This document discusses antibiotic-associated diarrhea (AAD) and Clostridium difficile infection (CDI). It provides information on the mechanisms by which antibiotics can cause diarrhea, such as altering intestinal flora and bacterial overgrowth. It also discusses various pathogens that can cause AAD, including C. difficile, C. perfringens, K. oxytoca, and S. aureus. The document outlines the clinical presentation, diagnosis, risk factors and complications of CDI. It describes treatments for CDI including metronidazole, vancomycin and newer approaches like fecal transplants.

1. Antibiotic-Associated Diarrhea
Samir Haffar M.D.
Assistant Professor of Gastroenterology
Al-Mouassat University Hospital – Damascus – Syria
Amphitheatre, 7th May 2012

2. Antibiotic-Associated Diarrhea (AAD)
5 – 25% depending on causative antibiotic
• Motilin receptor agonist Erythromycin
• Stimulate bowel motility Clavulanate
• Intestinal flora alteration Decreased carbohydrate metab
SCFA → Osmotic diarrhea
Decreased PBA metabolism
PBA → Secretory diarrhea
• Overgrowth of pathogenic micro-organisms
SCFA: Short Chain Fatty Acid
PBA: Primary Biliary Acid
Gorkiewicz G. Int J Antimicrobial Agents 2009 ; 33 : S37 – S41.

3. Major infectious agent in AAD
Causative agent unknown in most cases
• Candida overgrowth Controversial
• Clostridium Perfringens Food poisoning
Necrotizing entero-colitis
• Staphylococcus Aureus Food poisoning
Diarrhea (majority MRSA*)
• Klebsiella Oxytoca Antibiotic-associated hemorrhagic colitis
• Clostridium Difficile 30% of AAD in hospitals
* MRSA: Methicillin-Resistant Staphylococcus Aureus
Gorkiewicz G. Int J Antimicrobial Agents 2009 ; 33 : S37 – S41.

4. Candida overgrowth
• AAD accompanied by raised candida in stool (> 105 CFU/mL)
• Not different from patients taking antibiotics without diarrhea
• Not different in diarrhea patients without antibiotic use
• Result of antibiotic treatment or diarrhea & not cause of AAD
No direct causative role of candida in AAD
Gorkiewicz G. Int J Antimicrobial Agents 2009 ; 33 : S37 – S41.

5. Enterotoxin-producing C. perfringens
• Major cause of food poisoning worldwide
• Can cause necrotising enterocolitis in infants & adults
• Can cause AAD & sporadic diarrhea
15% of AAD tested positive for C. perfringens or its toxin
Mere colonization due to growth after antibiotic treatment
• Not generally accepted as causative agent of AAD
Testing considered in severe AAD negative for C. difficile
* MRSA: Methicillin-Resistant Staphylococcus Aureus
Gorkiewicz G. Int J Antimicrobial Agents 2009 ; 33 : S37 – S41.

6. Necrotizing colitis
Foodborne outbreak of enterotoxigenic C. perfringens type A
Residents & staff of care facility for mentally ill in Oklahoma (n=20)
7 cases of enterotoxigenic C. perfringens type A
3 developed acute necrotizing colitis & 2 of them died
Bos J et al. Clin Infect Dis 2005 ; 40 : e78 – e83.

7. Enterotoxin-producing S. aureus
Considered cause of PMC before discovery of CD
• Important cause of food poisoning
• Can induce diarrhea after antibiotic use
7% of AAD carry significant amounts of S aureus in stool
Great proportion positive for S. aureus positive for C. difficile
Majority of AAD-associated S. aureus are MRSA strains
• Not generally accepted as causative agent of AAD
Testing considered in severe AAD negative for C. difficile
* MRSA: Methicillin-Resistant Staphylococcus Aureus
Gorkiewicz G. Int J Antimicrobial Agents 2009 ; 33 : S37 – S41.

8. Klebsiella Oxytoca (AAHC)*
First described by Toffler in 1978
• Antibiotic Penicillin-like antibiotic – Intake of NSAID
• Presentation Bloody diarrhea – Severe abdominal cramps
• Endoscopy Mucosal hemorrhage & edema
Segmental: right colon – sparing rectum
• Biopsy Colitis induced by toxin-producing bacteria
Loss of goblet cells, mucosal hemorrhage
Mild to moderate inflammation
• Treatment Resolves if antibiotic stopped – Quinolones
* AAHC: Antibiotic-Associated Hemorrhagic Colitis
Gorkiewicz G. Int J Antimicrobial Agents 2009 ; 33 : S37 – S41.

9. Antibiotic-associated hemorrhagic colitis
Mucosal hemorrhage – Segmental distribution
View of transverse colon Close-up view
Mucosal edema & hemorrhage Mucosal hemorrhage
Most sensitive test for diagnosis: culture of colonic biopsy
Hŏgenauer C et al. N Engl J Med 2006 ; 355 : 2418 – 26.

10. Antibiotic-Associated Hemorrhagic Colitis
Recto-sigmoid view Sigmoid biopsy (H & E)
Hyperemic mucosa Extensive subepithelial hemorrhage
Submucosal hemorrhage Consistent with colitis & ischemic injury
Chen J et al. Gastrointest Endoscopy 2004 ; 60 : 142 – 145.

11. Clostidium Difficile
“Difficile”→ Unusual difficulty in isolating & culturing
Gram-positive bacterium
Obligate anaerobe
Spore-forming: Relapse
Persistence
Toxin-producing: Toxin A & B
Rivals MRSA* as most common organism to cause
healthcare-associated infections in US
* MRSA: Methicillin-Resistant Staphylococcus Aureus

12. Clostridium difficile pathogenicity locus
Five genes (TcdA – E)
TcdA Gene encoding toxin A
TcdB Gene encoding toxin B
TcdD Gene encoding positive regulator of toxin transcription
TcdC Gene encoding negative regulator of toxin production
TcdE Gene encoding toxin disrupting bacterial membrane

13. Pathogenesis of CD-associated diarrhea & colitis
Kyne L et al. Gastroenterol Clin North Am 2001; 30 : 753.

14. Clinical practice guidelines for CDI in adults
2010 update
Society for Healthcare Epidemiology of America
(SHEA)
Infectious Diseases Society of America
(IDSA)
Cohen SH et al. Infect Control Hosp Epidemiol 2010 ; 31(5) : 431 – 455.

15. CDI epidemiology
Incidence of CDI appears to be increasing in the US
348,950
138,954
Healthcare Cost and Utilization Project (HCUP).
http://hcupnet.ahrq.gov.

16. Increased incidence especially in patients ≥ 65 years
20.4/1,000
15.2/1,000
8.29/1,000
2.97/1,000
Healthcare Cost and Utilization Project (HCUP).
http://hcupnet.ahrq.gov.

17. Novel epidemic strain
First reported in Canada in 2003
“NAP1 / BI / 027”
North American PFGE 1 Restriction endonuclease PCR ribotype
(Pulsed-Field Gel Elctrophoresis) analysis pattern BI designation 027
Highly virulent: 16-fold higher levels of toxin A
23-fold higher levels of toxin B
Produces binary toxin CD toxin
Highly resistant to fluoroquinolones
Increased incidence, severity, mortality & relapse rate
Cartman ST et al. Int J Med Microbiol 2010 ; 300 : 387 – 395.

18. Risk factors for C. difficile infection
• Exposure to antimicrobial agents Most important
• Advanced age ≥ 65 years
• Duration of hospitalization
• Cancer chemotherapy Effect of neutropenia
• Human immunodeficiency virus
• Manipulation of GIT Surgery – Tube feeding
• Gastric acid suppression PPIs – H2RA
Clinical practice guidelines for Clostridium difficile infection in adults.
Infect Control Hosp Epidemiol 2010 ; 31 : 431 – 455.

19. Antimicrobial agents predisposing to CDI
Classification particularly useful
High risk Moderate risk Low risk
Cephalosporins Ampicillins Parenteral aminoglycosides
Clindamycin Macrolides Vancomycin
Tetracyclines Metronidazole
Fluoroquinolones Rifampin
Co-trimoxazole Rifaximin
Any antibiotic, at any dose, for any length of time,
potentially allowing C difficile to proliferate & cause disease
Shannon-Lowe J et al. BMJ 2010 ; 340 : 641 – 646.

20. Risk association of CD with PPI therapy
Random effect – 11 studies – 126 999 patients
Patients using PPIs who develop diarrhea should be evaluated for CD
Leonard J et al. Am J Gastroenterol 2007 ; 102 : 2047 – 2056.

21. Range of symptoms possible with CDI
Asymptomatic carriage 3 – 5% of adults
25 – 30% of hospitalized adults (acquired in HCF)
Mild-to-moderate diarrhea Watery diarrhea, usually not bloody
Abdominal cramping may occur
No significant abnormalities on colonoscopy
CD colitis without PM High-volume diarrhea with trace blood
Moderate-to-severe abdominal pain
Fever, malaise, & leukocytosis
Patchy & moderate colitis on colonoscopy
Pseudomembranous colitis Severe diarrhea that may be bloody
PMC Abdominal pain & tenderness
Fever & marked elevation of WBC (30 – 50 x 109/L)
Pseudo-membranes on colonoscopy
HCF: Health Care Facilities
McFee RB et al. Dis Mon 2009 ; 55 : 439 – 470.

22. Clinicians should consider possibility of CDI in
hospitalized patients who have unexplained
leukocytosis & request stool testing
Cohen SH et al. Infect Control Hosp Epidemiol 2010 ; 31(5) : 431 – 455.

23. Diagnosis of CDI
Tests Sensibility Specificity Time to results
Toxin testing
Toxin EIA 70 – 85% 95% Hours
Toxin A or toxins A & B Least sensitive
Cell cytotoxin assay 75 – 85% > 97% 2 – 3 days
Gold standard
Organism identification
Detection of GDH* 75 – 85% 95 – 99% Hours
Common antigen detection Good screening test
PCR > 90% > 97% Hours
Promising test
Stool culture > 90% > 95% 3 – 4 days
with cytotoxin testing Gold standard
* GDH: glutamate dehydrogenase
Simor AE. J Am Geriatr Soc 2010 ; 58 : 1556 – 1564.

24. 2-step method for diagnosis of CDI
Optimal testing method has yet to be established
• 1st step EIA for glutamate dehydrogenase
Negative assay considered negative
Positive assay requires further testing
• 2nd step Confirmatory test: CD strain is toxigenic
EIA for toxin A & B
Cell cytotoxin assay
Culture with cytotoxin testing
Cohen SH et al. Infect Control Hosp Epidemiol 2010 ; 31(5) : 431 – 455.

25. Real time PCR for C. difficile detection in stool
Meta-analysis – 10 studies – 7392 samples
Parameter Value 95% CI
Sensitivity 90% 88 – 91%
Specificity 96% 96 – 97%
Positive Likelihood Ratio 26.89 20.81 – 34.74
Negative Likelihood Ratio 0.11 .08 – 0.15
Diagnostic Odds Ratio 278.23 213.56 – 362.50
Area under ROC curve 0.98 0.98 – 0.99
Considerable heterogeneity (I2 > 50%) for statistical measures
Test accuracy depended on prevalence of C. difficile
Deshpande A et al. Clin Infect Dis 2011 ; 53 : e81 – e90.

26. Complications of CD associated-disease
• Pseudo-membraneous colitis (PMC)
• Toxic megacolon
• Perforation of colon
• Sepsis
• Death

27. Accordion sign in PMC
CT with oral contrast
Oral contrast media trapped between swollen haustra
Nonspecific: salmonella, shigella, compylobacter, ischemia
Macari M et al. Radiology 1999 ; 211 : 743 – 746.

28. Accordion sign in PMC
CT with only IV contrast
Modern CT machine with improved resolution
Optimal enhancement of wall with IV contrast
Razzaq R & Sukumar SA. Clin Radiol 2006 ; 61 ; 446 – 452.

29. Accordion sign in PMC
Ultrasound
Thickening of bowel wall (edematous mucosal & submucosal layers)
Effacement of colonic lumen
Prominent haustral pattern
Razzaq R & Sukumar SA. Clinical Radiology 2006 ; 61 ; 446 – 452.

30. CT in pseudo-menbranous colitis
Mucosal enhancement
Intraluminal fluid
Submucosal oedema (arrowhead)
Engorged peri-colonic vessels
Razzaq R & Sukumar SA. Clin Radiol 2006 ; 61 ; 446 – 452.

31. Endoscopic image of PMC
Raised adherent yellow plaques from 2 to 5 mm
Erythema of colonic mucosa between pseudomembranes
van Nispen tot Pannerden CMF et al. Drugs 2011 ; 71 : 853 – 868.

32. Colonic mucosa in pseudomembranous lesions
Hematoxylin & eosin stain
Volcanic eruption
Destruction of mucosa
Severe inflammatory response extending deep into lamina propria
Expulsion of mucous & cellular debris from crypts into lumen
McFee RB et al. Dis Mon 2009 ; 55 : 439 – 470.

33. Toxic megacolon in C. difficile infection
Plain abdominal X-ray
CT scan
Dilated loops of large bowel
Patient with toxic megacolon without history of IBD
should be assumed to have CDI until proven otherwise
Gouliouris T et al. Clinical Medicine 2011 ; 11 : 75 – 9.

34. Severity of CDI
• Mild to moderate WBC ≤ 15,000 cells/μl
Cr < 1.5 times pre-morbid level
• Severe WBC > 15,000 cells/μl
Cr ≥ 1.5 times pre-morbid level
• Severe complicated Hypotension
Shock
Ileus
Megacolon
Cohen SH et al. Infect Control Hosp Epidemiol 2010 ; 31 : 431 – 455.

35. General principles of treatment
• Discontinue therapy with antibiotic as soon as possible
May influence risk of recurrence
• Avoid use of antiperistaltic agents
May obscure symptoms & precipitate toxic megacolon
• When severe or complicated CDI suspected
Empirical treatment as soon as diagnosis suspected
Cohen SH et al. Infect Control Hosp Epidemiol 2010 ; 31(5) : 431 – 455.

36. CDI management approaches
“inside the box” “outside the box”
Antimicrobial agents Non-antimicrobial agents
Currently available agents Currently available agents
Metronidazole Fecal transplants
Vancomycin (FDA) IV immunoglobulin
Rifaximin Cholesteramine /Colestipol
Nitazoxanide Agents under development
Tigecycline Bovine whey protein
Bacitracin Tolevamer
Teicoplanin Nontoxigenic C. difficile
Fusidic acid Monoclonal antibodies
Agents under development Active vaccine
Fidaxomicin (FDA 2011)
Ramplanin
Gerding DN & Johnson S. Clin Infect Dis 2010 ; 51(11): 1306 – 1313.

37. Vancomycin more effective than metronidazole
for severe C difficile infection
p = 0.4 p = 0.02
90% 98% 76% 97%
Zar FA et al. Clin Infect Dis 2007 ; 45 : 302 – 307.

38. Equivalent response of low & high dose vancomycin
Fekety R et al. Am J Med 1989 ; 86 :15 – 19.

39. Treatment of initial CDI
Mild-to-moderate CDI
Metronidazole is drug of choice
500 mg PO tid for 10 – 14 days
Severe CDI
Vancomycin is drug of choice
125 mg PO qid for 10 – 14 days
Severe complicated CDI
Vancomycin (PO, NGT, rectal installation) + metronidazole IV
Vancomycin: 500 mg in 100 mL saline qid
Metronidazole: 500 mg IV tid
Consider subtotal colectomy with preservation of rectum
Cohen SH et al. Infect Control Hosp Epidemiol 2010 ; 31(5) : 431 – 455.

40. Surgery for C. difficile infection
Early surgical consultation for fulminant CDI
• Prolonging medical therapy beyond 6 days increases mortality
• Indications Megacolon
0.5 – 2.5% Colonic perforation
Acute abdomen
Septic shock (now also performed)
• Predicting factors Leukocytosis >1.5 109/l
Elevated serum lactate
• Treatment of choice Subtotal colectomy & ileostomy
Cohen SH et al. Infect Control Hosp Epidemiol 2010 ; 31(5) : 431 – 455.

41. Recurrence of CDI
Rate of recurrent CDI
20% after first episode
45% after first recurrence
65% after two or more recurrences
Treatment of 1st recurrence (1 month after successful tt)
Treat as first episode according to disease severity:
Mild-to-moderate – Severe – Severe complicated
Treatment of second recurrence
Metronidazole should not be used beyond first recurrence
Oral vancomycin (prolonged, pulsed, & tapering course)
Cohen SH et al. Infect Control Hosp Epidemiol 2010 ; 31(5) : 431 – 455.

42. Vancomycin
Prolonged, pulse-dosed, & tapering course
Week 1 : 125 mg qid
Week 2: 125 mg bid
Week 3: 125 mg qd
Week 4: 125 mg every other day
Week 5 – 6: 125 mg every 3 day
Management of non-responders or relapsers is challenging
Simor AE. J Am Geriatr Soc 2010 ; 58 : 1556 – 1564.

43. Treatment of multiple recurrences
Clinical challenge
• Fecal transplant Most effective treatment
Healthy donor (spouses) via enema, colonoscopy or NGT
• If patient refuse fecal transplant
 „Rifaximin chaser‟ approach
Vancomycin 125 mg qid po for 2 weeks then
Rifaximin 400 mg tid po for 2 weeks
 IV Immunoglobulin 300 – 500 mg/kg
Until resolution (max. 6 doses)
Leffler DA & Lamont JT. Gastroenterology 2009 ; 136 : 1899 – 1912.
Surawicz CM & Alexander J. Nat Rev Gastroenterol Hepatol 2011 ; 8 : 330 – 339.

44. Fecal transplantation for CDI
Systematic review
• No controlled studies were found
• 7 full text case series (124 patients) → weak evidence
Recurrent or refractory CDI
• Appears to be safe
• Symptoms improved immediately after first FT in 83%
Some patients stayed diarrhea free for months or years
Promising results – RCTs needed
Guo B et al. Aliment Pharmacol Ther 2012 ; 35 : 865 – 875.

45. Potential future CDI therapies
Monoclonal antibodies
200 CDI patients receiving metronidazole or vancomycin
Monoclonal antibodies (CDA1 & CDB1) 10 mg/kbw versus placebo
25% P< 0.001
Log rank test
7%
Lowy I et al. N Engl J Med 2010 ; 362 : 197 – 205.

46. Minimize transmission among healthcare personnel
Use of gloves
P = 0.015
Four wards randomized
Gloves when handling body substances (stool)
Gloves placed at bedside
Reduction in CDI and colonization on glove wards
Johnson S, et al. Am J Med 1990 ; 88 : 137 – 140.

47. Hand hygiene methods for removal
of C. difficile contamination from hands
Oughton M, et al. Infect Control Hosp Epidemiol. 2009 ; 30(10) : 939 – 944.

48. If your institution experiences an outbreak
Consider using only soap & water for hand hygiene when
caring for patients with C. difficile infection

49. Guidelines for prevention of C. difficile infection
Individual patient Limit antibiotics
Institution Hand washing after all patient contact
Isolation for patients infected with CD
Gloves & gowns when contact patients with CDI
Disinfect contaminated objects with:
Na hypochlorite, glutaraldehyde, or ethylene oxide
Regional Educate medical staff & at-risk population on CDI
Leffler DA & Lamont JT. Gastroenterology 2009 ; 136 : 1899 – 1912.

50. • antibiotics should be prescribed according to local
policies and guidelines for treatment and prophylaxis,
• avoiding broad spectrum agents
• indication for starting an antibiotic documented in
medical record, along with stop or review date;
• intravenous antibiotics should be avoided,
• shortest treatment course likely to be effective should
be prescribed;
• prescriptions should be reviewed daily
• single antibiotic doses should be used for surgical
prophylaxis if possible

51. Conclusion
• CDI can be effectively reduced by combination of prudent
antimicrobial prescribing & infection control measures
• Soap & water hand washing more effective than alcohol gel
• Wide range of symptoms in CDI
• Oral vancomycin is the treatment of choice for severe CDI
• Early surgical review is indicated for patients with
fulminant colitis & those worsening on medical therapy
• Treatment of recurrent CDI remains challenging
Gouliouris T et al. Clinical Medicine 2011 ; 11 : 75 – 9.

52. Thank You