TRANSPLANTAND ONCOLOGY (M ISON AND N THEODOROPOULOS, SECTION EDITORS)

Multidrug-Resistant Bacteria in Organ Transplantation: AnEmerging Threat with Limited Therapeutic Options

Gopi Patel & Meenakshi M. Rana & Shirish Huprikar

# Springer Science+Business Media New York 2013

Abstract Multidrug-resistant organisms (MDROs) are anemerging threat in solid organ transplantation (SOT). Thechanging epidemiology of these MDROs is reviewed alongwith the growing evidence regarding risk factors and out-comes associated with both colonization and infection inSOT. The management of these infections is complicated bythe lack of antimicrobial agents available to treat these infec-tions, and only a handful of new agents, especially for thetreatment of MDR GNR infections, are being evaluated inclinical trials. Due to the increased prevalence of MDROs andlimited treatment options, as well as organ shortages, trans-plant candidacy and use of organs from donors with evidenceof MDRO colonization and/or infection remain controversial.Increasing collaboration between transplant programs, indi-vidual practitioners, infection control programs, and re-searchers in antimicrobial development will be needed to facethis challenge.

Keywords MRSA .VRE . CRE . KPC . Acinetobacterbaumannii . Pseudomonas aeruginosa . Burkholderia

Introduction

Advances in surgical techniques, immunosuppressive regi-mens, and bundled approaches in infection control have im-proved outcomes in solid organ transplantation (SOT).

However, infections with multidrug-resistant organisms(MDROs) remain a threat to patient and graft survival.Advances have been made in Gram-positive antimicrobials,but limitations in available agents to treat multidrug-resistant(MDR)–Gram-negative infections have forced clinicians to turnto older antibiotics and combination regimens that are unprovenin clinical trials. In a population of patients where health-careand antimicrobial exposure is frequently extensive, the relative-ly dry antimicrobial pipeline is a serious threat to patient safety[1••].

In this review, we provide a contemporary perspective onissues related to MDROs in SOT. Most studies evaluating riskfactors and outcomes of infections with MDROs have been inheterogeneous populations. Studies specific to SOT are oftenlimited to single-center experiences and may reflect institution-al trends. In spite of limitations, these individual reports com-plement existing guidelines [2–4] and may be helpful to trans-plant clinicians treating MDRO infections. Due to heterogene-ity in the literature, a recent international panel of experts hasrecommended that MDR be defined as nonsusceptibility to atleast one agent in at least three antibacterial classes [5••]. Forthe purposes of this review, deviations from this proposeddefinition will be specified when appropriate.

Gram-Negative Bacteria

Infections with Gram-negative bacteria are associated withsignificant morbidity and mortality. Carbapenems are general-ly considered to be reliable in the treatment of Gram-negativeinfections. However, carbapenem resistance is growing, andcurrent options for treating these infections are limited.

Carbapenem-Resistant Enterobacteriaceae

Carbapenem resistance in Enterobacteriaceae (e.g.,Escherichiacoli andKlebsiella) is of increasing concern, since these bacteria

G. Patel :M. M. Rana : S. Huprikar (*)Division of Infectious Diseases, Department of Medicine, IcahnSchool ofMedicine atMount Sinai, One Gustave L. Levy Place, Box1090, New York, NY 10029, USAe-mail: shirish.huprikar@mssm.edu

G. Patele-mail: gopi.patel@mssm.edu

M. M. Ranae-mail: meenakshi.Rana@mssm.edu

Curr Infect Dis RepDOI 10.1007/s11908-013-0371-z

are common causes of both community-acquired and health-care-associated infections. Prior to 2001, carbapenem-resistantEnterobacteriaceae (CRE) were considered exceedingly rare.In a relatively short period of time, however, CRE have beendescribed worldwide [6]. According to the Centers for DiseaseControl and Prevention (CDC) National Healthcare SafetyNetwork (NHSN) [7••], the proportion of CRE associated withhealth-care-associated infections increased from 1.2 % in 2001to 4.2 % in 2011. Most of this increase was observed amongKlebsiella spp. In 2012, 4.6 % of acute-care hospitals partic-ipating in the NHSN reported clinical isolation of CRE.

Among the several mechanisms of carbapenem resistancein Enterobacteriaceae, carbapenemase production is the mostcommon [8•]. K. pneumoniae carbapenemase (KPC) expres-sion is the most frequent mechanism of carbapenem resistancein the U.S., but isolation of metallo-β-lactamases (MBLs)(e.g., New Delhi MBL (NDM) and VIM-1/2) [6] and, morerecently, carbapenem-hydrolyzing class D β-lactamases(oxacillinase-48 [OXA-48]) [9••] have been described. Ingeneral, due to concurrent carriage of other resistance genes,CRE tend to be multidrug resistant, and no commerciallyavailable agent has demonstrated universal activity againstCRE. Although specific mechanisms of carbapenem resis-tance do not affect in vitro susceptibilities for available agentsto treat CRE, this could affect the potential activity of agents inadvanced stages of development.

Frequently cited risk factors for acquisition of CRE includeexposure to a variety of antimicrobials, liver disease, use ofinvasive devices, ICU exposure, hematopoietic stem celltransplantation, and SOT [10–13]. Not uncommonly, the in-dex case of CRE at an institution is an SOT recipient or acandidate who may have received prior medical care in anendemic area [9••, 14, 15]. In-hospital mortality rates areespecially high among SOT recipients [16, 17•].

In addition to source control [11], case reports and smallcase series suggest the superiority of combination regimens[18, 19]. However, clinical trials in both the United States(U.S.) and Europe systematically evaluating the role of combi-nation therapy for CRE and other MDR Gram-negative organ-isms are in progress. Available therapeutic options includethe polymyxins (both colistin and polymyxin B), tigecycline,and aminoglycosides. When susceptible, fluoroquinolones,nitrofurantoin, and fosfomycin may be used to treat symptom-atic CRE cystitis. Only a handful of novel therapeutic agentsare in advanced clinical trials, with published data suggestingactivity against CRE (Table 1) [1••].

Avibactam, or NXL-104, is a β-lactamase inhibitor thathas been evaluated in combination with cephalosporins,imipenem, and aztreonam against CRE, including KPCs andOXA-48 [20–22]. The combinations of ceftaroline–avibactamand ceftazidime–avibactam are currently in phase 3 clinicaltrials. Unfortunately, cephalosporin–avibactam combinationsdo not inhibit MBLs. Avibactam in combination with aztreonam,

however, does seem to demonstrate activity against isolatesharboring a variety of carbapenem resistance mechanisms,including MBLs. Regrettably, this combination is not current-ly being evaluated in trials.

Few agents are in phase 2 clinical trials. MK-7655 is anothernovel β-lactamase inhibitor being evaluated in combinationwith imipenem, with potential activity against carbapenem-resistant Gram-negative bacilli [18]. Like avibactam, thereappears to be limited activity against MBLs. Plazomicin(ACHN-490) is an aminoglycoside derivative, or neoglycoside,with potent activity against some CRE, including KPCs andMBLs, even in the setting of nonsusceptibility to commerciallyavailable aminoglycosides [23–26]. However, plazomicin sus-ceptibility appears to be dependent on the mechanism of ami-noglycoside resistance. Etravacycline, TP-434, is a tetracyclinederivative or “fluorocycline.” Etravacycline demonstratesin vitro activity against KPC-producing K. pneumoniae [27].

Acinetobacter baumanii

Carbapenem-resistant Acinetobacter baumanii (CRAB) in-fections continue to plague SOT recipients. In a single-center study from China, 60 % of the A. baumannii isolateswere imipenem resistant [28]. Table 2 summarizes the recentliterature describing outcomes associated with CRAB infec-tions in SOT recipients. All studies were single-center caseseries with varying definitions of MDR and “extensively-drugresistant” (XDR) A . baumannii, and four of the six reportswere from two U.S. medical centers. Pneumonia was thepredominant infection, and mortality rates ranged from 33 %to 80 %, with persistence of infection and mortality morelikely among lung transplant recipients [29, 30•].

Shields et al. [30•] described the outcomes in 69 SOTrecipients who were either colonized (41 %) or infected(59 %) with XDR A. baumannii (resistant to agent[s] in allantimicrobial classes except polymyxins and tigecycline).Colonization appeared to be a risk factor for subsequentinfection, with 32 % of the 41 infected patients demonstratingprior colonization. Infection was more common in thoracictransplant recipients, as compared with abdominal transplantrecipients. In a series of liver and kidney transplant recipientswith A. baumannii infection from Brazil, 39 % percent weredue to CRAB. In multivariable analysis, mortality was lowerin patients who received “appropriate” empirical antibiotics[31]. However, carbapenem resistance had no impact on mor-tality, suggesting that A. baumannii infections are inherentlyassociated with poor outcomes, as has been supported byother recent studies [32, 33].

Treatment was assessed in two studies from one medicalcenter. Shields et al. [34] reported mortality in 91 % of SOTrecipients with XDR A. baumannii . On the basis of theseoutcomes, 17 XDR A. baumannii isolates from unique pa-tients were evaluated for in vitro susceptibility to single and

Curr Infect Dis Rep

combination antibiotics. Synergy was observed for combina-tions of colistin with either ampicillin-sulbactam or a carba-penem. Colistin and carbapenem synergy was further con-firmed by the checkerboard method and time-kill assays.Furthermore, tigecycline nonsusceptibility was noted in alltested isolates. As a result, 5 SOT patients with pneumoniawere treated with a combination of parenteral and inhaledcolistin and carbapenem. In a subsequent retrospective study,the same group reported that colistin–carbapenem combina-tions were independently associated with 28-day survival[30•]. Of note, colistin resistance emerged in 36 % of thepatients with available data, including patients who receivedcolistin with a carbapenem.

Carbapenem resistance in A. baumannii can be due tocarbapenemase production including MBLs (e.g., NDM-1)and carbapenem-hydrolyzing oxacillinases, constitutive ex-pression of cephalosporinases, and/or porin mutations [8•,35, 36]. In terms of novel therapeutics (Table 1), neither thecombination of aβ-lactam and avibactam nor the combinationof imipenem and MK-7655 has activity against A. baumannii[37]. Plazomicin may have activity against specific isolates ofA.baumannii depending on the mechanism of aminoglycosideresistance [25, 38]. Eravacycline has demonstrated in vitroactivity against A. baumannii , but data remain limited [27].

Pseudomonas aeruginosa

MDR P. aeruginosa is a well-described pathogen in SOTrecipients. In some centers, rates of MDR P. aeruginosabloodstream infections were significantly higher amongSOT recipients [39, 40]. In liver transplant (LT) recipients,rates of MDR P. aeruginosa (defined as resistance to at leasttwo classes of antibiotics) infections ranged from 19 % to56 % [28, 41, 42]. However, specific data regarding risk

factors and outcomes associated with MDR P. aeruginosa inLT recipients are limited.

P. aeruginosa is an important pathogen in lung transplantrecipients, particularly those with cystic fibrosis (CF), inwhom pan-resistant P. aeruginosa is consistently demonstrat-ed to colonize the airway [43–45]. However, conflicting dataexist regarding the impact of pan-resistant P. aeruginosa onlung transplant survival. Older studies demonstrate no differ-ence in survival of recipients colonized with pan-resistant P.aeruginosa , as compared with susceptible bacteria [43, 44]. Incontrast, a more recent retrospective two-center study demon-strated that 43 of 45 CF lung transplant recipients colonizedwith pan-resistant bacteria were colonized withP. aeruginosa ,and colonization with pan-resistant bacteria was associatedwith decreased survival [45].

Assessment of risk factors and outcomes of MDR P.aeruginosa infections in other SOT recipients remains limit-ed. An outbreak of carbapenem-resistant P. aeruginosa , me-diated by VIM-2, was recently described in a kidney trans-plant unit in Tunisia, with all strains exhibiting resistance to allantimicrobials except for colistin [46].

Like A. baumanii , a variety of mechanisms, including drugefflux, porin mutations, and β-lactamases includingcarbapenemases, may contribute to multidrug resistance in P.aeruginosa [47]. Although combination therapy for the treat-ment of Pseudomonas infections is historically recommended,even in the absence of multidrug resistance, combination ther-apy for treatment of MDR Pseudomonas infections cannot beroutinely recommended at this time, due to a lack of evidencethat combination therapy is superior to monotherapy and in-creasing resistance to available agents [48••]. However, similarto A. baumannii and CRE, there are laboratory evaluations,case reports, and small series that suggest a role for combina-tion therapy in MDR Pseudomonas infections [49–51].

Table 1 Antimicrobials in advanced development for the treatment of carbapenem-resistant Gram-negative bacilli

Drug Mechanism of Action Stage ofDevelopment

CRE MDRPseudomonas

MDRAcinetobacter

KPC MBL MDR MBL

Ceftolozane (CXA-101)-tazobactam[53, 54]

Novel anti-pseudomonal cephalosporin +β-lactamase inhibitor

Phase 3 X

Ceftazidime-avibactam(NXL104)[20, 37]

Anti-pseudomonal cephalosporin +β-lactamase inhibitor

Phase 3 X X*

Ceftaroline-avibactam(NXL-104)[21]

Anti-staphylococcal cephalosporin +β-lactamase inhibitor

Phase 2 X

Imipenem-MK7655[18] Carbapenem + β-lactamase inhibitor Phase 2 X Limited data

Plazomicin (ACHN-490) [23, 25] Neoglycoside Phase 2 X X Limited data Limited data

Eravacycline (TP-434) [27] Fluorocycline Phase 2 X X Limited data

Note. KPC, K. pneumoniae carbapenemase; MBL, metallo-β-lactamase; MDR, multidrug-resistant including carbapenem-resistant. Adapted withpermission from Boucher et al. [1••]

• Dependent on mechanism of resistance

Curr Infect Dis Rep

Tab

le2

Reportsof

multid

rug-resistant*

Acinetobacter

baum

anniiinfections

insolid

organtransplantation

Study,Publication

Year

Tim

ePeriod

Country

Num

berof

Subjects

Organs

Transplanted

Prior

Infection

PriorCarbapenem

Exposure

MedianTim

eto

Infection

Posttransplant

(days)

Site(s)of

Infection

Mortality

Sopiralaetal.,2008

[102•]

2005–2007

U.S.

6Lung

83%

NR

259(22–1,110)

PNA(4)

PNA+BSI(2)

33%

Reddy

etal.,2010†[103]

2004–2005

U.S.

5Liver–kidney(3)

Liver

(1)

Kidney(1)

80%

60%

51(14–219)

PNA(2)

PNA+BSI+UTI(2)

PNA+BSI+SSI(1)

80%

Nunleyetal.,2010

[29]

NR

U.S.

6Lung

NR

NR

349(49–1,308)

PNA(4)

PNA+BSI(1)

PNA+BSI+BTI(1)

67%

Kim

etal.,2011

[32]

2001–2010

Korea

26Liver

NR

NR

NR

NR

50%

Shields

etal.,2011‡[34]

2006–2009

U.S.

16Lung(7)

Liver

(3)

Heart(3)

Kidney(2)

Intestine(1)

NR

NR

NR(0–18years)

VAP(10)

VAP+BSI

(3)

VAP+EMP(1)

VAP+MED(1)

VAP+MED+EMP(1)

69%

Shieldsetal.,2012

[30•]

2006–2011

US

41Lung(18)

Liver

(7)

Kidney(6)

Pancreas

(1)

Intestine(1)

Multiv

isceral(1)

NR

NR

172(0–6,829)

VAP(27)

VAP+BSI

(5)

VAP+MED(2)

VAP+EMP(2)

VAT(3)

PNA(1)

BSI

(1)

54%

deGouveaetal.,2012

[31]

2002–2009

Brazil

19Liver

(12)

Kidney(6)

NR

63%

20(9–299)

PNA(6)

BSI

(5)

UTI(4)

SSI(3)

44%

Note.

PNA,p

neum

onia;BSI,b

loodstream

infection;

UTI,urinarytractinfection;

SSI,surgicalsiteinfection;

BTI,biliary

tractinfection;

VAP,ventilator-associated

pneumonia;EMP,em

pyem

a;MED,

mediastinitis;VAT,

ventilatorassociated

tracheitis;NR,not

reported

*Multid

rugresistant(MDR)isdefinedaccordingto

Magiorakosetal.[5••]unless

otherw

isestated

†MDRdefinedas

carbapenem

-resistant

A.baumannii

‡Extensively

resistant(XDR)definedas

resistanttoallclasses

ofantib

ioticswith

theexceptionof

tigecyclin

eandcolistin

Curr Infect Dis Rep

The combination of ceftazidime–avibactam has demonstrat-ed decreases in minimum inhibitory concentrations (MICs) inisolates of P. aeruginosa nonsusceptible to ceftazidime [37,52]. However, this combination will not have activity againstisolates where β-lactam resistance is mediated by an MBL.Depending on the mechanism of aminoglycoside resistance,plazomicin has demonstrated in vitro activity against P.aeruginosa isolates [23, 25]. The combination of imipenem-MK7655 does not demonstrate activity against MBLs. Finally,ceftolozane is a novel antipseudomonal cephalosporin, whichhas been combined with tazobactam in vitro and in vivo anddemonstrates activity against carbapenem-resistant P.aeruginosa [53, 54]. Unlike the more novel β-lactamases,tazobactam is unable to overcome carbapenemases.

Burkholderia cepacia Complex

Burkholderia cepacia complex is primarily a problem in CFlung transplant recipients, with older studies consistently dem-onstrating poor outcomes in patients colonized with B.cepacia complex [55]. More recent studies suggest that spe-cific genomovars such as B. cenocepacia may be uniquelyassociated with these poor outcomes [56, 57]. In a retrospec-tive single-center study of 75 CF lung transplant recipients,pretransplant colonization with B. cenocepacia was associat-ed with a sixfold increased risk of mortality, as compared withother B. cepacia complex spp. [58]. Outcomes associatedwith B. gladioli are conflicting, with satisfactory outcomesobserved in one report [59] but greater mortality demonstratedin a larger cohort study [60]. Treatment of B. cepacia complexis often individualized; and due to the rarity of infectionsoutside of transplant centers and outbreaks, there is a paucityof studies evaluating treatment [61].

Gram-Positive Bacteria

Unlike carbapenem-resistant Gram-negative bacilli, there area number of agents available to treat infections with resistantGram-positive bacteria, although controversy remains regard-ing the comparative efficacy of specific agents. Much empha-sis has been placed on the control of methicillin-resistantStaphylococcus aureus infections, since some legislaturesare mandating screening and reporting of infections. However,in clinical practice, nonsusceptibility to both linezolid and dap-tomycin is increasingly being reported among vancomycin-resistant enterococci.With the possible exception of oritavancin,the pipeline is relatively dry for infections with these MDROs.

Methicillin-resistant Staphylococcus aureus

Methicillin-resistant Staphylococcus aureus (MRSA) accountedfor themajority ofMDROHAIs reported to theNHSN in 2009–

2010 [62]. More recently, however, the overall rates of MRSAHAIs appear to be declining. The reasons for this remain unclearbut may be related to widespread implementation of infectioncontrol measures.

The majority of the published data in SOT recipients arelimited to MRSA infections in LT recipients. Singh et al. firstnoted that of 165 LT recipients over an 8-year period, 23 %developed MRSA infection early after LT, and 30-day mor-tality was noted to be 21% [63]. More recently, Florescu et al.found that about half of S. aureus infections in LT recipientswere MRSA infections [64]. MRSA infections have beenassociated with increased posttransplant complications andantibiotic use in liver and kidney transplant recipients [65].

Nasal colonization with MRSA has shown to be a signif-icant risk factor for MRSA infection after LT [66]. In a largesingle-center study, the prevalence of MRSA nasal coloniza-tion in LTcandidates and recipients was 6.7 %, and those whowere colonized with MRSA had an increased risk of MRSAinfection [67]. Those who were colonized with MRSA did nothave a significantly increased rate of death. However, the 30-day mortality of LT recipients who developed MRSA infec-tionwas 36%, similar to what was reported by Singh et al. andsignificantly higher, as compared with those who remaineduninfected.

In other SOT recipients, data regarding MRSA infectionsare limited. In lung transplant recipients, MRSA infectionappears to be associated with predominantly lower respiratorytract infections and associated BSIs [68]. In a retrospectivestudy, patients colonized with MRSAwere at increased risk ofinfection after lung transplant. While overall rates of rejectionand long-term mortality rates were higher in patients infectedwith S. aureus , there was no difference in mortality in patientsinfected withMRSA, as compared withmethicillin-susceptibleS. aureus [69].

Vancomycin remains the mainstay for treatment of MRSA.A largemeta-analysis found that high-vancomycinMICswereassociated with increased mortality in patients with MRSABSI [70•]. The reasons for this association remain unclear; andin the absence of further data, vancomycin is recommendedfor the treatment of MRSA infections with vancomycin MICof ≤2 μg/mL. The decision to use alternative antibioticsshould be based on clinical or microbiological failure whenthe vancomycin MIC ≤2 μg/mL [71].

Daptomycin is also licensed for treatment of MRSA BSIand is commonly used as salvage therapy in patients withclinical or microbiologic vancomycin treatment failure. Inpatients with prior vancomycin exposure, however, cautionshould be used, since exposure to vancomycin has beenassociated with decreased daptomycin susceptibility, ashighlighted in recent case reports in patients with daptomycinnonsusceptible MRSA LVAD infections who successfullyunderwent cardiac transplantation [72, 73]. Despite a well-publicized randomized controlled trial suggesting clinical

Curr Infect Dis Rep

superiority of linezolid versus vancomycin for pneumonia[74•], this finding is of unclear significance, since no survivaldifferences were observed. Other commercially availableMRSA treatment alternatives include tigecycline, telavancin,and ceftaroline, but trials have been limited to the treatment ofskin and soft tissue infections and pneumonia.

The isolation of vancomycin-intermediate or glycopeptide-intermediate Staphylococcus aureus (VISA/GISA) andvancomycin-resistant Staphylococcus aureus (VRSA)strains remain uncommon. Vancomycin heteroresistantStaphylococcus aureus (hVISA/hGISA), in which subpopu-lations of vancomycin intermediate strains exist, are beingincreasingly reported in the literature. One retrospective studyfound 13 hGISA strains in 48 LT recipients colonized orinfected with MRSA; most patients were successfully treatedwith vancomycin [75].

Vancomycin-Resistant Enterococcus

In the late 1990s, the CDC reported a 20-fold increase in theprevalence of vancomycin-resistant Enterococcus in U.S.hospitals [76]. VRE remains uniformly associated withhealth-care exposure. Similar to other MDROs, previous ex-posure to various antimicrobials—specifically, vancomycin,cephalosporins, and antianaerobic agents—is associated withVRE acquisition [2]. Additional risk factors include length ofstay, invasive devices, and contaminated environments [77].LikeMRSA, asymptomatic colonization often precedes infec-tion [78].

The prevalence of VRE in mixed populations of liver andkidney transplant candidates and recipients is reported to bebetween 3.4 % and 55 %, with the highest rates among LTrecipients in outbreak settings [2, 67, 79, 80]. Published ratesof VRE infections among colonized LT patients range from11.5 % to 32 %. VRE-associated mortality rates range from33 % to 82 % in SOT recipients, with most studies publishedprior to the commercial availability of quinupristin-dalfopristinand linezolid [2].

Not surprisingly, most VRE infections present early afterSOT in the setting of surgical complications, such as biliarystrictures or leaks in LT and the use of invasive devices [81].Hepatitis C infection, simultaneous kidney–pancreas trans-plantation, need for dialysis, reexploration, and nephrostomyinsertion are cited as potential risk factors for VRE in kidneytransplantation [82].

While a large percentage of E. faecalis remain susceptible toampicillin, the majority of E. faecium are both ampicillin andvancomycin resistant, with high levels of aminoglycoside re-sistance. As VRE commonly affected SOT recipients, thesepatients were represented in the clinical trials leading to theFDA approval of both quinupristin–dalfopristin (Q/D) andlinezolid. Q/D became commercially available in 1999 for the

treatment of E. faecium . However, its use decreased substan-tially with the licensure of linezolid, due to its better tolerability.

Linezolid is also licensed for the treatment of VRE and,unlike Q/D, has activity against E. faecalis as well as E.faecium . An early evaluation of SOT recipients receivinglinezolid described an overall survival of 62.4 %, with thehighest attributable mortality rates in those patients requiringrepeated surgical interventions and with polymicrobial infec-tions [83]. Linezolid resistance has been reported in SOTrecipients in the setting of linezolid exposure, as well as inthe setting of horizontal transmission [84–86, 87•].

Although not a licensed indication in the U.S., daptomycinhas been used in the treatment of VRE, with anecdotal success[88]. Resistance is described in the setting of both activetreatment and possible antimicrobial pressure [89, 90]. Whensusceptible, fluoroquinolones, nitrofurantoin, and fosfomycinmay be used to treat symptomatic VRE cystitis.

Other agents with potential activity but insufficient clinicaldata against VRE include telavancin, ceftrobiprole, andceftaroline. None of these agents demonstrate consistent ac-tivity against E. faecium , although telavancin may have ac-tivity again vanB strains [91]. Oritavancin, an investigationallipoglycopeptide, has demonstrated promising in vitro activityagainst enterococci with either vanA or vanB and, in phase 3trials, for the treatment of skin and soft tissue infections [92].

Infection Control and Prevention

Strategies to prevent transmission of MDROs include basicinfection control measures such as hand hygiene and the useof contact precautions. Interventions such as the use of activesurveillance with or without subsequent decolonization re-main controversial. Since colonization appears to precedeinfection, many institutions have instituted surveillance pro-tocols in their high-risk units (e.g., ICUs). In the absence of anoutbreak or an increased endemic rate, universal screening isnot recommended.

Routine use of active surveillance cultures alone was asso-ciated with a 3.4-fold decrease inMRSA health-care-associatedinfections [67]. In one study, decolonization with mupirocinwas ineffective in decreasing infections with S. aureus in LTrecipients [93]. In another study, a multifaceted approach, in-cluding active surveillance, contact isolation and cohorting, andmupirocin, was effective in reducing the number of S. aureusinfections among LT recipients [94]. The role of active surveil-lance for asymptomatic VRE colonization remains undefined.

Few institutions have implemented routine screening forCRE in their high-risk units, many in the setting of endemicityor an outbreak [15, 17•]. Due to increasing isolation of CRE inlong-term health-care facilities [7••] and the potential of novelresistance mechanisms being imported from outside institutionsor other geographic regions [9••], the CDC has recently

Curr Infect Dis Rep

recommended screening of patients for CRE with receipt ofhealth care from long-term health-care facilities and/or foreigncountries. The use of selective oral decontamination for CREis not currently recommended.

Although once considered specific to the control of infec-tions withMRSA, much interest has been placed on the use ofchlorhexidine bathing and the decrease of MDRO infectionsin ICU patients. A recent multicenter study suggested thatdecolonization with mupirocin and chlorhexidine decreasedbloodstream infections in ICU patients irrespective of MRSAcolonization status [95••]. Preoperative bathing with chlorhex-idine has been associated with decreased surgical site infec-tions [96••, 97, 98], but again the role in transplantationremains unclear but deserves further evaluation.

Donor and Recipient Considerations

Donor-derived MDR Gram-negative infections have recentlybeen reviewed [99••]. The use of organs from donors with ahistory of colonization and/or infections withMDROs remainscontroversial and should be individualized. Respiratory cul-tures with MDROs should raise concern for potential infectionin lung transplant recipients but, likely, do not pose a risk toabdominal organ transplant recipients. An Israeli workinggroup has recently published guidelines regarding the utiliza-tion of organs from donors with MDR Gram-negative bacte-ria—specifically, CRE [100•]. They recommend considerationof all organs from donors with asymptomatic gastrointestinalcarriage; all organs from donors with airway colonization,except for lungs in the setting of pan-resistance; and all organs,except for kidneys from donors with positive urine cultures.However, they recommend avoidance of organs from donorswith bacteremia in this setting.

Pretransplant colonization has rarely been associated withpoor posttransplant outcomes outside of lung transplantation.Thus, previous infection or colonization with MDROs, par-ticularlyMDRGram-negative bacteria, remains a challenge todetermining non-lung-transplant candidacy. In an era of organshortages, larger collaborative studies are needed to betterunderstand the strategies associated with more favorable pa-tient and graft survival. For now, transplant practitioners areencouraged to individualize decisions regarding transplantcandidacy in the setting of prior infection or colonization withMDR Gram-negative bacteria, taking into consideration thatMDR Gram-negative infections are associated with high mor-tality rates in SOT recipients [17•].

Conclusions

Knowledge of local microbiology is vital, since inadequate em-pirical therapy has been shown to be an independent predictor of

mortality in the setting of MDRO infections. Widespread useof antimicrobials not only has resulted in better organ trans-plant outcomes, but also has done so at the expense of anti-microbial susceptibilities. Outside of endocarditis, osteomye-litis, and endovascular infections, prolonged courses of thera-py are unlikely to be more effective than shorter antibioticregimens. Source control, including catheter removal andsurgical and/or percutaneous drainage of abscesses or collec-tions, is recommended when feasible. Implementation andcontinuing support of antimicrobial stewardship programsare imperative in order to conserve the few agents availableto treat these infections and prevent further resistance [101]. Inaddition, more funding and clinical trials are desperatelyneeded to explore therapeutic options for MDROs [1••].This new challenge will require not only increasing collabo-ration among transplant practitioners, but also input fromresearchers in drug development and infection control andprevention.

Compliance with Ethics Guidelines

Conflict of Interest Gopi Patel, Meenakshi M. Rana, and ShirishHuprikar declare that they have no conflict of interest.

Human and Animal Rights and Informed Consent This article doesnot contain any studies with human or animal subjects performed by anyof the authors.

References

Papers of particular interest, published recently, have beenhighlighted as:• Of importance•• Of major importance

1. •• Boucher HW, Talbot GH, Benjamin DK, et al. 10 × ′20 progress–development of new drugs active against gram-negative bacilli: anupdate from the infectious diseases society of America. Clin InfectDis. 2013;56(12):1685–94. An upate from the Infectious DiseasesSociety of America on drugs in development for the treatment ofmultidrug-resistant Gram-negative infections.

2. Patel G, Snydman DR. Vancomycin-resistant Enterococcus infec-tions in solid organ transplantation. Am J Transplant. 2013;13(s4):59–67.

3. van Duin D, van Delden C. Multidrug-resistant gram-negativebacteria infections in solid organ transplantation. Am J Transplant.2013;13(S4):31–41.

4. Garzoni C, Vergidis P. Methicillin-resistant, vancomycin-intermediate and vancomycin-resistant Staphylococcus aureus in-fections in solid organ transplantation. Am J Transplant. 2013;13(S4):50–8.

5. •• Magiorakos AP, Srinivasan A, Carey RB, et al. Multidrug-resistant, extensively drug-resistant and pandrug-resistant bacteria:an international expert proposal for interim standard definitions foracquired resistance. Clin Microbiol Infect. 2012;18(3):268–81. Aninternational consensus statement regarding standardization ofdefenitions of multidrug resistance .

Curr Infect Dis Rep

6. Gupta N, Limbago BM, Patel JB, Kallen AJ. Carbapenem-resistantEnterobacteriaceae: epidemiology and prevention. Clin Infect Dis.2011;53(1):60–7.

7. •• Jacob JT, Klein E, Laxminarayan R, Beldavs Z , Lynfield R, KallenAJ et al. Vital signs: carbapenem-resistant Enterobacteriaceae.MMWR Morb Mortal Wkly Rep. 2013; 62(9):165-70. Anupdate regarding the prevalence of carbapenem-resistantEnterobacteriaceae in health-care institutions in the U.S.

8. • Patel G, Bonomo RA. “Stormy waters ahead”: global emergence ofcarbapenemases. Front Microbiol. 2013. doi: 10.3389/fmicb.2013.00048. A review of mechanisms of carbapenem resistance amongGram-negative bacilli.

9. •• Mathers AJ, Hazen KC, Carroll J, et al. First clinical cases ofOXA-48-producing carbapenem-resistant Klebsiella pneumoniae inthe United States: the “menace” arrives in the new world. J ClinMicrobiol. 2013;51(2):680–3. The first case report(s) of carbapenemresistance mediated by OXA-48 in a transplant center in the U.S .

10. Nguyen M, Eschenauer GA, Bryan M, et al. Carbapenem-resistantKlebsiella pneumoniae bacteremia: factors correlated with clinicaland microbiologic outcomes. Diagn Microbiol Infect Dis.2010;67(2):180–4.

11. Patel G, Huprikar S, Factor SH, Jenkins SG, Calfee DP. Outcomesof carbapenem-resistant Klebsiella pneumoniae infection and theimpact of antimicrobial and adjunctive therapies. Infect ControlHosp Epidemiol. 2008;29(12):1099–106.

12. Kumarasamy KK, Toleman MA, Walsh TR, et al. Emergence of anew antibiotic resistance mechanism in India, Pakistan, and the UK:a molecular, biological, and epidemiological study. Lancet InfectDis. 2010;10(9):597–602.

13. Mathers AJ, Cox HL, Kitchel B, et al. Molecular dissection of anoutbreak of carbapenem-resistant enterobacteriaceae revealsIntergenus KPC carbapenemase transmission through a promiscu-ous plasmid. MBio. 2011;2(6):e00204–11.

14. Patel G, Perez F, Bonomo RA. Carbapenem-resistant Enterobac-teriaceae and Acinetobacter baumannii: assessing their impact onorgan transplantation. Curr Opin Organ Transplant. 2010;15:676–82.

15. Snitkin ES, Zelazny AM, Thomas PJ, et al. Tracking a hospitaloutbreak of carbapenem-resistant Klebsiella pneumoniae withwhole-genome sequencing. Sci Transl Med. 2012;4(148),148ra116.

16. Rana MM, Sturdevant M, Patel G, Huprikar S. Klebsiella necrotiz-ing soft tissue infections in liver transplant recipients: a case series.Transpl Infect Dis. 2013. doi:10.1111/tid.12103.

17. • Kalpoe JS, Sonnenberg E, Factor SH, et al. Mortality associatedwith carbapenem-resistant Klebsiella pneumoniae infections in livertransplant recipients. Liver Transpl. 2012;18(4):468–74. An evalu-ation of the effects of carbapenem-resistant K. pneumoniae in livertransplantation .

18. Hirsch EB, Ledesma KR, Chang KT, et al. In vitro activity of MK-7655, a novel beta-lactamase inhibitor, in combination withimipenem against carbapenem-resistant Gram-negative bacteria.Antimicrob Agents Chemother. 2012;56(7):3753–7.

19. Lee GC, Burgess DS. Treatment of Klebsiella pneumoniaecarbapenemase (KPC) infections: a review of published case seriesand case reports. Ann Clin Microbiol Antimicrob. 2012;11(32):97–100.

20. Livermore DM, Mushtaq S, Warner M, et al. Activities of NXL104combinations with ceftazidime and aztreonam against carbapenemase-producing enterobacteriaceae. Antimicrob Agents Chemother.2011;55(1):390–4.

21. Mushtaq S, Warner M, Williams G, Critchley I, Livermore DM.Activity of chequerboard combinations of ceftaroline and NXL104versus β-lactamase-producing Enterobacteriaceae. J AntimicrobChemother. 2010;65(7):1428–32.

22. Aktas Z, Kayacan C, Oncul O. In vitro activity of avibactam(NXL104) in combination with beta-lactams against Gram-negative

bacteria, including OXA-48 beta-lactamase-producing Klebsiellapneumoniae. Int J Antimicrob Agents. 2012;39(1):86–9.

23. Aggen JB, Armstrong ES, Goldblum AA, et al. Synthesis andSpectrum of the Neoglycoside ACHN-490. Antimicrob AgentsChemother. 2010;54(11):4636–42.

24. Endimiani A, Hujer KM, Hujer AM, et al. ACHN-490, aNeoglycoside with Potent In Vitro Activity against Multidrug-Resistant Klebsiella pneumoniae Isolates. Antimicrob AgentsChemother. 2009;53(10):4504–7.

25. Landman D, Kelly P, Bäcker M, et al. Antimicrobial activity of anovel aminoglycoside, ACHN-490, against Acinetobacterbaumannii and Pseudomonas aeruginosa from New York City. JAntimicrob Chemother. 2011;66(2):332–4.

26. Livermore DM, Mushtaq S, Warner M, Zhang J-C, Maharjan S,Doumith M, et al. Activity of aminoglycosides, including ACHN-490, against carbapenem-resistant Enterobacteriaceae isolates. JAntimicrob Chemother. 2011;66(1):48–53.

27. Sutcliffe JA. Antibiotics in development targeting protein synthesis.Ann N YAcad Sci. 2011;1241(1):122–52.

28. Shi SH, Kong HS, Xu J, et al. Multidrug resistant gram-negativebacilli as predominant bacteremic pathogens in liver transplantrecipients. Transpl Infect Dis. 2009;11(5):405–12.

29. Nunley DR, Bauldoff GS, Mangino JE, Pope-Harman AL. Mortal-ity associated with Acinetobacter baumannii infections experiencedby lung transplant recipients. Lung. 2010;188(5):381–5.

30. • Shields RK, Clancy CJ, Gillis LM, et al. Epidemiology, clinicalcharacteristics and outcomes of extensively drug-resistantacinetobacter baumannii infections among solid organ transplantrecipients. PLoS ONE. 2012;7(12):e52349. doi:10.1371/journal.pone.0052349. A multiyear restrospective review of solid organtransplant recipients with extensively drug-resistant Acinetobacterbaumannii infections, with an assessment of outcomes and possibleincreased survival with the use of carbapenem–colistin combinationtherapy.

31. de Gouvea EF, Martins IS, Halpern M, et al. The influence ofcarbapenem resistance on mortality in solid organ transplant recip-ients with Acinetobacter baumannii infection. BMC Infect Dis.2012. doi: 10.1186/1471-2334-12-351.

32. Kim YJ, Yoon JH, Kim SI, et al. High mortality associated withAcinetobacter species infection in liver transplant patients. Trans-plant Proc. 2011;43(6):2397–9.

33. Hsieh CE, Chen YL, Lin PY, et al. Liver transplantation in patientsinfected with gram-negative bacteria: non-Acinetobacter baumanniiand Acinetobacter baumannii. Transplant Proc. 2013;45(1):225–30.

34. Shields RK, Kwak EJ, Potoski BA, et al. High mortality ratesamong solid organ transplant recipients infected with extensivelydrug-resistant Acinetobacter baumannii: using in vitro antibioticcombination testing to identify the combination of a carbapenemand colistin as an effective treatment regimen. Diagn MicrobiolInfect Dis. 2011;70(2):246–52.

35. Perez F, Endimiani A, Bonomo RA. Why are we afraid ofAcinetobacter baumannii? Expert Rev Anti-Infect Ther. 2008;6(3):269–71.

36. Perez F, Hujer AM, Hujer KM, Decker BK, Rather PN, BonomoRA. Global challenge of multidrug-resistant Acinetobacterbaumannii. Antimicrob Agents Chemother. 2007;51(10):3471–84.

37. Mushtaq S, Warner M, Livermore DM. In vitro activity of ceftazi-dime + NXL104 against Pseudomonas aeruginosa and other non-fermenters. J Antimicrob Chemother. 2010;65(11):2376–81.

38. Aggen JB, Armstrong ES, Goldblum AA, et al. Synthesis andspectrum of the neoglycoside ACHN-490. Antimicrob AgentsChemother. 2010;54(11):4636–42.

39. Johnson LE, D'Agata EM, Paterson DL, et al. Pseudomonasaeruginosa bacteremia over a 10-year period: multidrug resistanceand outcomes in transplant recipients. Transpl Infect Dis. 2009;11(3):227–34.

Curr Infect Dis Rep

40. Iida T, Kaido T, Yagi S, et al. Posttransplant bacteremia in adultliving donor liver transplant recipients. Liver Transpl. 2010;16(12):1379–85.

41. Shi SH, Kong HS, Jia CK, et al. Risk factors for pneumonia causedbymultidrug-resistant Gram-negative bacilli among liver recipients.Clin Transplant. 2010;24(6):758–65.

42. Linares L, Garcia-Goez JF, Cervera C, et al. Early bacteremia aftersolid organ transplantation. Transplant Proc. 2009;41(6):2262–4.

43. Aris RM, Gilligan PH, Neuringer IP, et al. The effects ofpanresistant bacteria in cystic fibrosis patients on lung transplantoutcome. Am J Respir Crit Care Med. 1997;155(5):1699–704.

44. Dobbin C, Maley M, Harkness J, et al. The impact of pan-resistantbacterial pathogens on survival after lung transplantation in cysticfibrosis: results from a single large referral centre. J Hosp Infect.2004;56(4):277–82.

45. Hadjiliadis D, Steele MP, Chaparro C, et al. Survival of lungtransplant patients with cystic fibrosis harboring panresistant bacte-ria other than Burkholderia cepacia, compared with patients harbor-ing sensitive bacteria. J Heart Lung Transplant. 2007;26(8):834–8.

46. Hammami S, Boutiba-Ben Boubaker I, Ghozzi R, et al. Nosocomialoutbreak of imipenem-resistant Pseudomonas aeruginosa producingVIM-2 metallo-beta-lactamase in a kidney transplantation unit.Diagn Pathol. 2011. doi: 10.1186/1746-1596-6-106.

47. Poole K. Pseudomonas aeruginosa: resistance to the max. FrontMicrobiol. 2011. doi: 10.3389/fmicb.2011.00065.

48. •• Tamma PD, Cosgrove SE, Maragakis LL. Combination therapyfor treatment of infections with gram-negative bacteria. ClinMicrobiol Rev. 2012;25(3):450–70. A contemporary evidence-based review on the use of combination therapy in the treatmentof Gram-negative infections .

49. Sun HY, Shields RK, Cacciarelli TV, Muder RR, Singh N. A novelcombination regimen for the treatment of refractory bacteremia dueto multidrug-resistant Pseudomonas aeruginosa in a liver transplantrecipient. Transpl Infect Dis. 2010;12(6):555–60.

50. Bergen PJ, Tsuji BT, Bulitta JB, et al. Synergistic killingof multidrug-resistant Pseudomonas aeruginosa at multipleinocula by colistin combined with doripenem in an in vitropharmacokinetic/pharmacodynamic model. Antimicrob AgentsChemother. 2011;55(12):5685–95.

51. Florescu DF, Grant W, Botha JF, Fey P, Kalil AC. Shouldmultivisceral transplantation be considered in patients colonizedwith multidrug-resistant Pseudomonas aeruginosa? Microb DrugResist. 2012;18(1):74–8.

52. Levasseur P, Girard AM, Claudon M, et al. In vitro antibacterialactivity of the ceftazidime-avibactam (NXL104) combinationagainst Pseudomonas aeruginosa clinical isolates. AntimicrobAgents Chemother. 2012;56(3):1606–8.

53. Juan C, Zamorano L, Perez JL, Ge Y, Oliver A. Activity of a newantipseudomonal cephalosporin, CXA-101 (FR264205), againstcarbapenem-resistant and multidrug-resistant Pseudomonasaeruginosa clinical strains. Antimicrob Agents Chemother.2010;54(2):846–51.

54. Sader HS, Rhomberg PR, Farrell DJ, Jones RN. Antimicrobialactivity of CXA-101, a novel cephalosporin tested in combinationwith tazobactam against Enterobacteriaceae, Pseudomonasaeruginosa, and Bacteroides fragilis strains having various resis-tance phenotypes. Antimicrob Agents Chemother. 2011;55(5):2390–4.

55. De Soyza A, Corris PA. Lung transplantation and the Burkholderiacepacia complex. J Heart Lung Transplant. 2003;22(9):954–8.

56. De Soyza A,Meachery G, Hester KL, et al. Lung transplantation forpatients with cystic fibrosis and Burkholderia cepacia complexinfection: a single-center experience. J Heart Lung Transplant.2010;29(12):1395–404.

57. Boussaud V, Guillemain R, Grenet D, et al. Clinical outcomefollowing lung transplantation in patients with cystic fibrosis

colonised with Burkholderia cepacia complex: results from twoFrench centres. Thorax. 2008;63(8):732–7.

58. Alexander BD, Petzold EW, Reller LB, et al. Survival after lungtransplantation of cystic fibrosis patients infected with Burkholderiacepacia complex. Am J Transplant. 2008;8(5):1025–30.

59. Kennedy MP, Coakley RD, Donaldson SH, et al. Burkholderiagladioli: five year experience in a cystic fibrosis and lung transplan-tation center. J Cyst Fibros. 2007;6(4):267–73.

60. Murray S, Charbeneau J, Marshall BC, LiPuma JJ. Impact ofBurkholderia infection on lung transplantation in cystic fibrosis.Am J Respir Crit Care Med. 2008;178(4):363–71.

61. Horsley A, Jones AM. Antibiotic treatment for Burkholderiacepacia complex in people with cystic fibrosis experiencing apulmonary exacerbation. Cochrane Database Syst Rev. 2012.doi: 10.1002/14651858.CD009529.pub2.

62. Sievert DM, Ricks P, Edwards JR, et al. Antimicrobial-resistantpathogens associated with healthcare-associated infections: summa-ry of data reported to the National Healthcare Safety Network at theCenters for Disease Control and Prevention, 2009-2010. InfectControl Hosp Epidemiol. 2013;34(1):1–14.

63. Singh N, Paterson DL, Chang FY, Gayowski T, Squier C, WagenerMM, et al. Methicillin-resistant Staphylococcus aureus: the otheremerging resistant gram-positive coccus among liver transplantrecipients. Clin Infect Dis. 2000;30(2):322–7.

64. Florescu DF, McCartney AM, Qiu F, Langnas AN, Botha J, MercerDF, et al. Staphylococcus aureus infections after liver transplanta-tion. Infection. 2012;40(3):263–9.

65. Schneider CR, Buell JF, Gearhart M, Thomas M, Hanaway MJ,Rudich SM, et al. Methicillin-resistant Staphylococcus aureus in-fection in liver transplantation: a matched controlled study. Trans-plant Proc. 2005;37(2):1243–4.

66. Desai D, Desai N, Nightingale P, Elliott T, Neuberger J. Carriage ofmethicillin-resistant Staphylococcus aureus is associated with anincreased risk of infection after liver transplantation. Liver Transpl.2003;9(7):754–9.

67. Russell DL, Flood A, Zaroda TE, et al. Outcomes of colonizationwith MRSA and VRE among liver transplant candidates and recip-ients. Am J Transplant. 2008;8(8):1737–43.

68. Manuel O, Lien D, Weinkauf J, Humar A, Cobos I, Kumar D.Methicillin-resistant Staphylococcus aureus infection after lungtransplantation: 5-year review of clinical and molecular epidemiol-ogy. J Heart Lung Transplant. 2009;28(11):1231–6.

69. Shields RK, Clancy CJ, Minces LR, et al. Staphylococcus aureusinfections in the early period after lung transplantation: epidemiol-ogy, risk factors, and outcomes. J Heart Lung Transplant.2012;31(11):1199–206.

70. • van Hal SJ, Lodise TP, Paterson DL. The clinical significance ofvancomycin minimum inhibitory concentration in Staphylococcusaureus infections: a systematic review andmeta-analysis. Clin InfectDis. 2012;54(6):755–71. A large meta-analysis examining the sig-nificance of higher vancomycin minimum inhibitory concentrationsand clinical outcomes .

71. van Hal SJ, Fowler Jr VG. Is it time to replace vancomycin in thetreatment of methicillin-resistant Staphylococcus aureus infections?Clin Infect Dis. 2013;56(12):1779–88.

72. Levy DT, Steed ME, Rybak MJ, et al. Successful treatment of a leftventricular assist device infection with daptomycin non-susceptiblemethicillin-resistant Staphylococcus aureus: case report and reviewof the literature. Transpl Infect Dis. 2012;14(5):E89–96.

73. Swartz T, Huprikar S, LaBombardi V, et al. Heart transplantation ina patient with heteroresistant vancomycin-intermediate Staphylo-coccus aureus ventricular assist devicemediastinitis and bacteremia.Transpl Infect Dis. 2013. doi: 10.1111/tid.12123.

74. • Wunderink RG, Niederman MS, Kollef MH, et al. Linezolid inmethicillin-resistant Staphylococcus aureus nosocomial pneumonia:a randomized, controlled study. Clin Infect Dis. 2012;54(5):621–9. A

Curr Infect Dis Rep

randominzed controlled tiral evaluating linezolid versus vancomycinin the treatment of nosocomial pneumonia, with a specific emphasison pneumonia due to methicillin-resistant Staphylococcus aureus.

75. Bert F, Clarissou J, Durand F, et al. Prevalence, molecular epidemi-ology, and clinical significance of heterogeneous glycopeptide-intermediate Staphylococcus aureus in liver transplant recipients. JClin Microbiol. 2003;41(11):5147–52.

76. Centers for Disease Control and Prevention. Nosocomial enterococ-ci resistant to vancomycin–United States, 1989-1993. MMWRMorb Mortal Wkly Rep. 1993; 42(30):597-9.

77. Drees M, Snydman DR, Schmid CH, et al. Antibiotic exposure androom contamination among patients colonized with vancomycin-resistant enterococci. Infect Control Hosp Epidemiol. 2008;29(8):709–15.

78. Olivier CN, Blake RK, Steed LL, Salgado CD. Risk of vancomycin-resistant Enterococcus (VRE) bloodstream infection among patientscolonized with VRE. Infect Control Hosp Epidemiol. 2008;29(5):404–9.

79. Freitas MC, Pacheco-Silva A, Barbosa D, et al. Prevalence ofvancomycin-resistant Enterococcus fecal colonization among kid-ney transplant patients. BMC Infect Dis. 2006;6:133.

80. McNeil SA, Malani PN, Chenoweth CE, et al. Vancomycin-resistant enterococcal colonization and infection in liver transplantcandidates and recipients: a prospective surveillance study. ClinInfect Dis. 2006;42(2):195–203. Epub 2005 Dec 12.

81. Gearhart M,Martin J, Rudich S, et al. Consequences of vancomycin-resistant Enterococcus in liver transplant recipients: a matched con-trol study. Clin Transplant. 2005;19(6):711–6.

82. Linares L, Cervera C, Cofan F, et al. Epidemiology and outcomes ofmultiple antibiotic-resistant bacterial infection in renal transplanta-tion. Transplant Proc. 2007;39(7):2222–4.

83. El-Khoury J, Fishman JA. Linezolid in the treatment ofvancomycin-resistant Enterococcus faecium in solid organ trans-plant recipients: report of a multicenter compassionate-use trial.Transpl Infect Dis. 2003;5(3):121–5.

84. Gonzales RD, Schreckenberger PC, Graham MB, et al. Infectionsdue to vancomycin-resistant Enterococcus faecium resistant to li-nezolid. Lancet. 2001;357(9263):1179.

85. Herrero IA, Issa NC, Patel R. Nosocomial spread of linezolid-resistant, vancomycin-resistant Enterococcus faecium. N Engl JMed. 2002;346(11):867–9.

86. Pogue JM, Paterson DL, Pasculle AW, Potoski BA. Determinationof risk factors associated with isolation of linezolid-resistant strainsof vancomycin-resistant Enterococcus. Infect Control HospEpidemiol. 2007;28(12):1382–8.

87. • Santayana EM, Grim SA, Janda WM, et al. Risk factors andoutcomes associated with vancomycin-resistant Enterococcus infec-tions with reduced susceptibilities to linezolid. Diagn MicrobiolInfect Dis. 2012;74(1):39–42. A retrospective matched case–controlstudy of patients with vancomycin-resistant Enterococcus (VRE)with reduced susceptibility to linezolid that demonstrated that re-ceipt of linezolid was associated with reduced susceptibitiy and thatreduced susceptibility did not impact patient outcomes, as com-pared with linezolid-susceptible VRE .

88. Twilla JD, Finch CK, Usery JB, et al. Vancomycin-resistant Entero-coccus bacteremia: an evaluation of treatment with linezolid ordaptomycin. J Hosp Med. 2012;7(3):243–8.

89. Munoz-Price LS, Lolans K, Quinn JP. Emergence of resistance todaptomycin during treatment of vancomycin-resistant Enterococcusfaecalis infection. Clin Infect Dis. 2005;41(4):565–6.

90. Kelesidis T, Humphries R, Uslan DZ, Pegues DA. Daptomycinnonsusceptible enterococci: an emerging challenge for clinicians.Clin Infect Dis. 2011;52(2):228–34.

91. Mendes RE, Sader HS, Farrell DJ, Jones RN. Telavancin activitytested against a contemporary collection of Gram-positive patho-gens fromUSAHospitals (2007-2009). DiagnMicrobiol Infect Dis.2012;72(1):113–7.

92. Arias CA, Mendes RE, Stilwell MG, Jones RN, Murray BE. Unmetneeds and prospects for oritavancin in the management ofvancomycin-resistant enterococcal infections. Clin Infect Dis.2012;54(S3):S233–8.

93. Paterson DL, Rihs JD, Squier C, et al. Lack of efficacy of mupirocinin the prevention of infections with Staphylococcus aureus in livertransplant recipients and candidates. Transplantation. 2003;75(2):194–8.

94. Singh N, Squier C, Wannstedt C, et al. Impact of an aggressiveinfection control strategy on endemic Staphylococcus aureus infec-tion in liver transplant recipients. Infect Control Hosp Epidemiol.2006;27(2):122–6.

95. •• Huang SS, Septimus E, Kleinman K, et al. Targeted versusuniversal decolonization to prevent ICU infection. N Engl J Med.2013;368(24):2255–65. A large, randomized multicenter trialassessing the effect of universal decolonization and rates ofmethicillin-resistant Staphylococcus aureus and bloodstreaminfections .

96. •• Climo MW, Yokoe DS, Warren DK, et al. Effect of daily chlor-hexidine bathing on hospital-acquired infection. N Engl J Med.2013;368(6):533–42. A large multicenter randomized trial demon-strating reduction in the acquisition of multidrug-resistantorgansims and the development of health-care-acquired blood-stream infections with daily chlorhexidine bathing.

97. Karki S, Cheng AC. Impact of non-rinse skin cleansing with chlor-hexidine gluconate on prevention of healthcare-associated infec-tions and colonization with multi-resistant organisms: a systematicreview. J Hosp Infect. 2012;82(2):71–84.

98. O'Horo JC, Silva GL, Munoz-Price LS, Safdar N. The efficacy ofdaily bathing with chlorhexidine for reducing healthcare-associatedbloodstream infections: a meta-analysis. Infect Control HospEpidemiol. 2012;33(3):257–67.

99. •• Sifri CD, Ison MG. Highly resistant bacteria and donor-derivedinfections: treading in uncharted territory. Transpl Infect Dis.2012;14(3):223–8. A review of published cases of donor-derivedmultidrug-resistant infections in organ transplantation .

100. • Bishara J, Goldberg E, Lev S, et al. The utilization of solid organsfor transplantation in the setting of infection with multidrug-resistant organisms: an expert opinion. Clin Transplant.2012;26(6):811–5. A guidance document offering an opinion onthe utilization of organs from donors colonized or infected withmultidrug-resistant organisms from an area endemic forcarbapenem-resistant Enterobacteriaceae .

101. Marchaim D, Chopra T, Bhargava A, Bogan C, Dhar S,Hayakawa K, et al. Recent exposure to antimicrobials andcarbapenem-resistant Enterobacteriaceae: the role of antimicrobi-al stewardship. Infect Control Hosp Epidemiol. 2012;33(8):817–30.

102. • Swaminathan M, Sharma S, Poliansky Blash S, et al. Prevalenceand risk factors for acquisition of carbepenem-resistant Enterobac-teriaceae in the setting of endemicity. Infect Control HospEpidemiol. 2013;34(8):809–17. A multicenter study in New YorkCity demonstrated that in an area of endemicity, colonization pres-sure, mechanical ventilation, and days of antimicrobial exposurewere associated with carbapenem-resistant Enterobacteriaceaeacquisition .

103. Reddy P, Zembower TR, Ison MG, Baker TA, Stosor V.Carbapenem-resistant Acinetobacter baumannii infections after or-gan transplantation. Transpl Infect Dis. 2010;12(1):87–93.

Curr Infect Dis Rep