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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

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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