Clostridium difficile Infections:

Diagnosis, Treatment, and Prevention

Prepared for:
Agency for Healthcare Research and Quality (AHRQ)
www.ahrq.gov

Outline of this CME Activity

The comparative effectiveness review (CER) process
Overview of the CER
Introduction
Detailed Results
Direct comparisons of available diagnostic assays.
Comparative effectiveness and harms of antibiotic
treatments.
Comparative effectiveness of nonstandard interventions to
treat CDI or reduce the risk of recurrence.
Effectiveness of prevention strategies.

Conclusions

Agency for Healthcare Research and Quality (AHRQ)

Comparative Effectiveness Review (CER) Development
Topics are nominated through a public process, which includes
submissions from health care professionals, professional
organizations, the private sector, policymakers, the public, and
others.
A systematic review of all relevant clinical studies is conducted by
independent researchers, funded by AHRQ, to synthesize the
evidence in a report summarizing what is known and not known
about the select clinical issue. The research questions and the
results of the report are subject to expert input, peer review, and
public comment.
The results of these reviews are summarized into Clinician and
Consumer Research Summaries for use in decisionmaking and in
discussions with patients. The research reviews, full report, and a
link to the condensed research article in Annals of Internal Medicine
are available at: www.effectivehealthcare.ahrq.gov.

Rating the Strength of Evidence From the CER

The strength of evidence was classified into four broad
categories:
High - Further research is very unlikely to change the

confidence in the estimate of effect.

Moderate - Further research may change the confidence in
the estimate of effect and may change the estimate.
Low - Further research is likely to change the

confidence in the estimate of effect and is likely to

change the estimate.
Insufficient - Evidence either is unavailable or does
not permit estimation of an effect.

Overview: Objectives
To conduct a systematic review and synthesize evidence
for differences in:
The accuracy of diagnostic tests
The effects of standard antibiotics to treat Clostridium
difficile infection (CDI) in adult patients.
Nonstandard interventions to prevent and treat CDI in adult
patients.
Prevention strategies.

Butler M, et al. AHRQ Comparative Effectiveness Review No. XXX. Available at: http://effectivehealthcare.ahrq.gov/index.

Overview: Methods
Data Sources:
MEDLINE, the Cochrane Library, and Allied and Complementary
Medicine (AMED)
ClinicalTrials.gov and expert consultants
Reference lists from relevant literature

Review Methods:
Standard Evidence-based Practice Center methods
High-quality direct comparison studies were used to examine
differences in diagnostic tests.
Randomized controlled trials (RCTs) were used to examine
comparative effectiveness of antibiotic treatment for CDI
Qualitative narrative analysis was used to synthesize evidence
from all available study types for environmental prevention and
nonstandard prevention and treatment, with the exception of
probiotics as primary prevention.

Overview: Results for Diagnostic Testing

Direct comparisons of commercially available enzyme
immunoassays for C. difficile toxins A and B did not find
major differences in sensitivity or specificity.
(Low strength evidence)
Limited evidence suggests that tests for genes related to
the production of C. difficile toxins may be more
sensitive than immunoassays for toxins A and B while the
comparisons of these test specificities were inconsistent.
It is unclear whether the potential differences in the
accuracy of the diagnostic tests being employed in
practice would translate into differences in clinical
behaviors or patient outcomes.

Overview: Results for Treatment of CDI with

Standard Antibiotics
Initial cure rates are similar for oral vancomycin versus
metronidazole and vancomycin versus fidaxomicin.
(Moderate strength evidence)
Recurrence rates were about 10 percent lower after treatment
with fidaxomicin when compared with vancomycin (15 percent
versus 25 percent; P = 0.005).
(Moderate strength evidence)
Patients treated with vancomycin for a non-NAP1 strain
infection were about 3 times as likely to have a recurrence
than patients treated with fidaxomicin, but patients with the
NAP1 strain had recurrence rates that did not differ
significantly by treatment.
(Low strength evidence)
NAP1: North American Pulsed Field type 1 strain

Overview: Results for Nonstandard Interventions

to Treat CDI or Reduce the Risk of Recurrence
Adding certain probiotics to antibiotics for primary treatment may
increase the risk for fungemia-related complications in critically ill
patients and adds no known benefit.
(Low strength evidence)
Probiotics, prebiotics, and toxin-neutralizing antibodies alone do not
reduce primary hospital CDI incidence rates.
(Low strength evidence)
For patients who had one or more relapses in a 3-month time period,
CDIW was well-tolerated and the overall response rate was similar to
metronidazole. (Low strength evidence)
Fecal flora reconstitution via fecal transplantation prevents
recurrent infections for up to 1 year.
(Low strength evidence)
CDI recurrence rates were reduced three-fold when an oligofructose
prebiotic (low strength evidence) or toxin-neutralizing antibodies
(moderate strength evidence) were added to standard antibiotics.

Overview: Results for Prevention

Appropriate prescribing practices that decrease the use
of high-risk antimicrobials are associated with lower CDI
incidence rates. (Low strength evidence)
CDI incidence may be reduced by using disposable gloves
and thermometers and by disinfection with chemicals
that kill C. difficile spores. (Low strength evidence)
Risk factors for CDI include antibiotic use, severe
underlying disease, acid suppression, hospitalization in
an ICU, age, and nonsurgical gastrointestinal procedures.
(Low strength evidence)
Overall, the use of multiple component interventions
limits the ability to synthesize evidence in a meaningful
way.

Overview: Conclusions
Limited evidence on the comparisons of immunoassays and genetic
tests do not provide guidance to change current diagnostic
approaches.
Comparisons of oral vancomycin and metronidazole as well as
vancomycin and fidaxomicin demonstrate similar initial cure rates.
Fidaxomicin is associated with significantly lower recurrence rates
than vancomycin for patients infected with non-NAP1 strains of C.
difficile.
For patients with the NAP1 strain, recurrence rates did not differ by
treatment.
For patients with multiple recurrences, use of C. difficile immune
whey or fecal flora reconstitution show promise, but evidence is low.
Limited evidence supports current practices for prevention,
including appropriate antibiotic stewardship to reduce the use of
broad-spectrum antibiotics.

Introduction:
Incidence of C. difficile Infection (CDI)
Important healthcare-associated infection and growing health
care problem.
Estimated at 6.5 cases per 10,000 patient days in hospital.
About 250,000 hospitalizations were associated with CDI in
2005.
Elderly people in hospitals account for the majority of severe
morbidity and mortality.
Residents of long-term care facilities are also at higher risk.
Incidence rates may increase by four or five-fold during
outbreaks.
Incidence and severity may be increasing due to the
emergence of a hypervirulent strain of C. difficile.

Introduction: C. difficile Etiology

C. difficile is a Gram-positive, spore-forming, anaerobic
bacterium that can cause CDI when a toxigenic strain is
ingested by a susceptible person.
Toxigenic C. difficile strains produce toxin B (a cytotoxin) +/toxin A (an enterotoxin).
Asymptomatic colonization of a healthy persons colon is
common; if colonic flora is disturbed (e.g., through antibiotic
use), toxigenic C. difficile can cause disease.
Risk factors include antibiotic use, increasing age, female
gender, comorbidities, gastrointestinal procedures, and use of
gastric acid suppression medications.
C. difficile is also common in the community, being easily
isolated from soil and water samples.
New, more virulent strains have emerged since 2000 that put a
larger population at risk.

Introduction: Symptoms of CDI

CDI symptoms can include varying levels of diarrhea
severity, pseudomembranous colitis, or toxic megacolon.
CDI recurs in about 20 percent of patients.
A subset of recurrent patients spiral into several
subsequent recurrences.

Introduction: Current State of the Research on

Antibiotic Therapy for CDI
Standard Antibiotic Treatment:
Oral vancomycin and fidaxomicin are the only FDA-approved
antibiotics to treat CDI.
Other antibiotics such as metronidazole are commonly used to
treat mild-to-moderate CDI.
Only 11 trials were identified that evaluated different
antimicrobials for treatment of CDI.

Antibiotic Treatment for Recurrent/Refractory CDI:

There was insufficient data to determine the most effective
regimen and therefore not addressed in this research review.

Nonstandard Interventions for Primary and Recurrent CDI:

CER authors consolidated the evidence for alternative or
nonstandard/nonantibiotic interventions that clinicians are using
to treat primary and recurrent or refractory CDI patients.

Comparative Effectiveness of Diagnostic

Assays for C. difficile
Immunoassays for toxins A and B
Toxin gene detection tests

Assays Commonly Used in CDI Diagnostics

Cytotoxicity assays
C. difficile culture
Immunoassays for toxins
Toxin gene detection tests

Methods Evaluated for Detecting

Toxigenic C. difficile
Diagnostic Assays Investigated
Toxin A and B Immunoassays

Number of
Studies (n)

Premier Toxin A&B, Meridian

Tox A/B II, TechLab

Tox A/B QUIK CHEK, TechLab

ImmunoCard A&B, Meridian

Xpect Toxin A/B, Remel

ProSpecT Toxin A/B, Remel

VIDAS C. diff Tox A/B, bioMerieux

Gene Detection Tests

GeneOhm, Becton Dickinson

GeneXpert, Cepheid

Results of Direct Comparisons of Available

Diagnostic Assays
16 paired comparisons of seven commonly used
immunoassays for toxins A and B could not determine if
significant differences existed in test sensitivities or
specificities. (Low level of confidence)
Tests that detect fragments of toxin-related genes may
increase sensitivity, but may lose specificity.
(Low level of confidence)
There was insufficient evidence to determine whether
any differences in sensitivity or specificity between
diagnostic tests depend on patient or specimen
characteristics or the clinical scenarios that lead to
testing for toxigenic C. difficile.

Comparative Effectiveness of Standard

Antibiotic Treatment for CDI
FDA-approved antibiotics
Other antibiotics

Comparative Effectiveness Results for Treating

CDI With Antibiotics
Initial cure rates are similar for oral vancomycin versus
metronidazole and vancomycin versus fidaxomicin.
(Moderate strength of evidence)
Similarly, none of the other head-to-head trials demonstrated
superiority of any single antimicrobial for initial clinical cure,
recurrence, or mean days to resolution of diarrhea.

Recurrence rates were about 10 percent lower after treatment

with fidaxomicin when compared with vancomycin (P = 0.005).
(Moderate strength of evidence)
Patients treated with vancomycin for a non-NAP1 strain
infection were about 3 times as likely to have a recurrence
than patients treated with fidaxomicin, but patients with the
NAP1 strain had recurrence rates that did not differ
significantly by treatment. (Low strength of evidence)

Nonstandard Interventions to Treat CDI

or Reduce the Risk of Recurrence
Antibiotics + probiotics
Probiotics
Oligofructose prebiotic
Fecal flora reconstitution
C. difficile-specific polyclonal antibody-enriched immune whey
Toxin-neutralizing antibodies
Toxin absorptive resins
IV immunoglobulin

Comparative Effectiveness Results for Treatment

of CDI With Antibiotics + Adjunctive Therapy
Adjunctive therapy added to standard antibiotic therapy in the
included studies consisted of:
Probiotic containing Saccharomyces boulardii was added to oral
vancomycin, metronidazole, or both.
Probiotic containing Lactobacillus plantarum was added to
metronidazole.
Overall conclusions:
Probiotics administered as an adjunct to antibiotic treatment
were not more effective than treatment with antibiotics alone.
(Low strength of evidence)
Adding probiotics containing Saccharomyces spp. to antibiotics
for primary treatment may increase the risk for fungemia-related
complications in critically ill patients and adds no known benefit.
(Low strength of evidence)

Nonstandard Interventions to Reduce the

Occurrence of Primary CDI
Primary hospital CDI incidence rates were not reduced in
response to these individual treatments:
Probiotics (Saccharomyces boulardii, Lactobacillus GG, L.
acidophilus + Bifidobacterium bifidum, L. casei + L.
bulgaris + Streptococcus thermophilus, L. plantarum)
An oligofructose prebiotic
Toxin-neutralizing antibodies (intravenous infusion of
human monoclonal antibodies against C. difficile toxins A
(CDA1) and B (CDB1)

Low strength of evidence

Nonstandard Interventions for Treatment of

Multiple Recurrences of CDI
For patients who had one or more relapses in a 3-month
time period, CDIW was well-tolerated and the overall
response rate was similar to metronidazole.
(Low strength of evidence)
Six case studies or case series indicated that fecal flora
reconstitution via fecal transplantation prevented
recurrent infections for up to 1 year.
(Low strength of evidence)

Nonstandard Interventions to Reduce CDI

Recurrence Rates
CDI recurrence rates decreased 3-fold when an
oligofructose prebiotic (low strength of evidence) or
toxin-neutralizing antibodies (moderate strength of
evidence) were added to standard antibiotics.

Overall Conclusions: Nonstandard Interventions

to Treat CDI or Reduce the Risk of Recurrence
C. difficile immune whey is well tolerated and may prevent
recurrence of CDI at rates similar to metronidazole.
(Low Strength of Evidence)
Fecal flora reconstitution via fecal transplantation may
prevent recurrent infections for up to 1 year. (Low Strength of
Evidence)
Probiotics, prebiotics, and toxin-neutralizing antibodies alone
may not reduce CDI incidence rates. (Low Strength of
Evidence)
Oligofructose prebiotic (Low Strength of Evidence) and toxinneutralizing antibodies (Moderate Strength of Evidence) have
the potential to help reduce the risk of recurrent infections.

Comparative Effectiveness of CDI

Prevention Strategies
Antibiotic prescribing policies
Institutional prevention strategies
Bundled intervention strategies
Sustainability of prevention strategies
CDI risk factors

Prevention Strategies for CDI Focusing on

Antibiotic Prescribing Policies
Appropriate prescribing practices that decrease the use
of high-risk antimicrobials may be associated with lower
CDI incidence rates. (Low strength of evidence)
The studies reviewed did not evaluate the cost,
toxicities, or other related outcomes from the
implementation of antibiotic stewardship policies.

Institutional Prevention Strategies for CDI

Low strength of evidence suggested that CDI incidence
may be reduced by using common contact barriers such
as:
Disposable gloves
Tympanic or disposable single-use thermometers

Disinfection with chemicals, including hypochlorite

solutions, aldehydes, and liquid vapor hydrogen peroxide,
that kill C. difficile spores may lower CDI incidence. (Low
strength of evidence)
No studies determined if hand washing was more
effective than alcohol gels; however, C. difficile spores
are known to be resistant to alcohol-based hand rubs and
other routinely used antiseptics.

Limitations of Research on CDI Prevention

They mainly evaluated effectiveness of CDI prevention during an
epidemic or in a hyperendemic environment.
Studies did not evaluate the sustainability of the interventions
beyond the study period.
The potential negative impact these interventions would have on the
institutional environment other than cost was not evaluated in these
studies but may include:
Time needed to perform disinfection;
Possible harm to surfaces or equipment from harsh decontamination
chemicals;
Failure of vapor disinfection systems;
Exposure of patients and personnel to toxic chemicals;
Rates of recontamination after hand washing that results from
touching equipment or surfaces in patient rooms contaminated with
C. difficile spores, which may persist on some surfaces for up to 5
months;
The reduction in direct patient-care contact due to isolation.

Gaps in Knowledge
Newer DNA-based diagnostic C. difficile assays have given promising
initial results; however, it is not clear how differences in diagnostic
test sensitivity and specificity affect clinical decisions and patient
outcomes.
Research is needed to determine the optimal institution-wide CDIprevention strategies for addressing multiple potential routes of
transmission and for reducing patient susceptibility.
Research is still needed to determine if nonantibiotic interventions
such as probiotics, prebiotics, toxin-absorbing compounds, and fecal
flora reconstitution, among otherscan be effective in preventing
primary or recurrent CDI.
More research is needed to determine if oral vancomycin may
provide higher initial cure rates for severely ill CDI patients;
however, more research is necessary in this patient population.
A consensus needs to be reached between clinical and researchoriented definitions of CDI with regard to diarrhea, that is, the
number and consistency of stools.

What To Discuss With Your Patients

What risk factors they may have that makes them or
someone they care for susceptible to CDI.
If they or someone they care for has CDI, how they can
help prevent the spread of the infection.
Which antibiotic treatment is appropriate for their CDI.
Whether or not nonstandard interventions would be
beneficial especially considering their availability and
potential costs to the patient.