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Does Oral Vancomycin Trump Metronidazole for Treatment of an Initial
Clostridium difficile Infection? How Low Does One Go?
Michelle Kennedy, PharmD PGY-1 Pharmacy Practice Resident
Methodist Hospital and Methodist Children’s Hospital, San Antonio, TX
Division of Pharmacotherapy, The University of Texas at Austin College of Pharmacy
Pharmacotherapy Education and Research Center
University of Texas Health Science Center at San Antonio
October 28, 2016
Learning Objectives ________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________
1. Discuss the nationwide initiative to reduce prevalence of Clostridium difficile infection (CDI)
2. Determine if a patient has CDI based on risk factors, signs and symptoms, and laboratory results
3. Devise a clinically appropriate treatment plan for an initial CDI infection
4. Describe the benefits of oral vancomycin over metronidazole in CDI
Kennedy │2
I. Epidemiology of CDI in the United States
______________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________
A. Occurred in 8.53 of 1000 hospital discharges in 20091-3
B. Caused close to half a million infections leading to 29,000 deaths in 20114-5
C. Contributed to approximately $4.8 billion annually in healthcare costs5
D. Centers for Disease Control and Prevention (CDC) requires reporting of CDI rates by healthcare
facilities5-6
1. Department of Health and Human Services (HHS) Action Plan set a goal to reduce CDI by 30% by
the end of 2013
2. Healthcare facilities failed to meet the goal, only achieving a 10% reduction
3. New 2020 national reduction targets are currently in the process of being set
II. Microbiology7
______________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________
Figure 1. Gram stain of Clostridium difficile
8
A. Genus: Clostridium
1. Gram positive anaerobic bacilli
2. Forms spores and toxins that cause disease in humans
3. Other species within the Clostridium genus
a. C. botulinum: causes botulism
b. C. perfringens: causes food poisoning and gas gangrene
c. C. tetani: causes tetanus
d. C. sordellii: rare, fatal post-abortion infection
B. Clostridium difficile
1. Colonizes human intestinal tract
2. Colonization rates vary between populations
Table 1: Colonization rates of C. difficile in various patient populations
Population Incidence (%)
Hospitalized Individual9-10
9-11
Long Term Care Resident11-12
5-7*
Healthy Adult13-15
5
*May be as high as 51%16
3. Can cause infectious diarrhea
4. Hypervirulent strains
a. Increased toxin production
b. Higher incidence of severe CDI
c. Increased recurrence and mortality
d. Strains
i. NAP1/B1/027 in North America
ii. NAP7-8/BK/078 in Europe, especially in the Netherlands
Kennedy │3
III. Pathophysiology7,17
______________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________
Figure 2: Pathophysiology of CDI
IV. Risk Factors
7
______________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________
Table 2. Risk factors for developing CDI
Initial Infection Recurrent Infection
Recent antibiotic use
Long duration of antibiotic use
Recent hospitalization
Age > 65 years
Proton pump inhibitor use
Severity of underlying illness
Enteral feeding (nasogastric tube)18
Gastrointestinal surgery
Chemotherapy
Hematopoietic stem cell transplantation
Long term care resident
Concomitant or post-CDI antibiotic use
Age ≥ 75 years
≥ 10 unformed stools in 24 hours
Serum creatinine ≥ 1.2 mg/dL
Prolonged or recent stay in health care facility
High severity of underlying illness
Proton pump inhibitor use
Hypervirulent strain
Absence of an antitoxin A antibody response
Inadequate antitoxin response Effective antitoxin response and
restoration of colonic microbiota
Effective antitoxin response Inadequate antitoxin response
Antibiotic exposure
Abnormal colonic microbiota
Toxigenic C. difficile exposure & colonization or activation of
prior colonization
Toxin production
Asymptomatic carriage
Diarrhea and colitis
Recurrence Resolution Complications and clinical
decline
Kennedy │4
VI. Clinical Presentation7
______________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________
A. Symptoms
1. Watery diarrhea
2. Lower abdominal pain
3. Cramping
4. Low grade fever
5. Nausea
6. Anorexia
7. Leukocytosis
B. Major complications
1. Toxic megacolon
2. Colectomy
3. Bowel perforation
4. Death
VII. Diagnosis15,19
______________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________
A. Clinical diagnosis is based on a combination of symptoms and laboratory findings or based on
radiographic evidence or endoscopy alone
1. Symptoms: three or more loose stools in 24 hours
2. Laboratory findings: positive toxin production
3. Endoscopic evidence: pseudomembranous colitis
B. For a true infection to exist, toxin must be produced in the presence of diarrhea
1. Due to potential colonization, testing without symptoms present may yield a false positive
2. Only individuals with clinically significant diarrhea or ileus in combination with risk factors should
be tested
C. Toxin can be shed up to 30 days post-cure20-21
D. Testing
1. Detect presence of C. difficile
a. Laboratory stool test
b. Glutamate dehydrogenase (GDH) antigen
2. Detect presence of toxin
a. Enzyme immunoassay (EIA)
b. Nucleic acid amplification tests (NAATs)/Polymerase Chain Reaction (PCR)
c. Toxigenic cultures
3. Adjunctive diagnostic tools include radiographic imaging and endoscopy
E. European Society of Clinical Microbiology and Infectious Diseases (ESCMID) recently published an
update and recommended two-part lab testing be performed to rule out colonization (Appendices D&E)
F. Classification22
Figure 3. Classification of mild to moderate CDI versus severe CDI
Mild to Moderate CDI
•White blood cell count ≤ 15,000 cells/mL
•Serum creatinine level < 1.5 times the baseline level
Severe CDI
•White blood cell count ≥ 15,000 cells/mL
•Serum creatinine level ≥ 1.5 times the baseline level
•Low blood albumin level (< 30 g/L)
•Complicated criteria: hypotension, shock, ileus, megacolon
Kennedy │5
VIII. Prevention23
______________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________
A. Proper hand hygiene
1. Alcohol does not kill spores
2. Must wash hands with soap and water
B. Antibiotic stewardship24-25
1. Antibiotic de-escalation when appropriate
2. Appropriate duration of antibiotic therapy
C. Contact precautions for visitors and staff
D. Proper cleaning of patient room and equipment
1. Can survive on hard surfaces for up to five months
2. Utilize 10% sodium hypochlorite to kill spores
E. Chlorhexidine gluconate (CHG) bathing
F. Avoid unnecessary gastric acid suppression26
IX. Treatment
______________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________
A. Infectious Diseases Society of America (IDSA) Guidelines22
1. Published in 2010, and an update is expected in Spring of 2017
2. No recommendations made for fecal microbiota transplant (FMT) or fidaxomicin (approved in 2011)
Table 3. IDSA guideline recommendations for treating CDI
Occurrence Disease Severity Level
Mild to Moderate Severe Severe, Complicated
Initial infection
Metronidazole 500
mg PO TID for
10-14 days
Vancomycin
125 mg PO QID
for 10-14 days
Vancomycin 500 mg QID PO or by
nasogastric tube
+
Metronidazole 500 mg IV TID
+/-
Rectal vancomycin (complete ileus)
1st recurrence Repeat above Repeat above Repeat above
2nd
recurrence
Vancomycin PO in
a tapered/pulsed
regimen
Vancomycin PO in
a tapered/pulsed
regimen
No recommendations made
B. ESCMID Guidelines27-28
1. Major differences from IDSA guidelines include: fidaxomicin and FMT recommendations
Table 4. ESCMID guideline for management of CDI, regimens with the highest level of support
Occurrence Disease Severity Level
Non-Severe Severe Severe, Complicated
Initial infection
Metronidazole 500
mg PO TID for 10
days
Vancomycin 125
mg PO QID for 10
days
Vancomycin 125 mg PO QID for 10 days
Oral Treatment Not Possible:
Metronidazole 500 mg IV TID for 10
days + Vancomycin 500 mg QID rectal
for 10 days
Patient at high
risk for
recurrence
Vancomycin 125 mg PO QID for 10 days or
Fidaxomicin 200 mg PO BID for 10 days
Multiple
recurrences
Vancomycin PO in a tapered/pulsed
regimen
No recommendations made
Kennedy │6
Table 5. Other treatment options for CDI7,29
Regularly Used in Practice
Fidaxomicin Utilized in recurrence due to high cost of drug
FMT Utilized in recurrence, but FDA strongly cautions use outside of clinical trials due to
varying quality of fecal products from stool banks
Less Routinely Used in Practice
Probiotics Inconclusive support for use
Nitazoxanide Off-label use; data from small cohort studies only
Rifaximin Off-label use; generally utilized after course of vancomycin or metronidazole in
order to decrease rates of recurrence
C. Metronidazole7,29
1. Background
a. Antiprotozoal agent approved in 1985
b. Effective treatment agent for CDI
2. Dosing
a. 500 mg IV or PO three times per day22
b. Higher doses required due to decreased fecal concentrations upon diarrhea resolution30
3. Mechanism of action29
a. Anionic nitro radical interacts with bacterial DNA and leads to cell death
b. Broad spectrum of action, including gram positive and gram negative anaerobic organisms
4. Efficacy data31
Table 6. Metronidazole efficacy data for treating CDI
Metronidazole Efficacy Data
Initial Clinical Cure 77% (severe CDI 68%)
Sustained Cure 72%
Recurrence Rate 18%
All-Cause Death Rate 9.5%
5. Failure rates
a. Resistance
i. Certain strains have higher MICs for metronidazole32
ii. Increasing rates of resistance seen in Spain for toxigenic isolates, 7.7% in 1994 to 12% in
200833,34
b. Risk factors for metronidazole failure35,36
i. Recent cephalosporin use
ii. Presence of CDI on admission
iii. Transfer from another hospital
iv. Low albumin level (< 2.5g/L)
v. Infection with certain C. difficile strains37
6. Adverse effects & events
a. Risk of optic and peripheral neuropathy with long term use38
b. Disulfiram-like reaction with alcohol39
c. Potential increase in vancomycin resistant enterococcus (VRE) with use40
Kennedy │7
D. Vancomycin7,29
1. Background
a. Glycopeptide antibiotic originally isolated from soil in Borneo, approved in 1958
2. Dosing Schemes22
a. 125-500 mg PO four times per day for 10-14 days
b. Pulse: 500 mg every 2-3 days for an extended period of time
c. Taper: start with 125 mg QID, then decrease to 125 mg daily over an extended period of time
3. Mechanism of action29
a. Binds D-ala-D-ala precursors, which inhibits transglycosylase and subsequent peptidoglycan
synthesis
b. Little to no systemic absorption when taken orally
c. Spectrum of action limited to gram positive bacteria
4. Efficacy data31
Table 7. Vancomycin efficacy data for treating CDI
Vancomycin Efficacy Data
Initial Clinical Cure 85% (severe CDI 81%)
Sustained Cure 65%
Recurrence Rate 16%
All-Cause Death Rate 7.6%
5. Adverse effects & events
a. Limited due to minimal systemic absorption
b. Mostly gastrointestinal
c. Potential increase in VRE with use of PO vancomycin40,41
6. Available formulations42
a. Capsules
b. Suspension
c. IV powder for injection
i. Can be compounded for oral administration
ii. Reduced palatability
E. Pricing42
1. Historically, PO vancomycin has been more expensive than PO metronidazole
2. Vancomycin powder for injection reconstituted into an oral solution shown to be more cost-effective
Figure 4. Cost of daily therapy for treating CDI
Metronidazole 500 mg tablet
$2.18
Vancomycin 125 mg capsule
$125.22
Vancomycin 125 mg reconsituted (oral syringe)
$10.32
Kennedy │8
X. Clinical Controversy: Part One ______________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________
A. Is there data to support the use of vancomycin over metronidazole in all severity levels of CDI?
B. Should metronidazole still be first line?
XI. Comparison of Literature for Metronidazole versus Vancomycin ______________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________
Table 8. A summary of trials comparing metronidazole versus vancomycin to treat CDI
Author Results Teasley et al., 1983
43
n = 94
Prospective, randomized, single center trial
Vancomycin 500 mg PO QID for 10 days versus metronidazole 250 mg PO
QID for 10 days
Similar efficacy, relapse rates, and tolerability
Metronidazole PO is more economical compared to vancomycin PO
Wilcox et al., 199544
n = 78
Retrospective, single center trial
Vancomycin 125 mg PO QID versus metronidazole 400 mg PO TID
Vancomycin had shorter duration of symptoms (3 days) versus
metronidazole (4.6 days)
No difference seen between response and relapse rates
Authors’ conclusions: higher cost may be justified due to potentially
shortened stay in hospital
Anti-motility agents did not impair response in mild-moderate CDI
Nelson et al., 200745
n = 1152
Cochrane review, included 15 studies
Compared: vancomycin, metronidazole, fusidic acid, nitazoxanide,
teicoplanin, rifampin, rifaximin, bacitracin and fidaxomicin
No superiority demonstrated by vancomycin or metronidazole
Al-Nassir et al, 200840
n = 90
Prospective, observational, single center study
VRE stool colonization before, during, and after treatment with
metronidazole PO and vancomycin PO (no disclosure of dosing)
Colonized patients on both drugs had an increase in VRE density during
therapy, but decreased after antibiotics were stopped
Of the 34 individuals not colonized with VRE at baseline, VRE was detected
in 3 and 1 instances in the metronidazole and vancomycin arms respectively
Al-Nassir et al., 200846
n = 52
Prospective, observational, single center trial
Initial CDI, comparing vancomycin PO versus metronidazole PO (no
disclosure of dosing)
Vancomycin patients were more likely to have resolution of diarrhea by day
5 & develop undetectable levels of C. difficile
10 out of 34 patients in metronidazole group switched to vancomycin due to
persistent symptoms
Wenisch et al., 201247
n = 265
Prospective, cohort, single center trial
Vancomycin 250 mg PO QID versus metronidazole 500 mg IV and PO TID
Metronidazole IV is inferior to vancomycin PO and metronidazole PO for all
cause 30-day mortality and less likely to recover
Metronidazole PO and vancomycin PO have similar efficacies
Kennedy │9
Zar FA, Bakkanagari SR, Moorthi KM, 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(3):302-7.
Overview
Objective Compare efficacy of metronidazole versus vancomycin in a head to head trial for CDI
stratified by disease severity (mild versus severe)
Trial Design
Prospective, randomized, double-blind, single center, placebo-controlled trial
Saint Francis Hospital (Evanston, IL) between October 1994 and June 2002
n = 150 (mild disease: n = 81, severe disease: n = 69)
Patients
Inclusion criteria:
≥ 3 non-formed stools in 24 hours
+
C. difficile toxin within 48 hours
OR
Pseudomembranous colitis on
endoscopy
Exclusion criteria:
Life-threatening conditions
Prior failure on either study drug or
use within past 14 days
Contraindications to either study drug
Outcomes
Primary:
Cure (diarrhea resolution by day 6 and
negative toxin at day 6 & 10)
Treatment failure (defined as
persistent diarrhea, positive toxin at
day 6, colectomy or death)
Recurrence (within 21 days after cure)
Secondary:
Post hoc analysis of risk factors for
metronidazole failure in severe CDI
Interventions
Metronidazole 250 mg QID + placebo liquid for 10 days
Vancomycin liquid 125 mg QID + placebo tablet for 10 days
Stratified by severity based on scoring system, ≥ 2 of the following was considered
severe
o 1 point each for: age > 60 years, temperature > 38.3°C, albumin < 2.5 mg/dL, or
WBC > 15,000 cells/mm3
o 2 points each for: endoscopic evidence of pseudomembranous colitis or
treatment in ICU
Statistics
Powered using two-tailed α of 0.05 and a β of 0.10, assuming 90% cure rate of both
groups, and attempting to detect a minimum of 10% difference
Fisher’s exact test or unpaired t test
Results
Baseline
Characteristics
MTZ = metronidazole; VANC = vancomycin
No statistically significant differences within severity groups
Characteristic Mild Disease (%) Severe Disease (%)
MTZ VANC MTZ VANC
Total number of patients 41 40 38 31
Age, years 57.9±16.8 56.8±11.5 57.5±9.5 61.9±16.4
> 60 years old 16 (39) 19 (48) 17 (45) 19 (61)
Antibiotics prior to CDI 41 (100) 40 (100) 38 (100) 31 (100)
Antibiotics within 14 days of
onset of CDI
39 (95) 39 (98) 37 (97) 28 (90)
Albumin < 2.5 mg/dL 7 (18) 13 (33) 15 (39) 18 (58)
Hospitalized in ICU 0 (0) 0 (0) 3 (8) 2 (6)
Presence of pseudomembranous
colitis
0 (0) 0 (0) 6 (16) 5 (16)
Kennedy │10
Zar et al., 2007, Continued
Primary
Outcomes
Rate of Cure of CDI by Disease Severity and Treatment
Disease
Severity
Number of Patients Cured/Number of Patients Treated (%)
Metronidazole Vancomycin Total p-value
Mild 37/41 (90) 39/40 (98) 76/81 (94) 0.36
Severe 29/38 (76) 30/31 (97) 59/69 (86) 0.02
All 66/79 (84) 69/71 (97) 135/150 (90) 0.006
Rate of Relapse of CDI by Disease Severity and Treatment
Disease
Severity
Number of Patients Relapsed/Number of Patients Treated (%)
Metronidazole Vancomycin Total p-value
Mild 3/37 (8) 2/39 (5) 5/76 (7) 0.67
Severe 6/29 (21) 3/30 (10) 9/59 (15) 0.30
All 9/66 (14) 5/69 (7) 14/135 (10) 0.27
Secondary
Outcomes
Characteristics of Patients with Severe CDI and Failured on Metronidazole
Therapy (%)
Characteristic Failed Therapy
Relative Risk for
Treatment Failure
p-value
Albumin level < 2.5 mg/dL 8/9 (89) 12.70 (1.70-88.40) 0.001
Presence of
pseudomembranous colitis
5/9 (56) 6.67 (2.49-17.84) 0.001
Hospitalized in the ICU 3/9 (33) 5.83 (2.81-12.09) 0.01
Conclusions
Authors’
Conclusions
Metronidazole and vancomycin have similar efficacy in mild disease severity
Vancomycin is superior to metronidazole in severe disease
Strengths
Head to head comparison
Comparable baseline characteristics
Ruled out other potential infectious causes of diarrhea
Limitations
Definition of cure involved testing for toxin
Multiple primary outcomes
Single center
Did not include recurrence patients
Non-standard dosing of metronidazole was used
CDI laboratory testing was one step
Take Home
Vancomycin was superior to metronidazole for cure of severe CDI
Sample size was inadequate to assess if it was also superior for mild severity
infections
Kennedy │11
Johnson S, Louie TJ, Gerding DN, et al. Vancomycin, metronidazole, or tolevamer for Clostridium
difficile infection: results from two multinational, randomized, controlled trials. Clin Infect Dis.
2014;59(3):345-54.
Overview
Objective Compare the efficacy and safety of tolevamer with metronidazole & vancomycin
Trial Design
Two identical, multinational, phase 3, randomized, double dummy, double-blind, active-
controlled, parallel-design, efficacy studies with 91 sites in North America and 109 sites
in Europe, Australia, and Canada between 2005 and 2007
n =1118 (Study 301: n = 574, Study 302: n = 544)
Patients
Inclusion criteria:
≥ 18 years old
Confirmed primary CDI or
presumed/confirmed recurrent CDI
o ≥ 3 loose/watery stools in 24 hours
o + C. difficile toxin assay or
pseudomembranous colitis on
endoscopy
Exclusion criteria:
Complicated CDI
Life threatening medical conditions
Unable to follow protocol
≥ 48 hours of treatment exposure prior
to randomization
Contraindications to intervention
medications
Outcomes
Primary:
Clinical success defined as resolution of
diarrhea and absence of severe abdominal
discomfort from CDI for > 2 consecutive
days including day 10
Secondary:
Time to resolution of diarrhea
Recurrence of CDI during the follow-
up period (4 weeks)
Interventions
2:1:1 tolevamer: vancomycin: metronidazole
Metronidazole 375 mg PO every 6 hours for 10 days
Tolevamer 9 g PO loading dose, followed by 3 g PO every 8 hours for 14 days
Vancomycin 125 mg PO every 6 hours for 10 days
Statistics
Cochran-Mantel-Haenszel test
Log-rank test
Logistic regression analysis
Results
Baseline
Characteristics
Characteristic Study 301
n (%)
Study 302
n (%) p-value
Age, years 62±17.7 68±16.4 < 0.0001
> 65 years old 252 (46) 323 (61) 0.98
Body weight, kg 75±24 68±17 < 0.0001
Inpatient status 306 (56) 482 (91) < 0.0001
Concomitant antibiotic use 105 (19) 137 (26) 0.044
CDI
History
Primary 384 (71) 436 (83)
0.22 1st recurrence 95 (17) 54 (10)
Multiple recurrences 63 (11) 36 (7)
CDI
Severity
Mild 136 (25) 172 (33)
0.34 Moderate 221 (41) 228 (43)
Severe 185 (34) 128 (24)
Kennedy │12
Johnson et al., Continued
Primary
Outcome
Clinical Success (%)
Study 301 Study 302 Combined p-value
Tolevamer 124/266 (46.6) 112/268 (41.8) 236/534 (44.2)
< 0.05 Metronidazole 103/143 (72.0) 99/135 (73.3) 202/278 (72.7)
Vancomycin 109/134 (81.3) 101/125 (80.8) 210/259 (81.1)
Secondary
Outcomes
Prediction factors for clinical success were vancomycin treatment, treatment-naïve
status, mild or moderate CDI severity
Prediction factor for recurrence was additional antibiotic use after cure
Median Time to Resolution of Diarrhea (days)
Study 301 Study 302 p-value
Tolevamer 12 (10,13) 12 (11, NE)
< 0.05 Metronidazole 5 (4,6) 4 (3,6)
Vancomycin 5 (4,6) 4 (4,5)
NE = not estimable
Recurrence (%)
Study 301 Study 302 Combined p-value
Tolevamer 4/117 (3.4) 6/105 (5.7) 10/222 (4.5)
< 0.05 Metronidazole 29/107 (27.1) 20/106 (18.9) 49/213 (23.0)
Vancomycin 25/107 (23.4) 18/102 (17.6) 43/209 (20.6)
Clinical Success (%) by CDI Severity (Combined Studies)
Tolevamer Metronidazole Vancomycin p-value
Mild 84/158 (53.2) 59/75 (78.7) 62/75 (82.7) 0.54
Moderate 94/220 (42.7) 82/111 (73.9) 97/118 (82.2) 0.14
Severe 58/156 (37.2) 61/92 (66.3) 51/65 (78.5) 0.059
Conclusions
Authors’
Conclusions
Tolevamer was inferior to antibiotic treatment
Metronidazole was inferior to vancomycin, especially for severe cases
Strengths
Large geographic spread
Large sample size
Double, dummy blinded
Included recurrence patients
Definition of cure
Limitations
Tolevamer reoccurrence is likely artificially low due to low clinical success rate
Selection bias
Post hoc analysis for factors for clinical success for vancomycin and metronidazole
Metronidazole did not follow normal dosing scheme
CDI laboratory testing was one step
Take Home Vancomycin was better than metronidazole for CDI for all severity levels
Tolevamer was inferior to both metronidazole and vancomycin
Kennedy │13
XII. Clinical Controversy: Part Two ______________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________
A. What is the appropriate dose of vancomycin for uncomplicated CDI?
B. Given the same frequency and duration, should all patients receive the same dose?
XIII. Vancomycin Dose ______________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________
Lam SW, Bass SN, Neuner EA, Bauer SR. Effect of vancomycin dose on treatment outcomes in
severe Clostridium difficile infection. Int J Antimicrob Agents. 2013;42(6):553-8.
Overview
Objective
Evaluate the differences in time to clinical cure, rate of overall cure, complications, and
recurrence for patients with severe CDI treated with high-dose versus low-dose
vancomycin
Trial Design Retrospective cohort, single center study from July 2006 to July 2011
n = 78 (low dose: n = 25, high dose: n = 53)
Patients
Inclusion criteria:
≥ 18 years old
CDI diagnosed by diarrhea & either
+ EIA or + PCR
Diagnosis of severe CDI based on
IDSA guidelines
Exclusion criteria:
Mild-moderate, severe complicated, or
recurrent CDI
Baseline conditions that could
confound the results (irritable bowel
disease, graft vs host disease,
neutropenia, or cirrhosis)
Outcomes
Primary:
Time to clinical cure of CDI defined
as ≥ 48 hours without diarrhea and no
complications (colectomy, colonic
perforation, ileus, and toxic
megacolon)
Secondary:
Clinical cure at day 10
Complication rates
Mortality by day 30
CDI recurrence rates within 30 days of
initial cure
Interventions Vancomycin ≤ 500 mg daily (125 mg QID)
Vancomycin > 500 mg daily (250 mg or 500 mg QID)
Statistics
Powered using two-tailed α of 0.05 70% cure rate of both groups, and attempting to
detect a minimum of 25% difference
Χ2 or Fischer’s exact test
Mann-Whitney U-test
Kaplan-Meier curves and log-rank test
Results
Baseline
Characteristics
SOFA = Sequential Organ Failure Assessment
Characteristic Low dose High dose p-value
Age, years 65 (58-72) 69 (59-76) 0.23
Weight, kg 75 (58-100) 82 (64-102) 0.40
Systemic antibiotic use
(%)
17 (68) 43 (81) 0.20
Combination therapy
with metronidazole (%)
10 (40) 33 (62) 0.09
SOFA score 2 (0-3) 3 (2-5) 0.04
Renal dysfunction (%) 11 (44) 37 (70) 0.03
Kennedy │14
Lam et al., Continued
Primary
Outcome
Time to Clinical Cure
Dosing Scheme Days 95% Confidence Interval p-value
High dose 8 6.3–9.7 0.49
Low dose 7 6.03–8.0
Secondary
Outcomes
Outcome Low Dose
n (%)
High Dose
n (%)
Odds Ratio p-value
Day 10 cure 16 (64) 32 (60) 0.85 (0.32-2.3) 0.76
Death 2 (8) 10 (19) 2.67 (0.54-13.3) 0.32
Recurrence 3 (12) 1 (2) 0.14 (0.014-1.43) 0.09
Any
complication
3 (12) 4 (8) 0.06 (0.12-2.9) 0.67
Colectomy 2 (8) 2 (4) 0.45 (0.06-3.4) 0.59
Colonic
perforation
1 (4) 0 (0) N/C 0.32
Ileus 2(8) 1 (2) 0.22 (0.02-2.56) 0.24
Toxic
megacolon
1 (4) 2 (4) 0.94 (0.08-10.9) 1.0
Conclusions
Authors’
Conclusions
No difference in treatment outcomes between high-dose and low-dose vancomycin for
treatment of severe CDI
Strengths Met power
Stringent inclusion criteria
Limitations
Retrospective review
No blinding
Grouped all the dosing schemes > 500 mg per day
Single center
Baseline discrepancies between groups
CDI laboratory testing was one step
Take Home
Points
No statistically significant difference in cure rates between the dosing regimens of
vancomycin
Kennedy │15
XIV. Summary of Evidence ______________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________
Table 9. A comparative summary of vancomycin and metronidazole
Metronidazole PO/IV Vancomycin PO
Advantages:
IDSA & ESCMID 1st line treatment option for
mild-moderate CDI
Established clinical utility
Lower cost
Dosing is three times per day
Disadvantages:
No evidence of superiority
Lower clinical success rate
Systemic absorption
Variable concentration depending on
consistency of stool
Broader spectrum of activity
Exposure may increase incidence of VRE
colonization
Long term use has risk of optic and peripheral
neuropathy
Disulfiram-like reaction
Advantages:
Higher clinical success rate
Little to no systemic absorption
Decreased spectrum of activity
Prompt resolution of CDI
Established clinical utility
Disadvantages:
Higher cost
Taste
Four times per day dosing
Exposure may increase incidence of VRE
colonization
Figure 5. Comparison of vancomycin dosing
XV. Recommendations ______________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________
A. Vancomycin 125 mg PO QID should be utilized first-line for initial, mild-severe,
uncomplicated CDI
B. Metronidazole 500 mg PO TID should be utilized as a second line option for CDI
Oral Vancomycin Dosing
• 125 mg QID
• Utilize for initial, severe CDI
• Achieves adequate stool concentrations
• Resolution rates similar to higher dosing
Low Dose
• 500 mg QID
• Recommended for complicated CDI (i.e. ileus, megacolon, etc.)
• No evidence that higher doses were more effective
High Dose
Kennedy │16
References ________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________
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Appendices ________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________
Appendix A. Definitions19
1) Sensitivity: probability that the index test result will be positive in a person with disease (a/a+c)
2) Specificity: probability that the index test result will be negative in a person without disease (d/b+d)
3) Positive Predictive Value: the probability that a person has the disease, given the positive test result
(a/a+b)
4) Negative Predictive Value: probability that a person is free of disease, given the negative test result
(d/c+d)
Appendix B. Index testing compared to reference test19
Diseased or reference test positive Not diseased or reference test
negative
Index test positive (a) True positive (b) False positive
Index test negative (c) False negative (d) True negative
Appendix C. Various testing methods of C. difficile and the associated strengths and weaknesses15,19
Test Sensitivity Specificity Time Cost
GDH antigen High Low Rapid Low
EIA for Toxin test Low High Rapid Low
NAAT/PCR test High Moderate Rapid Moderate
Culture Most High High Slow High
Appendix D. One ESCMID recommended algorithm for diagnosing CDI19
PCR or GDH EIA
If (+), then do Toxin A/B EIA
If (+), CDI likely If (-), clinical evaluation,
may be colonization
Optional: Perform TC or NAAT (if 1st test was GDH
EIA)
If (-), no further testing, CDI unlikely
Kennedy │20
Appendix E. Another ESCMID recommended algorithm for diagnosing CDI19
Appendix F. Additional studies evaluating the various doses of oral vancomycin for the treatment of CDI
GDH and TOX A/B EIA
If both (-), then CDI unlikely
If (-), no further testing, CDI unlikely
If (-), then CDI unlikely If (+), then clinical
evaluation, colonization possible
If (+), no further testing, CDI likely
Vancomycin Dosing
Author Results
Fekety et
al., 198951
n = 46
Prospective, randomized, single center trial
Oral Vancomycin 125 mg or 500 mg QID for an average of 10 days
No difference in time to resolution of abdominal pain, diarrhea, frequency of side effects,
duration of therapy, frequency of positive cultures after treatment, and rate of relapse
Authors’ favored vancomycin 125 mg preferred unless critically ill due to cost
Gonzalez
et. al,
201052
n = 15
Prospective, observational, single center trial
Fecal concentrations of vancomycin 125 mg QID versus 250 mg or 500 mg QID
Fecal levels are proportional to the dose given
Fecal concentrations were 100-1000 times higher than the MIC90 by day two for all
patients (MIC90 = 1.0 mg/L)
One patient on low-dose vancomycin had fecal concentrations of 15 and 30 mg/L the first
day of treatment
Patients with ≥ 4 stools per day had lower levels, but were still therapeutic (500-1000
times MIC90)
Major limitation: not all patients were diagnosed with CDI
Serum concentrations ranged from 0 to 0.77 mg/L
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