Metronidazole vs.

Oral Vancomycin for the

Treatment of Clostridium difficile Infection
Definition of C. difficile
Infection (CDI)
Combination of clinical and laboratory findings:
1) Presence of diarrhea
3 unformed stools in 24 consecutive hours

2) A stool test results positive for:
Toxigenic C. difficile or its toxins, or
Colonoscopic or histopathologic findings suggestive of
pseudomembranous colitis

Cohen SH, et al. Infect. Control Hosp. Epidemiol. 2010;31(5):431-455.
Classification of CDI
Clinical Definition Supportive Clinical Data
Mild or moderate Leukocytosis with a WBC count
15,000 cells/L
Or
SCr level < 1.5 times the premorbid
level
Severe Leukocytosis with a WBC count
15,000 cells/L
Or
SCr level 1.5 times the premorbid
level
Severe, complicated Hypotension or shock, ileus,
megacolon
Cohen SH, et al. Infect. Control Hosp. Epidemiol. 2010;31(5):431-455.
Clinical Manifestations
Asymptomatic to fulminant pseudomembranous colitis

Mucus or occult blood in stool
Melena or hematochezia rare
Fever

Cramping

Abdominal discomfort

Peripheral leukocytosis

Cohen SH, et al. Infect. Control Hosp. Epidemiol. 2010;31(5):431-455.
Why is the Rate of CDI on
the Rise?
Emergence of new epidemic strain BI/NAP1/027
More virulent
Increased production of toxins A and B
Production of additional toxin known as binary toxin

Associated with:
More severe disease
Increased number of relapses after metronidazole therapy
Occurrence of disease in previously uncommon populations.

More resistant to fluoroquinolones
May help resistant strain spread to hospitals where
fluoroquinolones are readily used



Frequently Asked Questions About Clostridium difficile for Healthcare Providers. CDC. Updated Mar. 6 2012.
Zar FA, et al. Clin Infect Dis 2007;45:302-7.

A Comparison of Vancomycin and Metronidazole for
the Treatment of Clostridium difficile-Associated
Diarrhea, Stratified by Disease Severity
Prospective, randomized, double-blind, placebo-controlled trial
(n = 150)
Inclusion criteria:
3 unformed stools in 24 hours
C. difficile toxin A in the stool within 48 hours after study
entry or pseudomembranous colitis

Primary outcomes: cure, treatment failure, and relapse

Patients stratified based on severity and randomized to receive
oral vancomycin or oral metronidazole
Zar FA, et al. Clin Infect Dis 2007;45:302-7.
A Comparison Of Vancomycin And Metronidazole
for the Treatment Of Clostridium Difficile-Associated
Diarrhea, Stratified by Disease Severity
0
10
20
30
40
50
60
70
80
90
100
Mild Severe
R
a
t
e

o
f

C
l
i
n
i
c
a
l

C
u
r
e

(
%
)

Disease Severity
Treatment Outcomes
metronidazole
vancomycin
P = 0.02 P = 0.36
Zar FA, et al. Clin Infect Dis 2007;45:302-7.
Clinical Implications: Clinical Practice
Guidelines for the Treatment of CDI
Clinical Definition Supportive Clinical Data Recommended
Treatment
Mild or moderate Leukocytosis with a WBC count
15,000 cells/L
Or
SCr level < 1.5 times the
premorbid level
Metronidazole, 500 mg 3 times per
day by mouth for 10-14 days
Severe Leukocytosis with a WBC count
15,000 cells/L
Or
SCr level 1.5 times the
premorbid level
Vancomycin, 125 mg 4 times per
day by mouth for 10-14 days
Severe, complicated Hypotension or shock, ileus,
megacolon
Vancomycin, 500 mg 4 times per
day by mouth or by nasogastric
tube, plus metronidazole, 500 mg
every 8 hours IV. If complete
ileus, consider adding rectal
instillation of vancomycin
First recurrence Same as for initial episode
Second recurrence Vancomycin in a tapered and/or
pulsed regimen
Cohen SH, et al. Infect. Control Hosp. Epidemiol. 2010;31(5):431-455.
Patient Case
Patient SJ recently responded to a course of IV antibiotics followed
by oral ciprofloxacin for a complicated cellulitis.
One week following the completion of antibiotics, SJ presented to the
ED with complaints of severe diarrhea, which he defined as 4
watery stools per day x 3 days. Upon evaluation, SJ was found to
have a WBC of 14,000 cells/mL and a serum creatinine of 1.6 mg/dL
(baseline of 1.2 mg/dL during his recent admission).

Which of the following is the most appropriate treatment for SJ?
A) Vancomycin 125 mg PO every 6 hours x 14 days
B) Metronidazole 500 mg PO every 8 hours x 14 days
C) Vancomycin 500 mg PO every 6 hours x 10 days
D) Vancomycin 500 mg PO every 6 hours + metronidazole 500 mg PO every 8
hours x 14 days
Patient Case
Patient SJ recently responded to a course of IV antibiotics followed
by oral ciprofloxacin for a complicated cellulitis.
One week following the completion of antibiotics, SJ presented to the
ED with complaints of severe diarrhea, which he defined as 4
watery stools per day x 3 days. Upon evaluation, SJ was found to
have a WBC of 14,000 cells/mL and a serum creatinine of 1.6 mg/dL
(baseline of 1.2 mg/dL during his recent admission).

Which of the following is the most appropriate treatment for SJ?
A) Vancomycin 125 mg PO every 6 hours x 14 days
B) Metronidazole 500 mg PO every 8 hours x 14 days
C) Vancomycin 500 mg PO every 6 hours x 10 days
D) Vancomycin 500 mg PO every 6 hours + metronidazole 500 mg PO every 8
hours x 14 days
Patient Case
On day 4 of metronidazole therapy SJ is still experiencing 4-5
loose stools per day, his WBC count is 15,800 cells/mL, and his
average Tmax is 102.3F.

What are you suspecting?




Patient Case
On day 4 of metronidazole therapy SJ is still experiencing 4-5
loose stools per day, his WBC count is 15,800 cells/mL, and his
average Tmax is 102.3F.

What are you suspecting?

When would you consider this a treatment failure?



Patient Case
On day 4 of metronidazole therapy SJ is still experiencing 4-5
loose stools per day, his WBC count is 15,800 cells/mL, and his
average Tmax is 102.3F.

What are you suspecting?

When would you consider this a treatment failure?

What are the possible causes of metronidazole treatment failure?


Comparison of Clinical and Microbiological Response
to Treatment of Clostridium difficile-Associated
Disease with Metronidazole and Vancomycin
Prospective observational study (n = 52)

Inclusion criteria:
3 unformed stools in 24 hours x 2 days
Presence of C. difficile toxin in stool

Investigated cause of metronidazole failure
Suboptimal microbiological response

Patients stratified based on disease severity and randomized
to receive oral metronidazole or oral vancomycin

Al-Nassir WN, et al. Clin Infect Dis 2008;47:56-62.
Comparison of Clinical and Microbiological Response
to Treatment of Clostridium difficile-Associated
Disease with Metronidazole and Vancomycin
Al-Nassir WN, et al. Clin Infect Dis 2008;47:56-62.
Figure A: time to resolution of diarrhea
Figure B: reduction of C. difficile concentration
to an undetectable level in stool
Clinical Implications
Results support the recommendations of the current treatment
guidelines

Resolution of diarrhea may take 6 days with metronidazole
therapy
Change in therapy indicated if no clinical improvement
Case-by-case basis always use clinical judgment

Al-Nassir WN, et al. Clin Infect Dis 2008;47:56-62.
Vancomycin, Metronidazole, or Tolevamer for
Clostridium difficile Infection: Results From Two
Multinational, Randomized, Controlled Trials
Two identical, phase 3, multicenter, randomized, double-
dummy, double-blind, active-controlled, parallel-design efficacy
studies (n = 1118)

Investigated the efficacy of tolevamer vs. metronidazole vs.
vancomycin
Focus on metronidazole vs. vancomycin

Patients stratified by disease severity and randomized to
receive tolevamer, metronidazole, or vancomycin in a 2:1:1
ratio

Johnson S, et al. Clin Infect Dis 2014;59(3):345-54.
Vancomycin, Metronidazole, or Tolevamer for
Clostridium difficile Infection: Results From Two
Multinational, Randomized, Controlled Trials
0
10
20
30
40
50
60
70
80
90
P
e
r
c
e
n
t
a
g
e

o
f

P
a
t
i
e
n
t
s

(
%
)

Disease Severity
Clinical Success by CDI
Severity
metronidazole
vancomycin
3 factors strongly
associated with clinical
success:
1) Vancomycin treatment
(p = 0.034)
2) Treatment-nave
status (p = 0.0051)
3) Mild or moderate CDI
severity (p = 0.036)
Johnson S, et al. Clin Infect Dis 2014;59(3):345-54.
P = 0.59
Clinical Implications
Supports current guideline recommendations
Lower efficacy of metronidazole than vancomycin

Identified factors associated with clinical success

Vancomycin should be used as first line therapy for severe
disease
May have a role in mild to moderate disease, as
metronidazole failures are observed
Johnson S, et al. Clin Infect Dis 2014;59(3):345-54.
Metronidazole Failure
Treatment failure defined as persistence of diarrhea and/or a
positive result of a C. difficile toxin A assay, need for colectomy,
or death

May be due to suboptimal microbiological response
Historically, metronidazole resistance in C. difficile has
been rare

Treatment options for metronidazole failure include
vancomycin or fidaxomicin
Al-Nassir WN, et al. Clin Infect Dis 2008;47:56-62.
Summary of
Recommendations
Metronidazole is the drug of choice for the initial episode of
mild to moderate CDI
Possibility of metronidazole failure
What should you watch out for?
What should you do when you see it?
DO NOT use metronidazole beyond first recurrence

Vancomycin is the drug of choice for the initial episode of
severe CDI

Vancomyin with or without IV metronidazole in the regimen of
choice for severe, complicated CDI

Cohen SH, et al. Infect. Control Hosp. Epidemiol. 2010;31(5):431-455.
References
[1] Cohen SH, Gerding DN, Johnson S, Kelly CP, Loo VG, McDonald LC, Pepin J, Wilcox MH. Clinical
Practice Guidelines for Clostridium difficile Infection in Adults: 2010 Update by the Society for
Healthcare Epidemiology of America (SHEA) and the Infectious Diseases Society of America (IDSA).
Infect. Control Hosp. Epidemiol. 2010;31(5):431-455.

[2] Frequently Asked Questions About Clostridium difficile for Healthcare Providers. CDC. Updated
Mar. 6 2012. Accessed from: http://www.cdc.gov/HAI/organisms/cdiff/Cdiff_faqs_HCP.html.

[3] Zar FA, Bakkanagari SR, Moorthi KMLST, Davis, MB. A Comparison of Vancomycin and
Metronidazole for the Treatment of Clostridium difficile-Associated Diarrhea, Stratified by Disease
Severity. Clin Infect Dis 2007;45:302-7.

[4] Al-Nassir WN, Sethi AK, Nerandzic MM, Bobulsky GS, Jump RL, Donskey CJ. Comparison of
Clinical and Microbiological Response to Treatment of Clostridium difficile-Associated Disease with
Metronidazole and Vancomycin. Clin Infect Dis 2008;47:56-62.

[5] Johnson S, Louie TJ, Gerding DN, Cornely OA, Chasan-Taber S, Fitts D, Gelone SP, Broom C,
Davidson DM, for the Polymer Alternative for CDI Treatment (PACT) investigators. Vancomycin,
Metronidazole, or Tolevamer for Clostridium difficile Infection: Results from Two Multinational,
Randomized, Controlled Trials. Clin Infect Dis 2014;59(3):345-54.