The role of tigecycline in the management of Clostridium difficile infection: a retrospective cohort study

The role of tigecycline in the management of Clostridium difficile infection: a retrospective cohort study

Accepted Manuscript The role of Tigecycline in the management of Clostridium difficile infection: a retrospective cohort study Eliza Manea, Jesús Sojo...

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Accepted Manuscript The role of Tigecycline in the management of Clostridium difficile infection: a retrospective cohort study Eliza Manea, Jesús Sojo-Dorado, Raluca E. Jipa, Serban N. Benea, Jesús Rodríguez-Baño, Adriana Hristea PII:

S1198-743X(17)30324-5

DOI:

10.1016/j.cmi.2017.06.005

Reference:

CMI 972

To appear in:

Clinical Microbiology and Infection

Received Date: 6 February 2017 Revised Date:

2 June 2017

Accepted Date: 5 June 2017

Please cite this article as: Manea E, Sojo-Dorado J, Jipa RE, Benea SN, Rodríguez-Baño J, Hristea A, The role of Tigecycline in the management of Clostridium difficile infection: a retrospective cohort study, Clinical Microbiology and Infection (2017), doi: 10.1016/j.cmi.2017.06.005. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.

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Article category: Original Article

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Title: The role of Tigecycline in the management of Clostridium difficile infection: a retrospective cohort study

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Authors: Eliza Manea1,2, Jesús Sojo-Dorado3, Raluca E. Jipa1,2, Serban N.

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Benea1,2, Jesús Rodríguez-Baño3, Adriana Hristea1,2

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Affiliations:

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1 National Institute for Infectious Diseases “Prof. Dr. Matei Bals”, Bucharest,

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Romania

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2 University of Medicine and Pharmacy “Carol Davila”, Bucharest, Romania

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3 Unidad de Enfermedades Infecciosas, Microbiología y Medicina Preventiva,

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Hospital Universitario Virgen Macarena / Universidad de Sevilla / Instituto de

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Biomedicina de Sevilla, Seville, Spain.

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The study was conducted at the National Institute for Infectious Diseases “Prof.

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Dr. Matei Bals” – Address: no1 Calistrat Grozovici Street, sect 2, Bucharest,

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021105, Romania.

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Corresponding author:

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Adriana Hristea: e-mail: [email protected]

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Address: National Institute of Infectious Diseases “Prof Dr Matei Bals”; no 1

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Calistrat Grozovici, street, sect 2, postal code: 021105, Bucharest, Romania

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Phone: +40213186100 ext 5204; Mobile phone: +40723562370; Fax: +40213186090 Conflict of interest: the authors have no conflicts of interest to declare. Funding: this study had no funding. Keywords: Clostridium difficile, tigecycline, outcome, propensity score,

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recurrence

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Word count of summary: 249

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Word count of text: 2341

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Number of references: 16; number of tables: 3; number of figures: 1 1

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Objective

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We aimed to compare the outcomes of patients with C.difficile infection (CDI)

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treated either with tigecycline associated with vancomycin, or with vancomycin

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alone.

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Methods

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This single-centre retrospective cohort study included all adults hospitalized from

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September 2014 through August 2015 for symptomatic, incident CDI confirmed

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by polymerase chain reaction for C.difficile toxin in stools. The primary outcome

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was the rate of favourable outcome, defined as a composite of clinical response

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(resolution of symptoms without need for additional CDI therapy) and achieving

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discharge without CDI-related surgery or intensive care; a secondary outcome

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was CDI recurrence. We constructed a non-parsimonious logistic regression

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model to calculate a propensity score (PS) for those receiving tigecycline.

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Results

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In all, 266 patients were included: 62 patients received both vancomycin and

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tigecycline, and 204 patients received vancomycin alone. The patients from the

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two groups were similar regarding demographics and comorbidities but patients in

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the tigecycline group had a more severe CDI A favourable outcome in the

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tigecycline group vs the vancomycin group was found in 50/62 (81%) vs 193/204

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(95%). We matched patients receiving tigecycline or not according to the PS and

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86 patients (43 pairs) could be matched. The OR for favourable outcome with tigecycline in the matched analysis was 0.92 (95% CI: 0.60-1.44; p=0.74). The rate of CDI recurrences was 8/62 (13%) in the tigecycline group versus 39/204

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(19%) in the vancomycin group (p=0.2).

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Conclusion

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Adding tigecycline to CDI standard therapy did not increase the clinical cure nor

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reduced the rate of CDI recurrences.

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Introduction

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In the past 10-15 years, Clostridium difficile infection (CDI) has re-emerged as a

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large epidemiological problem for hospitalized patients across the world [1,2].

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Despite the increasing incidence and worsening outcomes associated with CDI,

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there are few treatment options. Metronidazole and oral vancomycin are the most

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frequently drugs used for the treatment of CDI and are recommended by current

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guidelines [3-5].

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Tigecycline is a broad spectrum glycylcycline antibiotic, approved in 2005 for the

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treatment of complicated skin and soft tissue infections, intra-abdominal

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infections and subsequently for community-acquired pneumonia. Additionally, it

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is active in vitro against C. difficile isolates [6]. Faecal concentrations of

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tigecycline are generally much higher than the MIC for C. difficile (range of 3.0-

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14.1 µg/g faeces) due to the biliary elimination of the drug [7]. Also, some in vitro

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studies suggested that sub-MIC concentrations of tigecycline have inhibitory

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effects on both toxin production and sporulation of most C. difficile isolates,

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probably by inhibiting protein synthesis [8,9]. The biological significance of the inhibition of sporulation by sub-inhibitory concentrations of antibiotics in vitro seemed promising for CDI treatment but it remains to be determined in vivo.

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Nevertheless, a murine model showed that tigecycline may alter the microbiota

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leading to susceptibility to CDI [10]. Because many patients with CDI need to

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continue receiving antibiotics for other concomitant infections, tigecycline might 3

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be an interesting option in such special situations. This drug is mentioned in

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European Society of Clinical Microbiology and Infectious Diseases (ESCMID)

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guidelines for CDI treatment with a grade C-III recommendation (“marginally

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supported recommendation for use – expert opinion evidence”) and reserved for

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severe CDI cases when oral therapy is not possible [3]. A recently published

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retrospective study, comparing the administration of tigecycline monotherapy in

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severe CDI with vancomycin plus metronidazole suggested a better outcome,

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regarding clinical cure, in patients treated with tigecycline [11].

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The aim of this study was to compare the outcomes of patients with CDI treated

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with tigecycline in combination with vancomycin with those treated with

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vancomycin alone.

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Methods

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Study design and patients

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A retrospective cohort study was conducted in a tertiary care hospital in Romania

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with 280 beds in adult departments. All adult patients (age ≥18 years) hospitalized

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for incident CDI from September 2014 through August 2015 were eligible for

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inclusion in this study. Patients were identified by reviewing the microbiology

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records. Diagnosis of CDI was based on clinical symptoms (presence of

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diarrhoea) and detection of the gene coding for C. difficile toxin in stool using polymerase chain reaction. Diarrhoea was defined according to ESCMID guidelines as loose stools corresponding to Bristol stool chart types 5–7, plus a

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stool frequency of at least three loose stools within 24 hours [12]. We included

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patients treated with intravenous tigecycline plus oral vancomycin for at least 48

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hours or with oral vancomycin alone. Patients who received treatment with

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metronidazole, fidaxomicin, tigecycline in monotherapy or faecal microbiota

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transplantation were excluded. We also excluded the patients for whom the data

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to calculate the ATLAS severity score were not available, the patients with

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history of previous CDI and patients who died in the first 48 hours after the

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diagnosis of CDI [13]. The patients were followed for 8 weeks after the resolution

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of CDI episode. Hospital ethics committee approved the study.

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Study variables and definitions

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The primary outcome of this study was the proportion of patients with favourable

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outcome, defined as a composite including clinical response (see below), being

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discharged from hospital and no requirement for surgery or transfer to the

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intensive care unit due to the severity of CDI. Clinical response was classified as

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clinical cure if there was a resolution of diarrhoea, abdominal pain, fever and

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leucocytosis, and no need for addition of another anti-CDI therapy; CDI was

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considered refractory to standard therapy (vancomycin) when either the stool

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frequency did not decrease or stool consistency did not improve and/or

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parameters of disease severity (clinical, laboratory, radiological) did not improve,

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after at least 3-5 days of therapy, according to ESCMID guidelines [3]. The

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secondary outcome was CDI recurrence, defined as another episode of CDI within 8 weeks after the onset of a previous episode, provided the symptoms from the previous episode resolved after completion of initial treatment [14]. We routinely

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followed patients only until discharge, but CDI recurrences are unlikely to be

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missed given the setup of our healthcare system, with close communication with

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primary care physicians. The primary exposure was treatment with tigecycline

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plus vancomycin or with vancomycin alone.

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All the patients included in the final analysis were classified according to

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Charlson comorbidity score and ATLAS severity score (based on age, treatment

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with systemic antibiotics, leucocyte count, albumin and temperature) [13, 15].

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According to ESCMID guidelines, the criteria for severe CDI used in the analysis

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included were: age over 65 years, fever (core body temperature >38.5°C), marked

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leucocytosis (leukocyte count >15x109/L), markedly reduced serum albumin (<30

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g/L), rise in serum creatinine (>50% above the baseline), presence of toxic

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megacolon or sepsis [3]. We also classified patients according to the Society for

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Healthcare Epidemiology of America (SHEA) in severe (the presence of

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leukocytosis of 15x109/L or higher, or serum creatinine level greater than or equal

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to 1.5 times the premorbid level) and severe complicated (hypotension or shock,

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ileus, megacolon) CDI [4]. The definition used for toxic megacolon was: presence

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of radiological signs of distension of the colon (>6 cm in transverse width of

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colon) and signs of a severe systemic inflammatory response. Sepsis was defined,

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according to the previously accepted definition, as more than one of the following

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clinical findings: body temperature higher than 38°C or lower than 36°C, heart

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rate higher than 90/min, hyperventilation evidenced by respiratory rate higher than 20/min or PaCO2 lower than 32 mmHg and white blood cell count higher than 12x109/L or lower than 4x109/L [16]. Statistical analysis

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The data collected were analysed using the statistical analysis software package

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SPSS 18.0 (IBM SPSS, Chicago, IL, USA). We performed an analysis of all

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included (AI) patients in which all patients with the above criteria were

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considered. Differences between groups were analysed using the Mann-Whitney

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U test for continuous variables and the chi-square test or Fisher's exact test for

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dichotomous variables as appropriate. Multivariate analysis was performed using

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binary logistic regression, including the variables with a p value less than 0.1 in

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the univariate analysis.

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We constructed a non-parsimonious logistic regression model to calculate a

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propensity score (PS) for receiving tigecycline. For the AI analysis, the following

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covariates were included for calculating the PS: sex, age, Charlson's index,

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albumin, fever, creatinine, leukocytes, other concomitant infection, , ATLAS

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score, toxic megacolon and sepsis criteria. The PS model showed an area under

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the receiver operating characteristic curves (AUROC) of 0.84, showing a good

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predictive ability. The PS was used first as a covariate in the multivariate analysis

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and to match patients receiving tigecycline and vancomycin with those receiving

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vancomycin alone using calipers of 0.2 width of the standard deviation of the logit

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of the propensity score.

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Crude and multivariate analyses in the matched cohorts were performed by conditional logistic regression. Multivariate analyses of factors associated with a favourable outcome were performed using logistic regression; variables with a p

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value <0.1 in the univariate analysis and the propensity score for receiving

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tigecycline were introduced as predictors. Potential interactions of interested were

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also studied (i.e. treatment with tigecycline and presence of other infection or

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treatment with tigecycline and presence of sepsis). The goodness of fit of the final

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model was checked with the Hosmer-Lemeshow test, and the prediction ability by

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calculating the area under the receiver operating curve (ROC). The analyses were

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also performed for patients treated for seven days or more (T7D) with either

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tigecycline or vancomycin alone; in this analysis, patients who died in <7 days

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were also included and considered as failures.

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Results

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A total of 660 CDI episodes, recorded in 549 patients, were screened for inclusion

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in the study period. Of those, 266 patients with CDI were eligible and were

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included in the AI analysis; the reasons for exclusion are shown in Figure 1.

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Tigecycline was used to treat 62 episodes and vancomycin alone was used in 204

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episodes. The baseline characteristics of the patients are summarized in Table 1.

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Overall, the patients treated with tigecycline were more likely to have had severe

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CDI according to ESCMID guidelines and a concomitant infection. The median

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duration of tigecycline administration in the AI analysis was 9 days (interquartile

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range, IQR: 7-14 days). In 36 (58%) cases in the tigecycline group, this was

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added to vancomycin from the first day of CDI treatment. For the rest 26 (42%)

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cases, tigecycline was initiated after a median of 1 day (IQR: 1-4 days). The reasons for adding tigecycline to vancomycin were: CDI severity in 33 (53%) cases, the presence of a concomitant infection in 19 (31%) cases, refractory CDI

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in 5 (8%) cases, and unknown reason in 5 (8%) cases. Concerning the outcomes

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(Table 1), 50 (81%) of cases in the tigecycline group and 193 (95%) of those in

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the vancomycin group met the criteria for clinical cure in the AI analysis

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(p<0.001). The rate of CDI recurrences was 8 (13%) in the tigecycline group

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versus 39 (19%) in the vancomycin group, respectively (p=0.2).

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We analysed the CDI episodes according to SHEA classification, in severe CDI

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and severe complicated CDI. For severe CDI, a favourable outcome was seen in

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31/39 (80%) patients receiving tigecycline and vancomycin versus 67/73 (92%) in

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patients receiving vancomycin only (p=0.06). For severe complicated CDI, a

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favourable outcome was noted in 3/10 (30%) patients receiving tigecycline and

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vancomycin versus 2/2 (100%) patients receiving vancomycin only (p=0.3).

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The univariate analysis of factors associated with unfavourable outcome is shown

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in table 2. We then performed a multivariate analysis, adjusted by the PS (Table

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3). Interactions between tigecycline and concomitant infection and sepsis were

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investigated but were not significant, the p value for the Hosmer-Lemeshow test

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was 0.25, and the AUROC for observed data was 0.81 (95% CI: 0.70-0.92),

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showing good predictive ability. The negative association of tigecycline and

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favourable outcome found in the univariate analysis disappeared but we could not

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find a trend towards higher probability of favourable outcome with tigecycline.

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The analysis was repeated excludingthe other variables or including several

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interactions, but no significant changes in the lack of association between therapy with tigecycline and favourable outcome were found. We then matched patients receiving tigecycline and vancomycin with patients

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receiving vancomycin alone, according to the PS; 86 patients (43 pairs) could be

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matched. In the cohort of matched patients by the PS we found no significant

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difference between patients treated with vancomycin alone or those treated with

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the combination of vancomycin and tigecycline, suggesting that the PS worked

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(data not shown). The OR for favourable outcome with tigecycline in the matched

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analysis was 0.92 (95% CI: 0.60-1.44; p=0.74). The rate of CDI recurrences was

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6/43 (14%) in the tigecycline group versus 12/28 (28%) in the vancomycin group

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(p=0.27).

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In the T7D analysis, 251 patients were included; 47 were treated with tigecycline

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and 204 cases with vancomycin monotherapy. The features of patients included in

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the T7D analysis are shown in Table 1. The adjusted OR for favourable outcome

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of patient treated with tigecycline in this population was 0.63 (95% CI: 0.15-2.61;

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p=0.52).

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Discussion

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In this observational study, we could not find that treatment of CDI with

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tigecycline plus oral vancomycin in combination was associated with better

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outcomes than treatment with vancomycin alone after attempting to control for

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confounders and prescription bias.

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Tigecycline is frequently considered whenever the patients need an antibiotic to

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treat a concomitant infection as this drug could also contribute to the cure of CDI.

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In our setting tigecycline has been frequently used in severely ill patients, especially when an additional source of sepsis beyond CDI cannot be excluded and in patients who require antibiotics for a concomitant infection; in the vast majority of cases, tigecycline is used in association with oral vancomycin.

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In our study, patients in the tigecycline group had a more severe CDI and more

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frequent concomitant infections. We attempted to control for the obvious

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prescription bias with propensity score matching; analyses of this subgroup did

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not show an association between addition of tigecycline and improved outcomes.

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Furthermore, the rate of CDI recurrences was not significantly lowered after the

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treatment with tigecycline, both in patients with history of previous CDI and in

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those with primary episodes. In contrast to our findings, a recently published

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retrospective study compared the outcomes of patients with severe CDI (median

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ATLAS score, 8) treated with tigecycline as monotherapy with those treated with

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oral vancomycin plus intravenous metronidazole. The cure rate with tigecycline

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was 75.6%, which was significantly higher than in the standard therapy group

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(53.3%) [11]. However, the results of the multivariate analyses show a very wide

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95% confidence interval making the results difficult to interpret.

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The main limitations of our study are its observational and retrospective nature.

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Despite the fact that we tried to control for confounders using multivariate

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analysis and propensity score-based matching, we cannot exclude the influence of

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unmeasured confounders or residual confounding, such as confounding by

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indication (prescription bias). The propensity score is limited in its ability to

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mitigate prescription bias, because it mainly serves to reduce power and thus allows for a type II error (assuming there is no difference when there is one).

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Also, we excluded a high number of patients due to missing data, but the rate of

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favourable outcomes among these was similar to those included. Another

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limitation is that we could not analyse the duration and types of concomitant

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antimicrobial therapy other than tigecycline due to a large variety of

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antimicrobials administered.

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In conclusion, adding tigecycline to the standard therapy of CDI did not

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significantly increase the clinical cure nor reduced the rate of CDI recurrences.

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Randomised controlled trials assessing tigecycline as adjuvant therapy are needed.

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In the meantime, the clinical value of tigecycline as additional therapy remains

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undefined, and we can only stress the importance of limiting the unnecessary use

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of a broad spectrum antimicrobial in the context of an increasing antimicrobial

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resistance.

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Acknowledgments

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JRB received funding for research from Ministerio de Economía y

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Competitividad, Instituto de Salud Carlos III - co-financed by European

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Development Regional Fund "A way to achieve Europe" ERDF, Spanish Network

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for the Research in Infectious Diseases (REIPI RD16/0016).

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The authors have nothing to disclose.

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Table 1 – Characteristics and outcomes of patients. Data are expressed as number of patients (percentage) except where specified.

89 (44) 68 (57-78) 4 (3-5) 13 (6.07)

22 (36)

81 (40)

9 (15) 2 (3) 5 (8) 3 (5) 3 (5) 2 (3) 2 (3) 30 (48)

18 (9) 8 (4) 25 (12) 9 (4) 4 (2) 7 (3) 7 (3) 55 (27)

12 (40) 11 (37) 7 (23)

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p*

0.9 0.1 0.3 <0.001

20 (43) 69 (61-81) 4 (3-5) 12 (4.2)

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27 (44) 70 (61-81) 4 (3-5) 10 (4.8)

89 (44) 68 (57-78) 4 (3-5) 13 (6.07)

0.9 0.1 0.2 0.09

19 (40)

81 (40)

0.9

0.3 0.8 0.5 0.8 0.4 0.9 0.9 0.002

7 (15) 4 (9) 4 (9) 2 (4) 1 (2) 2 (4) 2 (4) 23 (49)

18 (9) 8 (4) 25 (12) 9 (4) 4 (2) 6 (3) 7 (3) 55 (27)

0.3 0.3 0.6 0.9 0.9 0.9 0.7 0.006

19 (35) 31 (56) 5 (9)

0.8 0.1 0.1

8 (35) 9 (39) 6 (26)

19 (35) 31 (56) 5 (9)

0.9 0.2 0.1

2 (7) 7 (23) 9 (30) 8 (27) 1 (3) 3 (10)

5 (9) 4 (7) 9 (16) 22 (40) 1 (2) 12 (22)

0.7 0.07 0.2 0.3 0.6 0.3

2 (9) 6 (26) 7 (30) 5 (22) 1 (4) 2 (9)

5 (9) 4 (7) 9 (16) 22 (40) 1 (2) 12 (22)

0.9 0.05 0.2 0.2 0.5 0.3

6 (10) 19 (31) 39 (63) 32 (52) 18 (29) 36 (58) 65 (74) 5 (4-6) 39 (63)

1 (0.5) 7 (3) 119 (58) 71 (35) 31 (15) 62 (30) 100 (49) 3 (2-4) 73 (36)

<0.001 <0.001 0.5 0.001 0.01 <0.001 <0.001 <0.001 <0.001

4 (9) 16 (34) 30 (64) 26 (55) 14 (30) 28 (60) 36 (77) 5 (4-6) 30 (64)

1 (0.5) 7 (3) 119 (58) 71 (35) 31 (15) 62 (30) 100 (49) 3 (2-4) 73 (36)

0.003 <0.001 0.6 0.01 0.03 <0.001 0.001 0.005 <0.001

10 (16)

2 (1)

<0.001

6 (13)

2 (1)

<0.001

48 (77) 8 (13)

193 (95) 39 (19)

<0.001 0.2

40 (85) 7 (15)

193 (95) 39 (19)

0.05 0.6

M AN U

0.8

TE D

Male sex Age in years (median, IQR) Median Charlson index (IQR) Length of CDI therapy in days (mean, SD) Underlying diseases Cardiovascular disease and/or hypertension Solid malignancy Hematologic malignancy Diabetes mellitus Renal failure Chronic respiratory disease Liver failure HIV infection Concomitant infection Aetiology of concomitant infection Unknown Monomicrobial Polymicrobial Site of concomitant infection Skin Intraabdominal Respiratory Urinary Osteoarticular Other Severity criteria Toxic megacolon Sepsis Age over 65 years Fever Acute renal insufficiency WBC >15x109/L Albumin <3 g/L Median ATLAS score (IQR) Severe CDI (according to SHEA guidelines) Severe complicated CDI (according to SHEA guidelines) Outcomes Favourable outcome Recurrence

Treated for seven days or more Tigecycline + Vancomycin Vancomycin p* (n=204) (n=47)

RI PT

All included patients Tigecycline + Vancomycin Vancomycin (n=204) (n=62)

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Transfer to another unit In-hospital mortality

9 (15) 5 (8)

6 (3) 5 (2)

<0.001 0.09

3 (6) 4 (9)

IQR: Interquartile range. SD: standard deviation. CDI: Clostridium difficile infection. WBC: White blood cell count.

AC C

EP

TE D

M AN U

SC

RI PT

(*) Chi-square (for categorical features) or U Mann-Whitney for continuous variables

6 (3) 5 (2)

0.4 0.1

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Table 2. Univariate analysis of variables associated with favourable outcome in all

RI PT

included patients. Data are number of patients (percentage) except where specified.

Favourable outcome (n=244)

OR (95% CI)

Male sex

10 (46)

106 (43)

1.08 (0.4-2.6)

Age over 65 years

14 (64)

149 (61)

0.9 (0.3-2.2)

79 (46-82)

69 (57-79)

-

5 (3-6)

4 (3-5)

-

Median Charlson index (IQR) Concomitant infection

M AN U

Median age in years (IQR)

SC

Unfavourable outcome (n=22)

6 (27)

79 (32)

1.2 (0.4-3.3)

6 (27)

1 (0.4)

0.01 (0.001-0.09)

4 (18)

22 (9)

0.4 (0.1-1.4)

8 (36)

95 (39)

1.1 (0.4-2.7)

1.3 (1.0-2.8)

0.9 (0.7-1.5)

-

9 (41)

49 (20)

0.3 (0.1-0.8)

15.8 (4.8-24.0)

11.7 (8.2-17.6)

-

12 (55)

86 (35)

0.4 (0.1-1.09)

2.6 (1.9-2.9)

2.9 (2.5-3.6)

-

Albumin <3 g/L

18 (82)

128 (53)

0.2 (0.08-0.7)

Median ATLAS score (IQR)

4 (3-6)

3 (2-5)

-

Severe CDI (according to SHEA guidelines)

100 (88)

14 (12)

2.5 (1.1-6.2)

Other antibiotic

62 (90)

181 (92)

1.4 (0.5-3.5)

Treatment with tigecycline

12 (55)

50 (21)

0.2 (0.08-0.5)

Toxic megacolon Sepsis Fever

TE D

Creatinine (mg/dL) (median, IQR) Acute renal insufficiency

WBC (x109) (median, IQR)

EP

WBC >15x109/L

AC C

Albumin (g/L) (median, IQR)

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IQR: Interquartile range. CDI: Clostridium difficile infection. WBC: White blood cell count.

AC C

EP

TE D

M AN U

SC

RI PT

(*) Chi-square (for categorical features) or U Mann-Whitney for continuous variables

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Table 3 – Multivariate analysis for characteristics associated with favourable

All included

PS-adjusted

PS matched

patients (n=266)

(n=266)

cohort (n=86)

OR (95%

p

0.8(0.6-

one point increase)

1.0)

to SHEA guidelines)

1x10 -3

0.9

<0.01

(0.0-0.1)

AC C

ATLAS score (per one point increase)

Treatment with tigecycline

0.8 (0.6-

OR

(95%

(95%

CI)

CI)

0.8 (0.6-

0.1

1.1)

3.1)

EP

Toxic megacolon

0.9(0.3-

0.08

TE D

Severe CDI (according

p

M AN U

CI)

Charlson index (per

OR

SC

Variables

RI PT

outcome in all included population, adjusted by the propensity score.

1.9 (0.3-

0.9

3.2)

1.1)

0.6

(0.91.3) 1.1

0.7

(0.52.3)

6.0 x10-3

<0.01

0.8 (0.6-

2.1x10-

0.9

6

(0.0-0.1) 0.2

1.0

p

0.1

1.1)

0.9

0.5

(0.71.2)

0.5 (0.21.5)

0.2

0.4 (0.11.3)

0.1

1.0 (0.61.5)

0.8

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Included all variables associated with favorable outcome, with a p-value < 0.1, in the univariate analysis (table 2) PS: propensity score

AC C

EP

TE D

M AN U

SC

RI PT

CDI: Clostridium difficile infection

AC C

EP

TE D

M AN U

SC

RI PT

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