Clinical pharmacology
GIT
Lenka Součková
Agenda
 Stress ulceration
 Clostridium difficile infection
STRESS ULCERATION
Stress Ulcers Definition
 Gastrointestinal ulcerations of the upper
alimentary tract
 Stomach
 Duodenum
 Ileum
 Jejunum
 Range depends on depth of ulcer
 Superficial: Asymptomatic
 Deep: Haemorrhage (Haematemesis /Melena)
5
What do you think causes ulcers?
A: Stress.
B: Excessive stomach acids.
C: Bacteria.
D: A bad diet and alcohol use.
E: Being overweight.
Epidemiology
 Up through the 1970 stress ulcers were much
more common (>30% of ICU patients)
 Today, less than 5% of ICU patients have stress
ulcers with macroscopic bleeding
1. ASHP Therapeutic Guidelines on Stress Ulcer Prophylaxis, AJHP 1999;56(4) 347-379
2. Del Valle, J. Chapter 287 - Peptic Ulcer Disease and Related Disorders , Harrison's Principles of
Internal Medicine - 17th Ed. (2008).
Epidemiology
 acute bleeding from mucosal defects in upper
GIT in critically ill patient is frequent
 1.5 to 8.5% GI bleeding for all patients in ICU
 15% -25% ICU patients had no prophylaxis
 75% of ICU patients - mucosal abnormalities
<72hod (multiple burns / head trauma)
Pathophysiology of Stress Ulcers
 Dysbalance of protective and agressive factors
 Multi-factorial:
Pathophysiology of Stress Ulcers
 Etiology is complex
 Decreased Gastric pH
 Ischemia
 Decreased mucous production
 Usually occur within 24-48 hours of
trauma/stress
 Gastric pH is a factor and a surrogate marker,
not the root cause of stress ulcers
Del Valle, J. Chapter 287 - Peptic Ulcer Disease and Related Disorders , Harrison's Principles of
Internal Medicine - 17th Ed. (2008).
Morbidity/Mortality
 Cook and collegues conducted a
large (n=2252) multicenter
prospective trial evaluating the risk
factors of significant bleeding
 Mortality for patients with a
significant bleed
 48.5% with significant bleeding
 9.1% without significant bleeding
Cook DJ, et al. Risk factors for gastrointestinal bleeding in critically ill patients. NEJM
1994;330(6):377-81
Morbidity/Mortality - Continued
 Two independent factors for a clinically
significant bleed:
 Respiratory failure (OR=15.6)
 Coagulopathy (OR=4.3)
 Incidence of significant bleeds
 With one or both risk factors 3.7%
 Without either risk factor 0.1%
 Number need to treat for significant bleeding
 Without risk factors = 900
 With risk factors = 30
Cook DJ, et al. Risk factors for gastrointestinal bleeding in critically ill patients. NEJM
1994;330(6):377-81
Who is at risk?
 Intubated patients> 48hrs (Cook. DJ et al '94)
 Patients with coagulopathy
 Other risk factors:
 SHOCK - any!
 Sepsis
 Liver and kidney failure
 Multiple trauma
 Burns> 35% will cast body
 Glucocorticoids
 Intolerance of enteral nutrition
Guidelines
 ASHP Therapeutic Guidelines on Stress Ulcer
Prophylaxis
Key Guideline Points – The Big 3
1. Coagulopathy
 platelet count of <50,000mm3
 INR>1.5
 PTT of >2 times the control
2. Mechanical Ventilation
 Longer than 24 hours
3. Recent GI ulcers/bleeding
 Within 12 months of admission
ASHP Therapeutic Guidelines on Stress Ulcer Prophylaxis, AJHP 1999;56(4) 347-379
Key Guideline Points – The Little
 2 or more of the following:
1. Sepsis
2. ICU>1 week
3. Occult Bleeding within 6 days
4. High dose corticosteroids
 250mg Hydrocortisone
 50mg Methylprednisone
 These factors are not consistently found to be
contributing factors, but they are significant in
some studies
ASHP Therapeutic Guidelines on Stress Ulcer Prophylaxis, AJHP 1999;56(4) 347-379
Guideline Summary
 Big 3
1. Coagulopathy
2. Mechanical Ventilation
3. GI Bleeding within 12 months
 Little 4 (2 or more)
1. Sepsis
2. ICU>1 week
3. Occult Bleeding within 6 days
4. High dose corticosteroids
Prophylaxis and treatment
1) Protecting stomach mucosa – nil buffering
Sucraflate - polysaccharide + Aluminium hydroxide
2) Prostaglandin analogues
Misoprostol – inhibit parietal cells to generate cAMP,
thus reduce stomach acid secretion
3) Neutralise stomach acid contents
Antacids (Gaviscon) – Bicarbonate neutralises pH
3) Block acid secretion
 Competitive H2 antagonists (Ranitidine)
 Proton pump inhibitors (Omeprazole)
Agents and Dosing – How much of a
good thing?
 IV Agents
 Pantoprazole 40 mg (Q12-24h)
 Ranitidine 50mg (Q8h)
 Oral Agents
 Omeprazole 40mg (Q24h)
 Powder for suspension is FDA Approved!
 Ranitidine 150mg (Q12h)
 Sucralfate 1-2 grams 4 times per day
 Hey this one has an FDA indication!
Proton Pump Inhibitors, High-dose, Criteria for Use, VHA Pharmacy Benefits Management Strategic
Healthcare Group and the Medical Advisory Panel
Duration of Therapy
 ASHP guidelines note that durations vary widely
by study
 Cook’s seminal prospective trial defined SUP as
2 or more doses of a H2RA, PPI, or antacid.
 The pathophysiology suggests that duration of
therapy as short as 2-3 days may be sufficient
 Clinical prudence might be to continue therapy
as long as risk factors are present
Cook DJ, et al. Risk factors for gastrointestinal bleeding in critically ill patients. NEJM
1994;330(6):377-81
Over-used PPI
Retrospective, chart review of non-ICU admits1
 22% received stress ulcer prophylaxis
 54% of those were discharged home on it
Retrospective chart review of nursing home admits2
 50% did NOT have an appropriate diagnosis for PPI
Retrospective chart review of C.diff positive patients3
 63% of did NOT have valid indication for PPI
Retrospective chart review of cirrhotics + SBP4
 47% did NOT have valid reason for PPI
What are the common S/Es of
pharmacological agents?
 Hospital Acquired Pneumonia (HAP)1
 C Difficile2
 Osteoporosis & Hip Fractures3,4
1. Herzig HJ et al, JAMA 2009;301(20):2120-2128
2. Dial, S, Delaney, AC, Barkun AN, et al. JAMA 2005;294(3):2989-2995
3. Yang et al. JAMA 2006:296(24):2947-2953
4. Targownik, LE et al. CMAJ 2008:179(4):319-326
HAP
 Prospective (n=63,878) pharmacoepidemiologic cohort
study
 Excluding ICU Patients
 PPIs associated with a significant 30% increase in HAP
 H2RA association was not significant after multivariate
analysis
Shoshana J. Herzig; Michael D. Howell; Long H. Ngo; et al, Acid-Suppressive Medication Use and the
Risk for Hospital-Acquired Pneumonia JAMA 2009;301(20):2120-2128
C Difficile
 Case-Control study in the UK showing an increased
risk associated with acid suppressive therapy
Dial, S, Delaney, AC, Barkun AN, et al. Use of gastric Acid-Suppressive Agents and the Risk of
Community-Acquired Clostridium Difficile-Associated Disease. JAMA 2005;294(3):2989-2995
Osteoporosis & Hip Fractures
 Significant increase in the risk of hip fracture in
high dose PPI (>1.75 average dose)
 Yang et al. JAMA 2006:296(24):2947-2953
 Significant increase in risk of hip fractures with
use of PPI over 5 years
 Case (n=15,792)-Control(n=47,289) study
 Targownik, LE et. al CMAJ 2008:179(4):319-326
 One year mortality in men with a hip fracture
may be as low as 50%
 Diamond, TH, et al. The Medical Journal of Australia1997;
167: 412-415
Applications for Pharmacy
 Document the indication for ongoing therapy
 Big 3
 Little 4
 Discontinue therapy if not indicated
 Reduce the risk to patients
 Reduce costs
 Discuss the indications with the patient/provider
 Appropriate indications and duration of therapy
Summary
 Give Stress Ulcer Prophylaxis therapy when
indicated
 Stress Ulcer have a high mortality (nearly ½)
 Big 3, Little 4
 Discontinue Stress Ulcer Prophylaxis when no
longer indicated
 Stress Ulcer Prophylaxis has risks (HAP, C diff,
Osteoporosis), in and outside the facility
 Document, Discontinue, Discuss
COMPARISON OF
PPI AND H2- ANTIHISTAMINES
EFFECTIVNESS
 Aim:
Determine efficacy and safety of proton pump inhibitors verses H2
receptor antagonists for the prevention of upper GI bleeding in ICU
 Methodology:
Search strategy –
MEDLINE (1948-March 2012)
EMBASE (1980-March 2012) Two researchers independently
ACPJC (1991-March 2012) extracted data
Cochrane (central) database
CINHAL.
 Type of study:
- Randomised Control Trials (RCTs)
 Population:
- ICU Adults (Medical and Surgical included)
 Intervention:
- Control=H2antihistamines=PPIs
- para-enteral/enteral
- irrespective of the dose, frequency and duration
Primary objectives:
1) Clinically important bleeding (12 Trials n=1614)
Significantly lower RR with PPIs vs H2RA:
(RR 0.36 95% CI 0.19-0.68 p=0.002)
2) Overt Bleeding ( 14 Trials n= 1720)
Significantly lower RR with PPIs vs H2RA:
(RR 0.35; 95%CI 0.21-0.59 p<0.0001)
 1) Nosocomial Pneumonia ( 8 Trials, n= 1100)
No significant difference: RR 1.06 95% CI (0.73-1.52)
p=0.76
2) Mortality ( 8 Trials n= 1196)
No significant difference: RR 1.01 95% CI (0.83-1.24)
p=0.91
3) ICU Length of stay ( 5 Trials n=555)
No significant difference :CI (-2.20-1.13) p=53
4) Clostridium difficile infection
No trials reported on C. Difficile infection
‘Significantly ↓ risk of both 10 outcomes with PPIs
- Clinically important GI bleeding – RR 0.36 (0.19-
0.68)
- Overt UGI bleeding – RR 0.35 (0.21-0.59)
‘No significant ↓ risk of 20 outcomes with PPIs vs
H2RA’
Nosocomial pneumonia – RR 1.06 (0.73-1.52)
ICU mortality – RR 1.01 (0.83-1.24)
ICU length of stay – RR 0.54 (-2.20-1.13)
CLOSTRIDIUM DIFFICILE
INFECTION
 Gram positive spore forming bacillus (rods)
 Obligate anaerobe
 Part of the GI Flora in
◦ 1-3% of healthy adult
◦ 70% of children < 12 months
 Some strains produce toxins A & B
 Toxins-producing strains cause C. diff Infection
(CDI)
 CDI ranges from mild, moderate, to severe and
even fatal illness
38
C. difficile : Microbiology
Clostridium Difficile colitis
- more virulent than ever
 incidence, deaths, and excess health care costs
are at historic highs
 +/- 1 billion dollars/year
 3x increase in decade - now 500,000 infections
and 29,000 deaths per year.
 More deaths than even MRSA infections.
C. difficile: Background
 #1 cause of increase - over use of antibiotics
 A common cause of nosocomial antibiotic-associated
diarrhea (AAD)
 #2 cause – appearance of a more virulent C.diff
strain associated with risk of greater mortality
 #3 cause- increased relapse rate – 20% of
cases have at least one relapse- difficult to treat
 #4 cause- overdiagnosis???
 Most common infectious cause of acute
diarrheal illness in LTCFs
 The only nosocomial organism that is anaerobic
and forms spores
 survive> 5 months and hard to destroy
 Pathogenesis is mainly due to toxins production
 Infective dose is < 10 spores
41
C. difficile: Background
42
CDI: Impact
 Fecal – oral route
 Contaminated hands of healthcare workers
 Contaminated environmental surfaces.
 Person to person in hospitals and LTCFs
 Reservoir:
 Human: colonized or infected persons
 Contaminated environment
 C. diff spores can survive for up 5 months on
environmental surfaces.
43
C. difficile : Transmission
Importance of Spores
 Resistant to heat, drying, pressure, and many
disinfectants
 Resistant to all antibiotics because antibiotics
only kill or inhibit actively growing bacteria
 Spores survive well in hospital environment
 Spores are not a reproductive form, they
represent a survival strategy
45
CDI: Pathogenesis
Step 1-
Ingestion
of spores
transmitted
from other
patients
Step 2- Germination
into growing
(vegetative) form
Step 3 - Altered lower
intestine flora (due to
antimicrobial use)
allows proliferation of
C. difficile in colon
Step 4 . Toxin B & A
production leads to colon
damage +/- pseudomembrane
46
CDI Pathogenesis
Admitted to
healthcare facility
Antimicrobials
C Diff exposure & acquisition
Colonized
no symptoms
Infected
Symptomatic
 Exposure to antimicrobials (prior 2-3 months)
 Exposure to healthcare (prior 2-3 months)
 Infection with toxogenic strains of C. difficile
 Old age > 64 years
 Underlying illness
 Immunosuppression & HIV
 Chemotherapy (immunosuppression & antibiotic-like
activities)
 Tube feeds and GI surgery
 Exposure to gastric acid suppression meds ??
47
CDI: Risk Factors
 Illness caused by toxin-producing strains of
C. difficile ranges from
 Asymptomatic carriers = Colonized
 Mild or moderate diarrhea
 Pseudo membranous colitis that can be fatal
 A median time between exposure to onset of
CDI symptoms is of 2–3 days
 Risk of developing CDI after exposure ranges
between 5-10 days to 10 weeks
48
Clinical Manifestations
49
CDI: Pathogenesis
Case Study 1
 60 years old male admitted to hospital for
community acquired pneumonia, treated with
levofloxacin and discharged
 7 days later, seen at another hospital because of
5 kg weight gain over last few days (“my
abdomen has never been so big”) and
hypertension (213/106)
 Afebrile, WBC of 8.5, albumin 3.1, creatinine 0.9, no
diarrhea noted
 Admitted, treated for hypertension and ciprofloxacin
given to complete treatment for CAP; discharged 3
days later
Case Study 1 (cont’d)
Day 1 Presents to ER 3 days after discharge
• Fever (37,9), diarrhea, generally feeling ill,
no abdominal pain
• WBC 27.8K, albumin 2.9, creatinine 1.2
• Admitted with C. difficile colitis listed as a
possible dx, but not treated (except for
levofloxacin)
Day 2 10 stools/day, altered mental status
• C. difficile EIA positive; put on metronidazole
500 mg TID
Case Study 1 (cont’d)
Day 3 Transferred to SICU, anuric,
abdominal pain, distension,
developed cardiac complications,
ventilated, renal failure. Poor
prognosis and colectomy ruled out
following surgical consult
• Oral and rectal vancomycin added
• WBC > 30K, albumin 2.3, creatinine 3.1
Day 4 WBC 59.6K, toxic megacolon
Day 5 WBC 88K, made DNI/DNR, died
Historical Perspective
 In the 1960s it was noted that patients on
antibiotics developed diarrhea1
 “staphylococcal colitis”
 Originally thought to be caused by S. aureus and treated with
oral bacitracin
 Stool cultures routinely ordered for S. aureus
 Early 1970s, a new explanation
 “clindamycin colitis”
 Severe diarrhea, pseudomembranous colitis, and occasional
deaths documented in patients on clindamycin
1. Gorbach SL. NEJM. 1999;341:1689-1691.
“Antibiotic Associated
Pseudomembranous Colitis Due to
Toxin-Producing Bacteria”
 Bartlett and co-workers demonstrated
cytotoxicity in tissue culture and enterocolitis in
hamsters from stool isolates from patients with
pseudomembranous colitis
 Isolate was C. difficile
 Bacillus difficilis (now confirmed as C. difficile)
was cultured from healthy neonates (with
difficulty, hence the name) in 19352
1. Bartlett JG, et al. NEJM. 1978;298: 531-534.
2. Hall JC and O’Toole E. Am J Dis Child. 1935;49:390-402.
Quiz Time
Q. Why did it take so long to associate the
organism C. difficile with the disease?
A. Organism was (is) found in healthy infants
Q. Why do antibiotics sometimes cause diarrhea
(unrelated to C. difficile)?
A. Disrupt the intestinal flora which plays a major
role in digestion of food
Role of Antibiotics
 All antibiotics (including metronidazole and
vancomycin) are associated with CDI
 High-risk group
 Clindamycin
 Cephalosporins/penicillins/beta-lactams
 Fluoroquinolones
 Alteration of normal colonic flora thought to favor
growth of C. difficile
 Antibiotics do not know they are suppose to kill/inhibit
only the “bad guys”
Very commonly related Less commonly related Uncommonly related
Clindamycin
Ampicillin
Amoxicillin
Cephalosporins
Fluoroquinolons
Sulfa
Macrolides
Carbapenems
Other penicillins
Aminoglycosides
Rifampin
Tetracycline
Chloramphincol
57
Antimicrobials Predisposing to CDI
 Among symptomatic patients with CDI:
• 96% received antimicrobials within the 14 days before onset
•100% received an antimicrobial within the previous 3 months
 20% of hospitalized patients are colonized with C. diff
Pathogenesis
Historical Perspective
 Most CDI were mild
 Diarrhea was main symptom
 Pseudomembranous colitis and toxic megacolon were
rare
 Discontinuing antibiotics worked in many cases
 High response rate to metronidazole and vancomycin
 Asymptomatic colonization
 Diarrhea
mild  moderate  severe
 Abdominal pain and distension
 Fever
 Pseudomembranous colitis
 Toxic megacolon
 Perforated colon  sepsis  death
59
CDI: Symptoms
Markers of Severe Disease
 Leukocytosis
 Prominent feature of severe disease
 Rapidly elevating WBC
 Up to >100 K
 >10 BM/day
 Albumin < 2.5
 Creatinine 2x baseline
 Hypertension
 Pseudomembranous colitis
 Toxic megacolon
 Severe distension and abdominal pain
TESTING AND PREVENTION
OF CDAD
Test Advantage Disadvantage
Testing
Toxins
Enzyme
immuno-assay
(EIA)
• Detects toxin A or both A & B
• Rapid (same day)
Less sensitive
63-94%
Tissue culture
cytotoxicity
assay
Provides specific and sensitive
results for C. diff
67-100%
-Detect toxin B
-Technical expertise
-Expensive
-24-48 hours
Organism
ID
Glutamate
Dehydrogenase
Rapid, sensitive, may
prove useful as a triage or
screening tool
Not specific, toxin
testing required to
verify diagnosis
PCR Rapid, sensitive, detects
presence of toxin gene
Expensive
Special equipment
Stool culture Most sensitive test
available when performed
appropriately
False-positive
results if isolate is not
tested for toxin
labor-intensive; requires
48–96 hours
CDI: Testing
 Testing should be performed only on diarrheal
stool
 Testing asymptomatic patients is not indicated
 Testing for cure is not recommended
63
Best Strategy for C. difficile
Testing
 For clinical use: two-step testing uses initially EIA
detection of GDH for screening followed by cytotoxicity
assay or toxigenic culture for confirmation
 Gold standard is stool culture followed by toxigenic
culture assay
 Toxin is very unstable, degrades at room temperature,
and undetectable within 2 hours (false negative results)
64
Best Strategy for C. difficile
Testing
65
CDI Pathogenesis
Antimicrobial
stewardship
Admitted to
healthcare facility
Antimicrobials
C Diff exposure & acquisition
Colonized
no symptoms
Infected
Symptomatic
Optimizing Environmental
cleaning and Hand Hygiene
 Regardless of setting, ~ 50% antibiotic use is
“inappropriate”
 The best CDI preventative measure
 Decrease in number of patients at risk (susceptible)
 Decrease in number of patients with CDI (reservoirs)
66
Antimicrobial stewardship
 Recommendations:
 Minimize the frequency and duration of antimicrobial
therapy
 Decrease the number of antimicrobial agents
prescribed,
 Targeted antimicrobials should be based on the local
epidemiology and the C. difficile strains
 Restrict the use of cephalosporin and clindamycin
 Audit and feedback targeting broad-spectrum
antibiotics
67
Antimicrobial stewardship
 Contact Precautions for duration of diarrhea
 Hand hygiene (HH) in compliance with CDC/WHO
 Cleaning and disinfection of equipment and
environment
 Laboratory-based alert system for immediate
notification of positive test results
 Educate HCP, housekeeping, admin staff, patients,
families, visitors, about CDI 68
Prevention Strategies
TREATMENT OF CDAD
Treatment of
Mild to Moderate Disease
 Stop antibiotic(s) if medically reasonable
 Metronidazole
 Oral or IV, 500 mg TID for 10-14 days is standard
therapy
 5–20% failure rate
 20% relapse rate
 Can use a full 2nd course for failure/relapse but
beyond 2 courses, switch to vancomycin
 Failures not due to metronidazole resistance
Initial Treatment Options for CDI
 Historical response (96%) and relapse rates (20%)
similar between metronidazole and vancomycin1
 More recently, efficacy of metronidazole for severe
disease called into question2-4
 Recent prospective trials report vancomycin to be
superior to metronidazole in severe CDI5-7
1. Aslam S, et al. Lancet Infect Dis. 2005;5:549-557.
2. Fernandez A, et al. J Clin Gastroenterol. 2004;38:414-418.
3. Gerding DN. Clin Infect Dis. 2005;40:1598-1600.
4. Musher DM, et al. Clin Infect Dis. 2005;40:1586-1590.
5. Lahue BJ, Davidson DM. The 17th ECCMID Meeting, March 31 to April 4, 2007; Munich, Germany.
Abstract 1732_215.
6. Zar FA, et al. Clin Infect Dis 2007;45:302-307.
7. Louie T, et al. The 47th Annual ICAAC Meeting, Sept. 17-20, 2007; Chicago, IL. Abstract k-425-a.
Initial Treatment Options for CDI
Metronidazole
250 mg QID or
500 mg TID
• May be administered PO or IV
• Development of resistance rare
• Historical first-line agent
Vancomycin
125 mg QID
• Effective in enteral (oral or rectal) form only
• Typically reserved for severe disease, those
failing to respond to metronidazole, or
cases in which metronidazole is
contraindicated
IV=intravenously; PO=orally.
Fekety R. Am J Gastroenterol. 1997;92:739-750.
Gerding DN, et al. Infect Control Hosp Epidemiol. 1995;16:459-477.
American Society of Health-System Pharmacists. Am J Health-Syst Pharm. 1998;55:1407-1411.
Metronidazole vs Vancomycin
 Zar et al1 classified patients as mild or severe
CDI
 In mild disease, vancomycin was slightly better
than metronidazole (98% vs 90%)
 Not statistically significant
 In severe disease, vancomycin was significantly
better than metronidazole (97% cure vs 76%
cure)
1. Zar FA, et al. CID. 2007;45: 302-307.
Clinical Success by Disease
Severity: Tolevamer Phase III Results
Mild CDI 3–5 BM/day
WBC ≤15,000/mm3
Mild abdominal pain due to CDI
Moderate CDI 6–9 BM/day
WBC 15,001 to 20,000/mm3
Moderate abdominal pain due to CDI
Severe CDI ≥ 10 BM/day
WBC ≥20,001/mm3;
Severe abdominal pain due to CDI
Defining CDI Disease Severity
Louie T, et al. The 47th Annual ICAAC Meeting, Sept. 17-20, 2007; Chicago, IL. Abstract k-425-a.
Any one of the 3 defining characteristics assigns a patient to the more severe category.
Metronidazole vs Vancomycin vs
Tolevamer
 Patients stratified as mild, moderate, or severe
 Original goal of study was to evaluate tolevamer
as a treatment for CDI
Drug Mild Moderate Severe
Tolevamer 59 46 37
Metronidazole 79 76 65
Vancomycin 85 80 85
Louie et al. ICAAC AbstractK-425-9 2007
Recurrent Clostridium difficile infection
 Rates of recurrence
 20% after 1st episode
 45% after 1st recurrence
 65% after two or more recurrences
 No reports of Metronidazole or Vancomycin
resistance following treatment
Original Article
Duodenal Infusion of Donor Feces for Recurrent
Clostridium difficile
Els van Nood, M.D., Anne Vrieze, M.D., Max Nieuwdorp, M.D., Ph.D.,
Susana Fuentes, Ph.D., Erwin G. Zoetendal, Ph.D., Willem M. de Vos, Ph.D.,
Caroline E. Visser, M.D., Ph.D., Ed J. Kuijper, M.D., Ph.D., Joep F.W.M.
Bartelsman, M.D., Jan G.P. Tijssen, Ph.D., Peter Speelman, M.D., Ph.D.,
Marcel G.W. Dijkgraaf, Ph.D., and Josbert J. Keller, M.D., Ph.D.
N Engl J Med
Volume 368(5):407-415
January 31, 2013
Rates of Cure without Relapse for Recurrent Clostridium difficile Infection.
van Nood E et al. N Engl J Med 2013;368:407-415.
Case Report
 79-year-old woman with multiple medical problems admitted to
hospital for treatment of community-acquired pneumonia
 Responds slowly to levofloxacin 750 mg daily
 After 6 days
 Develops diarrhea (9 loose BMs)
 WBC count: 11,500/mm3
 Day 7–14 loose BMs, WBC count rises to 19,500/mm3
 Stool testing for C. difficile toxins A and B is requested
 Continued antibiotic therapy for pneumonia is deemed necessary
 How would you manage her care?
A. Await stool test results and monitor her progress
B. Empirically start metronidazole PO
C. Empirically start metronidazole IV
D. Empirically start vancomycin PO
Case Report
 79-year-old woman with multiple medical problems admitted to
hospital for treatment of community-acquired pneumonia
 Responds slowly to levofloxacin 750 mg daily
 After 6 days
 Develops diarrhea (9 loose BMs)
 WBC count: 11,500/mm3
 Day 7–14 loose BMs, WBC count rises to 19,500/mm3
 Stool testing for C. difficile toxins A&B is requested
 Continued antibiotic therapy for pneumonia is deemed necessary
 How would you manage her care?
A. Await stool test results and monitor her progress
B. Empirically start metronidazole PO
C. Empirically start metronidazole IV
D. Empirically start vancomycin PO
Treatment of Severe Disease
 Follow definition of severe disease
 >10 BM/day, high WBC, low albumin
 This is a life-threatening infection
 Surgical consultation recommended as patient
may require a colectomy
 Oral vancomycin drug of choice
 Dose varies based on severity
 Can add metronidazole (oral or IV)
Management of Severe CDI
 Early recognition is critical
 Initiate therapy as soon as diagnosis is suspected
 Manage as for mild CDI plus:
 Oral vancomycin (125 mg QID for 10 to 14 days) as initial
treatment
 If patient is unable to tolerate oral medication, consider
intracolonic vancomycin instillation (by enema)
 0.5–1 g vancomycin (IV formulation) in 0.1 to 0.5 L of normal
saline via rectal (or Foley) catheter
 Clamp for 60 minutes
 Repeat every 4–12 hours
Gerding DN, et al. Infect Control Hosp Epidemiol. 1995;16:459-477.
Zar FA, et al. Clin Infect Dis. 2007;45:302-307.
Louie T, et al. The 47th Annual ICAAC Meeting, Sept. 17-20, 2007; Chicago, IL. Abstract k-425-a.
Apisarnthanarak A, et al. Clin Infect Dis. 2002;35:690-696.
 Potential role of intravenous immunoglobulin G (IVIG)1-6
 Antitoxin A IgG predicts clinical outcome of CDI
 Serum antibodies to toxins A and B are prevalent in
healthy populations
 Recent studies in severe disease5,6
 Well tolerated in small numbers of patients
 Conflicting data regarding outcome improvement
(mortality and need for colectomy)
 Often administered when surgery is considered imminent
1. Salcedo J, et al. Gut 1997;41:366-370.
2. Beales ILP. Gut. 2002;51:456.
3. Kyne L, et al. N Engl J Med. 2000;342:390-397.
4. Kyne L, et al. Lancet. 2001;357:189-193.
5. McPherson S, et al. Dis Colon Rectum. 2006;49:640-645.
6. Juang P, et al. Am J Infect Control 2007;35:131-137.
Management of Severe,
Complicated CDI
Treatment for Clostridium difficile -
Summary
 Discontinue preciptitatingantibiotics
 Oral Vancomycin125/250 mg qid for 10-14 d
 Oral Metronidazole 500 mg tid or qit for 10-14 d
 Recent reports of resistance to metronidazole
 IV give both antibiotics together 200 mg bid for 10 d
 Fidaxomicin
 Experimental fecal transplant (enemas)
TEST TIME
I. Which fact is incorrect about C. diff?
a. Causes 500,000 cases per year
b. Severity of illness has increased last few years
c. Majority of C. diff cases are community
acquired
d. Relapses are major problem with C. diff and
may respond to stool transplant
II. Which of the following is incorrect regarding
medical management of C. diff?
a. Oral metronidazole is recommended for mild C.
diff
b. Oral vancomycin is preferred for moderate or
severe C.diff
c. Patients with fulminant C. diff with ileus should
receive intravenous vancomycin
III. Manifestations of fulminant C. diff include
all the following except:
a. Severe abd pain and worsening diarrhea
b. Hypotension requiring vasopressors
c. Dropping WBCs
d. Respiratory failure requiring intubation
e. Elevated lactate levels
f. Renal failure
IV. New approaches to C. diff infection include
all of the following except:
 PCR testing for quicker and more sensitive
diagnosis – but may result in over-treatment of a
carrier state
 Stool transplant for recurrent disease
 Less invasive surgical techniques to improve
outcome and allow for earlier intervention
 Fidaxomicin as an inexpensive and effective oral
therapy for NAP-1 strain infections