Epidemiology and Clinical Features of Post-Transplant Bloodstream Infection: An Analysis of 222 Consecutive Liver Transplant Recipients

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1 Originl Article Infect Chemother 2013;45(3): pissn eissn Infection & Chemotherpy Epidemiology nd Clinicl Fetures of Post-Trnsplnt Bloodstrem Infection: An Anlysis of 222 Consecutive Liver Trnsplnt Recipients Hyun Kyung Kim 1, Yong Keun Prk 2, Hee-Jung Wng 2, Bong Wn Kim 2, So Youn Shin 1, Seung-Kwn Lim 1, nd Young Hw Choi 1 Deprtments of 1 Infectious Diseses nd 2 Surgery, Ajou University School of Medicine, Suwon, Kore Bckground: Bloodstrem infection (BSI) is significnt cuse of morbidity nd mortlity in liver trnsplnt (LT) recipients. This study imed to investigte the epidemiology nd clinicl fetures of post-trnsplnt BSI in LT recipients. Mterils nd Methods: The microbiology, frequency, nd outcome of post-trnsplnt BSI in the first yer fter LT were retrospectively nlyzed in 222 consecutive ptients who hd received liver trnsplnts t single center between 2005 nd The risk fctors for post-trnsplnt BSI nd deth were evluted. Results: During 1-yer period fter LT, 112 episodes of BSI occurred in 64 of the 222 ptients (28.8%). A totl of 135 microorgnisms were isolted from 112 BSI episodes including 18 polymicrobil episodes. The medin time to BSI onset rnged from 8 dys for Klebsiell pneumonie to 101 dys for enterococci, nd the overll medin for ll microorgnisms ws 28 dys. The most frequent pthogens were Enterobctericee members (32.5%), enterococci (17.8%), yests (14.0%), Stphylococcus ureus (10.3%), nd Acinetobcter bumnnii (10.3%); most of them showed resistnce to mjor ntibiotics. The mjor sources of BSI were biliry trct (36.2%), bdominl nd/or wound (28.1%), nd intrvsculr ctheter (18.5%) infections. The independent risk fctors for post-trnsplnt BSI were biliry complictions (odds rtio [OR]: 2.91, 95% confidence intervl [CI]: 1.29 to 6.59, P = 0.010) nd longer hospitliztion in the intensive cre unit (OR: 1.04, 95% CI: 1.00 to 1.08, P < 0.001) fter LT. BSI ws n independent risk fctor for deth (hzrd rtio [HR]: 3.92, 95% CI: 2.22 to 6.91, P < 0.001), with poorer survivl rte observed in ptients with BSI thn in those without BSI (1-yer survivl rte: 60.0% versus 89.5%, respectively, P < 0.001) fter LT. The strongest predictors for deth in ptients with BSI were heptocellulr crcinom (HR: 3.82, 95% CI: 1.57 to 9.32, P = 0.003), cndidemi (HR: 3.71, 95% CI: 1.58 to 8.71, P = 0.003), polymicrobil bcteremi (HR: 3.18, 95% CI: 1.39 to 7.28, P = 0.006), nd post-trnsplnt hemodilysis (HR: 2.44, 95% CI: 1.02 to 5.84, P = 0.044). Conclusions: BSI ws frequent post-trnsplnt compliction, nd most of the custive pthogens were multi-drug resistnt. Biliry complictions nd BSIs resulting from biliry infection re mjor problems for LT recipients. The prevention of BSI nd biliry complictions is criticl in improving prognosis in liver trnsplnt recipients. Key Words: Bcteremi, Bloodstrem infection, Liver trnsplnttion, Epidemiology Received: Februry 18, 2013 Revised: My 14, 2013 Accepted: June 3, 2013 Corresponding Author : Young Hw Choi, MD, PhD Deprtment of Infectious Diseses, Ajou University School of Medicine, 164 World Cup-ro, Yeongtong-gu, Suwon , Kore Tel: , Fx: Emil: yhw1805@jou.c.kr This is n Open Access rticle distributed under the terms of the Cretive Commons Attribution Non-Commercil License ( which permits unrestricted non-commercil use, distribution, nd reproduction in ny medium, provided the originl work is properly cited. Copyrights 2013 by The Koren Society of Infectious Diseses Koren Society for Chemotherpy

2 316 Kim HK, et l. Bcteremi fter liver trnsplnttion Introduction Liver trnsplnttion (LT) is life-sving tretment for end stge liver disese. Despite improved grft survivl owing to recent dvnces in periopertive mngement nd surgicl techniques, mortlity nd morbidity rtes ssocited with periopertive infection in LT recipients remin reltively high [1-3]. Bloodstrem infection (BSI) is the most frequent infectious compliction, with n incidence rnge of 24-49%; BSI is significnt predictor of post-trnsplnt deth [2, 4-6]. Some studies hve suggested tht grm-positive (GP) cocci re the mjor pthogens of post-trnsplnt BSI. However, others hve implicted grm-negtive (GN) bcilli s the predominnt pthogens. Furthermore, multi-drug resistnce (MDR) rtes mong GN bcilli hve been incresing, further ffecting the prognosis of LT recipients [4, 7-11]. Understnding the epidemiology of nd the risk fctors ssocited with post-trnsplnt BSI my fcilitte identifiction of high-risk ptients, guide pproprite initition of ntibiotic therpy, nd improve infection control prctices. In this retrospective nlysis, 222 consecutive ptients who underwent LT were studied to ssess the epidemiology nd clinicl significnce of BSI in the yer following LT. Mterils nd Methods 1. Ptient enrollment Over 6-yer period from Februry 2005 to My 2011, 231 LT were performed in 222 ptients t Ajou University Hospitl, university-ffilited, 1,087-bed tertiry-cre institute in Kore. We retrospectively reviewed the medicl records of these 222 liver trnsplnt recipients. Decesed donor LT hs been performed t this institute since 1995 nd dult living donor LT since ABO-incomptible LT begn in Mrch 2007, nd 11 ABO-incomptible LTs were performed during the study period [11]. 2. Cultures Microbiologicl surveillnce cultures were routinely done fter LT. Blood cultures were obtined by stndrd procedures nd processed by n utomted system. The utomts used were the BcT/ALERT 3D system (biomérieux, Durhm, NC, USA) nd the BACTEC FX system (BD Dignostic Systems, USA) for rpid microbil detection. Antimicrobil susceptibility ws determined by the miniml inhibitory concentrtion gr dilution method ccording to the recommendtions of the Clinicl nd Lbortory Stndrds Institute. 3. Antimicrobil prophylxis Initil ntimicrobil prophylxis ws cefoperzone/sulbctm until Jnury 2007 nd pipercillin/tzobctm subsequently. Vncomycin ws routinely dministered to prevent methicillin-resistnt stphylococcl infections. For fungl prophylxis, mphotericin B deoxycholte ws used until December 2009, but it ws replced by liposoml mphotericin B in Jnury The bove ntimicrobil regimen continued for pproximtely 5-7 dys fter LT. Intrvenous gnciclovir followed by orl cyclovir or orl vlcyclovir ws used for cytomeglovirus prophylxis. Pneumocystis pneumoni prophylxis consisted of trimethoprim/sulfmethoxzole, nd ws continued for 1 yer fter LT. Selective bowel decontmintion with orl neomycin ws performed for recipients of elective living donor LT. Ptients who received liver trnsplnts for heptitis B ssocited liver cirrhosis were mnged with ntivirl prophylxis nd heptitis B immunoglobulin. 4. Immunosuppression Primry stndrd immunosuppressive therpy included tcrolimus (FK506) or cyclosporine, bsiliximb, nd low-dose prednisone. Rejection episodes were minly treted with high-dose methylprednisolone nd by incresing tcrolimus blood concentrtions. 5. Definitions Infections were defined using the criteri proposed by the Centers for Disese Control nd Prevention [12]. BSI ws defined s the isoltion of pthogenic microorgnism from t lest 1 blood culture specimen. Skin flor orgnisms commonly ssocited with contmintion were required to be isolted from 2 seprte blood culture specimens. Polymicrobil BSI ws defined s the isoltion of > 2 orgnisms from single blood culture specimen, nd ech orgnism ws considered seprte isolte in the nlysis. Multiple cultures tht were positive for the sme pthogen constituted single BSI episode if they were not seprted by > 2 weeks nd the ptient did not recover with negtive blood culture in the interim. Pre- LT ntibiotic therpy ws defined s the ppliction of brodspectrum ntibiotics for > 5 dys in the month before LT. The definition of MDR bcteri ws bsed on previous studies [13]. 6. Sttisticl nlysis Sttisticl clcultions were performed using the SPSS Advnced Sttistics Modules, version 20.0 (SPSS, Chicgo, IL,

3 Infect Chemother 2013;45(3): USA). Continuous dt normlly distributed, re expressed s men (SD) nd nlyzed using the Student's t-test. All other continuous dt not normlly distributed re presented s medin (interqurtile rnge) nd nlyzed using the Mnn- Whitney U-test. The risk fctors for BSI were exmined by multiple logistic regression nlysis. A cox regression model ws used to identify independent risk fctors for mortlity in ptients with BSI nd ll ptients. Kpln-Meier sttistics were used to generte Tble 1. Bseline chrcteristics of the 222 liver trnsplnttion recipients Chrcteristics No. of ptients (%) Totl 222 Sex Mle 168 (75.7) Femle 54 (24.3) Age, men (SD), yr 49.1 (8.9) Underlying liver diseses Heptitis B ssocited liver cirrhosis 170 (76.6) Heptocellulr crcinom b 106 (47.7) Alcoholic liver cirrhosis 58 (26.1) Acute heptic filure c 5 (2.3) Mlignnt neoplsm other thn HCC d 5 (2.3) Primry biliry cirrhosis 4 (1.8) Heptitis C ssocited liver cirrhosis 3 (1.4) Cryptogenic liver cirrhosis 3 (1.4) Others e 4 (1.8) Dibetes mellitus 23 (10.3) Brod-spectrum ntibiotics in 1 mon f 125 (56.3) Slvge liver trnsplnttion cndidte 33 (14.8) Ch ild-pugh score g, medin (IQR) Score 10 (50.4% of recipients) MELD score h, medin (IQR) Score 25 (27.4% of recipients) 10 (6-12) 12 (10-13) 16 (11-26) 32 (28-37) SD, stndrd devition; HCC, heptocellulr crcinom; IQR, interqurtile rnge; MELD, model for end stge liver disese. My hve > 1 underlying liver disese. b A few cses were proven to hve smll HCC t postopertive exmintion. c Includes toxic heptitis (n = 3) nd A-virl heptitis (n = 2). d Includes cholngiocrcinom (n = 3), ngiosrcom (n = 1), nd hemngioendotheliom (n = 1). e Includes Budd-Chiri syndrome (n = 2), hemophili (n = 1), nd Wilson disese (n = 1). f Use of brod-spectrum ntibiotics for > 5 dys in the month before liver trnsplnttion. g Score indictes the severity of liver disese, nd rnges from 5 to 15 ccording to the degree of s cites, the serum concentrtions of bilirubin nd lbumin, the prothrombin time, nd the degree of encephlopthy. h Score indictes heptic dysfunction, nd rnges from 6 to 40 or more ccording to the following formul: MELD = 3.8 [Ln serum bilirubin (mg/dl)] [Ln INR] [Ln serum cretinine (mg/dl)] survivl curves for ptients with nd without BSI. All P-vlues were 2-tiled, nd P-vlue < 0.05 ws considered significnt. Results 1. Chrcteristics of the study popultion The bsic demogrphic nd clinicl chrcteristics of the 222 LT recipients re illustrted in Tble 1. The men ge ws 49 yers nd three-qurters of ptients were men. The most frequent liver diseses leding to LT were B-virl liver cirrhosis (76.6%, 170 ptients), heptocellulr crcinom (HCC; 47.7%, 106 ptients), nd lcoholic liver cirrhosis (26.1%, 58 ptients); 2 of these diseses overlpped in some ptients. Becuse of the smll number of other dignoses leding to LT, only heptitis B ssocited liver cirrhosis, heptocellulr crcinom, nd lcoholic liver cirrhosis were nlyzed s dignostic pretrnsplnt vribles. The study popultion included 33 recipients who underwent slvge LT for tumor recurrence or liver function deteriortion fter prtil heptectomy. Eight ptients underwent second LT for primry (n = 2) or secondry grft filure (n = 6). The medin Child-Pugh score ws 10 nd the men model for end stge liver disese (MELD) score ws Time nd frequency of BSI Post-trnsplnt BSIs occurred in 28.8% (64 of 222) of ll re- Frequency GPC GNB Fungi Dy Figure 1. Time nd frequency of custive orgnisms (n = 135) isolted in bloodstrem infections fter liver trnsplnttion. GPC, grm-positive cocci; GNB, grm-negtive bcilli.

4 318 Kim HK, et l. Bcteremi fter liver trnsplnttion cipients in the yer fter LT. A totl of 135 bcteril nd fungl orgnisms were isolted from the 112 BSI episodes including 18 polymicrobil BSIs. Thirteen ptients hd 1 polymicrobil BSI. One BSI occurred in 38 of 64 ptients, wheres multiple episodes of BSI occurred in the remining 26 ptients, rnging from 1 to 9 episodes per ptient. The medin follow-up period ws 1,306 (rnge 2-2,803) dys. Figure 1 shows the isolted time nd frequency of pthogenic microorgnisms in BSIs during the yer fter trnsplnttion. Most of the BSIs (50.8%; 57 of 112) occurred in the first month fter LT. The medin time to BSI onset fter LT ws 28 dys (dshed line) with n interqurtile rnge (IQR) of 6-89 dys; the men time to onset ws 57 ± 69 dys (solid line). GP cocci, GN bcilli, nd fungi were responsible for 32.8%, 52.9%, Tble 2. Custive orgnisms in 112 episodes of bloodstrem infection in liver trnsplnt recipients Orgnisms No. of isoltes (%) Grm positives 44 (32.8) Stphylococcus ureus 14 (10.3) CoNS 5 ( 3.7) Enterococcus fecium 21 (15.6) Enterococcus feclis 3 ( 2.2) lph-streptococcus 1 ( 0.7) Grm negtives 72 (52.9) Klebsiell pneumonie 19 (14.2) Escherichi coli 17 (11.9) Enterobcter cloce 6 ( 4.4) Acinetobcter bumnnii 14 (10.3) Pseudomons species 12 ( 8.9) Stenotrophomons mltophili 4 ( 3.0) Serrtimrcescens 1 ( 0.7) Pntoe species 1 ( 0.7) Fungi b 19 (14.0) Cndid lbicns 9 ( 6.7) Cndid tropiclis 5 ( 3.7) Cndid krusei 2 ( 1.5) Cndid glbrt 1 ( 0.7) Cndid prpsilosis 1 ( 0.7) Cndid lusitnie 1 ( 0.7) Totl 135 (100) CoNS, cogulse-negtive stphylococci. Includes P. eruginos (10), P. fluoroscens (1), P. putid (1). b No fungus other thn Cndid species ws isolted. nd 14.0% of isolted orgnisms in BSIs, respectively. The medintime to onset of BSI episode from the dte of trnsplnttion (dy 0) for ech group of pthogens ws dy 40 (IQR: ) for GP cocci (n = 44), dy 23 (IQR: 6-66) for GN bcilli (n = 71), nd dy 12 (IQR: 5-95) for fungi (n = 19). 3. Custive pthogens nd source of BSI The distribution of species is illustrted in Tble 2. Enterobctericee members represented the mjority of GN isoltes, with the most frequent species being Klebsiell pneumonie nd Escherichi coli. Among GP orgnisms, Enterococcus fecium ws the most common, followed by Both GP nd GN pthogens showed high rte of resistnce to mjor ntibiotics: 92.8% of S. ureus were methicillin-resistnt; 38.0% of E. fecium were vncomycin-resistnt; 68.4% of K. pneumonie nd 82.3% of E. coli produced extended-spectrum bet-lctmse (ESBL); nd 92.8% of Acinetobcter bumnnii nd 91.6% of were crbpenem-resistnt. However, neither linezolid-resistnt enterococc or crbpenem-resistnt Enterobctericee were identified. Cndid species ccounted for 14.0% (19 of 135) of ll isoltes, nd pproximtely 50% of these (10 of 19) were non-lbicns species. All Cndid species were susceptible to fluconzole. The primry sources nd time to onset of BSIs ccording to ech isolted pthogen re listed in Tble 3. BSIs cused by K. pneumonie tended to occur erly (medin: 8 dys, IQR: 4-83 dys), wheres enterococcl BSIs developed lter (medin: 101 dys, IQR: dys). The most common source ws biliry trct infection (36.2%), followed by bdominl nd/or wound (28.1%) nd intrvsculr ctheter (18.5%) infections. Enterococcemi or Enterobctericee bcteremi from biliry trct or bdominl nd/or wound infections ws the most frequent type of BSI. The primry pthogens of ctheter-relted BSIs were Cndid nd A. bumnnii. Polymicrobil BSIs predominntly consisted of enterococci, stphylococci, nd Cndid species, nd most of them originted from the biliry trct. 4. Risk fctors for post-trnsplnt BSI The clinicl nd opertive vribles ssocited with posttrnsplnt BSI re illustrted in Tble 4. Ptients with BSIs were significntly more likely to hve post-trnsplnt hemodilysis, reopertive or retrnsplnttion episodes, higher Child- Pugh score nd MELD score, more trnsfusion during surgery, longer postopertive intensive cre unit (ICU) sty nd dmission dys, nd more biliry complictions. In logistic regression nlysis, biliry complictions (odds rtio [OR]: 2.91, 95% confidence intervl [CI]: 1.29 to 6.59, P = 0.010) nd longer

5 Infect Chemother 2013;45(3): Tble 3. Source of bloodstrem infection nd time to onset in the yer following liver trnsplnttion Custive orgnism Abd/ Wound Primry source of bloodstrem infection (No. of isoltes in BSI) Biliry trct IVC Lung Urinry trct did BSI (HR: 3.71, 95% CI: 1.58 to 8.71, P = 0.003) nd polymi- Unknown Totl No. (%) Dys to onset of BSI Medin (IQR) Stphylococcus ureus (10.3) 30 (2 to 41) CoNS (3.7) 36 (23 to 46) Enterococci (17.7) 101 (24 to 153) Klebsiell pneumonie (14.0) 8 (4 to 83) Escherichi coli (12.5) 23 (4 to 96) Enterobcter cloce (4.4) 32 (12 to 125) Pseudomons b (8.9) 39 (19 to 74) Acinetobcter bumnnii (10.3) 19 (5 to 64) Cndid c (14.0) 12 (5 to 95) Others d (3.7) Polymicrobil e 3/38 9/49 2/25 2/8 1/3 1/12 18/135 (13.3) Totl No. (%) 38 (28.1) 49 (36.2) 25 (18.5) 8 (5.9) 3 (2.2) 12 (8.9) (6 to 89) BSI, bloodstrem infection; IQR, interqurtile rnge; Abd/Wound, bdominl or wound infection; IVC, intrvsculr ctheter infection; CoNS, cogulse-negtive stphylococci. Medin time in dys from the dte of liver trnsplnttion to the onset of bloodstrem infection. b Includes P. eruginos (10), P. fluoroscens (1), P. putid (1). c Includes C. lbicns (9), C. tropiclis (5), C. krusei (2), C. glbrt (1), C. prpsilosis (1), C. lusitnie (1). d Includes Serrti mrcescens (1 from bdomen), Pntoe species (1 from bdomen), nd Stenotrophomons mltophili (1 from bdomen nd the other from lung). e Shows isolted orgnisms in episodes of polymicrobil BSI/totl BSI strtified by its origin. Ech isolte ws counted s single cse, which resulted in 135 orgnisms from 112 BSI episodes. ICU sty (OR: 1.040, 95% CI: to 1.080, P = 0.038) were significnt independent risk fctors of post-trnsplnt BSI (Tble 5). 5. Survivl curve nd predictors for deth in LT recipients The mortlity rte in LT recipients with BSI ws higher thn tht in those without BSI in both the erly (30-dy mortlity: 22.9% vs. 5.9%) nd lte (1-yer mortlity: 40.0% vs. 10.5%) postopertive periods. Survivl time (men ± SD) ws significntly lower in ptients with BSI (1,310 ± 147 dys; 1-yer survivl rte 60.0%) thn in those without BSI (2,362 ± 77 dys; 1-yer survivl rte 89.5%) throughout the 1-yer post-trnsplnt period nd beyond 1 yer fter LT (< 0.001) (Fig. 2). In those with BSI, fungl BSI ws ssocited with the poorest 1-yer survivl rte (fungl BSI 35.7% vs. non-fungl BSI 66.1%). LT recipients with polymicrobil BSI lso hd significntly lower 1-yer survivl rte thn those with BSI cused by single pthogen (polymicrobil BSI 26.7% vs. monomicrobil BSI 69.1%). Significnt predictors of mortlity in the entire study popultion were BSI (hzrd rtio [HR]: 3.92, 95% CI: 2.22 to 6.91, P < 0.001), post-trnsplnt hemodilysis (HR: 3.38, 95% CI: 1.70 to 6.70, P < 0.001), comorbid HCC (HR: 2.14, 95% CI: 1.20 to without BSI with BSI P < Figure 2. Effect of bloodstrem infection in the yer fter trnsplnttion on Kpln-Meier survivl curves of liver trnsplnt recipients. BSI, bloodstrem infection. 3.82, P = 0.009), nd longer ICU sty fter LT (HR: 1.024, 95% CI: to 1.047, P = 0.030). In those ptients with BSI, Cn-

6 320 Kim HK, et l. Bcteremi fter liver trnsplnttion Tble 4. Chrcteristics ssocited with bloodstrem infection by univrite nlysis Chrcteristics Ptients with BSI Ptients without BSI P-vlue Totl, n(%) 64 (28.8) 158 (71.2) Pretrnsplnt vribles b Age, medin (IQR) 50 (43 to 56) 50 (44 to 55) 0.73 Mle sex 51 (79.6) 117 (74.0) 0.50 Underlying liver diseses Heptitis B ssocited liver cirrhosis 46 (71.8) 124 (78.4) 0.12 Alcoholic liver cirrhosis 10 (15.6) 21 (13.2) 0.12 Heptocellulr crcinom 28 (43.7) 78 (49.3) 0.32 Dibetes mellitus 8 (11.4) 15 (9.9) 0.72 Brod-spectrum ntibiotics c 42 (65.6) 84 (53.1) 0.30 Child-Pugh score, medin (IQR) 11 (7 to 13) 9 (6 to 11) 0.03 MELD score, medin (IQR) 20 (12 to 32) 15 (11 to 23) Opertive vribles Living donor grft 44 (68.7) 116 (73.4) 0.27 ABO-incomptible 6 (9.3) 5 (3.1) 0.13 Splenectomy 15 (23.4) 39 (24.6) 0.99 prbc trnsfusion unit, medin (rnge) 10 (0 to -68) 6 (0 to 56) Opertion hours, medin (IQR) 718 (645 to 780) 680 (600 to 758) 0.53 Post-trnsplnt vribles Post-trnsplnt hemodilysis 36 (51.4) 35 (23.0) < Reopertive episodes within 3 mon 26 (40.6) 38 (24.0) Acute rejection 15 (23.4) 36 (22.7) 0.75 Retrnsplnttion 7 (10.0) 1 (0.7) Biliry compliction d 27 (42.1) 37 (23.4) ICU dys fter LT, medin (IQR) 6 (4 to 20) 4 (3 to 6) < Admission dys fter LT, medin (IQR) 37 (28 to 70) 29 (24 to 39) < Continuous dt normlly distributed re expressed s men (SD) nd nlyzed using students t-test. All other continuous dt not normlly distributed re presented s medin (IQR) nd nlyzed using Mnn-Whitney U-test. BSI, bloodstrem infection; IQR, interqurtile rnge; MELD, model for end stge liver disese; prbc, pcked red blood cell; ICU, intensive cre unit; LT, liver trnsplnttion. Binry logistic regression model ws used for univrite nlysis. b My hve > 1 underling liver disese. c Use of brod-spectrum ntibiotics for > 5 dys in 1 month before liver trnsplnttion. d Includes biliry lekge (n = 20), biliry stricture (n = 42), nd other overlpping biliry complictions (n = 10). crobil BSI (HR: 3.18, 95% CI: , P = 0.006), in prticulr, were independent risk fctors for post-trnsplnt deth (Tble 6). Discussion We found tht BSI is common compliction for LT recipients: 28.8% of our ptients developed t lest 1 BSI episode inthe yer following trnsplnttion. In our study popultion, the rte of BSI episodes nd the overll 1-yer mortlity rte fter LT were higher thn those reported by other investigtors [2, 5, 14, 15]. The greter number of BSIs nd the higher mortlity rte in this study cn be prtly explined by the poor generl condition of our LT recipients, whose medin MELD scores (16) nd Child-Pugh scores (10) were reltively high. A lerning curve effect, by including in the smple those ptients from the erly period of our living donor LT progrm ( highly complex technique), might lso hve contributed to the incresed rtes of mortlity nd postopertive infectious complictions in the erly trnsplnt period [16, 17]. Previous studies show tht fctors ssocited with post-

7 Infect Chemother 2013;45(3): Tble 5. Risk fctors for bloodstrem infection fter liver trnsplnttion by multivrite nlysis Vribles Ptients with BSI Ptients without BSI P-vlue OR (95% CI) Biliry compliction No. of cses/totl (%) 27/64 (42.1) 37/158 (23.4) (1.290 to 6.592) ICU dys fter LT, medin (IQR) 37 (28 to 70) 29 (24 to 39) (1.002 to 1.080) BSI, bloodstrem infection; OR, odds rtio; CI, confidence intervl; ICU, intensive cre unit; LT, liver trnsplnttion; IQR, interqurtile rnge. Binry logistic regression model ws used for multivrite nlysis. Cndidte risk fctors in Tble 5 were ll entered nd only significnt prmeters re listed. Tble 6. Significnt predictors of deth fter liver trnsplnttion Vribles All Ptients Ptients with BSI HR 95% CI P-vlue HR 95% CI P-vlue Heptitis B ssocited liver cirrhosis to to Admission dys fter LT to 0.98 < to 0.97 < Age to to ICU sty fter LT to to Heptocellulr crcinom to to Post-trnsplnt hemodilysis to 6.70 < to Bloodstrem infection to 6.91 < Cndidemi to Polymicrobil bcteremi to BSI, bloodstrem infection; ICU, intensive cre unit; LT, liver trnsplnttion; HR, hzrd rtio; CI, confidence intervl. Cox regression model ws used for multivrite nlysis. Cndidte risk fctors in Tble 6 were ll entered but only significnt prmeters re listed. trnsplnt BSI include dibetes mellitus, low serum lbumin level, lengthy ICU sty, reopertions, cute rejection, higher MELD score, intropertive trnsfusion, biliry compliction, older ge, post-trnsplnt hemodilysis, nd greter number of intrvsculr ctheter dys [2, 5, 9, 15]. In this study, biliry compliction ws prticulrly importnt risk fctor for BSI: 42% of LT recipients with biliry compliction developed BSI. Biliry lek ge or biliry stricture ws mjor postopertive compliction, with n incidence of 10-15% in decesed donor LT nd 15-30% in living donor LT [14, 18]. Biliry infections need to be studied further given the clinicl significnce of biliry-origin BSI in LT recipients. BSI episodes were predominntly cused by GN bcilli, which ccounted for 52.9% of ll isoltes. Consistent with other studies, we found tht GN infections with incresed MDR were common [8, 9, 15, 19, 20]. The microbil etiology of BSI vried ccording to the time to onset [21]. During the erly period, GN bcilli including K. pneumonie, E. coli, nd A. bumnnii were more frequent cuses of BSIs. In the lte posttrnsplnt period, biliry-origin enterococcemi ws the most frequent type of BSI. Other common BSI sources were bdominl nd/or wound K. pneumonie infection nd intrvsculr ctheter infection with Cndid species or A. bumnnii. It is concerning tht ctheter-relted BSI, which is exclusively nosocomil, ccounted for one-fifth of post-trnsplnt BSIs. Further identifiction of BSI chrcteristics would id physicins in determining the potentil etiology of posttrnsplnt BSI. MDR pthogens ccounted for the vst mjority of ll GN nd GP bcteremi cses in this study. It ws reported tht resistnt Acinetobcter infection hs prticulrly poor prognosis in LT recipients [22] nd tht erly definite therpy seemed to influence outcomes [23]. However, therpeutic options for these orgnisms re often limited, expensive, nd of low efficcy. Approximtely one-third of enterococci showed vncomycin resistnce. It is possible tht our periopertive prophylxis with vncomycin my hve prevented more cses of GP BSI; however, it ws not optiml in preventing infections cused by vncomycin-resistnt enterococci (VRE), nd my hve contributed to the development of resistnt orgnisms. Although VRE is known to be less-virulent pthogen, VRE coloniztion in LT recipients hs been ssocited with higher mortlity rtes regrdless of the cuse of deth [11]. Extensive exposure to brod spectrum ntibiotics in the pretrnsplnt phse could lso hve influenced the incresed incidence of MDR orgnisms. We believe tht prospective studies re needed to help design strtegies for the prevention of infection with these MDR pthogens nd to find the optiml ntibiotic prophylxis nd empiricl tretment in LT. BSI during the yer fter LT ws the strongest predictor of

8 322 Kim HK, et l. Bcteremi fter liver trnsplnttion post-trnsplnt mortlity, nd recipients with BSI hd poorer survivl throughout the postopertive period thn those without BSI. HCC, post-trnsplnt hemodilysis, nd prolonged ICU sty were independent risk fctors for mortlity in ptients with BSI s well s for mortlity in ll ptients. Mny of our LT recipients hd HCC (47.7%; 106 of 222 ptients), nd 45% of HCC cses were in n dvnced stge beyond Miln criteri with history of ntitumor therpy when LT ws performed. A deteriorted condition resulting from dvnced cncer nd the complexity of the surgery becuse of previous invsive therpy my hve resulted in more postopertive complictions nd poor oncologic outcomes in these ptients. Approximtely one-third of our LT recipients underwent hemodilysis fter LT. It hs been reported tht post-trnsplnt renl dysfunction occurs in 9-33% of LT recipients nd is ssocited with incresed mortlity, especilly when renl replcement therpy is required [24]. Our preopertive prophylxis regimen included routine use of glycopeptide, mphotericin B, nd gnciclovir, ll of which re known to be nephrotoxic; this might hve plyed role in incresing the rte of post-trnsplnt renl dysfunction. Since mny LT cndidtes with end stge liver diseses lso hve mrginl renl function, efforts to limit nephrotoxic mediction re necessry. BSI cused by Cndid nd polymicrobil BSI were significnt predictors of deth. One-third of cndidemi cses were polymicrobil with synchronous bcteremi or other species of Cndid. Cndidemi nd polymicrobil bcteremi my be indictors of generlly debilitted stte ssocited with incresed morbidity nd mortlity [25, 26]. In this study, both cndidemi nd polymicrobil bcteremi most frequently originted in the biliry trct or intrvsculr ctheter. Ptients with cndidemi or polymicrobil bcteremi my need prompt initition of ntifungl therpy, more empiricl ntibcteril coverge, nd ctive intervention such s the removl of intrvsculr ctheters. Becuse of concerns over drug interctions, zole-ssocited heptotoxicity, nd ntifungl drug resistnce, mphotericin B ws used for ntifungl prophylxis t our institute. However, the use of mphotericin B needs to be evluted, given the high frequency of renl dysfunction, cndidemi, nd ssocited mortlity observed in our study. LT recipients with underlying chronic heptitis B hd better prognosis fter LT in our study. United Network for Orgn Shring (UNOS) dt show tht, thnks to dvnces in ntivirl therpies, recipients with heptitis B hve better posttrnsplnt outcomes thn those with heptitis C, heptitis B nd C coinfection, nd those with other liver diseses [27]. Our study hs limittions becuse of its retrospective design, single-center study, nd smll smple size; therefore, our findings my not be generlizble to other institutes. BSI episodes cused by GP cocci my hve been under-reported becuse we used strict criteri when interpreting blood culture results to rule out contminnts. The impct of BSI on post-lt mortlity my lso hve been over-represented, since ptients with BSI often hd severe pre-lt sttus when compred with those without BSI. Becuse the min source of infection nd the depth of infection were difficult to determine, surgicl wound infections nd bdominl orgn/spce infections were combined into single infectious source in our study. A more sophisticted clssifiction system should be used in future studies. Possible correltions between the ntibiotics received by LT recipients nd their subsequent infections including BSIs were not evluted. As conclusion, Post-trnsplnt BSI occurred t high rte during the yer fter LT, prticulrly within the month following surgery. Ptients with BSI hd significntly lower survivl rte thn those without BSI. GN bcilli were more frequent thn GP cocci s BSI pthogens, nd most of them were highly drug resistnt. Biliry compliction ws the strongest predictor for BSI, nd BSIs resulting from biliry infection were mjor problems for LT recipients. Prevention of BSI nd biliry compliction is importnt for improving prognosis in liver trnsplnt recipients. BSIs cused by fungi nd polymicrobil BSIs in prticulr were strongly ssocited with incresed mortlity. Our study provides detiled informtion on posttrnsplnt BSI occurrence, nd the dt cn be used to guide empiricl ntimicrobil therpy nd improve infection control prctices. Acknowledgement The uthors thnk Hyun Young Lee for her helpful sttisticl nlysis. References 1. Snydmn DR. Infection in solid orgn trnsplnttion. Trnspl Infect Dis 1999;1: Kim SI, Kim YJ, Jun YH, Wie SH, Kim YR, Choi JY, Yoon SK, Moon IS, Kim DG, Lee MD, Kng MW. Epidemiology nd risk fctors for bcteremi in 144 consecutive living-donor

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10 324 Kim HK, et l. Bcteremi fter liver trnsplnttion 25. Nieto-Rodriguez JA, Kusne S, Mñez R, Irish W, Linden P, Mgnone M, Wing EJ, Fung JJ, Strzl TE. Fctors ssocited with the development of cndidemi nd cndidemirelted deth mong liver trnsplnt recipients. Ann Surg 1996;223: Klotz SA, Chsin BS, Powell B, Gur NK, Lipke PN. Polymicrobil bloodstrem infections involving Cndid species: nlysis of ptients nd review of the literture. Dign Microbiol Infect Dis 2007;59: Wki K, Sugwr Y, Tmur S, Mieno MN, Ymshiki N, Kdowki T, Kokudo N. Outcome of liver trnsplnttion for recipients with heptitis B nd heptitis C virus coinfection: nlysis of the UNOS dt. Trnsplnttion 2011;92: