Antimicrobial Stewardship Program Based on the Detection and Monitoring of Patients With Clostridium Difficile Infection (PACTA-ICD)
Conditions: Clostridium Difficile, Enterocolitis, Pseudomembranous
Sponsor: José María Aguado García, MD, PhD

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Antimicrobial Stewardship Program 
Based on the Detection and 
Monitoring of Patients with 
Clostridium difficile infection. 
 
 
 
NCT02951481   Protocol ID: JMA-MET-2016-01 
 
 
Version 2.0 
February 15, 2016 
 
 
 
 
 
 
 
 
Infectious Diseases Unit. 
Fundación de Investigación “i+12” 
University Hospital “12 de Octubre” 
 
 
 
H12O 

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IP Name:  
 
 
José María Aguado García. 
Researcher:   
 
Julia Origüen Sabater. 
Title:  
 
 
Full Professor of Medicine 
Address 1 
Hospital Universitario 12 de Octubre, Av. Andalucía km 
5,400. 28041 Madrid, Spain 
Address 2 
Universidad Complutense, Av. Complutense s/n. 28040 
Madrid, Spain 
City, ST, Zip  
 
28041 Madrid 
Phone/Fax:  
 
#34-639742393 
E-mail: 
 
 
jaguadog1@gmail.com 
 
 
 
Background and Rationale  
 
Clostridium difficile is one of the most common causes of health care–associated 
infection. The incidence and severity of the CDI have increased alarmingly in many 
countries around the world since the outbreak of the hypervirulent strain NAP1 / BI / 027 
at the beginning of the last decade. In Spain, it has also been a clear increase in 
incidence from 39 to 122 cases per 100,000 hospitalizations over 1999-2007 (1,2), 
despite the fact that the presence of the NAP1 / BI / 027 has been anecdotal until 2015. 
The higher incidence of CDI in Spain is related with the increment of antibiotic use, aging 
and more complex comorbidities of the hospitalized population (2). It is also likely that 
physicians’ higher degree of suspicion and improved sensitivity of diagnostic tests had 
also contributed to magnify this rise. 
 
In our country it has been shown that the use of antibiotics (in DDD) in the outpatient 
setting, especially fluoroquinolones and penicillin with beta-lactamase inhibitors (mainly 
amoxicillin-clavulanate) has increased significantly (3). Besides, the prevalence of 
fluoroquinolone use in hospital settings (patients receiving antibiotic per 100 hospitalized 
patients) has also risen significantly, going from 5.8 in 1999 to 10.2%in 2010 (4). In a 
recent study conducted in Canada, all antibiotics prescribed in hospital within 8 weeks 
of C. difficile infection (CDI) diagnosis were reviewed for appropriateness. More than 
45% of antibiotic courses were deemed to be inappropriate because of incorrect 
diagnosis, inadequate or excessively broad spectrum of activity and prolonged duration 
of therapy (5). For this reason, programs of antibiotic stewardship have shown to 

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decrease the selective pressure that facilitates the emergence of multidrug resistant 
microorganisms and CDI. Development of hospital policies to limit the number and 
duration of antibiotic treatments has proved useful in reducing the incidence of CDI (6-
9). In case of hospital outbreaks, programs improving antimicrobial use and strict 
cleaning measures and contact precautions are essential to control the spread of 
infection (10). 
 
On the other hand, the risk of recurrence of CDI is high (between 20 and 30%). Patients 
with a first recurrence are at special risk of developing further episodes of recurrence, 
with the consequent inconveniences of that situation (repeated emergency department 
consults, numerous hospital admissions, negative effect on life quality, familiar 
disturbance…). Close monitoring of all patients with a CDI diagnosis may help to identify 
patients at particular risk of recurrence, in order to eliminate those potentially modifiable 
risk factors (11,12). 
 
Early diagnosis and appropriate treatment of recurrent episodes, according to clinical 
practice guidelines (13), would improve patients’ prognosis. Besides, monitoring by an 
infectious diseases physician who provided appropriate information to patients and 
families would ensure compliance with contact precautions and hygiene measures that 
would reduce the C. difficile dissemination. While prevention efforts have traditionally 
focused on the hospital setting, the recommendations should expand at community level 
(14). To sum up, CDI is a frequent nosocomial infection that often causes an increase in 
the average stay and medical expenses. Treatment, especially of successive 
recurrences, does not often conform to the guidelines for clinical practice. On the other 
hand, information that patients and families receive from physicians is usually poor. 
Specifically, it is unusual to provide information on measures to prevent the spread of 
infection once at home.  
 
Evidence-based elements have been shown to reduce the incidence of multiple health-
care associated and hospital acquired infections and, when bundled, led to even greater 
benefit than each of the strategies alone (15-19). Some studies have demonstrated a 
reduction in the incidence of CDI using a checklist of hospital interventions (20) or 
achieved the control of important outbreaks by means of a comprehensive “bundle” 
approach (21). A “bundle” for CDI should be based on interventions that have already 
shown to exert a high impact in reducing the risk of CDI (6, 22-25): prudent antibiotic 
prescribing, hand hygiene, environmental decontamination, isolation/cohort nursing and 
use of personal protective equipment. Apart from reducing the indiscriminate use of 

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antimicrobials, a stewardship program based on the detection and close monitoring of 
patients diagnosed with CDI, could offer personalized attention to this especially 
susceptible group of population, through systematic monographic medical visits and 
extended follow-up during the period of maximum risk of recurrence. 
 
REFERENCES: 
 
1. Asensio A, Monge D. Epidemiology of Clostridium difficile infection in Spain. 
Enferm Infecc Microbiol Clin. 2012 Jun;30(6):333-7.  
2. Asensio A, Vaque-Rafart J, Calbo-Torrecillas F, et al. EPINE Working Group. 
Increasing rates in Clostridium difficile infection (CDI) among hospitalised 
patients, Spain 1999-2007. Euro Surveill. 2008; 13(31). 
3. Lázaro E, De Abajo FJ, Montero D. Uso de antibióticos en España. Agencia 
Española del medicamento (AGEMED). 2010. [Acceso Jul 2011]. Disponible en: 
http://www.aemps.gob.es/medicamentosUsoHumano/observatorio/docs/antibiot
icos.pdf. 
4. Asensio A, Alvarez-Espejo T, Fernandez-Crehuet J, Ramos A, Vaque-Rafart J, 
Bishopberger C, et al. Trends in yearly prevalence of third-generation 
cephalosporin and fluoroquinolone resistant Enterobacteriaceae infections and 
antimicrobial use in Spanish hospitals Spain, 1999 to 2010. Euro Surveill. 2011; 
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5. Srigley JA, Brooks A, Sung M et al. Inappropriate use of antibiotics and 
Clostridium difficile infection. American Journal of Infection Control 41 (2013) 
1116-8. 
6. Vonberg RP, Kuijper EJ, Wilcox MH, Barbut F, Tüll P, Gastmeier P, et al. Infection 
control measures to limit the spread of Clostridium difficile. Clin Microbiol Infect. 
2008; 14 (Suppl. 5):2-20. 
7. Aldeyab MA, Kearney MP, Scott MG. An evaluation of the impact of antibiotic 
stewardship on reducing the use of high-risk antibiotics and its effect on the 
incidence of Clostridium difficile infection in hospital settings. J Antimicrob 
Chemother 2012; 67: 2988–2996. doi:10.1093/jac/dks330. 
8. Brown K, Valenta K, Fisman D. Hospital Ward Antibiotic Prescribing and the 
Risks of Clostridium difficile Infection. JAMA Intern Med. 2015;175(4):626-633. 
doi:10.1001/jamainternmed.2014.8273. Published online February 23, 2015. 
9. Rachel B. Slayton, R. Douglas Scott, II, James Baggs, Fernanda C. Lessa, L. 
Clifford McDonald and John A. Jernigan (2015). The Cost–Bene t of Federal 
Investment in Preventing Clostridium dif cile Infections through the Use of a 

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Multifaceted Infection Control and Antimicrobial Stewardship Program. Infection 
Control & Hospital Epidemiology, 36, pp 681-687 doi:10.1017/ice.2015.43. 
10. Freeman J, Bauer MP, Baines SD, Corver J, Fawley WN, Goorhuis B, et al. The 
changing epidemiology of Clostridium difficile infections. Clin Microbiol. 2010; 
23:529-49. 
11. Kelly CP. Can we identify patients at high risk of recurrent Clostridium difficile 
infection? Clin Microbiol Infect 2012; 18 (Suppl. 6): 21–27. 
12. Deshpande A, Pasupuleti V, Priyaleela T. Risk Factors for Recurrent Clostridium 
difficile Infection: A Systematic Review and Meta-Analysis. Infect Control Hosp 
Epidemiol 2015;36(4):452–460. 
13. Debast SB, Bauer MP, Kuijper EJ; Committee. European Society of Clinical 
Microbiology and Infectious Diseases: update of the treatment guidance 
document for Clostridium difficile infection. Clin Microbiol Infect. 2014 Mar;20 
Suppl 2:1-26. 
14. Vindigni SM and Surawicz CM. C. difficile Infection: Changing Epidemiology and 
Management Paradigms. Clinical and Translational Gastroenterology (2015) 6, 
e99; doi:10.1038/ctg.2015.24 
15. Institute for Healthcare Improvement. What is a bundle? http://www.ihi.org/IHI/ 
Topics/CriticalCare/IntensiveCare/ImprovementStories/WhatIsaBundle.htm 
(accessed 20 Sep 2009). 
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IHI/Topics/CriticalCare/IntensiveCare/ImprovementStories/BundleUpforSafety.h
tm (accessed 20 Sep 2009). 
17. Joint Commission. Raising the Bar with Bundles. Treating patients with an allor-
nothing standard. Jt Comm Perspect 2006;l6:5e6. 
18. Pronovost P, Needham D, Berenholtz S, et al. An intervention to decrease 
catheter-related bloodstream infections in the ICU. N Engl J Med 
2006;355:2725e32. 
19. DePalo VA, McNicoll L, Cornell M, Rocha JM, Adams L, Pronovost PJ. The 
Rhode Island ICU collaborative: a model for reducing central line-associated 
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Health Care. 2010 Dec;19(6):555-61. doi: 10.1136/qshc.2009.038265 
20. Sarah K. Abbett, Deborah S. Yokoe, Stuart R. Lipsitz, Angela M. Bader, William 
R. Berry, Elise M. Tamplin and Atul A. Gawande (2009). Proposed Checklist of 
Hospital Interventions to Decrease the Incidence of Healthcare-Associated 
Clostridium difficile Infection. Infection Control & Hospital Epidemiology, 30, pp 
1062-1069. doi:10.1086/644757. 

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21. Muto CA. Blank MK, Marxh JW et al. Control of an Outbreak of Infection with the 
Hypervirulent Clostridium difficile BI Strain in a University Hospital Using a 
Comprehensive “Bundle” Approach. Clinical Infectious Diseases 2007; 45:1266–
73. 
22. Vassallo A, Tran MC, Goldstein EJ. Clostridium difficile: improving the prevention 
paradigm in healthcare settings. Expert Review of Anti-infective Therapy. Vol. 12, 
Iss. 9, 2014 
23. Wilcox MH. Policy development for Clostridium difficile J. Antimicrob. Chemother. 
(2012) 67 (suppl 1): i19-i22. doi: 10.1093/jac/dks203. 
24. Brumley PE, Malani AN, Kabara JJ, Pisani J, Collins CD. Effect of an 
antimicrobial stewardship bundle for patients with Clostridium difficile infection. J 
Antimicrob Chemother. 2016 Mar;71(3):836-40. doi: 10.1093/jac/dkv404. Epub 
2015 Dec 11. 
25. Gerding DN, Muto CA and Owens RC. Measures to Control and Prevent 
Clostridium difficile Infection. Clinical Infectious Diseases 2008; 46:S43–9. 
26. Ronald L Castelino, MPharm, PhD, Beata V Bajorek, BPharm Dip Hosp Pharm 
PhD, Timothy F Chen, BPharm Dip Hosp Pharm PhD. Targeting Suboptimal 
Prescribing in the Elderly:A Review of the Impact of Pharmacy Services. Annals 
of Pharmacotherapy, vol. 43, 6: pp. 1096-1106. 
27. Annemie Somers, PharmD1 ; Louise Mallet, PharmD2 ; Tischa van der Cammen, 
MD, PhD3 ; Hugo Robays, PharmD1 ; and Mirko Petrovic, MD, PhD4. 
Applicability of an adapted medication appropriateness index for detection of 
drug-related problems in geriatric inpatients. Am J Geriatr Pharmacother 2012; 
10(2): 101-109. DOI 10.1016/j.amjopharm.2012.01.003 
28. Hanlon JT, Schmader KE & Samsa G et al. A method for assessing drug therapy 
appropriateness. J Clin Epidemiol 1992;45:1045–1051. 
29. Knapp DA. Development of criteria for drug utilization review. Clin Pharmacol 
Ther 1991;5:600–602. 
 
 
 
 
 
 
 

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Objectives 
 
This study aims to evaluate the impact of an intervention, consisting on a bundle of 
measures. 
 
Primary objective: 
- 
To reduce the recurrence rate of patients with a first episode of CDI hospitalized 
during the period of intervention by increasing the compliance with clinical 
practice guidelines (appropriate length and choice of drug for CDI specific 
treatment according to the severity of the initial episode) and by a close follow-
up during the period of higher risk, avoiding factors that are known to predispose 
to recurrence.  
 
Secondary objectives: 
- 
To reduce the rate of second and further recurrences by increasing the 
compliance with clinical practice guidelines (appropriate length and choice of 
drug for the treatment of first and further recurrences). 
- 
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. 
 
 
Hypothesis  
 
1. A bundle of measures specifically designed for patients with ICD and applied by 
and Infectious Diseases expert would improve the prognosis and reduce the risk 
of recurrence.  
2. Some measures have proved to be effective to improve the prognosis of patients 
with a first episode of CDI. Probably the most relevant action is to stop the 
antibiotic treatment as soon as possible (grade of recommendation AII according 

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to the IDSA guidelines), or at least to choose a low-risk antimicrobial treatment 
with minimum detrimental effect over the patient’s microbiota. This measures 
cannot always be applied, but we hypothesize that an early assessment and 
monitoring by an Infectious Diseases expert would encourage attending 
physicians to evaluate the necessity of the inciting antimicrobial treatment and 
enable the decision of discontinue it, without substantial risk for the patient. 
3. Although treatments shorter than 10 days of metronidazole have proved to 
increase the risk of recurrence and the recommendation is 10-14 days of 
metronidazole for a first mild or moderate episode of CDI (grade of 
recommendation AI), courses of 7 days are frequently prescribed. An initial 
assessment by an Infectious Diseases expert who makes a non-impositive 
recommendation would increase physicians’ compliance with evidence-based 
recommendations. 
4. Although oral vancomycin is the drug of choice for an initial episode of severe 
CDI (grade of recommendation BI) and vancomycin administered orally (and per 
rectum, if ileus is present) with or without intravenously administered 
metronidazole is the regimen of choice for the treatment of severe, complicated 
CDI, however, it is relatively frequent that the severity of the episode is not 
accurately assessed at diagnosis, which delays the start of appropriate therapy. 
An initial assessment by an Infectious Diseases expert who makes a non-
impositive recommendation would increase physicians’ compliance with 
evidence-based recommendations. 
5. Although metronidazole should not be used beyond the first recurrence of CDI or 
for long-term chronic therapy because of potential for cumulative neurotoxicity, it 
is not uncommon that patients with multiple recurrences receive several courses 
of metronidazole. Patients with multiple recurrences would benefit from a close 
follow-up by an Infectious Diseases expert who appropriately diagnoses and 
treats every episode, following the evidence-based recommendations. 
 
 
 
MATERIAL AND METHODS: 
 
Study Design: Exploratory, interventional before-after prospective, quasi-experimental 
study comparing the baseline phase (2015) with the interventional phase (2017) 
 

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Study Subjects:  
Inclusion criteria: 
- 
Patients diagnosed with a first episode of CDI in the University Hospital “12 de 
Octubre”, Madrid, Spain, requiring hospitalization or emergency room admission 
longer than 48 hours, from the beginning of the study on (1-February-2017). 
- 
Patient or his/her representative sign the inform consent 
 
Exclusion criteria: 
- 
Patients younger than 18 years of age. 
- 
Patients with the diagnosis of inflammatory bowel disease. 
 
 
Patients selection and follow-up: 
 
The first 100 patients fulfilling the inclusion criteria will be included in the prospective 
phase of the study. Patients will be identified by means of daily report of the positive 
results from the Microbiology lab. They will be prospectively followed 8 weeks after the 
end of treatment for the episode of CDI. If there are one or more recurrences, the follow-
up will endure until 8 weeks after the end of the last CDI treatment. 
They will be retrospectively compared with patients diagnosed with a first episode of CDI 
during the previous year (2015) in which there was not a systematical intervention by a 
member of the Infectious Diseases Unit.  
To ensure comparability, patients from the retrospective period will be chosen and 
matched with patients included in the prospective period according to the severity of the 
initial episode of CDI and to the Charlson Age-Comorbidity Index (CACI). 
If patients diagnosed during 2015 are not enough to fulfil those comparison criteria, we 
will search backwards through patients diagnosed with a first episode of CDI during 2014 
to be matched. 
The retrospective follow-up will also endure until 8 weeks after the end of the last CDI 
treatment. 
 
 
Microbiological methods:  
 
All unformed stools (taking the shape of the container) from patients with a clinical 
suspicion of CDI will be processed immediately or, when logistically unfeasible, kept at 
4º C or frozen at −70º C until processing. Samples will be simultaneously tested for GDH 

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and toxin A/B with a single immunochromatographic assay, the TechLab® C. diff Quik 
Chek Complete™ (Inverness Medical Innovations, Princeton, NJ, USA). For samples 
with discordant results (GDH-positive, toxin A/B-negative), toxin production will be 
confirmed by the Xpert® C. difficile PCR assay (Cepheid, Sunnyvale, CA, USA).  
The diagnostic algorithm used during the retrospective period was exactly the same, as 
it was implemented in our hospital in February 2011. 
 
 
Specific "bundle" of measures for patients with ICD: 
 
These measures are based in well-known and evidence-based elements that reduce the 
incidence and limit the spreading of Clostridium difficile (see references 6,13,22-25): 
 
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: 
o To remove unnecessary treatments. 
o To shorten antibiotic courses as far as possible. 
o To avoid, if possible, broad-spectrum or high risk for developing CDI 
antibiotics. 
• 
To reduce indiscriminate use of proton-pump inhibitors (PPI) or H2 receptor 
antagonists (H2 blockers). 
• 
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: 
o 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. 

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- 
Detection of patients who could benefit from fecal microbiota 
transplantation. 
o 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. 
 
 
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/non-severe CDI: Diarrhoea without systemic symptoms, 
leukocytosis with a white blood cell count lower than 15,000 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/Fulminant 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. 
 

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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). 
 
 
 
 
 
 
 

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Table S3. Risk classification of antibiotics 
 
 
 
Charlson Age-Comorbidity Index (CACI): This index will be calculated by the 
electronic calculator www.pmidcalc.org/7722560 (Charlson M, Szatrowski TP, Peterson 
J, Gold J. Validation of a combined comorbidity index. J Clin Epidemiol. 
1994;47(11):1245-51). 
 
Based on previous authors (26-29) we proposed several terms to describe the 
appropriateness of prescription in each episode: 
 
- 
Right choice: According to the current guidelines, the medication is effective for 
the condition an also used at optimal doses and duration, without duplication or 
association with unnecessary drugs. 
- 
Inapropriate/suboptimal prescription: 
o Overuse: inclusion of unnecessary medication for the condition, which 
may result in an increased risk of adverse reactions, drug-drug 
interactions and increased costs. 
o Underuse: omission of a drug when there is a clear indication and no 
contraindications. The failure to prescribe essential medications may 
result in the worsening of the illness or therapeutic failure. 
 
Our definition of right choice will be judged according to the latest European Society of 
Clinical Microbiology and Infectious Diseases guidelines (Debast SB, Bauer MP, Kuijper 
EJ; Committee. European Society of Clinical Microbiology and Infectious Diseases: 
High risk 
Medium risk 
Low risk 
Second-generation cephalosporins [J01DC; 
cefaclor, cefuroxime]. 
Combinations of penicillins including β-
lactamase inhibitors [J01CR; 
amoxicillin/clavulanic acid] 
Combinations of penicillins including β-lactamase inhibitors [J01CR; piperacillin/tazobactam] 
Penicillins with extended spectrum [J01CA; amoxicillin, ampicillin; pivmecillinam] 
β-Lactamase-sensitive penicillins [J01CE; phenoxymethylpenicillin, benzylpenicillin] 
Third-generation cephalosporins [J01DD; 
cefotaxime, ceftazidime, ceftriaxone] 
Macrolides [J01FA; azithromycin, 
clarithromycin, erythromycin] 
β-Lactamase-resistant penicillins [J01CF; flucloxacillin] 
First-generation cephalosporins [J01DB; cefalexin, cefradine] 
Trimethoprim and derivatives [J01EA] 
Carbapenems [J01DH; ertapenem, meropenem] 
Fluoroquinolones [J01MA; mainly 
iprofloxacin; others: norfloxacin; ofloxacin; 
levofloxacin] 
 
Combination of sulphonamides and trimethoprim [J01EE] 
Aminoglycosides [J01GB; amikacin, gentamicin, neomycin] 
Glycopeptides [J01XA; teicoplanin, vancomycin] 
Lincosamides [J01FF; clindamycin] 
Steroid antibacterials [J01XC; sodium fusidate] 
 
 
Imidazole derivatives [J01XD; metronidazole] 
Nitrofuran derivatives [J01XE; nitrofurantoin] 
Other antibacterials [J01XX; linezolid] 
Tetracyclines [J01A; demeclocycline, doxycycline, minocycline, oxytetracycline, tetracycline, 
lymecycline, tigecycline] 

 pág. 14 
update of the treatment guidance document for Clostridium difficile infection. Clin 
Microbiol Infect. 2014 Mar;20 Suppl 2:1-26). 
 
Data collection and analysis 
 
Patients in the pre-intervention period will be retrospectively identified from 
microbiological data. All isolates of Clostridium difficile from 2015 (and 2014, if 
necessary) will be revised backwards to choose comparable patients with those included 
in the prospective period, according to the severity of the first episode.  
Data will be collected from electronic medical records which include daily medical 
evaluations and daily treatments administered to the patient. 
Patients in the intervention period will be identified by daily reporting of positive tests for 
CDI from the Microbiology laboratory and prospectively followed by a member of the 
research team. 
The variables will be collected in a coded database for further analysis. 
 
 
Statistical Plans 
 
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 review1 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. 
 
1. Vardakas KZ, Polyzos KA, Patouni K, Rafailidis PI, Samonis G, Falagas ME. 
Treatment failure and recurrence of Clostridium difficile infection following 

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treatment with vancomycin or metronidazole: a systematic review of the 
evidence. Int J Antimicrob Agents 2012; 40:1–8. 
2. Ralph B. D'Agostino, Sr, Sylva H. Collins, Karol M. Pencina, Yin Kean, and 
Sherwood Gorbach. Risk Estimation for Recurrent Clostridium difficile Infection 
Based on Clinical Factors. Clinical Infectious Diseases 2014 58: 1386-1393. 
 
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 for 
paired samples. Continuous variables will be compared using the Student’s t-test or the 
Mann-Whitney U test for paired samples.  
The impact of our intervention will be analyzed as a categorical variable and will be 
entered as a predictor variable into a conditional logistic regression model, adjusted by 
potential confounding factors. Associations will be given as relative risks.  
A set of sensitivity analyses will be explored by restricting the overall cohort according to 
the type of episode (first episode versus recurrence) and by hospital ward (medical 
versus surgical).  
Statistical analysis will be conducted using SPSS version 22.0 (SPSS Inc, Chicago, 
Illinois, USA). 
 
 
MANAGEMENT AND REPORTING OF ADVERSE REACTIONS 
 
Under current legislation, any adverse events appeared throughout the study should be 
notified by the standard notification procedure and clinical practice. 
 
Definitions 
According to the legislation regulating pharmacovigilance of medical products for human 
use (“Real Decreto” 1344/2007, 11 October), the following definitions shall apply: 
 
Adverse reaction (AR): 
Any response to a drug which is noxious and unintended, and which occurs at doses 
normally used in man for prophylaxis, diagnosis or treatment of disease or for the 
restoration, correction or modification of physiological function. This term also includes 
all adverse clinical consequences resulting from dependence, abuse and misuse of 

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drugs, including those caused by use outside of approved conditions or caused by 
medication errors. 
The AR is characterized by the suspicion that there is a causal relationship between the 
drug and the episode. 
 
Serious adverse reaction (SAR): 
Any AR that results in death, are life-threatening, requires hospitalization or prolongation 
of existing hospitalization, results in persistent or significant disability or incapacity, or in 
a congenital anomaly or birth defect. For the purposes of notification, those suspected 
adverse reactions that are considered important from a medical point of view are also 
treated as serious, though not meet the above criteria, such that threatening to the 
patient or that require intervention to prevent any of previous outcomes. Likewise, for the 
purposes of notification, all suspected transmission of an infectious agent through a drug 
shall also be treated as serious. 
 
Unexpected adverse reaction (UAR): 
Any adverse reaction whose nature, severity or outcome is not consistent with the 
information described in the instructions linked with the product characteristics summary 
(for a product with marketing authorisation). 
 
Management and communication of adverse reactions 
According to paragraph 8.3 of the SAS / 3470/2009 Order, "Communication of suspected 
adverse reactions", and considering that the sponsor is formed by a group of 
professionals, suspicions of AR observed during this observational study will be reported 
sending yellow card to the corresponding regional pharmacovigilance center, indicating 
the name and code of the study from which it comes in the paragraph dedicated to 
“observations”. 
 
 
PLANS TO DISEMINATE THE RESULTS OF THE STUDY 
 
The data and / or results of this study will not be published or disseminated without the 
prior consent of the sponsor of the study. The results obtained in this study will be 
disseminated through international communications and posters at national and / or 
international conferences. The findings will be published in national and / or international 
scientific journals by the sponsor or by any person or entity that has been authorized by 
the sponsor. 

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RESOURCES FOR THE CONDUCT OF THE STUDY AND TASK ALLOCATION. 
FINANCING 
 
The sponsor will finance the expenditure relating to the implementation and completion 
of the study, including materials and logistics necessary for recording, monitoring and 
statistical analysis of the data. 
Partial funding will be requested of Astellas Pharma, SA to meet part of the budget costs 
associated with the study. 
Since this is an observational study, there is no obligation to hire any insurance for 
patients. 
The investigator is responsible for ensuring that the drugs given to patients have been 
prescribed in accordance with the approved indications in common medical practice, 
regardless of their participation in this study. Therefore, the corresponding insurance of 
the drug used will assume the potential costs of adverse reactions. 
 
 
MONITORING AND FINAL REPORTS 
 
Once the study is completed, the sponsor will send a final report to the responsible ethics 
committee and to relevant organizations, communicating with it CEIC study completion. 
Moreover, all relevant incidents occurring during the study must be reported immediately 
to the Ethics Committee of the University Hospital 12 de Octubre, and responsible health 
authorities.  
 
 
ETHICAL ASPECTS: 
 
Before the beginning of the study, this protocol will be submitted for consideration by the 
Spanish Agency for Medicines and Health Products (“AEMPS”) for classification and by 
the Ethics Committee for Clinical Research (EC) of the University Hospital 12 de 
Octubre, to obtain the approval. 
 
Since no active intervention on the pre-intervention group will be performed, the data will 
be collected in a database to which only research team have access and all information 
related to the study will be strictly confidential and treated according to the Organic Law 

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15/1999 on Protection of Personal Data, and Law 14/2007 of Biomedical Research, 
Ethics Committee will be asked to accept the study without the necessity of informed 
consent for this group. 
 
Informed consent for the patients included in the study during the period of intervention 
will be requested. 
 
The entire study will be conducted in accordance with the principles of the revision of 
Seoul, Korea (October 2008) of the Declaration of Helsinki for research in humans. 
Copies of the Declaration of Helsinki and its subsequent amendments will be provided 
upon specific request or can be downloaded from the website of the World Medical 
Association in http://www.wma.net/e/policy/b3 .htm. 
The study will be conducted according to the protocol, which ensures compliance with 
the rules of Good Clinical Practice (GCP), as described in harmonised tripartite 
guidelines on Good Clinical Practice of 1996. 
 
According to the guidelines of the SAS / 3470/2009 Order on post-authorization 
observational studies, such projects must be reviewed by an independent committee 
(except in certain specific cases). For these reasons, this study was sent to a clinical 
research ethics committee for evaluation and timely notification to the Spanish Agency 
for Medicines and Health Products (AEMPS) for classification will be sent. 
 
Benefit-risk assessment for patients  
This study does not involve additional risks for patients, as different tests from which are 
applied in routine clinical practice to patients who are in the same clinical situation won´t 
be made. 
 
Interference with the doctor prescribing habits 
Because the study was observational, at any time participation of patients may interfere 
with treatment decisions; the involvement of patients won’t affect the treatment they need 
and which their doctor considers appropriate according to their clinical situation. 
Furthermore, in accordance with the Order SAS / 3470/2009, the study investigators 
must ensure that the treatment given to patients included in the study met the conditions 
of clinical practice and current recommendations, always within the framework of the 
indication authorized in the product data sheet. The decision to administer a treatment 
will be taken previously, independently and dissociated from the patient's inclusion in the 
study.