1. Clostridium Difficile
Case Presentation
Introductory slide
Clostridium Difficile

2. Patient G. R. - 88 yo WM - Previous hospital admission for
Patient G.R yo WM - Previous hospital admission for pneumonia treated with piperacillin/tazobactam - Admitted to KMC on 1/17/02 for scrotal edema and diarrhea.
G.R. is a 88 y.o. WM admitted to KMC on 1/17/02 for scrotal edema and diarrhea. This patient had previously been admitted to another hospital for pneumonia and was treated with Zosyn IV. The patient subsequently was discharged to an ECF on IV ABX and developed scrotal edema and diarrhea. He was having 6-8 diarrheal stools per day.
PMH: A fib, dementia, PVD, HTN, hard of hearing
FH: unavailable
SH: short-term resident of nursing home while being treated for pneumonia
Surgical Hx: negative
Diet/Exercise: Normal diet and quite active prior to pneumonia- he was driving his car.
Patient’s Level of Understanding of Condition: weak and confused at times. Does answer questions appropriately on some days
Allergies: NKDA
Social Drug Hx: Negative

3. Physical Exam. WD thin, frail confused WM
Physical Exam WD thin, frail confused WM A & O to Person Only Mild Tenderness in RLQ Scrotal Edema Without erythema Ht: 152.4cm Wt: 40 Kg IBW: 52 Kg CrCl: 21ml/min U/S Revealed Cysts in Scrotum W/o Testicular Involvement. No Evidence of Infection.
P.E.: CV- IRRR, grade 2/6 SEM at apex
HEENT: PERRLA
Lungs: crackles in bases
Neuro: unremarkable
GI: soft abdomen, + bowel sounds, mild tenderness in RLQ
GU: scrotal edema without erythema
Musculoskeletal: unremarkable
Mental: confused
General: WD thin, frail WM A & O to person only
Ht: 152.4cm
Wt: 40 kg
IBW: 52 kg
CrCl: 21ml/min
U/S revealed cysts in scrotum w/o testicular involvement. No evidence, as well, of infection.

4. G. R. ’S Meds:. Zosyn 2. 5gm IV Q 6h. Tylenol 10gr Po Q 4 H prn
G.R.’S Meds: Zosyn 2.5gm IV Q 6h Tylenol 10gr Po Q 4 H prn Phenergan 12.5mg IV Q 6 H prn IV Fluids With KCl at 120ml/hr Coumadin 2.5mg Po qd Lanoxin 0.25mg Po qd ASA 81mg Po qd
G.R.’s medications when ID saw him:
Zosyn 2.5Gm IV q 6h
Tylenol 10gr po q 4 h prn
Phenergan 12.5mg IV q 6 h prn
IV fluids with KCl at 120ml/hr
Coumadin 2.5mg po qd
Lanoxin 0.25mg po qd
ASA 81mg po qd

5. G. R. ’S Meds: (cont’d). Atenolol 50mg Po qd
G.R.’S Meds: (cont’d) Atenolol 50mg Po qd Cardizem(diltiazem) IV for HR > Ensure Plus 1 can tid Vancomycin 125mg Po qid * Bacid 1 Capsule Po tid* Questran(cholestyramine) 1 scoopful* Lactinex 1 tablet po bid* Flagyl(metronidazole) 250mg po tid* *= Treatment related therapy
G.R.’S Meds when ID saw him:
Atenolol 50mg po qd Cardizem IV for HR > 100 Vancomycin 125mg po qid Bacid 1 capsule po tid Ensure Plus 1 can tid Questran 1 scoopful
Lactinex 1 tablet po bid Flagyl 250mg po tid

6. Cultures/Studies Stool Toxin Positive for C
Cultures/Studies Stool Toxin Positive for C. difficile 1/19/02 Urine Cx – negative 1/18/02
Stool culture on sent on 1/19/02 were positive for c. difficile

7. Treatment Changes. -Discontinue Zosyn. -Change Flagyl to 250mg po qid
Treatment Changes -Discontinue Zosyn -Change Flagyl to 250mg po qid -Discontinue Vancomycin po -Discontinue Questran -Discontinue Bacid
Treatment changes:
Discontinued Zosyn because there was no evidence of infection- pneumonia or scrotal
The Flagyl was changed to qid because the typical dose is 250mg qid or 500mg tid po
The treatment of C. difficile is the use of vancomycin or flagyl. The use of Questran, if not staggered with vancomycin po, could chelate the vancomycin. The Bacid was discontinued due to duplication with Lactinex.

8. Summary. The patient’s diarrhea gradually improved over a
Summary The patient’s diarrhea gradually improved over a period of several days and the patient was discharged to an ECF
The diarrhea symptoms improved over a few days after starting the medications and he was discharged from the hospital about 10 days later.

9. Antibiotic-Associated Diarrhea
Antibiotic-Associated Diarrhea -AAD is defined as otherwise unexplained diarrhea that occurs in association with the administration of antibiotics.
AAD is defined as otherwise unexplained diarrhea that occurs in association with the administration of antibiotics.

10. AAD Frequency of Complication
5-10% of pts treated with ampicillin
Freq. Of complications:
10-25% of pts treated with amox/clav.
15-20% of pats treated with cefixime
2-5% of those treated with other cephalosporins, quinolones, azithromycin, clarithromycin, erythromycin, and tetracycline
The rates of diarrhea assoc. with parenterally administered abxs, esp. those with enterohepatic circulation, are similar to rates assoc. with orally administered agents.
10-25% of pts treated with amoxicillin/clavulanate.
15-20% of pts treated with cefixime.
2-5% of those treated with other cephalosporins, quinolones, azithromycin, clarithromycin, erythromycin, and tetracycline.
5-10% of pts treated with ampicillin.
1 in 10 to 1 in 10,000 treated w/ clindamycin- in hospital

11. Spectrum of Findings Nuisance diarrhea Colitis Abdominal cramping
The spectrum of findings in AAD ranges from nuisance diarrhea, which is defined as freq loose and watery stools with no other complications, to colitis with clinical manifestations including Fever,leukocytosis, Fecal leukocytosis, Hypoalbuminemia, and Colonic thickening on CT and endoscopic changes
Nuisance diarrhea
Colitis
Abdominal cramping
Fever
Leukocytosis
Fecal leukocytosis
Hypoalbuminemia
Colonic thickening on CT and endoscopic changes

12. Colitis www.gicare.com/pated/ eicnclcc.htm
In the left image you see a patchy inflammation in the bowel wall. It is a mild case. In the right image, there are fluffy membranes caused by exudate and white blood cells. This is an advanced, serious case called pseudomembranous colitis.
eicnclcc.htm

13. Clostridium difficile -Gm +, spore-forming anaerobic bacillus
Clostridium difficile -Gm +, spore-forming anaerobic bacillus. -accounts for approx. 25% of the cases of AAD -accounts for the majority of cases of colitis associated with antibiotic therapy. -Causes 300,000 to 3,000,000 cases of diarrhea and colitis in the U.S. every year
-One of the more notable pathogens that cause AAD is C. difficile and it is the most common identifiable and treatable pathogen that causes AAD.
-It is a Gm +, spore-forming anaerobic bacillus. First described in 1935, but it was not associated with AAD until the late 1970’s.
C. difficile accounts for approx 25% of the cases of AAD, and accounts for the majority of cases of colitis associated with antibiotic therapy.
Causes 300,000 to 3,000,000 cases of diarrhea and colitis in the U.S. every year. This can lead to severe complications and currently is the most common cause of nosocomial diarrhea, often adding up to 2 weeks to the length of the hospitalization, at an additional cost of $6000- $10,000 per case.
The next slide describes differential diagnoses for C. difficile

14. Note the differences in chararacteristics between C
Note the differences in chararacteristics between C. difficile and other causes. Also see page 335 of the article if slide is not legible.
Bartlett J, Antibiotic-Associated Diarrhea, N Engl J Med, Vol. 346, No. 5, Jan. 31, 2002

15. Clostridium difficile
-Other Causes of AAD
-Other enteric pathogens
-Direct effects of antimicrobial agents
-Reduced fecal flora
-salmonella,
-C. perfringens type A,
-Staphylococcus aureus, and possibly
-C. albicans overgrowth
AAD may also be caused by other enteric pathogens, by the direct effects of antimicrobial agents on the intestinal mucosa, and by the metabolic consequences of reduced concentrations of fecal flora. Consequently there is reduced metabolism of –CHO, which causes osmotic diarrhea, and the rate of breakdown of primary bile acids, which are potent colonic secretory agents, may be reduced.
Other enteric pathogens that can cause diarrhea include salmonella, C. perfringens type A, Staphylococcus aureus, and possibly C. albicans. C. perfringers type A produces an enterotoxin known to cause food poisoning; more recently, a different genotype has been implicated in AAD. Infection is generally self-limiting and resolves w/I 24 hours.
S. Aureus was implicated as the chief cause of AA pseudomembraneous enterocolitis in the 1950s- perhaps a misdiagnosis for C. difficile infection or S. aureus caused a different disease- enterocolitis instead of colitis. Metonidazole is effective for C. difficile but not S. aureus.

16. Clostridium difficile
-Other Causes of AAD
-FQ-resistant disease
-Drug effects independent of motility
-Effects of non-antibiotic drugs
- Laxatives - Antacids
- Contrast Agents - Antiarrhythmics - NSAIDs - Cholinergic Agents
- Products containing lactose or sorbitol
FQ-resistant enteric disease caused by salmonella has also been reported.
Drugs affect the GI tract independent of motility. Erythromycin accelerates the rate of gastric emptying. The clavulanate in amox-clav. Appears to stimulate small-bowel motility, and in rare instances, PCN may cause segmental colitis.
Non-antibiotic drugs may be the cause of diarrhea attributed to ABX- such as laxatives, antacids, contrast agents, products with lactose or sorbitol, nonsteroidal antiinflammatory agents, antiarrhythmics agents, and cholinergic agents.

17. Pathogenesis 1. Advanced age 2. Hospitalization
Major Risk Factors for C. difficile infection:
1. Advanced age
2. Hospitalization
3. Exposure to antibiotics
A population-based study in Sweden showed that, in people who were older than 60 y.o, the incidence of positive assays for C. difficile toxin was 20 to 100 times as high as the incidence in people who were 10 to 20 years of age.
Major Risk Factors for C. difficile infection:
1. Advanced age
2. Hospitalization
3. Exposure to antibiotics

18. Clostridium Difficile - Antibiotics most frequently associated with the infection are: - Clindamycin - Ampicillin - Amoxicillin - Cephalosporins
Antibiotics most frequently associated with the infection are: - Clindamycin - Ampicillin - Amoxicillin - Cephalosporins but all antibiotics may predispose patients to C difficile infection including vancomycin and metronidazole. Oral amoxicillin/clav hs been associated with diarrhea in as many as 10% of those exposed, however, overgrowth of colonic C. difficile is less frequent with b-lactam/b-lactamase inhibitor combinations than with cephalosporins alone.

19. Clostridium difficile
Clostridium difficile Epidemiology: -Most cases occur in hospitals or LTC (rate of per 100,000 occupied bed-days) -incidence in the OP setting is 7.7 cases per 100,000 person-years
Most cases occur in hospitals or LTC (rate of per 100,000 occupied bed-days) -incidence in the OP setting is 7.7 cases per 100,000 person-years or approx cases per year in the US. Overall, the risk for developing c. difficile-assoc diarrhea within 6 weeks of a course of abx in the OP setting is low (6.7 cases per 100,000 exposures)

20. Pathogenesis
Toxinogenic C. difficile is isolated from stool specimens in only 0% to 3% of healthy adults whereas it is commonly harbored in infants and children in fecal flora, but the number of carriers decline as children age. Antibodies against c. difficile are present in most adults and older children (>60%).
During hospitalization, colonization frequently occurs (21% of patients in one study) as compared to 3% in outpatients. Colonization requires disruption of the normal flora of the colon, usually caused by aBxs, or in unusual cases, by antineoplastic or immunosuppressive drugs. Colonization occurs by the fecal-oral route, ingested spores of C difficile survive the gastric acid barrier and germinate in the colon. Symptoms of CDAD may start on the first day of ABX therapy or 6 weeks or longer after ABX therapy is stopped.
C. difficile forms spores that persist in the environment for years and contamination by C. difficile is common in hospitals and LTC facilities, esp. in rooms occupied by an infected individual. Patient-to patient transmission of the organism occurs, and the organism can be cultured from many environmental surfaces in rooms of infected patients and on hands, clothing, and stethoscopes of health care workers.
Toxinogenic C. difficile is isolated from stool specimens in only 0% to 3% of healthy adults.
During hospitalization, colonization frequently occurs.
C. difficile forms spores that persist in the environment for years and contamination by C. difficile is common in hospitals and LTC facilities

21. Pathogenesis
Clinical symptoms develop in only about 1/3 of colonized patients, and
asymptomatic colonization with C difficile may be associated with a decreased risk for development of C. Difficile-associated diarrhea.
Clinical symptoms develop in only about 1/3 of colonized patients, and
asymptomatic colonization with C difficile may be associated with a decreased risk for development of C. difficile-associated diarrhea.

22. Pathogenesis
-Two factors have recently been shown to increase the probability of symptomatic disease in patients who acquire C difficile colonization in the hospital:
1. Severity of other illnesses
2. Reduced levels of serum IgG antibody to toxin A.
Two factors have recently been shown to increase the probability of symptomatic disease in patients who acquire C difficile colonization in the hospital:
1. Severity of other illnesses
2. Reduced levels of serum IgG antibody to toxin A.
These results suggest that preexisting anti-toxin A antibody may ameliorate severity of disease and that immunization might be efficacious in preventing and controlling nosocomial CDAD.

23. Pathogenesis
-Clinically significant strain of C. difficile that cause disease produce 2 protein exotoxins, toxin A, and toxin B.
-Full tissue damage requires the action of both toxins
Clinically significant strain of C. difficile that cause disease produce 2 protein exotoxins, toxin A, and toxin B. These toxins are largely responsible for disease manifestations. Toxin B is not enterotoxic in animals (as is toxin A), but it is a much more potent cytotoxin in tissue culture than toxin A, and full tissue damage requires the action of both toxins.

24. Clinical Manifestations
The clinical presentation of CDAD is variable and includes diarrhea, colitis without pseudomembranes, pseudomembranous colitis, and fulminant colitis. Some individuals with toxigenic strains in stool remain totally asymptomatic.
-diarrhea
-colitis without pseudomembranes
-pseudomembranous colitis
-fulminant colitis
-hyperpyrexia

25. Clinical Manifestations
Mild to moderate CDAD is usually accompanied by lower abdominal cramping pain but no systemic symptoms or physical findings.
-Moderate to severe colitis usually presents with profuse diarrhea, abdominal distention with pain, and, in some cases, occult colonic bleeding.
Also, systemic symptoms such as fever, nausea, anorexia, and malaise are usually present. A minority of patients have disease primarily in the cecum and right colon, presenting with marked leukocytosis and abdominal pain but little or no diarrhea.
-Mild to moderate CDAD is usually accompanied by lower abdominal cramping pain but no systemic symptoms or physical findings.
-Moderate to severe colitis usually presents with profuse diarrhea, abdominal distention with pain, and, in some cases, occult colonic bleeding.

26. Clinical Manifestations
Fulminant Colitis- develops in approximately in 1% to 3% of patients with ileus, diarrhea, toxic megacolon, perforation, and death.
Others: hyperpyrexia, chronic diarrhea, and hypoalbuminemia with anasarca. C difficile may occasionally complicate idiopathic inflammatory bowel disease. A reactive arthritis occurring 1-4 weeks after C. difficile colitis develops in some patients.
Fulminant Colitis- develops in approximately in 1% to 3% of patients
Others: hyperpyrexia, chronic diarrhea, and hypoalbuminemia with anasarca.
C difficile may occasionally complicate idiopathic inflammatory bowel disease.
A reactive arthritis occurring 1-4 weeks after C. difficile colitis develops in some patients.

27. Diagnosis
Non-specific laboratory abnormalities: leukocytosis with left shift and fecal leukocytes in about 50-60% of cases.
Avg peripheral WBC is 12 x 109/L to 20 x 109/L.
Gram staining of fecal specimens are no value since C. difficile constitutes only a small part of the colonic flora, and its morphologic features are identical to that of other Clostridia species.
Anaerobic culture of stool (takes 2-3 days and does not distinguish between toxinogenic from nontoxinogenic strains)
-Non-specific laboratory abnormalities: leukocytosis with left shift and fecal leukocytes in about % of cases.
Avg peripheral WBC is 12 x 109/L to 20 x 109/L.
Gram staining of fecal specimens are no value
Anaerobic culture of stool (takes 2-3 days and does not distinguish between toxinogenic from nontoxinogenic strains)

28. Diagnosis
The Gold Standard test is the tissue culture assay for the cytotoxicity of toxin B (but it takes 1-3 days and requires tissue culture facilities). This test can detect as little as 10 pg of toxin in stool and has a high sensitivity (94%-100%) and specificity (99%).
ELISA- detects toxin A and/or B in stool. Rapid turnaround. Detects 100 to 1000 pg of either toxin, and has sensitivity of 71% to 94% and a specificity of 92% to 98%.
Stool samples- If results are negative, 1-2 additional samples should be sent. If first is positive, no further specimens are required.
Diagnostic testing during or at the end of treatment or during f/u is not needed, until symptoms recur. Transmission of infection to other patients is associated with ongoing diarrhea and not with the presence of the toxin in stool. Enteric precautions can be removed when diarrhea subsides, without the need for repeated diagnostic testing.
Most sensitive and specific test is a tissue culture assay for the cytotoxicity of toxin B (takes 1-3 days and requires tissue culture facilities)- GOLD STANDARD
ELISA- detects toxin A and/or B in stool. Rapid turnaround.
Stool samples- If results are negative, 1-2 additional samples should be sent. If first is positive, no further specimens are required.

29. Bartlett J, Antibiotic-Associated Diarrhea, N Engl J Med, Vol. 346, No
Bartlett J, Antibiotic-Associated Diarrhea, N Engl J Med, Vol. 346, No. 5, Jan. 31, 2002

30. Treatment Table 4. General Guidelines for the Management
of Clostridium difficile–Associated Diarrhea*
1. Isolate the patient.
2. Educate personnel to use gloves when in contact with patient and for the handling of bodily substances.
3. If possible, discontinue inciting antibiotic therapy and avoid anti-peristaltic and opiate drugs.
4. Confirm the diagnosis with a test for C difficile toxin. If the results of the first specimen are negative and diarrhea persists, 1 or 2 additional stool samples should be sent.
About 50% of all recurrences of symptoms are actually due to reinfection and not to relapse of the primary infection.

31. Treatment
5. If clinically indicated (moderate or severe diarrhea, systemic symptoms, significant leukocytosis, etc), consider antimicrobial treatment against C difficile. If the clinical suspicion is high and the patient is severely ill, empiric antimicrobial treatment may be started awaiting laboratory confirmation.
6. Oral metronidazole (250 mg 4 times per day or 500 mg 3 times per day) for d is usually adequate.
7. Oral vancomycin hydrochloride (125 mg 4 times per day) for d is indicated for those who cannot tolerate oral metronidazole, those in whom metronidazole therapy fails, pregnant patients, and, perhaps, severely ill patients.
If clinically indicated (moderate or severe diarrhea, systemic symptoms, significant leukocytosis, etc), consider antimicrobial treatment against C difficile. If the clinical suspicion is high and the patient is severely ill, empiric antimicrobial treatment may be started awaiting laboratory confirmation.
6. Oral metronidazole (250 mg 4 times per day or 500 mg 3 times per day) for d is usually adequate.
7. Oral vancomycin hydrochloride (125 mg 4 times per day) for d is indicated for those who cannot tolerate oral metronidazole, those in whom metronidazole therapy fails, pregnant patients, and, perhaps, severely ill patients.
Most C. difficile infections respond to either vancomycin or metronidazole, and the lack of a response should prompt an evaluation of compliance, a search for an alternative diagnosis, or an assessment forileus or toxic megacolon, since these conditions may prevent the drug from reaching the target site.

32. Treatment
8. The first relapse/recurrence of C difficile colitis can be treated with another 10- to 14-d course of oral metronidazole or vancomycin
9. Therapy of patients with multiple relapses of C difficile colitis has not been examined by randomized, prospective, controlled clinical trials. A tapering course of metronidazole or vancomycin for 4-6 wk has been used.
* Adapted from Johnson and Gerding and Fekety.
Mylonakis E, et al, Clostridium difficile-Associated Diarrhea A Review. Archives of Internal Medicine, Vol. 161, No. 4, Feb. 26, 2001
The first relapse/recurrence of C difficile colitis can be treated with another 10- to 14-d course of oral metronidazole or vancomycin which should give a response rate of approx. 95%.
Therapy of patients with multiple relapses of C difficile colitis has not been examined by randomized, prospective, controlled clinical trials. A tapering course of metronidazole or vancomycin for 4-6 wk has been used.

33. Treatment Tapering Schedule Week Vanco dose 1 125mg qid 2 125mg bid
mg qd
mg q.o.d.
5 & mg q 3 d
Mylonakis E, et al, Clostridium difficile-Associated Diarrhea A Review. Archives of Internal Medicine, Vol. 161, No. 4, Feb. 26, 2001
The 6 week tapering schedule which may allow the spores to germinate during days between Vanco therapy with killing of vegetative forms on reexposure.

34. -Vancomycin with cholestyramine resin (4gm BID)
Treatment
Other Approaches
-Vancomycin with cholestyramine resin (4gm BID)
- Oral Vancomycin 125mg qid, oral rifampin 600mg bid x 7 days
- Saccharomyces cerevisiae (Brewer’s Yeast)_
- IgG infusion at dose of 200 to 300mg/kg
Other approaches to relapsing CDAD is:
-Vanco with cholestyramine resin (4gm BID). The cholestyramine binds C. difficile toxins and may assist in amelioration of CDAD. Since the cholestyramine also binds the Vanco, the doses should be staggered by at least 3 hours.
Oral Vancomycin 125mg qid, oral rifampin 600mg bid x 7 days may also have some efficacy compared to Vanco alone.
- Saccharomyces cerevisiae (Brewer’s Yeast) may be beneficial in refractory cases.
- A small number of patients have responded to antimicrobial therapy in conjunction with a IgG infusion at dose of 200 to 300mg/kg to bolster IgG levels against Toxin A.

35. Data from the Society for Hospital Epidemiology of America.