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Development of an ecological model to predict risk for acquisition of Clostridium difficile-associated diarrhea during a...

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Material Information

Title:
Development of an ecological model to predict risk for acquisition of Clostridium difficile-associated diarrhea during acute care hospitalization
Physical Description:
Book
Language:
English
Creator:
Steele, Susan Elaine
Publisher:
University of South Florida
Place of Publication:
Tampa, Fla
Publication Date:

Subjects

Subjects / Keywords:
Nosocomial
Infection
Epidemiology
Intestinal
Pseudomembranous colitis
Dissertations, Academic -- Nursing -- Doctoral -- USF   ( lcsh )
Genre:
non-fiction   ( marcgt )

Notes

Abstract:
ABSTRACT: Background: The traditional model of infection control has failed to stop the spread of emerging infectious diseases such as Clostridium difficile-associated diarrhea (CDAD) in the acute care environment. Ecological models, which rely upon identification of susceptible hosts, offer an alternative to the prevention of deadly outbreaks. Previous epidemiological research has identified a number of risk factors associated with CDAD. Utilization of this body of research by nurses is limited due to methodological issues that introduce bias and confounding, and use of variables that have limited meaning to the practicing clinical nurse. Aim: The aim of this study was to develop an ecological model useful for nurses in predicting the susceptibility of individuals to CDAD during an acute care hospital stay. Method: A case-control study compared 66 cases with CDAD to 66 controls matched for the temporal and spatial risk factors of hospital admission date and geographic nursing care unit within the institution. The two subject groups were compared on variables of age, antibiotic burden, laxative or bowel preparation exposure, nutritional status, gastric acid suppression therapy, enteral feeding exposure, and severity of illness as measured on the Horn Severity of Illness index. All subjects were hospitalized between January 1, 2000 and December 31, 2006. Results: On univariate analysis, age, severity of illness, serum albumin levels, length of exposure, and proton pump inhibitor drug burden were significantly associated with CDAD status. Following multivariate analysis, only severity of illness, length of exposure, and decreased antibiotic drug burden were significantly associated with the development of hospital-acquired CDAD. Conclusions: This study supports the use of an ecological perspective in identifying risk factors and interventions to prevent the future spread of this infectious disease.
Thesis:
Dissertation (Ph.D.)--University of South Florida, 2008.
Bibliography:
Includes bibliographical references.
System Details:
Mode of access: World Wide Web.
System Details:
System requirements: World Wide Web browser and PDF reader.
Statement of Responsibility:
by Susan Elaine Steele.
General Note:
Title from PDF of title page.
General Note:
Document formatted into pages; contains 106, 1 pages.
General Note:
Includes vita.

Record Information

Source Institution:
University of South Florida Library
Holding Location:
University of South Florida
Rights Management:
All applicable rights reserved by the source institution and holding location.
Resource Identifier:
aleph - 001992188
oclc - 315876272
usfldc doi - E14-SFE0002367
usfldc handle - e14.2367
System ID:
SFS0026685:00001


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D e ve l opm e nt of a n E c ol ogi c a l M ode l t o P r e di c t R i s k f or A c qui s i t i on o f C l os t r i di um di f f i c i l e A s s oc i a t e d D i a r r he a D ur i ng A c ut e C a r e H os pi t a l i z a t i on by S us a n E l a i ne S t e e l e A di s s e r t a t i on s ubm i t t e d i n pa r t i a l f u l f i l l m e nt of t he r e qui r e m e nt s f or t he de g r e e of D oc t or of P hi l os ophy C ol l e ge of N ur s i ng U ni ve r s i t y of S ou t h F l o r i da M a j or P r of e s s or : S us a n C M c M i l l a n, P h D A R N P P hi l i p R F oul i s M D M P H L oi s O G onz a l e z P h. D A R N P B r e nt S m a l l P h. D D a t e of A ppr ova l : M a r c h 24, 2008 K e yw or ds : nos oc om i a l i nf e c t i on, e pi de m i ol ogy i nt e s t i na l ps e udom e m br a nous c ol i t i s C opyr i ght 2008 S us a n E l a i ne S t e e l e

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D e di c a t e d t o t he m e m or y of t hr e e i ndi v i dua l s w ho f ue l e d m y de s i r e f or s c hol a r s hi p: E dw a r d L e r oy S t e e l e 1918 2007 I m oge ne M K i ng E d. D R N 1923 2007 R e na M a e L a w r e nc e P h. D R N 1933 2005

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A c know l e dge m e nt s T he j our ne y i n w r i t i ng a doc t or a l di s s e r t a t i on i s ne ve r unde r t a ke n i n s ol i t ude I w oul d l i ke t o a c know l e dge t he f ol l ow i ng i ndi vi dua l s f or t he i r m e nt or s hi p, gui da nc e a nd s uppor t dur i ng t he c om pl e t i on of t hi s w or k S us a n C M c M i l l a n, P h. D A R N P f o r c ons t a nt l y k e e pi ng m e on t he r i ght pa t h, pr oddi ng m e w he n ne c e s s a r y, a nd f or a ns w e r i ng num e r ou s q ue s t i ons a l l i n good hum o r P hi l i p R F oul i s M D M P H f or ge ne r ous l y s ha r i ng t i m e t a l e nt a nd o f f i c e s pa c e t o e na bl e da t a c ol l e c t i on. T hi s t r ul y w oul d not ha ve be e n pos s i bl e w i t hout hi s da t a m i ni ng e xpe r t i s e L oi s O G onz a l e z P h. D A R N P f or t hou ght f ul c r i t i que a nd s uppor t o f t he m a nus c r i pt s B r e nt S m a l l P h. D f or gui da nc e i n m a ki ng s e ns e of a n e nor m ous qua nt i t y of da t a L C ur t i s B e nt l e y, m y hus ba nd, w ho of t e n r e m i nde d m e w hy I s t a r t e d on t hi s j ou r ne y a nd t he j oy t ha t w oul d c om e o f i t s c om pl e t i o n. K a t hr yn E S B e nt l e y, m y da ught e r w ho w a s t r a ns f or m e d f r om a c hi l d t o a n a m a z i ng young w om a n dur i ng t he c om pl e t i on of t hi s w or k

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i T a bl e of C ont e nt s L i s t of T a bl e s I v L i s t of F i gur e s v A bs t r a c t vi C ha pt e r O ne I nt r oduc t i on 1 P r obl e m S t a t e m e nt 8 H ypot he s e s 8 D e f i ni t i on of T e r m s 9 D i a r r he a 9 C l os t r i di um di f f i c i l e a s s oc i a t e d di a r r he a 9 A nt i bi ot i c bur de n 9 L e ngt h of e xpos ur e / r i s k pe r i od 9 S i gni f i c a nc e t o N ur s i ng 10 S um m a r y 12 C ha pt e r T w o R e vi e w of t he L i t e r a t ur e 13 Q ua l i t a t i ve A s s e s s m e nt 14 R e por t Q ua l i t y 15 I nt e r na l V a l i di t y 16 E xt e r na l V a l i di t y 19 F undi ng D i s c l os ur e 19 Q ua nt i t a t i ve A s s e s s m e nt of E c ol ogi c a l V a r i a bl e s 20 A ge 20 A c i d S uppr e s s i on 23 A nt i bi ot i c A dm i ni s t r a t i on 25 D i e t 35 T ube F e e di ng 35 M a l nut r i t i on 36 C a t ha r t i c A dm i ni s t r a t i on 37 S e ve r i t y of I l l ne s s 38 E c ol ogi c a l M ode l f or t he S t udy of C D A D 42 S um m a r y 44 C ha pt e r T hr e e M e t hods 45 R e s e a r c h D e s i gn 45 S e t t i ng 45

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i i S a m pl e 46 M e a s ur e m e nt of V a r i a bl e s 49 A ge 49 N ut r i t i ona l S t a t us 49 A nt i bi ot i c B ur de n 50 L a xa t i ve s a nd B ow e l P r e pa r a t i on M e di c a t i ons 51 G a s t r i c A c i d S uppr e s s i on 51 E nt e r a l F e e di ng 51 S e ve r i t y of I l l ne s s 51 P r oc e dur e s 52 A ppr ova l s 52 V a l i da t i on of D a t a C ol l e c t i on P r oc e dur e 53 D a t a C ol l e c t i on 53 D a t a A na l ys i s 54 C ha pt e r F our R e s ul t s 55 S a m pl e 55 T e m por a l a nd S pa t i a l C l us t e r i ng 56 U ni va r i a t e A na l ys i s 57 M ul t i va r i a t e A na l ys i s a nd M ode l E va l ua t i on 58 H ypot he s i s 63 C ha pt e r F i ve D i s c us s i on 64 S e ve r i t y of I l l ne s s 64 L e ngt h of E xpo s ur e 65 M a l nut r i t i on 65 A ge 67 M i c r oe nvi r onm e nt a l E xpos ur e V a r i a bl e s 67 T ube F e e di ng 68 C a t ha r t i c B ur de n 68 A c i d S uppr e s s i on B ur de n 68 A nt i bi ot i c B ur de n 69 L i m i t a t i ons of t he S t udy 70 G e ne r a l i z a bi l i t y 71 I m pl i c a t i ons f or N ur s i ng P r a c t i c e a nd E d uc a t i on 72 R e c om m e nda t i ons f or F ut ur e R e s e a r c h 73 C onc l us i ons 74 R e f e r e nc e s C i t e d 76 A ppe ndi x A : D a t a C ol l e c t i on W or ks he e t 92 A ppe ndi x B : R e c or d R e vi e w P r ot oc ol 97

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i i i A ppe ndi x C : I ns t i t ut i ona l R e vi e w B oa r d A ppr ova l 102 A ppe ndi x D : J a m e s A H a l e y V A M C R e s e a r c h C om m i t t e e A ppr ova l 105 A bout t he A ut hor E nd pa ge

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i v L i s t of T a bl e s T a bl e 1 P r e ve nt i on a nd T r e a t m e nt o f I nf e c t i ous D i s e a s e s : T r a di t i ona l V e r s us E c ol ogi c a l M ode l s 11 T a bl e 2 N um be r a nd P e r c e nt of S t udi e s M e e t i ng E va l ua t i o n C r i t e r i a 15 T a bl e 3 R e por t e d S i gni f i c a nc e of T e s t R e s ul t s f or A nt i bi ot i c E xpos ur e by D r ug C a t e gor y 29 T a bl e 4 L a bor a t or y R e f e r e nc e R a nge s f or N ut r i t i ona l I ndi c a t or s 51 T a bl e 5 C om pa r i s on of C a s e a nd C ont r ol M e a ns S c or e s on C ont i nuous P r e di c t or s T a bl e 6 S a m pl e D e s c r i pt i on a nd P r e di c t or s of H os pi t a l A c qui r e d C D A D 57 T a bl e 7 C ondi t i ona l L ogi s t i c R e gr e s s i on of V a r i a bl e s P r e di c t i ve of C D A D C a s e S t a t us 58 T a bl e 8 C ondi t i ona l L ogi s t i c R e gr e s s i on of I nt e r a c t i on E f f e c t s a s P r e di c t or s of C a s e S t a t us 60

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v L i s t of F i gur e s F i gur e 1 C onc e pt ua l m ode l f or t he s t udy of e c ol ogi c a l va r i a bl e s a f f e c t i ng de ve l opm e nt of C l os t r i di um di f f i c i l e a s s oc i a t e d di a r r he a 44 F i gur e 2 S a m pl e s e l e c t i on pr oc e s s 48 F i gur e 3 R O C c ur ve f or S e ve r i t y o f I l l ne s s I nde x 62 F i gur e 4 R O C c ur ve f or a nt i b i ot i c bur de n 62 F i gur e 5 R O C c ur ve f or l e ngt h of e xpos ur e 63

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vi D e ve l opm e nt of a n E c ol ogi c a l M ode l t o P r e di c t R i s k f or A c qui s i t i on o f C l os t r i di um di f f i c i l e A s s oc i a t e d D i a r r he a D ur i ng A c ut e C a r e H os pi t a l i z a t i on S us a n E l a i ne S t e e l e A B S T R A C T B a c kgr ound: T he t r a di t i ona l m ode l of i nf e c t i on c o nt r ol ha s f a i l e d t o s t op t he s pr e a d of e m e r gi ng i nf e c t i ous di s e a s e s s uc h a s C l os t r i di um di f f i c i l e a s s oc i a t e d di a r r he a ( C D A D ) i n t he a c ut e c a r e e nvi r onm e nt E c ol ogi c a l m ode l s w hi c h r e l y u pon i de nt i f i c a t i on of s us c e pt i bl e hos t s of f e r a n a l t e r na t i ve t o t he pr e ve n t i on of de a dl y out br e a ks P r e vi ous e pi de m i ol ogi c a l r e s e a r c h ha s i de nt i f i e d a num be r o f r i s k f a c t or s a s s oc i a t e d w i t h C D A D U t i l i z a t i on of t hi s body o f r e s e a r c h by nur s e s i s l i m i t e d due t o m e t hodol ogi c a l i s s ue s t ha t i nt r oduc e bi a s a nd c onf oundi ng a nd us e of va r i a bl e s t ha t ha ve l i m i t e d m e a ni ng t o t he pr a c t i c i ng c l i ni c a l nur s e A i m : T he a i m of t hi s s t udy w a s t o de ve l op a n e c ol ogi c a l m ode l us e f ul f or nu r s e s i n pr e di c t i ng t he s us c e pt i b i l i t y of i ndi vi dua l s t o C D A D dur i ng a n a c ut e c a r e hos pi t a l s t a y. M e t hod: A c a s e c ont r ol s t udy c om pa r e d 66 c a s e s w i t h C D A D t o 66 c ont r ol s m a t c he d f or t he t e m por a l a nd s pa t i a l r i s k f a c t o r s of hos pi t a l a dm i s s i on da t e a nd ge ogr a phi c nur s i ng c a r e uni t w i t hi n t he i ns t i t ut i on T he t w o s ubj e c t gr oups w e r e c om pa r e d on va r i a bl e s of a ge a nt i bi ot i c bu r de n, l a xa t i ve or bow e l pr e pa r a t i o n e xpos ur e nut r i t i ona l s t a t us ga s t r i c a c i d s uppr e s s i on t he r a py, e nt e r a l f e e di ng e xpos ur e a nd s e ve r i t y of i l l ne s s a s m e a s ur e d on t he H or n S e ve r i t y of I l l ne s s i nde x. A l l s ubj e c t s w e r e hos pi t a l i z e d be t w e e n J a nua r y 1, 2000 a nd D e c e m be r 31, 2006.

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vi i R e s ul t s : O n uni va r i a t e a na l ys i s a ge s e ve r i t y of i l l ne s s s e r um a l bum i n l e ve l s l e ngt h of e xpos ur e a nd pr ot on pum p i nhi bi t or dr ug bur de n w e r e s i gni f i c a nt l y a s s oc i a t e d w i t h C D A D s t a t us F ol l ow i ng m ul t i va r i a t e a na l ys i s on l y s e ve r i t y of i l l ne s s l e ngt h o f e xpos ur e a nd de c r e a s e d a nt i bi ot i c dr ug bur de n w e r e s i gni f i c a nt l y a s s oc i a t e d w i t h t he de ve l opm e nt of hos pi t a l a c qui r e d C D A D C onc l us i ons : T hi s s t udy s uppor t s t he us e of a n e c ol ogi c a l pe r s pe c t i ve i n i de nt i f y i ng r i s k f a c t or s a nd i nt e r ve nt i ons t o pr e ve nt t he f ut u r e s pr e a d of t hi s i nf e c t i ous di s e a s e

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1 C ha pt e r O ne I nt r oduc t i on C l os t r i di um di f f i c i l e ( C d i f f i c i l e ) i s a gr a m pos i t i v e s por e f o r m i ng a na e r obe f i r s t i de nt i f i e d i n 1935 i n t he nor m a l e nt e r i c f l or a of i nf a nt s ( H a l l & O T ool e 1935) A c a s e s e r i e s a na l ys i s publ i s he d i n t he e a r l y 1960 s di s c ou nt e d a s e r i ous he a l t h t hr e a t f r om C di f f i c i l e c onc l udi ng t ha t e i t he r t he t ox i n w a s not p r oduc e d w i t hi n t he hum a n body o r t ha t hum a ns di d not e xhi bi t a m a r ke d s e ns i t i vi t y t o t he t oxi ns pr oduc e d by t he ba c t e r i a ( S m i t h & K i ng, 1962) H ow e ve r di s c ove r y o f a l i nk be t w e e n a nt i bi ot i c a s s oc i a t e d ps e udom e m br a nous c ol i t i s a nd a t oxi n p r oduc i ng s t r a i n of a C l os t r i di um s pe c i e s i n t he 1970 s c l e a r l y e s t a bl i s he d t he or ga ni s m a s a hum a n pa t hoge n a nd t r i gge r e d a s e r i e s of i nve s t i ga t i ons a s s oc i a t i ng va r i ous a nt i bi ot i c s w i t h t he de ve l opm e nt of t he di s e a s e ( B a r t l e t t 2004 ) B y 1980, C di f f i c i l e a s s oc i a t e d di a r r he a ( C D A D ) w a s i de nt i f i e d a s a s e r i ous nos oc om i a l i nf e c t i on ( M ul l i ga n, G e or ge R ol f e & F i ne gol d, 1980; P e i ki n G a l di bi ni & B a r t l e t t 1980) S i nc e t he 1980 s r e s e a r c h ha s e xpa nde d unde r s t a ndi ng t ha t C di f f i c i l e i nf e c t i on oc c ur s i n a c ont i nuum e xt e ndi ng f r o m a s ym pt om a t i c c a r r i a ge t o f ul m i na t i ng ps e udom e m br a nous c ol i t i s T ox i ge ni c s t r a i ns of C di f f i c i l e ha ve be e n i s ol a t e d f r om f e c e s of he a l t hy a dul t s not r e c e nt l y e xpos e d t o a nt i bi ot i c s w i t h r e por t e d p r e va l e nc e r a ngi ng f r o m 4 2% t o 53 3% ( I i z uka e t a l 2004; K a t o e t a l 2001; N a ka m ur a e t a l 1981) i nd i c a t i ng t ha t t r a ns m i s s i on a nd c a r r i a ge of t he or ga ni s m m a y oc c ur unde t e c t e d

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2 a m ong t he ge ne r a l popul a t i on a s w e l l a s a m ong i n s t i t ut i ona l i z e d i ndi vi dua l s A l t hough s uc h c ol oni z a t i on i s be l i e ve d t o be t r a ns i e nt i n m os t c a s e s t he r e i s e vi de nc e t ha t pe r s i s t e nt C di f f i c i l e c ol oni z a t i on doe s oc c ur i n s om e i ndi vi dua l s ( O z a ki e t a l 2003) A m ong hos pi t a l pa t i e nt s c ol oni z a t i on f ol l ow e d by a n I gG a nt i body r e s pons e ha s be e n a s s oc i a t e d w i t h a de c r e a s e d r i s k o f C D A D a c qui s i t i on a f t e r a dj us t m e nt f or a ge s e x a nd di s e a s e s e ve r i t y ( K yne W a r ny Q a m a r & K e l l y, 2 000) a nd a n a c qui r e d i m m une r e s pons e t o t oxi n A f ol l ow i ng a n e pi s ode of C D A D i s be l i e v e d t o be p r ot e c t i ve a ga i ns t r e c ur r e nc e of di a r r he a ( K yne W a r ny, Q a m a r & K e l l y, 2001) T he r e i s i ndi c a t i on t ha t i nc r e a s i ng num be r s of pe r s ons a r e e xpe r i e nc i ng t he m os t s e ve r e out c om e s of C di f f i c i l e i nf e c t i on i nc l udi ng ps e udom e m br a nous c ol i t i s a nd de a t h ( D a l l a l e t a l 2002; F r os t C r a un & C a l de r on, 199 8; M or r i s e t a l 2002; P e pi n e t a l 2004) M os t r e c e nt l y a c ha nge i n t he e pi de m i ol o gi c pa t t e r n of t he d i s e a s e ha s be e n not e d, i nc l udi ng ge ogr a phi c a l l y di s pe r s e d out br e a k s ( K r a us z e t a l 2005; L oo e t a l 2005; M c D ona l d e t a l 2005; W a r ny e t a l 2005 ) a n i nc r e a s i ngl y vi r ul e nt s t r a i n of t he or ga ni s m ( M or r i s e t a l 2002; P e pi n e t a l 2004; P e pi n, V a l i que t t e & C os s e t t e 2005) a nd s us c e pt i bi l i t y of popul a t i ons p r e vi ous l y be l i e v e d t o be l ow r i s k f or a c qui s i t i on of C D A D ( C e nt e r s e t a l 2005) B e c a us e pe r s ons w h o de ve l op nos oc om i a l C D A D e xpe r i e nc e a m or e t ha n 50% i nc r e a s e i n hos pi t a l c os t s i nc r e a s e d l e ngt h of s t a y a nd a s i gni f i c a nt l y hi g he r m o r t a l i t y r a t e t he bur de n of t h i s di s e a s e t hr e a t e ns t he he a l t h c a r e s ys t e m ( K yne H a m e l P ol a va r a m & K e l l y 2002; M i l l e r H yl a nd, O f ne r A gos t i ni G our de a u, & I s ha k, 2002 ) I nve s t i ga t i ons i n pr e ve nt i on o f C D A D ha ve i nc l ud e d a nt i bi ot i c r e s t r i c t i on pol i c i e s va c c i ne de ve l opm e nt ( K ot l of f e t a l 2001 ; S ougi oul t z i s e t a l 2005) a nd di e t a r y

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3 m odul a t i on of i nt e s t i na l m i c r o f l or a D i e t a r y i nt e r v e nt i ons ha ve i nc l ude d us e of pr e bi ot i c s non di ge s t i bl e f i be r a ge nt s t ha t f e r m e nt a nd f os t e r g r ow t h o f no r m a l f l or a pr obi ot i c s l i ve or ga ni s m s f ound i n he a l t hy f l or a a nd s y nbi ot i c s a c om bi na t i on o f a pr e bi ot i c a nd pr obi ot i c a ge nt ( B e ngm a r k, 2003; C o l l i ns & G i bs on, 1999) T he s e r e s e a r c h e f f or t s w hi l e s om e w ha t pr om i s i ng, c ur r e nt l y l a c k s uf f i c i e nt e vi de nc e t o s uppor t t he i r us e a nd pr e ve nt i on of C D A D i s de pe nde nt upon t r a di t i ona l i nf e c t i on c ont r ol pr oc e s s e s s uc h a s ha nd hygi e ne i s ol a t i on, a nd e nvi r onm e nt a l de c ont a m i na t i on. E pi de m i ol ogi c a l a nd b i om e di c a l m ode l s f o r t he pr e ve nt i on of i n f e c t i ous di s e a s e s a r e ba s e d upon i de nt i f i c a t i on a nd de s t r uc t i on or e l i m i na t i on of t he c a us a t i ve or ga ni s m S uc h a n a ppr oa c h i gno r e s t he e vol ut i ona r y pot e nt i a l of a n e nor m ous l y di ve r s e pr oka r yot i c dom a i n ( G a l va ni 2003; P ur s s e l l 2005 a , 2005b) a s w e l l a s t he e nvi r onm e nt a l a nd s oc i a l f a c t or s i n t he m ode r n a ge t ha t ha ve a l t e r e d t he r e l a t i ons hi p be t w e e n m a n a n d m i c r obe ( de A l buque r que P os s a s 2001; M c M i c ha e l 200 4; W a l dvoge l 2004) I n c ont r a s t a n e c ol ogi c a l m ode l o f i n f e c t i o us di s e a s e of f e r s a n unde r s t a ndi ng of t he w a y t e m por a l a nd s pa t i a l r e l a t i ons hi ps be t w e e n hos t a nd pa t hoge n c a n be a l t e r e d t o r e duc e t he r i s k o f di s e a s e ( K or e n & C r a w f or d B r o w n, 2004) T he hum a n i nt e s t i ne c a n be de s c r i be d a s a c om pl e x e c os ys t e m c om pr i s e d of a c ons t a nt l y r e s ur f a c i ng or ga n pl a yi ng hos t t o bot h r e s i de nt a nd t r a ns i e nt m i c r obe s e xi s t i ng i n a s t a t e of m ut ua l i s m ( X u & G o r don, 2003) I n h e a l t hy a dul t s t he i nd i ge nous ba c t e r i a w i t hi n t he i nt e s t i ne c ont r ol pa t hoge ni c i nva s i on v i a c ol oni z a t i on r e s i s t a nc e ( va n de r W a a i j 1989) I n r e t ur n t he hos t pr ovi de s m uc us s he d e pi t he l i a l c e l l s a nd i nge s t e d f ood pa r t i c l e s w hi c h a l l ow t he ba c t e r i a t o t h r i ve i n a ph ys i ol ogi c bi or e a c t or ( B a c khe d, L e y, S onne nbur g, P e t e r s on, & G or don 2005)

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4 C D A D r e pr e s e nt s a di s r upt i on of t he i nt e s t i na l e c o s ys t e m m a ni f e s t e d by a n i nc r e a s e i n e nt e r oc oc c i ( H opki ns & M a c F a r l a ne 2 002; O z a ki e t a l 2003) a de c l i ne i n B i f i dobac t e r i a a nd B ac t e r oi de s c ol oni z a t i on ( H op ki ns & M a c F a r l a ne 2002) a nd pr ol i f e r a t i on of C di f f i c i l e A num be r of c a s e s e r i e s r e por t e d s uc c e s s f ul t r e a t m e nt of r e c ur r e nt C D A D by r e c t a l o r na s oga s t r i c a dm i n i s t r a t i on of donor s t ool f ur t he r s uppor t i ng t he i m po r t a nc e of a he a l t hy i nt e s t i na l e c os ys t e m i n c om ba t i ng t he di s e a s e ( A a s G e s s e r t & B a kke n, 2003; B ow de n, M a ns be r ge r & L yki ns 1981; E i s e m a n, S i l e n, B a s c om & K a uva r 1958 ; P e r s ky & B r a ndt 2000; S c hw a n, S j ol i n T r ot t e s t a m & A r ons s on, 1984; T ve de & R a s k M a ds e n, 19 89) R e s t or a t i on of t he no r m a l c ol oni c f l or a ha s be e n t he f oc us of i nc r e a s i ng r e s e a r c h r e ga r di ng a num be r of d i s e a s e s i nc l udi ng C di f f i c i l e d r i ve n by a dva nc e s i n ge nom i c s a nd gl ob a l a w a r e ne s s of e m e r gi ng i n f e c t i ous di s e a s e s ( M c M i c ha e l 2004; R a s t a l l e t a l 2005) H ow e ve r t he r e r e m a i ns a l a c k o f c l i ni c a l t r i a l da t a t o he l p t a r ge t popul a t i ons m os t l i ke l y t o be ne f i t a nd t o s ubs t a nt i a t e t he s pe c i f i c a ge nt s a ppr opr i a t e f or p r e ve nt i on a nd t r e a t m e nt of C D A D A l t e r a t i on i n i nt e s t i na l e c ol ogy c a n e f f e c t di a r r he a t hr ough di s t ur ba nc e s i n m ot i l i t y, de f e c t s i n t he i m m une s ys t e m a nd f a i l ur e of c ol oni z a t i on r e s i s t a nc e ( H a w r e l a k & M ye r s 2004) T he de ve l opm e nt a nd m a i nt e na nc e of t he no r m a l i n t e s t i na l e c os ys t e m i s i nf l ue nc e d by s e ve r a l f a c t o r s i nc l udi ng a ge di e t a r y i nt a ke a nd s ys t e m i c dr ug t he r a py. I ndi ge nous ba c t e r i a be gi n t o f or m c ol oni e s a t t he t i m e of bi r t h a s a r e s ul t of e xpos ur e t o m a t e r na l ba c t e r i a i n t he va gi na a nd w i t hi n t he f i r s t f e w da ys of l i f e t he di ve r s i t y of t he f e c a l f l or a c ha nge s r a pi dl y ( P a r k e t a l 2005) E a r l y i n l i f e C di f f i c i l e c ol oni z a t i on i s c om m on, a nd C di f f i c i l e ha s be e n de m ons t r a t e d w i t hi n t he i n t e s t i na l m i c r obi ot a of he a l t hy i n f a nt s i n hos pi t a l hom e a n d da y c a r e e nvi r on m e nt s ( L a r s on

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5 B a r c l a y, H onour & H i l l 1982; M a t s uki e t a l 200 5; P a r k e t a l 2005; P e nde r s e t a l 20 05; S t a r k L e e & P a r s ona ge 1982 ) A s a n i ndi v i dua l m a t ur e s c ha nge s i n ba c t e r i a l c om pos i t i on r e s ul t i n g r e a t e r s pe c i e s di ve r s i t y a c c om pa ni e d by a de c l i ne i n C di f f i c i l e ( H opki ns & M a c F a r l a ne 2002; H opki ns S ha r p, & M a c f a r l a ne 2001) H ow e ve r a s a n i ndi vi dua l a ppr oa c he s a dva nc e d a ge a de c l i ne i n B i f i dobac t e r i a a nd a n i nc r e a s e i n e nt e r oc oc c i oc c ur s ( H e but e r ne 2003; H opki ns & M a c F a r l a ne 2002; H opki ns S ha r p, & M a c f a r l a ne 2001) D i e t a r y i nt a ke pl a ys a s i gni f i c a nt r ol e i n f e c a l ba c t e r i a l c ol oni z a t i on. I nge s t i on of non di ge s t i bl e c a r bohydr a t e s pr ovi de s nut r i t i on t o s uppor t t he pr oduc t i on of va r i ous ba c t e r i a l s pe c i e s B ot h na t ur a l l y oc c ur r i ng a nd e x pe r i m e nt a l s uppl e m e nt i nduc e d di e t a r y i nt a ke of ol i gos a c c ha r i de s r e s ul t s i n a n i nc r e a s e i n f e c a l B i f i dobac t e r i a l e ve l s ( B oe hm e t a l 2004 ; G i bs on, B e a t t y, W a ng, & C um m i ngs 19 95; L a ngl a nds H opki ns C ol e m a n, & C um m i ngs 2004; P e nde r s e t a l 2005; S t a r k L e e & P a r s ona ge 1982 ) a nd t he i nc r e a s e i s dos e de pe nde nt ( B ouhni k e t a l 1999 ) O l i gos a c c ha r i de s uppl e m e nt a t i on r e s ul t e d i n a de c r e a s e i n C di f f i c i l e c ol oni z a t i on bot h i n vi t r o ( H opk i ns & M a c F a r l a ne 2003) a nd i n he a l t hy a dul t s r e c e i vi ng t he s uppl e m e nt du r i ng a c our s e of a n o r a l c e pha l os por i n a nt i bi ot i c ( O r r ha ge S va nt e & N or d 2000) H os pi t a l i z a t i on f or i l l ne s s or i nj ur y of t e n r e qui r e s nut r i t i ona l s uppor t vi a e nt e r a l nut r i t i on ( t ube f e e di ng ) A c om m on ga s t r oi nt e s t i n a l c om pl i c a t i on of e nt e r a l f e e di ng i s di a r r he a w i t h r e por t e d i nc i de nc e r a ngi ng f r om 2. 3 % t o 38 % a m ong ge ne r a l hos pi t a l popul a t i ons a nd a s hi gh a s 68% a m ong c r i t i c a l l y i l l a dul t s ( C a t a l di B e t c he r S e l t z e r S l oc um & J one s 1983; E l pe r n S t u t z P e t e r s on, G ur ka & S ki ppe r 2004; H e i m bur ge r S oc kw e l l & G e e l s 1994; H om a nn K e m e n, F ue s s e ni c h, S e nka l & Z um t obe l 1994;

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6 M ont e j o, 1999; P a nc or bo H i da l go, G a r c i a F e r na n de z & R a m i r e z P e r e z 2001; C S m i t h e t a l 1990) S ugge s t e d c a us e s f or t ube f e e di ng a s s oc i a t e d di a r r he a i nc l ude hypoa l bum i ne m i a f o r m ul a i nt o l e r a nc e c onc om i t a nt us e of s or bi t o l c ont a i ni ng e l i x i r m e di c a t i ons ( E i s e nbe r g, 2002 ) a nd c ol oni c r e s pons e t o a non phys i ol ogi c f o r m of f e e di ng ( B ow l i ng & S i l k, 1998) H ow e ve r e nt e r a l nut r i t i o n a l s o r e s ul t s i n a de c r e a s e i n a na e r obi c a nd a n i nc r e a s e i n a e r ob i c ba c t e r i a i n f e c e s ( S c hne i de r e t a l 2000; W he l a n, J udd, P r e e dy, & T a yl or 2004) a t r e nd t ha t m a y be a l t e r e d by f or m ul a s s uppl e m e nt e d w i t h f i be r ( N a ka o e t a l 2002) E nt e r a l f e e di ng a n d t he pr e s e nc e of na s oga s t r i c or pe r c ut a ne ous l y i ns e r t e d e nt e r a l f e e di ng t ube s ha ve be e n f ound t o ha ve s i gni f i c a nt a s s oc i a t i on w i t h t he a c qui s i t i on of C D A D ( D Z B l i s s e t a l 1998; K om a t s u e t a l 2003; K yne e t a l 1999; L a i M e l vi n, M e na r d, K ot i l a i ne n & B a ke r 1997 ) I l l ne s s a nd m e di c a l t r e a t m e nt a l s o i s a s s oc i a t e d w i t h a l t e r a t i on i n t he gut e c os ys t e m A l t hough a nt i bi ot i c s ha ve r e c e i ve d t he m os t a t t e nt i on i n i nve s t i ga t i ons bot h a c i d s uppr e s s i ve a nd l a xa t i ve m e di c a t i ons a l s o ha ve be e n i m pl i c a t e d i n a l t e r i ng c ol oni c f l or a T he e f f e c t of a nt i b i ot i c s upon i nt e s t i na l m i c r of l or a va r i e s bot h be t w e e n a nd w i t hi n dr ug c a t e gor i e s A s t r uc t ur e d r e s e a r c h r e vi e w o f p a pe r s publ i s he d be t w e e n 1991 a nd 2000 i de nt i f i e d a de c r e a s e i n obl i ga t e a na e r obe s s uc h a s B ac t e r oi de s B i f i dobac t e r i um a nd L ac t obac i l l us a n i nc r e a s e i n f a c ul t a t i ve a na e r obe s s uc h a s E nt e r oc oc c us a nd St r e pt oc oc c us a nd a n i nc r e a s e i n a e r obi c or ga ni s m s s u c h a s P s e udom onas ( S ul l i va n, E dl und, & N or d 2001 ) a s c om m on a nt i bi ot i c e f f e c t s T hi s s a m e r e vi e w i de nt i f i e d a l a r ge num be r of c e pha l os por i n a ge nt s a s s oc i a t e d w i t h ove r gr ow t h of C di f f i c i l e M or e r e c e nt publ i c a t i ons r e por t s i m i l a r f i ndi ngs of f l or a l s uppr e s s i on a nd pr ol i f e r a t i on o f c om pe t i ng ba c t e r i a ( B a r t os c h, F i t e M a c f a r l a ne & M c M ur do, 2004; B uhl i ng R a dun, M ul l e r &

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7 M a l f e r t he i ne r 2001; H a w r e l a k & M ye r s 2004; M a dde n e t a l 2005; M onr e a l P e r e i r a & L ope s 2005; T a ke s ue e t a l 2002 ) T he e c os ys t e m c ha nge s w hi c h oc c ur a s a r e s ul t of a nt i bi ot i c us a ge a r e not i m m e di a t e l y r e ve r s i bl e w i t h c e s s a t i on of a nt i bi ot i c t he r a py, a nd i t m a y t a ke m or e t ha n a m ont h t o r e t ur n t o p r e t r e a t m e nt l e ve l s of dom i na n t m i c r obi a l s pe c i e s ( B uhl i ng, R a dun, M ul l e r & M a l f e r t he i ne r 2001; D e L a C oc he t i e r e e t a l 2005) T he us e of ga s t r i c a c i d s uppr e s s i ve m e di c a t i ons ha s be e n a s s oc i a t e d w i t h t he de ve l opm e nt of C D A D i n r e s i d e nt s of l ong t e r m c a r e f a c i l i t i e s a s w e l l a s hos pi t a l i z e d a nd c om m uni t y ba s e d i ndi vi dua l s ( A l T ur e i h i H a s s oun, W ol f K l e i n & I s e nbe r g, 2005; C unni ngha m D a l e U ndy & G a unt 2003; D i a l A l r a s a di M a nouki a n, H ua ng, & M e nz i e s 2004; D i a l D e l a ne y, B a r kun, & S ui s s a 2005; L V M c F a r l a nd S u r a w i c z & S t a m m 1990 ) T he e xa c t e f f e c t of a c i d s uppr e s s i ve a ge nt s upon i nt e s t i na l m i c r o f l or a i s not know n. I t i s hypot he s i z e d t ha t s uppr e s s i on of ga s t r i c a c i d a l l ow s a n i nc r e a s e d num be r of pot e nt i a l pa t hoge ns t o s ur vi ve t r a ns i t i on f r om s t om a c h t o i n t e s t i ne ( D ons ke y, 2004) L a xa t i ve dr ugs a l s o m a y a l t e r i nt e s t i na l f l or a C hr oni c c ons t i pa t i on i n a dul t s i s a s s oc i a t e d w i t h a l t e r a t i ons i n c ol oni c e c ol ogy a s c o m pa r e d t o he a l t hy c ont r ol s T r e a t m e nt w i t h bot h bi s a c odyl a nd l a c t ul os e r e s ul t i n nor m a l i z a t i on o f t he f l o r a ( B ouhni k e t a l 2004; K ha l i f Q ui gl e y, K onovi t c h, & M a xi m ova 2005; Z oppi e t a l 1998 ) but pol ye t hyl e ne gl yc ol 4000 doe s not e xe r t t he s a m e e c ol ogi c a l e f f e c t ( B ouhni k e t a l 2004 ) L a c t ul os e i n pa r t i c ul a r ha s be e n f ound t o p r om ot e t he g r ow t h o f l a c t i c a c i d ba c t e r i a a nd B i f i dobac t e r i a ( S a l m i ne n & S a l m i ne n 1997) a nd t o s uppr e s s t he pr ol i f e r a t i on of po t e nt i a l pa t hoge ns s uc h a s C l os t r i di um di f f i c i l e ( B a l l ongue S c hum a nn & Q ui gnon, 1997; I t o e t a l 1997) L a xa t i ve us a ge i s a pot e nt i a l c onf ounde r i n r e s e a r c h

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8 r e ga r di ng C D A D s i nc e bot h t he di s e a s e a nd t he dr ug m a y a l t e r s t ool c ons i s t e nc y a nd f r e que nc y. P r obl e m St at e m e nt T hr ough pr e vi ou s r e s e a r c h, a num be r of e c ol ogi c a l r i s k f a c t o r s pe r t i ne nt t o hos pi t a l i z e d a dul t s ha ve be e n i de nt i f i e d f or t he de v e l opm e nt of C D A D T he s e r i s k f a c t or s i nc l ude a dva nc e d a ge us e of t ube f e e di ng, m a l nut r i t i on, s e ve r i t y of i l l ne s s a nd t he us e of m e di c a t i ons t ha t a l t e r t he i nt e s t i na l f l o r a i nc l udi ng ga s t r i c a c i d s uppr e s s a nt a ge nt s a nt i bi ot i c s a nd c a t ha r t i c s T he pur pos e of t hi s s t udy w a s t o de ve l op a nd t e s t a n e c ol ogi c a l m ode l us e f ul t o nur s e s i n pr e di c t i ng r i s k f or t he de ve l opm e nt of C l os t r i di um di f f i c i l e a s s oc i a t e d di a r r he a I t w a s a nt i c i pa t e d t ha t t he m ode l w oul d s e r ve t hr e e pur pos e s : ( 1 ) s e r ve a s a f ounda t i on f or de ve l opm e nt o f a va l i d a nd r e l i a bl e r i s k a s s e s s m e nt t ool ( 2) a i d i n t he de s i gn of f ut u r e c l i ni c a l t r i a l s of nur s e di r e c t e d p r e ve nt i on s t r a t e g i e s a nd ( 3) a s s i s t c l i ni c i a ns i n m odi f yi ng i nf e c t i on c ont r ol pr a c t i c e s i n i ns t i t ut i ona l s e t t i ngs w he n c a r i ng f or hi gh r i s k i ndi vi dua l s H y pot he s e s T hi s s t udy i s de s i gne d t o t e s t a hypot he s i s a bout t h e r i s k f a c t or s f or de ve l opm e nt of hos pi t a l a c qui r e d C D A D : H 1: S e ve r i t y of i l l ne s s l e ngt h of e xpos ur e a nd m a l nut r i t i on, a r e s i gni f i c a nt pr e di c t or s f or t he de ve l opm e nt of C D A D a m ong c a s e s a s c om pa r e d t o C di f f i c i l e ne ga t i ve c ont r ol s w i t h di a r r he a w he n m a t c he d f or a dm i s s i on da t e a nd ge ogr a phi c uni t of hos pi t a l a nd a f t e r c ont r ol l i ng f or t he e f f e c t s of a ge t ube f e e di ng c a t ha r t i c a dm i ni s t r a t i on, a nt i bi ot i c t he r a py, a nd a c i d s uppr e s s i on t he r a py.

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9 D e f i ni t i on of T e r m s D i ar r he a. F or pur pos e s of t hi s s t udy, di a r r he a w a s de f i ne d a s a t l e a s t t hr e e s t ool s w i t hi n a 24 hour pe r i od doc um e nt e d w i t hi n t he m e di c a l r e c or d a s l i qui d l oos e un f or m e d or di a r r he a or 250 m i l l i l i t e r s o f l i qu i d s t ool c ol l e c t e d vi a a c ol os t om y, a dhe s i ve f e c a l i nc ont i ne nc e c ol l e c t i on pouc h, o r a r e c t a l l y i ns e r t e d bow e l m a na ge m e nt t ube or a t l e a s t 1500 m i l l i l i t e r s of l i qui d s t ool f r om a n i l e os t om y p ouc h. C l os t r i di um di f f i c i l e as s oc i at e d di ar r he a. D i a r r he a oc c ur r i ng c onc ur r e nt l y w i t h or w i t hi n 7 d a ys of a pos i t i ve c yt ot oxi n a s s a y, s t ool c ul t ur e o r e ndos c opi c e xa m i na t i on c o ns i s t e nt w i t h p s e udom e m br a nous c ol i t i s A nt i bi ot i c bur de n. A nt i bi ot i c bur de n w a s de f i ne d a s t he s um o f t he a v e r a ge da i l y m a i nt e na nc e dos e s of or a l or i nt r a ve nous l y a dm i ni s t e r e d a nt i bi ot i c s r e c e i ve d by t he pa t i e nt du r i ng t he r i s k pe r i od. T he s e a ve r a ge da i l y dos e s w e r e de t e r m i ne d by us e of t he W or l d H e a l t h O r ga ni z a t i on D e f i ne d D a i l y D os e s ys t e m ( W H O C ol l a bor a t i ng C e nt r e f or D r ug S t a t i t i s t i c s M e t hodol ogy, 2007) L e ngt h of e x pos ur e / r i s k pe r i od. T he l e ngt h o f e xpos ur e or r i s k pe r i od f or t hi s s t udy c om m e nc e d on t he da t e of a dm i s s i on t o t he a c ut e c a r e hos pi t a l a nd e nde d on t he da t e t ha t a s t ool s pe c i m e n w a s s ubm i t t e d f or C l os t r i di um di f f i c i l e t e s t i ng

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10 Si gni f i c anc e t o N ur s i ng N ur s e s s pe nd t he m os t t i m e i n t he phys i c a l pr oxi m i t y of i nf e c t e d a nd pot e nt i a l l y vul ne r a bl e pa t i e n t s w i t hi n t he he a l t h c a r e s ys t e m B e c a us e nur s i ng r ol e f unc t i ons i nc l ude a s s i s t a nc e w i t h t oi l e t i ng, t he y a r e of t e n a bl e t o pr e di c t a pos i t i ve C l os t r i di um di f f i c i l e c yt ot oxi n t e s t r e s ul t ba s e d upon know l e dge of a pa t i e nt s pr i or a nt i bi ot i c us e a nd t he pr e s e nc e of a di s t i nc t i ve f e c a l odo r ( J oha ns e n, V a s i s ht a E di s on, & H os e i n, 2002) N ur s e s ha ve be e n i m pl i c a t e d a s pos s i bl e a ge nt s i n t he s pr e a d of t he di s e a s e i n hos pi t a l s ( C ha ng & N e l s on, 2000; P e r r y, M a r s ha l l & J one s 2001) a nd a r e r e s pons i bl e i n i ns t i t ut i ona l s e t t i ngs f or s upe r vi s i ng t he e nvi r onm e nt a l de c ont a m i na t i on of i ndi vi dua l pa t i e nt r oom s a nd ge ogr a phi c uni t s c r i t i c a l t o t he pr e ve nt i on of di s e a s e t r a ns m i s s i on ( C ha ng & N e l s on, 2000; K r oke r B ow e r & A z a di a n, 2001; M a yf i e l d, L e e t M i l l e r & M undy, 2000; V e r i t y W i l c ox, F a w l e y, & P a r ne l l 2001; W i l c ox e t a l 2003) D i a r r he a i s a f r e que nt c a us e of f e c a l i nc ont i ne nc e i n a c ut e l y i l l hos pi t a l i z e d a dul t s ( B l i s s J ohns o n, S a vi k, C l a bot s & G e r d i ng, 2000) r e qui r i ng i nc r e a s e d nur s i ng c a r e hou r s a nd s uppl i e s f or s ki n c l e a ns i ng, t r e a t m e nt o f s ki n b r e a kdow n, a nd l i ne n c ha nge s C D A D i s now r e c ogni z e d a s t he m os t c om m on t ype o f i n f e c t i ous nos oc om i a l di a r r he a ( M c F a r l a nd, 1995) O ut br e a ks of C D A D ha ve be e n w e l l doc um e nt e d ( B l ot e t a l 2003; J ohns on e t a l 1999 ; K ui j pe r e t a l 2001) a nd r e po r t e d i nc i de nc e r a t e s of nos oc om i a l C D A D r a nge f r om 0. 19 t o 6. 8 pe r 100 hos pi t a l a d m i s s i ons ( D i a l A l r a s a di M a nouki a n, H ua ng, & M e nz i e s 2004; T hom a s S t e ve ns on, W i l l i a m s on, & R i l e y 2002) A gl oba l s hor t a ge of qua l i f i e d pr of e s s i ona l nur s e s c om pr om i s e s c ont a i nm e nt of e m e r gi ng i nf e c t i ous di s e a s e s i n he a l t h c a r e s e t t i ngs ( S t one C l a r ke C i m i ot t i & C or r e a de A r a uj o, 2004)

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11 T r a di t i ona l m e t hods of p r e ve nt i ng t he s pr e a d o f i n f e c t i ous di s e a s e s w i t hi n hos pi t a l s ha ve not pr ove n s uf f i c i e nt t o c om ba t e m e r gi ng i nf e c t i ons s uc h a s C D A D A n a l t e r na t i ve e c ol ogi c a l a ppr oa c h t o di s e a s e pr e ve nt i on r e qui r e s c ha nge i n nur s i ng pr a c t i c e t o de c r e a s e t he i m pa c t of t he o r ga ni s m upon hum a n hos t s B y s t r e ngt he ni ng t he na t ur a l f l or a of t he hos pi t a l i z e d i nd i vi dua l a nd i nc r e a s i ng t he s pa t i a l a nd t e m por a l d i s t a nc e be t w e e n s us c e pt i bl e pe r s ons a nd pot e nt i a l l y i nf e c t i ous or ga ni s m s t he de gr e e o f ha r m c a us e d by t he or ga ni s m c a n be r e duc e d ( P u r s s e l l 2 005a ) T a bl e 1 c om pa r e s a nd c ont r a s t s t he bi om e di c a l a nd e c ol ogi c a l a ppr oa c he s t o i nf e c t i ous di s e a s e pr e ve nt i on. T a bl e 1 P r e v e nt i on and T r e at m e nt of I nf e c t i ous D i s e as e s : T r adi t i onal V e r s us E c ol ogi c al M ode l s M ode l A s pe c t of C a r e T r a di t i ona l E c ol ogi c a l D e t e c t i on I de nt i f i c a t i on o f pe r s ons w i t h di s e a s e I de nt i f i c a t i on o f pe r s ons s us c e pt i bl e t o di s e a s e S ym pt om t r e a t m e nt T r e a t s ym pt om s T r e a t onl y s ym pt om s t ha t ha ve no be ne f i t f or t he hos t C he m opr ophyl a xi s P r ophyl a c t i c a dm i ni s t r a t i on of a nt i m i c r obi a l a ge nt s A dm i ni s t r a t i on of bi ot he r a pe ut i c a ge nt s t o m a i nt a i n or r e s t or e hos t f l or a I s ol a t i on I s ol a t e pe r s ons w i t h di s e a s e I s ol a t e pe r s ons w i t h s ym pt om s a nd s us c e pt i bl e pe r s ons ba s e d on l e ve l of s us c e pt i bi l i t y a nd de gr e e of i m m unos uppr e s s i on E nvi r onm e nt a l C ont r ol s U ni f or m e nvi r onm e nt a l c l e a ni ng pr ot oc ol s t o r e m ove pa t hoge ns I n a ddi t i on t o e nvi r on m e nt a l c l e a ni ng pr ot oc ol s i nc r e a s e s pa t i a l a nd t e m por a l i nt e r va l s be t w e e n s us c e pt i bl e hos t a nd pa t hoge n c ont a c t N ot e A da pt e d f r om P ur s e l l 2005a a nd P ur s e l l 20 05b.

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12 K e y di f f e r e nc e s i n t he t w o a ppr oa c he s l i e i n t he de t e c t i on of s us c e pt i bi l i t y t o di s e a s e a nd t he m odul a t i on of hos t f l or a t o c om ba t t he gr ow t h o f pot e nt i a l l y pa t hoge ni c m i c r obi a l s pe c i e s T o ut i l i z e s uc h a n a ppr oa c h, nu r s e s r e qui r e a s i m pl e a nd r e l i a bl e r i s k a s s e s s m e nt t ool f or e s t i m a t i ng s us c e pt i bi l i t y t o C D A D T he de ve l opm e nt o f a pr e di c t i ve m ode l w oul d e na bl e f u r t he r de ve l opm e nt of s uc h a t ool Sum m ar y C D A D i s a s e r i ous i nf e c t i on t ha t c a n be unde r s t oo d a s a di s t ur ba nc e of t he i nt e s t i na l e c ol ogy. I de nt i f i c a t i on of t he f a c t or s t ha t m a ke a n i ndi v i dua l m os t s us c e pt i bl e t o C D A D w oul d e na bl e t he de s i gn o f i n f e c t i on c on t r ol i nt e r ve nt i ons ba s e d on e c ol ogi c a l pr i nc i pl e s t o de c r e a s e t he e xt e nt o f ha r m c a us e d by t hi s m i c r o o r ga ni s m A dva nc i ng a ge s e ve r i t y of i l l ne s s di e t a nd us e of a nt i b i ot i c a c i d s uppr e s s i ve a nd c a t ha r t i c m e di c a t i ons ha ve be e n i de nt i f i e d a s f a c t or s t ha t di s r upt t he nor m a l i nt e s t i na l e c ol ogy a nd m a y pr om ot e t he de ve l opm e nt of C D A D

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13 C ha pt e r T w o R e vi e w of t he L i t e r a t ur e B y vi r t ue of i t s i nc r e a s i ng i nc i de nc e vi r ul e nc e a nd gl oba l ge ogr a phi c r a nge C D A D i s c ons i de r e d a n e m e r gi ng i nf e c t i ous di s e a s e C ha nge s w i t hi n t he e nvi r onm e nt a nd i n hum a n e c ol ogy a r e pr e c i pi t a t i ng f a c t or s w hi c h a c c ount f or t he e m e r ge nc e of m os t s uc h di s e a s e s ( de A l buque r que P os s a s 2001; L e de r be r g, S hope & O a ks 1992 ; M c M i c ha e l 2004; M or s e 1995 ) C ha nge s i n hum a n de m ogr a phi c s a nd be ha vi or i nc r e a s e bot h e xpos ur e t o i nf e c t i ous a ge nt s a nd s us c e pt i bi l i t y t o t he i r de l e t e r i ous e f f e c t s T hi s c ha pt e r w i l l pr e s e nt a r e vi e w of t he a na l yt i c e pi de m i ol og y r e s e a r c h l i t e r a t u r e i de nt i f yi ng hum a n de m ogr a phi c a nd be ha vi or a l r i s k f a c t or s f o r t he de ve l opm e nt of C di f f i c i l e a s s oc i a t e d di a r r he a A n e c ol ogi c a l m ode l t o gui de t he s t udy of C D A D w i l l be de ve l ope d. A l i t e r a t ur e s e a r c h w a s c onduc t e d i n bot h M e dl i ne a nd C I N A H L e l e c t r oni c da t a ba s e s f or t he ye a r s 1995 t h r ough M a r c h 2006 T he ke yw or ds C l os t r i di um di f f i c i l e w a s pa i r e d us i ng t he B ool e a n c onne c t or A N D w i t h e a c h of t he f ol l ow i ng ke yw or ds : r i s k f a c t or s a ge a nt i bi ot i c t ube f e e di ng l a xa t i ve O R bow e l pr e pa r a t i on s e ve r i t y of i l l ne s s a nd a c i d s uppr e s s i on A r t i c l e s w e r e l i m i t e d t o t hos e publ i s he d i n t he E ngl i s h l a ngua ge a nd s t udi e s c onc e r ni ng a dul t s ubj e c t s i n a hos pi t a l or i ns t i t ut i ona l s e t t i ng, de s i gne d t o unde r s t a nd r i s k f a c t or s f or a n i ni t i a l e pi s ode of C l os t r i di um di f f i c i l e a s s oc i a t e d di a r r he a T he e l e c t r oni c s e a r c h w a s s uppl e m e nt e d w i t h a nc e s t r a l r e t r i e va l s f or a f i na l yi e l d of 73 publ i c a t i ons

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14 T he s a m pl e i nc l ude d one m e t a a na l ys i s a nd one s t r uc t ur e d l i t e r a t ur e r e vi e w T he r e m a i ni ng 71 o r i gi na l r e s e a r c h r e por t s i nc l ude d 36 c a s e c ont r ol s t udi e s 13 pr os pe c t i ve a nd ni ne r e t r os pe c t i ve c ohor t s t udi e s t hr e e c l i ni c a l t r i a l s a nd t e n de s c r i pt i ve s t udi e s T he m a j or i t y of t he s t udi e s i n t he r e vi e w w e r e c onduc t e d i n N or t h A m e r i c a a nd E ur op e ; how e ve r t he s a m pl e di d i nc l ude s t udi e s c onduc t e d i n A s i a a nd O c e a ni a A us t r a l a s i a i ndi c a t i ng pot e nt i a l f o r s om e ge ne t i c d i ve r s i t y a m o ng t he s t udy popul a t i ons S ubj e c t s w e r e be i ng t r e a t e d bot h m e di c a l l y a nd s ur gi c a l l y f or a va r i e t y of c ondi t i ons i nc l ud i ng c a nc e r pne um oni a c om p l i c a t i ons of hum a n i m m u node f i c i e nc y vi r us i nf e c t i on a nd c a r di a c di s e a s e Q ual i t at i v e A s s e s s m e nt T o s ys t e m a t i c a l l y a s s e s s t he qua l i t y of t he c l i ni c a l t r i a l c a s e c ont r ol a nd c ohor t s t udy publ i c a t i ons a c r i t e r i on ba s e d c he c kl i s t w a s a da pt e d ( D ow ns & B l a c k, 1998 ) T he or i gi na l c he c kl i s t w a s m od i f i e d ba s e d upon i m por t a nt dom a i ns a nd e l e m e nt s f or s ys t e m a t i c r e vi e w a dvoc a t e d by t he A ge nc y f or H e a l t hc a r e R e s e a r c h a nd Q ua l i t y ( W e s t e t a l 2002) T he c he c kl i s t i t e m s w e r e e nt e r e d i nt o a n E xc e l s pr e a ds he e t a nd e a c h publ i c a t i on w a s s ubj e c t e d t o t he s a m e que s t i ons r e ga r di ng qua l i t y of t he publ i s he d r e po r t i nt e r na l va l i di t y a nd e xt e r na l va l i di t y o f t he r e s e a r c h m e t ho ds de s c r i be d, a nd di s c l os ur e of f undi ng s our c e P ubl i c a t i ons w e r e a s s i gne d a c ode of one i f t he e l e m e nt w a s pr e s e nt w i t hi n t he publ i c a t i on a nd a c ode of z e r o i f t he e l e m e nt w a s a bs e n t T hus t he bot h t he num be r a nd t he pe r c e nt a ge of pub l i c a t i ons t ha t m e t e a c h of t he s pe c i f i e d c r i t e r i a c oul d be c a l c ul a t e d. T he t e n de s c r i pt i ve s t udi e s w e r e not s ubj e c t e d t o t hi s c he c kl i s t a s s e s s m e nt a s t he c onduc t of t he s t udi e s a nd t he m e t hod of r e po r t i ng w e r e i nc om pa t i bl e w i t h t hi s t ool

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15 T he s e publ i c a t i ons a l ong w i t h t he t w o s ys t e m a t i c r e vi e w s w e r e us e d t o he l p f u r t he r s ha pe unde r s t a ndi ng of t he e c ol ogi c a l c onc e pt s T a bl e 2 s um m a r i z e s t he r e s ul t s of t hi s qua l i t a t i ve r e vi e w of t he publ i c a t i ons T a bl e 2 N um be r and P e r c e nt of St udi e s M e e t i ng E v al uat i o n C r i t e r i a C he c kl i s t I t e m N um be r % R e por t i ng Q ua l i t y W a s a hypot he s i s a i m o r s t udy obj e c t i ve s t a t e d? 52 85. 25 W e r e t he m a i n f i ndi ngs of t he s t udy c l e a r l y de s c r i be d? 55 90. 16 E xt e r na l V a l i di t y W e r e i nc l us i on a nd e xc l us i on c r i t e r i a us e d t o de t e r m i ne e l i gi bi l i t y f o r pa r t i c i pa t i on i n t he s t udy? 20 32. 79 W e r e onl y i nc l us i on c r i t e r i a a nd not e xc l us i on c r i t e r i a i de nt i f i e d i n t he pa pe r ? 20 32. 79 W e r e t he s ubj e c t s r e pr e s e nt a t i ve of t he e nt i r e popu l a t i on f r om w hi c h t he y w e r e r e c r u i t e d? 40 65. 57 I nt e r na l V a l i di t y ( bi a s a nd c on f oundi ng) W a s a n a t t e m pt m a de t o b l i nd s ubj e c t s t o t he i nt e r ve nt i on t he y ha ve r e c e i ve d ( c l i ni c a l t r i a l s n= 3) ? 1 33. 33 W a s a n a t t e m pt m a de t o b l i nd t hos e m e a s ur i ng t he m a i n out c om e s of t he i nt e r ve nt i on ( c l i n i c a l t r i a l s n= 3) ? 1 33. 33 W e r e t he s t a t i s t i c a l t e s t s us e d t o a s s e s s t he m a i n ou t c om e s a ppr opr i a t e t o t he r e s e a r c h que s t i on? 55 90. 16 W e r e t he m e a s ur e m e nt s us e d t o a s s e s s t he m a i n out c om e a c c ur a t e ( va l i d a nd r e l i a bl e ) ? 52 85. 25 W e r e s ubj e c t s i n di f f e r e nt i nt e r ve nt i on gr oups ( t r i a l s a nd c ohor t s t udi e s ) or w e r e c a s e s a nd c ont r ol s ( c a s e c ont r ol s t udi e s ) r e c r ui t e d f r om t he s a m e popul a t i on? 32 52. 46 W e r e s t udy s ubj e c t s r a ndom i z e d t o i nt e r ve nt i on gr oups ( c l i ni c a l t r i a l s ? ) 1 33. 33 W a s t he r e a de qua t e a dj us t m e nt f or c on f oundi ng i n t he s t a t i s t i c a l a na l ys i s f r om w hi c h t he m a i n f i ndi ngs w e r e dr a w n? 35 57. 38 D i s c l os ur e W a s t he f undi ng s our c e f o r t he s t udy i de nt i f i e d? 13 21. 31 R e por t qual i t y W i t hi n t hi s body o f l i t e r a t ur e r e por t i ng qua l i t y w a s hi gh f or t w o o f t he c r i t e r i a c ons i de r e d. T he m a j or i t y of t he publ i s he d r e por t s i nc l ude d a n e xpl i c i t o r i m pl i e d

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16 hypot he s i s a i m or obj e c t i ve f or t he s t udy ( 85% ) a nd c l e a r l y de s c r i be d t he m a i n f i nd i ngs of t he s t udy ( 90% ) A l l t hr e e i nt e r ve nt i ona l s t udi e s c l e a r l y de s c r i be d t he i nt e r ve nt i on H ow e ve r onl y 16 ( 26 % ) o f t he obs e r va t i ona l s t udi e s c l e a r l y r e por t e d a m e t hod o f m e a s ur e m e nt f or t he e xpos ur e s or r i s k f a c t or s of i n t e r e s t I nt e r nal v al i di t y A s s e s s m e nt of i nt e r na l va l i di t y i nc l ude d f a c t or s s uc h a s bl i ndi ng a nd r a ndom i z a t i on f or t he i n t e r ve nt i ona l s t udi e s s t a t i s t i c a l a na l ys i s m e t hods a nd pr e s e nc e or a bs e nc e of bi a s O f t he t h r e e i nt e r ve nt i ona l s t udi e s onl y one bl i nde d bot h s ubj e c t s a nd t hos e m e a s ur i ng out c om e s t o t he g r oup a s s i gnm e nt ( C l e a r y e t a l 1998) T he ot he r i nt e r ve nt i ona l s t udi e s us e d no bl i ndi ng i n t he s t udy de s i gn ( R a o, R a o, & S t a r ke 2003; S e t t l e W i l c ox F a w l e y, C or r a do & H a w ke y, 1998 ) C l e a r y e t a l a l s o w a s t he onl y s t udy t o i nc l ude r a ndom i z a t i on i n t he a s s i gnm e nt of s ubj e c t s t o i nt e r ve nt i on g r oups S t a t i s t i c a l a na l ys i s m e t hods us e d t o a s s e s s s t udy da t a w e r e a ppr opr i a t e t o t he r e s e a r c h que s t i on a nd de s i gn i n m os t s t udi e s ( 86 % ) A l t hough a num be r of t he obs e r va t i ona l s t udi e s c ons i de r e d m or e t ha n one r i s k f a c t or f or t he de ve l opm e nt o f C D A D onl y 35 s t udi e s ( 57 % ) de s c r i be d a de qua t e a dj us t m e nt f or t he e f f e c t s of c onf oundi ng i n d i s c us s i ng t he m a i n f i ndi ngs of t he s t udi e s T w e nt y f i ve s t udi e s ( 41% ) us e d m ul t i va r i a t e s t a t i s t i c a l t e c hni que s i n a n e f f or t t o c ont r ol t he e f f e c t s o f c o nf oundi ng dur i ng da t a a na l ys i s T he m os t f r e que nt l y r e por t e d t ype of m ul t i va r i a t e da t a a na l ys i s s t r a t e gy w a s s t e pw i s e l ogi s t i c r e gr e s s i on. R e s ul t s of s t e pw i s e pr oc e dur e s i n m ul t i va r i a t e a na l ys i s a r e e a s i l y m i s i nt e r pr e t e d be c a us e pr e di c t or s m a y be e xc l ude d w hi c h a r e i n f a c t hi ghl y c or r e l a t e d w i t h t he ou t c om e of i nt e r e s t ( T a b a c hni c k & F i de l l 2001) T o m i ni m i z e

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17 t hi s pr obl e m m or e l i be r a l c r i t e r i on f or i nc l us i on of pr e di c t or s f o l l ow i ng uni va r i a t e a na l ys i s ( p < 15 or 20) i s a dvi s e d. O nl y f our of t he m ul t i va r i a t e s t udi e s i n t hi s r e vi e w s pe c i f i c a l l y i de nt i f i e d va r i a bl e s e l e c t i on c r i t e r i a w i t h a uni va r i a t e s i gni f i c a nc e l e ve l gr e a t e r t ha n p < 05 ( K om a t s u e t a l 2003; K yne S ougi oul t z i s M c F a r l a nd, & K e l l y 2002; M ut o e t a l 2005; P u l vi r e nt i e t a l 2002 ) T he r e m a i nde r o f t he s t udi e s e l i m i na t e d va r i a bl e s t ha t m i ght ha ve ha d a n i nde pe nde nt a s s oc i a t i on w i t h t he de ve l opm e nt of C D A D f ol l ow i ng m ul t i va r i a t e t e s t i ng, a nd i nde e d l i m i t e d i nc l us i on of va r i a bl e s t ha t m a y ha ve c l i ni c a l r e l e va nc e S t e pw i s e pr oc e dur e s hol d t he a l l ur e of s t a t i s t i c a l c r i t e r i a f or de c i s i ons a bout i nc l us i on of p r e di c t or s r a t he r t ha n t he t e di u m of f or m ul a t i ng s pe c i f i c hypot he s e s a bout t he r ol e of m ul t i pl e va r i a bl e s i n a s s oc i a t i on w i t h C D A D H ow e ve r s uc h a s t r a t e gy l i m i t s t he a ppl i c a bi l i t y of t he pr e di c t i ve m ode l t o c l i ni c a l pr a c t i c e A l i m i t a t i on c om m on t o m os t of t he s t udi e s w i t hi n t hi s r e vi e w i s t he l a c k of a c ons i s t e nt c a s e de f i ni t i on f or C D A D a m ong s t udi e s C l i ni c a l l y, bo t h t he p r e s e nt a t i on of di a r r he a a nd c onf i r m a t or y l a bor a t or y s t ool t e s t i ng or e ndos c opi c e xa m i na t i on a r e c ons i de r e d e s s e nt i a l f or a di a gnos i s of C D A D A l t hough 73% o f t he s t udi e s i nc l ude s om e t ype of c ha nge i n bow e l f unc t i on a s a pa r t of t he c a s e de f i ni t i on, t he de f i ni t i on of di a r r he a va r i e d g r e a t l y be t w e e n s t udi e s T hi s p r ob l e m of de f i ni ng di a r r he a a nd i t s i m pa c t on t he i nt e r p r e t a t i on of di a r r he a s t udy f i ndi ngs ha s be e n pr e vi ous l y di s c us s e d ( B l i s s G ue nt e r & S e t t e l 1992; S t e e l e 2006 ) D i a r r he a d e f i ne d by t he num be r o f bo w e l m ove m e nt s c ons i s t e nc y of s t ool a nd dur a t i on of t he s ym pt om va r i e s a m ong s t udi e s m a ki ng m e t a a na l ys i s unr e a l i s t i c R e l i a bl e i ns t r u m e nt s e xi s t f or c l a s s i f i c a t i on of s t ool c ha r a c t e r i s t i c s ( B l i s s L a r s on, B ur r & S a vi k 2001 ; W he l a n, J udd, & T a yl or 2004) H ow e ve r t he i r us e i n r e t r os pe c t i ve de s i gns t ha t r e l y upon m e di c a l r e c or d doc um e nt a t i on

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18 i s i m pr a c t i c a l M or e t ha n ha l f o f t he s t udi e s i n t hi s s a m p l e w e r e of a r e t r os pe c t i ve c ohor t or c a s e c ont r ol de s i gn. C onf i r m a t or y t e s t i ng w a s pa r t of t he c a s e de f i ni t i on f or 83% of t he or i gi na l s t udi e s H ow e ve r a va r i e t y of t e s t i ng m e t hods w e r e us e d, m a ki ng m e t a a na l ys i s a s a dvoc a t e d by B i gna r di que s t i ona bl e T w o s t udi e s a s s i gne d s ubj e c t s t o c a s e s t a t us ba s e d onl y on t he di a gnos i s r e c or de d i n t he m e di c a l r e c or d by a c l i ni c i a n ( B uc hne r & S onne nbe r g, 2001; H a r ba r t h, S a m or e & C a r m e l i 2001) a nd a t hi r d publ i c a t i on, a l e t t e r t o t he e di t or r e por t i ng r e s e a r c h f i nd i ngs di d not i nc l ude de t a i l s r e ga r di ng c a s e de f i ni t i on ( I i z uka e t a l 2004) A l a r ge por t i on of t he s t udi e s r e l i e d upon l a bor a t o r y r e c or ds of di a gnos t i c s t ool t e s t i ng f or t he s e l e c t i on of s ubj e c t s a nd c a s e s T hi s s t r a t e gy a s s um e s t ha t a l l s pe c i m e ns s ubm i t t e d f or C di f f i c i l e t e s t i ng a r e f r om s ym pt om a t i c i ndi vi dua l s a nd t ha t a l l pe r s ons w i t hout s t ool t e s t i ng a r e bot h a s ym pt om a t i c a nd w oul d pr oduc e ne ga t i ve s t ool t e s t i ng r e s ul t s T hus a t ype of di a gnos t i c bi a s w a s i n he r e nt i n t he de s i gn of t he s e s t udi e s C om pa r i s on of s t udi e s i s a l s o c om pl i c a t e d by t he v a r i e t y of w a ys i n w hi c h s pe c i f i c r i s k f a c t or e xpos ur e w a s m e a s ur e d. T hi s i s e s pe c i a l l y e vi de nt i n a s s e s s i ng a nt i bi ot i c e xpos ur e a nd s e ve r i t y o f i l l ne s s A nt i bi o t i c e xpos ur e w a s m e a s ur e d by num be r of dr ugs num be r of dos e s num be r of da ys on a s pe c i f i c a ge nt a ppr op r i a t e ve r s us i na ppr opr i a t e us e s pe c i f i c d r ug r e gi m e n, a nd by a s i m pl e bi na r y m e a s ur e of e xpos ur e O nl y one s t udy ( A l E i da n : M c E l na y, S c ot t & K e a r ne y, 2000) a t t e m pt e d t o us e a s t a nda r di z e d m e a s ur e of a nt i bi ot i c e xpos ur e t he D e f i ne d D a i l y D os e s e s t a bl i s he d by t he W or l d H e a l t h O r ga ni z a t i on f o r d r ug ut i l i z a t i on r e s e a r c h. S i m i l a r l y, t he c onc e pt o f s e ve r i t y o f i l l ne s s r e s pons i bl e f or hos pi t a l i z a t i on w a s m e a s ur e d i n a num be r of w a ys T he num be r of m e di c a l or s ur gi c a l p r oc e dur e s num be r

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19 of or ga n s ys t e m s a f f e c t e d, c r i t i c a l c a r e or ve nt i l a t o r us e p r ol onge d hos pi t a l s t a y a nd di s e a s e s t a gi ng w e r e a l l f or m s of s e ve r i t y a s s e s s m e nt O nl y t w o i ns t r um e nt s w e r e us e d f or c a t e gor i z a t i on of t hi s va r i a bl e i n a c o ns i s t e nt m a nne r T he H o r n s S e ve r i t y of I l l ne s s i nde x w a s us e d i n t hr e e s t udi e s ( K yne S ougi oul t z i s M c F a r l a nd, & K e l l y, 2002; L M c F a r l a nd, 1995; V e s t a W e l l s G e nt r y & S t i pe k, 2005) w hi l e t he C ha r l s on I nde x of C om or bi di t y w a s us e d i n t w o i nve s t i ga t i ons ( D i a l A l r a s a di M a nouki a n, H ua ng, & M e nz i e s 2004; L oo e t a l 2005) O nl y K yne e t a l a ddr e s s e d t he s e ns i t i vi t y, s pe c i f i c i t y, a nd pr e di c t i ve va l ue o f t he t ool i n di s c us s i on of t he f i ndi ngs E x t e r nal v al i di t y S ubj e c t s c hos e n f or t he s t udi e s w i t hi n t hi s r e vi e w w e r e de s c r i be d a s r e pr e s e nt a t i ve of t he t a r ge t popul a t i on i n 40 ( 66 % ) publ i c a t i ons T w e nt y s t udi e s ( 33 % ) de s c r i be d i nc l us i on c r i t e r i a f o r s t udy e l i gi bi l i t y a nd a n a ddi t i ona l 20 de s c r i be d bot h i nc l us i on a nd e xc l us i on c r i t e r i a f or pa r t i c i pa t i on. F or t hi s r e a s on, ge ne r a l i z a t i on o f s t udy f i ndi ngs t o a s pe c i f i c t a r ge t popul a t i on i s r a t he r l i m i t e d. F undi ng di s c l os ur e O nl y 13 ( 21 % ) publ i c a t i ons a c know l e dge d a f undi ng s our c e or s t udy s pons or s hi p e i t he r w i t hi n t he body o f t he pa pe r or t he no t e s a nd a c know l e dge m e nt s T hi s m a y due t o l a c k of s pons or s hi p, j ou r na l s t a nda r ds a nd r e s t r i c t i ons r e ga r di ng a c know l e dge m e nt s or s i m pl y r e f l e c t i ve of t he pe r i od o f t i m e i n w hi c h t he s t udi e s w e r e publ i s he d. I n t he c he c kl i s t pr opos e d by D ow ns a nd B l a c k ( 1998) t h e r e i s no que s t i on r e ga r di ng s pons or s hi p. H ow e ve r i n t he 2002 r e por t by W e s t e t a l f or t he A ge nc y f o r H e a l t hc a r e R e s e a r c h a nd Q ua l i t y, s pons or s hi p i s c ons i de r e d a n e s s e nt i a l c r i t e r i on f o r e va l ua t i ng qua l i t y. O f t he 42 s t udi e s publ i s he d be f o r e 2003, onl y 14% i nc l ude f undi ng i nf o r m a t i on,

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20 but 37% o f t hos e publ i s he d i n 2003 or l a t e r i nc l ud e t hi s i nf or m a t i on. I t i s a nt i c i pa t e d t ha t t hi s pe r c e nt w i l l i nc r e a s e ove r t i m e a s qua l i t a t i ve a s s e s s m e nt of r e s e a r c h f i ndi ngs be c om e s m or e r e f i ne d. Q uant i t at i v e A s s e s s m e nt of R e s e ar c h F i ndi ngs I n or de r t o e va l ua t e t he s t r e ngt h o f t he a s s oc i a t i on be t w e e n s pe c i f i c e c ol ogi c a l va r i a bl e s a nd t he de ve l opm e nt of C D A D publ i s he d odds r a t i o ( O R ) a nd r e l a t i ve r i s k ( R R ) da t a w e r e s ys t e m a t i c a l l y e xa m i ne d s i m i l a r t o t he m e t hod us e d i n t he qua l i t a t i ve por t i on of t he m e t a a na l ys i s publ i c a t i on ( B i gna r di 1998) W he n O R or R R da t a w a s not pr ovi de d, i t w a s c a l c ul a t e d, i f pos s i bl e f r om d a t a w i t hi n t he pub l i s he d a r t i c l e E vi de nc e s uppor t i ve of t he a s s oc i a t i on of a r i s k f a c t or w i t h t he de ve l opm e nt o f C D A D w a s de f i ne d e i t he r of t he f ol l ow i ng: ( 1 ) a s t a t i s t i c a l l y s i gni f i c a nt ( p< 0. 05) pos i t i ve uni va r i a t e O R or R R i n t he m a j or i t y of s t udi e s u s i ng uni va r i a t e a na l ys i s t o e va l ua t e t he r i s k f a c t or o r ( 2) a s t a t i s t i c a l l y s i gni f i c a nt ( p< 0 05) pos i t i ve m ul t i va r i a t e O R E vi de nc e w a s c ons i de r e d non s uppor t i ve of a n a s s oc i a t i on i f i t f a i l e d t o m e e t e i t he r of t he a bove c r i t e r i a or i f t w o o r m o r e s t udi e s us i ng m ul t i va r i a t e a na l ys i s f a i l e d t o i de nt i f y a s t a t i s t i c a l l y s i gni f i c a nt pos i t i ve a s s oc i a t i on f or t he r i s k f a c t or A ge T h e e f f e c t o f a ge upon t he de ve l opm e nt of C D A D i n hos pi t a l i z e d popul a t i ons i s unc e r t a i n. W i t hi n t hi s body of l i t e r a t u r e a ge ha s be e n s t udi e d a s a c onf ounde r a r i s k f a c t or a nd a n e f f e c t m odi f i e r A ge i s o f t e n c ons i d e r e d a c onf oundi ng va r i a bl e i n e pi de m i o l ogi c a l i nve s t i ga t i ons E i ght s t udi e s us e d m a t c hi ng t o c ont r ol f or pot e nt i a l c onf oundi ng e f f e c t s of a ge t hus e l i m i na t i ng i t f or c ons i de r a t i on a s a r i s k f a c t or f or t he de ve l opm e nt of C D A D ( B l i s s e t a l 1998; C ha nge l a e t a l 2004; C unni ngha m D a l e

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21 U ndy, & G a unt 2003; K r e i s e l T hom a s S i l ve r & C unni ngha m 1995; L oo e t a l 2005; M a c G ow a n e t a l 1997; T ha m l i ki t kul D a npa kdi & C hokl oi ka e w 1996; V e s t a W e l l s G e nt r y, & S t i pe k 2005; Y i p, L oe b, S a l a m a M os s & O l de 2001) A n a ddi t i ona l s t udy di d not us e m a t c hi ng f or a ge bu t s e l e c t e d c ont r ol s w i t hi n t he s a m e a ge r a nge a s c a s e pa t i e nt s t he r e by m i ni m i z i ng t he pos s i bi l i t y of di f f e r e nc e s i n a ge be t w e e n c a s e s a nd c ont r ol s ( C ha nge l a e t a l 2004 ) T w e nt y e i ght publ i c a t i ons i nc l ude d a ge a s a va r i a b l e i n t he s t a t i s t i c a l a na l ys i s of s t udy f i ndi ngs E i ght publ i c a t i ons r e po r t e d s t a t i s t i c a l l y s i gni f i c a nt di f f e r e nc e s i n m e a n a ge be t w e e n C D A D s ubj e c t s a nd non C D A D c om pa r i s on s ubj e c t s w i t hi n t he pr e s e nt a t i on of de m ogr a phi c da t a ( A c ke r m a nn e t a l 2005; B a r but e t a l 2005 ; B uc hne r & S onne nbe r g, 2002; C l i m o e t a l 1998; H a r ba r t h S a m or e & C a r m e l i 2001; K e nt R ubi n, W r obl e w s ki H a nf f & S i l e n, 1998; M c F a r l a nd, 19 95; S ve nungs s on, L a ge r g r e n, & L undbe r g, 2001) A ge w a s e va l ua t e d a s a s pe c i f i c r i s k f a c t or f or C D A D i n 13 s t udi e s O f t he f i ve s t udi e s r e por t i ng onl y uni va r i a t e a na l ys i s f ou r r e por t e d s t a t i s t i c a l l y s i gni f i c a nt pos i t i ve a s s oc i a t i on s w i t h C D A D ( A c ke r m a nn e t a l 2005; K a r l s t r om F r yk l und, T u l l us B ur m a n & G r oup, 1998; K yne S oug i oul t z i s M c F a r l a nd, & K e l l y, 2002 ; W a t a na kuna kor n, W a t a na kuna kor n, & H a z y, 1996) I nc r e a s i ng a ge w a s f ound t o ha ve a s t a t i s t i c a l l y s i gni f i c a nt pos i t i ve a s s oc i a t i on i n f i ve a ddi t i ona l s t udi e s us i ng m ul t i va r i a t e da t a a na l ys i s ( A ndr e w s R a boud, K a s s e n, & E nns 2003; C ha ng & N e l s on, 2000; M ode na B e a r e l l y, S w a r t z & F r i e de nbe r g 2005; M ut o e t a l 2005; S t a r r M a r t i n, M c C oubr e y, G i bs on, & P oxt on, 2003 ) A l t hough H a r ba r t h e t a l ( 2001 ) r e por t e d a uni va r i a t e O R of 2. 5 w i t h a s i gni f i c a nc e l e ve l s uf f i c i e nt f o r e nt r y i nt o m ul t i va r i a t e a na l ys i s ( p = 08 ) a ge w a s not

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22 e nt e r e d a s a va r i a bl e i n t he l ogi s t i c r e gr e s s i on a na l ys i s O nl y one publ i c a t i on w i t hi n t h i s r e vi e w r e por t e d a non s i gni f i c a nt a s s oc i a t i on ( K yne e t a l 1999 ) T he r e f or e t he f i ndi ngs of t hi s r e vi e w a r e c ons i s t e nt w i t h t hos e o f B i gna r di ( 1998) w ho r e po r t e d s ubs t a nt i a l e vi de nc e f or i nc r e a s i ng a ge a s a r i s k f a c t or f o r C D A D A pr obl e m not e d i n c om pa r i ng r e s e a r c h f i ndi ngs r e ga r di ng t hi s va r i a bl e i s t he di s pa r i t y i n a ge s c ons i de r e d r e f l e c t i ve of a dva nc e d a ge W hi l e s om e i nve s t i ga t i ons c o ns i de r e d s ubj e c t s 60 ye a r s a nd ol de r t o be ge r i a t r i c ot he r s us e d 70 or 75 ye a r s a s a c ut poi nt N one of t he publ i s he d s t udi e s i nc l ude d i n f o r m a t i on a bout w hy a pa r t i c ul a r a ge r a nge w a s s e l e c t e d a s a r i s k f a c t or f or da t a c ol l e c t i on a nd a na l ys i s I t i s l i ke l y t ha t a ge i s a l s o a n e f f e c t m odi f i e r f o r de ve l opm e nt of C D A D A s a ge i nc r e a s e s t he l i ke l i hood of e xpos ur e t o t oxi ge ni c s t r a i ns of t he or ga ni s m i nc r e a s e s pr i nc i pa l l y t hr ough i ns t i t ut i ona l i z a t i on i n a hos pi t a l r e ha bi l i t a t i on, or l ong t e r m c a r e s e t t i n g. I ns t i t ut i ona l i z a t i on w i l l not be i nve s t i ga t e d a s a pot e nt i a l r i s k f a c t or f or C D A D i n t he pr e s e nt s t udy be c a us e a l l s ubj e c t s w i l l be i npa t i e nt s w i t hi n a n a c ut e c a r e hos pi t a l S e ve r a l i nve s t i ga t i ons w i t hi n t hi s r e vi e w r e por t e d s i gni f i c a nt di f f e r e nc e s i n C D A D r a t e s f or nu r s i ng hom e ve r s us c om m uni t y dw e l l i ng a dul t s ( A l E i da n : M c E l na y S c ot t & K e a r ne y, 2000; C oope r L e de r m a n, & S a l a t a 1995 ; K e nt R ubi n W r ob l e w s ki H a nf f & S i l e n, 1998 ) A de s c r i pt i ve s t udy de m ons t r a t i ng a r e duc t i on i n C D A D w i t hi n ge r i a t r i c w a r ds of s e ve r a l a c ut e c a r e hos pi t a l s f ol l ow i ng i m pl e m e nt a t i on of a n e nha nc e d i nf e c t i on c ont r ol pr og r a m s ugge s t s t ha t i nf e c t i on e xpos ur e m a y pl a y a l a r ge r r o l e t ha n a ge i n di s e a s e de ve l opm e nt ( S t one B e r i c Q ui c k, B a l e s t r i ni & K i bbl e r 1998) T r e a t m e nt of c hr oni c i l l ne s s e s i s m or e c om m on i n ol d a ge a nd a c ut e e xa c e r ba t i ons a nd c om pl i c a t i ons i nc r e a s e t he l i ke l i hood of m ul t i pl e dr ug e xpos ur e s i nc l udi ng a nt i bi ot i c s A s i gni f i c a nt

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23 di f f e r e nc e ha s be e n de m ons t r a t e d i n t he m e a n a ge of s ubj e c t s e xpos e d t o a nt i bi ot i c s pr i o r t o t he de ve l opm e nt o f C D A D a nd t ho s e w i t h no p r e vi ous a nt i bi ot i c e xpos ur e ( S ve nungs s on, L a ge r gr e n & L undbe r g 2001 ) A g i ng a l s o m a ke s a n i ndi vi dua l m or e l i ke l y t o be e xpos e d t o t ube f e e di ng a s a s ubs t i t ut e or s uppl e m e nt t o o r a l f e e di ng. T hi s t ype of a r t i f i c i a l nu t r i t i on i s a s s oc i a t e d w i t h m a j or c ha nge s i n f e c a l f l or a ( S c hne i de r e t a l 2000) a nd ha s be e n i de nt i f i e d a s a s i gni f i c a nt r i s k f a c t or f or bot h a c qui s i t i on of t he or ga ni s m a nd de ve l opm e nt of C D A D ( B l i s s e t a l 1998; K om a t s u e t a l 2003 ) A c i d Suppr e s s i on T he a dm i ni s t r a t i on o f d r ugs t o s uppr e s s or ne ut r a l i z e ga s t r i c a c i d pr oduc t i on ha s be e n e xpl o r e d a s a bi ol ogi c a l l y pl a us i bl e r i s k f a c t o r f o r t he de ve l opm e nt of C D A D B i gna r di ( 1998) f ound s ubs t a nt i a l e vi de nc e f or us e of a nt i ul c e r m e di c a t i on i nc l udi ng a nt a c i ds a nd H 2 bl oc ke r s ( p. 5 ) A t ot a l of 16 s t ud i e s w e r e i de nt i f i e d w hi c h c ons i de r e d a l t e r a t i on of ga s t r i c a c i d a s a r i s k f a c t or H ow e ve r w i t hi n t hi s r e vi e w a c i d s uppr e s s i ve m e di c a t i ons w e r e e xa m i ne d i n t h r e e s e pa r a t e c a t e gor i e s : a nt a c i ds hi s t a m i ne 2 bl oc ki ng a ge nt s ( H 2) a nd pr ot on pum p i nh i bi t or s ( P P I ) a s e a c h c l a s s of dr ugs ha s a di s t i nc t l y di f f e r e nt phys i ol ogi c m e c ha ni s m of a c t i on A nt a c i d m e di c a t i ons w e r e s t udi e d i n s i x pub l i c a t i o ns T w o w e r e a na l yz e d us i ng uni va r i a t e t e c hni que s onl y, w hi l e f ou r de s c r i be d m ul t i va r i a t e da t a a na l ys i s N on s i gni f i c a nt f i ndi ngs w e r e r e por t e d f or f i ve s t ud i e s ( A z i z A yi s G oul d & R a w l i ns 2001; B a r but e t a l 1997; H or nbuc kl e e t a l 1998; K yne e t a l 1999; W a t a na kuna kor n W a t a na kuna k or n, & H a z y, 1996) O nl y one o f t he s e publ i c a t i ons r e por t e d s t a t i s t i c a l l y s i gni f i c a nt pos i t i ve a s s oc i a t i ons f or a nt a c i d m e di c a t i on us e ( T a c c one l l i e t a l 1998 )

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24 O f t he ni ne s t udi e s m e a s ur i ng e xpos ur e t o H 2 bl oc k i ng a ge nt s t hr e e r e por t e d non s i gni f i c a nt uni va r i a t e t e s t r e s ul t s ( D i a l A l r a s a di M a nouki a n, H ua ng & M e nz i e s 2004; L oo e t a l 2005 ; W a t a na kuna kor n, W a t a na kuna kor n, & H a z y, 1996 ) a nd a not he r r e por t e d non s i gni f i c a nt m ul t i va r i a t e r e s ul t s ( K yne e t a l 1999 ) A hi gh m a gni t ude s t a t i s t i c a l l y s i gni f i c a nt pos i t i ve a s s oc i a t i on w a s i de nt i f i e d i n one uni va r i a t e s t udy ( Y i p L oe b, S a l a m a M os s & O l de 2001 ) a nd a m or e m ode r a t e s i gni f i c a nt m ul t i va r i a t e a s s oc i a t i on w a s r e por t e d by M ut o ( 2005) T he us e of p r ot on pu m p i nhi bi t or ( P P I ) a ge nt s ha s ge ne r a t e d t he m os t c ons i s t e nt a s s oc i a t i on s f or a c i d s uppr e s s i ve e xpos ur e a c r os s s t udi e s T e n publ i c a t i ons i n t hi s r e vi e w a s s e s s e d t he r e l a t i ons hi p be t w e e n P P I d r ugs a nd C D A D T hr e e uni va r i a t e a na l ys e s pr oduc e d s t a t i s t i c a l l y s i gni f i c a nt pos i t i ve a s s oc i a t i ons ( A l T u r e i hi H a s s o un, W ol f K l e i n, & I s e nbe r g, 2005; C unni ngha m D a l e U ndy & G a unt 2003; Y e a r s l e y e t a l 2006 ) but K yne ( 1999) a nd L oo ( 2005) bot h r e por t e d non s i g ni f i c a nc e T w o r e por t s i ndi c a t e d s t a t i s t i c a l l y s i gni f i c a nt m ul t i va r i a t e O R f or P P I e xpos ur e ( D i a l A l r a s a di M a nouki a n, H ua ng, & M e nz i e s 2004; M ut o e t a l 2005) A l l of t he s t udi e s i nve s t i ga t i n g a c i d s uppr e s s i on a s a r i s k f a c t or f or C D A D m e a s ur e d e xpos ur e di c hot om ous l y; t he r e f or e a do s e r e s pons e c oul d not be a s s e s s e d f r om t hi s r e vi e w N o e vi de nc e w a s f ound t o s ugge s t t ha t a nt a c i ds w hi c h ne ut r a l i z e t he pH l e ve l of ga s t r i c s e c r e t i ons a r e a s s oc i a t e d w i t h t he de ve l opm e nt of C D A D H ow e ve r H 2 bl oc ke r s a nd P P I a ge nt s w hi c h e xe r t a n e f f e c t a t t he c e l l ul a r l e ve l a nd r e s ul t i n a de c r e a s e i n a c i d pr oduc t i on ha ve s om e e vi de nc e t o s ugge s t t he i r i nf l ue nc e F ut ur e r e s e a r c h s houl d c ons i de r t he s e a s s e pa r a t e dr ug c a t e gor i e s f or da t a c ol l e c t i on, a nd a n a t t e m pt s houl d be m a de t o de t e r m i ne i f t he r e i s a dos e r e s pons e f or e i t he r t ype o f a ge nt

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25 A nt i bi ot i c A dm i ni s t r at i on T he r i s k f a c t or f or C D A D de ve l opm e nt i nve s t i ga t e d t he m os t e xt e ns i ve l y ove r t he pa s t t hi r t y ye a r s i s a nt i bi ot i c e xpos ur e T he s c i e nt i f i c l i t e r a t u r e i nc l ude s s t udi e s of bot h t he a m ount of a nt i bi ot i c e xpos ur e a s s oc i a t e d w i t h C D A D a nd t he s pe c i f i c a nt i bi ot i c s m os t l i ke l y t o be a s s oc i a t e d w i t h t he di s e a s e A l t h ough one m e t a a na l ys i s r e por t e d a s i g ni f i c a nt a s s oc i a t i on be t w e e n a nt i bi ot i c e xpos ur e a nd C D A D ( B i gna r di 1998) a s ys t e m a t i c r e vi e w of publ i s he d e pi de m i ol ogi c s t ud i e s be t w e e n 1978 a nd 2001 i de nt i f i e d t hr e a t s t o i nt e r na l va l i di t y i n a m a j o r i t y o f t he s t udi e s due t o i nc or r e c t c ont r ol gr oup s e l e c t i on, i na de qua t e s a m pl e s i z e s i na de qua t e c ont r ol of c onf ounde r s a nd m i s c l a s s i f i c a t i on bi a s i n c a s e i de nt i f i c a t i on ( T hom a s S t e ve ns on, & R i l e y 2003 ) T he or i gi na l l i t e r a t u r e s e a r c h i de nt i f i e d 66 publ i c a t i ons i n w hi c h a nt i bi ot i c e xpos ur e w a s c ons i de r e d a s a r i s k f a c t or f or t he de ve l opm e nt of C D A D I n a ddi t i on t o a m e t a a na l ys i s a nd s t r uc t ur e d r e vi e w t he r e w e r e 64 or i gi na l r e s e a r c h publ i c a t i ons i de nt i f i e d. O f t he s e s t udi e s s e ve n w e r e de s c r i pt i ve a nd pr ovi de d no i nf o r m a t i on a bout t he di s e a s e f r e que nc y, t he r o l e of c ha nc e or t he s t r e ngt h of t he a s s oc i a t i on ( B ul s t r ode e t a l 1997 ; C r a bt r e e P e l l i t i e r G l e a s on, P r ue t t & S a w ye r 1999; G or e c ki S c he i n, R uc i ns ki & W i s e 1999; I m pa l l om e ni G a l l e t l y W or t S t a f f & R oge r s 1995; K ha n & C he e s br ough, 2003; S he k, S t a c e y, R e nde l l H e l l i e r & H a ns on, 2000; S t one B e r i c Q ui c k, B a l e s t r i ni & K i bbl e r 1998 ) A m a j or di f f i c ul t y i n a s s e s s i ng t he s t r e ngt h of e vi d e nc e r e ga r di ng a nt i bi ot i c e xpos ur e a s a C D A D r i s k f a c t or i s t he m ul t i pl e w a ys i n w hi c h e xpos ur e ha s be e n ope r a t i ona l i z e d a nd m e a s ur e d. M or e t ha n 25 % of t he s t udi e s m e a s ur e d a nt i bi ot i c e xpos ur e vi a m or e t ha n one m e t hod T he m os t f r e que nt l y de s c r i be d m e a s ur e r e por t e d i n

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26 41 pa pe r s a nd w a s a s i m pl e bi na r y a s s e s s m e nt of e xpos ur e t o a s pe c i f i c a nt i bi ot i c dr ug c l a s s i f i c a t i on. T w e nt y t w o pa pe r s m e a s ur e d a ny a nt i bi ot i c e xpos ur e w hi l e 12 m e a s ur e d t he num be r o f di f f e r e nt d r ug a ge nt s us e d. T h r e e s t udi e s e xa m i ne d s pe c i f i c a nt i bi ot i c r e gi m e ns a nd t w o c l a s s i f i e d a nt i bi ot i c us e a s a ppr opr i a t e or i na ppr op r i a t e S ur pr i s i ngl y, onl y f our of t he publ i c a t i ons a t t e m pt e d t o qua nt i f y a nt i bi ot i c e xpos ur e by m e a s ur i ng t he num be r o f dos e s a nd onl y one d i d s o t hr ough t he us e of a s t a nda r di z e d dos e m e a s ur e A uni t of m e a s ur e t he de f i ne d da i l y dos e ( D D D ) r e pr e s e nt s t he a ve r a ge da i l y a dul t dos e f o r a d r ug w he n us e d f or i t s pr i m a r y i ndi c a t i on ( P e l l e G i l c hr i s t L a w s on, J a c kl i n, & F r a nkl i n, 2006) T hi s m e a s ur e h a s be e n a dvoc a t e d f or dr ug e xpos ur e r e s e a r c h by t he W or l d H e a l t h O r ga ni z a t i on t o f a c i l i t a t e c om pa r i s ons of dr ug us a ge de s pi t e i nt e r na t i ona l va r i a t i ons i n c l i ni c a l p r a c t i c e pa t t e r ns O nl y one o f t he s t udi e s i nc l ude d i n t hi s r e vi e w us e d t he D D D uni t f o r m e a s ur i ng a nt i b i ot i c e xpos ur e a l t hough t he s ys t e m ha s be e n i n e f f e c t f or ove r 20 ye a r s ( A l e i da n) I n c ons i de r i ng a l l a nt i bi ot i c e xpos ur e a s a w hol e s t udy r e s ul t s pr e s e nt c onf l i c t i ng e vi de nc e B i gna r di ( 1998) r e por t e d a pool e d O R of 5. 9 f o r a bi na r y m e a s ur e of a nt i bi ot i c e xpos ur e O ne m ul t i va r i a t e s t udy publ i s he d a f t e r 1998 ( C unni ngha m D a l e U ndy, & G a unt 2003 ) a nd f i ve uni va r i a t e s t udi e s r e por t e d s t a t i s t i c a l l y s i gni f i c a nt pos i t i ve a s s oc i a t i ons f or a nt i bi ot i c e xpos ur e ( B l ot e t a l 2003; L oo e t a l 2005; S t a r r M a r t i n, M c C oubr e y, G i bs on, & P oxt on, 2003; S ve nungs s on, L a ge r gr e n, & L undbe r g, 2001; Y e a r s l e y e t a l 2006 ) T hi s pr ovi de s s t r ong e vi de nc e f or a nt i bi ot i c e xpos ur e a s a c ons i s t e nt a nd i nde pe nde nt r i s k f a c t or f or C D A D a c qui s i t i on. I n c ont r a s t f our s t udi e s p ubl i s he d a f t e r t he B i gna r di pa pe r r e po r t e d non s i gni f i c a nt m ul t i va r i a t e O R f or t hi s s a m e va r i a bl e ( C ha ng & N e l s on, 2000; H a r ba r t h,

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27 S a m or e & C a r m e l i 2001; L oo e t a l 2005; M c C us ke r H a r r i s P e r e nc e vi c h, & R oghm a nn, 2003) T w o c a s e c ont r ol ( K om a t s u e t a l 2003 ; V e s t a W e l l s G e nt r y, & S t i pe k, 2005 ) a nd t w o pr os pe c t i ve c ohor t s t udi e s ( C l e a r y e t a l 1998; K yne S ougi oul t z i s M c F a r l a nd, & K e l l y 2002 ) di d not e nt e r a nt i bi ot i c e xpos ur e i nt o m ul t i va r i a t e a na l ys i s ba s e d upon ove r l y s t r i nge nt b i va r i a t e t e s t r e s ul t s B a r but e t a l ( 2005) di d not i nc l ude a nt i bi ot i c e xpos ur e i n t he m ul t i va r i a t e a na l ys i s due t o bot h l ow m a gni t ude a nd non s i gni f i c a nc e on uni va r i a t e t e s t i ng. I n a s a m pl e of onc ol ogy pa t i e nt s a nt i bi ot i c e xpos ur e w a s a s s oc i a t e d w i t h C D A D on l y i n pa t i e nt s a l s o r e c e i vi ng c he m ot he r a py ( B l ot e t a l 2003) B ot h t r e a t m e nt w i t h a ny a nt i bi ot i c a nd t r e a t m e nt w i t h s pe c i f i c c l a s s e s of a nt i bi ot i c s w e r e e nt e r e d i nt o l og i s t i c r e gr e s s i on m ode l s i n a pr os pe c t i ve c ohor t s t udy, a nd bot h f a i l e d t o de m on s t r a t e s t a t i s t i c a l s i gni f i c a nc e ( B l i s s e t a l 1998 ) T hi s di s c r e pa nc y i n f i ndi ngs i ndi c a t e s t he ne e d f or a m or e a c c ur a t e a nd qua nt i t a t i ve m e a ns of m e a s ur i ng a nt i b i ot i c e xpos ur e i n f ut u r e r e s e a r c h. A num be r o f s t udi e s di d a t t e m pt t o ope r a t i ona l i z e t he bur de n of a nt i bi ot i c e xpos ur e t hr ou gh m e a s ur e m e nt of t he num be r of d i f f e r e nt a nt i b i ot i c a ge nt s t o w hi c h s ubj e c t s w e r e e xpos e d. T hr e e s t udi e s r e po r t e d s t a t i s t i c a l l y s i gni f i c a nt di f f e r e nc e s be t w e e n c a s e s a nd c om pa r i s on s ubj e c t s i n t he m e a n num be r o f a nt i bi ot i c a ge nt s us e d, but t he s e s t udi e s di d not r e por t m e a s ur e s of a s s oc i a t i on or p r ovi de s uf f i c i e nt i nf o r m a t i on w i t hi n t he publ i c a t i on t o c a l c ul a t e t he s e m e a s ur e s ( C l i m o e t a l 1998; K yne S ougi oul t z i s M c F a r l a nd, & K e l l y 2002; L oo e t a l 2005) P ul vi r e nt i e t a l ( 2002A ) r e por t e d a s t a t i s t i c a l l y s i gni f i c a nt pos i t i ve m ul t i va r i a t e O R f or t he num be r of a nt i bi ot i c s D i a l e t a l ( 2004 ) a l s o r e por t e d a s t a t i s t i c a l l y s i gni f i c a nt pos i t i ve m ul t i va r i a t e O R s f or t he num be r of a nt i bi ot i c s i n a c ohor t s t udy, but a c a s e c ont r ol s t udy r e por t e d i n

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28 t he s a m e pa pe r di d not ha ve s t a t i s t i c a l l y s i gni f i c a nt f i ndi ngs S t a t i s t i c a l l y s i gni f i c a nt pos i t i ve uni va r i a t e a s s oc i a t i ons w e r e r e por t e d by f i ve ot he r s t udi e s ( A ndr e w s R a boud, K a s s e n, & E nns 2003; H a r ba r t h S a m o r e & C a r m e l i 2001; L a i M e l vi n, M e na r d, K ot i l a i ne n, & B a ke r 1997; L V M c F a r l a nd, 1995 ; J J P u l vi r e nt i e t a l 2002 ) A s s e s s m e nt of a nt i bi ot i c bur de n m e a s ur e d ba s e d on a s i m pl e c ount o f t he num be r of dos e s ha s not yi e l de d c l i ni c a l l y i m por t a nt i nf o r m a t i on. N o s i gni f i c a nt di f f e r e nc e w a s f ound i n t he m e a n num be r of a nt i bi ot i c dos e s r e c e i ve d be t w e e n c a s e s a nd c om pa r i s on s ubj e c t s i n one i nve s t i ga t i on ( M a c G ow a n e t a l 19 9 7) a nd K yne e t a l ( 1999) r e por t e d a pos i t i ve but not s t a t i s t i c a l l y s i gni f i c a nt m ul t i va r i a t e O R f or t he num be r of a nt i bi ot i c dos e s I t w oul d a ppe a r t ha t a c ount o f dos e s a dm i n i s t e r e d i s not us e f ul i n qua nt i f yi ng a nt i bi ot i c bur de n. A l E i da n e t a l ( 2 000 ) a t t e m pt e d t o qua nt i f y dos e s us i ng t he D e f i ne d D a i l y D os e s ys t e m H ow e ve r t he num be r of dos e s us e d f or e a c h dr ug w e r e c a l c ul a t e d ba s e d upon P ha r m a c y pur c ha s i ng da t a a nd w e r e n ot obt a i ne d f r om i nd i vi dua l pa t i e nt r e c or ds T he r e f o r e t he a c t ua l de g r e e of a nt i bi ot i c e xpos ur e f or i ndi vi dua l s ubj e c t s w a s not a c c ur a t e l y m e a s ur e d. W i t hi n t hi s r e vi e w r e s e a r c he r s i de nt i f i e d a num be r of a nt i m i c r obi a l dr ug c a t e gor i e s a s e xpos ur e s a s s oc i a t e d w i t h C D A D T h e s e f i ndi ngs a r e s um m a r i z e d i n T a bl e 3. A nt i bi ot i c a ge nt s a r e gr oupe d by t he i r pha r m a c ol ogi c dr ug c a t e gor y i n c ol um n 1. S t udi e s r e por t i ng non s i gni f i c a nt a s s oc i a t i ons a r e l i s t e d i n c ol um n 2 t hos e r e por t i ng s t a t i s t i c a l l y s i gni f i c a nt uni va r i a t e a s s oc i a t i ons a r e l i s t e d i n c ol um n 3 a nd s t udi e s r e por t i ng s t a t i s t i c a l l y s i gni f i c a nt m ul t i va r i a t e a s s oc i a t i ons a r e l i s t e d i n c ol u m n 4

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29 T a bl e 3 R e por t e d Si gni f i c anc e of T e s t R e s ul t s f or A nt i bi o t i c E x pos ur e by D r ug C at e gor y S i g n i f i c a n c e o f t h e A s s o c i a t i o n w i t h C D A D D r u g C a t e g o r y N o n s i g n i f i c a n t + U n i v a r i a t e + M u l t i v a r i a t e A m i n i o g l y c o s i d e s J o h n s o n e t a l 1 9 9 9 ; K o m a t s u e t a l 2 0 0 3 M u t o e t a l 2 0 0 5 P a l m o r e S o h n M a l a k E a g a n & S e p k o w i t z 2 0 0 5 S h a h L e w i s L e o p o l d D u n s t a n & W o o d h o u s e V e s t a W e l l s G e n t r y & S t i p e k 2 0 0 5 W a t a n a k u n a k o r n W a t a n a k u n a k o r n & H a z y 1 9 9 6 Y i p L o e b S a l a m a M o s s & O l d e 2 0 0 1 B a r b u t e t a l 1 9 9 7 B l i s s e t a l 1 9 9 8 C h a n g e l a e t a l 2 0 0 4 C o o p e r L e d e r m a n & S a l a t a 1 9 9 5 H a l i m P e t e r s o n F r i e s e n & O t t 1 9 9 7 H a r b a r t h S a m o r e & C a r m e l i 2 0 0 1 K y n e 2 0 0 2 S c h w a b e r e t a l 2 0 0 0 T a l o n e t a l 1 9 9 5 L o o e t a l 2 0 0 5 P e n e c i l l i n s A z i z G o u l d & R a w l i n s 2 0 0 1 H a r b a r t h S a m o r e & C a r m e l i 2 0 0 1 J o h n s o n K o m a t s u e t a l 2 0 0 3 K y n e e t a l 1 9 9 8 K y n e e t a l 1 9 9 9 L o o e t a l 2 0 0 5 M c C u s k e r H a r r i s P e r e n c e v i c h & R o g h m a n n 2 0 0 3 M o d y S m i t h & d e v e r 2 0 0 1 P a l m o r e S o h n M a l a k E a g a n & S e p k o w i t z 2 0 0 5 S h a h L e w i s L e o p o l d D u n s t a n & W o o d h o u s e V e s t a W e l l s G e n t r y & S t i p e k 2 0 0 5 W a t a n a k u n a k o r n W a t a n a k u n a k o r n & H a z y 1 9 9 6 Y i p L o e b S a l a m a M o s s & O l d e 2 0 0 1 A l E i d a n M c E l n a y S c o t t & K e a r n e y 2 0 0 0 e t a l 2 0 0 0 C h a n g e l a C o o p e r L e d e r m a n & S a l a t a 1 9 9 5 D i a l A l r a s a d i M a n o u k i a n H u a n g & M e n z i e s 2 0 0 4 R a o R a o & S t a r k e 2 0 0 3 S c h w a b e r e t a l 2 0 0 0 S t a r r M a r t i n M c C o u b r e y G i b s o n & P o x t o n 2 0 0 3 T a l o n e t a l 1 9 9 5 B a r b u t e t a l 1 9 9 7 T a l o n e t a l 1 9 9 5 C e p h a l o s p o r i n s D i a l A l r a s a d i M a n o u k i a n H u a n g & M e n z i e s 2 0 0 4 J o h n s o n e t a l 1 9 9 9 K o m a t s u e t a l 2 0 0 3 K y n e e t a l 1 9 9 A l E i d a n M c E l n a y S c o t t & K e a r n e y 2 0 0 0 ; A r r a n g o e t a l 2 0 0 6 B a r b u t e t a l 1 9 9 7 C h a n g e l a e t a l 2 0 0 4 C o o p e r L e d e r m a n & A z i z G o u l d & R a w l i n s 2 0 0 1 B l i s s e t a l 1 9 9 8 L o o e t a l 2 0 0 5 Y i p L o e b S a l a m a M o s s & O l d e 2 0 0 1

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30 T a bl e 3 ( C ont i nue d) S i g n i f i c a n c e o f t h e A s s o c i a t i o n w i t h C D A D D r u g C a t e g o r y N o n s i g n i f i c a n t + U n i v a r i a t e + M u l t i v a r i a t e C e p h a l o s p o r i n s c o n t i n u e d M c C u s k e r H a r r i s P e r e n c e v i c h & R o g h m a n n 2 0 0 3 M o d y S m i t h & d e v e r 2 0 0 1 ( 1 s t g e n e r a t i o n ) M u t o e t a l 2 0 0 5 ( 1 s t a n d 2 n d g e n e r a t i o n ) P a l m o r e S o h n M a l a k E a g a n & S e p k o w i t z 2 0 0 5 V e s t a W e l l s G e n t r y & S t i p e k 2 0 0 5 S a l a t a 1 9 9 5 H a l i m P e t e r s o n F r i e s e n & O t t 1 9 9 7 H a r b a r t h S a m o r e & C a r m e l i 2 0 0 1 K y n e e t a l 1 9 9 8 M o d y S m i t h & d e v e r 2 0 0 1 ( 3 rd g e n e r a t i o n ) M u t o e t a l 2 0 0 5 ( 3 rd a n d 4 t h g e n e r a t i o n ) R a o R a o & S t a r k e 2 0 0 3 S c h w a b e r e t a l 2 0 0 0 S e t t l e W i l c o x F a w l e y C o r r a d o & H a w k e y 1 9 9 8 S h a h L e w i s L e o p o l d D u n s t a n & W o o d h o u s e S t a r r M a r t i n M c C o u b r e y G i b s o n & P o x t o n 2 0 0 3 T a l o n e t a l 1 9 9 5 T u m b a r e l l o T a c c o n e l l i L e o n e C a u d a & O r t o n a 1 9 9 5 W a t a n a k u n a k o r n W a t a n a k u n a k o r n & H a z y 1 9 9 6 Q u i n o l o n e s D i a l A l r a s a d i M a n o u k i a n H u a n g & M e n z i e s 2 0 0 4 ( c a s e c o n t r o l ) K o m a t s u e t a l 2 0 0 3 K y n e e t a l 1 9 9 8 K y n e S o u g i o u l t z i s M c F a r l a n d & K e l l y 2 0 0 2 M o d y S m i t h & d e v e r 2 0 0 1 M u t o e t a l 2 0 0 5 ( c i p r o f l o x a c i n ) P a l m o r e S o h n M a l a k E a g a n & S e p k o w i t z 2 0 0 5 R a o R a o & S t a r k e 2 0 0 3 S h a h L e w i s L e o p o l d D u n s t a n & W o o d h o u s e T a l o n e t a l 1 9 9 5 W a t a n a k u n a k o r n W a t a n a k u n a k o r n & H a z y 1 9 9 6 B a r b u t e t a l 1 9 9 7 B i l g r a m i e t a l 1 9 9 9 C h a n g e l a D i a l A l r a s a d i M a n o u k i a n H u a n g & M e n z i e s 2 0 0 4 ( c o h o r t ) H a r b a r t h S a m o r e & C a r m e l i 2 0 0 1 M u t o e t a l 2 0 0 5 ( l e v o f l o x a c i n ) P u l v i r e n t i 2 0 0 2 A S c h w a b e r e t a l 2 0 0 0 L o o e t a l 2 0 0 5 M c C u s k e r H a r r i s P e r e n c e v i c h & R o g h m a n n 2 0 0 3 Y i p L o e b S a l a m a M o s s & O l d e 2 0 0 1

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31 T a bl e 3 ( C ont i nue d) S i g n i f i c a n c e o f t h e A s s o c i a t i o n w i t h C D A D D r u g C a t e g o r y N o n s i g n i f i c a n t + U n i v a r i a t e + M u l t i v a r i a t e M a c r o l i d e s H a r b a r t h S a m o r e & C a r m e l i 2 0 0 1 K o m a t s u e t a l 2 0 0 3 K y n e 1 9 9 8 L o o e t a l 2 0 0 5 M o d y S m i t h & d e v e r 2 0 0 1 P a l m o r e S o h n M a l a k E a g a n & S e p k o w i t z 2 0 0 5 S h a h L e w i s L e o p o l d D u n s t a n & W o o d h o u s e W a t a n a k u n a k o r n W a t a n a k u n a k o r n & H a z y 1 9 9 6 C h a n g e l a e t a l 2 0 0 4 M u t o e t a l 2 0 0 5 P u l v i r e n t i e t a l 2 0 0 2 A S c h w a b e r e t a l 2 0 0 0 C l i n d a m y c i n D i a l A l r a s a d i M a n o u k i a n H u a n g & M e n z i e s 2 0 0 4 ( c a s e c o n t r o l s t u d y ) K o m a t s u e t a l 2 0 0 3 K y n e e t a l 1 9 9 8 K y n e S o u g i o u l t z i s M c F a r l a n d & K e l l y 2 0 0 2 M c C u s k e r H a r r i s P e r e n c e v i c h & R o g h m a n n 2 0 0 3 W a t a n a k u n a k o r n W a t a n a k u n a k o r n & H a z y 1 9 9 6 Y i p L o e b S a l a m a M o s s & O l d e 2 0 0 1 C h a n g e l a H a r b a r t h S a m o r e & C a r m e l i 2 0 0 1 J o h n s o n M o d y S m i t h & d e v e r 2 0 0 1 M u t o e t a l 2 0 0 5 R a o R a o & S t a r k e 2 0 0 3 S c h w a b e r e t a l 2 0 0 0 T h a m l i k t k u l D a n p a k d i & C h o k l o i k a e w 1 9 9 6 T u m b a r e l l o T a c c o n e l l i L e o n e C a u d a & O r t o n a 1 9 9 5 B a r b u t 1 9 9 7 C h a n g & N e l s o n 2 0 0 0 L o o e t a l 2 0 0 5 P a l m o r e S o h n M a l a k E a g a n & S e p k o w i t z 2 0 0 5 S u l f o n a m i d e s A z i z G o u l d & R a w l i n s 2 0 0 1 H a r b a r t h S a m o r e & C a r m e l i 2 0 0 1 K y n e 2 0 0 2 S h a h L e w i s L e o p o l d D u n s t a n & W o o d h o u s e Y i p L o e b S a l a m a M o s s & O l d e 2 0 0 1 B a r b u t e t a l 1 9 9 7 D i a l A l r a s a d i M a n o u k i a n H u a n g & M e n z i e s 2 0 0 4 M u t o e t a l 2 0 0 5 S c h w a b e r e t a l 2 0 0 0 T u m b a r e l l o T a c c o n e l l i L e o n e C a u d a & O r t o n a 1 9 9 5 T e t r a c y c l i n e s C h a n g e l a e t a l 2 0 0 4 K y n e S o u g i o u l t z i s M c F a r l a n d & K e l l y 2 0 0 2 M u t o e t a l 2 0 0 5 C a r b a p e n e m s K o m a t s u e t a l 2 0 0 3 L o o e t a l 2 0 0 5 M u t o e t a l 2 0 0 5 C h a n g e l a e t a l 2 0 0 4 H a r b a r t h S a m o r e & C a r m e l i 2 0 0 1

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32 T a bl e 3 ( C ont i nue d) S i g n i f i c a n c e o f t h e A s s o c i a t i o n w i t h C D A D D r u g C a t e g o r y N o n s i g n i f i c a n t + U n i v a r i a t e + M u l t i v a r i a t e G l y c o p e p t i d e s J o h n s o n e t a l 1 9 9 9 K o m a t s u e t a l 2 0 0 3 L o o e t a l 2 0 0 5 M o d y S m i t h & d e v e r 2 0 0 1 M u t o e t a l 2 0 0 5 P a l m o r e S o h n M a l a k E a g a n & S e p k o w i t z 2 0 0 5 S h a h L e w i s L e o p o l d D u n s t a n & W o o d h o u s e W a t a n a k u n a k o r n W a t a n a k u n a k o r n & H a z y 1 9 9 6 A r r a n g o e t a l 2 0 0 6 B a r b u t e t a l 1 9 9 7 C h a n g e l a e t a l 2 0 0 4 D i a l A l r a s a d i M a n o u k i a n H u a n g & M e n z i e s 2 0 0 4 S c h w a b e r e t a l 2 0 0 0 M e t r o n i d a z o l e K y n e S o u g i o u l t z i s M c F a r l a n d & K e l l y 2 0 0 2 M o d y S m i t h & d e v e r 2 0 0 1 P a l m o r e S o h n M a l a k E a g a n & S e p k o w i t z 2 0 0 5 W a t a n a k u n a k o r n W a t a n a k u n a k o r n & H a z y 1 9 9 6 W r e n A h m e d J a m a l & S a f a d i 2 0 0 5 B a r b u t e t a l 1 9 9 7 C h a k r a b a r t i L e e s J o n e s & M i l l i g a n 2 0 0 0 D i a l A l r a s a d i M a n o u k i a n H u a n g & M e n z i e s 2 0 0 4 P u l v i r e n t i e t a l 2 0 0 2 A P u l v i r e n t i e t a l 2 0 0 2 B S c h w a b e r e t a l 2 0 0 0 S t a t i s t i c a l l y s i g n i f i c a n t p o s i t i v e O R w i t h m a g n i t u d e > 1 0 W i t hi n t he pe ni c i l l i n c l a s s r e s ul t s w e r e ve r y va r i e d. T w o s t udi e s de m ons t r a t e d i nde pe nde nc e f or pe ni c i l l i n e xpos ur e a nd s e ve n de m ons t r a t e d c ons i s t e nc y. T he ove r a l l num be r of s t udi e s w i t h non s i gni f i c a nt f i ndi ngs h ow e ve r out num be r s t hos e w i t h s i g ni f i c a nt f i ndi ngs T he pe ni c i l l i n c l a s s of dr ugs i s one i n w hi c h s uc c e s s i ve ge ne r a t i ons ha ve be e n de ve l ope d i n a n a t t e m pt t o a voi d dr ug r e s i s t a nc e F or t h i s r e a s on, a s i m pl e gr oupi ng of a l l pe ni c i l l i n s m a y not be a de qua t e f o r e pi de m i ol ogi c a l pu r pos e s F ut u r e r e s e a r c h r e ga r di ng dr ug c l a s s e s a nd e xpos ur e s hou l d di s t i ngui s h t he s e gr oupi ngs i n a ddi t i on t o de t e r m i ni ng i f t he r e i s a dos e r e s pons e t o s ub gr oup pe ni c i l l i n.

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33 C e pha l os por i n a nt i bi ot i c s w e r e i nve s t i ga t e d i n t he l a r ge s t num be r of s t udi e s F our r e por t e d i nde pe nde nt a s s oc i a t i ons a f t e r m ul t i va r i a t e a na l ys i s a nd 17 r e po r t e d s i gni f i c a nt uni va r i a t e f i ndi ngs c ons i de r a bl y m or e t ha n t he n i n e t ha t r e por t e d non s i gni f i c a nt f i ndi ngs T he r e i s s t r ong e vi de nc e t o s uppor t c e ph a l os por i n dr ug e xpos ur e a s a r i s k f a c t or f o r C D A D W i t hi n t he qui nol one c l a s s of a nt i bi ot i c s t he r e w e r e t hr e e s t udi e s r e por t i ng i nde pe nde nt a s s oc i a t i on w i t h qui nol one e xpos ur e a f t e r m ul t i va r i a t e a na l ys i s t o c ont r o l f o r c onf ounde r s T he r e w e r e a l s o s e ve n uni va r i a t e s t u di e s w i t h s t a t i s t i c a l l y s i gni f i c a nt r e s ul t s H ow e ve r t he a ut hor a l s o r e vi e w e d 12 s t udi e s t ha t r e por t e d ne ga t i ve f i ndi ngs f or qui nol one a s a r i s k f a c t or F ut ur e r e s e a r c h ne e ds t o e xa m i ne t hi s e xpos ur e m or e f ul l y T he qui nol one s r e pr e s e nt a c l i ni c a l l y i m po r t a nt c a t e gor y of a nt i bi ot i c a nd t he i r us e a s a r i s k f a c t or ha s be e n i nve s t i ga t e d i n s e ve r a l hos pi t a l out br e a ks M a c r ol i de a nt i bi ot i c s di d not ha ve s uf f i c i e nt e vi de nc e i n t hi s r e vi e w t o c ons i de r t he m a s ubs t a nt i a l r i s k f a c t or i n t he de ve l opm e nt o f C D A D T he r e w e r e no s t udi e s t ha t m e t t he c r i t e r i on of i nde pe nde nc e a nd on l y f ou r t h a t m e t t he c r i t e r i on of c ons i s t e nc y. T he r e w e r e s e ve n s t udi e s t ha t r e por t e d non s i gni f i c a nt r e s ul t s f or t hi s r i s k f a c t or N ot s ur pr i s i ngl y, e vi de nc e c ont i nue s t o s uppor t c l i nda m yc i n a s a r i s k f a c t or f o r C D A D A l t hough t he r e w e r e s e ve n s t udi e s r e por t i ng non s i gni f i c a nt r e s ul t s f or c l i nda m yc i n e xpos ur e w i t hi n t hi s body of l i t e r a t u r e t he s e s t udi e s w e r e ove r s ha dow e d by t hos e w i t h s i gni f i c a nt f i nd i ngs F our s t udi e s r e por t e d s i gni f i c a nt m ul t i va r i a t e r e s ul t s a nd ni ne r e por t e d s i gni f i c a nt uni va r i a t e r e s ul t s f or c l i n da m yc i n e xpos ur e T he c a t e gor y o f c a r ba pe ne m s ha d no r e por t s w i t h m ul t i va r i a t e s uppor t a nd a n e ve n num be r of r e por t s w i t h s i gni f i c a nt a nd non s i gni f i c a nt f i ndi ngs T he r e i s not

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34 s uf f i c i e nt e v i de nc e a t t hi s t i m e t o c ons i de r t he c a r b a pe ne m s a s e r i ous r i s k f a c t or f or t he de ve l opm e nt of C D A D L e s s t ha n ha l f of t he s t udi e s t ha t i nve s t i ga t e d gl yc ope pt i de a nt i bi ot i c us e a s a r i s k f a c t or r e por t e d s t a t i s t i c a l l y s i gni f i c a nt uni va r i a t e m e a s ur e s of a s s o c i a t i on, a nd t he r e w e r e no s t udi e s w i t h s i gni f i c a nt m ul t i va r i a t e f i ndi ngs T hi s i s not s ur p r i s i ng, s i nc e va nc om yc i n, a m a j or gl yc ope pt i de us e d t o t r e a t r e c ur r e nt or r e s i s t a nt C D A D i s i n t hi s c a t e gor y of d r ug. H ow e ve r t he a s s e s s m e nt of e vi de nc e r e ga r di ng m e t r oni da z ol e w a s une xpe c t e d. M e t r oni da z ol e i s c ons i de r e d by m a ny c l i ni c i a ns t o be t he f i r s t l i ne d r ug us e d t o t r e a t C D A D c a s e s t ha t f a i l t o r e s pond t o w i t hd r a w a l of a nt i bi ot i c t he r a py. S t udi e s w i t h s i gni f i c a nt a nd non s i gni f i c a nt m e a s ur e s of a s s oc i a t i o n f or m e t r oni da z ol e us e w e r e a l m os t e qua l l y di vi de d. T he m os t di f f i c ul t a s pe c t of e va l ua t i ng t he a s s oc i a t i on of C D A D w i t h a nt i bi ot i c e xpos ur e i s t he di f f i c ul t y i n e s t a bl i s hi ng a dos e r e s pons e I nc ons i s t e nt m e t hods of m e a s ur i ng a nt i bi ot i c e xpos ur e c om pl i c a t e c om pa r i s ons be t w e e n s t udi e s M e di a n num be r of dos e s gi ve n t o a s pe c i f i c s ubj e c t da i l y a ve r a ge a nt i bi ot i c dos e s di s pe ns e d by a n i ns t i t ut i ona l pha r m a c y, a nd s i m pl e f r e que nc y c oun t s of t he nu m be r o f s ubj e c t s r e c e i vi ng a pa r t i c ul a r a nt i bi o t i c a ge nt ha ve a l l be e n us e d t o m e a s ur e a nt i bi ot i c e xpos ur e A l t hough bi ol ogi c m a r ke r s s uc h a s s e r um dr ug l e ve l s a r e n ot a va i l a bl e f or a l l a nt i m i c r obi a l d r ugs e ve n w he n s uc h t e s t i ng i s a va i l a bl e i t i s not i nc l ud e d i n publ i s he d de s c r i pt i ons of a nt i bi ot i c e xpos ur e a nd i s not pos s i bl e i n a ny t ype of r e t r os pe c t i ve s t udy.

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35 D i e t T ube f e e di ng ha s be e n i nve s t i ga t e d a s a r i s k f a c t or f or t he de ve l opm e nt of C D A D a s ha s m a l nut r i t i on a nd hypoa l bum i ne m i a W i t hi n t hi s r e vi e w 12 s t udi e s w e r e l oc a t e d t ha t e xa m i ne d t ube f e e di ng a nd s i x c ons i de r i ng nu t r i t i ona l de f i c i t s a s a r i s k f a c t o r T ube F e e di ng. T w e l ve a na l yt i c a l e pi de m i ol ogy s t udi e s w e r e l oc a t e d t ha t c ons i de r e d t ube f e e di ng vi a e i t he r na s oga s t r i c or p e r c ut a ne ous a bdom i na l r out e s a s a pot e nt i a l r i s k f a c t o r f o r t he a c qui s i t i on of C D A D A l e t t e r t o t he e di t o r de s c r i bi ng da t a s uppor t i ng e l e m e nt a l di e t s a s a r i s k f a c t or f or C D A D w a s e xc l ude d due t o l a c k o f de t a i l s ( I i z uka e t a l 2004) O f t he t w o s t udi e s w hi c h a na l yz e d da t a us i ng onl y uni va r i a t e a na l ys i s one r e por t e d da t a s uf f i c i e nt t o c a l c ul a t e a n O R of 2. 3 8 ( p< 0. 05 ) ( H a l i m P e t e r s on, F r i e s e n, & O t t 1997) a nd t he ot he r r e po r t e d a non s i gni f i c a nt pos i t i ve a s s oc i a t i on ( W a t a na kuna kor n, W a t a na kuna kor n, & H a z y, 199 6) T he r e f or e s a t i s f a c t i on of t he c ons i s t e nc y c r i t e r i on w a s unc l e a r T e n s t udi e s us e d m ul t i va r i a t e da t a a na l ys i s m e t hod s O f t he s e s t udi e s t hr e e e va l ua t e d e nt e r a l f e e di ng a s a va r i a bl e a nd de t e r m i ne d t ha t i t w a s s uf f i c i e nt l y r e l a t e d t o ot he r va r i a bl e s t o e l i m i na t e f o r c ons i de r a t i on a s a n i nde pe nde nt r i s k f a c t or ( K yne S ougi oul t z i s M c F a r l a nd, & K e l l y 2002; L oo e t a l 2005; S ha h, L e w i s L e opol d, D uns t a n, & W oodhous e 2000 ) T w o s t udi e s r e por t e d non s i gni f i c a nt O R ( K e nt R ubi n W r obl e w s ki H a nf f & S i l e n, 1998; Y i p, L oe b, S a l a m a M os s & O l de 2001) a l t hough t he s pe c i f i c va l ue s w e r e not publ i s he d. F our s t udi e s f ound e nt e r a l f e e di n g t o be a n i nde pe nde nt r i s k f a c t or f or C D A D ( D B l i s s G ue nt e r & S e t t e l 1992; B uc hne r & S onne nbe r g, 2001; K o m a t s u e t a l 2003; T a l on e t a l 1995 ) a nd a f i f t h f ound e nt e r a l

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36 f e e di ng by na s oga s t r i c t ube but not vi a pe r c ut a ne o us l y i ns e r t e d ga s t r os t om y t ube ( K yne e t a l 1999) t o be i nde pe nde nt l y a s s oc i a t e d w i t h t h e di s e a s e L a i r e por t e d a s t a t i s t i c a l l y s i gni f i c a nt ne ga t i ve a s s oc i a t i on be t w e e n t he pr e s e nc e of a na s oga s t r i c t ube a nd C D A D E nt e r a l f e e di ng a ppe a r s t o be a s ubs t a nt i a l r i s k f a c t or f o r C D A D H ow e ve r s i nc e t hi s m ode of f e e di ng c a nnot e xi s t w i t hout t he p r e s e nc e of t he a dm i ni s t r a t i on t ube t he pos s i bi l i t y t ha t e nt e r a l f e e di ng i s a c onf ounde r r a t he r t ha n a r i s k f a c t or s houl d be c ons i de r e d. B i gna r di ( 1998) i de nt i f i e d na s oga s t r i c t ube s a s a s ubs t a nt i a l r i s k f a c t or but di d not a ddr e s s e nt e r a l f e e di ng. A n a l t e r na t i ve e xp l a na t i on f or t he a ppa r e nt a s s oc i a t i on be t w e e n e nt e r a l f e e di ng a nd C D A D ha s be e n p r op os e d a s f e e di ng t ube s a r e f r e que nt l y gi ve n t o i m m une c om pr om i s e d pa t i e nt s w i t h di e t a r y de f i c i e nc i e s a nd m ul t i pl e o t he r c om or bi d c ondi t i ons w ho ha ve s pe nt a ppr e c i a bl e a m ount of t i m e i n t he hos pi t a l M os t i m por t a nt l y, a l l pe r c ut a ne ous t ube s a r e i ns e r t e d un de r a nt i bi ot i c pr ophyl a xi s ( S onne nbe r g, 2005 ) M al nut r i t i on. O f t he s t udi e s t ha t e xa m i ne d nu t r i t i ona l de f i c i t s i n a s s oc i a t i on w i t h C D A D f our us e d uni va r i a t e a na l ys i s m e t hods onl y O f t he s e s t udi e s t h r e e r e por t e d s t a t i s t i c a l l y s i gni f i c a nt pos i t i ve a s s oc i a t i ons be t w e e n C D A D a nd m a l nut r i t i on ( A l T ur e i hi H a s s oun, W ol f K l e i n & I s e nbe r g, 2005; A ndr e w s R a boud, K a s s e n, & E nns 2003; R ubi n, B ode ns t e i n, & K e nt 1995) a s m e a s ur e d by s e r um hypoa l bum i ne m i a T he ot he r r e por t m e a s ur e d m a l nut r i t i on vi a t he P r ognos t i c N ut r i t i ona l I nde x, a c a l c ul a t i on ba s e d on a num be r o f l a bor a t o r y a nd c l i ni c a l f a c t or s ( D a ns i nge r e t a l 1996 ) a nd i de nt i f i e d a n a s s oc i a t i on be t w e e n pr ot e i n l os i ng e nt e r opa t hy a nd C D A D F our s t udi e s a l s o r e por t e d m ul t i va r i a t e t e s t i ng, ho w e ve r t he M ode na e t a l a nd A ndr e w s e t a l s t udi e s om i t t e d e nt r y of t he nut r i t i o na l va r i a bl e i nt o m ul t i va r i a t e a na l ys i s

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37 due t o e xc e s s m i s s i ng da t a poi nt s B uc hne r a nd S o nne nbe r g r e por t e d a s t a t i s t i c a l l y s i gni f i c a nt O R of 2 01 f or t he va r i a b l e o f m a l nut r i t i on a s a n i nde pe nde nt p r e di c t or o f C D A D but S ha h d i d not r e por t t he m u l t i va r i a t e O R i ndi c a t i ng t ha t i t w a s no l onge r s t a t i s t i c a l l y s i gni f i c a nt T he l os s of s e r um pr ot e i n i de nt i f i e d by D a ns i nge r e t a l r a i s e s i m por t a nt que s t i ons a bout t he r e l a t i ons hi p be t w e e n m a l nut r i t i on s us c e pt i bi l i t y t o i nf e c t i on a nd d i a r r he a T hi s va r i a bl e s houl d be c ons i de r e d a s ubs t a nt i a l r i s k f a c t or f or i nc l us i on i n f ut ur e r e s e a r c h. C at har t i c A dm i ni s t r at i on T he i m pa c t o f l a xa t i ve s a nd bow e l pr e pa r a t i on r e gi m e n s upon de ve l opm e nt of C D A D ha s not be e n e xt e ns i ve l y s t udi e s A m ong t he publ i c a t i ons r e vi e w e d, s i x i nc l ude d da t a r e ga r di ng l a xa t i ve us e a nd one r e ga r di ng bow e l pr e pa r a t i on r e gi m e ns A s t a t i s t i c a l l y s i gni f i c a nt R R o f 3 2 w a s r e po r t e d i n a s s oc i a t i on w i t h m e c ha ni c a l bow e l pr e pa r a t i on a m ong a c ohor t of s ur gi c a l pa t i e nt s ( M c C a r t e r A bul a r r a ge V e l a s c o, D a vi s & D a l y, 1996) T hi s r i s k f a c t or w a s not i nc l ude d i n t he B i gna r d i l i s t but m os t l i ke l y w a r r a nt s i nc l us i on i n f ut u r e s t udi e s S i x s t udi e s i nve s t i ga t e d l a xa t i ve us e i n a s s oc i a t i on w i t h t he de ve l opm e nt o f C D A D W a t a na kuna kor n e t a l ( 1996) r e por t e d a non s i gni f i c a nt ne ga t i ve a s s oc i a t i on i n a s t udy of a ge ne r a l hos pi t a l popul a t i on H ow e ve r a n i nve s t i ga t i on of C D A D ge ne r a t e d f r om a n H I V i n f e c t e d popul a t i on i de nt i f i e d a s t a t i s t i c a l l y s i gni f i c a nt pos i t i ve a s s oc i a t i on ( P ul ve r e nt i e t a l 2002 ) F ou r publ i c a t i ons i nc l ude d l a xa t i ve us e i n m ul t i va r i a t e s t udi e s B a r but e t a l f ound a ne ga t i ve a s s oc i a t i on be t w e e n C D A D a nd l a xa t i ve us e on uni va r i a t e t e s t i ng, but di d not i nc l ude t he va r i a bl e i n m u l t i va r i a t e a na l ys i s a l t hough t he p va l ue of

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38 0. 20 w oul d ha ve be e n s uf f i c i e nt f or i nc l us i on i n a c ondi t i ona l l ogi s t i c r e gr e s s i on a na l ys i s K e nt e t a l ( 1998) a l s o r e por t e d a non s i gni f i c a nt p va l ue a nd t he r e f or e di d not i nc l ude l a xa t i ve us e i n t he r e gr e s s i on a na l ys i s K yne e t a l ( 1999) r e por t e d a non s i gni f i c a nt ne ga t i ve a s s oc i a t i on. O nl y one pa pe r r e por t e d s t a t i s t i c a l s i gni f i c a nc e a f t e r m ul t i va r i a t e a na l ys i s but i t w a s a ne ga t i ve a s s oc i a t i on f or bot h t he ge ne r a l dr ug c a t e gor y of l a xa t i ve s a s w e l l a s t he s pe c i f i c a ge nt l a c t ul os e ( S ha h, L e w i s L e opol d D uns t a n, & W oodhous e 2000) L a xa t i ve us e doe s not a ppe a r t o i nc r e a s e t he r i s k of C D A D I t i s pos s i bl e t ha t l a xa t i ve us e m a y e xe r t a p r ot e c t i ve e f f e c t upon t he bow e l by f a c i l i t a t i ng t he e l i m i na t i o n of pot e nt i a l l y t oxi ge ni c or ga ni s m s I t m a y, how e v e r s e r ve a s a c on f ounde r i n s t udi e s i n w hi c h s ubj e c t s a r e s e l e c t e d ba s e d upon hos pi t a l i z e d pe r s ons w ho ha ve s t ool s s ubm i t t e d f or l a bor a t o r y t e s t i ng due t o l oos e or di a r r he a l s t oo l s B ow e l pr e pa r a t i on i s a s s oc i a t e d w i t h C D A D i n s ur gi c a l pa t i e nt s but t hi s ne e ds m o r e s t udy t o de t e r m i ne i f t he a s s oc i a t i on i s c ons i s t e nt a c r os s m or e popul a t i ons Se v e r i t y of I l l ne s s T he i m m une r e s pons e t o i nf e c t i ous a ge nt e xpos ur e c a n be i m pa i r e d by a va r i e t y of m e c ha ni s m s i nc l udi ng di s e a s e a nd i nj ur y A n um be r of i nve s t i ga t i ons ha ve e xpl or e d t he c onc e pt of s e ve r i t y of i l l ne s s i n a s s oc i a t i on w i t h t he de ve l opm e nt o f C D A D A t o t a l of 22 s t udi e s w e r e i nc l ude d i n t he r e vi e w t ha t e xpl or e d t he a s s oc i a t i on be t w e e n c onc om i t a nt i l l ne s s or i nj u r y a nd C D A D T he c on c e pt w a s ope r a t i ona l i z e d i n a va r i e t y of w a ys i nc l udi ng c om or bi di t y, s t a ge of i l l ne s s hos pi t a l l e ngt h o f s t a y, i nt e ns i ve c a r e uni t s t a y, a nd a s e ve r i t y o f i l l ne s s i nde x ( H or n & H or n 1986)

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39 T he m os t f r e que nt l y us e d m e t hod us e d t o m e a s ur e s e ve r i t y of i l l ne s s w i t hi n t hi s gr oup of s t udi e s w a s c om or bi di t y. F i ve s t udi e s c ons i de r e d t he pr e s e nc e or a bs e nc e of s pe c i f i c di s e a s e s a s a m e a s ur e of c om or bi di t y S i g ni f i c a nt pos i t i ve uni v a r i a t e a s s oc i a t i on s w e r e r e por t e d f or c h r oni c r e na l f a i l ur e ( C unne y, M a ge e M c N a m a r a S m yt h, & W a l s he 1998; H a r ba r t h, S a m or e & C a r m e l i 20 01) a nd r e na l i ns uf f i c i e nc y ( R ubi n, B ode ns t e i n, & K e nt 1995) A l t hough Y i p e t a l ( 2 001) r e por t e d a non s i gni f i c a nt uni va r i a t e O R f or r e na l f a i l ur e t he m a gni t ude a s s oc i a t i on w a s 7. 0. D i a l e t a l a l s o r e por t e d a s i gni f i c a nt pos i t i ve m ul t i va r i a t e O R of 4. 3 f o r c hr oni c r e na l f a i l ur e O t he r s t a t i s t i c a l l y s i gni f i c a nt pos i t i ve uni va r i a t e a s s oc i a t i ons ha ve be e n r e por t e d f or ga s t r oi nt e s t i na l i l l ne s s a nd a ne m i a ( H a r ba r t h, S a m or e & C a r m e l i 2001) c hr oni c obs t r uc t i ve pul m ona r y di s e a s e ( R ubi n, B ode ns t e i n, & K e nt 1995) a nd m a l i gna nc y ( R ubi n, B ode ns t e i n, & K e nt 1995; Y i p L oe b, S a l a m a M os s & O l de 2001) A ndr e w s e t a l ( 2003) r e por t e d a s i gni f i c a nt pos i t i v e m ul t i va r i a t e O R f or i nc r e a s i ng num be r of or ga n s ys t e m s a f f e c t e d by c om or bi d i l l ne s s T w o r e por t s i nd i c a t e d a s t a t i s t i c a l l y s i gni f i c a nt di f f e r e nc e i n t he nu m be r of di a gnos e s be t w e e n C D A D c a s e s a nd c ont r ol s ( B uc hne r & S onne nbe r g, 2001; M ody, S m i t h, & D e ve r 2001 ) but m e a s ur e s of a s s oc i a t i on w e r e not r e por t e d. L i ke w i s e B uc hne r a nd S onne nbe r g r e po r t e d s t a t i s t i c a l l y s i gni f i c a nt di f f e r e nc e s i n t he num be r of m e di c a l a n d s ur gi c a l pr oc e dur e s pe r f o r m e d on c a s e s ve r s u s c ont r ol s A pr obl e m c om m on t o a l l of t he s e s t ud i e s i s t he f a c t t ha t t he r e be t w e e n s ubj e c t s t he r e m a y be a gr e a t de a l o f va r i a t i on i n t he i m pa c t i n w hi c h a m e di c a l di a gnos i s m a ke s on t he ove r a l l he a l t h of t he i ndi v i dua l T he r e f or e a di a gnos i s c a t e gor y, or a c ount o f di a gnos e s i s not a va l i d m e a s ur e of c om o r bi di t y. W he n a s t a nda r di z e d m e a s ur e t he

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40 C ha r l s on I nde x of c om o r bi di t y w a s us e d t o a s s e s s di f f e r e nc e s be t w e e n C D A D c a s e s a nd a c om pa r i s on gr oup, no s i gni f i c a nt di f f e r e nc e s w e r e f ound ( L oo e t a l 2005 ) T he s t a ge of i l l ne s s f or H um a n I m m unode f i c i e nc y V i r us ( H I V ) i nf e c t e d a dul t s w a s e xa m i ne d i n t w o s e pa r a t e s t udi e s A l t hough P ul ve r e nt i e t a l ( 2005) f ound pos i t i ve a s s oc i a t i on s t hr ough pr og r e s s i ve s t a ge s of H I V i nf e c t i on, t he s e a s s oc i a t i ons w e r e not s t a t i s t i c a l l y s i gni f i c a nt on uni va r i a t e a na l ys i s H o w e ve r l ow C D 4 c e l l c ount ha s be e n s i gni f i c a nt l y a s s oc i a t e d w i t h C D A D i n uni va r i a t e a na l ys i s ( T a c c one l l i e t a l 1998 ) a nd bot h a hi s t or y of oppo r t uni s t i c i n f e c t i on ( P u l ve r e nt i e t a l 2005 ) a nd a C D 4 c ount be l ow 50 m m 3 ( B a r but e t a l 1997 ) ha ve be e n r e por t e d t o ha ve s t a t i s t i c a l l y s i gni f i c a nt pos i t i ve a s s oc i a t i on s f ol l ow i ng m ul t i va r i a t e a na l ys i s T he s e f i ndi ngs pr ovi de bi ol ogi c a l l y pl a us i bl e s uppor t f or i m m unos uppr e s s i on, m a ni f e s t e d by bot h oppor t uni s t i c i n f e c t i on a nd a de c l i ne i n C D 4, a s a f a c t or i n t he c a us a t i on of C D A D T he l e ngt h o f hos pi t a l i z a t i on i s s i gni f i c a nt l y l onge r f o r pe r s ons w ho de ve l op C D A D ( B uc hne r & S onne nbe r g 2002; M a c G ow a n e t a l 1997; P ul ve r e nt i e t a l 2002) H ow e ve r l e ngt h o f s t a y da t a doe s not i ndi c a t e w he t he r t he p r ol onge d hos pi t a l i z a t i on i s a r i s k f a c t or o r a c ons e que nc e of C D A D T hr e e s t ud i e s s ugge s t t ha t a pr ol onge d hos pi t a l s t a y i nc r e a s e s r i s k f or t he d i s e a s e S i gni f i c a nt pos i t i ve m ul t i va r i a t e a s s oc i a t i ons ha ve be e n r e por t e d f o r p r ol onge d pos t ope r a t i ve hos pi t a l s t a y ( H a r ba r t h S a m o r e & C a r m e l i 2001) hos pi t a l i z a t i on gr e a t e r t ha n or e qua l t o e i gh t da ys dur i ng a r i s k pe r i od ( P ul vi r e nt i e t a l 2002) a nd hos pi t a l i z a t i on m or e t ha n t e n da y s i n t he m ont h pr e c e di ng i n f e c t i on ( P ul vi r e nt i e t a l 2002) A l t hough a n i nc r e a s i ng l e ngt h of s t a y i nc r e a s e s e xpos ur e t o m i c r obe s i n t he e nvi r onm e nt i t s s e ns i t i vi t y a nd s p e c i f i c i t y a s a m e a s ur e of C D A D r i s k i s unc e r t a i n. I t m a y r e pr e s e nt a c onf ounde r r a t he r t h a n a r i s k f a c t o r

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41 M ode na e t a l de f i ne d s e ve r i t y of i l l ne s s i n t e r m s o f bot h m e c ha ni c a l ve nt i l a t i on a nd t he ne e d f o r c a r e w i t h i n a n i nt e ns i ve c a r e uni t ( I C U ) ( 2005 ) M e c ha ni c a l ve nt i l a t i o n us e ha d a s i gni f i c a nt pos i t i ve a s s oc i a t i on w i t h C D A D i n uni va r i a t e a na l ys i s a nd a n I C U s t a y w a s s t a t i s t i c a l l y s i gni f i c a nt i n m ul t i va r i a t e a na l ys i s T hi s c a t e gor i c a l da t a l a c ks pr e c i s i on. L i ke l e ngt h of hos pi t a l s t a y, i t m a y r e pr e s e nt a c onf oundi ng va r i a bl e r a t he r t ha n a r i s k f a c t or M c F a r l a nd ( 1995) p r ovi de d t he e a r l i e s t publ i c a t i on i n t hi s r e vi e w t o us e t he H or n S e ve r i t y of I l l ne s s I nde x a s a m e a s ur e S t a t i s t i c a l l y s i gni f i c a nt di f f e r e nc e s i n s e ve r i t y i nde x s c or e w e r e r e por t e d w i t hi n t he publ i c a t i on R e l a t i ve r i s ks c a l c ul a t e d f r om publ i s he d da t a f ound a s t a t i s t i c a l l y s i gni f i c a nt pos i t i ve a s s oc i a t i on f or t he c a t a s t r ophi c l e ve l of i l l ne s s but not f or t he s e ve r e l e ve l K yne ( 2002) r e por t e d s t a t i s t i c a l l y s i gni f i c a nt pos i t i ve a s s oc i a t i ons f or bot h t he c a t a s t r ophi c a nd s e ve r e l e ve l s of i l l ne s s K yne a l s o e xa m i ne d t he pr e di c t i ve va l ue o f t he i ns t r um e nt w i t h a s c or e of t hr e e o r m o r e a nd r e por t e d s e ns i t i vi t y 79 87 s pe c i f i c i t y 39 73, pos i t i ve pr e di c t i ve va l ue 11 27 a nd ne ga t i ve pr e di c t i ve va l ue 96 97 M or e r e c e nt l y, V e s t a ( 200 5) publ i s he d s t udy da t a t ha t e na bl e d c a l c ul a t i on of a s t a t i s t i c a l l y s i gni f i c a nt O R of 7 6 7 f or c a t a s t r ophi c i l l ne s s T he r e i s s t r ong e vi de nc e t ha t i l l ne s s t ha t w e a ke ns t he body s i m m une s ys t e m i nc r e a s e s t he r i s k of C D A D A l t hough s t i l l a c a t e gor i c a l m e a s ur e of s e ve r i t y of i l l ne s s t he H o r n I nde x pr e s e nt s a m or e pr e c i s e m e a s ur e of r i s k t ha n a s i m pl e bi na r y va r i a bl e U s e of a m e a s ur e s uc h a s t he H or n i nde x i s m o r e a ppr opr i a t e i n t he de ve l opm e nt of a n e c ol ogi c a l m ode l f or t he s t udy of C D A D t ha t i s r e l e va nt t o nur s i ng p r a c t i c e S uc h a n i ns t r um e nt a t t e m pt s t o qua nt i f y t he hum a n r e s pons e t o i l l ne s s r a t he r t ha n l a be l i ng t he di s e a s e pr oc e s s

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42 E c ol ogi c al M ode l f or St udy of C D A D T he c onc e pt ua l m ode l f or t hi s s t udy i s de r i ve d f r o m a m ode l c r e a t e d f or t he s t udy of e c os ys t e m s a s t he y a f f e c t hum a n he a l t h ( K or e n & C r a w f or d B r ow n 2004 ) T hi s m ode l c ons i de r s t he m a c r oe nvi r onm e nt t he e xt e r n a l e nvi r onm e nt w i t hi n w hi c h a pot e nt i a l hos t f unc t i ons a nd t he m i c r oe nvi r onm e nt t he phys i ol ogi c a l f a c t or s t ha t a l t e r t he s us c e pt i bi l i t y of t he hos t T he m ove m e nt o f hum a n be i ngs w i t hi n t he he a l t hc a r e s e t t i ng c r e a t e s e nvi r onm e nt a l s t r e s s or s t ha t c a n l e a d t o c ont a c t o r e xpos ur e be t w e e n a pot e nt i a l hos t a nd a pot e nt i a l l y i n f e c t i ous m i c r oor ga ni s m E xpos ur e how e ve r doe s not a ut om a t i c a l l y r e s ul t i n di s e a s e f or s e ve r a l r e a s ons F i r s t t he a m o unt of e xpos ur e a n i ndi vi dua l s us t a i ns i s i nf l ue nc e d by t he de gr e e of t e m por a l a nd s pa t i a l di s t a nc e be t w e e n t he a r e a of c ont a m i na t i on a nd t he hum a n be i ng. E xt r i ns i c r i s k f a c t or s s uc h a s a nt i bi ot i c us a ge pol i c i e s i nf e c t i on c ont r ol c om pl i a nc e a nd t he us e of s t a n da r di z e d c l e a ni ng pr oc e dur e s a r e de s i gne d t o i nc r e a s e t he t e m por a l a nd s pa t i a l di s t a nc e be t w e e n m i c r oor ga ni s m s a nd hum a ns S e c ond, a nd pe r ha ps m o r e i m po r t a nt l y, t he hos t r e s pons e i s de pe nde nt upon i nt r i ns i c f a c t or s t ha t m odul a t e t he i m m une r e s pons e t hr oug h c ha nge s i n t he m i c r oe nvi r onm e nt I n t he c a s e of C D A D s pe c i f i c f a c t or s know n t o ha ve s ubs t a nt i a l e vi de nc e f or a n a s s oc i a t i on w i t h C D A D a r e s e ve r i t y of i l l ne s s c ha nge s i n t he m i c r of l or a of t he gut due t o a gi ng, a nt i bi ot i c o r c he m ot he r a py us a ge us e of e nt e r a l f e e di ng s ys t e m s m a l nut r i t i on, ga s t r i c a c i d s uppr e s s i on, a nd pr e ope r a t i ve bow e l pr e pa r a t i on r e gi m e ns A n e xpos e d i ndi vi dua l w i l l r e s pond t o C l os t r i di um di f f i c i l e e xpos ur e by f o r m i ng a nt i bod i e s be c om i ng a n unpr ot e c t e d c a r r i e r or by de ve l opi ng a c t i ve C d i nf e c t i on i n va r y i ng de gr e e s

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43 H U M A N A C T I V I T Y WI T H I N H O S P I T A L M A C R O E N V I R O N M E N T E nvi r onm e nt a l c l e a ni ng a nd di s i nf e c t i on M ove m e nt of he a l t hc a r e w or ke r s V i s i t a t i on A dm i s s i on of pa t i e nt E N V I R O N M E N T A L S T R E S S O R S E nvi r onm e nt a l c ont a m i na t i on w i t h C l os t r i di um di f f i c i l e or ga ni s m E X P O S U R E E N V I R O N M E N T A L S Y S T E M S A F F E C T I N G H O S T R E S P O N S E E xt r i n s i c I n t r i n s i c S pa t i a l a nd t e m por a l di s t a nc e f r om m i c r oor ga ni s m s i nf l ue nc e d by: A nt i bi ot i c r e s t r i c t i on pol i c i e s I nf e c t i on c ont r ol c om pl i a nc e T ube f e e di ng s y s t e m s P e r s i s t e nc e of s por e s S e ve r i t y of i l l ne s s A ge A nt i bi ot i c e xpos ur e E nt e r a l f e e di ng M a l nut r i t i on C a t ha r t i c a dm i ni s t r a t i on G a s t r i c a c i d s uppr e s s i on R E S P O N S E T O E X P O S U R E I n f e c t i on C on t i n u u m P r ot e c t e d C ar r i e r U n p r ot e c t e d C ar r i e r M i l d C D A D P e r s i s t e n t C D A D P M C E X C R E T I O N F i gur e I M ode l f or t he s t udy of e c ol ogi c a l va r i a bl e s a f f e c t i ng de ve l opm e nt of C l os t r i di um di f f i c i l e a s s oc i a t e d di a r r he a T hi s s t udy w i l l f oc us onl y on t he po r t i on o f t he m o de l t ha t c ons i de r s t he i nt r i ns i c a nd e xt r i ns i c f a c t or s t ha t a f f e c t a hos t r e s pons e t o C d e xpos ur e B e c a us e t he C d or ga ni s m c a n pe r s i s t i n a n e nvi r onm e nt f o r pr o l onge d pe r i od s of t i m e i n i t s s por e s t a t e r e l i a nc e s ol e l y upon e xt r i ns i c e nvi r onm e nt a l f a c t or t o s t op t he i nf e c t i on m a y not be s uf f i c i e nt D e s pi t e ne a r l y t w o de c a de s of w i de s pr e a d us e i n t he de ve l ope d w or l d o f pe r s ona l

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44 pr ot e c t i ve e qui pm e nt f o r t he ha ndl i ng o f a l l pot e nt i a l l y i nf e c t i ous m a t e r i a l a s w e l l a s na t i ona l c a m pa i gns t o pr om ot e ha ndw a s hi ng a nd j udi c i ous a nt i bi ot i c us a ge out br e a ks of C D A D c o nt i nue T he r e f or e a n a l t e r na t i ve m e a ns of i de nt i f yi ng t he m os t s us c e pt i bl e hos t s a nd pr ovi di ng e c ol ogi c a l l y ba s e d c a r e m a y p r e s e nt of m or e e f f e c t i ve m e a ns of c ont r ol l i ng t hi s d i s e a s e Sum m ar y T hi s r e vi e w of l i t e r a t u r e ha s i de nt i f i e d e c ol ogi c a l v a r i a bl e s t ha t a f f e c t t he r e s pons e of a hos pi t a l i z e d a dul t e xpos e d t o t he C d or ga ni s m T he s e va r i a bl e s w i l l be us e d i n t he de s i gn of a c a s e c ont r ol s t udy t o i de nt i f y a n e c ol ogi c a l m ode l us e f ul f or nur s e s T he s e va r i a bl e s i nc l ude a ge a nt i bi ot i c e xpos ur e bow e l pr e pa r a t i on e nt e r a l f e e di ng, m a l nut r i t i on, ga s t r i c a c i d s uppr e s s i on, a nd s e ve r i t y of i l l ne s s

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45 C ha pt e r T hr e e R e s e a r c h M e t hod s R e s e ar c h D e s i gn T he pur pos e of t hi s s t udy w a s t o de ve l op a nd t e s t a pr e di c t i ve m ode l f or t he de ve l opm e nt of C l os t r i di um di f f i c i l e a s s oc i a t e d di a r r he a I t i s a nt i c i pa t e d t ha t s uc h a m ode l c a n s e r ve t hr e e pu r pos e s : ( 1) s e r ve a s a f ou nda t i on f or de ve l opm e nt of a va l i d a nd r e l i a bl e r i s k a s s e s s m e nt t ool ( 2) a i d i n t he de s i gn o f f ut u r e c l i ni c a l t r i a l s of nur s e di r e c t e d pr e ve nt i on s t r a t e gi e s a nd ( 3) a s s i s t c l i ni c i a ns i n m odi f yi ng i n f e c t i on c ont r ol pr a c t i c e s i n i ns t i t ut i ona l s e t t i ngs w he n c a r i ng f or h i gh r i s k i nd i vi dua l s T he s t udy us e d a c a s e c ont r ol de s i gn t o de ve l op a p r e di c t i ve m ode l t o i de nt i f y e c ol ogi c a l r i s k f a c t or s m os t c l os e l y a s s oc i a t e d w i t h t he de ve l opm e nt of hos pi t a l a c qui r e d C l os t r i di um di f f i c i l e a s s oc i a t e d di a r r he a Se t t i ng T he s e t t i ng w a s a V e t e r a n s A dm i ni s t r a t i on M e di c a l C e nt e r l oc a t e d i n t he s t a t e of F l or i da T he M e di c a l C e nt e r i s a 327 be d t e r t i a r y c a r e t e a c hi ng hos pi t a l w i t h 300 a ddi t i ona l a ut hor i z e d nu r s i ng hom e c a r e be ds a nd s e r ve s a n e s t i m a t e d popul a t i on of 435, 442 ve t e r a ns T he f ul l r a nge o f i npa t i e nt a nd out pa t i e nt c a r e i s pr ovi de d i nc l udi ng M e di c i ne ( 111 be ds ) S ur gi c a l ( 61 be ds ) P s yc hi a t r y ( 50 be ds ) N e ur ol ogy ( 7 be ds ) a s w e l l a s a 60 be d S pi na l C or d I nj ur y S e r vi c e a nd a 38 be d C om pr e he ns i ve R e ha bi l i t a t i on C e nt e r T he c e nt e r a l s o pr ovi de s a num be r o f out pa t i e nt c l i ni c s on s i t e a nd a t s a t e l l i t e l oc a t i ons

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46 T he C e nt e r i s a f f i l i a t e d w i t h a U ni ve r s i t y C ol l e ge o f M e di c i ne a nd pr ovi de s r e s i de nc y t r a i ni ng p r ogr a m s i n t he f ol l ow i ng s pe c i a l t i e s : I nt e r na l M e di c i ne O r t hope di c s H e m a t ol ogy, P a t hol ogy, R a di os ur ge r y, O pht ha l m ol ogy D e r m a t ol ogy, P od i a t r y, N e ur ol ogy N e ur os ur ge r y U r ol ogy, N e phr o l ogy, G e ne r a l S ur ge r y, O t ol a r yngol ogy P s yc hi a t r y R a di ol ogy. Sam pl e T he s t udy s a m pl e c ons i s t e d of 66 c a s e s a nd 66 m a t c he d c ont r ol s f or a t ot a l of 132 s ubj e c t s C a s e s a nd c ont r ol s w e r e s e l e c t e d f r om t h e e l e c t r oni c m e di c a l r e c or d da t a ba s e of t he s t udy s i t e m e di c a l c e nt e r E l e c t r oni c m e di c a l r e c or ds ge ne r a t e d be t w e e n J a nua r y 1, 2000 a nd D e c e m be r 31, 2006 w e r e ut i l i z e d. F i gur e 2 i l l us t r a t e s t he s e que nt i a l s t e ps us e d i n s e l e c t i ng t he c a s e s s e l e c t i ng pot e nt i a l c ont r ol s a nd m a t c hi ng c ont r ol s t o c a s e s A t ot a l of 1, 739 m e di c a l r e c or ds w e r e s e l e c t e d by da t a m i ni ng t he m e di c a l r e c or ds da t a ba s e C r i t e r i a s pe c i f i e d f or t he da t a m i ni ng w e r e ( 1) i npa t i e nt hos pi t a l a dm i s s i on be t w e e n J a nua r y 1 2000 a nd D e c e m be r 31, 2006 a nd ( 2) l a bor a t o r y s t udi e s f o r C l os t r i di um di f f i c i l e c yt o t oxi n a s s a y, t ot a l l ym phoc yt e c ount s e r um a l bum i n a nd s e r um pr e a l bum i n l e ve l doc um e nt e d dur i ng t hi s t i m e f r a m e O f t he 1 739 r e c or ds 330 w e r e s e l e c t e d a s pot e nt i a l c a s e s f r om t he o r i gi na l g r oup be c a us e t he y a l s o ha d a m e di c a l r e c or d d i a gnos t i c c odi ng f or C l os t r i di um di f f i c i l e a s s oc i a t e d di a r r he a W i t hi n t hi s s e t 155 r e c or ds w e r e i de nt i f i e d w hi c h m e t t he i nc l us i on c r i t e r i a of hos pi t a l a c qui r e d i nf e c t i on a s de f i ne d by a di a gnos i s m a de > 2 da ys a f t e r hos pi t a l a dm i s s i on a nd < 31 da ys a f t e r hos pi t a l di s c ha r ge t he c ut poi nt s s e l e c t e d f or de t e r m i na t i on of a hos pi t a l a c qui r e d C D A D

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47 1, 737 r e c or ds s e l e c t e d f o r s c r e e ni ng ba s e d on p r e s e nc e of l a bor a t or y t e s t i ng f o r C l os t r i di um di f f i c i l e s e r um a l bum i n s e r um pr e a l b um i n a nd t ot a l l ym phoc yt e c ount be t w e e n J a nua r y 1, 2000 a nd D e c e m be r 31, 2006. 330 r e c or ds s e l e c t e d f or f ur t he r s c r e e ni ng w i t h di a gnos t i c c odi ng f o r C D A D 1, 636 r e c or ds s e l e c t e d f o r f u r t he r s c r e e ni ng us i ng c r i t e r i a of no pos i t i ve C l os t r i di um di f f i c i l e t e s t 155 r e c or ds w i t h di a gnos t i c c ode e nt e r e d 2 da ys a f t e r a dm i s s i on a nd 31 da ys a f t e r di s c ha r ge T e m por a l m a t c hi ng R e c or ds s e l e c t e d i f hos pi t a l a dm i s s i on da t e + 31 da ys of one or m or e c a s e s 106 r e c or ds m e t d i a gnos t i c c r i t e r i a f or S H E A a nd ha d no doc um e nt a t i ons of a ny m e di c a l c ondi t i ons s pe c i f i e d f or e xc l us i on f r om s t udy S pa t i a l m a t c hi ng. R e c or ds s e l e c t e d i f a dm i s s i on uni t O R un i t w i t h gr e a t e s t l e ngt h of s t a y m a t c he d one or m or e c a s e s 6 r e c or ds de l e t e d due t o s ub a c ut e s t a y > 150 da ys f or t ot a l o f 100 pot e nt i a l c a s e s P ot e nt i a l m a t c he s s c r e e ne d f or pr e s e nc e of di a r r he a a bs e nc e of ot he r di a gnos t i c t e s t i ng s ugge s t i ve of C D A D a nd a bs e nc e of t he e xc l us i on c r i t e r i a 66 c a s e s m a t c he d 71 c ont r ol s w i t h 4 c ont r ol s e a c h m a t c hi ng 2 di f f e r e nt c a s e s C ont r ol s w i t h a dm i s s i on da t e c l os e s t t o c a s e s e l e c t e d f or f i na l s a m pl e 66 c a s e s 66 c ont r ol s F i gur e 2. S a m pl e s e l e c t i on p r oc e s s T he s e t of 155 m e di c a l r e c or ds w a s e xa m i ne d t o d e t e r m i ne i f t he r e c or d w a s c ons i s t e nt w i t h c r i t e r i a f o r C D A D c a s e de f i ni t i on o ut l i ne d i n t he S he a P os i t i on P a pe r

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48 ( G e r di ng, J ohns on, P e t e r s on, M ul l i ga n & S i l va 1 995) T he s e c r i t e r i a w e r e ( 1) di a r r he a ( 2) doc um e nt e d c onc ur r e nt l y o r w i t hi n 7 da ys o f a pos i t i ve r e s ul t on one o r m o r e of t he f ol l ow i ng di a gnos t i c t e s t s : E ndos c opy w i t h c onf i r m a t i on o f ps e udom e m br a no us c ol i t i s S t ool c ul t ur e f or t oxi ge ni c s t r a i n of C di f f i c i l e C e l l c ul t ur e c yt ot oxi n t e s t E I A t oxi n t e s t T o r e duc e s e l e c t i on bi a s t ha t m i ght oc c ur i n pe r s ons t e s t e d f or C di f f i c i l e due t o r e c ur r e nc e of d i a r r he a f ol l ow i ng a pr e vi ous l y di a g nos e d i nf e c t i on c a s e s w e r e e xc l ude d i f t he da t a ba s e i nc l ude d a di a gnos i s of C D A D w i t hi n 12 m ont hs p r e c e di ng t he pos i t i ve t e s t r e s ul t B e c a us e pe r s ons w i t h c hr oni c di a r r he a r e f e r r e d f o r s t ool t e s t i ng m a y e xpe r i e nc e c ol oni z a t i on w i t h C di f f i c i l e a nd m i ght be e a s i l y m i s c l a s s i f i e d, c a s e s w e r e a l s o e xc l ude d i f t he r e w a s a hi s t or y o f a ny o f t he f ol l ow i ng: s ur gi c a l r e m ova l of s uf f i c i e nt bow e l t o r e s ul t i n c hr oni c di a r r he a c hr oni c ul c e r a t i ve c ol i t i s not pr e vi ous l y s ubj e c t e d t o s ur gi c a l c ur e C r ohn s d i s e a s e di a r r he a pr e dom i n a nt i r r i t a bl e bow e l s yndr om e or d i a be t i c ne ur opa t hy w i t h c hr on i c di a r r he a T he s c r e e ni ng pr oc e s s i de nt i f i e d 106 m e di c a l r e c or ds t ha t qua l i f i e d f or i nc l us i on i n t he s t udy. B e c a us e t he f oc us of t he s t udy w a s a c qui s i t i on of C D A D dur i ng a c ut e c a r e hos pi t a l i z a t i on, r e c or ds a l s o w e r e e xa m i ne d f or l e n gt h of s t a y i n s ub a c ut e a r e a s of t he i ns t i t ut i on. S i x r e c or ds w e r e di s c a r de d due t o s ub a c ut e l e ngt h of s t a y i n e xc e s s of 150 da ys T hi s y i e l de d a f i na l s e t of 100 c a s e s A t ot a l of 1, 636 r e c or ds i n t he A c c e s s da t a ba s e w e r e s c r e e ne d f or s e l e c t i on of c ont r ol s T he s e 1, 636 r e c or ds w e r e ba s e d on a que r y t o i de nt i f y r e c or ds t ha t ne ve r

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49 r e c or de d a pos i t i ve C di f f i c i l e a s s a y. B e c a us e e c o l ogi c a l di s e a s e m ode l s c ons i de r bot h t e m por a l a nd s pa t i a l di s t a nc e t o be a f a c t o r i n t he s pr e a d of c om m uni c a bl e di s e a s e c ont r ol s w e r e m a t c he d t o c a s e s by hos pi t a l a dm i s s i on da t e a nd ge ogr a phi c un i t o f hos pi t a l F o r pu r pos e s of m a t c hi ng, w he n a r e c or d i ndi c a t e d t ha t t he s ubj e c t w a s t r e a t e d i n m or e t ha n one uni t t he uni t w i t h t he l onge s t l e n gt h of s t a y w a s us e d f o r s pa t i a l m a t c hi ng. T o s e l e c t t he pot e nt i a l c a s e s r e c or ds w e r e f i r s t m a t c he d ba s e d on a dm i s s i on da t e + 31 da ys us i ng a n A c c e s s que r y. R e c or ds w e r e t he n m a nua l l y i ns pe c t e d t o m a t c h pot e nt i a l c ont r ol s t o c a s e s by a dm i s s i on uni t or uni t w i t h t he l onge s t l e ngt h o f s t a y. R e c or ds t ha t m a t c he d a c a s e f or bot h a dm i s s i on da t e a nd ge ogr a phi c uni t of t he hos pi t a l w e r e r e vi e w e d t o e ns ur e p r e s e nc e of t he f ol l ow i ng: ( 1) di a r r he a doc um e nt e d w i t hi n 7 da ys of t he C l os t r i di um di f f i c i l e a s s a y t e s t a nd ( 2 ) a bs e nc e of bot h e ndos c opy a nd s t ool c ul t ur e r e s ul t s i ndi c a t i ve of C D A D A t ot a l of 71 r e c or ds w e r e i de nt i f i e d a s m a t c he s W i t hi n t he 71 r e c or ds t he r e w e r e 4 dupl i c a t e m a t c he s T o e na bl e a 1: 1 m a t c hi ng, t he c ont r ol r e c or d t ha t m os t c l os e l y m a t c he d t he c a s e r e c or d a dm i s s i on da t e w a s s e l e c t e d f or t he s t udy. M e as ur e m e nt of V ar i abl e s A ge A ge of s ubj e c t s w a s r e c or de d a s t he c hr onol og i c a l a ge i n ye a r s on t he da t e o f hos pi t a l a dm i s s i on. N ut r i t i onal St at us N ut r i t i ona l s t a t us w a s m e a s ur e d t hr ough us e o f t h r e e c ont i nuous va r i a bl e s : s e r um a l bum i n, s e r um p r e a l bum i n, a nd l ym phoc yt e c ount L a bor a t or y va l ue s w e r e r e c or de d

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50 onl y f or s pe c i m e ns c ol l e c t e d w i t hi n s e ve n da ys of hos pi t a l a dm i s s i on. L a bo r a t or y r e f e r e nc e r a nge s f or t he s e t e s t s a t t he r e s e a r c h s i t e a r e i de nt i f i e d i n t a bl e 4 T a bl e 4 L abor at or y R e f e r e nc e R ange s f or N ut r i t i onal I ndi c at or s T e s t L ow H i gh P r e A l bum i n ( m g/ 100 m l ) 18 45 A l bum i n ( m g/ 100 m l ) 3. 8 4. 8 L ym phoc yt e c ount ( 10 9 / L ) 1. 1 3. 4 A nt i bi ot i c B ur de n A nt i bi ot i c bur de n w a s c a l c ul a t e d f o r e a c h s ubj e c t by a nt i bi ot i c a ge nt a s a num e r i c a l s um of a l l D e f i ne d D a i l y D os e s T he D e f i ne d D a i l y D os e i s t he a s s um e d a ve r a ge m a i nt e na nc e dos e pe r da y f o r a d r ug w he n i t i s us e d f or i t s m a i n i ndi c a t i on i n a dul t s w i t h nor m a l or ga n f unc t i on. T hi s m e a s u r e w a s de ve l ope d f or t he W o r l d H e a l t h O r ga ni z a t i on ( W H O ) C ol l a bor a t i ve C e nt r e f o r D r u g S t a t i s t i c s M e t hodol ogy t o e na bl e m e a s ur e m e nt of dr ug c ons um pt i on i nde pe nde nt of f or m ul a t i on o r p r i c e A l l D D D c a l c ul a t i ons w e r e c a l c ul a t e d us i ng t he W H O i nde x on t he w o r l d w i de w e b a t ht t p: / / w w w w hoc c no/ a t c ddd/ F o r e a c h a nt i bi o t i c a ge nt a dm i ni s t e r e d, da t a w a s r e c or de d f r om t he e l e c t r oni c r e c or d r e ga r di ng t he p r e s c r i be d dos e of t he dr ug a nd t he num be r of dos e s a dm i ni ns t e r e d dur i ng t he l e ngt h of t he e xpos ur e pe r i od ( hos pi t a l a dm i s s i on t o da t e of C D A D t e s t i ng) T he s e pr e s c r i be d dos e s w e r e t h e n c onve r t e d t o D D D uni t s a nd a s um of t he D D D un i t s w a s c om put e d f o r e a c h dr ug T h e dr ug bu r de n f o r e a c h s ubj e c t w a s t he s um t ot a l of a l l D D D s f or a l l a nt i bi ot i c a ge nt s

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51 L ax at i v e s and B ow e l P r e par at i on M e di c at i ons U s e of a ny c a t ha r t i c s a dm i ni s t e r e d o r a l l y or vi a a f e e di ng t ube f or e i t he r ( a ) bow e l c l e a ns i ng r e gi m e ns pr i or t o s ur gi c a l o r e ndos c opi c pr oc e dur e s or ( b ) p r e ve nt i on or t r e a t m e nt of c ons t i pa t i on w e r e r e c or de d i n a m a nn e r s i m i l a r t o a nt i bi ot i c s a nd a D D D w a s c a l c ul a t e d f or e a c h s ubj e c t B ow e l pr e pa r a t i o ns w e r e e xc l ude d i f t he r e w a s doc um e nt a t i on i n t he m e di c a l r e c or d i ndi c a t i ng a d m i ni s t r a t i on f o r a d i a gnos t i c pr oc e dur e t o i de nt i f y ps e udom e m br a nous c ol i t i s i n a n i ndi vi d ua l be l i e ve d i nf e c t e d w i t h C d. G as t r i c A c i d Suppr e s s i on G a s t r i c a c i d s uppr e s s i on w a s m e a s ur e d f or e a c h s ubj e c t by dr ug dos a ge dos a ge uni t s a nd num be r of dos a ge s a dm i ni s t e r e d be t w e e n t he da t e o f hos pi t a l a dm i s s i on a nd t he da t e a s t ool s a m pl e w a s s ubm i t t e d f or C D A D t e s t i ng. T hi s i nf o r m a t i on w a s t he n c onve r t e d t o D e f i ne d D a i l y D os e s ( D D D ) a nd a s u m of t he D D D uni t s w a s c om put e d. F or c om pa r i s on pu r pos e s dr ugs c l a s s i f i e d a s pr ot o n pum p i nhi bi t or s a nd t hos e c l a s s i f i e d a s hi s t a m i ne 2 bl oc ki ng a ge nt s w e r e r e c o r de d s e pa r a t e l y a nd D D D uni t s w e r e c a l c ul a t e d a s s e pa r a t e c a t e gor i e s E nt e r al F e e di ng E nt e r a l f e e di ng w a s m e a s ur e d by t he nu m be r o f da ys i n w hi c h a na s oga s t r i c na s oe nt e r a l or pe r c ut a ne ous l y i ns e r t e d e nt e r a l f e e di ng t ube w a s us e d t o p r ovi de nut r i t i ona l s u ppor t be t w e e n t he da t e o f a dm i s s i on a nd t he da t e a s t ool s a m pl e w a s s ubm i t t e d f or C D A D t e s t i ng. Se v e r i t y of I l l ne s s S e ve r i t y of i l l ne s s l e ve l w a s a s s i gne d by t he pr i nc i pa l i nve s t i ga t or us i ng t he S e ve r i t y of I l l ne s s i nde x ( H or n & H or n 1986 ) T h i s i nde x i s a n i ns t r um e nt de s i gne d t o

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52 c r e a t e a ge ne r i c m e a s ur e i nde pe nde nt of c l i n i c i a n pr a c t i c e pa t t e r ns w hi c h qua nt i f i e s a pa t i e nt s i l l ne s s s e ve r i t y ba s e d on r e t r os pe c t i ve r e v i e w of r e c or ds a t t he t i m e of di s c ha r ge T he i nde x g r oups pa t i e nt s w i t hi n a f our l e ve l or d i n a l s c a l e w i t h one r e pr e s e nt i ng t he l e a s t s e ve r e a nd f our t he m os t s e ve r e i l l ne s s T he s c a l e i s a ppl i e d t o s e ve n di f f e r e nt di m e ns i ons : s t a ge of pr i nc i p a l di a gnos i s c om pl i c a t i ons i nt e r a c t i ons de pe nde nc y, non ope r a t i ve pr oc e dur e s t he r a t e o f r e s pons e t o t he r a py, a nd t he de gr e e t o w hi c h a c ut e s ym pt om s a r e r e s ol ve d a t t he t i m e of di s c ha r ge a n d t he ove r a l l s e ve r i t y s c or e i s t he m oda l s c or e f or t he s e ve n c a t e gor i e s D a t a f r om 18 di f f e r e nt hos pi t a l s f ound a n ove r a l l w e i ght e d i nt e r r a t e r r e l i a bi l i t y of 93. 5% T he i nde x ha s be e n f ound t o e xpl a i n 69 87% of t he va r i a bi l i t y i n r e s our c e us e w i t hi n D i a gnos t i c R e l a t e d G r oups ( D R G s ) a nd w he n us e d t o a dj us t f or D R G s pr e di c t s 61% o f t he va r i a bi l i t y i n c os t pe r c a s e K yne e t a l ( 2002) r e por t e d a s e ns i t i vi t y o f 87 s pe c i f i c i t y o f 39 pos i t i ve pr e di c t i ve va l ue o f 11 a nd ne ga t i ve pr e di c t i ve va l ue of 97 f or a H or n s i nde x of 3 o r m or e ( s e ve r e or c a t a s t r ophi c i l l ne s s ) w he n us e d w i t h a c ohor t of hos pi t a l i z e d a dul t pa t i e nt s r e c e i vi ng a nt i bi ot i c s I n a s e c ond c ohor t us e d t o va l i da t e t he m ode l t he t e a m r e por t e d s e ns i t i vi t y of 79 s pe c i f i c i t y of 73 pos i t i ve pr e di c t i ve va l ue of 27 a nd ne ga t i ve pr e di c t i ve va l ue of 96. P r oc e dur e s A ppr ov al s A ppr ova l t o c onduc t t hi s s t udy w a s obt a i ne d f r om t he U ni ve r s i t y of S out h F l or i da I ns t i t ut i ona l R e vi e w B oa r d a nd t he J a m e s A H a l e y V A M C H um a n S ubj e c t s R e s e a r c h a nd D e ve l opm e nt C om m i t t e e R e que s t w a s obt a i ne d f r om bot h boa r ds t o w a i ve i n f or m e d c ons e nt T o pr ot e c t t he pr i va c y o f a l l s ubj e c t s e l e c t r oni c m e di c a l r e c or ds w e r e de i de nt i f i e d pr i o r t o t he s t a r t of da t a c ol l e c t i on. A m e m be r of t he m e di c a l s t a f f of t he

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53 V A M C w ho s e r ve d on t he di s s e r t a t i on c om m i t t e e pe r f or m e d dow nl oa di ng o f pot e nt i a l r e c or ds i nt o a n A c c e s s da t a ba s e pr i or t o a c c e s s i on by t he pr i nc i pa l i nve s t i ga t or E a c h r e c or d w a s t he n a s s i gne d a uni que poi nt e r num be r t ha t w a s a c om put e r a s s i gne d s e que nt i a l num be r ha vi ng no a s s oc i a t i on w i t h i de nt i f yi ng da t a A c ode br e a ki ng l og of s u bj e c t s w a s r e t a i ne d by t he V A M C e m pl oye e w i t hi n a l oc ke d o f f i c e i n a s e c ur e d a r e a of t he m e di c a l c e nt e r unt i l da t a c ol l e c t i on a nd a na l ys i s w a s c om pl e t e d. T he l og w a s t he n de s t r oye d a c c or di ng t o V A M C pr oc e dur e s V al i dat i on o f D at a C ol l e c t i on P r oc e dur e A t t he s t a r t o f da t a c ol l e c t i on a s a m pl e of t e n e l e c t r oni c m e di c a l r e c or ds w a s s e l e c t e d a nd da t a r e c or de d us i ng a n E xc e l w or kbo ok de ve l ope d by t he pr i nc i pa l i nve s t i ga t or T o va l i da t e t he a c c ur a c y of t he p r i nc i pa l i nve s t i ga t or ( P I ) i n us e of t he e l e c t r oni c m e di c a l r e c or d s ys t e m t he V A M C c o i n ve s t i ga t or a l s o r e vi e w e d t he s a m e r e c or ds T he w or kbook of t he P I a nd c o i nve s t i ga t or w e r e c om pa r e d f or c onc or da nc e of da t a e l e m e nt s A l l di s c r e pa nc i e s be t w e e n t he da t a w e r e c l a r i f i e d a nd r e vi e w e d unt i l 100% c onc or da nc e w a s obt a i ne d be t w e e n t he t w o s e t s of da t a T he P I t he n de ve l ope d da t a c ol l e c t i on r e f e r e nc e gui de l i ne s t o e ns ur e c ons i s t e nc y dur i ng t he r e m a i nde r of t he da t a c ol l e c t i on pr oc e s s D at a C ol l e c t i on A l l da t a w e r e r e t r i e ve d f r om t he e l e c t r oni c m e di c a l r e c or d a n d r e c or de d i n a n E xc e l w or kbook de ve l ope d by t he p r i nc i pa l i nve s t i ga t or ba s e d upon a pa pe r w or ks he e t pr e vi ous l y a ppr ove d by t he di s s e r t a t i on c om m i t t e e T he w o r ks he e t l i s t i ng a l l da t a e l e m e nt s c ol l e c t e d i s i n A ppe ndi x A T he w r i t t e n da t a c ol l e c t i on r e f e r e nc e gui de i s f ound

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54 i n A ppe ndi x B A l l m e di c a l r e c or d da t a w a s r e c or de d unde r t he un i que i de nt i f i e r num be r de ve l ope d i n t he i ni t i a l da t a m i ni ng ope r a t i on D at a A nal y s i s T he S t a t i s t i c a l P a c ka ge f o r S oc i a l S c i e nc e s ( S P S S ) ve r s i on 15 s of t w a r e w a s us e d f or a l l da t a a na l ys i s I ni t i a l i ns pe c t i on of da t a r e ve a l e d m i s s i ng va l ue s f or t he va r i a bl e s pr e a l bum i n a nd a l bum i n B e c a us e m or e t ha n one t hi r d of t he s ubj e c t s w e r e m i s s i ng pr e a l bum i n da t a t hi s va r i a bl e w a s not ut i l i z e d i n t he s t a t i s t i c a l a na l ys i s M i s s i ng va l ue s f or a l bum i n w e r e i m pu t e d by us e o f t he m e a n f or e a c h gr oup. C r os s t a bul a t i on r e ve a l e d t ha t 25% of t he c e l l s f o r t he va r i a bl e s e ve r i t y o f i l l ne s s i nc l ude d f e w e r t ha n 5 s ubj e c t s T o i nc r e a s e pow e r of t he a na l ys i s t he f ou r c a t e gor i e s o f t he s e ve r i t y of i l l ne s s va r i a bl e w e r e c ol l a ps e d i nt o t w o: m i l d/ m ode r a t e a nd s e ve r e / c a t a s t r ophi c H ow e ve r t hi s p r oc e s s r e s ul t e d i n 31 uni nf or m a t i ve pa i r s a nd t he de c i s i on w a s m a de t o r e t a i n a l l f our c a t e gor i e s of s e ve r i t y of i l l ne s s f or t he r e m a i nde r of t he da t a a na l ys i s D a t a w e r e e nt e r e d i nt o S P S S a s a s a m pl e of 66 pa i r s w i t h t he c a s e s c ode d a s 1 f or out c om e a nd c ont r ol s c ode d a s 0 F or e a c h c ova r i a t e t he di f f e r e nc e be t w e e n c a s e a nd c ont r ol va l ue s w a s c om put e d, a nd t he di f f e r e nc e s c or e s w e r e us e d a s t he c ova r i a t e s i n pe r f or m i ng l ogi s t i c r e gr e s s i on a na l ys i s ( H os m e r & L e m e s how 2000 ) C ondi t i ona l l ogi s t i c r e gr e s s i on w a s t he n pe r f or m e d us i ng t he C ox r e gr e s s i on pr oc e dur e w i t h da t a s t r a t i f i e d by t he m a t c he d pa i r s B ot h uni va r i a t e a n d m ul t i va r i a t e l ogi s t i c r e gr e s s i on a na l ys i s w e r e pe r f or m e d f o r a l l c ova r i a t e s us i ng a f or c e d e nt r y m e t hod.

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55 C ha pt e r F our R e s ul t s T hi s c ha pt e r pr e s e nt s t he f i ndi ngs f r o m t he s t udy F ol l ow i ng de s c r i pt i on o f t he c a s e s a nd c ont r ol s r e s ul t s of a na l yt i c a l t e s t i ng, i nc l udi ng t he l ogi s t i c r e gr e s s i on m ode l i ng, i s p r e s e nt e d. Sam pl e T he da t a m i ni ng a nd s c r e e ni ng pr oc e s s yi e l de d a s a m pl e of 66 pa i r s m a t c he d f or a dm i s s i on da t e a nd ge ogr a phi c l oc a t i on w i t hi n t he hos pi t a l T he s a m pl e w a s 98% m a l e ( 64 c a s e s a nd 65 c ont r ol s ) c ons i s t e nt w i t h t he v e t e r a n popul a t i on f r om w hi c h t he s a m pl e w a s s e l e c t e d. T he a ge r a nge f or c a s e s w a s 46. 48 t o 88. 6 ye a r s w hi l e c ont r ol a ge r a nge w a s 31. 4 t o 90 7 T he m a j o r i t y o f t he s a m pl e ha d e xpos ur e t o a nt i bi ot i c ( 83 % ) a nd pr ot on pum p i nhi bi t or ( 65 % ) d r ugs how e ve r t he r e w a s l i m i t e d e xpos ur e t o t ube f e e di ng ( 17% ) a nd hi s t a m i ne 2 bl oc ki ng a ge nt s ( 14% ) i n t hi s s a m pl e S ubj e c t s w e r e t r e a t e d i n a va r i e t y of pa t i e nt c a r e uni t s w i t hi n t he i ns t i t ut i on, w i t h t he m a j or i t y of t he m a t c he d pa i r s t r e a t e d i n m e di c a l s ur gi c a l uni t s r a t he r t ha n c r i t i c a l c a r e or r e ha bi l i t a t i on or i e nt e d s e t t t i ngs S ubj e c t s w e r e c l a s s i f i e d i n a l l c a t e gor i e s of s e ve r i t y of i l l ne s s w i t h t he l a r ge s t por t i on ( 45 % ) c l a s s i f i e d a s ha vi ng m ode r a t e i l l ne s s a nd a t hi r d of t he s a m pl e ( 33 % ) e xpe r i e nc i ng m a j or i l l ne s s A l t hough onl y 6 s ubj e c t s ( 16% ) e xpe r i e nc e d c a t a s t r ophi c i l l ne s s 4 of t he s e 6 s ubj e c t s w e r e c l a s s i f i e d a s c a s e s

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56 A ppr oxi m a t e l y ha l f t he s a m pl e ha d l ym phoc yt ope ni a pr e s e nt i n a s l i ght l y hi ghe r pe r c e nt a ge of c a s e s ( 59% ) t ha n c ont r ol s ( 45% ) H ypoa l bum i ne m i a w a s pr e s e nt f or 58% of bot h g r oups L ym phoc yt e c ount a nd s e r um a l bu m i n va l ue s c or r e l a t e d s i gni f i c a nt l y ( S pe a r m a n s r ho= 409 p< 01 ) A c om pa r i s on of m e a ns w a s c om put e d f or a l l c ont i nuous va r i a bl e s vi a pa i r e d t t e s t s T he r e w a s a s t a t i s t i c a l l y s i gni f i c a nt di f f e r e n c e be t w e e n m e a ns ( p< 01) f or a l l va r i a bl e s e xc e pt hi s t a m i ne 2 bur de n a nd t ube f e e di ng da ys T ube f e e di ng da ys w a s s i gni f i c a nt a t p< 05 a nd hi s t a m i ne 2 bu r de n w a s n on s i gni f i c a nt T a bl e 5 i de nt i f i e s t he va r i a bl e s m e a ns a nd r e s ul t s o f t he pa i r e d t e s t i ng f or e a c h of t he s e va r i a bl e s T a bl e 5 C om par i s on of C as e and C ont r ol M e ans Sc or e s on C ont i nuous P r e di c t or s P r e di c t or C a s e s ( n= 66) C ont r ol s ( n= 66 t p L e ngt h of e xpos ur e / r i s k pe r i od 17. 65 24. 77 9. 80 000 L a xa t i ve / bow e l pr e p bu r de n 6. 68 6. 12 3. 43 001 P r ot on P um p I nhi b i t or bur de n 8. 81 15. 56 7. 53 000 H i s t a m i ne 2 bur de n 2. 02 1. 29 2. 94 769 A nt i bi ot i c bur de n 16. 95 15. 42 6. 70 000 T ube f e e di ng da ys 4. 12 4. 97 2. 17 032 S e r um a l bum i n 3. 72 3. 58 30. 93 000 T ot a l l ym phonc yt e c ount 1. 24 1. 12 4. 25 000 A ge 68. 47 71. 27 66. 77 000 T e m por al and Spat i al C l us t e r i ng E xa m i na t i on of t he num be r of c a s e s by uni t by m o nt h r e ve a l e d no pa t t e r ns s ugge s t i ve of a n i ns t i t ut i on w i de out br e a k dur i ng t he t i m e f r a m e of t he s t udy. T he r e

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57 w e r e 7 i ns t a nc e s of t e m por a l a nd s pa t i a l c l us t e r i ng of c a s e s i de nt i f i e d. F ou r o f t he 7 c l us t e r s oc c ur r e d on t he s a m e m e di c a l nu r s i ng c a r e uni t A l l of t he c l us t e r i ng oc c ur r e d dur i ng t he m ont hs of M a r c h t hr ough A ugus t i n di f f e r e nt ye a r s T hi s t e m po r a l a nd s pa t i a l c l us t e r i ng unde r s c or e s t he i m por t a nc e o f t he m a c r oe nvi r onm e nt i n t he s pr e a d of t hi s di s e a s e U ni v ar i at e A nal y s i s T a bl e 6 i l l us t r a t e s r e s ul t s of t he uni va r i a t e l ogi s t i c r e gr e s s i on f or hos t m i c r oe nvi r onm e nt a l a nd m a c r oe nvi r onm e nt a l c ha r a c t e r i s t i c s f or bot h c a s e s a nd c ont r ol s T a bl e 6 Sam pl e D e s c r i pt i on and P r e di c t or s of H os pi t al A c qui r e d C D A D G r oup U ni va r i a t e l ogi s t i c r e gr e s s i on C ha r a c t e r i s t i c T ot a l ( N = 1 32) C ont r ol s ( n= 66) C a s e s ( n= 66) O R 95% C I L ow e r U ppe r p H os t c ha r a c t e r i s t i c s A ge ( ye a r s ) M 69. 87 71. 27 68. 47 1. 013 997 1. 029 124 S D 11. 69 10. 28 12. 88 S e ve r i t y of i l l ne s s % m i nor i l l ne s s 16. 67 25. 76 7. 58 1. 845 1. 322 2. 574 000 % m ode r a t e i l l ne s s 45. 45 54. 55 36. 36 % m a j or i l l ne s s 33. 33 16. 67 50. 00 % c a t a s t r oph i c i l l ne s s 4. 54 3. 03 6. 06 S e r um a l bum i n ( m g/ dl ) M 3. 65 3. 65 3. 65 0. 863 752 989 034 S D 0. 73 0. 72 0. 74 % hypoa l bum i ne m i c 57. 58 57. 58 57. 58 L ym phoc yt e s M 1. 18 1. 12 1. 24 0. 915 735 1. 139 424 S D 0. 74 0. 77 0. 72 % l ym phoc yt ope ni c 52. 27 45. 45 59. 09 M a c r oe nvi r onm e nt a l c ha r a c t e r i s t i c L e ngt h of e xpos ur e ( da ys ) M 21. 21 24. 77 17. 65 1. 008 999 1. 018 085 S D 23. 03 26. 21 18. 87

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58 T a bl e 6 ( C ont i nue d) G r oup U ni va r i a t e l ogi s t i c r e gr e s s i on C h a r a c t e r i s t i c T ot a l ( N = 1 32) C ont r ol s ( n= 66) C a s e s ( n= 66) O R 95% C I L ow e r U ppe r p M i c r oe nvi r onm e nt a l e xpos ur e c ha r a c t e r i s t i c s L a xa t i ve s / pr e ps M 6. 40 6. 12 6. 68 999 989 1. 009 851 S D 16. 44 15. 98 17. 01 % e xpos e d ( > 1D D D ) 31. 82 31. 82 31. 82 P r ot on p um p i nhi bi t o r s M 12. 18 15. 56 8. 81 1. 017 1. 002 1. 032 023 S D 18. 20 21. 72 13. 13 % e xpos e d ( > 1D D D ) 65. 15 65. 15 65. 15 H i s t a m i ne 2 bl oc ke r s M 1. 65 1. 29 2. 02 990 961 1. 020 516 S D 5. 98 4. 22 7. 35 % e xpos e d ( > 1D D D ) 14. 39 15. 15 13. 64 A nt i bi ot i c bur de n M 16. 18 15. 418 16. 95 1. 002 994 1. 010 684 S D 25. 14 24. 642 25. 804 % e xpos e d ( > 1D D D ) 78. 03 72. 73 83. 33 T ube f e e di ng ( da ys ) M 4. 55 4. 97 4. 12 1. 002 991 1. 012 768 S D 16. 10 17. 37 14. 85 % e xpos e d ( > 1da y) 17. 42 16. 67 15. 15 T hi s a na l ys i s i de nt i f i e d a ge s e ve r i t y of i l l ne s s s e r um a l bum i n l e ve l l e ngt h of e xpos ur e a nd pr ot on pum p i nhi bi t o r d r ug bur de n a s s t a t i s t i c a l l y s i gni f i c a nt p r e di c t or s of c a s e s t a t us ( p< 25) M ul t i v ar i at e A nal y s i s and M ode l E v al uat i on C ondi t i ona l l ogi s t i c r e gr e s s i on a na l ys i s vi a a C ox r e gr e s s i on pr oc e dur e w a s us e d t o i de nt i f y pr e di c t or va r i a bl e s s i gni f i c a nt l y a s s oc i a t e d w i t h c l a s s i f i c a t i on of C D A D c a s e s t a t us F ol l ow i ng a n i ni t i a l m ode l i ng p r oc e s s onl y t hr e e v a r i a bl e s r e m a i ne d a s s i gni f i c a nt pr e di c t or s of c a s e s t a t us : s e ve r i t y of i l l ne s s a nt i bi ot i c e xpos ur e a nd l e ngt h of e xpos ur e / r i s k pe r i od. T a bl e 7 p r e s e nt s t he r e s ul t s of t he c ondi t i ona l l ogi s t i c r e gr e s s i on

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59 m ode l i ng. I nc r e a s e d s e ve r i t y of i l l ne s s a de c r e a s e i n t he num be r o f D e f i ne d D a i l y D os e s of a nt i bi ot i c a nd a n i nc r e a s e i n t he l e ngt h of hos pi t a l i z a t i on pr i or t o s ym pt om de ve l opm e nt w e r e a l l s i gni f i c a nt l y a s s oc i a t e d w i t h C D A D c a s e s t a t us T he ove r a l l m ode l w a s s i gni f i c a nt a t p= 000. T he c a l c ul a t e d H os m e r a nd L e m e s how e s t i m a t i on of R 2 w a s 25 274, i ndi c a t i ng t ha t t he m ode l e xpl a i ns a ppr oxi m a t e l y 25 % of t he va r i a nc e i n C D A D out c om e I t s houl d be not e d, how e ve r t ha t l ow R 2 va l ue s i n l ogi s t i c a r e t he nor m ( H os m e r & L e m e s how 2000, p 167) T a bl e 7 C ondi t i onal L ogi s t i c R e gr e s s i on of V ar i abl e s P r e di c t i v e of C D A D C as e St at us V a r i a bl e B W a l d p O R 95% C I S e ve r i t y of i l l ne s s 739 13. 506 000 2. 094 1. 412, 3. 106 A nt i bi ot i c e xpos ur e 021 6. 007 014 979 962, 996 L e ngt h of e xpos ur e 022 5. 933 015 1. 022 1. 004 1. 040 N ot e : R 2 = 25. 274 ( H os m e r & L e m e s how ) M ode l 2 = 23. 123 p= 000 O R = O dds R a t i o, C I = C onf i de nc e I nt e r va l A s c ova r i a t e s w e r e r e m ove d f r o m t he m ode l t he O dds R a t i os ( O R ) f or a l l ot he r c ova r i a t e s r e m a i ni ng i n t he m ode l w e r e e xa m i ne d t o de t e r m i n e i f t he r e w a s a l a r ge m a gni t ude i n t he c ha nge of t he O R w hi c h m i ght i n di c a t e c onf oundi ng. O nl y one c l i ni c a l l y s i gni f i c a nt c ha nge w a s not e d. B ot h a l bu m i n a nd l ym phoc yt e c ount a ppe a r e d t o s e r ve a s s l i ght c onf ounde r s f or t he m e a s ur e o f s e ve r i t y of i l l ne s s a l t hough t he m a gni t ude of t he c ha nge i n t he s e ve r i t y c oe f f i c i e nt w a s s m a l l f or e a c h va r i a bl e ( 5 % f or s e r um a l bum i n, 3 % f o r l ym phoc yt e c ount )

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60 F ol l ow i ng t he i de nt i f i c a t i on o f t he i ni t i a l m ode l a num be r of i nt e r a c t i ons w e r e t e s t e d vi a f or c e d e nt r y P ot e nt i a l i nt e r a c t i ons w e r e i de nt i f i e d f or num e r ous c om bi na t i ons t ha t m i ght be c l i ni c a l l y i m po r t a nt r e l a t e d t o a ge s e r um a l bum i n a nt i bi ot i c dr ug bur de n, a nd t he l e ngt h o f e xpos ur e / r i s k pe r i od. T a bl e 8 l i s t s t he i nt e r a c t i ons t e s t e d a nd t he out c om e of e a c h t e s t N one o f t he s e i nt e r a c t i ons w a s f ound s t a t i s t i c a l l y s i gnf i c a nt T a bl e 8 C ondi t i onal L ogi s t i c R e gr e s s i on of I nt e r ac t i on E f f e c t s as P r e di c t or s of C as e St at us I nt e r a c t i on B W a l d p O R 95% C I A ge x A nt i bi ot i c s 021 076 783 980 846, 1 135 A ge x A l bum i n 1 56 018 893 1. 169 120, 11. 414 A ge x L ym phoc yt e s 116 008 927 1. 123 094, 13. 432 A ge x L a xa t i ve s 000 034 853 1. 00 1. 00, 1. 00 A ge x P r ot on pum p i nhi bi t or 031 076 783 1. 031 8289, 1. 283 A ge x H 2 bl oc ke r A ge x L e ngt h of e xpos ur e 015 038 846 985 844, 1. 149 A l bum i n x L ym phoc yt e 2. 520 018 893 12. 431 000, 1E + 017 A l bum i n x P r ot on pu m p i nhi bi t or 426 376 540 1. 532 392, 5. 984 A l bum i n x L e ngt h of e xpos ur e 194 076 783 824 207, 3. 275 A nt i bi ot i c s x A l bum i n 425 250 617 654 12 3, 3. 460 A nt i bi ot i c s x H 2 bl oc ke r s 076 403 526 926 732, 1. 173 L e ngt h of e xpos ur e x L ym phoc yt e s 195 038 846 823 116, 5. 859

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61 D F B e t a r e s i dua l s w e r e e xa m i ne d t o i de nt i f y da t a p oi nt s t ha t m a y ha ve be e n undul y i nf l ue nt i a l f or a pa r t i c ul a r c ova r i a t e o r w hi c h di d not f i t t he m ode l w e l l A l l of t he s e r e s i dua l s w e r e ve r y s m a l l ( < 0 06) C ol l i ne a r i t y w a s a s s e s s e d vi a ge ne r a t i on of a m a t r i x of c o r r e l a t i ons us i ng t he non pa r a m e t r i c S pe a r m a n r ho S t a t i s t i c a l l y s i gni f i c a nt c or r e l a t i ons w e r e a l l of l ow m a gni t ude ( < 50) e xc e pt f o r t he c or r e l a t i ons be t w e e n l e ngt h of e xpos ur e w i t h a nt i b i ot i c bur de n ( 541, p= 000) a nd t ube f e e di ng da ys w i t h a nt i bi ot i c bur de n ( 513 p= 000) C ol l i ne a r i t y di a gnos t i c s i n t he l i ne a r r e g r e s s i on f unc t i on r e ve a l e d no t ol e r a nc e va l ue s < 0. 1 a nd no V I F va l ue s > 10, i ndi c a t i ng t ha t t he r e w e r e no s e r i ous pr obl e m s w i t h c ol l i ne a r i t y c a us e d by t he s e c or r e l a t i ons R e c e i ve r O pe r a t or C ha r a c t e r i s t i c ( R O C ) c ur ve s w e r e ge ne r a t e d f o r e a c h of t he pr e di c t or s i n t he m ode l F i gur e 3 i l l us t r a t e s t he p l ot of s e ns i t i vi t y ve r s us 1 s pe c i f i c i t y f or t he S e ve r i t y o f I l l ne s s i nde x f or a l l pos s i bl e c ut poi nt s T he a r e a unde r t he c u r ve i s 776 i ndi c a t i ng a n a c c e pt a bl e l e ve l of di s c r i m i na t i on. T he a r e a unde r t he c ur ve f or l e ngt h of e xpos ur e w a s l e s s a c c e pt a bl e a t 620. T he pl ot f o r a nt i bi ot i c bur de n w a s ne a r l y non di s c r i m i na t or y w i t h a n a r e a unde r t he c ur ve of 53 7.

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62 F i gur e 3. R O C c ur ve f o r S e ve r i t y o f I l l ne s s i nde x. A r e a unde r t he c u r ve = 776. F i gur e 4. R O C c ur ve f o r l e ngt h of e xpos ur e A r e a unde r c ur ve = 620.

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63 F i gur e 5. R O C c ur ve f o r a nt i bi o t i c bur de n A r e a unde r c ur ve = 537. H y pot he s i s T he s t udy or i g i na l l y hypot he s i z e d t ha t s e ve r i t y of i l l ne s s l e ngt h of e xpos ur e a nd m a l nut r i t i on a r e s i gni f i c a nt p r e di c t or s of C D A D c a s e s s t a t us w he n c a s e s a nd c ont r ol s a r e m a t c he d f or a dm i s s i on da t e a nd ge ogr a phi c uni t o f hos pi t a l a nd a f t e r c ont r ol l i ng f o r t he e f f e c t s of a ge t ube f e e di ng c a t ha r t i c a dm i ni s t r a t i o n, a nt i bi ot i c t he r a py, a nd a c i d s uppr e s s i on t he r a py. T h i s s a m pl e s ugge s t s t ha t bot h s e ve r i t y of i l l ne s s a nd l e ngt h o f e xpos ur e a r e s i gni f i c a nt pr e di c t o r s but t ha t m a l nut r i t i on e s t i m a t e d by t w o l a bor a t o r y i ndi c a t or s s e r um a l bum i n a nd l ym phoc yt e c ount i s not a n a c c ur a t e pr e di c t o r I t w a s a nt i c i pa t e d t ha t a nt i bi ot i c e xpos ur e m i ght r e pr e s e nt a n e f f e c t m odi f i e r r a t he r t ha n a pr e di c t or H ow e ve r a nt i bi ot i c e xpos ur e qua nt i f i e d by c um ul a t i ve D e f i ne d D a i l y D os e s w a s i de nt i f i e d a s a s i gni f i c a nt i nde pe nde nt p r e di c t or of C D A D c a s e s t a t us a nd f a i l e d t o de m ons t r a t e a ny i nt e r a c t i on e f f e c t s w he n t e s t e d i n c om bi n a t i on w i t h a num be r o f bi ol ogi c a l l y pl a us i bl e c ova r i a t e s

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64 C ha pt e r F i ve D i s c us s i on T he pur pos e of t hi s s t udy w a s t o t e s t a n e c ol ogi c a l m ode l f or i t s us e f ul ne s s i n pr e di c t i ng t he de ve l opm e nt of C l os t r i di um di f f i c i l e a s s oc i a t e d di a r r he a i n hos pi t a l i z e d a d ul t s T hi s c ha pt e r di s c us s e s t he f i ndi ngs of t he s t udy, c onc l us i ons a bout t he f i ndi ngs l i m i t a t i ons of t he s t udy, a nd i m pl i c a t i ons f or nu r s i ng pr a c t i c e a nd e duc a t i on, a s w e l l a s f ut ur e nur s i ng r e s e a r c h. B a s e d on a n e c ol ogi c a l m ode l i t w a s hypot he s i z e d t h a t s e ve r i t y o f i l l ne s s l e ngt h of e xpos ur e a nd m a l nut r i t i on w oul d s i gni f i c a nt l y p r e di c t t he de ve l opm e nt o f C D A D c a s e s t a t us w he n c a s e s a nd c ont r ol s a r e m a t c he d f or a d m i s s i on da t e a nd ge ogr a phi c un i t of hos pi t a l a nd a f t e r c ont r ol l i ng f o r t he e f f e c t s of a g e t ube f e e di ng, c a t ha r t i c a dm i ni s t r a t i on, a nt i bi ot i c t he r a py, a nd a c i d s uppr e s s i on t he r a py. Se v e r i t y of I l l ne s s A l t hough t he por t i on of t he s a m pl e r a t e d a s c a t a s t r ophi c on t he S e ve r i t y o f I l l ne s s I nde x w a s l e s s t ha n 20% t he po r t i on o f c a s e s r a t e d a s c a t a s t r ophi c w a s doubl e t ha t of c ont r ol s A n e ve n gr e a t e r di s pa r i t y w a s obs e r ve d i n t he c a t e gor y o f m a j o r i l l ne s s w i t h 50% of c a s e s a nd onl y 16. 67 % of c ont r ol s e xhi bi t i ng c ha r a c t e r i s t i c s of m a j or i l l ne s s M or e t ha n 80% of c ont r ol s f e l l i nt o e i t he r m ode r a t e or m i no r s e ve r i t y of i l l ne s s c a t e gor i e s but onl y l e s s t ha n 45% o f c a s e s w e r e s i m i l a r l y r a nke d S e ve r i t y of i l l ne s s w a s i de nt i f i e d a s a s t a t i s c a l l y s i gni f i c a nt i nde pe nde nt pr e di c t o r of C D A D c a s e s t a t us f or t hi s s a m pl e f o l l ow i ng c on di t i ona l l ogi s t i c r e g r e s s i on a na l ys i s

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65 T hi s f i ndi ng i s c ons i s t e nt w i t h pr e vi ous s t udi e s us i ng t he H or n S e ve r i t y of I l l ne s s i nde x ( M c F a r l a nd, 1995; K yne 2002; V e s t a 2005 ) L i k e w i s e i t i s c ons i s t e nt w i t h t he w or k o f M ode na ( 2005) w ho c ha r a c t e r i z e d s e ve r i t y i n r e l a t i on t o e ve n t s s uc h a s m e c ha ni c a l ve nt i l a t i on a nd I C U u t i l i z a t i on, c r i t e r i a t ha t a r e pa r t of t he H or n S e ve r i t y i nde x. L e ngt h of E x pos ur e L e ngt h of e xpos ur e w a s de f i ne d a s t he nu m be r o f da ys w hi c h e l a ps e d f r om t he da t e of hos pi t a l a dm i s s i on unt i l t he s ubm i s s i on of a s t ool s a m pl e f or C l os t r i di um di f f i c i l e l a bor a t or y t e s t i ng. T hi s va r i a bl e w a s de r i ve d f or t hi s s t udy f r om t he e c ol ogi c a l m ode l s pe c i f yi ng e xt r i ns i c e c ol ogi c f a c t or s a f f e c t i ng i nf e c t i ous di s e a s e e xpos ur e B a s e d on t he m ode l bot h t e m por a l a nd s pa t i a l di s t a nc e m us t be i nc r e a s e d t o pr e ve nt t he t r a ns m i s s i on of m i c r obi a l c ont a m i na nt s t o s us c e pt i bl e hos t s P r e vi ous r e s e a r c he r s ha ve c ons i de r e d l e ngt h of t o t a l hos pi t a l s t a y a s a va r i a bl e bu t t hi s w a s s t udi e d pr i m a r i l y a s a p r oxy f or s e ve r i t y of i l l ne s s T he a ut ho r i s una w a r e of pr e vi ous s t udi e s c ons i de r i ng t e m por a l di s t a nc e a s a r i s k f a c t or f or a c qui s i t i on of t hi s di s e a s e I n t hi s s t udy, t he r e w a s a s t a t i s t i c a l l y s i gni f i c a nt di f f e r e nc e be t w e e n t he m e a n l e ngt h of e xpos ur e f or c a s e s a nd c ont r ol s ( 17. 65 ve r s us 24. 7 7 da ys ) L e ngt h of e xpos ur e w a s a l s o i de nt i f i e d a s a s t a t i s t i c a l l y s i gni f i c a nt i nd e pe nde nt pr e di c t or of C D A D c a s e s t a t us f ol l ow i ng m ul t i va r i a t e m ode l i ng. S pe c i f i c a l l y, t he l onge r a s ubj e c t ha d be e n hos pi t a l i z e d pr i or t o t he de ve l opm e nt of d i a r r he a a nd s u bs e que nt s t ool s a m pl e c ol l e c t i on, t he m or e l i ke l y t ha t t he di a r r he a w a s c a us e d by C l os t r i di um di f f i c i l e M al nut r i t i on T hi s s t udy a t t e m pt e d t o ope r a t i ona l i z e m a l nut r i t i o n by m e a ns of t hr e e c om m onl y a va i l a bl e l a bor a t or y t e s t s : s e r um a l bum i n, l ym pho c yt e c o unt a nd s e r um pr e a l bum i n

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66 S i nc e i m m unoc om pe t e nc e i s pa r t i a l l y de pe nde nt u pon pos i t i ve ni t r oge n ba l a nc e a nd i nt a ke of e s s e nt i a l vi t a m i ns a nd m i ne r a l s i t w a s hy pot he s i z e d t ha t m a l nut r i t i on e vi de nc e d by va l ue s be l ow t he l a bor a t or y s r e f e r e nc e va l ue s w oul d be a s s oc i a t e d w i t h C D A D s t a t us A l t hough t he or i gi na l da t a m i ni ng p r oc e s s us e d pr e a l bum i n t e s t r e s ul t s a s one of t he c r i t e r i a f or s e l e c t i on of a r e c or d f or s c r e e ni ng, onl y a s m a l l num be r of t he r e c or ds i nc l ude d pr e a l bum i n t e s t r e s ul t s dur i ng t he s a m e ho s pi t a l i z a t i on a s t he di a r r he a e pi s ode T he r e f or e t hi s va r i a bl e c oul d not be i nc l ude d i n t he a na l ys i s B e t w e e n c a s e s a nd c ont r ol s i de nt i c a l p r opor t i ons of s ubj e c t s de m ons t r a t e d hypoa l bum i ne m i a w hi l e a gr e a t e r pr opor t i on of c a s e s t ha n c ont r ol s e xhi bi t e d l ym phoc yt ope ni a ba s e d on t he l a bor a t o r y s r e f e r e nc e va l ue s f or e a c h t e s t H ow e ve r i n t hi s s a m pl e c a s e s de m ons t r a t e d s i gni f i c a nt l y hi gh e r m e a n a l bum i n a nd l ym phoc yt e va l ue s t ha n c a s e s . L ym phoc yt e c ount w a s not s i gni f i c a nt l y a s s oc i a t e d w i t h C D A D s t a t us i n e i t he r uni va r i a t e or m ul t i va r i a t e a na l ys i s S e r um a l bum i n w a s a s s oc i a t e d on uni va r i a t e a na l ys i s w i t h C D A D c a s e s t a t us but f a i l e d t o de m ons t r a t e a s i gni f i c a nt a s s oc i a t i on dur i ng m ul t i va r i a t e a na l ys i s T he uni va r i a t e a s s oc i a t i on i s c ons i s t e nt w i t h ot he r r e por t e d uni va r i a t e a s s oc i a t i ons be t w e e n s e r um a l bum i n a nd C D A D ( A l T ur e i hi e t a l 2005 A ndr e w s e t a l 2003, R a ve h, R a bi now i t z B r e ue r R ude ns ky, & Y i nnon, 2006 ; R ubi n e t a l 1995 ) R e c e nt l y, a s i gni f i c a nt m ul t i va r i a t e a s s oc i a t i on w a s r e por t e d be t w e e n hypoa l bum i ne m i a a nd C D A D ( P e l e d e t a l 2007 ) I n t ha t s t udy, a s i gni f i c a nt di f f e r e nc e e xi s t e d be t w e e n m e a n a l bum i n s c or e s of c a s e s a nd c ont r ol s a nd s ubj e c t s w e r e c a t e gor i z e d f or t he l ogi s t i c r e g r e s s i on a na l ys i s ba s e d on a s e l e c t e d c ut poi nt t o i nd i c a t e hypoa l bum i ne m i a T he da t a gr oup i n t hi s p r e s e nt s t udy a l s o e xhi bi t e d a s t a t i s t i c a l l y

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67 s i gni f i c a nt di f f e r e nc e i n m e a n a l bum i n s c or e s be t w e e n c a s e s a nd c ont r ol s on uni va r i a t e t e s t i ng w i t h a pa i r e d t t e s t I t s houl d be not e d t ha t i n t hi s s a m pl e i de nt i c a l pr opor t i ons of c a s e s a nd c ont r ol s ha d s e r um a l bum i n l e ve l s l ow e r t ha n t he l a bo r a t or y r e f e r e nc e l ow va l ue of 3 8 m g/ 100 m l O nl y 26% of t he e nt i r e s a m pl e ha d a l bum i n l e ve l s l ow e r t ha n a va l ue of 3 4 m g/ 100 m l A ge T hi s s a m pl e de m ons t r a t e d a s t a t i s t i c a l l y s i gni f i c a nt di f f e r e nc e be t w e e n t he m e a n a ge of c a s e s a nd c ont r ol s but f a i l e d t o p r oduc e a n i nde pe nde nt a s s oc i a t i on be t w e e n a ge a nd C D A D s t a t us on m ul t i va r i a t e a na l ys i s T hi s f i ndi ng i s i n c ont r a s t t o t he s ubs t a nt i a l s uppor t i n t he r e s e a r c h l i t e r a t ur e f or a dva nc i ng a ge a s a r i s k f a c t or f o r C D A D ( B i gna r d i 1998) T he s a m pl e i n t hi s s t udy w a s r e l a t i ve l y he t e r oge ne ous i n t e r m s of a ge a nd t hi s r e pr e s e nt s a de pa r t ur e f r om s a m pl e s i n ot he r s t udi e s T hi s br oa de r r a nge of s ubj e c t a ge s m a y be a r e f l e c t i on of t he s pe c i f i c V e t e r a n s A dm i ni s t r a t i on M e di c a l C e nt e r popul a t i on f r om w hi c h t he s a m pl e w a s dr a w n. M i c r oe nv i r onm e nt al E x pos ur e V ar i abl e s T hi s s t udy i nc l ude d a nu m be r o f e xpos ur e s pr e vi o us l y i de nt i f i e d i n t he l i t e r a t ur e a s a f f e c t i ng t he ba c t e r i a l e c ol ogy of t he i nt e s t i na l t r a c t T he s e e xpos ur e s i nc l ude d l a xa t i ve or c a t ha r t i c dr ugs a c i d s uppr e s s i on dr ugs a nt i bi ot i c s a nd t ube f e e di ng I t w a s hypot he s i z e d t ha t t he s e va r i a bl e s w oul d not be s i gni f i c a nt pr e di c t or s o f C D A D s t a t us i n a s t udy de s i gn t ha t c a r e f ul l y c ons i de r e d c r i t e r i a f or c a s e a nd c ont r ol s e l e c t i on a nd m a t c he d f or bot h t e m por a l a nd s pa t i a l e xpos ur e da t a F or pur pos e s of t hi s s t udy, a n a t t e m pt w a s m a de t o qua nt i f y t he dos e r e s pons e phe nom e non f or m i c r oe nvi r onm e nt a l e xpos ur e t hr ough us e of s t a nda r di z e d m e a s ur e s

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68 F or dr ug e xpos ur e t he W or l d H e a l t h O r ga ni z a t i on s D e f i ne d D a i l y D os e s w e r e c om put e d f or e a c h c l a s s of d r ug a nd s um m e d t o p r oduc e a c o nt i nuous m e a s ur e of e xpos ur e F o r t ube f e e di ng, t he m e a s ur e w a s t he num be r of da ys of t ube f e e di ng pr i o r t o t he ons e t o f di a r r he a a nd s t ool t e s t i ng A l t hough a num be r o f s t udi e s ha ve c ons i de r e d t he s e s a m e va r i a bl e s e xpos ur e ha s of t e n be e n m e a s ur e d s t r i c t l y a s a di c hot om ous va r i a bl e T ube F e e di ng T hi s da t a f a i l e d t o de m ons t r a t e t ube f e e di ng e xpos ur e a s a s i gni f i c a nt p r e di c t or o f C D A D A l t hough ne a r l y a l l of t he s ubj e c t s t ube f e d dur i ng t he pe r i od e xpe r i e nc e d e nt e r a l nut r i t i on f o r m or e t ha n 2 w e e ks t he r e w e r e s i m pl y not e nough s ubj e c t s i n t he s a m pl e a m ong e i t he r c a s e s or c ont r ol s w ho r e c e i ve d t hi s t he r a py. T he r e f o r e t he r e w a s not s uf f i c i e nt pow e r t o de t e c t a di f f e r e nc e be t w e e n t he t w o g r oups C at har t i c B ur de n W he n m e a s ur e d a s dr ug bur de n ba s e d on t he t ot a l num be r of D e f i ne d D a i l y D os e s i nge s t e d dur i ng t he e xpos ur e pe r i od, c a t ha r t i c dr ug s f a i l e d t o de m ons t r a t e a s i gni f i c a nt e xpos ur e r i s k. A l t hough t he r e w a s a s t a t i s t i c a l l y s i gni f i c a nt di f f e r e nc e be t w e e n m e a n c a t ha r t i c dr ug bu r de ns of t he t w o g r oups bot h uni va r i a t e a nd m ul t i va r i a t e l ogi s t i c r e gr e s s i on r e ve a l e d non s i gni f i c a nt O R s f o r t hi s va r i a bl e A c i d Suppr e s s i on B ur de n A c i d s uppr e s s i on bur de n c ons i de r e d t he D D D s f o r bot h p r ot on pu m p i nhi bi t or dr ugs a nd hi s t a m i ne 2 bl oc ki ng a ge nt s N e i t he r c a t e gor y of dr ug w a s f ound t o be a s t a t i s t i c a l l y s i gni f i c a nt pr e di c t or o f C D A D w he n m e a s ur e d t hi s w a y. I n t h i s s a m pl e i de nt i c a l o r ne a r l y i de nt i c a l po r t i ons of bot h c a s e s a nd c ont r ol s ha d e xpos ur e t o a c i d s uppr e s s i on t he r a py, s o t ha t e ve n i f t hi s va r i a bl e ha d be e n m e a s ur e d a s bi na r y da t a

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69 s i m i l a r t o s om e p r e vi ous s t udi e s i t i s unl i ke l y t ha t i t w oul d ha ve p r ove n t o be a p r e di c t or A l t hough t w o p r os pe c t i ve c a s e s t udi e s ha ve r e c e nt l y r e por t e d s i gni f i c a nt m ul t i va r i a t e a s s oc i a t i on s f or a c i d s uppr e s s i on, bot h m e a s ur e d e xpos ur e ba s e d on s ubj e c t s r e por t i ng o f pr e s c r i be d dr ugs pr i o r t o hos pi t a l i z a t i on ( P e l e d e t a l 2007; Y e a r s l e y e t a l 2006) a nd t hus w e r e s ubj e c t t o r e c a l l bi a s L i ke w i s e ne i t he r s t udy f oc us e d on hos pi t a l a dm i ni s t e r e d a c i d s uppr e s s i ve dr ugs t he m os t m e a ni ngf ul i nf o r m a t i on a va i l a bl e t o t he be ds i de c l i ni c i a n. A nt i bi ot i c B ur de n T hi s s t udy de m ons t r a t e d t ha t a n i nc r e a s e i n a nt i bi o t i c dr ug bu r de n a c t ua l l y pr ovi de d a s l i ght de c r e a s e i n r i s k of t he de ve l opm e nt of hos pi t a l a c qui r e d C D A D T hi s f i ndi ng c ont r a s t s s ha r pl y w i t h ot he r s t udi e s w hi c h m e a s ur e e xpos ur e i n ot he r t e r m s s uc h a s t he num be r of dr ugs num be r of p r e s c r i be d dos e s num be r o f da ys of t he r a py. I n pr e vi ous r e s e a r c h, a dos e r e s pons e r e l a t i ons hi p ha s be e n de m ons t r a t e d f o r a nt i bi ot i c e xpos ur e T he de c r e a s e d dos e r e s pons e i n t hi s s t udy m a y ha ve oc c ur r e d f or s e ve r a l r e a s ons T he c om bi ne d D D D s of a l l c a t e gor i e s of a nt i bi ot i c s w e r e c ons i de r e d t oge t he r a s a gr oup, r e ga r dl e s s of t he t he r a pe ut i c or c he m i c a l c l a s s i f i c a t i on of t he a nt i b i ot i c w hi c h m a y a c c ount f or s om e of t he di f f e r e nc e s A na l ys i s of da t a by s pe c i f i c dr ug c a t e gor i e s m a y ha ve r e s ul t e d i n s om e de m ons t r a t i on of i nc r e a s e d r i s k. C a s e c ont r ol s t udi e s w hi c h e xa m i ne s pe c i f i c dr ugs or d r ug c a t e gor i e s a r e s ubj e c t t o c ons i de r a bl e s e l e c t i on bi a s pa r t i c ul a r l y i n pr os pe c t i ve s t udi e s i n w hi c h t he dr u g e xpos ur e of i n t e r e s t i s us e d a s a c r i t e r i on f o r s t udy pa r t i c i pa t i on. D r ug pr e s c r i bi ng pa t t e r ns va r y ge ogr a phi c a l l y a nd be t w e e n di f f e r e nt he a l t h s ys t e m s a nd t he a nt i bi ot i c f or m ul a r y a va i l a bl e t o c l i ni c i a ns va r i e s be t w e e n i ns t i t ut i ons m a ki ng c r os s c om pa r i s ons di f f i c ul t I t a l s o i s pos s i bl e t ha t

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70 a nt i bi ot i c e xpos ur e i n s om e s t udi e s m a y a c t ua l l y r e pr e s e nt t he c onf oundi ng f a c t or o f s e ve r i t y of i l l ne s s T he m or e s e ve r e l y i l l i ndi v i dua l r e m a i ns hos pi t a l i z e d l onge r t hus i s e xpos e d t o m or e dr ug t he r a py ove r a l l a nd m o r e e n vi r onm e nt a l s t r e s s or s L i m i t at i ons of t he St udy A s e r i ous l i m i t a t i on o f t hi s s t u dy w a s t he s m a l l s a m pl e s i z e obt a i ne d f or t he num be r of va r i a bl e s s c r e e ne d. A l a c k of s t a t i s t i c a l pow e r m a y ha ve i nf l ue nc e d t he f a i l ur e t o obt a i n s t a t i s t i c a l s i gni f i c a nc e f or s om e pr e di c t o r s A l t hough t he or i gi na l da t a pool w a s ve r y l a r ge t he s c r e e ni ng c r i t e r i a a nd m a t c hi ng c r i t e r i a w e r e ve r y s t r i c t t o de c r e a s e bi a s i de nt i f i e d i n e a r l i e r r e s e a r c h. A s a r e s ul t of t hi s s c r e e ni ng a nd m a t c hi ng pr oc e s s onl y 66 pa i r s c oul d be i de nt i f i e d f r om t he i ni t i a l 1, 737 r e c or ds T he hom oge ne i t y o f ge nde r f or t hi s s a m p l e i s a l s o a l i m i t a t i on. T he pr e dom i na nc e of m a l e s ubj e c t s i s not r e pr e s e nt a t i v e of t he ge ne r a l a c ut e c a r e hos pi t a l popul a t i on. T he da t a c ol l e c t i on pr oc e s s m a de no a t t e m pt t o de t e r m i ne e t hni c i t y of t he s ubj e c t s A l t hough pr e vi ous r e s e a r c h ha s not i de nt i f i e d a ny e t hni c di f f e r e nc e s i n t he de ve l opm e nt of C D A D i t i s pos s i bl e t ha t di f f e r e nc e s i n r e s pons e t o e xpos ur e s pa r t i c ul a r l y dr ug e xpos ur e s m a y va r y ba s e d on ge n om i c di f f e r e nc e s T he l a r ge num be r of m i s s i ng va l ue s f or t he p r e a l bum i n va r i a bl e ne c e s s i t a t e d r e m ova l of t hi s va r i a bl e f r om a ny t ype o f s t a t i s t i c a l m ode l i ng. E l i m i na t i on of t hi s va r i a bl e c om bi ne d w i t h t he s m a l l num be r o f t ube f e d s ubj e c t s m a ke s i t e xt r e m e l y di f f i c ul t t o de t e r m i ne t he i m pa c t of nu t r i t i ona l s t a t us on de ve l opm e nt of C D A D a m ong t hi s s a m pl e A l t hough l ym phoc yt e c ount pr ovi de s s om e i nf or m a t i on a bout nut r i t i ona l s t a t us s e r um a l bum i n i s i n f l ue nc e d by m a ny bi ol o gi c f a c t or s i n a ddi t i on t o nut r i t i on a nd c a nnot be c ons i de r e d a n a c c ur a t e m e a s ur e of nut r i t i ona l s t a t us

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71 T hi s s t udy us e d a r e t r os pe c t i ve c a s e c ont r ol de s i gn. A l t hough a n a t t e m p t w a s m a de t o e s t a bl i s h a t e m por a l r e l a t i ons hi p be t w e e n e xpos ur e a nd di s e a s e by e xc l udi ng s ubj e c t s hos pi t a l i z e d l e s s t ha n 2 da ys or di s c ha r ge d m or e t ha n 31 da ys be f o r e t he ons e t o f di a r r he a s ym pt om s i t i s s t i l l pos s i bl e t ha t a c t ua l e x pos ur e t o C l os t r i di um di f f i c i l e m i c r oor ga ni s m s oc c ur r e d pr i or t o or a f t e r hos pi t a l i z a t i on. T he de s i gn w a s a l s o vul ne r a bl e t o s e l e c t i on bi a s s i nc e c a s e s w e r e i ni t i a l l y i de nt i f i e d vi a da t a m i ni ng m e di c a l r e c or ds t o i de nt i f y t h os e w i t h a va i l a bl e da t a poi nt s f or f our s pe c i f i c l a bor a t or y t e s t s one be i ng t he t oxi n a s s a y f or t he d i s e a s e T he r e f o r e t h e c l i ni c i a ns c a r i ng f o r t he s ubj e c t s a t t he t i m e di a r r he a s ym pt om s w e r e i de nt i f i e d, i nt r od uc e d a f or m of di a gnos t i c bi a s i nt o t he s t udy, w hi c h w a s be yond t he c ont r ol o f t he r e s e a r c he r I f a c l i ni c i a n be l i e ve d t ha t C D A D w a s a pos s i bl e di f f e r e nt i a l di a gnos i s a s pe c i m e n w a s l i ke l y s ubm i t t e d. T he r e m a y ha ve be e n a ddi t i ona l pot e nt i a l s s ubj e c t s w i t h di a r r he a s ym pt om s w ho w oul d ha ve t e s t e d e i t he r pos i t i ve or ne ga t i ve f or C D A D c yt ot oxi n G e ne r al i z abi l i t y G i ve n t he l i m i t a t i ons o f t he s a m pl e a nd t he r e t r os pe c t i ve c a s e c ont r ol de s i gn, c a ut i on s houl d be us e d i n a ny a t t e m pt s t o ge ne r a l i z e t he s e f i ndi ngs t o ot he r a c ut e c a r e hos pi t a l s e t t i ngs T he l a c k of f e m a l e s ubj e c t s a nd t he c ons t r i c t e d a ge r a nge i ndi c a t e t he s e f i ndi ngs m a y not be a ppl i c a bl e t o ot he r s e t t i ngs T he s t udy s i t e i s l oc a t e d i n a m a j or m e t r opol i t a n a r e a w i t h nu m e r ous ot he r c om pr e he ns i ve hos pi t a l s a va i l a bl e G i ve n t he m e a n a ge of s t udy pa r t i c i pa nt s M e di c a r e i ns ur a nc e c ove r a ge w oul d qua l i f y m a ny o f t he s ubj e c t s f or t r e a t m e nt a t a ny of t he s e ot he r i ns t i t ut i ons I t i s i m pos s i bl e t o know w hy a n i ndi vi dua l m i ght be hos pi t a l i z e d a t a pa r t i c ul a r i ns t i t ut i on. T he r e f or e i t i s pos s i bl e t h a t

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72 ot he r hos t r e l a t e d va r i a bl e s e xi s t i nhe r e nt l y w i t h i n t he ve t e r a n s popul a t i on, w hi c h w e r e not m e a s ur e d i n t hi s s t udy I m pl i c at i ons f or N ur s i ng E duc at i on and P r ac t i c e T hi s s t udy pr e s e nt s s om e i m por t a nt i m pl i c a t i ons f or nur s i ng e duc a t i on a nd c l i ni c a l p r a c t i c e T he f r a m e w or k us e d t o o r ga ni z e t he s t udy s ugge s t s t ha t i f c l i ni c i a ns c a n i de nt i f y i nt r i ns i c hos t c ha r a c t e r i s t i c s t ha t m a ke t he m m or e s us c e pt i bl e t o di s e a s e t he c l i ni c i a n c a n a l t e r t he e xt e r na l e nvi r on m e nt a l c ond i t i ons t o i nc r e a s e s pa t i a l a nd t e m por a l di s t a nc e be t w e e n t he vul ne r a bl e i ndi vi dua l a nd t he ha r m f ul e nvi r onm e nt a l e xpos ur e T hi s s t udy i de nt i f i e d i nc r e a s e d l e ngt h of e xpos ur e i nc r e a s e d s e ve r i t y of i l l ne s s a nd a de c r e a s e i n a nt i bi ot i c dr ug bur de n a s i nde pe nde nt pr e di c t or s of C D A D de ve l opm e nt a m ong hos pi t a l i z e d a dul t s A s m or e vi r ul e nt s t r a i n s of C l os t r i di um di f f i c i l e c ont i nue t o e m e r ge c l i ni c i a ns m us t de ve l op ne w s t r a t e gi e s f or i nc r e a s i ng t e m por a l a nd s pa t i a l di s t a nc e be yond t he c ur r e nt l y e m pl oye d s ys t e m of uni ve r s a l pr e c a ut i ons c om bi ne d w i t h i s ol a t i on of i n f e c t e d pe r s ons S om e m e a ns of i s ol a t i ng w i l l ne e d t o oc c ur f or t he m os t s e ve r e l y i l l pe r s ons T hi s i s pa r t i c ul a r l y e vi de nt i n t he c r i t i c a l c a r e e nvi r onm e nt w he r e m os t pa t i e nt s ha ve e xt e ns i ve or ga n i nvol ve m e nt r e qui r e m ul t i pl e m e a n s of l i f e s uppor t a nd ha ve c om pl e x i nt e r r e l a t e d pa t hophys i ol ogi c de r a nge m e nt s U nf o r t una t e l y, t hi s i s a l s o t he s a m e e nvi r onm e nt i n w hi c h t r a di t i ona l s pa t i a l di s t a nc e i s l i m i t e d by de s i gn of t he uni t a nd t e m por a l di s t a nc e i s r a r e l y pos s i bl e due t o t he hi gh de m a nd f or c r i t i c a l c a r e be d pl a c e m e nt i n m ode r n hos pi t a l s T he r e f or e ne w s t r a t e gi e s m a y be ne c e s s a r y t o a c hi e ve s pa t i a l di s t a nc e s uc h a s s t r i c t s t ool c ont a i nm e nt a nd di s pos a l l i m i t a t i on of c a r e gi ve r s a nd a s s i gnm e nt of i nf e c t e d a nd non i nf e c t e d pa t i e nt s t o t ot a l l y di f f e r e nt c a r e t e a m s

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73 N ur s e e duc a t or s w or ki ng i n bot h p r e l i c e ns ur e a nd c ont i nui ng e duc a t i on s e t t i ngs f a c e a num be r o f c ha l l e nge s T h r ough c ont a m i na t i on of ha nds e qui pm e nt a nd uni f o r m s nur s e s c a n s e r ve a s a ve c t or f or t r a ns m i s s i on of C l os t r i di um di f f i c i l e s por e s C ont i nui ng t o t e a c h s t ude nt s a nd pr a c t i t i one r s p r e ve nt i on of i n f e c t i ous di s e a s e t hr ough t r a di t i ona l m e c ha ni s m s of i de nt i f i c a t i on a nd i s ol a t i on doe s no t f ul l y e na bl e t he m t o a ppr e c i a t e t he i m por t a nc e of i de nt i f yi ng t he vul ne r a bl e a t r i s k po pul a t i on t o p r ot e c t t he m f r om e xpos ur e N ur s e s w or ki ng i n p r a c t i c e s e t t i ngs w i t h c l i e nt s a t hi gh r i s k f o r i n f e c t i on, s uc h a s ne ona t a l a nd bone m a r r ow t r a ns pl a nt uni t s ha v e de m ons t r a t e d t ha t l i m i t a t i on of vi s i t a t i on, r e s t r i c t i on of a c c e s s t o t he c a r e uni t a nd a dhe r e nc e t o us e of ha ndw a s hi ng a nd ba r r i e r p r oduc t s c a n r e duc e t he i nc i de nc e of i n f e c t i ons a m ong hi gh r i s k pe r s ons E duc a t or s t e a c hi ng a bout i n f e c t i ous di s e a s e ne e d t o i nc l ude c ont e nt a bout i de nt i f i c a t i on of a t r i s k c l i e nt s a nd i nc r e a s i ng s pa t i a l a nd t e m po r a l di s t a nc e be t w e e n a t r i s k i ndi vi dua l s a nd i nf e c t e d i ndi vi dua l s N ur s e a dm i ni s t r a t or s m a y a l s o ne e d t o c ons i de r c h a nge s i n w or k a s s i gnm e nt vi s i t a t i on pol i c i e s a nd t he s pa t i a l a s s i gnm e nt of i n di vi dua l pa t i e nt s T hi s w i l l be pr obl e m a t i c gi ve n a g l oba l nur s i ng s hor t a ge H ow e ve r nos oc om i a l i nf e c t i ons m a y pr ove t o be a n e c onom i c bu r de n t ha t t hr e a t e ns t he c ont i n ue d vi a bi l i t y o f i ns t i t ut i ons pa r t i c ul a r l y i n a n e r a w he n t hi r d pa r t y pa ye r s a r e c hoos i ng t o w i t hhol d c om pe ns a t i on f or pr ob l e m s t ha t de ve l op du r i ng a n i ndi vi dua l pa t i e nt s s t a y w i t hi n a n a c ut e c a r e hos pi t a l R e c om m e ndat i ons f or F ut ur e R e s e ar c h N ur s e s m us t be c om e i nc r e a s i ngl y i nvol ve d i n r e s e a r c h c onc e r ni ng t he e pi de m i ol ogy a nd pr e ve nt i on of a l l t ype s of hos pi t a l a c qui r e d i nf e c t i o ns t o e ns ur e t ha t p r e di c t or s a nd pr e ve nt i on m e a s ur e s a r e w e l l gr ounde d a nd c l i ni c a l l y us e f ul

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74 F ut ur e r e s e a r c h r e ga r di ng C D A D s houl d i nc l ude m e a s ur e s t o de t e r m i ne i f ot he r c om m onl y us e d m e a s ur e s of di s e a s e s e ve r i t y or pa t i e nt a c ui t y m i ght be a s us e f ul i n pr e di c t i ng r i s k a s t he H or n S e ve r i t y o f I l l ne s s i nde x, pa r t i c ul a r l y t ool s t ha t a r e a l r e a dy w i de l y us e d by nur s e s s uc h a s t he A P A C H E I I s c o r i ng s ys t e m M or e r e s e a r c h i s ne e de d t o unde r s t a nd t he r e l a t i on s hi p be t w e e n dr ug e xpos ur e a nd C D A D A pr os pe c t i ve m ul t i c e nt e r c a s e c ont r ol s t udy w oul d e na bl e a c c um ul a t i on of s uf f i c i e nt da t a poi nt s t o de t e r m i ne m ul t i va r i a t e a s s oc i a t i on s T he r e i s a de f i ni t e ne e d f or a s t a nda r di z e d m e a s ur e o f d r ug e xpos ur e A l t h ough s om e w ha t t e di ous t hi s s t udy de m ons t r a t e s t ha t t he D D D s ys t e m i s one w a y i n w hi c h s t a nda r di z e d m e a s ur e s of dr ug e xpos ur e c oul d be c om pa r e d a c r os s s t udi e s T w o r e c e nt publ i c a t i ons ha ve i de nt i f i e d c ol oni z a t i on pr e s s ur e t he s um of da i l y poi nt pr e va l e nc e r a t e s of di s e a s e f or e a c h da y s pe n t i n t he e nvi r onm e nt o f e xpos ur e a s s i gni f i c a nt pr e di c t or s of C D A D de ve l opm e nt ( D ub be r k e e t a l 2007; L a w r e nc e e t a l 2007) C ol oni z a t i on pr e s s ur e i s a qua nt i f i a bl e w a y t o m e a s ur e t he va r i a bl e of e nvi r onm e nt a l s t r e s s or s i de nt i f i e d i n t he c onc e pt ua l f r a m e w or k f or t hi s s t udy. I nt e r ve nt i on s t udi e s t o de t e r m i ne s t r a t e gi e s f or di s e a s e pr e ve n t i on c oul d us e t hi s c onc e pt a s a n out c om e va r i a bl e A s a c ont i nuous va r i a bl e t hi s w oul d of f e r be ne f i t s i n s t udy de s i gn a nd da t a a na l ys i s ove r t r a di t i ona l bi na r y ou t c om e s C onc l us i ons T hi s s t udy c onf i r m e d s e ve r i t y of i l l ne s s a nd l e ngt h of e xpos ur e a s i nde pe nde nt pr e di c t or s of t he a c qui s i t i on of hos pi t a l a c qui r e d C l os t r i di um di f f i c i l e a s s oc i a t e d di a r r he a I t di d not c onf i r m m a l nut r i t i on a s a r i s k f a c t or a s hypot he s i z e d. A n i nc r e a s e i n t he num be r o f D e f i ne d D a i l y D os e s of a nt i bi ot i c s w a s f ound t o i ndi c a t e a s l i ght de c r e a s e

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75 i n di s e a s e r i s k, a de pa r t u r e f r om p r e vi ous r e s e a r c h m e a s ur i ng dr ug e xpos ur e i n ot he r w a ys T he s t udy s uppor t s t he us e o f a n e c ol ogi c m ode l t o he l p e xpl a i n t he phe nom e non of hos pi t a l a c qui r e d C D A D a nd i ndi c a t e s a f r a m e w or k f or f ut u r e r e s e a r c h r e ga r d i ng i nt r i ns i c hos t c ha r a c t e r i s t i c s s ugge s t i ng i nc r e a s e d r i s k, a nd i nt e r ve nt i on s t r a t e gi e s t o de c r e a s e e nvi r onm e nt a l s t r e s s or s on t he vul ne r a bl e hos t

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76 R e f e r e nc e s C i t e d A a s J G e s s e r t C E & B a kke n, J S ( 2003) R e c ur r e nt C l os t r i di um di f f i c i l e c ol i t i s : c a s e s e r i e s i nvol vi ng 18 pa t i e nt s t r e a t e d w i t h dono r s t ool a dm i ni s t e r e d v i a a na s oga s t r i c t ube C l i ni c al I nf e c t i ous D i s e as e s 36 ( 5) 580 586. A c ke r m a nn, G T hom a l i a S A c ke r m a nn F S c h a um a nn, R R odl of f A C & R uf B R ( 2005) P r e va l e nc e a nd c ha r a c t e r i s t i c s of ba c t e r i a a nd hos t f a c t or s i n a n out br e a k s i t ua t i on of a nt i bi ot i c a s s oc i a t e d di a r r he a J our nal of M e di c al M i c r obi ol ogy 54 149 153. A l E i da n, F : M c E l na y, J S c ot t M & K e a r ne y, M ( 2000) C l os t r i di um di f f i c i l e a s s oc i a t e d di a r r hoe a i n hos pi t a l i z e d pa t i e nt s J our nal of C l i ni c al P har m ac y and T he r ape ut i c s 25 101 109 A l T ur e i hi F I J H a s s oun, A W ol f K l e i n, G & I s e nbe r g, H ( 2005) A l bum i n l e ngt h of s t a y, a nd pr ot on pum p i nhi b i t or s : ke y f a c t or s i n C l os t r i di um di f f i c i l e a s s oc i a t e d di s e a s e i n nur s i ng hom e pa t i e nt s J our nal of t he A m e r i c an M e di c al D i r e c t or s A s s oc i at i on, 6 ( 2) 105 108. A ndr e w s C N R a boud, J K a s s e n, B O & E nn s R ( 2003) C l os t r i di um di f f i c i l e a s s oc i a t e d di a r r he a : pr e di c t or s of s e ve r i t y i n pa t i e n t s pr e s e nt i ng t o t he e m e r ge nc y de pa r t m e nt C anadi an J our nal o f G as t r oe nt e r ol ogy 17 ( 6 ) 369 373. A z i z E E A yi s S G oul d F K & R a w l i ns M D ( 2001 ) R i s k f a c t or s f o r t he de ve l opm e nt of C l os t r i di um di f f i c i l e t oxi n a s s oc i a t e d d i a r r hoe a : a pi l ot s t udy P har m ac oe pi de m i ol ogy & D r ug Saf e t y 10 ( 4 ) 30 3 308. B a c khe d, F L e y R E S onne nbur g J L P e t e r s on, D A & G or don J I ( 2005 ) H os t ba c t e r i a l m ut ua l i s m i n t he hum a n i n t e s t i ne Sc i e nc e 307 ( 5717 ) 1915 1920. B a l l ongue J S c hum a nn, C & Q ui gnon P ( 1997 ) E f f e c t s o f l a c t ul os e a nd l a c t i t ol on c ol oni c m i c r of l o r a a nd e nz ym a t i c a c t i vi t y Sc andi n av i an J our nal of G as t r oe nt e r ol ogy Suppl e m e nt 222 41 44. B a r but F D e c r e D L a l a nde V B ur gho f f e r B N ous s a i r L G i ga ndo n A e t a l ( 2005) C l i ni c a l f e a t ur e s o f C l os t r i di um di f f i c i l e a s s oc i a t e d di a r r hoe a due t o bi na r y t oxi n ( a c t i n s pe c i f i c A D P r i bos yl t r a ns f e r a s e ) pr oduc i ng s t r a i ns J our nal of M e di c al M i c r obi ol ogy 54 181 185 B a r but F M e yna r d, J L G ui gue t M A v e s a ni V B oc he t M V M e yoha s M C e t a l ( 1997 ) C l os t r i di um di f f i c i l e a s s oc i a t e d di a r r he a i n H I V i nf e c t e d pa t i e nt s : e pi de m i ol ogy a nd r i s k f a c t or s J our nal of A c qui r e d I m m une D e f i c i e nc y Sy ndr om e s & H um an R e t r ov i r ol ogy 16 ( 3) 176 18 1.

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90 T ha m l i ki t kul V D a npa kdi K & C hokl oi ka e w S ( 1996 ) I nc i de nc e of di a r r he a a nd C l os t r i di um di f f i c i l e t oxi n i n s t ool s f r om hos pi t a l i z e d pa t i e nt s r e c e i vi ng c l i nda m yc i n, be t a l a c t a m s o r nona nt i bi ot i c m e di c a t i ons J our nal of C l i ni c al G as t r oe nt e r ol ogy 22 ( 2) 161 163 T hom a s C S t e ve ns on, M & R i l e y, T V ( 2003) A nt i bi ot i c s a nd hos pi t a l a c qui r e d C l os t r i di um di f f i c i l e a s s oc i a t e d di a r r hoe a : a s ys t e m a t i c r e vi e w J our nal o f A nt i m i c r obi al C he m ot he r apy 51 1339 1350 T hom a s C S t e ve ns on, M W i l l i a m s on, D J & R i l e y, T ( 2002) C l os t r i di um di f f i c i l e a s s oc i a t e d di a r r he a : e pi de m i ol ogi c a l da t a f r om W e s t e r n A us t r a l i a a s s oc i a t e d w i t h m odi f i e d a nt i bi ot i c pol i c y. C l i ni c al I n f e c t i ous D i s e as e s 35 ( 12) 1457 1463 T ve de M & R a s k M a ds e n, J ( 1989) B a c t e r i ot he r a py f or c hr oni c r e l a ps i ng C l os t r i di um di f f i c i l e di a r r hoe a i n s i x pa t i e nt s L anc e t 8648 11 56 1160. va n de r W a a i j D ( 1989) T he e c ol ogy o f t he hum a n i nt e s t i ne a nd i t s c ons e que nc e s f o r ove r gr ow t h by pa t hoge ns s uc h a s C l os t r i di um di f f i c i l e A nnual R e v i e w s of M i c r obi ol ogy 43 69 87 V e r i t y, P W i l c ox, M H F a w l e y, W & P a r ne l l P ( 2001) P r os pe c t i ve e va l ua t i on o f e nvi r onm e nt a l c ont a m i na t i on by C l os t r i di um d i f f i c i l e i n i s ol a t i on s i d e r oom s J our nal of H os pi t al I nf e c t i on 49 204 209. V e s t a K S W e l l s P G G e nt r y, C A & S t i pe k, W J ( 2005 ) S pe c i f i c r i s k f a c t or s f or C l os t r i di um di f f i c i l e a s s oc i a t e d di a r r he a : a pr os pe c t i ve m ul t i c e nt e r c a s e c ont r ol e va l ua t i on. A m e r i c an J our n al of I nf e c t i on C ont r ol 33 ( 8) 469 472. W a l dvoge l F A ( 2004) I nf e c t i ous di s e a s e s i n t he 21s t c e nt ur y: ol d c ha l l e nge s a nd ne w oppor t uni t i e s I nt e r nat i onal J our nal of I nf e c t i ous D i s e as e s 8 5 12. W a r ny, M P e pi n J F a ng A K i l l gor e G T hom ps on, A B r a z i e r J e t a l ( 2005) T oxi n P r oduc t i on by a n E m e r gi ng S t r a i n o f C l os t r i di um di f f i c i l e a s s oc i a t e d w i t h H i gh O ut br e a ks of S e ve r e D i s e a s e i n N or t h A m e r i c a a nd E ur ope L anc e t 366 ( 9491) 1053 1054 W a t a na kuna kor n, P W W a t a na kuna kor n, C & H a z y, J ( 1996 ) R i s k f a c t or s a s s oc i a t e d w i t h C l os t r i di um di f f i c i l e d i a r r he a i n hos pi t a l i z e d a dul t pa t i e nt s : a c a s e c ont r ol s t udy s uc r a l f a t e i nge s t i on i s not a ne ga t i ve r i s k f a c t or I n f e c t i on C ont r ol & H os pi t al E pi de m i ol ogy 17 ( 4) 232 235. W e s t S K i ng V C a r e y T S L ohr K N M c K oy, N S ut t on, S F e t a l ( 2002 ) Sy s t e m s t o R at e t he St r e ngt h of Sc i e nt i f i c E v i de nc e ( N o. 02 E 016) R oc kvi l l e M D : A ge nc y f or H e a l t hc a r e R e s e a r c h a nd Q ua l i t y.

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91 W he l a n, K J udd, P A P r e e dy, V R & T a yl o r M A ( 2004 ) E nt e r a l f e e di ng: t he e f f e c t on f a e c a l out put t he f a e c a l m i c r of l or a a nd S C F A c onc e nt r a t i ons P r oc e e di ngs of t he N ut r i t i on Soc i e t y 63 ( 1) 105 1 13. W he l a n, K J udd, P A & T a yl or M A ( 2004 ) A s s e s s m e nt of f e c a l out put i n pa t i e nt s r e c e i vi ng e nt e r a l t ube f e e di ng: va l i da t i on of a nove l c ha r t E ur ope an J our nal of C l i ni c al N ut r i t i on, 58 ( 7 ) 1030 1037 W i l c ox, M H F a w l e y, W N W i ggl e s w or t h, N P a r ne l l P V e r i t y P & F r e e m a n, J ( 2003) C om pa r i s on of t he e f f e c t of de t e r ge nt ve r s us hypoc hl or i t e c l e a ni ng on e nvi r onm e nt a l c ont a m i na t i on a nd i nc i de nc e of C l o s t r i di um di f f i c i l e i n f e c t i on. J our nal of H os pi t al I nf e c t i on 54 ( 2) 109 114. W H O C ol l a bor a t i ng C e nt r e f o r D r ug S t a t i s t i c s M e t hodol ogy. A bout t he A T C / D D D s ys t e m R e t r i e ve d J ul y 14, 2007 ht t p: / / w w w w ho c c no/ a t c ddd/ X u, J & G or don, J I ( 2003) H ono r t hy s ym bi ont s P r oc e e di ng of t he N at i onal A c ade m y of Sc i e nc e s of t he U ni t e d St at e s of A m e r i c a, 100 ( 18 ) 10452 10459. Y e a r s l e y, K A G i l by, L J R a m a da s A V K ub i a k, E M F one D L & A l l i s on, M C ( 2006) P r ot on pum p i nhi b i t or t he r a py a s a r i s k f a c t or f o r C l os t r i di um di f f i c i l e a s s oc i a t e d di a r r hoe a A l i m e nt ar y P har m ac ol ogy & T he r ape ut i c s 24 613 619. Y i p, C L oe b, M S a l a m a S M os s L & O l de J ( 2001 ) Q ui nol one us e a s a r i s k f a c t or f or nos oc om i a l C l os t r i di um di f f i c i l e a s s oc i a t e d di a r r he a [ s e e c om m e nt ] I nf e c t i on C ont r ol & H os pi t al E pi de m i ol ogy 22 ( 9) 572 575 Z oppi G C i nque t t i M L uc i a no A B e ni ni A M une r A & B e r t a z onni M i ne l l i E ( 1998) T he i nt e s t i na l e c os ys t e m i n c hr oni c f unc t i o na l c ons t i pa t i on. A c t a P ae di at r i c a, 87 ( 8 ) 836 841

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93 D at a C ol l e c t i on Wor k s h e e t E xc l u s i on C r i t e r i a N O N E of t he f ol l ow i ng l oc at e d i n m e di c al r e c or d: D i a gnos i s of C D A D w i t hi n 12 m ont hs p r e c e di ng hos pi t a l i z a t i on H i s t or y of s ur gi c a l l y c r e a t e d c h r oni c di a r r he a H i s t or y of C r ohn s di s e a s e or unt r e a t e d c hr oni c u l c e r a t i ve c ol i t i s H i s t or y of di a r r he a p r e dom i na nt i r r i t a bl e b ow e l s yndr om e D i a be t i c ne ur opa t hy w i t h c hr oni c di a r r he a I n c l u s i on C r i t e r i a C as e D i ar r h e a C on t r ol D i a r r he a : D i a r r he a : > 2 s t ool s i n 24 hou r s > 2 s t ool s i n 24 hou r s l oos e a nd unf or m e d o r l i qui d c ons i s t e nc y l oos e a nd unf or m e d o r l i qui d c ons i s t e nc y c onc ur r e nt or w i t hi n 7 da ys of pos i t i ve f i ndi ng( s ) f or : c onc ur r e nt or w i t hi n 7 da ys of n e ga t i ve f i ndi ng( s ) f or : S t ool c ul t ur e f or t oxi n pr oduc i ng s t r a i n o f C d D a t e : S t ool c ul t ur e f or t oxi n pr oduc i ng s t r a i n o f C d D a t e : C e l l c ul t ur e c yt ot oxi n a s s a y D a t e : C e l l c ul t u r e c yt ot oxi n a s s a y D a t e : E I A t oxi n t e s t D a t e : E I A t oxi n t e s t D a t e : E ndos c opy w i t h ps e udom e m br a nous c ol i t i s D a t e : E ndos c opy w i t h ps e udom e m br a nous c ol i t i s D a t e : D e m ogr aph i c D at a A ge on da t e of a dm i s s i on: G e nde r : M a l e F e m a l e

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94 M at c hi ng I nf or m at i on D at e U n i t D at e U n i t D at e U n i t A d m i t T r a ns f e r T r a ns f e r T r a ns f e r T r a ns f e r T r a ns f e r T r a ns f e r T r a ns f e r D i s c h ar ge Se v e r i t y of I l l ne s s I nde x L E V E L S C h ar ac t e r i s t i c 1 2 3 4 Sta g e o f P ri nci pa l D i a g no s i s A s ym pt om a t i c M ode r a t e M a ni f e s t a t i on s M a j or M a ni f e s t a t i ons C a t a s t r ophi c M a ni f e s t a t i on s C o m pl i ca ti o ns N one or ve r y m i nor M ode r a t e l e s s i m por t a nt t ha n pr i nc i pa l di a gnos i s M a j or a s or m or e i m por t a nt t ha n pr i nc i pa l D x C a t a s t r ophi c de a t h or m a j or pe r m a ne nt di s a bi l i t y I ntera cti o ns N one or m i nor M ode r a t e M a j or C a t a s t r ophi c D e pe nd ency L ow M ode r a t e M a j or E xt r e m e P ro ced ur es ( N o n O. R ) N oni nva s i ve D i a gnos t i c or M i nor T he r a pe ut i c T he r a pe ut i c or I nva s i ve D i a gnos t i c N one m e r ge nc y L i f e S uppor t E m e r ge nc y L i f e S uppo r t R a t e P r om pt M ode r a t e D e l a y S e r i ous D e l a y N o R e s pons e R es po ns e to thera py R es o l u ti o n o f A cu te Sy m pto m s C om pl e t e E xt e ns i ve but i nc om pl e t e I nc om pl e t e a nd D i s a bl i ng N o R e s ol ut i on B ow e l pr e par at i on r e gi m e n N o l axat i ve s or b ow e l p r e p ar at i on d oc u m e n t e d E ne m a C ol os t om y i r r i ga t i on C a t ha r t i c : ____________________________________ C a t ha r t i c : __ __________________________________ N O E V I D E N C E t ha t pr e p be i ng a dm i ni s t e r e d f or c ol onos c opy t o di a gnos e P s e udom e m br a nous c ol i t i s

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95 T ube f e e di ng N o t u b e f e e d i n g d oc u m e n t e d T y pe of t u be N um be r of day s us e d pe r c ut a ne ous l y i ns e r t e d t ube ga s t r i c e nt e r a l na s oe nt e r a l t ube na s oga s t r i c or or oga s t r i c t ube N ut r i t i onal i ndi c e s w i t hi n f i r s t 7 day s of hos pi t al i z at i on L ab or at or y i n d i c at or L ab n or m al V al u e D at e H os p i t al D ay # Se r um al bum i n P r e al bum i n L y m phoc y t e c ount G as t r i c ac i d s uppr e s s i on A D r u g n am e B C at e gor y C D os age D D D D E D D D U n i t s F # D os e s G ( E ) x ( F ) B u r d e n P P I H 2 b l o c k e r P P I H 2 b l o c k e r P P I H 2 b l o c k e r P P I H 2 b l o c k e r

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96 A nt i bi ot i c e x pos ur e A D r u g n am e B C at e gor y C D os a ge D D D D E D D D U n i t s F # D os e s G ( E ) x ( F ) B u r d e n T O T A L A N T I B I O T I C B U R D E N

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97 A ppe ndi x B : R e c or d R e vi e w P r ot oc ol

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98 E l e c t r oni c M e di c a l R e c or d R e vi e w P r ot oc ol D a t a C ol l e c t i on S t e p L oc a t i on of I nf o r m a t i on 1. V e r i f y t ha t pot e nt i a l s ubj e c t doe s not m e e t e xc l us i on c r i t e r i a H i s t or y a nd phys i c a l A dm i t t i ng di a gnos i s 2. V e r i f y t ha t pot e nt i a l s ubj e c t m e e t s c r i t e r i a f o r i nc l us i on a s e i t he r c a s e or c on t r ol B ow e l r e c or d L a bor a t or y da t a E ndos c opy da t a 3. R e c or d a ge P a t i e nt i nf or m a t i on 4. R e c or d ge nde r P a t i e nt i nf or m a t i on 5. R e c or d da t e s of a dm i s s i on a nd di s c ha r ge P a t i e nt i nf or m a t i on 6. R e c or d da t e s of t r a ns f e r w i t hi n t he f a c i l i t y by r oo m num be r M e di c a t i on R e c or d 7. C om pl e t e S e ve r i t y of I l l ne s s I nde x: a S t a ge of p r i nc i pa l di a gnos i s a t a dm i s s i on = pe a k e xt e nt of o r ga n i nvol ve m e nt a s m a ni f e s t e d by t he pa t i e nt a t a dm i s s i on H i s t or y a nd phys i c a l e xa m i na t i on f i ndi ngs b. C om pl i c a t i ons = c om pl i c a t i ons of t he pr i nc i pa l di a gnos i s or c om pl i c a t i ons t ha t a r e a di r e c t r e s ul t of t he t he r a py, hos pi t a l i z a t i on or a c c i de nt s t ha t a r i s e dur i ng hos pi t a l i z a t i on D i s c ha r ge s um m a r y c I nt e r a c t i ons = c ondi t i ons or pr obl e m s ot he r t ha n t he pr i nc i pa l di a gnos i s a nd c om pl i c a t i ons t ha t ha ve no D i s c ha r ge s um m a r y d. P hys i ol ogi c r e l a t i ons hi p t o t he pr i nc i pa l di a gnos i s or t ha t c ont r i but e d t o or c a us e d t he i l l ne s s r e pr e s e nt e d by t he pr i nc i pa l di a gnos i s H i s t or y a nd phys i c a l D i s c ha r ge s um m a r y e D e pe nde nc y = de gr e e t o w hi c h t he pa t i e nt r e qui r e s m or e t ha n t he m i ni m a l l e ve l o f di r e c t c a r e f or t he pr i nc i pa l d i a gnos i s I t i nc l ude s de pe nde nc y t ha t i s a c ons e que nc e of t he p r i nc i pa l N ur s i ng a c ui t y r a t i ng N ur s i ng c a r e r e c or ds

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99 D a t a C ol l e c t i on S t e p L oc a t i on of I nf o r m a t i on di a gnos i s c om pl i c a t i ons a nd a c t i ve i nt e r a c t i ons T he r a t i ng s houl d be r e pr e s e nt a t i ve of t he pa t i e nt s m os t of t he t i m e de pe nde nc y d ur i ng t he e nt i r e hos pi t a l i z a t i on a nd t he de gr e e t o w hi c h m os t of t he t i m e l e ve l of c a r e i s gr e a t e r t ha n t he m i ni m um e xpe c t e d f o r t ha t pr i nc i pa l d i a gnos i s f N on ope r a t i ng r oom pr oc e dur e s = pe a k pr oc e dur a l i nt e r ve nt i ons unde r t a ke n E X C L U D I N G s ur gi c a l p r oc e dur e s pe r f or m e d i n a n ope r a t i ng r oo m T he T Y P E o f p r oc e dur e not t he num be r o f pr oc e dur e s pe r f or m e d de t e r m i ne s t he l e ve l of t hi s di m e ns i on C a r di a c a r r e s t r e c or d M e c ha ni c a l ve nt i l a t i on L a bor a t or y D i a gnos t i c i m a g i ng g. R a t e of r e s pons e t o t he r a py = r e s pons e t o t he t he r a pi e s i ns t i t ut e d f or t he pr i nc i pa l di a gnos i s a nd t he i m pa c t of c om pl i c a t i ons a nd a c t i ve i nt e r a c t i ons on t he hos pi t a l i z a t i on D i s c ha r ge s um m a r y h. R e m i s s i on of a c ut e s ym pt om s = e xt e nt t o w hi c h a pa t i e nt s t i l l s how s e vi de nc e of t he a c ut e i nj ur y or i l l ne s s r e l a t e d t o t he p r i nc i pa l di a gnos i s c om pl i c a t i ons or a c t i ve i nt e r a c t i ons a t t he t i m e o f di s c ha r ge e xc l udi ng pr e e xi s t i ng c ondi t i ons t ha t di d not c ha nge du r i ng t he hos pi t a l i z a t i on a nd f o r w hi c h no c ha nge w a s e xpe c t e d D i s c ha r ge s um m a r y 8. D e t e r m i ne i f bow e l pr e pa r a t i on w a s a dm i ni s t e r e d dur i ng hos pi t a l s t a y, a nd i f s o, r e c or d t he t ype o f pr e pa r a t i on a dm i ni s t e r e d. M e di c a t i on a dm i ni s t r a t i on r e c or d 9. D e t e r m i ne i f t ube f e e di ng w a s us e d dur i ng hos pi t a l i z a t i on, a nd i f s o, r e c or d t he num be r of da y s a dm i ni s t e r e d by t he a ppr op r i a t e t ype of f e e di ng t u be D i e t r e c or d 10. R e c or d t he l a bor a t or y va l ue f o r t he f i r s t t e s t c om pl e t e d dur i ng t he hos pi t a l i z a t i on R e c or d t he da t e o f s pe c i m e n c ol l e c t i on. T o de t e r m i ne t he hos pi t a l da y n um be r c ount t he da t e of a dm i s s i on a s da y 1. L a bor a t or y r e c or d 11. D e t e r m i ne ga s t r i c a c i d s uppr e s s i on e xpos ur e :

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100 D a t a C ol l e c t i on S t e p L oc a t i on of I nf o r m a t i on a R e c or d dr ug na m e i n c ol um n A M e di c a t i on R e c or d b. C he c k box f or c o r r e c t d r ug c a t e gor y i n c ol um n B c R e c or d t he dr ug dos a ge i n C ol um n C M e di c a t i on R e c or d d. R e c or d t he D e f i ne d D a i l y D os e ( D D D ) i n C ol um n D e D i vi de C ol um n C by C ol um n D t o de t e r m i ne t he num be r of D D D uni t s a nd r e c or d va l ue w i t h t w o de c i m a l pl a c e s i n C ol um n E P oc ke t c a l c ul a t or f R e c or d t he num be r o f dos e s r e c e i ve d pr i o r t o di a gnos t i c t e s t i ng f or C l os t r i di um di f f i c i l e i n C ol um n F M e di c a t i on R e c or d g. M ul t i pl y t he va l ue s i n C ol um ns E a nd F w i t h t w o de c i m a l pl a c e s t o de t e r m i ne t he dr ug bu r de n a nd r e c or d i n C ol um n G P oc ke t c a l c ul a t or h. A dd t he va l ue s of C ol um n G a nd r e c or d t he t ot a l A c i d S uppr e s s a nt bur de n P oc ke t c a l c ul a t or 12. D e t e r m i ne t he a nt i bi ot i c e xpos ur e a R e c or d dr ug na m e i n c ol um n A M e di c a t i on R e c or d b. C he c k box f or c o r r e c t d r ug c a t e gor y i n c ol um n B A nt i bi ot i c G ui de c R e c or d t he dr ug dos a ge i n C ol um n C M e di c a t i on R e c or d d. R e c or d t he D e f i ne d D a i l y D os e ( D D D ) i n C ol um n D A nt i bi ot i c G ui de e D i vi de C ol um n C by C ol um n D t o de t e r m i ne t he num be r of D D D uni t s a nd r e c or d va l ue w i t h t w o de c i m a l pl a c e s i n C ol um n E P oc ke t c a l c ul a t or f R e c or d t he num be r o f dos e s r e c e i ve d pr i o r t o di a gnos t i c t e s t i ng f or C l o s t r i di um di f f i c i l e i n C ol um n F num be r of dos e s r e c e i ve d dur i ng hos pi t a l da ys 1 30 onl y M e di c a t i on R e c or d

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101 D a t a C ol l e c t i on S t e p L oc a t i on of I nf o r m a t i on g. M ul t i pl y t he va l ue s i n C ol um ns E a nd F w i t h t w o de c i m a l pl a c e s t o de t e r m i ne t he dr ug bu r de n a nd r e c or d i n C ol um n G P oc ke t c a l c ul a t or h. A dd t he va l u e s of C ol um n G a nd r e c or d t he t ot a l A nt i bi ot i c bur de n

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102 A ppe ndi x C : I ns t i t ut i ona l R e vi e w B oa r d A ppr ova l

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105 A ppe ndi x D : J a m e s A H a l e y V A M C R e s e a r c h C om m i t t e e A ppr ova l

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1 A bout t he A ut hor S us a n E l a i ne S t e e l e r e c e i ve d a B a c he l or of S c i e nc e de gr e e i n N ur s i ng f r om A l br i ght C ol l e ge i n R e a di ng P e nns yl va ni a i n 1977 S he c om pl e t e d t he M a s t e r of S c i e nc e de gr e e i n A dul t H e a l t h N ur s i ng a t t he U ni ve r s i t y o f S out h F l or i da i n T a m pa F l o r i da i n 1984. I n a nur s i ng c a r e e r s pa nni ng m or e t ha n 30 y e a r s M s S t e e l e ha s w or ke d i n c om m uni t y he a l t h a nd a c ut e c a r e hos pi t a l s e t t i ngs i n t he r ol e of c l i ni c i a n, e duc a t or a nd a dm i ni s t r a t or S he s e r ve d f or 14 ye a r s a s w ound, os t om y a nd c ont i ne nc e c l i ni c a l nur s e s pe c i a l i s t a t B a yf r ont M e di c a l C e nt e r i n S t P e t e r s bur g, F l or i da i nc l udi ng a por t i on of t he t i m e e nga ge d i n doc t o r a l s t udi e s a t t he U ni ve r s i t y of S out h F l or i da M s S t e e l e ha s be e n a c t i ve l y i nvol ve d i n m a ny nu r s i ng or ga ni z a t i ons a nd s e r ve d a s t he P r e s i de nt of t he F l o r i da N ur s e s A s s oc i a t i on, D i s t r i c t T hi r t e e n, t he P r e s i de nt of t he S out he a s t R e gi on W ound, O s t om y a nd C ont i ne nc e N ur s e s A s s oc i a t i on ( W O C N ) a nd a m e m be r of S i gm a T he t a T a u t he i nt e r na t i ona l nur s i ng honor s oc i e t y. S he s e r ve s on t he C e nt e r f or C l i ni c a l I nve s t i ga t i on boa r d f o r t he W O C N a nd ha s publ i s he d i n t he s oc i e t y s j our na l S he i s a pr e s e nt e r a t na t i ona l c onf e r e nc e s a nd c ur r e nt l y s e r ve s a s a n A s s i s t a nt P r of e s s or of N u r s i ng a t G e or gi a C ol l e ge a nd S t a t e U ni ve r s i t y i n M i l l e dge vi l l e G e or gi a


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Steele, Susan Elaine.
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Development of an ecological model to predict risk for acquisition of Clostridium difficile-associated diarrhea during acute care hospitalization
h [electronic resource] /
by Susan Elaine Steele.
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[Tampa, Fla] :
b University of South Florida,
2008.
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Dissertation (Ph.D.)--University of South Florida, 2008.
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Text (Electronic dissertation) in PDF format.
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ABSTRACT: Background: The traditional model of infection control has failed to stop the spread of emerging infectious diseases such as Clostridium difficile-associated diarrhea (CDAD) in the acute care environment. Ecological models, which rely upon identification of susceptible hosts, offer an alternative to the prevention of deadly outbreaks. Previous epidemiological research has identified a number of risk factors associated with CDAD. Utilization of this body of research by nurses is limited due to methodological issues that introduce bias and confounding, and use of variables that have limited meaning to the practicing clinical nurse. Aim: The aim of this study was to develop an ecological model useful for nurses in predicting the susceptibility of individuals to CDAD during an acute care hospital stay. Method: A case-control study compared 66 cases with CDAD to 66 controls matched for the temporal and spatial risk factors of hospital admission date and geographic nursing care unit within the institution. The two subject groups were compared on variables of age, antibiotic burden, laxative or bowel preparation exposure, nutritional status, gastric acid suppression therapy, enteral feeding exposure, and severity of illness as measured on the Horn Severity of Illness index. All subjects were hospitalized between January 1, 2000 and December 31, 2006. Results: On univariate analysis, age, severity of illness, serum albumin levels, length of exposure, and proton pump inhibitor drug burden were significantly associated with CDAD status. Following multivariate analysis, only severity of illness, length of exposure, and decreased antibiotic drug burden were significantly associated with the development of hospital-acquired CDAD. Conclusions: This study supports the use of an ecological perspective in identifying risk factors and interventions to prevent the future spread of this infectious disease.
538
Mode of access: World Wide Web.
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Advisor: Susan C. McMillan, Ph.D.
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Nosocomial
Infection
Epidemiology
Intestinal
Pseudomembranous colitis
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Dissertations, Academic
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x Nursing
Doctoral.
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t USF Electronic Theses and Dissertations.
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u http://digital.lib.usf.edu/?e14.2367