Characteristics and Antibiotic Use Associated With Short-Term Risk of Clostridium difficile Infection Among Hospitalized Patients

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1 AJCP / Originl Article Chrcteristics nd Antiiotic Use Associted With Short-Term Risk of Clostridium difficile Infection Among Hospitlized Ptients Sol del Mr Aldrete, MD, 1 Mtthew J. Mgee, MPH, PhD, 2 Rchel J. Friedmn-Morco, MD, 1 Austin W. Chn, MD, 3 Grier G. Bnks, 4 Eileen M. Burd, PhD, 1,5 nd Colleen S. Krft, MD 1,5 From the 1 Division of Infectious Diseses, Emory University School of Medicine, Atlnt, GA; 2 Division of Epidemiology nd Biosttistics, Georgi Stte University School of Pulic Helth, Atlnt; 3 Division of Infectious Diseses, Duke University, Durhm, NC; 4 Emory Helthcre, Atlnt, GA; nd 5 Deprtment of Pthology nd Lortory Medicine, Emory University, Atlnt, GA. Key Words: Clostridium difficile; Moleculr; PCR; Repet; CDI Am J Clin Pthol June 2015;143: ABSTRACT Ojectives: Polymerse chin rection (PCR) hs een shown to hve n excellent sensitivity nd specificity for the detection of Clostridium difficile infection (CDI). Little is known out risk fctors for CDI within 14 dys of n initil negtive test. We sought to determine the chrcteristics mong hospitlized ptients ssocited with risk of shortterm cquisition of CDI. Methods: A cse-control study ws conducted. Cses were ptients who converted from PCR negtive to positive within 14 dys. Ech cse ws mtched with three controls. Conditionl logistic regression ws used to estimte the ssocition etween ptient chrcteristics nd CDI. Results: Of the 30 ptients in our study who hd positive PCR within 14 dys of first negtive PCR (cses), 15 (50%) occurred within 7 dys of the initil test. Cses hd higher proportion of intrvenous vncomycin use in the previous 8 weeks (odds rtio [OR], 3.38; 95% confidence intervl [CI], ) nd were less likely to hve recent ntivirl gent use (OR, 0.30; 95% CI, ) compred with controls. Conclusions: In hospitlized ptients, tretment with intrvenous vncomycin within the prior 8 weeks of first negtive PCR test for C difficile is risk fctor for short-term risk for hospitl-cquired CDI. Repet testing guidelines for C difficile PCR should tke into considertion ptients who my e t high risk for shortterm cquisition of CDI. Clostridium difficile ws not identified s the custive cteril gent for ntiiotic-relted dirrhe until the lte 1970s 1-3 nd is now recognized s the leding cuse of infectious nosocomil (hospitl-cquired) dirrhe. 3,4 The medin onset of symptomtic infection fter coloniztion with toxigenic C difficile spores is typiclly 2 to 3 dys. 5 Recently, moleculr testing hs een recognized s n importnt tool for C difficile infection (CDI) dignosis, with sensitivity nd specificity of 73% to 100% nd 91% to 100%, respectively. 6 Due to the high specificity of the test, most institutions using polymerse chin rection (PCR) to dignose CDI dvocte ginst repet testing within 7 dys of n initil negtive test. 7 Short-term cquisition of CDI, mening positive PCR test on repet testing fter n initil negtive test within 14 dys, is rre, ut it does occur in 1% to 4% of ptients who undergo repet testing, nd the specific risk fctors re unknown Ptients with short-term cquisition of CDI re exclusively inptients since they re most likely to undergo expedited repeted testing. 7,8 Since repet PCR testing for C difficile is costly, determining which ptients would likely enefit from repet testing could e used to guide lortory policies. 13 The overll gol of this study ws to determine if identifile ptient chrcteristics would improve the efficiency of short-term repet testing protocol for detecting C difficile. The ojectives of this study were to determine the rte of short-term cquisition (within 14 dys) of CDI fter n initil negtive PCR in our institution nd to determine ptient chrcteristics nd ntiiotic regimens ssocited with cquisition. Am J Clin Pthol 2015;143:

2 Aldrete et l / Risk of Short-Term CDI in Inptients Mterils nd Methods All PCR tests (n = 12,021, 100%) Repet PCR tests for sme ptient nd sme hospitl sty (n = 2,709, 22.5%) Initil negtive PCR test (n = 2,279, 19.0%) Repet testing t 14 dys (n = 1,500, 12.5%) Controls (n = 180, 1.5%) Cses (n = 60, 0.5%) Figure 1 Cses nd controls selected from the totl cohort of polymerse chin rection (PCR) tests performed from Novemer 2010 to Septemer n represents the numer of PCR tests (not ptients), nd % represents the percentge in comprison to the totl cohort of PCR tests (100% cohort = 12,021 PCR tests). This cse-control study ws conducted t universityffilited helth cre system in lrge metropolitn re in the Southest United Sttes. Adult ptients (ged 18 yers) hd feces smple ordered in ny clinicl setting (if the clinicin hd ny concern tht the ptient my hve hd CDI sed on the presence of fever, leukocytosis, dominl pin, dirrhe, or ileus). All PCR tests sent for testing for C difficile from Novemer 2010 to Septemer 2012 were eligile for the study. From the totl pool of PCR tests, those tht were repeted within 14 dys were identified. Cses were defined s ptients with n initilly negtive PCR test followed y susequent positive PCR test within 14 dys of the previous negtive test. Controls were chosen from the sme pool of repet PCR testing ut remined negtive during the entire hospitl sty Figure 1. Cses were mtched to three rndomly selected controls y (1) dys of hospitliztion to first C difficile PCR test (±1 dy) nd (2) ge (rnge ±10 yers). Two of the cses needed to e pired with two controls outside the ge rnge (±15 yers). These vriles were selected for mtching ecuse they re estlished confounders for risk of CDI. 14,15 All cses hd dirrhel disese indictive of CDI confirmed y chrt review nd were not considered colonized y C difficile. Retrospective chrt reviews were performed to otin ptient informtion on seline demogrphics, clinicl chrcteristics, nd comoridities from the electronic medicl record. We chose the following ptient chrcteristics to strct sed on the literture, including ge, 14 immunosuppression (chemotherpy 16, neutropeni 17, humn immunodeficiency virus 18 ), recent gstrointestinl (GI) surgery, 19 tue feeding, 20 use of proton pump inhiitors (PPIs), 21 nd durtion of hospitliztion. 22,23 Antimicroil use ws collected for the following mediction clsses (oth 8 weeks efore nd 14 dys fter first negtive test): -lctm, mcrolide, quinolone, minoglycoside, trimethoprimsulfmethoxzole, metronidzole, intrvenous vncomycin, orl vncomycin, ntifungl, ntivirl (cyclovir prophylxis), linezolid, tetrcycline, clindmycin, ztreonm, dptomycin, nd n other ctegory. Other clinicl vriles collected included if the ptient hd GI procedure 8 weeks prior to the first negtive test, PPI therpy use within 7 dys prior to the first negtive test, chronic steroid use ( 10 mg dily prednisone for 3 months), intensive cre unit (ICU) dmission within 7 dys prior to testing nd/or 48 hours fter testing, nd concurrent coinfections (either GI or systemic). Vriles tht were collected specificlly fter the first negtive test include ICU dmission s listed ove, ntiiotics during the 14-dy time period fter the first negtive test, nd tretment for CDI. All dt were entered into REDCp electronic dtse. 24 Lortory Mesures All feces smples sent to the clinicl microiology lortory for C difficile testing were processed ccording to the mnufcturer s instructions for the Xpert C difficile test (Cepheid, Sunnyvle, CA), which detects the presence of the toxin B gene y rel-time PCR. 25 Sttisticl Anlyses Dt were nlyzed using SAS version 9.3 (SAS Institute, Cry, NC) nd OpenEpi (Open Source Epidemiologic Sttistics for Pulic Helth, Atlnt, GA). The underlying rte for the helth cre system of short-term cquisition of CDI fter first negtive test ws clculted using the numer of new CDI cses divided y the person dys of hospitlized ptients who were tested for C difficile. This clcultion ssumed tht ll other individuls in the hospitl were not tested nd did not hve CDI. Those t risk included the sum of the person dys of the cses until their positive PCR nd the totl hospitl dys of the individuls who hd repet testing ut did not ecome PCR positive. The χ 2 test (for ctegoricl vriles) or Wilcoxon rnk-sum test (for continuous vriles) ws used to ssess the ssocition etween ptient chrcteristics nd incident CDI. A two-sided P vlue less thn.05 ws considered sttisticlly significnt. Conditionl logistic regression ws used to estimte the djusted ssocition (djusted odds rtios [ORs] 896 Am J Clin Pthol 2015;143:

3 AJCP / Originl Article Tle 1 Bseline Chrcteristics of Cses nd Controls Chrcteristic nd 95% confidence intervls [CIs]) etween covrites nd cquisition of C difficile, controlling for the mtched ptient chrcteristics (ge nd dys of hospitliztion to first PCR test). Ethicl Review The Emory University Institutionl Review Bord reviewed the study protocols with expedited pprovl for miniml risk. Results Cses (n = 30) Controls (n = 90) P Vlue Dys to first test, medin (IQR) 7.8 (5.8) 7.8 (5.7).95 Age, medin y (IQR) 58.8 (13.5) 58.6 (13.5).98 Sex Femle 11 (36.7) 46 (51.1).17 Mle 19 (63.3) 44 (48.9) Hospitl sty, medin d (IQR) 27.0 (18.0) 22.5 (18.0).39 Deth (ll cuses) 5 (16.7) 9 (10.0).33 Intensive cre unit sty c 11 (36.7) 43 (47.8).29 Dietes mellitus d 7 (23.3) 22 (24.4).90 Coinfection e 18 (60.0) 47 (52.2).46 Proton pump inhiitor 26 (86.7) 76 (84.4).77 Recent GI procedure f 8 (26.7) 12 (13.3).09 End-stge renl disese 6 (20.0) 11 (12.2).29 Leukemi 7 (23.3) 32 (35.6).22 Solid tumor 5 (16.7) 9 (10.0).33 Chemotherpy g 10 (33.3) 31 (34.4).91 Stem cell trnsplnt 1 (3.3) 1 (1.1).41 Solid orgn trnsplnt 2 (6.7) 9 (10.0).58 GI, gstrointestinl; IQR, interqurtile rnge. Vlues re presented s numer (%) unless otherwise indicted. Dys of hospitliztion prior to first Clostridium difficile polymerse chin rection (PCR) test. c Intensive cre unit sty within 7 dys efore or 48 hours fter first PCR test. d Defined s HA1c of more thn 6.5%. e Infection of ny type nd ny source t the time of PCR testing. f GI procedure of ny type within 8 weeks prior to first PCR test. g Received chemotherpy for mlignncy within the pst 8 weeks. During the study period, totl of 12,021 C difficile PCR tests were performed, nd of those, 9,312 PCR tests were excluded ecuse those ptients received only single test (Figure 1). Of the 2,709 tests tht remined, 430 PCR tests were further excluded ecuse the repeted testing ws performed fter first positive test. Of the 2,279 tht hd repet PCR test fter first negtive PCR, 1,500 were within 14 dys. From these, we identified 60 PCR tests or 30 cses of ptients with short-term CDI cquisition who hd n initil negtive PCR followed y positive PCR within 14 dys. Fifteen (50%) of the 30 cses cquired CDI within 7 dys of the first negtive PCR, which is within the window tht repet testing is typiclly rejected from the lortory. 7 Tle 2 Antiiotics Used 8 Weeks Prior to First PCR Test Antiiotic Cses (n = 30) No. (%) Controls (n = 90) P Vlue -Lctm 22 (73.3) 50 (55.6).09 Quinolone 14 (46.7) 40 (44.4).83 Aminoglycoside 1 (3.3) 6 (6.7).50 Metronidzole (PO/IV) 2 (6.7) 9 (10.0).58 Vncomycin IV 20 (66.7) 35 (38.9).009 Acyclovir prophylxis 6 (20.0) 40 (44.4).02 Antiiotic use 14 dys fter first PCR test -Lctm 19 (63.3) 62 (68.9).58 Quinolone 12 (40.0) 33 (36.7).75 Aminoglycoside 3 (10.0) 6 (6.7).55 Metronidzole (PO/IV) 10 (33.3) 15 (16.7).05 Vncomycin IV 9 (30.0) 43 (47.8).09 Vncomycin PO 5 (16.7) 3 (3.3).01 Acyclovir prophylxis 8 (26.7) 37 (41.1).16 IV, intrvenous; PCR, polymerse chin rection; PO, orl. Other ntiiotics nlyzed ut not shown (s totl numer of ptients receiving them 5) were mcrolides, trimethoprim-sulfmethoxzole, ntifungls, linezolid, tetrcyclines, clindmycin, ztreonm dptomycin, nd others (crpenem, dpsone, meropenem, nitrofurntoin, nd tigecycline). None ws sttisticlly significnt. Bold signifies sttisticl significnce, two-sided P <.05. The rte of short-term cquisition of CDI in the study popultion ws 142 per 100,000 person yers (95% CI, per 100,000 person yers). The ptients clinicl chrcteristics re shown in Tle 1. In totl, 120 ptients were included (30 cses nd 90 controls), 52.5% (63/120) were mle, medin ge ws 60 (rnge, 25-88) yers, nd the medin hospitl sty ws 24 (rnge, 4-143) dys. Sixty-one percent (73/120) hd dirrhel disese during the first PCR test; of the cses, 13 (43.3%) hd dirrhe efore the first test, nd 20 (66.6%) hd dirrhe efore the second test. There were no significnt differences etween cses nd controls in ptient chrcteristics nd comoridities. Compred with controls, cses were more likely to e mle (63.3% vs 48.9%), hve hd recent GI procedure (26.7% vs 13.3%), nd were less likely to hve leukemi (23.3% vs 35.6%), lthough these differences were not sttisticlly significnt. Tle 2 shows ntiiotic use. In the 8 weeks prior to the first negtive PCR test, cses were more likely thn controls to e receiving intrvenous vncomycin (66.7% vs 38.9%; P =.009) nd less likely to e tking ntivirl mediction (20.0% vs 44.4%; P =.02). In the 14 dys fter the first negtive PCR test, cses were more likely thn the controls to e tking orl vncomycin (16.7% vs 3.3%; P =.01) or metronidzole (33.3% vs 16.7%; P =.05), which re the tretments for CDI. 23 After djusting for ge nd dys of hospitliztion prior to first PCR, no ptient chrcteristics were strongly ssocited with cses or controls Tle 3. In djusted nlysis, Am J Clin Pthol 2015;143:

4 Aldrete et l / Risk of Short-Term CDI in Inptients Tle 3 Conditionl Logistic Regression Mtched Odds Rtios for Ptient Chrcteristics nd Antiiotic Use Associted With Short-Term Acquisition of Clostridium difficile Chrcteristic OR (95% CI) Mle sex 1.87 ( ) Deth (ll cuses) 1.85 ( ) Intensive cre unit sty c 0.59 ( ) Dietes mellitus d 0.94 ( ) Coinfection e 1.49 ( ) Proton pump inhiitor 1.18 ( ) Recent GI procedure f 2.41 ( ) End-stge renl disese 1.72 ( ) Leukemi 0.49 ( ) Solid tumor 1.85 ( ) Chemotherpy g 0.94 ( ) Stem cell trnsplnt 3.00 ( ) Solid orgn trnsplnt 0.67 ( ) Antiiotic use 8 weeks prior to first PCR test h -Lctm 2.35 ( ) Quinolone 1.10 ( ) Aminoglycoside 0.50 ( ) Metronidzole 0.67 ( ) Vncomycin IV 3.38 ( ) Acyclovir prophylxis 0.30 ( ) Antiiotic use 14 dys fter first PCR test h -Lctm 0.81 ( ) Quinolone 1.18 ( ) Aminoglycoside 1.50 ( ) Metronidzole 2.39 ( ) Vncomycin IV 0.47 ( ) Vncomycin PO 6.63 ( ) Acyclovir prophylxis 0.51 ( ) CI, confidence intervl; GI, gstrointestinl; IV, intrvenous; OR, odds rtio; PCR, polymerse chin rection; PO, orl. OR mtched on ge nd dys to first PCR test. Bold signifies sttisticl significnce. c Intensive cre unit sty within 7 dys efore or 48 hours fter first PCR test. d Defined s HA1c of more thn 6.5%. e Infection of ny type nd ny source t the time of PCR testing. f GI procedure of ny type within 8 weeks prior to first PCR test. g Received chemotherpy for mlignncy within the pst 8 weeks. h Other ntiiotics nlyzed ut not shown were mcrolides, trimethoprimsulfmethoxzole, ntifungls, linezolid, tetrcyclines, clindmycin, ztreonm, dptomycin, nd others (crpenem, dpsone, meropenem, nitrofurntoin, nd tigecycline). None ws sttisticlly significnt. cses were more likely to hve end-stge renl disese (ESRD) (OR, 1.71; 95% CI, ) nd e ptients with recent GI procedure (OR, 2.41; 95% CI, ), ut the detected differences were not sttisticlly significnt. When compring ntiiotic use efore the first performed PCR test (Tle 3), the odds of previous intrvenous vncomycin ws more common mong cses thn controls (OR, 3.38; 95% CI, ), while the use of cyclovir for prophylxis ws more common mong the controls (OR, 0.30; 95% CI, ). When compring ntiiotic use 14 dys fter the first PCR test, the odds of tking metronidzole or orl vncomycin (which re estlished tretments for CDI) were more common mong cses. When comining ntiiotic clsses Tle 4, intrvenous vncomycin therpy with -lctm ntiiotic in the 8 Tle 4 Mtched Odds Rtio for Comined Antiiotic Clsses Associted With Short-Term Acquisition of Clostridium difficile Antiiotic weeks prior to the first PCR test showed n incresed odds in cses (OR, 2.72; 95% CI, ). The sme effect ws seen when comining intrvenous vncomycin, -lctm, nd quinolone (OR, 2.60; 95% CI, ). No ntiiotic comintion 14 dys fter the first test showed sttisticl significnce. Discussion OR (95% CI) Antiiotic clss dministered 8 weeks prior to first test -Lctm 2.35 ( ) Quinolone 1.10 ( ) Vncomycin IV 3.38 ( ) -Lctm + vncomycin IV 2.72 ( ) -Lctm + vncomycin IV + quinolone 2.60 ( ) Antiiotic clss dministered 14 dys fter first test -Lctm 0.81 ( ) Quinolone 1.18 ( ) Vncomycin IV 0.47 ( ) -Lctm + vncomycin IV 0.49 ( ) -Lctm + vncomycin IV + quinolone 0.78 ( ) CI, confidence intervl; IV, intrvenous; OR, odds rtio. OR mtched on ge nd dys to first test. Bold signifies sttisticl significnce. The rte of short-term cquisition in this study is comprle to the crude incidence rtes in other studies, 26 nd the percentge of PCR tests (4.2%) tht were initilly negtive nd susequently positive within 14 dys is similr to other studies (2.1%-3.4%). 7,8,12 In this cse-control study of short-term cquisition of CDI mong hospitlized ptients, we found tht intrvenous vncomycin (within 8 weeks prior to the first PCR-negtive test) ws significntly more common mong cses thn mong controls (OR, 3.38; 95% CI, ), even fter djusting for ge nd length of hospitliztion. In ddition, we found tht compred with controls, cses were significntly less likely to hve history of cyclovir prophylxis (OR, 0.30; 95% CI, ). The finding tht intrvenous vncomycin ws ssocited with short-term cquisition of CDI could e prtilly explined y the fct tht more cses were highly helth cre experienced nd lso hd sustntil underlying comoridities such s immunosuppression nd ESRD. This finding hs een descried efore, 15 nd one study ttriuted n djusted OR of 1.9 for incident CDI (95% CI, ) if dministered for more thn 7 dys. 27 Intrvenous vncomycin cn e used for surgicl prophylxis, ut in this study, it ws used in ptients with culture-directed infections or s empiricl 898 Am J Clin Pthol 2015;143:

5 AJCP / Originl Article tretment for ferile syndromes in complicted (immunocompromised, long-term steroid use, or criticlly ill) ptients (dt not shown). In this ptient popultion, lmost hlf were in the ICU during their hospitliztion. Intrvenous vncomycin is not indicted s therpy for C difficile due to poor GI penetrtion (ie, low concentrtions found in feces of ptients receiving intrvenous vncomycin). 28 However, intrvenous vncomycin is ssocited with ltered microiot, specificlly selecting for vncomycinresistnt enterococci. 29 While intrvenous vncomycin my not e in the cusl pthwy of short-term cquisition of C difficile, it is clerly importnt. Two recent met-nlyses of ntiiotic clsses nd their risk of incident CDI focused exclusively on communityssocited CDI 30,31 ; our hospitlized ptient cohort is different, with lmost no ptients receiving ntimicroils (such s clindmycin), which re typiclly given on n outptient sis. Our ptients tended to e tking intrvenous ntiiotics nd were eing exposed to the hospitl reservoir of C difficile. Given this finding, the ssumption ws tht the incresed odds ssocited with intrvenous vncomycin might hve een surrogte for poly-ntimicroil use. Previous reserch demonstrted tht ntiiotic perturtion is necessry for dysiosis tht llows C difficile to cuses disese. 32,33 Therefore, chronic comoridities tht my require frequent ntiiotic use (nd, consequently, hospitl exposure to C difficile spores) or tht result in immune compromise my plce individuls t incresed risk for short-term cquisition of CDI. The strong ssocition with intrvenous vncomycin reported in our study my e surrogte for individuls who re more chroniclly ill. 34 We think tht the estimted protective effect of cyclovir ws ised due to higher proportion of ptients with hemtologic mlignncy in the control popultion. Our cohort of 750 individuls from which we drew the cses nd controls were hospitlized for lengthy periods (such s hemtopoietic stem cell trnsplnt ptients), nd we rndomly oversmpled group tht used cyclovir for prophylxis. Our study ws suject to limittions. First, systemtic error due to residul confounding my hve occurred due to the limited covrites from study ptients tht were ville for collection during chrt review. Second, chrt reviews performed could not determine the exct indictions for previous ntiiotic use. If the indiction for ntiiotic use ws cuslly relted to short-term CDI risk nd ssocited with other ptient covrites used in this study, confounding y indiction could result in ised estimtes. 35 However, we do not elieve this to e mjor prolem ecuse most of the time, ntiiotics were used for culture-directed infections or s empiricl use in ferile syndromes in complicted ptients. Another limittion is tht we were unle to determine if ptients hd previously hd CDI. Our institution used different test to dignose CDI (enzyme immunossy lone) efore Novemer 2010, so it would e very difficult to compre previous dignosed cses with our current highly sensitive moleculr method. 36 Third, the study s lortory policy is to utomticlly reject feces sumitted within 7 dys of n initil negtive test unless the prctitioner requests test to e performed gin, which mens we could hve missed some cses/controls due to the clinicin not eing concerned enough to request repet test. The purpose of this study ws to delinete sugroup of ptients who would ssist lortorins in determining clinicl history tht my e ssocited with short-term risk of CDI. Given tht short-term cquisition while in the hospitl is reltively rre, this group of ptients hs not een studied to determine if there is chrcteristic ssocited with CDI. While the stndrd prctice in the clinicl microiology lortory is to reject feces smples tht re sent for C difficile PCR within 7 dys, 7 this intervl is not derived from iologic studies tht show tht C difficile cn e detected within 3 to 7 dys of infection. 5 Although it is cler tht most ptients do not need repeted C difficile testing within 14 dys, there re still individuls who test positive within this time frme, nd this is n importnt dignosis to mke from n individul s stndpoint. 3 In conclusion, intrvenous vncomycin use within the 8 weeks prior ws predictive of short-term cquisition of C difficile in hospitlized ptients. The prcticl implictions for this in terms of repeted testing my include eliciting this ntiiotic history when clinicins request repet testing erlier thn 7 dys in hospitlized ptient. Address reprint requests to Dr Krft: Emory University Hospitl, F145C, 1364 Clifton Rd, NE, Atlnt, GA 30322; colleen.krft@ emory.edu. 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