A SYSTEMATIC REVIEW OF THE LITERATURE

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SUPPLEMENTARY MATERIAL

Supplementary Table S1: Search terms used in each of the databases.

Database “CDI” related search terms “Cost” related search terms

Medline®

Embase

exp Clostridium difficile/ OR exp Clostridium/ OR exp Clostridium Infections/ OR clostridium difficile.mp.

OR difficile.mp. OR Cdifficile.mp. OR (C adj difficile).mp. OR difficile

clostridium.mp. OR Cdiff.mp. OR (C adj diff).mp.

exp Economics/ OR Economics.mp. OR exp "costs and cost analysis"/ OR (cost$ adj analysis).mp. OR exp Cost allocation/

OR cost allocation.mp. OR exp "Cost-benefit analysis"/ OR (cost-benefit adj analysis).mp. OR exp Cost control/ OR cost control.mp. OR exp Cost savings/ OR cost savings.mp. OR exp

"Cost of illness"/ OR (cost adj2 illness).mp. OR exp Cost sharing/ OR cost sharing.mp. exp "deductibles and

coinsurance"/ OR (deductibles adj coinsurance).mp. OR exp Medical savings accounts/ OR medical savings accounts.mp.

OR exp Health care costs/ OR health care costs.mp. OR exp Direct service costs/ OR Direct service costs.mp. OR exp Drug costs/ OR drug costs.mp. OR exp Employer health costs/ OR Employer health costs.mp. OR exp Hospital costs/ OR hospital costs.mp. OR exp Health expenditures/ OR Health

expenditures.mp. OR exp Capital expenditures/ OR Capital expenditures.mp. OR exp "Value of life"/ OR (value adj life).mp.

OR exp economics, hospital/ OR exp economics, medical/ OR exp Economics, nursing/ OR exp OR Economics,

pharmaceutical/ OR exp "fees and charges"/ OR exp budgets/

OR (low adj cost).mp. OR (high adj cost).mp. OR (health?care adj cost$).mp. OR (fiscal or funding or financial or finance).tw.

OR (cost adj estimate$).mp. OR (unit adj cost$).mp. OR (economic$ or pharmacoeconomic$ or price$ or pricing).tw.

OR (cost adj variable).mp. OR (cost-effect* or "cost

effect*").mp. OR exp Quality-Adjusted Life Years/ OR quality- adjusted life years.mp. OR quality adjusted life years.mp. OR qaly.mp. OR (life adj years).mp. OR cost utili*.mp. OR (cost adj2 utili*).mp. OR (cost adj2 effect*).mp. OR exp models,

economic/ OR (economic$ adj2 model$).mp. OR (cost adj2 utilit*).mp. OR (cost adj2 consequenc*).mp. OR net benefit.mp. OR (willingness adj2 pay).mp.

Health Technology Assessment Database NHS Economic Evaluation Database Cost-

Effectiveness Analysis Registry EconLit

Clostridium difficile None

CDI - C. difficile infection, NHS – National Health Service

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Supplementary Table S2: Quality assessment tool and how it was applied the COI studies.

Questions from Drummond

and Jefferson (1) The application of each question to a COI study

Section(s) in which the item should be found

Answer options

1. The research question is stated

 Does the objective state that the economic impact of the disease is being determined? Examples of other terms that can be used include: cost, expenses, economic burden, financial impact

 If the actual disease (e.g., CDI) is not mentioned in the objective but represented within a group of diseases (e.g., hospital acquired infections), then put

“partially”

Objective

Y N P

2. The economic importance of the research question is stated

 If question 1 is "yes" or “partially” then is the rationale behind the cost analysis stated?

 If question 1 is "no" then put “not applicable”

Introduction Objective

Y N NA

3. The viewpoint(s) of the analysis are clearly stated and justified

 Does the study state the "perspective" or

"viewpoint" of the cost analysis? Examples of perspectives include: hospital, government, patient, insurance company, society, caregiver

 A justification behind the perspective chosen should also be stated

 If the perspective is only stated and not justified, then put "partially"

Introduction Objective

Y N P

4. The form of economic evaluation used is stated

 Are the epidemiological approach (e.g.,

incidence/prevalence-based approach (2, 3)) and method of resource quantification (e.g., top- down/bottom-up approach (2, 3)) stated?

 If one or the other is stated then put “partially”

Objective Methods

Y N P

5. The primary outcome measure(s) for the economic evaluation are clearly stated

 Does the study state which cost outcomes are being evaluated? For example, cost per patient, cost per episode, total cost

Methods Results

Y N 6. Details of the subjects

from whom valuations were obtained are given

 Does the study provide details on the sample population in which the costs are being obtained

from? For example, demographics Results Y

N 7. Productivity changes (if

included) are reported separately

 Does the study evaluate indirect costs? Objective Methods

Y N NA 8. The relevance of

productivity changes to the study question is discussed

 If question 7 is "yes" then answer "yes" or "no"

 If question 7 is "no" then put "not applicable"

Introduction Objective Methods Discussion

Y N NA

2

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Section(s) in which the item should be found

Answer options 9. Quantities of resources

are reported separately from their unit costs

 Are resource utilization variables reported separately from their costs? For example, if hospitalization costs are reported, is length of stay provided? Or if physician costs are provided, are number of physician visits reported?

Results Y

N

10.Methods for the estimation of quantities and unit costs are described

 Does the study describe how resource utilization and costs are estimated? For example, are they obtained from a survey, a database, or expert opinion?

 If the methods of either the resource utilization variables or costs are only reported, then put

"partially"

 If the methods are discussed in the results or discussion sections then put “partially”

Methods

Y N P

11.Currency and price data are recorded

 Does the study state the year and currency in which the costs are evaluated in?

 If only one or the other is stated then put "partially"

Methods Results

Y N P 12.Time horizon of costs

and benefits is stated

 Does the study state the time horizon in which the costs are evaluated over? For example, costs over hospitalization/admission, year, lifetime

Methods Results

Y N 13.The discount rate(s) is

stated

 If future costs are calculated, are the costs

discounted? Methods

Y N NA 14.The choice of rate(s) is

justified

 If question 13 is "no" then put down "not

applicable" Methods

Y N NA 15.An explanation is given if

costs or benefits are not discounted

 If question 13 is "no" then put down "not

applicable" Methods

Y N NA 16.Details of statistical tests

and confidence intervals are given for stochastic data

 Are descriptive statistics presented for cost estimates (e.g., mean, median, standard deviation, max, min, range)?

 Are confidence intervals or p-values given?

 If either/or is stated, then put "partially"

Results

Y N P

17.The approach to sensitivity analysis is given

 Is a sensitivity analysis conducted around costs?

 If the description of sensitivity analysis is found in the results and discussion sections, put “partially”

Methods

Y N P 18.The choice of variables

for sensitivity analysis is justified

 If question 17 is "no" then put "not applicable" Methods

Y

N

NA

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Section(s) in which the item should be found

Answer options 19.The ranges over which

the variables are varied are stated

 If question 17 is "no" then put "not applicable" Methods

Y N NA

20.Incremental analysis is reported

 Did the study mention the use of a comparison group?

 If this is done for only part of the cohort then put

“partially”

Results

Y N P 21.Major outcomes are

presented in a

disaggregated as well as aggregated form

 Are the costs reported by subgroups, such as sex,

age, region, resource? Results Y

N 22.Conclusions are

accompanied by the appropriate caveats

 Are the limitations around the cost analysis (e.g.,

cohort, cost methods) discussed? Discussion Conclusions

Y N

COI - Cost of illness; CDI - C. difficile infection; Y- Yes; N – No; P- Partially; NA- Not applicable.

4

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Supplementary Table S3: Summary of CDI COI studies by country.

Author and year of publication Patient population CDI defnition based on Sample size of those with CDI Sample size of comparison group Resource utilization variables included Resource and cost sources Time frame of dataextraction Time horizon forcosts Cost outcome(s) Type of method tocalculate costs Cost of those withCDI Cost of comparisongroup Atributable cost (US2014 $) p-value

Australia Jackson 2011

(4) Hospitalized ICD code 233 - Hospitalization

Computerized clinical costing systems

2 y (2005 to

2007) LO

S

Mean cost per

episode RA - - $13,819 <0.05

Canada

Miller 2002 (5) CDI readmission LAB, SYM 10 -

Hospitalization and antibiotic

therapy

Study results and expert opinion

6 w (Jan and Apr 1997)

LO S

Mean cost per

patient SUM $11,240 - - -

Butterworth

1998 (6) Hospitalized LAB 100 -

Laboratory and antibiotic

therapy

St. Paul’s Hospital 1 y

(1996) 1 y Cost per

patient SUM $714 - - -

Germany Vonberg 2008

(7) Hospitalized LAB, SYM 45 -

Hospitalization, procedures,

drugs

Hannover Medical School finance

department

1 y (2006)

LO S

Median cost

per patient HM - - $9,730 -

Ireland Al-Eidan 2000

(8) Hospitalized LAB, SYM 87 -

Hospitalization, laboratory, drug

therapy

Antrim Area Hospital Corporate

Information Department

2 y LO

S

Mean cost per

case SUM - - $4,124 -

Japan

Yasunaga 2012 (9)

Hospitalized, underwent elective digestive tract surgery

for cancer

ICD code 409

143,243 409 (PSM)

Surgery, pharmaceuticals

, laboratory, radiology, nursing care,

and other

Japanese Diagnosis Procedure Combination

database

2 y (Jul to Dec for each year

from 2007 to

2010) LO

S Total costs

SUM RA PSM

$33,547 -

$33,547

$23,670 -

$26,580 -

$6,814

$6,967

<0.001

United Kingdom Wilcox 1996 (10)

Hospitalized, >65

years LAB, SYM 50 92 Bed, treatment,

laboratory

Study results, government sources, and expert

opinion

7 m (Dec 1994 to Jun 1995)

LO S

Mean cost per

patient SUM - - $9,703 -

United States

Campbell 2013 (11)

Hospitalized: 1) > 65 years; 2) renal disease; 3) cancer; 4)

IBD; 5) concomitant antibiotic use

LAB 4,521 - Hospitalization

Health Facts electronic health record database

6 y and 2 m (Apr 2005 to Jun 2011)

LO S

Mean hospital costs (depending on the patient

group)

SUM

PSM

$40,186-

$78,933 -

-

-$1,522-

$18,563 -

<0.05 for groups

1, 2, and 5

Jiang 2013 (12) Hospitalized ICD

code 1,211 6,053 Hospitalization

Rhode Island Department of Health’s Centre for

Health Data and Analysis

2 y (Jan 2010

to Dec 2011)

LO S

Mean costs

Median costs PSM $35,473

$20,998

$17,474

$9,714

$17,999

$11,284

<0.000 1 -

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Author and year of publication Patient population CDI defnition based on Sample size of those with CDI Sample size of comparison group Resource utilization variables included Resource and cost sources Time frame of dataextraction Time horizon forcosts Cost outcome(s) Type of method tocalculate costs Cost of those withCDI Cost of comparisongroup Atributable cost (US2014 $) p-value Pant 2013 (13) Hospitalized, children

with IBD ICD code 447 12,163 Hospitalization

Healthcare Cost and Utilization Project

Kids’ Inpatient Database

1 year (2009)

LO S

Mean hospitalizatio

n charges

RA $46,084 $35,439 $10,644 <0.001

Quimbo 2013 (14)

Hospitalized: 1) immunocompromised

; 2) CDI history; 3) concomitant antibiotic use; 4) renal impairment; 5)

IBD; 6) > 65 years

ICD code 933- 10,933

933-

32,799 Hospitalization

HealthCore Integrated Research

Database

5 y and 10 m (Jan

2005 to Oct 2010)

LO S

Mean hospitalizatio

n cost

RA $42,027-

$201,174

$22,196- 78,878

$11,823-

$122,295 <0.001

Sammons 2013 (15)

Hospitalized, children, community- and hospital-onset of CDI

ICD code,

LAB 4,474 8,821 Hospitalization

Pediatric Health Information System

database

5 y and 8 m (Jan 2006 to Aug 2011)

LO S

Mean total

cost PSM, RA - - $19,207-

$95,118 -

Tabak 2013 (16) Hospitalized LAB 255 765 Hospitalization

Hospitals, clinical research database from CareFusion, and Centers for

Medicare and Medicaid Services

1.5 y (Jan 2007

to Jun 2008)

LO S

Mean cost per case Median cost

per case

PSM

$32,921

$21,245

26,674

$16,987

$6,247

$4,258 -

-

Wilson 2013 (17)

Hospitalized, underwent closure of

loop ileostomy

ICD code 217 13,245 Hospitalization Nationwide

Inpatient Sample 5 y (2004 to

2008) LO

S Mean costs SUM

RA

$41,232 -

$17,635 -

$23,597

$20,399 -

<0.001

Ali 2012 (18)

Hospitalized, underwent liver

transplants

ICD code 5,159 193,174 Hospitalization Nationwide

2008) LO

S

Mean hospital

charges SUM $148,173 $75,641 - <0.01

Kim 2012 (19)

Hospitalized, underwent radical

cystectomy for bladder cancer

ICD code - - Hospitalization Nationwide

2008) LO

S

Hospitalizatio

n cost RA $57,368 $32,359 - <0.001

Kuntz 2012 (20)

Patients identified with CDI in an outpatient and inpatient setting

ICD code, LAB, AT (OPTS) ICD code

(IPTS)

1,316-

1,650 -

Emergency department visits, laboratory, pharmacy, physician visits,

hospitalization

Kaiser Permanente Northwest/Colorado , Medicare and

Medicaid

3 y and 3 m (Jun 2005 to Sept 2008)

18 0 d

Costs per

patient SUM $1,875-

$12,503 - - -

Lipp 2012 (21) Hospitalized ICD code - - Hospitalization

New York State Department of Health’s Statewide

Planning and Research Cooperative System

2 y (2007 to

2008) LO

S

Mean cost per

infection RA - - $30,049 -

McGlone 2012 (22)

Hypothetical sample, hospitalized, >65 years (recurrence of

CDI included in economic model)

- - -

Hospitalization, diagnostic procedures, drugs, surgical procedures, loss

in productivity

Government and

published sources - 1 y

Median cost per case (depending

on the perspective

and recurrence

rate)

- - - $9,745-

$17,962 -

Pant 2012 (23) Hospitalized, ICD code - - Hospitalization Nationwide 1 y LO Median SUM $55,755 $32,627 - <0.001

6

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Author and year of publication Patient population CDI defnition based on Sample size of those with CDI Sample size of comparison group Resource utilization variables included Resource and cost sources Time frame of dataextraction Time horizon forcosts Cost outcome(s) Type of method tocalculate costs Cost of those withCDI Cost of comparisongroup Atributable cost (US2014 $) p-value underwent solid

organ transplants Inpatient Sample (2009) S

hospital charges Mean hospital

charges

RA - - $72,167 <0.001

Pant 2012 (24)

Hospitalized with end-stage renal

disease

Inpatient Sample 1 y (2009)

LO

S Mean charges SUM

RA

$129,363 -

$58,713 -

-

$65,097

<0.001

<0.001 Peery 2012 (25) Hospitalized ICD code 110,553

discharges - Hospitalization Nationwide

LO

S Median costs SUM $7,019 - - -

Verlee 2012

(26) Hospitalized ICD code 49,516 - Hospitalization Michigan Health and

Hospital Association 7 y (Jan 2002

to Dec 2008)

LO S

Mean charges (depending on if principal

or non- principal diagnosis)

SUM $27,458-

$90,185 - - -

Arora 2011 (27) Hospitalized LAB, SYM 85 -

Daily ward, ICU, diagnostic tests, physician visits, other health professionals,

pharmacy

St Luke’s Episcopal Hospital accounting

database

1 y and 2 m (Mar 2007 to May 2008)

3 m

Median hospital costs

(depending on Horn’s index score)

SUM $9,080-

$72,667 - - -

Glance 2011 (28)

Hospitalized with

trauma ICD code 768 148,888 Hospitalization Nationwide

2006) LO

S Median cost SUM $35,212 $13,589 - -

Lesperance 2011 (29)

Hospitalized with elective colon

resections

ICD code 10,077 695,010 Hospitalization Nationwide Inpatient Sample

3 y (2004 to

2006) LO

S

Hospital

charges SUM $141,939 $65,863 - <0.05

Nylund 2011

(30) Hospitalized, children ICD code 21,274 10,474,45

4 Hospitalization

Healthcare Cost and Utilization Project

Kids’ Inpatient Database

4 y (1997, 2000, 2003, and 2006)

LO S

Median hospitalizatio n charges per

patient (depending on the year)

SUM $25,544-

$35,437

$9,611-

$12,079 -

<0.001 for 1997, 2000, and 2006

Pakyz 2011 (31) Hospitalized ICD code,

AT 10,857 19,214

Hospital care, laboratory, and

drugs

University Health System Consortium

Clinical Resource Manager program

6 y (Apr 2002

to Mar 2007)

LO S

Mean hospitalizatio

n cost Median hospitalizatio

n cost Mean cost per

patient

SUM

RA

$64,720

$39,590

$63,988

$33,546

$15,139

$32,825 -

-

<0.001

- Stewart 2011

(32) Hospitalized ICD code 41,207 41,207-

4,032,865 Hospitalization Nationwide Inpatient Sample

1 y (2007)

LO S

Mean hospitalizatio

n cost

SUM PSM

$24,689

$9,781

$15,778 -

$8,911 -

<0.000 1

Wang 2011 (33) Hospitalized ICD code 78,273 - Hospitalization

Pennsylvania Health Care Cost Containment

Council

4 y (2005 to

2008) LO

S

Mean hospital cost per admission

Median hospital cost per admission

PSM

$24,413

$12,078

$12,005

$7,166

$12,408

$4,913

<0.000 1

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Author and year of publication Patient population CDI defnition based on Sample size of those with CDI Sample size of comparison group Resource utilization variables included Resource and cost sources Time frame of dataextraction Time horizon forcosts Cost outcome(s) Type of method tocalculate costs Cost of those withCDI Cost of comparisongroup Atributable cost (US2014 $) p-value Bajaj 2010 (34) Hospitalized with

cirrhosis ICD code - - Hospitalization Nationwide

LO S

Total hospitalizatio

n charges

RA $86,572 $38,934 - <0.001

Fuller 2009 (35) Hospitalized ICD code

1,282 (Maryland

) 2,478 (California

)

- Hospitalization

Maryland: Health Services and Cost Review Commission California: Office of Statewide Planning and Development

Maryland : 1 y (Jul 2007

to Jun 2008) California

: 1 y (Oct 2005

to Sept 2006)

LO S

Mean patient

cost RA - -

Maryland : $18,529 California

:

$28,167 -

Reed 2009 (36)

Hospitalized, DRG 127, 148, 182, 415,

and 416

- 524 7,107 - Hospital’s private

administrative data 5 y (2002 to

2006) LO

S

Charges (depending on the DRG)

SUM $8,527-

$44,217

$5,080-

$26,347 - <0.001

Zilberberg 2009 (37)

Hospitalized with prolonged acute mechanical ventilation

ICD code 3,370 3,363-

61,442 Hospitalization Nationwide Inpatient Sample

1 y (2005)

LO S

Mean hospital costs Total cost

SUM

PSM

$82,860

-

$63,219

-

$11,483

<0.001

-

Ananthakrishna

n 2008 (38) Hospitalized with IBD ICD code 2,804 77,366 Hospitalization Nationwide Inpatient Sample

1 y (2003)

LO S

Median hospital charges Mean hospital

charges

SUM

RA

$21,600

-

$14,885 -

$12,604 -

-

Dubberke 2008 (39)

Hospitalized,

nonsurgical LAB 342-439 342-

24,252

Room and board, pharmacy, laboratory, radiology, respiratory therapy, physical therapy

Barnes-Jewish Hospital’s Medical

Informatics and Trendstar financial

databases

1 y (2003)

LO S an

d 18 0 d

Median total costs Mean costs (depending on the time horizon)

Median costs (depending on the time horizon)

SUM

RA

PSM

$17,575

$9,275-

$16,088

$16,099-

$30,259

$7,537

$6,563-

$10,517

$10,777-

$16,541 -

$2,712-

$5,571

$3,580-

$7,932

<0.001

-

Nguyen 2008 (40)

Hospitalized with IBD (Crohn’s disease and Ulcerative colitis)

2004) LO

S

Mean hospital

charges SUM

Ulcerativ e colitis:

$40,854 Crohn’s disease:

$39,038

Ulcerativ e colitis:

$27,372 Crohn’s disease:

$23,379

- <0.000 1

Song 2008 (41) Hospitalized LAB 630 630 -

John Hopkins Hospital administrative finance system

4 y and 10 m (Jan 2000

to Oct 2005)

LO

S Median costs PSM $22,824 $26,024 -$3,200 -

8

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Author and year of publication Patient population CDI defnition based on Sample size of those with CDI Sample size of comparison group Resource utilization variables included Resource and cost sources Time frame of dataextraction Time horizon forcosts Cost outcome(s) Type of method tocalculate costs Cost of those withCDI Cost of comparisongroup Atributable cost (US2014 $) p-value Lawrence 2007

(42) Hospitalized, ICU LAB 75 1,760 Hospitalization

Barnes-Jewish Hospital financial accounting system

2.5 y (Jul 1997

to Dec 1999)

LO S

Median cost

per patient SUM $60,711 $24,623 - <0.001

O'Brien 2007

(43) Hospitalized ICD code

Principal diagnosis:

1,036 Non- principal diagnosis:

2,656 -

Hospitalization, pharmacy, laboratory, imaging, emergency department

Massachusetts hospital discharge

databases

1 y (2000)

LO S

Mean cost per stay Median cost

per stay

Principal diagnosis:

SUM, non- principal diagnosis:

HM

$11,717-

$34,377

$6,840-

$15,876 -

Non- principal diagnosis:

$15,690

$6,244 -

Zerey 2007 (44) Hospitalized, surgical ICD code 8,113 1,553,597 Hospitalization Nationwide Inpatient Sample

5 y (1999 to

2003) LO

S

Median total charges Total charges

SUM

RA

$72,496

-

$19,772

-

$88,902

<0.000 1

Kyne 2002 (45) Hospitalized LAB. SYM - - Hospitalization

Beth Israel Deaconess Medical

Centre Hospital billing system

5 m (Jan 1998

to May 1998

LO S

Median hospital cost Hospital cost

SUM

RA

$16,263 $7,616 -

$4,852

<0.000 1

0.003

McFarland

1999 (46) Recurrent CDI LAB, SYM 209 -

Clinic visits, antibiotics, laboratory tests,

enteric pathogen and fecal leukocyte examinations, room charge, physician visit, and procedures

Medical billing records and laboratory charges

3y and 5m (Aug 1993 to

Dec 1996)

LT Mean per

person SUM $15,665 - - -

Kofsky 1991

(47) Hospitalized LAB 155 -

Bed, laboratory tests, medical

treatment

Hospital 1 y

(1988) LO

S

Mean charges

per patient SUM $3,764 - - -

Yannelli 1988 (48)

Hospitalized,

suspected CDI SYM

126 (positive

and negative)

- Laboratory

testing -

1.5 y (Jan 1986

to Jun 1987)

1.5 y

Total cost to

the hospital SUM $4,591 - - -

CDI – C. difficile infection; COI – Cost-of-illness; US – United States; ICD – International Classification of Diseases; y – Year(s); LOS – Length of stay; RA – Regression analysis; LAB – Laboratory tests (related to CDI); SYM – Symptoms (related to CDI); w – Week(s); SUM – Summation; HM – Hard matching; PSM – Propensity score matching; m – Month(s); IBD – Inflammatory bowel disease; AT – Antibiotic therapy (vancomycin and/or metronidazole); OPTS – Outpatient setting; IPTS – Inpatient setting; d – Day(s); DRG – Diagnosis Related Groups; ICU – intensive care unit; LT – Lifetime.

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Supplementary Table S4: Quality assessment results.

Country

Author and year 1 2 3 4 5 6 7 8 9 10 11 1

2 13 14 15 16 17 18 19 20 2

1 2 2

Australia Jackson 2011 (4) [+

] + + - + - N

A N

A - [+

] [+

] + N

A N A

N

A + - N

A N

A + - +

Canada

Miller 2002 (5) - N

A - - - - N

A N

A + [+

] [+

] + N

A N A

N A

[+

] - N

A N

A - - -

Butterworth 1998 (6) + - - - + - N

A N

A + [+

] - + N

A N A

N

A - - N

A N

A - + -

Germany Vonberg 2008 (7) + + - - + + N

A N

A + + - + N

A N A

N

A + - N

A N

A + + +

Ireland Al-Eidan 2000 (8) + - - - + + N

A N

A + + [+

] + N

A N A

N A

[+

] - N

A N

A + + -

Japan Yasunaga 2012 (9) + + - - + + N

A N

A + + [+

] + N

A N A

N

A + - N

A N

A + + +

United

Kingdom Wilcox 1996 (10) + + - - + + N

A N

A + [+

] [+

] + N

A N A

N A

[+

] - N

A N

A + + +

United States

Campbell 2013 (11) + + - - + + N

A N

A + + [+

] + N

A N A

N

A + + - + + - +

Jiang 2013 (12) + + - - + + N

A N

A + + [+

] + N

A N A

N

A + - N

A N

A + - +

Pant 2013 (13) - N

A - - + + N

A N

A + + - + N

A N A

N

A + - N

A N

A + + -

Quimbo 2013 (14) + + - - + + N

A N

A + + + + N

A N A

N

A + - N

A N

A + + +

Sammons 2013 (15) - N

A - - + + N

A N

A + + - + N

A N A

N

A + - N

A N

A + + +

Tabak 2013 (16) + + - - + + N

A N

A + + - + N

A N A

N

A + + - + + - +

Wilson 2013 (17) + - - - + + N

A N

A + + + + N

A N A

N

A + - N

A N

A + - +

Ali 2012 (18) - N

A - - + + N

A N

A + + - + N

A N A

N

A + - N

A N

A + + +

Kim 2012 (19) [+

] + - - + - N

A N

A + + + + N

A N A

N

A + - N

A N

A + - +

Kuntz 2012 (20) + + - - + + N

A N

A + + + + N

A N A

N

A - - N

A N

A - + +

Lipp 2012 (21) + + + - + - N

A N A

+ + - + N

A N A

N A

[+

]

- N

A N A

+ - +

10

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Country

Author and year 1 2 3 4 5 6 7 8 9 10 11 1

2 13 14 15 16 17 18 19 20 2

1 2 2

McGlone 2012 (22) + + + - + + + + + + + + + - N

A + + + + + + +

Pant 2012 (23) - N

A - - + + N

A N

A + + - + N

A N A

N

A + - N

A N

A + - +

Pant 2012 (24) - N

A - - + + N

A N

A + + - + N

A N A

N

A + - N

A N

A + - -

Peery 2012 (25) - N

A - - + - N

A N

A + + [+

] + N

A N A

N A

[+

] - N

A N

A - - +

Verlee 2012 (26) + + - - + + N

A N

A + + + + N

A N A

N A

[+

] - N

A N

A - + +

Arora 2011 (27) + + - - + + N

A N

A - [+

] - + N

A N A

N A

[+

] - N

A N

A - - +

Glance 2011 (28) + + - - + + N

A N

A + + - + N

A N A

N A

[+

] - N

A N

A + + +

Lesperance 2011 (29) - N

A - - + + N

A N

A + + - + N

A N A

N A

[+

] - N

A N

A + - +

Nylund 2011 (30) - N

A - - + + N

A N

A + + [+

] + N

A N A

N

A + - N

A N

A + - +

Pakyz 2011 (31) + + + - + + N

A N

A + + + + N

A N A

N

A + [+

] - + + + +

Stewart 2011 (32) + + - - + + N

A N

A + + [+

] + N

A N A

N

A + - N

A N

A + - +

Wang 2011 (33) + + - - + + N

A N

A - + [+

] + N

A N A

N

A + [+

] - + + + +

Bajaj 2010 (34) + - - - + + N

A N

A + + - + N

A N A

N

A + - N

A N

A + - +

Fuller 2009 (35) [+

] + + - + - N

A N

A - + - + N

A N A

N A

[+

] - N

A N

A + - +

Reed 2009 (36) + - [+

] - + - N

A N

A + - - + N

A N A

N

A + - N

A N

A + + -

Zilberberg 2009 (37) + + - - + + N

A N

A + + [+

] + N

A N A

N

A + - N

A N

A + - +

Ananthakrishnan 2008

(38) - N

A - - + + N

A N

A + + - + N

A N A

N

A + - N

A N

A + - +

Dubberke 2008 (39) + + - - + + N

A N

A + + [+

] + N

A N A

N

A + - N

A N

A + + +

Nguyen 2008 (40) - N - - + - N N + + + + N N N + - N N + - +

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Country

Author and year 1 2 3 4 5 6 7 8 9 10 11 1

2 13 14 15 16 17 18 19 20 2

1 2 2

A A A A A A A A

Song 2008 (41) + + + - + + N

A N

A + + - + N

A N A

N A

[+

] - N

A N

A + + +

Lawrence 2007 (42) - N

A - - + + N

A N

A + + + + N

A N A

N

A + - N

A N

A + + +

O'Brien 2007 (43) + - - - + + N

A N

A + + + + N

A N A

N A

[+

] - N

A N A

[+

] - +

Zerey 2007 (44) + + - - + + N

A N

A + + - + N

A N A

N

A + - N

A N

A + + +

Kyne 2002 (45) + + - - + + N

A N

A + + [+

] + N

A N A

N

A + - N

A N

A + - +

McFarland 1999 (46) - N

A - - + + N

A N

A - + - + N

A N A

N A

[+

] - N

A N

A - - +

Kofsky 1991 (47) + + + - + + N

A N

A + + - + N

A N A

N A

[+

] - N

A N

A - + -

Yannelli 1988 (48) - N

A - - - - N

A N

A + - - + N

A N A

N

A - - N

A N

A - + -

1 The research question is stated; 2 The economic importance of the research question is stated; 3 The viewpoint(s) of the analysis are clearly stated and justified; 4 The form of economic evaluation used is stated; 5 The primary outcome measure(s) for the economic evaluation are clearly stated; 6 Details of the subjects from whom valuations were obtained are given; 7 Productivity changes (if included) are reported separately; 8 The relevance of productivity changes to the study question is discussed; 9 Quantities of resources are reported separately from their unit costs; 10 Methods for the estimation of quantities and unit costs are described; 11 Currency and price data are recorded; 12 Time horizon of costs and benefits is stated; 13 The discount rate(s) is stated; 14 The choice of rate(s) is justified; 15 An explanation is given if costs or benefits are not discounted; 16 Details of statistical tests and confidence intervals are given for stochastic data; 17 The approach to sensitivity analysis is given; 18 The choice of variables for sensitivity analysis is justified; 19 The ranges over which the variables are varied are stated; 20 Incremental analysis is reported; 21 Major outcomes are presented in a disaggregated as well as aggregated form; 22 Conclusions are accompanied by the appropriate caveats; “+” refers to “yes”; “[+]” refers to “partially”; “-“ refers to “no”; “NA” refers to “not applicable”; Questions 1 to 22 are from Drummond and Jefferson (1); See Supplementary Table 2 for our interpretation of each question; Table format is based on Davis et al (49).

12

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Journal of Urology 2012;187:2011-2017.

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Hospital Epidemiology 2012;33:1031-8.

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22. McGlone SM, Bailey RR, Zimmer SM, et al. The economic burden of Clostridium difficile. Clinical Microbiology & Infection 2012;18:282-9.

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24. Pant C, Deshpande A, Anderson MP, et al. Clostridium difficile infection is associated with poor outcomes in end-stage renal disease. Journal of Investigative Medicine 2012;60:529-532.

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26. VerLee KE, Finks JL, Wilkins MJ, et al. Michigan Clostridium difficile hospital discharges:

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27. Arora V, Kachroo S, Ghantoji SS, et al. High Horn's index score predicts poor outcomes in patients with Clostridium difficile infection. Journal of Hospital Infection 2011;79:23-6.

28. Glance LG, Stone PW, Mukamel DB, et al. Increases in mortality, length of stay, and cost

associated with hospital-acquired infections in trauma patients. Archives of Surgery 2011;146:794-801.

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29. Lesperance K, Causey MW, Spencer M, et al. The morbidity of Clostridium difficile infection after elective colonic resection-results from a national population database. American Journal of Surgery 2011;201:141-8.

30. Nylund CM, Goudie A, Garza JM, et al. Clostridium difficile infection in hospitalized children in the United States. Archives of Pediatrics & Adolescent Medicine 2011;165:451-7.

31. Pakyz A, Carroll NV, Harpe SE, et al. Economic impact of Clostridium difficile infection in a multihospital cohort of academic health centers. Pharmacotherapy:The Journal of Human Pharmacology & Drug Therapy 2011;31:546-51.

32. Stewart DB, Hollenbeak CS. Clostridium difficile colitis: factors associated with outcome and assessment of mortality at a national level. Journal of Gastrointestinal Surgery 2011;15:1548-55.

33. Wang L, Stewart DB. Increasing hospital costs for Clostridium difficile colitis: type of hospital matters. Surgery 2011;150:727-35.

34. Bajaj JS, Ananthakrishnan AN, Hafeezullah M, et al. Clostridium difficile is associated with poor outcomes in patients with cirrhosis: A national and tertiary center perspective. American Journal of Gastroenterology 2010;105:106-13.

35. Fuller RL, McCullough EC, Bao MZ, et al. Estimating the costs of potentially preventable hospital acquired complications. Health Care Financing Review 2009;30:17-32.

36. Reed IJF, Edris BA, Eid S, et al. Clostridium difficile: The new epidemic. Internet Journal of Infectious Diseases 2009;7.

37. Zilberberg MD, Nathanson BH, Sadigov S, et al. Epidemiology and outcomes of clostridium difficile-associated disease among patients on prolonged acute mechanical ventilation. Chest 2009;136:752-8.

38. Ananthakrishnan AN, McGinley EL, Binion DG. Excess hospitalisation burden associated with Clostridium difficile in patients with inflammatory bowel disease. Gut 2008;57:205-10.

39. Dubberke ER, Reske KA, Olsen MA, et al. Short- and long-term attributable costs of Clostridium difficile-associated disease in nonsurgical inpatients. Clinical Infectious Diseases 2008;46:497-504.

40. Nguyen GC, Kaplan GG, Harris ML, et al. A national survey of the prevalence and impact of Clostridium difficile infection among hospitalized inflammatory bowel disease patients. American Journal of Gastroenterology 2008;103:1443-50.

41. Song X, Bartlett JG, Speck K, et al. Rising economic impact of clostridium difficile-associated disease in adult hospitalized patient population. Infection Control & Hospital Epidemiology

2008;29:823-8.

42. Lawrence SJ, Puzniak LA, Shadel BN, et al. Clostridium difficile in the intensive care unit:

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43. O'Brien JA, Lahue BJ, Caro JJ, et al. The emerging infectious challenge of clostridium difficile- associated disease in Massachusetts hospitals: clinical and economic consequences. Infection Control &

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44. Zerey M, Paton BL, Lincourt AE, et al. The burden of Clostridium difficile in surgical patients in the United States. Surgical Infections 2007;8:557-66.

45. Kyne L, Hamel MB, Polavaram R, et al. Health care costs and mortality associated with nosocomial diarrhea due to Clostridium difficile. Clinical Infectious Diseases 2002;34:346-53.

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48. Yannelli B, Gurevich I, Schoch PE, et al. Yield of stool cultures, ova and parasite tests, and Clostridium difficile determinations in nosocomial diarrheas. American Journal of Infection Control 1988;16:246-9.

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