Clostridium difficile Infections: Diagnosis, Treatment, and Prevention

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Clostridium difficile Infections Diagnosis,
Treatment, and Prevention

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

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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

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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.

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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.

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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//effectiveheal
thcare.ahrq.gov/index.
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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.

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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.

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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

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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.

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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.

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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.

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IntroductionIncidence 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.

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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.

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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.

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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.

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Comparative Effectiveness of Diagnostic Assays
for C. difficile

• Immunoassays for toxins A and B
• Toxin gene detection tests

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Assays Commonly Used in CDI Diagnostics

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

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Methods Evaluated for Detecting Toxigenic C.
difficile
Diagnostic Assays Investigated Number of Studies (n)
Toxin A and B Immunoassays
Premier Toxin AB, Meridian 7
Tox A/B II, TechLab 6
Tox A/B QUIK CHEK, TechLab 4
ImmunoCard AB, Meridian 7
Xpect Toxin A/B, Remel 4
ProSpecT Toxin A/B, Remel 2
VIDAS C. diff Tox A/B, bioMerieux 4
Gene Detection Tests
GeneOhm, Becton Dickinson 3
GeneXpert, Cepheid 2
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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.

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Comparative Effectiveness of Standard Antibiotic
Treatment for CDI

• FDA-approved antibiotics
• Other antibiotics

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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)

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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

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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)

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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

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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)

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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.

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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 toxin-neutralizing antibodies
  (Moderate Strength of Evidence) have the
  potential to help reduce the risk of recurrent
  infections.

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Comparative Effectiveness of CDI Prevention
Strategies

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

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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.

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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.

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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.

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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 CDI-prevention strategies for
  addressing multiple potential routes of
  transmission and for reducing patient
  susceptibility.
• Research is still needed to determine if
  nonantibiotic interventionssuch 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 research-oriented definitions of CDI with
  regard to diarrhea, that is, the number and
  consistency of stools.

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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.