Antibiotic Associated Diarrhoea

Transcription

1 Antibiotic Associated Diarrhoea DOES IT BLOODY MATTER? Dr Sarah Wong Infectious Diseases Advanced Trainee Austin Health 2015

2 Mr JB 71 year old presents from the community with acute left iliac fossa pain, vomiting, multiple episodes of bloody diarrhoea Past History 1. Previous heavy alcohol use 2. Open appendicectomy

3 Recent hospital admission 4 days prior no clear diagnosis on discharge Presented with colicky diffuse abdominal pain and vomiting. No diarrhoea. WCC 13.8/ Neut 12,CRP 3.4, lipase 12 CT AP: epiploic appendagitis adjacent to recto sigmoid junction Received parenteral gentamicin/ amoxicillin/ metronidazole, discharged on oral Augmentin duo forte

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5 This admission- Day 1 Day 3 on oral Augmentin duo forte hours of abdominal pain Multiple episodes of bloody diarrhoea. Clinical Examination BP 130/70, HR 110, Temperature 37.2, O2sat 96% RA, RR 22 Abdominal: moderate LIF/RIF pain, not peritonitic Bloody diarrhoea with mucous noted in ED

6 Laboratory investigations- Day 1 FBE 177/15.2 / 215 Neut 12.8 Na 140 /4.1/96/ Ur 4.7/Cr96/eGFR 78 LFT normal CRP 3.5 Lipase 19 Lactate Not performed

7 CT Abdomen Pelvis Day 2 CT AP 5 days earlier

8 CT Abdomen Pelvis Day 2 Presumed infective colitis/ C. difficile colitis IV ceftriaxone, oral metronidazole

9 Faecal Specimen Day 2 Macroscopic description Microscopy Loose Leucocytes not seen Erythrocytes not seen Clostridium Toxin gene assay by PCR Toxin B not detected Enteric Bacterial PCR panel Salmonella spp. - Shigella spp./ Enteroinvasive E coli - Campylobacter jejuni/coli - Shiga toxin 1 & 2 (Shiga producing E coli or Shigella dysenteriae) -

10 Faecal specimen Faecal Specimen Day 2 Day 3 Macroscopic description Loose Loose Microscopy Clostridium Toxin gene assay by PCR Leucocytes not seen Erythrocytes not seen Toxin B not detected Leucocytes + Erythrocytes not seen Not performed Enteric Bacterial PCR panel Negative Not performed Culture Not performed Not performed

11 ID Consult Day 3 Infective colitis Pseudomembranous colitis E. coli O157:H7 Shigella, Campylobacter, and Salmonella species Non infective colitis Ischemic colitis Inflammatory bowel disease OR

12 Faecal sample 27/6/2015 HBA MAC

13 The Question being Could this be Antibiotic associated haemorrhagic colitis w Klebsiella oxytoca?

14 Antibiotic Associated Diarrhoea Aetiology Clostridium difficile Controversial/ poorly understood Staphylococcal enterocolitis 1??Candida? In the elderly hospitalised patient 2 Enterotoxigenic Clostridium perfringens 12 Salmonellosis 13,14 1. Mandell et al., Levine et al., 1995 CID 13. Neal et al., 1994 BMJ 14. Olsen et al., 2001 NEJM 12. Asha et al., 2002 JMM

15 Antibiotic Associated Haemorrhagic Colitis Cause unknown 4 Antibiotic associated colitis not associated with Clostridium difficile 4 Mechanism?: allergy, mucosal odema, infection with Klebsiella oxytoca AAHC with Ko Specific clinical, endoscopic, histopathological and microbiological characteristics 3,4,5 3. Hogenauer et al., 2008 Emerging Infections 4. Hogenauer et al., 2006 NEJM 5. Miller et al., 1998 J Gastro. Hep

16 Klebsiella oxytoca Detected in intestines of 2-10% of healthy subjects 11 AAHC is associated with antibiotic driven enterobacterial overgrowth 12 Antibiotic clearance of a niche in the colon facilitates growth of K oxytoca ( 10 7 CFU/g faeces in acute AAHC vs 10 2 CFU/g in healthy subjects ) 12 Specific Ko strains have cytotoxic effects on human epithelial cells Zollner-Schwetz et al., 2008 CID 12. Schneditz et al., 2014 PNSA

17 Attempts to prove association Author/ Year Content No. w AAHC/(%) Sakurai 1979 (Japan) Benoit 1992 (France) Beaugerie 2003 (France) Hogenauer 2006 (Graz, Austria) N=56 acute colitis 8 patients with bloody diarrhoea post ampicillin Positive for Klebsiella Oxytoca - 3/8 patients N=20 AAD 11 (55%)? 8/11 patients N=93 acute colitis (colonic bxp) 12 patients had C. difficile, non HC 4 patients had AAHC (2 Salmonella) N= patients had AAD 4 (4%) 2/4 patients 6 (5%) 5/6 patients Zollner-Schwetz 2008 (Graz, Austria) N= patients had C. difficile 3 (3%) 3/3 patients

18 Klebsiella oxytoca as a Causative Organism of Antibiotic-Associated Haemorrhagic Colitis Hogenauer et al., 2006 NEJM Study period Setting Ko prevalence Diagnosis of infectious diarrhoea (38 months) Tertiary hospital Austria 10,000 admissions /yr 1.6% (6/385 healthy subjects) 74 cases Salmonella 54 cases campylobacter 2 cases Shigella 121 cases of C. difficile 0 cases of Yersinia/ EHEC Diagnosis of AAHC Ko 5/22 consecutive patients with suspected AAC - Positive culture for Ko - Negative for C difficile

19 Klebsiella oxytoca as a Causative Organism of Antibiotic-Associated Haemorrhagic Colitis Hogenauer et al., 2006 NEJM Ko strain AHC 1 from patient 1 70 Female Sprague- Dawley rats Ko + Aug DF Aug DF Ko Ko+ Aug DF+NSAID Aug DF+ NSAID NSAID

20 Ko + Aug DF was associated with right sided haemorrhagic colitis Ko + Aug DF Ko+ Aug DF+NSAID Morphologic change in caecum of rats 1. Mucosal inflammation 2. Epithelial alteration 3. Mucosal haemorrhage 4. Erosion (more severe in rats given indomethacin) 4. Hogenauer et al., 2006 NEJM

21 Clinical presentation AAHC Clostridium difficile AAC 8 Antibiotic exposure to Sx 2-7 days Risk factor : NSAID use 3 Symptoms Severe abdominal cramps 3,6 Bloody diarrhoea 3,6 Laboratory investigations Mild Leucocytosis 3,6 5 days to 10 weeks (longer) Fever Abdominal pain and cramping Watery profuse diarrhoea occult colonic bleeding Leucocytosis Toxin mediated Cytotoxin 3,6 Toxin B, Toxin A, Binary Toxin Colonoscopy Mucosal haemorrhage and oedema 7 Segmental distribution R side ascending colon and caecum 3 Histology 3. Hogenauer 2008 Emerging Infections 6. Green et al., 2009 CMN 7. Kishida et al., 1992 JMNS 8. Cheng et al., 2011 MJA Coagulative necrosis of surface epithelium Crypts with focal ulceration and fibrin deposition Microvascular fibrin thrombus formation Vascular engorgement Subepithelial erythrocytes 7 Non Specific Pseudomembranous colitis: Adherent inflammatory membrane (pseudomembrane) overlying sites of mucosal injury surface erosion of the superficial colonic crypts LP adjoining necrosis has infiltrate of neutrophils and eosinophils Plaque like pseudomembrane of neutrophils, fibrin, cellular debris over mucosal surface

22 Clostridium Difficile AAC 1 AAHC 3 1. Mandell et al., Hogenauer et al., 2008 Emerging Infections

23 Clinical presentation AAHC Clostridium difficile AAC Potential Complications Minimal Duration of Illness Spontaneous resolution within days once antibiotic stopped Toxic mega colon, intestinal perforation, death Brief OR profuse diarrhoea over 7-14 days Approach to treatment Withdraw antibiotics Withdraw antibiotics Add antibiotics 6. Green et al., 2009 CMN

24 TOXIN EFFECT % Cytotoxins associated with AAHC University of Graz subtypes of KO produce cytotoxin AAHC 04/1 0 clinical isolate from AAHC patient ATCC laboratory strain of KO Growth Curve 9. Joainig et al., 2010 jcm

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27 Did Mr JB have AAHC with Ko? Missed alternative pathology Limitations of C. difficile testing Presence of genetic cluster supports but does not prove cytotoxin production resulting in AAHC

28 Did Mr JB have AAHC with Ko? symptoms of bloody diarrhoea negative results for C difficile tests (toxin B) CT demonstration of colitis of the ascending colon Significant growth of K oxytoca in the stool culture The patient s rapid clinical response when Augmentin duo forte therapy was discontinued Presence of genetic cluster supports possibility of cytotoxin production resulting in AAHC

29 Consideration in the Laboratory Unformed stool specimen BOTH C difficile toxin and enteric PCR negative with WCC 2 Discuss with Medical Micro? Need for Further Bacterial Culture Clinically consistent presentation Further Bacterial culture: CIN, TCBS, XLD, MAC # Considerations on the ward-future project Radiology audit of patients over last months with CT evidence of colitis, found not to have Clostridium difficile infection or ischaemia Denominator for potential AAHC cases

30 Acknowledgements Austin Health Infectious Diseases Team Austin Health Laboratory Staff Dr Marcel Leroi Dr Jason Kwong Melbourne Diagnostics Unit Dr Sarah Sparham