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

1

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”

ObjectiveY NP

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 NNA

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"

IntroductionObjective

YNP

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”

ObjectiveMethods

YNP

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

MethodsResults

YN

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? ObjectiveMethods

YNNA

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"

IntroductionObjective Methods Discussion

YNNA

2

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

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 YN

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”

MethodsYNP

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

YNP

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

MethodsResults

YN

13.The discount rate(s) is stated

If future costs are calculated, are the costs discounted? Methods

YNNA

14.The choice of rate(s) is justified

If question 13 is "no" then put down "not applicable" Methods

YNNA

15.An explanation is given if costs or benefits are not discounted

If question 13 is "no" then put down "not applicable" Methods

YNNA

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"

ResultsYNP

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”

MethodsYNP

18.The choice of variables for sensitivity analysis is justified

If question 17 is "no" then put "not applicable" MethodsYNNA

3

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

19.The ranges over which the variables are varied are stated

If question 17 is "no" then put "not applicable" MethodsYNNA

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”

ResultsYNP

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

YN

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

4

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

thor

and

yea

r of

pub

licati

on

Patie

nt

popu

latio

n

CDI d

efini

tion

base

d on

Sam

ple

size

of

thos

e w

ith C

DI

Sam

ple

size

of

com

paris

on

grou

p

Reso

urce

uti

lizati

on

varia

bles

in

clud

ed

Reso

urce

and

co

st so

urce

s

Tim

e fr

ame

of

data

ext

racti

on

Tim

e ho

rizon

for

cost

s

Cost

out

com

e(s)

Type

of m

etho

d to

cal

cula

te

cost

s

Cost

of t

hose

w

ith C

DI(U

S 20

14 $

)

Cost

of

com

paris

on

grou

p(U

S 20

14 $

)

Attrib

utab

le

cost

(US

2014

$)

p-va

lue

Australia

Jackson 2011 (4) Hospitalized ICD code 233 - HospitalizationComputerized clinical costing

systems

2 y(2005 to

2007)

LOS

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)

LOS

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)

LOS

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 LOS

Mean cost per case SUM - - $4,124 -

Japan

Yasunaga 2012 (9)

Hospitalized, underwent elective

digestive tract surgery for cancer

ICD code 409143,243

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)

LOS Total costs

SUMRA

PSM

$33,547-

$33,547

$23,670-

$26,580

-$6,814$6,967

<0.001<0.001<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)

LOS

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 - HospitalizationHealth Facts

electronic health record database

6 y and 2 m (Apr 2005 to

Jun 2011)

LOS

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 ICDcode 1,211 6,053 Hospitalization

Rhode Island Department of

Health’s Centre for Health Data and

Analysis

2 y(Jan 2010

to Dec 2011)

LOS

Mean costsMedian costs PSM $35,473

$20,998$17,474$9,714

$17,999$11,284

<0.0001-

5

Auth

or a

nd y

ear

of p

ublic

ation

Patie

nt

popu

latio

n

CDI d

efini

tion

base

d on

Sam

ple

size

of

thos

e w

ith C

DI

Sam

ple

size

of

com

paris

on

grou

p

Reso

urce

uti

lizati

on

varia

bles

in

clud

ed

Reso

urce

and

co

st so

urce

s

Tim

e fr

ame

of

data

ext

racti

on

Tim

e ho

rizon

for

cost

s

Cost

out

com

e(s)

Type

of m

etho

d to

cal

cula

te

cost

s

Cost

of t

hose

w

ith C

DI(U

S 20

14 $

)

Cost

of

com

paris

on

grou

p(U

S 20

14 $

)

Attrib

utab

le

cost

(US

2014

$)

p-va

lue

Pant 2013 (13) Hospitalized, children with IBD ICD code 447 12,163 Hospitalization

Healthcare Cost and Utilization Project

Kids’ Inpatient Database

1 year (2009)

LOS

Mean hospitalizatio

n chargesRA $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)

LOS

Mean hospitalizatio

n costRA $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)

LOS

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)

LOS

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 ileostomyICD code 217 13,245 Hospitalization Nationwide

Inpatient Sample

5 y(2004 to

2008)

LOS 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 Inpatient Sample

5 y(2004 to

2008)

LOS

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

Kim 2012 (19)

Hospitalized, underwent radical

cystectomy for bladder cancer

ICD code - - Hospitalization Nationwide Inpatient Sample

8 y(2001 to

2008)

LOS

Hospitalization 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)

180 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)

LOS

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

Auth

or a

nd y

ear

of p

ublic

ation

Patie

nt

popu

latio

n

CDI d

efini

tion

base

d on

Sam

ple

size

of

thos

e w

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DI

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ple

size

of

com

paris

on

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p

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on

varia

bles

in

clud

ed

Reso

urce

and

co

st so

urce

s

Tim

e fr

ame

of

data

ext

racti

on

Tim

e ho

rizon

for

cost

s

Cost

out

com

e(s)

Type

of m

etho

d to

cal

cula

te

cost

s

Cost

of t

hose

w

ith C

DI(U

S 20

14 $

)

Cost

of

com

paris

on

grou

p(U

S 20

14 $

)

Attrib

utab

le

cost

(US

2014

$)

p-va

lue

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

diseaseICD code - - Hospitalization Nationwide

Inpatient Sample1 y

(2009)LOS 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

Inpatient Sample1 y

(2009)LOS 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)

LOS

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

Inpatient Sample

2 y(2005 to

2006)

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

Lesperance 2011 (29)

Hospitalized with elective colon

resectionsICD code 10,077 695,010 Hospitalization Nationwide

Inpatient Sample

3 y(2004 to

2006)

LOS

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)

LOS

Median hospitalization 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)

LOS

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)

LOS

Mean hospitalizatio

n cost

SUMPSM

$24,689$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)

LOS

Mean hospital cost per

admission

Median hospital cost

per admission

PSM

$24,413

$12,078

$12,005

$7,166

$12,408

$4,913

<0.0001

Bajaj 2010 (34) Hospitalized with ICD code - - Hospitalization Nationwide 1 y LO Total RA $86,572 $38,934 - <0.001

7

Auth

or a

nd y

ear

of p

ublic

ation

Patie

nt

popu

latio

n

CDI d

efini

tion

base

d on

Sam

ple

size

of

thos

e w

ith C

DI

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ple

size

of

com

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on

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ed

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s

Tim

e fr

ame

of

data

ext

racti

on

Tim

e ho

rizon

for

cost

s

Cost

out

com

e(s)

Type

of m

etho

d to

cal

cula

te

cost

s

Cost

of t

hose

w

ith C

DI(U

S 20

14 $

)

Cost

of

com

paris

on

grou

p(U

S 20

14 $

)

Attrib

utab

le

cost

(US

2014

$)

p-va

lue

cirrhosis Inpatient Sample (2005) S hospitalization charges

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)

LOS

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)

LOS

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 Sample1 y

(2005)LOS

Mean hospital costs

Total cost

SUM

PSM

$82,860

-

$63,219

-

-

$11,483

<0.001

-

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

Inpatient Sample1 y

(2003)LOS

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)

LOS

and

180 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)ICD code - - Hospitalization Nationwide

Inpatient Sample

7 y(1998 to

2004)

LOS

Mean hospital charges SUM

Ulcerative colitis: $40,854

Crohn’s disease: $39,038

Ulcerative colitis: $27,372

Crohn’s disease: $23,379

- <0.0001

Song 2008 (41) Hospitalized LAB 630 630 -

John Hopkins Hospital

administrative finance system

4 y and 10 m

(Jan 2000 to Oct 2005)

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

Lawrence 2007 Hospitalized, ICU LAB 75 1,760 Hospitalization Barnes-Jewish 2.5 y LO Median cost SUM $60,711 $24,623 - <0.001

8

Auth

or a

nd y

ear

of p

ublic

ation

Patie

nt

popu

latio

n

CDI d

efini

tion

base

d on

Sam

ple

size

of

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DI

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and

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s

Tim

e fr

ame

of

data

ext

racti

on

Tim

e ho

rizon

for

cost

s

Cost

out

com

e(s)

Type

of m

etho

d to

cal

cula

te

cost

s

Cost

of t

hose

w

ith C

DI(U

S 20

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)

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of

com

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p(U

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Attrib

utab

le

cost

(US

2014

$)

p-va

lue

(42) Hospital financial accounting system

(Jul 1997 to Dec 1999)

S per patient

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)

LOS

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)

LOS

Median total charges

Total charges

SUM

RA

$72,496

-

$19,772

-

-

$88,902

<0.0001

<0.0001

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

Beth Israel Deaconess Medical

Centre Hospital billing system

5 m(Jan 1998

to May 1998

LOS

Median hospital cost

Hospital cost

SUM

RA

$16,263 $7,616 -

$4,852

<0.0001

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

treatmentHospital 1 y

(1988)LOS

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.

9

Supplementary Table S4: Quality assessment results.Country Author and year 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22

Australia Jackson 2011 (4) [+] + + - + - NA NA - [+] [+] + NA NA NA + - NA NA + - +

CanadaMiller 2002 (5) - NA - - - - NA NA + [+

] [+] + NA NA NA [+] - NA NA - - -

Butterworth 1998 (6) + - - - + - NA NA + [+] - + NA NA NA - - NA NA - + -

Germany Vonberg 2008 (7) + + - - + + NA NA + + - + NA NA NA + - NA NA + + +Ireland Al-Eidan 2000 (8) + - - - + + NA NA + + [+] + NA NA NA [+] - NA NA + + -Japan Yasunaga 2012 (9) + + - - + + NA NA + + [+] + NA NA NA + - NA NA + + +

United Kingdom Wilcox 1996 (10) + + - - + + NA NA + [+] [+] + NA NA NA [+] - NA NA + + +

United States Campbell 2013 (11) + + - - + + NA NA + + [+] + NA NA NA + + - + + - +Jiang 2013 (12) + + - - + + NA NA + + [+] + NA NA NA + - NA NA + - +Pant 2013 (13) - NA - - + + NA NA + + - + NA NA NA + - NA NA + + -Quimbo 2013 (14) + + - - + + NA NA + + + + NA NA NA + - NA NA + + +Sammons 2013 (15) - NA - - + + NA NA + + - + NA NA NA + - NA NA + + +Tabak 2013 (16) + + - - + + NA NA + + - + NA NA NA + + - + + - +Wilson 2013 (17) + - - - + + NA NA + + + + NA NA NA + - NA NA + - +Ali 2012 (18) - NA - - + + NA NA + + - + NA NA NA + - NA NA + + +Kim 2012 (19) [+] + - - + - NA NA + + + + NA NA NA + - NA NA + - +Kuntz 2012 (20) + + - - + + NA NA + + + + NA NA NA - - NA NA - + +Lipp 2012 (21) + + + - + - NA NA + + - + NA NA NA [+] - NA NA + - +McGlone 2012 (22) + + + - + + + + + + + + + - NA + + + + + + +Pant 2012 (23) - NA - - + + NA NA + + - + NA NA NA + - NA NA + - +Pant 2012 (24) - NA - - + + NA NA + + - + NA NA NA + - NA NA + - -Peery 2012 (25) - NA - - + - NA NA + + [+] + NA NA NA [+] - NA NA - - +Verlee 2012 (26) + + - - + + NA NA + + + + NA NA NA [+] - NA NA - + +

Arora 2011 (27) + + - - + + NA NA - [+] - + NA NA NA [+] - NA NA - - +

Glance 2011 (28) + + - - + + NA NA + + - + NA NA NA [+] - NA NA + + +Lesperance 2011 (29) - NA - - + + NA NA + + - + NA NA NA [+] - NA NA + - +Nylund 2011 (30) - NA - - + + NA NA + + [+] + NA NA NA + - NA NA + - +

Pakyz 2011 (31) + + + - + + NA NA + + + + NA NA NA + [+] - + + + +

Stewart 2011 (32) + + - - + + NA NA + + [+] + NA NA NA + - NA NA + - +Wang 2011 (33) + + - - + + NA NA - + [+] + NA NA NA + [+

]- + + + +

10

Country Author and year 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22Bajaj 2010 (34) + - - - + + NA NA + + - + NA NA NA + - NA NA + - +Fuller 2009 (35) [+] + + - + - NA NA - + - + NA NA NA [+] - NA NA + - +Reed 2009 (36) + - [+] - + - NA NA + - - + NA NA NA + - NA NA + + -Zilberberg 2009 (37) + + - - + + NA NA + + [+] + NA NA NA + - NA NA + - +Ananthakrishnan 2008 (38) - NA - - + + NA NA + + - + NA NA NA + - NA NA + - +

Dubberke 2008 (39) + + - - + + NA NA + + [+] + NA NA NA + - NA NA + + +Nguyen 2008 (40) - NA - - + - NA NA + + + + NA NA NA + - NA NA + - +Song 2008 (41) + + + - + + NA NA + + - + NA NA NA [+] - NA NA + + +Lawrence 2007 (42) - NA - - + + NA NA + + + + NA NA NA + - NA NA + + +O'Brien 2007 (43) + - - - + + NA NA + + + + NA NA NA [+] - NA NA [+] - +Zerey 2007 (44) + + - - + + NA NA + + - + NA NA NA + - NA NA + + +Kyne 2002 (45) + + - - + + NA NA + + [+] + NA NA NA + - NA NA + - +McFarland 1999 (46) - NA - - + + NA NA - + - + NA NA NA [+] - NA NA - - +Kofsky 1991 (47) + + + - + + NA NA + + - + NA NA NA [+] - NA NA - + -Yannelli 1988 (48) - NA - - - - NA NA + - - + NA NA NA - - NA NA - + -

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).

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