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Journal of Hospital Infection (2008) 70, 142e147

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A clinical risk index for Clostridium difcile infection in hospitalised patients receiving broad-spectrum antibiotics
K.W. Garey a,b,*, T.K. Dao-Tran b, Z.D. Jiang c, M.P. Price b, L.O. Gentry b, H.L. DuPont b,c,d
a

University of Houston College of Pharmacy, Houston, TX, USA St Lukes Episcopal Hospital, Houston, TX, USA c University of Texas School of Public Health, Houston, TX, USA d Baylor College of Medicine, Houston, TX, USA
b

Received 14 April 2008; accepted 30 June 2008 Available online 23 August 2008

KEYWORDS
Clostridium difcile; Prevention cohort; Risk index

Summary Identication of a population at high risk for Clostridium difcile infection (CDI) would enable CDI prevention strategies to be designed. The purpose of this study was to create a clinical risk index that would predict those at risk for CDI. A CDI risk index was therefore developed, based on a cohort of hospital patients given broad-spectrum antibiotics, and divided into a development and validation cohort. Logistic regression equations helped identify signicant predictors of CDI. A scoring algorithm for CDI risk was created using identied risk factors and collapsed to create four categories of CDI risk. The area under the receiver operating characteristic (aROC) curve was used to measure goodness-oft. Among 54 226 patients, 392 tested positive for C. difcile. Age 50e 80 years [odds ratio (OR: 0.5; P < 0.0116)], age >80 years (OR: 2.5; P < 0.0001), haemodialysis (OR: 1.5; P 0.0227), non-surgical admission (OR: 2.2; P < 0.0001) and increasing length of stay in the intensive care unit (OR: 2.1; P < 0.0001) were signicantly associated with CDI. A simple risk index using presence of signicant variables was signicantly associated with increasing risk for CDI in both development (OR: 3.57; P < 0.001; aROC: 0.733) and validation (OR: 3.31; P < 0.001; aROC: 0.712) cohorts. An OR-derived risk index did not perform as well as the simple risk index. This easily implemented risk index should allow

* Corresponding author. Address: Texas Medical Center University of Houston, 1441 Moursund Street, Houston TX 77030, USA. Tel.: 1 713 795 8386; fax: 1 713 795 8383. E-mail address: kgarey@uh.edu 0195-6701/$ - see front matter 2008 The Hospital Infection Society. Published by Elsevier Ltd. All rights reserved. doi:10.1016/j.jhin.2008.06.026

CDI risk index

143 stratication of patients into risk group categories for development of CDI and help fashion preventive strategies. 2008 The Hospital Infection Society. Published by Elsevier Ltd. All rights reserved.

Introduction
The incidence of Clostridium difcile infection (CDI) is increasing in the USA.1 This has been attributed to an increasingly complicated patient population with multiple comorbidities, more frequent use of broad-spectrum antibiotics and increasing disease burden from a newly described hypervirulent strain of C. difcile.2e4 Diagnosis is generally performed based on clinical suspicion and detection of C. difcile toxin in stool, using a tissue culture assay or enzyme immunoassay.5 The disease is almost always restricted to the colon and signs and symptoms can range from asymptomatic colonisation and mild diarrhoea to life-threatening colitis and sepsis. The three major risk factors for infection with C. difcile include antibiotic exposure, advanced age and hospitalisation.6e8 Other identied risk factors have included haemodialysis, non-surgical admission, intensive care unit admission, mechanical ventilation and parenteral nutrition.9e11 Due to the increasing incidence and associated mortality, preventive CDI strategies have gained increased interest.2 A number of strategies are possible including enhanced infection control policies, replacement of normal ora with probiotics and decreased use of proton pump inhibitors.12 All of these strategies are hampered by the ability to identify a population at high enough risk for CDI to study prophylaxis possibilities. Rates of CDI typically range from 5 to 10 cases per 1000 hospital admissions in patients receiving broad-spectrum antibiotics.11,13,14 In order to identify a patient population at high risk for CDI, other variables in addition to broad-spectrum antibiotic use will be required. The purpose of this study was to create a clinical risk index based on known CDI risk factors that would predict a high risk population for CDI.

years old and had received broad-spectrum antibiotics (intravenous glycopeptides, uoroquinolones, penicillins, cephalosporins and/or carbapenems) during their hospitalisation. Patients admitted for <48 h or who were diagnosed with C. difcile infection within 48 h of hospital admission were excluded. This study was approved by the Institutional Review Boards of St Lukes Episcopal Hospital (SLEH) and the University of Houston.

C. difcile infection
C. difcile testing is typically requested by the attending physician upon clinical suspicion of CDI. C. difcile is conrmed by tissue culture cell cytotoxicity assay using a broblast cell line (Diagnostic Hybrids, Inc., Athens, OH, USA) with antitoxin neutralisation (Tech-Lab, Blacksburn, VA, USA).15 The microbiology laboratory maintains a database of all C. difcile test results (positive and negative), including patient demographics, room location and the date the specimen was collected.

Data collection
The information technology (IT) department at SLEH provided data on patient demographics (age, gender, race) and risk factors for CDI based on patient charges and dates of charges. Patient charge data for antibiotics (intravenous glycopeptides, uoroquinolones, penicillins, cephalosporins and/or carbapenems), central venous catheter insertion and care, haemodialysis, admission to an intensive care unit (ICU), mechanical ventilation, total parenteral nutrition or admission to a surgical suite were used. One hundred medical charts from patients in this study were randomly selected to ensure validity of the data.

Methods
The study was carried out at a 627-bed (including 143 critical care beds) tertiary care teaching hospital at the Texas Medical Center in Houston, Texas, USA between March 2005 and October 2007. All patients were hospitalised >48 h, were !18

Statistical analysis
The clinical microbiology laboratory database and IT database were merged using MS Access (Microsoft Corp., Seattle, WA, USA) and analysed using SAS software version 9.1 (SAS Institute, Cary, NC, USA). All tests were two-tailed, and P < 0.05 was

144 considered signicant. Continuous variables (for example, length of ICU stay) were calculated up to the date of the C. difcile stool test (for CDI positive patients) or hospital discharge (for CDInegative patients). The data set was divided into two time periods to create a development cohort (March 2005 to December 2006) and a validation cohort (January 2007 to October 2007). The development cohort was used to create two risk indices to predict patients at high risk of CDI. The validation cohort was then used to assess the goodnessof-t of each risk index. To assess for inclusion into the risk index, univariate analyses were performed separately for each of the variables and odds ratios (ORs) and 95% condence intervals (CIs) were calculated for categorical variables. Fishers exact test or c2-test was used for categorical variables and Students t-test for continuous variables. Variables with P < 0.1 in the univariate analyses were included in the logistic regression model for the multivariable analysis. Forward selection processes were used. Any variable with P < 0.05 was included in the risk index. Two risk indices were created. To create the rst risk index, the OR derived from the parameter estimates of the logistic regression equation were rounded to the nearest whole digit to create a numerical scoring system for each variable (referred to as OR-derived risk index). In the second risk index, a simplied scoring system was used by assigning each variable as present or not present (referred to as the simple risk index). For each risk index, the risk categories were collapsed to create an index with four categories: (1) very low risk; (2) low risk; (3) medium risk; and (4) high risk. Grouping variables were chosen based on a plot of potential categories versus predicted risk of infection and using a comparison of the areas under the receiver operating characteristic (aROC) curve. Finally, the discriminatory power of the two risk indices was assessed in the development and validation cohorts using a comparison of the aROC curves.

K.W. Garey et al. the average age was 58 18 years and 30 064 (55.4%) were female. Most common ethnicities were caucasian (59.0%), black (23.5%) or hispanic (13.7%). In univariate analyses, older age, presence of a central venous catheter, haemodialysis, medical admission, increasing length of time in the ICU, requirement for mechanical ventilation or total parenteral nutrition were all signicantly associated with CDI (P < 0.001 for all variables).

Creation and validation of risk indices


All signicant variables identied in the univariate analysis were used in a stepwise logistic regression equation from the 41 224 patients in the development cohort (Table II). Age 50e80 years (OR: 1.5; 95% CI: 1.1e2.1; P 0.0116), age >80 years (OR: 2.5; 95% CI: 1.7e3.7; P < 0.0001), requirement for haemodialysis (OR: 1.5; 95% CI: 1.1e2.0; P 0.0227), a non-surgical admission (OR: 2.2; 95% CI: 1.9e2.2; P < 0.0001) and number of weeks in the ICU (OR: 2.1; 95% CI: 1.7e2.9; P < 0.0001) were identied as signicant independent risk factors for CDI.

Simple risk index


For creation of the simple risk index, one point was given if a patient was between 50 and 80 years old, if they were undergoing haemodialysis, if they had a non-surgical admission and for each week they were admitted to an ICU. Two points were given if the patient was aged >80 years (Table III). Patient scores for the simple risk index ranged from 0 to 10. Categorisation of the simple risk index is shown in Table IV. Increasing scores on this index were signicantly associated with increasing risk for CDI (OR: 3.57; 95% CI: 3.13e4.08; P < 0.001; aROC: 0.733). Infection rates ranged from 1.9 cases per 1000 patient admissions in the low risk group and up to 81.3 cases per 1000 admissions in the very high risk group (Table V). The simple risk index was tested for 13 002 patients in the validation cohort. Increasing scores for the simple risk index were signicantly associated with increasing risk for CDI and were similar to results observed in the development cohort (OR: 3.31; 95% CI: 2.61e 4.19; P < 0.001; aROC: 0.712).

Results
Descriptive epidemiology
Among the 54 226 patients in the entire study period, 392 tested positive for C. difcile (7.2 cases per 1000 patient admissions; Table I). There were 41 224 patients in the development cohort, of whom 288 were C. difcile positive, and 13 002 in the validation cohort, of whom 104 tested C. difcile positive. For the entire cohort,

OR-derived risk index


For creation of the OR-derived risk index, the presence of each variable was multiplied by the OR derived from the multivariate logistic regression equation. The OR for non-surgical admission

CDI risk index

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Table I Association of risk factors with Clostridium difcile infection (CDI) in 54 226 patients admitted for >48 h to a large, university-afliated medical centre, 2005e2007, given broad-spectrum antibioticsa Overall No. N Age (years) <50 50e79 !80 CVC ESRD ICU (days) 1e7 8e14 15e21 22e28 >28 Mechanical ventilation (days) 1e7 8e14 15e21 22e28 >28 Non-surgical admission TPN (days) 1e7 8e14 15e21 54 226 16 217 31 143 6474 5621 3849 18 626 14 585 2409 800 356 476 8564 7076 680 341 178 289 28 794 1806 882 505 202 29.9 57.4 11.9 10.4 34.3 26.9 4.4 1.5 0.7 0.9 15.8 13.0 1.3 0.6 0.3 0.5 53.1 3.3 1.6 0.9 0.4 % No. 392 74 234 84 121 69 227 72 53 32 21 49 140 63 27 16 12 22 250 52 12 14 15 CDI patients % 72.0 <0.0001 18.9 59.7 21.4 30.9 17.6 57.9 18.4 13.5 8.2 5.4 12.5 35.7 16.1 6.9 4.1 3.1 5.6 63.8 13.3 3.1 3.6 3.8 P

<0.0001 <0.0001 <0.0001

<0.0001

<0.0001 <0.0001

CVC, central venous catheter; ESRD, end-stage renal disease; ICU, intensive care unit; TPN, total parenteral nutrition. a Variables were present >48 h prior to onset of CDI.

and number of weeks in the ICU were rounded down to 2.0. The nal score was calculated by adding the product of each variable. Patient scores for the OR-derived risk index ranged from 0 to 20. The categorisation of the OR-derived risk index is shown in Table IV. For the development cohort, increasing scores on the OR-derived risk index were signicantly associated with increasing risk for

CDI (OR: 4.58; 95% CI: 3.93e5.33; P < 0.001; aROC: 0.713). Infection rates ranged from 2.0 cases per 1000 patient admissions in the low risk group and up to 120.7 cases per 1000 admissions in the very high risk group (Table V). The OR-derived risk index was tested in the 13 002 patients in the validation cohort. Increasing scores on the

Table II Variables signicantly associated with Clostridium difcile infection in hospitalised patients given broad-spectrum antibiotics using multivariate logistic regression identied using the development cohort Variable Age (years) 50e80 >80 Haemodialysis Non-surgical admission ICU stay (weeks) OR (95% CI) 1.5 2.5 1.5 2.2 2.1 (1.1e2.1) (1.7e3.7) (1.1e2.0) (1.9e2.2) (1.7e2.9) P 0.0116 <0.0001 0.0227 <0.0001 <0.001

Table III Creation of Clostridium difcile infection risk index among hospitalised patients given broadspectrum antibiotics Patient risk factor Score if variable present Simple risk OR-derived risk index index Age (years) 50e80 >80 years Haemodialysis Non-surgical admission ICU length of stay 1 2 1 1 No. of weeks in ICU 1.5 2.5 1.5 2.0 2.0 no. of weeks in ICU

OR, odds ratio; CI, condence interval; ICU, intensive care unit.

OR, odds ratio; ICU, intensive care unit.

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Table IV Categorisation of Clostridium difcile infection risk index Risk level Simple risk index 1 2 3 4 (low) (medium) (high) (very high) 0e2 3e4 5e6 !6 Score OR-derived risk index 0e3 3.5e9.0 9.5e11.5 >12.0

K.W. Garey et al. in the development cohort (range of CDI rates was 0.20e120.7 cases per 1000 patient admissions; aROC: 0.713), but not as well in the validation cohort (2.4e83.3 cases per 1000 patient admissions; aROC: 0.684). Strengths of this study include a large sample size of 54 226 in a patient population receiving broad-spectrum antibiotics. To the best of our knowledge, this is the rst risk index created for the specic purpose of identifying a high risk CDI patient population from a non-infected population of patients given broad-spectrum antibiotics. Data used in this study were collected electronically and could be used to build real-time cohorts of patients to enrol into prospective CDI prophylaxis or prevention studies. Antibiotics are the main modiable and most widely recognised risk factor for CDI.16,17 More than 50% of patients receive an antibiotic during hospital stay.18e20 Thus, using antibiotics alone as a sole risk factor for a CDI risk index would be impractical. For this reason, we decided to focus on additional risk factors among a population of patients receiving broad-spectrum antibiotics. We chose known risk factors that we were able to obtain electronically through the hospital IT network and we identied high risk groups with rates of CDI of w80 cases per 1000 patient admissions. We did not focus on any specic antibiotic class but instead chose antibiotic groups known to be risk factors for CDI.21 We excluded aminoglycosides as they are not commonly used at our hospital and they have a low risk of causing CDI relative to penicillins, cephalosporins, uoroquinolones and carbapenems. Future studies should focus on types and duration of antibiotic use to add to this risk index. The simple risk index that assigned a point

OR, odds ratio.

OR-derived risk index were signicantly associated with increasing risk for CDI (OR: 3.97; 95% CI: 2.91e5.40; P < 0.001). Goodness-of-t was less than that observed in the development cohort, however, and the incidence of CDI in risk group 4 was less than that in risk group 3 (aROC: 0.684).

Discussion
This study identied risk factors for CDI including advanced age, haemodialysis, non-surgical admission and number of weeks in the ICU in a hospitalised patient population receiving broad-spectrum antibiotics. These variables were used to create two risk indices that placed patients at increasingly higher risk for CDI. Rates of CDI using the simple risk index ranged from 1.9 to 81.3 cases per 1000 patient admissions in the development cohort (aROC: 0.733) with similar rates (2.3e76.9 cases per 1000 patient admissions; aROC: 0.712) in the validation cohort. A risk index that used the OR from the logistic regression analysis performed well

Table V The number and rate of Clostridium difcile infection (CDI) for each category of the CDI risk index in hospitalised patients given broad-spectrum antibiotics Development cohort Level of risk for simple risk index 1 32 16 601 2 141 21 081 3 68 2964 4 47 578 aROC 0.733 Level of risk for odds ratio risk index 1 35 17 515 2 184 22 849 3 41 628 4 28 232 aROC 0.713 Validation cohort No. of CDI cases No. in risk group Infection ratea No. of CDI cases No. in risk group Infection ratea 1.9 6.7 22.9 81.3 12 56 25 11 0.712 13 75 15 1 0.684 5127 6815 917 143 2.3 8.2 27.3 76.9

2.0 8.1 65.3 120.7

5405 7378 180 39

2.4 10.2 83.3 25.6

aROC, area under the receiver operating characteristic curve. a Per 1000 admissions.

CDI risk index system for each risk factor performed better than a more complicated risk index based on the OR derived from the logistic regression equations. This ease of calculation may also allow use of the simple risk index in clinical practice. This study has many limitations. As mentioned above, we did not sub-stratify our patient population by type of antibiotics received or calculate an antibiotic exposure index. This would have been technically demanding and it is likely that other hospitals would also have had difculty incorporating a level of antibiotic exposure into a risk index. This was a single-centre study and results should be tested in other institutions. We divided our population into a development and validation cohort to decrease the probability of reporting associations that were due to chance alone. Because of this, the validation cohort contained 104 patients with CDI. Larger multicentre studies may be able to produce a more precise risk index and will be required to validate these models. Finally, numerous other host factors have been identied as risk factors for CDI, including immunoglobulin response to toxin A and polymorphisms in the interleukin-8 gene.22e24 Incorporation of these variables into a risk index would increase the complexity of the risk index but may better stratify patients into risk groups. In conclusion, the risk index described should allow stratication of patients into risk group categories for development of CDI and facilitate development of preventive strategies. Conict of interest statement None declared. Funding sources Viropharma, Inc.

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