Unknown
Penicillin G
Died
Thalasemia minor, recurrent tonsilitis
Not tested
Splenic abscess, ascitic fluid No
Recovered
Alcoholic liver disease
Positive
IV vancomycin, amoxicillinclavulanic acid, cefotaxime IV vancomycin, IV piperacillintazobactam
SC
AC C
No
M AN U
TE D
EP
Yes
Yes
Unknown
RI PT
Choi, 2013
No
Died
ACCEPTED MANUSCRIPT
RI PT
Reports of Polymicrobial Clostridium difficile bacteremia:
PubM ed ID
Age Sex
Presenting signs
Surgery or Perforation
Recent abx use
Other comorbidities
Stool toxin
C. diff recovered from other sites
Treatment
Outcome
Other microbes recovered
Spencer, 1984
64321 76
65, M
Claudication, painful and swollen left foot (toe gangrene)
Aorto femoral bypass
No
Not Reported
Negative
Unknown
PO vancomycin, cefuroxime, IV metronidazole
Recovered from current episode and died due to staph aureus septicemia
Bacteroides Fragilis
Rampling, 1985
38572 33
35, F
Abdominal pain, Fever, Diarrhea, Jaundice
No
Yes
Positive
Unknown
PO vancomycin, IV metronidazole
Died
Bacteroides spp,and group D streptococci
Rampling, 1985
38572 33
69, F
Admitted for CNS metastasis of leukemia
No
Positive
No
IV metronidazole, cloxacillin, cotrimoxazole, ampicillin, and gentamicin
Died
Bacteroides spp, Escherichia coli
Gerard, 1989
24970 02
39, M
Fevers, Left mandible radionecrosis
No
Feldman, 1995
75485 12
85, F
Recurrent diarrhea, fever, hypotension
Escherichia coli, Enterococcus fecalis, Bacteroides vulgatos Enterococcus fecalis
M AN U
TE D
Acute myeloid leukemia, neutropenic post cytotoxic therapy, Jaundice Acute lymphoblastic leukemia
AC C
EP
yes
SC
Author, Year
Unknown
Oral cancer
Unknown
Unknown
IV and PO vancomycin, metronidazole, perfloxacin
Recovered
No
Yes
CVA
Positive
Unknown
vancomycin, gentamycin
Recovered
ACCEPTED MANUSCRIPT
97877 41
17, M
Ileus, partial small bowel obstruction
No
Yes
Duchenne musculai dystrophy
Not tested
Unknown
Unknown
Recovered
Candida Parapsilosis
Wolf, 1998
97877 41
33, F
Pelvic abscess and rectovaginal fistula
No
Yes
Metastatic cervical cancer
Not tested
Unknown
Unknown
Died
Wolf, 1998
97877 41
77, M
Perforated sigmoid diverticulum
No
Yes
Severe emphysema on steroids
Unknown
Unknown
Died
Clostridium cadaveris, Bacteroides melaninogenicu s, Fusobacterium spp. Eubacterium lentum
GarciaLechuz, 2001
11591 212
66, M
Pyelonephriti s
No
Unknown
GarciaLechuz, 2001
11591 212
65, M
Ischemic colitis
Cardiac surgery, ischemic colitis
Unknown
Zheng, 2007
17531 516 17531 516 19723 585
40, M
Abdominal Pain, diarrhea, vomiting, fever
Lee, 2010
20678 312
45, M
abdominal pain
No
No
SC
M AN U
Not tested
Bladder cancer with metastasis
Not tested
Unknown
Imipenem
Died
Obesity
Not tested
Unknown
ceftriaxone and ciprofloxacin
Died
Unknown
Unknown
ceftriaxone
Recovered
Staphylococcus epidermidis
Positive
Unknown
ceftriaxone
Died
Coagulasenegative, Staphylococcus spp.
TE D
EP
Eliott, 2009
Yes
AC C
Zheng, 2007
No patient related information reported No patient related information reported
RI PT
Wolf, 1998
Unknown
Liver failure, alcoholism, bone marrow suppresion from alcohlism, pancreatitis Liver cirrhosis
Enterococcus faecium, Bacteroids fragilis Enteroccus faecium, Bacteroides ovatus
ACCEPTED MANUSCRIPT
20678 312
83, M
Fever, Bloody stool
No
Unknown
None
Negative
Unknown
Imipenem
Died
Escherichia coli
Lee, 2010
20678 312
87, F
Bloody stool
No
Unknown
CHF, ESRD
Positive
Unknown
vancomycin and meropenem
Recovered
Lee, 2010
20678 312
80, F
Bloody stool
No
Unknown
Liver cirrhosis
Positive
Unknown
metronidazole
Recovered
Lee, 2010
20678 312
66, F
Fever, abdominal pain, lower GI bleeding
Yes - Hip surgery
Unknown
Pseudomonas aeruginosa, Enterococcus faecium, E. coli, ESBL– Klebsiella oxytoca Coagulasenegative staphylococcus spp. Enterobacter cloacae
Lee, 2010
20678 312
75, F
No
Unknown
Hemminger, 2011
21509 425
83, M
Fever, abdominal pain, vomiting Fever, Abdominal pain, nausea, vomiting, confusion, respiratory distress
Hemminger, 2011
21509 425
39, M
Yes- Cecal Perforation
No
SC
M AN U Femoral neck fracture
Negative
Unknown
cefepime and metronidazole
Recovered
Lymphoma
Unknown
Unknown
cefepime and metronidazole
Recovered
K. pneumoniae, Clostridium perfringens
CAD, ESRD, Right hemicolecto my (10 months prior), malnutrition
Negative
Unknown
IV metronidazole
Recovered
Escherichia coli
Gastric adenocarcino ma s/p tumor resection and chemoradiati on
Not tested
Unknown
Unknown
Recovered but discharged hospice to advanced cancer
Candida glabrata
TE D No
EP
AC C
Abdominal pain, vomiting, obstipation
Yes localized bowel perf
RI PT
Lee, 2010
ACCEPTED MANUSCRIPT
24179 365
50, M
nausea, vomiting from small bowel obstruction
Yes perforation, free bowel abscess, and partial obstruction of jejunum.
No
Crohn's disease on biologics
Negative
Studemeister , 1987
35653 49
62, M
nausea, vomiting fever
No
Unknown
Unknown
Matilla E, 2013
23771 984
72, F
Fevers, diarrhea
Yes Resection of colon
Unknown
HTN, coronary bypass surgery, appendectom y, cholecystecto my, aortofemoral bypass grafting Colon cancer with peritoneal carcinomatos is
Recovered
Escherichia coli, Enterococcus Faecalis, and Klebsiella Oxytoca
Splenic abscess
piperacillin, netilmycin, metronidazole
Recovered
Pseudomonas paucimobilis
Unknown
Unknown
Died
Bacteroides fragilis
SC
M AN U
TE D
ampicillin/ sulbactam, gentamicin, pipercillintazobactam
Unknown
RI PT
Daruwala, 2009
Unknown
AC C
EP
Abbreviations: CHF, Congestive heart failure; ESRD, end-stage renal disease; GI, gastrointestinal; AAA, abdominal aortic aneurysm; UTI, urinary tract infection; PO, oral; IV, intravenous; Mo, month
ACCEPTED MANUSCRIPT
Technical Appendix Table 2: Laboratory Results at admission of our patient Patient's results
Reference range
Leukocyte Count
6.8 billion cells/L
4.00 - 10.00 x billion cells/L
Hemoglobin
13.0 gm/dL
14.3-18.3 g/dL
Platelets
131 billion cells/L
150-400 x 10 /L
Sodium
114 mmol/L
136-145 mmol/L
Potassium
3.7 mmol/L
3.5-5.1 mmol/L
Bicarbonate
16 mmol/L
Urea
8 mmol/L
Creatinine
1.62 mg/dL
Total bilirubin
17.5 mg/dL
Conjugated bilirubin
9.5 mg/dL
0.0-0.3 mg/dL
Total protein
6.4 g/dL
6.4-8.6 g/dL
Albumin
2.3 gm/dL
35–52 g/L
Alkaline phosphatase
234 U/L
40–120 U/L
SC
M AN U
TE D
EP
AC C
Alanine transaminase
9
23-29 mmol/L 8-22 mg/dL
0.6-1.4 mg/dL
0.3-1.2 mg/dL
83 U/L
10–40 U/L
294 U/L
15–40 U/L
65 µmol/L
11-35 µmol/L
Hepatitis A IgM antibody
Negative
Negative
Hepatitis B surface antigen
Negative
Negative
Aspartate transaminase Ammonia
RI PT
Laboratory investigation
ACCEPTED MANUSCRIPT
Negative
Negative
Hepatitis C antibody
Negative
Negative
INR
2.4
1 international units
Lactic acid
8.2 mmol/L
0.5-2.2 mmol/L
Blood ethanol level
59 mg/dL
< 10 mg/dL
AC C
EP
TE D
M AN U
SC
RI PT
Hepatitis B core IgM antibody
ACCEPTED MANUSCRIPT
RI PT
Technical Appendix Table 3: Culture Data
Time Collected
Initial Identification
Final Identification
Time to final positivity
Blood venipuncture
Day 1
Gram-negative bacilli
Clostridium difficile
6 days, 2 hrs
Blood venipuncture
Day 1
Gram-variable bacilli
Blood venipuncture
Day 3
Gram-variable bacilli
Blood venipuncture
Day 3
Gram-variable bacilli
Clostridium difficile
4 days
Urine culture
Day 3
No growth
No growth
1 day
Stool Nucleic Acid Amplification
Day 4
Toxigenic C. difficile
7 hrs
M AN U Clostridium difficile
5 days, 19 hrs
Clostridium difficile
4 days
TE D
EP AC C
SC
Source