Open Forum Infectious Diseases MAJOR ARTICLE

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1 Open Forum Infectious Diseses MAJOR ARTICLE Epidemiology of Dibetic Foot Infection in the Metro-Detroit Are With Focus on Independent Predictors for Pthogens Resistnt to Recommended Empiric Antimicrobil Therpy Oryn Henig, 1 Json M. Pogue, 2,3 Rymond Ch, 4 Pul E. Kilgore, 4 Umr Hyt, 5 Mhmoud J r, 5 Rz Muhmd Ali, 6 Slmn Mhboob, 7 Rhul Pnsre, 8 Kthryn Deeds, 2 Bushr Jorder, 2 Hyndvi Kndl, 9 Sorbh Dhr, 2,5 nd Keith S. Kye 1 1 Division of Infectious Diseses, Deprtment of Internl Medicine, University of Michign Medicl School, Ann Arbor, Michign; 2 School of Medicine, Wyne Stte University, Detroit, Michign; 3 Deprtment of Phrmcy Services, Detroit Medicl Center, Sini-Grce Hospitl, Detroit, Michign; 4 Eugene Applebum College of Phrmcy nd Helth Sciences, Wyne Stte University, Detroit, Michign; 5 Deprtment of Internl Medicine, Detroit Medicl Center, Detroit, Michign; 6 Allm Iqbl Medicl College, Jinnh Hospitl Lhore, Lhore, Pkistn; 7 Krmnos Cncer Institute, Wyne Stte University, Detroit, Michign; 8 Deprtment of Internl Medicine, St Mry Mercy Hospitl, Livoni, Michign; 9 Deprtment of Internl Medicine, Nssu University Medicl Center, Est Medow, New York Bckground. The polymicrobil nture of dibetic foot infection (DFI) nd the emergence of ntimicrobil resistnce hve complicted DFI tretment. Current tretment guidelines for deep DFI recommend coverge of methicillin-resistnt Stphylococcus ureus (MRSA) nd susceptible Enterobctericee. This study imed to describe the epidemiology of DFI nd to identify predictors for DFI ssocited with multidrug-resistnt orgnisms (MDROs) nd pthogens resistnt to recommended tretment (PRRT). Methods. Adult ptients dmitted to Detroit Medicl Center from Jnury 2012 to December 2015 with DFI nd positive cultures were included. Demogrphics, comorbidities, microbiologicl history, sepsis severity, nd ntimicrobil use within 3 months before DFI were obtined retrospectively. DFI-PRRT ws defined s DFI ssocited with pthogen resistnt to both vncomycin nd ceftrixone. DFI-MDRO pthogens included MRSA in ddition to PRRT. Results. Six-hundred forty-eight unique ptients were included, with men ge of 58.4 ± 13.7 yers. DFI-MDRO ccounted for 364 (56%) of the cohort, nd 194 (30%) ptients hd DFI-PRRT. Independent predictors for DFI-PRRT included history of PRRT in dibetic foot ulcer, ntimicrobil exposure in the prior 90 dys, peripherl vsculr disese, nd chronic kidney disese. Long-term cre fcility residence ws independently ssocited with DFI due to ceftrixone-resistnt Enterobctericee, nd recent hospitliztion ws n independent predictor of DFI due to vncomycin-resistnt Enterococcus. Conclusions. An unexpectedly high prevlence of DFI-PRRT pthogens ws identified. History of the sme pthogen in prior dibetic foot ulcer nd recent ntimicrobil exposure were independent predictors of DFI-PRRT nd should be considered when selecting empiric DFI therpy. Keywords. dibetic foot infection; empiric therpy; multidrug-resistnt orgnisms; PRRT. The choice of ntibiotic gents for dibetic foot infection (DFI) is chllenging considering the complex microbiology of DFI, which is often polymicrobil [1]. In ddition, ptients who hve dibetic foot ulcers (DFUs) frequently hve conditions tht re ssocited with coloniztion nd/or infection with multidrug-resistnt orgnisms (MDROs), including frequent helth cre exposures, chronic wound cre, nd recurrent nd prolonged ntibiotic tretment courses [2]. Received 31 July 2018; editoril decision 14 September 2018; ccepted 25 September Correspondence: O. Henig, MD, University of Michign Medicl School, 5510A MSRB I, 1150 W. Medicl Center Drive, Ann Arbor, MI (horyn@med.umich.edu). Open Forum Infectious Diseses The Author(s) Published by Oxford University Press on behlf of Infectious Diseses Society of Americ. This is n Open Access rticle distributed under the terms of the Cretive Commons Attribution-NonCommercil-NoDerivs licence ( by-nc-nd/4.0/), which permits non-commercil reproduction nd distribution of the work, in ny medium, provided the originl work is not ltered or trnsformed in ny wy, nd tht the work is properly cited. For commercil re-use, plese contct journls.permissions@oup.com DOI: /ofid/ofy245 The microbiology of DFI hs been ssessed in severl studies outside the United Sttes, nd geogrphic vrition of predominnt pthogens hs been reported [1, 3 5]. In ddition, microbiologicl vrition exists s function of the cuity nd depth of DFI. Wheres cute nd superficil infections tend to be monomicrobil nd the most common pthogens re Grmpositive cocci, chronic nd deep infections re more commonly polymicrobil nd more frequently involve Grm-negtive bcilli [6]. Current ntionl guidelines from the Infectious Diseses Society of Americ (IDSA) recommend empiric tretment of severe nd deep moderte DFI with ntimicrobil gents tht hve ctivity ginst Stphylococcus ureus, Streptococci spp., nd Enterobctericee, wheres empiric coverge of MDROs is recommended only if MDROs re common in the locle where the infection is being mnged or if specific MDRO risk fctors re present. 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2 Although erly pproprite ntibiotic therpy my be ssocited with fvorble outcomes (such s wound heling nd limb slvge) [3, 4], overuse of brod-spectrum ntibiotics my further contribute to the occurrence of DFI ssocited with MDROs. As MRSA prevlence is reltively high throughout the United Sttes, guidelines recommend tht empiric therpy typiclly include MRSA coverge. However, routine Pseudomons eruginos coverge is not dvocted, nd guideline-recommended empiric ntimicrobil regimens generlly trget more susceptible forms of Enterobctericee. Thus, in ccordnce with IDSA guidelines nd bsed on locl susceptibility ptterns of S. ureus nd Enterobctericee, vncomycin + ceftrixone is commonly employed empiric regimen for DFI t the Detroit Medicl Center (DMC). Dt relted to the overll microbiologicl epidemiology of DFI in the United Sttes nd risk fctors for DFI due to MDROs re scrce. Furthermore, risk fctors for specific popultions with DFI due to pthogens tht re resistnt to recommended empiric therpeutic regimens, such s vncomycin + ceftrixone, re unknown. The primry objectives of this study were to describe the microbiologic nd clinicl epidemiology of DFI in ptients who were dmitted to the DMC nd to identify risk fctors for MDRO pthogens (DFI-MDRO). The secondry objective ws to identify risk fctors for DFI ssocited with pthogens resistnt to vncomycin + ceftrixone in order to identify ptients who wrrnt empiric therpy tht provides broder spectrum of ntimicrobil coverge. METHODS Study Setting nd Cohort Description Multiple nested retrospective cse control studies were performed within lrge cohort to determine predictors of DFI ssocited with resistnt pthogens. All dult ptients with DFI who were dmitted to the DMC ( helth system including 4 cute cre hospitls nd 1 rehbilittion center) between Jnury 2012 nd December 2015 with positive cultures from DFI lesions were included. DFI subjects were identified bsed on Interntionl Clssifiction of Diseses, 9th revision (ICD- 9), codes for dibetes mellitus nd either skin nd soft tissue infection (SSTI) nd/or osteomyelitis (ICD-9 codes tht were used were 249, 250, , 730). In ddition, dmission nd dischrge notes, s well s poditry nd infectious diseses consultnt notes, were reviewed. Confirmtion of n ctul dibetic foot infection ws corroborted by documented signs nd symptoms of infection (erythem, wrmth, pus dringe nd/or fetid odor). Ptients were excluded from the study if (1) infection sttus of the ulcer could not be determined from chrt review or infection ws ruled out by cre providers, (2) the SSTI ws not relted to the foot, (3) infection following frcture nd/or surgicl site infection ws present, (4) the only orgnisms recovered from DFI were cogulse-negtive stphylococcus nd/or corynebcterium (unless recovered on multiple occsions under sterile conditions [eg, in the opertive room nd/or from bone]). This study ws pproved by the institutionl review bords of Wyne Stte University nd the Detroit Medicl Center. Definitions The dte of DFI dignosis ws defined s the dy of first positive culture for DFI episode. An index episode ws defined s the following: mong subjects who hd n episode of DFI ssocited with n MDRO during the study period, the index episode ws the first DFI episode ssocited with n MDRO (DFI-MDRO). Among subjects who did not hve DFI ssocited with n MDRO during the study period, the index episode ws the first DFI episode during the study period nd ws considered DFI- Non-MDRO. Prior nd recurrent DFI episodes for ll subjects were cptured throughout the study period. Thus, during the study period, ll DFI episodes for study subjects were cptured. For the purposes of this nlysis, MDROs included methicillin-resistnt Stphylococcus ureus (MRSA), vncomycin-resistnt Enterococci (VRE), Enterobctericee resistnt to third-genertion cephlosporins nd/or to crbpenem, nd ll ntimicrobil susceptibility phenotypes of Pseudomons eruginos, Acinetobcter bumnnii, nd Stenotrophomons mltophili. Guidelines for empiric tretment of DFI recommended coverge of MRSA nd susceptible strins of Enterobctericee. As ceftrixone offered significnt in vitro ctivity dvntge over erlier-genertion cephlosporins t the DMC, ceftrixone ws considered n pproprite empiric regimen for susceptible strins of Enterobctericee [1]. Therefore, for this study, pthogens resistnt to recommended empiric tretment (PRRT) were defined s erobic Grm-negtive bcilli resistnt to ceftrixone (including resistnt strins of Enterobctericee nd ll strins of P. eruginos, A. bumnnii, nd S. mltophili) nd Enterococci resistnt to vncomycin. MRSA ws excluded from the PRRT definition. As coverge for nerobic orgnisms is controversil nd not routinely recommended in guidelines, these orgnisms were not considered with regrds to determining the ppropriteness of therpy. Study Vribles Dt pertining to demogrphics, source of dmission (home, long-term cre fcility [LTCF], trnsfer from nother hospitl), hospitliztion within the pst 90 dys, comorbidities included in Chrlson Comorbidity Index (ccording to ICD-9 codes nd/ or physicin documenttion), insurnce type, severity of sepsis t time of DFI episode dignosis (defined by the most bnorml vlues of systemic inflmmtory response syndrome score nd vitl signs within 2 dys of DFI dignosis) [7], dmission unit, highest HbA1C vlue within 3 months of DFI episode, dibetes-relted end-orgn dmge, nd nkle-brchil index (ABI) vlues were obtined from the medicl record. The depth of involvement of DFI ws determined bsed on providers documenttion, Downloded from by guest on 06 November OFID Henig et l

3 rdiology findings, nd pthology findings nd ws clssified s superficil, deep tissue, or bone involvement [8]. Antimicrobil tretment informtion in the prior 3 months ws bstrcted from the medicl record. Intensive cre unit (ICU) dmission nd mechnicl ventiltion nd cute hemodilysis sttus were cptured within 7 dys of the dte of the DFI dignosis. Surgicl interventions were recorded for current nd prior DFI episodes, including bedside debridement, operting room debridement, nd mputtions. Microbiology Microbiology dt for ech ptient included cultures obtined from DFI lesions nd were ctegorized ccording to the ntomic depth of the lesion from which the culture ws obtined nd the type of specimen obtined. Specimen types were ctegorized s swb cultures obtined t the bedside, tissue cultures obtined t the bedside, swb cultures obtined in the operting room, tissue cultures obtined in the operting room, nd bone cultures collected in the operting room. For given episode, ll cultures from the DFI site tht were obtined within period of 14 dys of the initil culture (nd thus, within 14 dys of the index episode) were considered prt of the index DFI episode. A polymicrobil episode ws defined s n episode during which more thn 1 pthogen ws recovered. Bloodstrem infection ssocited with DFI ws defined s growth of the sme pthogen in the blood s ws recovered from the DFI lesion within 7 dys of DFI dignosis. A prior recovery of n MDRO in dibetic foot ulcer ws defined s history of infection or coloniztion of DFU with 1 or more MDROs during the study period nd, for subjects enrolled during the first yer of the study, for 1 yer before the subject s index DFI episode. Dt Anlysis Epidemiology of the cohort nd prevlence of MDROs were clculted using mens nd stndrd devitions, nd medins with interqurtile rnges (IQRs). To identify risk fctors for DFI ssocited with MDRO (DFI-MDRO) nd for DFI ssocited with PRRT (DFI-PRRT), ptients who hd DFI-MDRO were compred with ptients who hd DFI ssocited with susceptible pthogens (DFI-Non-MDRO), nd ptients who hd DFI- PRRT were compred with ptients who hd DFI ssocited with non-prrt pthogens (DFI-Non-PRRT), using the t test or Wilcoxon rnk-sum test for continuous vribles nd the Fisher exct test or chi-squre test for dichotomous nd ctegoricl vribles. Risk fctor nlyses for individul pthogens were performed using the sme methodology s ws used to determine risk fctors for the PRRT group. For exmple, ptients who hd DFI ssocited with P. eruginos (DFI-P. eruginos) were compred with ptients who hd DFI ssocited with ll other pthogens, excluding P. erugnios (DFI-Non-P. eruginos). Multivrible nlysis ws performed using logistic regression. Vribles with P vlue of <.2 in bivrible nlysis were included in the cndidte multivrible model ( primry model ). Bckwrds stepwise regression ws performed to identify independent predictors for DFI-MDRO. Vribles not selected were evluted for confounding. If vrible impcted the Bet coefficient vlue of 1 or more of the selected vribles by 10%, it ws considered confounder nd ws left in the model. Similr nlysis methodology ws implemented to identify independent predictors for DFI-PRRT nd for ech of PRRT pthogens individully. All P vlues were 2-sided. RESULTS Cohort Between 2012 nd 2015, 1210 subjects who hd dibetes mellitus, SSTI nd/or osteomyelitis, nd wound culture obtined were identified. Five hundred sixty-two ptients were excluded for the following resons: bsence of positive cultures, SSTI locted in n re other thn the foot, documenttion of noninfected DFU, or isoltion of cogulse-negtive Stphylococci or Corynobcterium spp. from single nonsterile culture. Six-hundred forty-eight unique ptients were determined to hve DFI per the study definition nd were included in the study cohort (Figure 1). Overll, there were 963 DFI episodes throughout the entire study period, 648 were ctegorized s 93 Prior DFI episodes 1210 Unique ptients with SSTI or Osteoyelitis nd dibetes mellitus 648 Unique ptients with dignosed with DFI during DFI episodes for 648 unique ptients 648 DFI index episodes 562 Ptients excluded: 1. Absence of positive cultures 2. Skin nd soft tissue infection locted in n re other thn the foot 3. Documenttion of noninfected dibetic foot uber 4. Isoltion of cogulse-negtive stphylococci or corynobcterium spp. from 1 nonsterile culture. 222 Recurrent DFI episodes Figure 1. Flow chrt of ptients who were included nd excluded from the study cohort. Abbrevitions: DFI, dibetic foot infection; SSTI, skin nd soft tissue infection. Downloded from by guest on 06 November 2018 Predictors of DFI Associted With PRRT OFID 3

4 index episodes, 93 were DFI episodes occurring before MDRO- DFI, nd 222 were recurrent DFI episodes, following the index episode. ceftrixone-resistnt Enterobctericee nd crbpenem-resistnt Enterobctericee; n = 79; 15.9% of MDRO episodes), nd VRE (n = 68; 13.7% of MDRO episodes). Prevlence of DFI During the Entire Study Period There were 2450 orgnisms recovered from DFI lesions of the 963 episodes during the study period (Tble 1). Seventytwo percent (n = 691) of the episodes were polymicrobil. The medin number of pthogens recovered from DFI (IQR) ws 2 (1 3). S. ureus (MSSA or MRSA) ccounted for 57% of monomicrobil cultures. Most of the orgnisms (68%) grew from smples obtined in the operting room (Supplementry Figures 1 nd 2): 18% were obtined from the bone, 28% were obtined from deep tissue, nd 22% were obtined from swbs. In ddition, 9% of the orgnisms grew from tissue cultures tht were obtined t the bedside, nd 22% grew in swb cultures tht were obtined t the bedside. The distribution of orgnism source ws consistent cross ll types of bcteril species included in the cohort. Of 963 episodes (Tble 1), DFI ws ssocited with Grmpositive cocci (GPC) in 86% of the episodes, nd S. ureus ws the most common pthogen (53% of GPC; MRSA represented 58.5% of S. ureus). Grm-negtive bcilli were present in 56.8% of DFI episodes, nd Enterobctericee were the most common Grm-negtive pthogens (80.6%). More thn hlf of ll episodes (n = 495; 51.4%) were ssocited with t lest 1 MDRO. The most common MDRO ws MRSA (299 episodes; present in 60% of MDRO episodes), followed by P. eruginos (n = 131; 26.4% of MDRO episodes), resistnt Enterobctericee (including Tble 1. Demogrphics nd Epidemiology of Index Episode nd Risk Fctors for DFI-MDRO Six hundred forty-eight unique ptients hd index DFI episodes during the study period. The men ge of this cohort ws 58.4 ± 13.7 yers, 64.3% were mle, nd 72.8% were Africn Americn. The mjority of ptients (86.9%) were dmitted from home (Tble 1). One hundred ninety-seven ptients (30.4%) were hospitlized within the 90 dys before the DFI index episode. The medin Chrlson Comorbidity Index score (IQR) ws 5 (3 6). Additionl chrcteristics of the cohort re presented in Tble 2. Approximtely one-qurter of the ptients presented with severe sepsis or septic shock. The mjority of ptients who were evluted for depth of infection were ctegorized s hving deep infections (n = 586; 90.4%), nd 407 of these (69.5%) involved bone. Three-hundred sixty-four ptients (56.2%) hd t lest 1 MDRO (DFI-MDRO). The most common MDRO ws MRSA (n = 224 ptients; 61.5% of ptients who hd DFI-MDRO), followed by P. eruginos (n = 94; 26% of DFI-MDRO), ceftrixone-resistnt Enterobctericee, nd VRE (Figure 2). Most cultures were polymicrobil nd were obtined in the operting room or from bone biopsy (70%). In bivrible nlysis, ptients who hd DFI-MDRO were more likely to hve comorbid conditions nd to be hospitlized within 90 dys before the index episode thn ptients who hd DFI-Non-MDRO (39% vs 19.8%; P <.001) (Tble 2). Severe Number of Orgnisms Recovered From DFI Lesions During the Entire Study Period nd During the Index Episode Pthogen Pthogens During Entire Study Period (No. Episodes = 963), No. (%) Pthogens During Index Episode (No. Episodes = 648), No. (%) Grm-positive 829 (86.0) 579 (89.4) MRSA 299 (31.4) 224 (34.6) MSSA 231 (23.6) 160 (24.7) Streptococci 265 (32.0) 195 (30.1) Enterococci (vncomycin-susceptible) 229 (23.8) 166 (25.6) VRE 68 (7.1) 52 (8.0) Cogulse-negtive Stphylococci 129 (13.4) 115 (17.8) Grm-negtive 547 (56.8) 375 (57.9) Enterobctericee (ceftrixone-susceptible) 394 (40.9) 275 (42.4) Enterobctericee (ceftrixone-resistnt) 74 (7.7) 51 (7.9) CRE 6 (0.6) 6 (0.6) P. eruginos 131 (13.6) 94 (14.5) A. bumnnii 29 (3.0) 22 (3.4) Other GNB 74 (7.9) 57 (8.8) Anerobes 197 (28.8) 160 (24.7) Others b 124 (12.9) 115 (17.7) Downloded from by guest on 06 November 2018 Abbrevitions: CRE, crbpenem-resistnt Enterobctericee; GNB, Grm-negtive bcilli; MRSA, methicillin-resistnt Stphylococcus ureus; MSSA, methicillin-susceptible Stphylococcus ureus; VRE, vncomycin-resistnt Enterococci. The percentges for ech of the pthogens represent the proportion of pthogens of number of episodes. As some of the ptients hd more thn 1 pthogen per episode, the sum of the percentges is >100%. b Others: Corynobcterium spp., Cndid spp. 4 OFID Henig et l

5 Tble 2. Cohort Description nd Bivrible nd Multivrible Anlyses of Risk Fctors for DFI Associted With MDRO nd PRRT Entire Cohort (n = 648) DFI-MDRO (n = 364) DFI-Non-MDRO (n = 293) P Vlue Undjusted Adjusted OR e (95% CI) DFI-PRRT (n = 194) DFI-Non-PRRT (n = 454) P Vlue Undjusted Adjusted OR f (95% CI) Age, men ± SD, y 58.4 ± ± ± ± ± 13.6 <.001 Femle 231 (35.7) 135 (37.1) 96 (33.8) (37.6) 158 (34.8).53 Insurnce type.26 <.001 Privte 168 (25.9) 88 (24.2) 80 (28.3) 42 (21.7) 126 (27.8) Medicre 320 (49.4) 190 (52.2) 130 (45.8) 119 (61.3) 201 (44.3) Medicid or no insurnce 160 (24.7) 86 (23.6) 77 (26.2) 33 (17.0) 127 (28.0) Origin Home 563 (86.9) 307 (84.3) 256 (90.1) 159 (82.8) 404 (90.0) LTCF 58 (8.95) 40 (11.0) 18 (6.3) 27 (13.9) 31 (6.8) Other 20 (3.1) 14 (3.9) 6 (2.4) 6 (3.1) 14 (3.1) LTCF (vs others) 58 (8.95) 40 (11.0) 18 (6.3) ( ) 20 (14.0) 38 (7.5) ( ) Dependent sttus (bedridden) 110 (17.7) 74 (21.1) 36 (13.2) ( ) 48 (25.8) 62 (14.2) < ( ) Recent hospitliztion 197 (30.4) 141 (38.7) 56 (19.7) < ( ) 91 (46.9) 106 (23.4) < ( ) Comorbid conditions Chrlson Comorbidity Index, medin (IQR) 5 (3 6) 5 (3 7) 4 (3 6) < (4 7) 4 (3 6) <.001 CHF 210 (32.4) 125 (34.3) 85 (29.9) (38.1) 136 (30.0).04 Chronic lung disese 158 (24.4) 97 (26.7) 61 (21.5) (31.4) 97 (21.4).007 CKD 183 (28.2) 118 (32.4) 65 (22.9) ( ) 75 (38.7) 108 (23.8) < ( ) PVD 442 (68.2) 270 (74.2) 172 (60.6) < ( ) 163 (84.0) 279 (61.5) < ( ) Mlignncy 61 (9.4) 30 (8.2) 31 (10.9) (9.8) 42 (9.3).88 Dementi 62 (9.6) 39 (10.7) 23 (8.1) (11.9) 39 (8.6).24 Cerebrovsculr disese 123 (19.0) 80 (22.0) 43 (15.1) (22.2) 80 (17.6).19 Dibetes-ssocited conditions Retinopthy 117 (18.1) 68 (18.7) 49 (17.3) (19.6) 79 (17.4).51 Neuropthy 535 (82.6) 308 (84.6) 227 (79.9) (83.5) 373 (82.2).74 HbA1c, men ± SD 9 ± ± ± ± ± ABI, medin (IQR) 0.99 ( ) 0.99 ( ) 0.99 ( ) ( ) 0.99 ( ).85 (n = 243) Mx glucose on presenttion 249 (38.4) 134 (36.8) 115 (40.5) (33.5) 184 (40.5).09 >300 mg/dl Min glucose on presenttion 130 (20.1) 80 (22.0) 50 (17.6) (23.7) 84 (18.5).14 <70 mg/dl BMI, medin (IQR), kg/m ( ) 29.4 ( ) 30.2 ( ) ( ) 30 ( ).28 Severity of illness Severe sepsis nd septic 154 (23.8) 98 (26.9) 56 (19.7) (26.3) 103 (22.7).36 shock b BSI 64 (9.9) 39 (10.9) 25 (8.8) (9.3) 46 (10.1).78 ICU dmission c 62 (9.6) 39 (10.7) 21 (7.4) (11.9) 37 (8.2).14 Mechnicl ventiltion 24 (3.7) 15 (4.1) 9 (3.2) (6.7) 11 (2.4).01 Downloded from by guest on 06 November 2018 Predictors of DFI Associted With PRRT OFID 5

6 Tble 2. Continued Entire Cohort (n = 648) DFI-MDRO (n = 364) DFI-Non-MDRO (n = 293) P Vlue Undjusted Adjusted OR e (95% CI) DFI-PRRT (n = 194) DFI-Non-PRRT (n = 454) P Vlue Undjusted Adjusted OR f (95% CI) Acute kidney injury 155 (23.9) 91 (25.0) 64 (22.5) (24.2) 108 (23.8).92 Highest WBC, medin (IQR) 16.4 ( ) 16.6 ( ) 16.3 ( ) ( ) 16.2 ( ).12 (n = 289) MAP <65 mmhg 95 (18.3) 66 (18.1) 29 (10.2) (23.7) 49 (10.8) <.001 Bone involvement 407 (62.8) 243 (66.8) 164 (57.8) (70.1) 271 (59.7).01 Osteomyelitis per pthology 276 (42.6) 157 (43.1) 119 (41.9) (45.9) 187 (41.2).30 Prior DFI d 58 (9.0) 16 (13.5) 3 (4.2) (16.1) 9 (7.0).07 History of dibetic foot ulcer 74 (11) 58 (15.9) 16 (5.6) < ( ) 21 (10.8) 20 (4.4) ( ) ssocited with MDRO or PRRT, respectively Prior debridement of foot 180 (27.8) 125 (34.3) 55 (19.4) < ( ) 70 (36.1) 110 (24.2) ( ) ulcer/infection Prior ntibiotic use (pst 239 (36.9) 168 (46.2) 71 (25.0) < ( ) 112 (57.7) 127 (28.0) < ( ) 3 mo) BLBLI 83 (12.8) 66 (18.1) 17 (6.0) < (24.2) 36 (7.9) < ( ) Third-genertion 33 (5.0) 25 (6.9) 8 (2.8) (7.7) 18 (4.0).05 cephlosporin Cefepime 37 (5.7) 29 (8.2) 8 (2.8) (11.3) 15 (3.3) < ( ) Quinolones 50 (7.7) 38 (10.4) 12 (4.2) (11.9) 27 (6.0) ( ) Vncomycin 117 (18.1) 94 (25.8) 23 (8.1) < (33.0) 53 (11.7) < ( ) Clindmycin 41 (6.3) 31 (8.5) 10 (3.5) (11.3) 19 (4.2) ( ) Dt re No. (%) unless otherwise presented. Abbrevitions: ABI, nkle-brchil index; BLBLI, bet-lctm/bet-lctmse inhibitor; BMI, body mss index; BSI, bloodstrem infection; CHF, congestive hert filure; CKD, chronic kidney disese; DFI, dibetic foot infection; ICU, intensive cre unit; LTCF, long-term cre fcility, including nursing home nd long-term fcilities; MAP, men rteril pressure; MI/CAD, myocrdil infrction nd/or coronry rtery diseses with stent inserted; PRRT, pthogens resistnt to empiric recommended tretment; TMP/SMZ, trimethoprim, sulfmethoxzole; WBC, white blood cell count. Highest WBC ws clculted mong ptients who hd WBC > b Defined s systemic inflmmtory response syndrome ccompnied by end orgn compromise, with or without the need for vsopressors support. c Within 7 dys of DFI dignosis. d For the nlysis of prior DFI episode, only ptients who hd DFIs during the first yer of the study period were included (n = 190) becuse ptients with DFI-Non-MDRO could only hve prior DFI episodes if they were before the study period (per inclusion criteri, mong DFI-Non-MDRO, the first episode within the study period ws included, wheres for DFI-MDRO, the first DFI-MDRO episode ws included). e DFI-MDRO model ws djusted for prior hospitliztion, LTCF residency, dependent sttus, nd prior debridement. Odds rtios of vribles tht were included in the finl model re presented. f DFI-PRRT model ws djusted for prior hospitliztion, LTCF residency, dependent sttus, prior debridement, prior use of cefepime, quinolones, vncomycin, nd clindmycin. Odds rtios of vribles tht were included in the finl model re presented. Downloded from by guest on 06 November OFID Henig et l

7 MRSA P. eruginos Percentge of ech MDRO of ll MDROs (n = 364) VRE Ceftrixone-R-E MDRO type A. bumnnii Stenotrophomons spp. Figure 2. Index episode, dibetic foot infection multidrug-resistnt orgnism types. As some ptients hd >1 multidrug-resistnt orgnism, the sum of the percentges is >100%. Abbrevitions: Ceftrixone-R E, ceftrixone-resistnt Enterobctericee; CRE, crbpenem-resistnt Enterobctericee; MDRO, multidrug-resistnt orgnism; MRSA, methicillin-resistnt Stphylococcus ureus; VRE, vncomycin-resistnt Enterococcus spp. sepsis nd septic shock occurred more frequently upon presenttion in ptients with DFI-MDRO compred with those with DFI-Non-MDRO (26.9% vs 19.7%, respectively; P =.03). Interestingly, both groups hd poor glycemic control (men HbA1C, 9 ± 2.6 for the entire cohort), but ptients who hd DFI-MDRO hd significntly lower men HbA1C vlues thn ptients who hd DFI-Non-MDRO (8.8 vs 9.4; P =.02) (Tble 2). In multivrible nlysis, independent predictors for DFI- MDRO included tretment with ny ntibiotic within 90 dys before the index episode (odds rtio [OR], 1.81; 95% confidence intervl [CI], ), history of coloniztion or infection of dibetic foot lesion with n MDRO (OR, 2.62; 95% CI, ), peripherl vsculr disese (PVD; OR, 1.45; 95% CI, ), nd chronic kidney disese (CKD; OR, 1.48; 95% CI, ) (Tble 2). Risk Fctors for DFI-PRRT Ptients with DFI-PRRT ccounted for 29.9% of DFI index episodes (n = 194). Most DFI-PRRT were due to P. eruginos (Figure 2). In bivrible nlysis, ptients with DFI-PRRT were older nd hd higher prevlence of comorbid conditions thn did ptients who hd DFI due to being non-prrt (DFI-Non- PRRT). In ddition, ptients with DFI-PRRT were more likely to be dmitted from n LTCF (14% vs 7.5%; P =.006) nd to be hospitlized in the 90 dys before the index episode (46.9% vs 23.4%; P <.001) (Tble 2). Ptients who hd DFI-PRRT hd significntly lower men HbA1C vlues thn did ptients who hd DFI-Non-PRRT (8.6 vs 9.3; P =.004). In multivrible nlysis, independent predictors for DFI- PRRT included PVD (OR, 2.38; 95% CI, ), CKD (OR, 1.56; 95% CI, ), history of coloniztion or infection of dibetic foot ulcer with PRRT (OR, 2.45; 95% CI, ), nd prior use of bet-lctm bet-lctmse inhibitor combintion (OR, 2.16; 95% CI, ) (Tble 2). CRE Risk Fctors for DFI Associted With Individul Pthogens Among the PRRT Group Cohort chrcteristics nd risk fctors for ech individul pthogen re presented in Supplementry Tble 1. There were 94 ptients with DFI ssocited with P. eruginos, 51 with ceftrixone-resistnt Enterobctericee, nd 52 with VRE. Of note, ptients with DFI ssocited with ceftrixone-resistnt Enterobctericee hd the highest rte of severe sepsis nd septic shock (40%). In multivrible nlysis, hving hd prior dibetic foot culture positive for the sme PRRT pthogen ws n independent predictor for DFI ssocited with P. eruginos (OR, 3.06; 95% CI, ) nd for DFI ssocited with VRE (OR, 7.83; 95% CI, ) (Tble 3). Different prior ntibiotic exposures were significntly ssocited with different types of Grm-negtive PRRT. Prior use of bet-lctm/bet-lctmse inhibitor (BLBLI), third- nd fourth-genertion cephlosporins ws n independent predictor for DFI ssocited with ceftrixone-resistnt Enterobctericee (BLBLI: OR, 2.69; 95% CI, ; third-genertion cephlosporins: OR, 2.95; 95% CI, ; cefepime: OR, 3.27; 95% CI, ), nd prior use of cefepime ws n independent predictor for DFI due to P. eruginos (OR, 2.41; 95% CI, ). With regrds to prior helth cre exposure, residence in n LTCF ws n independent predictor only for DFI ssocited with ceftrixone-resistnt Enterobctericee (OR, 3.85; 95% CI, ), nd recent hospitliztion ws n independent predictor only for DFI ssocited with VRE (OR, 3.37; 95% CI, ) (Tble 3). The only comorbid condition tht ws PRRT risk fctor ws PVD, which ws significntly ssocited with DFI-VRE (OR, 17.51; 95% CI, ) nd DFI-ceftrixone-resistnt Enterobctericee (OR, 3.45; 95% CI, ). DISCUSSION The proportion of DFI ssocited with pthogens tht were not covered by guideline-recommended empiric therpy regimens ws higher thn expected. Almost one-third of the index episodes exhibited 1 or more pthogens resistnt to the recommended empiric therpies, most commonly P. eruginos, followed by ceftrixone-resistnt Enterobctericee nd VRE (7.7% nd 7.1%, respectively). Importntly, P. eruginos ws n unexpectedly common pthogen, being present in 15% of index episodes in this study. This is notble s P. eruginos is typiclly reported to occur in less thn 10% of DFI in the United Sttes [9 12]. In ddition, this study dds importnt nd striking dt pertining to the prevlence of DFI-MDRO due to VRE nd ceftrixone-resistnt Enterobctericee [2, 13, 14]. Consistent with published dt, MRSA, which occurred in lmost one-third of DFI cses, ws the most common MDRO [2]. Downloded from by guest on 06 November 2018 Predictors of DFI Associted With PRRT OFID 7

8 Tble 3. Independent Predictors for Individul DFI-PRRT PA b vs Non-PA, OR (95% CI) (n = 94) In this study, the use of ny ntibiotic in the preceding 3 months ws n independent predictor for DFI-MDRO, s ws prior history of n MDRO isolted in dibetic foot ulcers, PVD, nd CKD. Previous vncomycin nd BLBLI pproched sttisticl significnce in the multivrible model for DFI-MDRO (OR, 1.78; 95% CI, ; OR, 1.77; 95% CI, , respectively). To our knowledge, this is the first study evluting risk fctors for hving DFI ssocited with pthogens not covered by recommended empiric therpy of DFI. Similr to risk fctors for DFI-MDRO, prior use of ny ntibiotic ws independently ssocited with DFI- PRRT (OR, 2.79; 95% CI, ). Other independent predictors for DFI-PRRT (nd for DFI-MDRO) included prior history of recovery of PRRT in dibetic foot ulcer, s well s PVD nd CKD. In this study, ptient who hd history of recovery of PRRT in dibetic foot ulcer hd >2-fold risk for subsequently hving DFI-PRRT. This ssocition between prior coloniztion with resistnt orgnisms nd subsequent infection hs been reported with other types of infections [15, 16]. Therefore, in ddition to previous ntimicrobil exposure, prior growth of PRRT (or MDRO) in DFU should be considered when choosing empiric tretment for DFI. Peripherl vsculr disese nd CKD were reltively common in the study cohort. Hving PVD ws independently ssocited with >2-fold incresed risk of hving DFI-PRRT. Poor vsculr VRE c vs Non-VRE, OR (95% CI) (n = 52) 3GCE-RE d vs Non-3GCE-RE, OR (95% CI) (n = 51) Recent hospitliztion 1.50 ( ) 3.37 ( ) 1.00 ( ) Residence of LTCF 1.11 ( ) 3.85 ( ) Peripherl vsculr disese 1.68 ( ) ( ) 3.45 ( ) Congestive hert filure 1.31 ( ) Dementi 1.70 ( ) Dependent sttus (bedridden) 1.74 ( ) 1.21 ( ) Prior debridement 0.97 ( ) History of dibetic foot ulcer ssocited 3.06 ( ) with PA History of dibetic foot ulcer ssocited 7.83 ( ) with VRE History of dibetic foot ulcer ssocited 8.95 ( ) with 3GCE-RE Prior BLBLI use 2.69 ( ) Prior cephlosporin, third genertion 2.95 ( ) Prior cefepime use 2.41 ( ) 3.27 ( ) Prior vncomycin use 1.67 ( ) Abbrevitions: 3GCE-RE, third-genertion cephlosporin-resistnt Enterobctericee; BLBLI, bet-lctm/bet-lctmse inhibitor; DFI, dibetic foot infection; LTCF, long-term cre fcility; NS, nonsignificnt; PA, Pseudomons eruginos; PRRT, pthogens resistnt to empiric recommended tretment; VRE, vncomycin-resistnt Enterococcus spp. Vribles were not included in the model. b Controlled for LTCF, dependent sttus, recent hospitliztion, chronic kidney disese, peripherl vsculr disese, prior quinolone use, history of PA in dibetic foot ulcer, nd prior use of cefepime. c Controlled for LTCF, chronic kidney disese, prior debridement, nd prior vncomycin use. d Controlled for dependent sttus, recent hospitliztion, congestive hert filure, dementi, nd history of 3GCE-RE in dibetic foot ulcer. supply impirs wound heling nd chieves pproprite ntibiotic concentrtions t the site of infection, both of which hve been ssocited with selection of resistnt bcteri [17, 18]. However, becuse PVD prevlence ws lso very high mong ptients with DFI-Non-PRRT (>60%), there ws little predictive vlue for the presence of PVD in determining the likelihood of DFI-PRRT. In ddition, hving CKD incresed the risk of DFI-PRRT by more thn 50%. Among ptients with CKD, it is plusible tht use of lower doses of ntibiotics, prticulrly in the presence of poor vsculr supply nd tissue penetrtion, might led to subtherpeutic concentrtions t the site of infection nd subsequent development of ntimicrobil resistnce. When individul PRRT were evluted, vriety of different ntibiotic risk fctors were identified. Consistent with previous reports in infections other thn DFI [19, 20], prior third-genertion cephlosporin exposure ws ssocited with ceftrixone-resistnt Enterobctericee, nd previous cefepime ws ssocited with P. eruginos. This ssocition between previous use of cefepime nd/or BLBLI nd higher prevlence of P. eruginos my be mrker for ptients with comorbid conditions tht plce them t incresed risk for P. eruginos infection. Alterntively, exposure to these ntibiotics might hve inhibited the growth of competing bcteri, giving P. eruginos selective dvntge. Interestingly, residence in LTCF ws n independent predictor for DFI-ceftrixone-resistnt Enterobctericee but not for other MDROs. Similrly, recent Downloded from by guest on 06 November OFID Henig et l

9 hospitliztion ws n independent predictor only for DFI- VRE. Due to the to numerous published reports noting ssocitions between LTCF exposure nd recent hospitliztion with vriety of MDRO infections, we believe tht these helth cre exposures re n importnt risk fctor to consider when choosing empiric therpy for DFI [21]. This study hs limittions. As result of its retrospective design, dt for the durtion of dibetes before DFI, outptient mngement vribles, nd wound chrcteristics could not be fully cptured. However, expnsive medicl chrt evlution llowed for the extrction of clinicl informtion pertining to depth of infection nd sepsis severity, which enbled the clssifiction of >90% of the ptients in the index cohort s hving DFI severity levels tht were moderte or severe ccording to IDSA criteri [1]. Also, the omission of ptients from this study who either hd no culture obtined or only negtive cultures my hve provided n overestimtion of the incidence of DFI- MDRO. The results pertining to DFI-PRRT predictors re most relevnt to the prctice t the study institution, which is in line with guideline recommendtions, but cnnot be generlized to institutions tht use different regimens tht include broder-spectrum empiric ntibiotics. Twenty-two percent of the cultures in the study were from bedside swbs. Bedside swb cultures my be less specific for pthogens thn other types of cultures in the cohort. In subgroup nlysis tht included DFI episodes with deep cultures only (deep tissue nd bone), the distribution of MDROs ws similr to tht of the originl cohort, nd the independent predictors for DFI-MDRO in this cohort were similr except for PVD, which ws no longer predictor for DFI-MDRO (dt not shown). In conclusion, this study demonstrted tht the prevlence of MDROs nd PRRT, prticulrly P. eruginos, ws unexpectedly high mong dibetic ptients with culture-positive DFI. History of the sme MDRO in prior dibetic foot ulcer nd prior ntibiotic exposure were risk fctors for most individul types of PRRT. In ddition, PVD ws n independent predictor of DFI-MDRO, DFI-PRRT, nd DFI-P. eruginos. Clinicins nd ntimicrobil stewrds cn utilize these vribles to help guide empiric therpeutic decisions nd guidelines. Supplementry Dt Supplementry mterils re vilble t Open Forum Infectious Diseses online. Consisting of dt provided by the uthors to benefit the reder, the posted mterils re not copyedited nd re the sole responsibility of the uthors, so questions or comments should be ddressed to the corresponding uthor. Acknowledgments Finncil support. This study ws not funded. Potentil conflicts of interest. All uthors: no reported conflicts of interest. All uthors hve submitted the ICMJE Form for Disclosure of Potentil Conflicts of Interest. Conflicts tht the editors consider relevnt to the content of the mnuscript hve been disclosed. References 1. 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