Antimicrobial Stewardship Program for Clostridium Difficile Infection.
Condition: Clostridium Difficile; Enterocolitis, Pseudomembranous
MeSH terms: Clostridium Infections; Enterocolitis, Pseudomembranous; Enterocolitis
Study type: Observational

Summary: 
      The purpose of this study is to determine whether a bundle of measures specifically designed
      for patients with ICD and applied by and Infectious Diseases expert during a year period
      (2017) will improve the prognosis and reduce the rate of recurrence, compared with the
      baseline phase (2015) in which no intervention was made.
    

Detailed description: 
      Patients with CDI benefit from the assessment and monitoring by an Infectious Diseases (ID)
      expert. Early intervention in patients diagnosed with a first episode of CDI would reduce the
      unnecessary use of antibiotics, improve prognosis by ensuring compliance with the clinical
      practice guidelines and reduce the number of recurrences.

      Primary objective:

      • To improve the prognosis of patients with CDI hospitalized during the period of
      intervention:

        -  Increasing the compliance with clinical practice guidelines about specific treatment for
           CDI (for the episode that generated the intervention), depending on the severity of the
           episode and the existence of previous episodes

        -  Reducing the recurrence rate by means of a close follow-up during the period of higher
           risk, avoiding factors that are known to predispose to recurrence.

      Secondary objectives:

        -  To discontinue or to reduce the spectrum of unnecessary antibiotic treatments in this
           population ("antimicrobial stewardship"), especially during the episode of CDI and
           during the following 8 weeks.

        -  To discontinue inappropriate treatment of asymptomatic patients colonized by Clostridium
           difficile.

        -  To identify clinical and biological markers that could be used as predictors of
           recurrence.

        -  To identify patients with a high number of recurrences, that could benefit from novel or
           experimental treatments.

      MATERIAL AND METHODS:

      The first 100 patients fulfilling the inclusion criteria will be included in the study.

      They will be retrospectively compared with the first 100 patients diagnosed with CDI during
      de previous year (2015) in which there was not a systematical intervention by a member of the
      Infectious Diseases Unit.

      Specific "bundle" of measures for patients with ICD:

      This measures are based in well-known and evidence-based elements that reduce the incidence
      and limit the spreading of Clostridium difficile:

        -  Systematic evaluation of all patients diagnosed with CDI by an Infectious Disease expert
           with the implementation of the following interventions:

             -  To ensure compliance with clinical practice guidelines about specific treatment for
                CDI, depending on the severity of the episode and the existence of previous
                episodes, thus improving the prognosis of these patients and avoiding side effects.

             -  To optimize concomitant antibiotic therapy (antimicrobial stewardship) through the
                following interventions: remove unnecessary treatments, shorten antibiotic courses
                as far as possible and avoid, if possible, broad-spectrum or high risk for
                developing CDI antibiotics.

             -  To reduce indiscriminate use of proton-pump inhibitors or H2 receptor antagonists.

             -  To provide clear instructions to patients and their families about the measures
                that should be implemented at home after discharge. To answer their questions and
                calm their fears about the CDI and need for isolation.

        -  To ensure appropriate monitoring during the period of greatest risk of relapse (8 weeks
           after completion of antibiotic treatment for CDI) in order to reduce as far as possible,
           the number of relapses by the following interventions:

             -  Personalized assistance by telephone or by email for early consultation in case of
                recurrence of symptoms, in order to make:

                  -  Early diagnostic of relapses.

                  -  Appropriate treatment of subsequent episodes.

                  -  Detection of patients who could benefit from fecal microbiota transplantation.

                  -  Personalized assistance by telephone or by email for consultation in case of
                     necessity of a new antibiotic course in order to:

                  -  Avoid unnecessary antimicrobial treatments.

                  -  Choose the antibiotic class with less risk of selecting C. difficile.

                  -  Evaluate preventive measures in an attempt to prevent the development of CDI.

      Study timetable

        -  Patients will be evaluated by a member of the research team at CDI diagnosis. Specific
           treatment will be revised by the investigator with patient's physician in order to adapt
           it to the clinical guidelines, depending on the severity of the episode and the
           existence of previous episodes. Concomitant antibiotic treatments will be dropped or
           adjusted if possible. It is important to clarify that the study investigator will always
           make a suggestion according to the current evidence, but the final decision about
           treatment will be always made by patient's physician in charge.

        -  At the end of CDI treatment patient will be evaluated again by phone or at the
           outpatient's clinic in order to ensure resolution of symptoms and detect possible
           adverse events.

           o In this moment, a blood test will be performed in all study patients including: Full
           blood count, basic biochemistry analysis, Iron metabolism parameters: total iron-binding
           capacity, total serum iron, ferritin and transferrin. Nutritional parameters.
           Inflammatory markers: C-reactive protein and erythrocyte sedimentation rate. Serum
           immunoglobulin levels, serum complement levels (C3 and C4) and peripheral blood
           lymphocyte subpopulations.

        -  Beyond that point, there will be a personalized assistance by telephone or by email once
           a week until 8 weeks after the end of treatment.

        -  In case of recurrence of symptoms, need for admission or a new antimicrobial treatment,
           patient will be seen at the outpatient's clinic and will receive and individualized
           advice in order to achieve an early diagnose of relapse and to reduce the risk of
           recurrence.

      Definitions:

      Diarrhoea: Loose stools, i.e. taking the shape of the receptacle or corresponding to Bristol
      stool chart types 5-7, plus a stool frequency of three stools in 24 or fewer consecutive
      hours or more frequently than is normal for the individual.

      An episode of CDI is defined as: A clinical picture compatible with CDI and microbiological
      evidence of free toxins and the presence of C. difficile in stool without reasonable evidence
      of another cause of diarrhoea or Pseudomembranous colitis as diagnosed during endoscopy,
      after colectomy or on autopsy.

      Mild or moderate CDI: Diarrhoea without systemic symptoms, leukocytosis with a white blood
      cell count lower than15,000 cells/mL and a serum creatinine level less than 1.5 times the
      premorbid level.

      Severe CDI: systemic symptoms of infection and/or leukocytosis with a white blood cell count
      of 15,000 cells/mL or higher or a serum creatinine level greater than or equal to 1.5 times
      the premorbid level.

      Severe Complicated CDI: was defined by the presence of severe disease accompanied by
      life-threatening conditions such as ileus, toxic megacolon, refractory hypotension and/or
      multi-organ failure attributable to CDI.

      Ileus: Signs of severely disturbed bowel function such as vomiting and absence of stool with
      radiological signs of bowel distension.

      Toxic megacolon: Radiological signs of distension of the colon (>6 cm in transverse width of
      colon) and signs of a severe systemic inflammatory response (nausea, vomiting, dehydration,
      lethargy or tachycardia addition to fever and abdominal pain).

      Leukocyte count to consider severity of the CDI: Any white blood cell count (WBC) measured
      between two days before and two days following the date of the stool sample. If a patient had
      WBC measured on the date of the stool sample then this was selected. If they did not have WBC
      measured on the date of the stool sample but had WBC measured between one day before and one
      day following their stool sample, then this was selected. If they did not have WBC measured
      between one day before and one day following their stool sample but had WBC measured between
      two days before and two days following their stool sample, then this was selected. If they
      did not have WBC measured on the date of the stool sample but had WBC measured both one day
      before and one day following the date of stool sample, or had WBC measured both two days
      before and two days after the stool sample but not between these measurements, then the
      highest of the two measurements was selected.

      Definition of treatment response: Treatment response is present when either stool frequency
      decreases or stool consistency improves and parameters of disease severity (clinical,
      laboratory, radiological) improve and no new signs of severe disease develop.

      Definition of recurrent CDI: Recurrence is present when CDI re-occurs within 8 weeks of
      successfully completing treatment for CDI.

      Duration of diarrhea: was the sum of days from day 1 to the last day with diarrhea, followed
      by 2 or more days without diarrhea.

      Antibiotics of high, medium and low risk for CDI: according to the table proposed by Aldeyab
      et al (S3. J Antimicrob Chemother 2012; 67: 2988-2996).

      Data collection and analysis Patients in the pre-intervention period will be retrospectively
      identified from data microbiology (all isolates of Clostridium difficile of 2015 will be
      revised). Patients in the intervention period will be identified and prospectively followed
      by a member of the research team.

      The variables will be collected in a coded database for further analysis.

      Sample size calculation We present an exploratory study which aim is to evaluate the impact
      of an intervention, consisting on a bundle of measures for patients diagnosed with a first
      episode of CDI. The bundle includes antimicrobial stewardship, close follow-up, optimization
      of specific treatment for CDI and potential search for clinical and biological markers of
      recurrence.

      The required sample size was estimated under the hypothesis that the application of a
      strategy based on a bundle to improve the management of CDI, would decrease the risk of
      recurrence as compared to the usual care performed in the retrospective period.

      A recent review that evaluated the frequency of treatment failure and recurrence of CDI
      showed a recurrence rate after metronidazole treatment of 27.6% in studies performed in
      Europe during the previous 10 years.

      Based in the previous literature, we expected a cumulative incidence of recurrence in the
      control group of 27.6%. The study would require a sample size of 99 for each group (i.e. a
      total sample size of 198, assuming equal group sizes), to achieve a power of 80% for
      detecting a reduction in proportions of 0.15 between the two groups (reference group -
      intervention) at a two sided p-value of 0.05.

      Statistical Plans In 2014, in our institution 188 new cases of CDI were diagnosed. We assume
      that approximately 30% were recurrences of previous cases, so we extrapolate than 1 year will
      be enough to achieve the estimated sample size of 100 patients for the prospective period.

      The data of qualitative variables will be expressed as absolute values and relative
      frequencies. The data of quantitative variables will be shown as mean ± standard deviation
      should be demonstrated normal distribution or median with interquartile range otherwise.
      Categorical variables will be compared using X ^ 2 or Fisher's exact test. Continuous
      variables will be compared using the Student's t-test or the Mann-Whitney U test. Statistical
      analysis will be conducted using SPSS version 15.0 (SPSS Inc, Chicago, Illinois, USA).
    

Intervention name(s): Systematic evaluation by an ID expert.
Intervention type(s): Behavioral
Intervention description(s): Specific "bundle" of measures:
Systematic evaluation of all patients diagnosed with CDI by an Infectious Disease expert To ensure compliance with clinical practice guidelines about specific treatment for CDI, depending on the severity of the episode and the existence of previous episodes and to optimize concomitant antibiotic therapy ("antimicrobial stewardship").
To ensure appropriate monitoring during the period of greatest risk of relapse in order to reduce as far as possible, the number of relapses. Personalized assistance by telephone or by email for early consultation in case of recurrence of symptoms or need for a new antibiotic course.
Observational model: Cohort
Time perspective: Other
Sampling method: Non-Probability Sample
Study population: 
        Adult patients diagnosed with CDI during 2015 in the University Hospital 12 de Octubre
        (retrospective historic cohort) or adult patients diagnosed with CDI during 2017 in the
        University Hospital 12 de Octubre (prospective cohort in which intervention was made).
      
Biospecimen description: 
      As patients with CDI are going to be prospectively followed, apart from the routine
      hematology and biochemistry analysis, serum immunoglobulin levels, serum complement levels
      (C3 and C4) and peripheral blood lymphocyte subpopulations will be measured at the end of CDI
      treatment.

      The levels of these immunological parameters will be tested as markers for relapse by
      retrospectively comparing them between patients with and without recurrence.

      A stool sample will be collected at the end of treatment to evaluate predictors of bad
      outcome or recurrence: Inflammatory markers (lactoferrin, calprotectin) We will
      retrospectively compare these parameters between patients with and without recurrence.
    
Keywords: Clostridium difficile.; Antimicrobial Stewardship.; Enterocolitis, Pseudomembranous