Epidemiology and Prevention of Early Infections by Multi-Drug-Resistant Organisms in Adults Undergoing Liver Transplant: A Narrative Review

Invasive bacterial infections are a leading cause of morbidity and mortality after liver transplant (LT), especially during the first months after LT, and infections due to multi-drug-resistant organisms (MDRO) are increasing in this setting. Most of the infections in patients in intensive care unit arise from the endogenous microflora and, for this reason, pre-LT MDRO rectal colonization is a risk factor for developing MDRO infections in the post-LT. Moreover, the transplanted liver may carry an increased risk of MDRO infections due to organ transportation and preservation, to donor intensive care unit stay and previous antibiotic exposure. To date, little evidence is available about how MDRO pre-LT colonization in donors and recipients should address LT preventive and antibiotic prophylactic strategies, in order to reduce MDRO infections in the post-LT period. The present review provided an extensive overview of the recent literature on these topics, with the aim to offer a comprehensive insight about the epidemiology of MDRO colonization and infections in adult LT recipients, donor-derived MDRO infections, possible surveillance, and prophylactic strategies to reduce post-LT MDRO infections.


Introduction
Invasive bacterial infections are a leading cause of morbidity and mortality after liver transplant (LT) [1,2], with approximately two third of early deaths due to sepsis [3,4]. Bacterial infections are the most common cause of complications within the first month after LT [2] and are often due to nosocomial organisms [5]. Changes in transplant policies and techniques increased the number of LT, including marginal organs and both donors and LT candidates in critical conditions. These policies increase the risk of time in intensive care units (ICU), leading to increased risk of multi-drug-resistant organism (MDRO) colonization and infections for both liver donors and recipients [6,7].
LT recipients have multiple risk factors for MDRO colonization and infections, including immunosuppression, cirrhosis-related immune-dysfunction, prolonged hospitalization and ICU stay, and previous antibiotic exposure. Patients with end-stage liver disease and those hospitalized in ICU are fragile and at high risk of MDRO colonization. Rectal colonization with MDRO in the pre-LT period is a commonly considered risk factor for developing a MDRO-infection in the post-LT period [8][9][10][11] and it is associated with both Table 1. Risk factors and epidemiology of MDR-colonization and MDR-infections in LT-recipients.
Although rates of ESBLE infections in LT recipients varied in different geographical areas and hospitals, they were the most prevalent MDR-Gram-negative bacilli isolates in LT recipients [39,70,73] and their prevalence is growing worldwide [39,74]. According to the literature, almost half of ESBLE-colonized LT recipients developed an ESBLE-infection, with roughly a 12 times higher risk that was 12 times higher compared to non-ESBLE-colonized LT recipients [47].
Independent predictors of ESBLE infection were pre-transplant Klebsiella pneumoniae fecal carriage, model for end stage liver disease (MELD) score > 25, preoperative spontaneous bacterial peritonitis prophylaxis, and antimicrobial exposure during the previous month [45]. Table 2 summarizes the epidemiology of ESBLE-colonization and infections in LT-recipient.  Half of the studies in the literature dedicated to ESBLE colonization and infection in LT were from the same French cohort, representing almost 75% of the published LT recipients [45,46,75]. The retrospective study by Bert et al. [75]  In our cohort, between 2010 and 2020, of 473 LT-recipients, 45 (9.5%) were colonized by ESBLE pre-LT. At our center, a target prophylaxis was administered to ESBLE carriers. Post-LT infection (SSI and BSI only) during the first month post-LT was identified only in five patients (1%) [79,80].
The geographical distribution of carbapenemases were different. KPC enzyme was the most common in the United States of America (USA), South America, Southern Europe, Israel, and China [81][82][83]. NDM was the most common in India, Pakistan, and the United Kingdom [84,85]. OXA-48-family was common in North Africa, Turkey, and India [86]. From the initial identification of CRE around 15 years ago, CRE increased worldwide. Due to the clinical impact of numerous hospital outbreaks, especially in high complexity and ICU settings, CRE colonization and infections represented one of the most investigated subjects in transplant patients over the last decade. Most of the studies were performed in Italy and Brazil.

Post-LT CRE SSI
On the basis of these findings, researchers elaborated several algorithms for colonization, infection, and mortality prediction. A Brazilian study described a host of predisposing factors for pre-LT CRE colonization, including patient antibiotic exposure, hepato-renal syndrome, worst CLIF-SOFA score [91], and the use of beta-lactam/beta-lactamase inhibitors within 90 days prior to LT. Researchers engaged a machine learning approach to develop a CRE colonization at LT predictive model algorithm [90].
CRE colonization, acquired pre-LT, at LT or immediately after LT, was identified as risk factor for CRE infection. An Italian monocentric cohort study found that between 2010 and 2013 [10], 20 out of 237 (8.4%) LT recipients developed a carbapenem-resistant K. pneumoniae (CR-KP) infection within 6 months post-LT (18 BSIs and 2 pneumonia); 11 patients were CR-KP colonized at LT and 30 acquired CR-KP colonization post-LT. Acquired CR-KP colonization post-LT had a highest risk of CR-KP infection (46.7%) compared to patients with CR-KP colonization at LT. Multivariate analysis identified CR-KP rectal carriage at any time, together with post-LT renal replacement therapy, mechanical ventilation >48 h, and HCV recurrence as independent risk factors for infection.
Giannella et al. [9] reported that CRE colonization was the strongest risk factor for CRE infection, along with combined transplant, higher MELD at LT, prolonged mechanical ventilation, re-intervention, and rejection. On the basis of these predisposing factors, a normogram to predict 30-and 60-day CRE infection risk was developed [93]. The risk prediction model considered pre-and post-LT colonization, multisite post-LT colonization, prolonged mechanical ventilation, acute renal injury, and surgical reintervention.

Multi-Drug-Resistant Pseudomonas Aeruginosa (MDR-PA)
Pseudomonas aeruginosa has a wide variety of mechanisms of antimicrobial resistance related to both inherent chromosomal mutations and transmissible resistance determinants.
MDR pseudomonal phenotypes likely arise from a combination of several resistance determinants [96].
Epidemiology of MDR-PA infections in solid organ transplant (SOT) varied widely between geographical regions and transplant centers. However, the overall, worldwide trend showed an increased MDR P. aeruginosa incidence [39,70]. MDR P. aeruginosa bacteremia were associated with mortality rates approaching 40% in LT recipients [59]. Risk factors for P. aeruginosa BSIs were reported in general SOT studies, without any dedicated to LT recipients. Risk factors in SOT recipients include hospital-acquired BSI and ICU admission within 1 year [11,59]. The epidemiology of MDR-PA colonization and infections in LT-recipients are summarized in Table 4. Few studies reported MDR-PA colonization and infections, representing a general knowledge gap. A Japanese cohort [97] of 170 living-donor LT reported five infections (2.9%) by MDR-PA during 3 months post-LT, while in a Chinese cohort [34], DR-PA was isolated in only 1 of the 178 isolates of pneumonia during 6 months post-LT.

Carbapenem-Resistant Acinetobacter baumanii (CRAB)
Acinetobacter baumannii is a saprophytic lactose non-fermentative Gram-negative bacillus and an opportunistic pathogen. It is often carbapenem-resistant and its most common mechanism of carbapenem resistance is the presence of the class D β-lactamases, including genes OXA-23, OXA-24/40, and OXA-58. Other mechanisms are the reduction in carbapenem-associated outer membrane porin (CarO), associated with higher imipenem minimum inhibiting concentrations, and upregulated efflux pumps [70]. A combination of groin cutaneous swabs and rectal swabs seems to be more sensitive in detecting A. baumannii colonization than rectal swab alone [44]. CRAB is extremely difficult to eradicate from healthcare facilities, frequently causing nosocomial outbreaks [44,[60][61][62]. For this reason, its epidemiology deeply varied not only between different geographical regions, but also among hospitals in the same areas and wards in the same hospital. A. baumannii is often MDR, especially in SOT recipients [11]. Shi et al. [57] reported that 62% of the A. baumannii isolated from blood cultures in their cohort was MDR. Therefore, post-LT CRAB infections have high mortality rates of 50-65% [44,[60][61][62].
Risk factors for post-LT CRAB infection include pre-LT CRAB colonization, fulminant hepatitis, higher pre-transplant MELD, severe encephalopathy, lower donor body mass index, longer cold ischemia time, prolonged post-LT ICU stay and intubation, post-LT dialysis, and reintervention. Epidemiology studies of CRAB colonization and infections in LT-recipient is summarized in Table 5. A Brazilian cohort study conducted between 2009 and 2011 reported a CRAB colonization prevalence as high as 11% in LT candidates, the highest MDR-colonization rate among their patients [44,98]. CRAB colonization prevalence raised to 43% in the post-LT period, with 29% recipients developing a CRAB infection.
A Chinese cohort [34] reported 21 cases of CRAB (11.8%) among 178 post-LT pneumonia isolates. Another cohort study conducted in China by Min et al. [60] reported a 2.8% prevalence of CRAB bacteriaemia within 30 days post-LT, with cumulative mortality incidence on days 5, 10, and 30 from the index positive blood culture date, of 58.6%, 65.5%, and 65.5%. Independent risk factors for 30-day CRAB-bacteriaemia included pre-transplant MELD, severe encephalopathy, lower donor body mass index, and reintervention.
In a South Korean cohort [62], 3.6% of LT recipients developed a post-LT CRAB BSI, and reported a 50% associated mortality rate.

Other Non-Fermentative Gram Negative Bacilli
Stenotrophomonas maltophilia, Burkholderia cepacia complex (BCC), and Achromobacter xylosoxidans are less common causes of infections compared to other non-fermentative Gram-negative bacilli but are pathogens of concern in SOT recipients [99]. They are ubiquitous in the environment, specifically water and soil, and are known to cause severe infections, especially in people with underlying pulmonary conditions and in immunocompromised hosts [100][101][102]. When isolated in respiratory samples, it can be difficult to understand when they are simply colonizing or true pathogens. These microorganisms are often difficult to treat due to a variety of intrinsic and acquired resistance traits, ranging from intrinsically resistance to aminoglycosides and β-lactams, including the carbapenems (due to the chromosomally encoded βlactamases [L1, a MBL, and L2, a serine cephalosporinase] typical of S. maltophilia [103,104]), through to high production of efflux pumps, changes in lipopolysaccharide structure, and decreased outer membrane permeability (more characteristic of BCC) [105,106].
As these pathogens are often isolated in underling pulmonary conditions, among SOT, they are most often isolated in lung transplants patients. However, a few case reports were recently reported in LT [99].
A total of 26 S. maltophilia BSIs were reported in a recent study [99]. Six (37%) of them occurred in LT patients and, in particular, four occurred within 30 days after LT. No data about eventual pre-LT colonization were available.
More studies are necessary to identify specific risk factor for colonization and infection by these pathogens in LT patients.

Vancomycin-Resistant Enterococcus (VRE)
VRE were reported as the second most frequently occurring MDR pathogen causing nosocomial infections in the USA [107]. The majority of VRE isolates are Enterococcus faecium.
LT recipients are the most commonly VRE-colonized patients among SOTs. Risk factors for VRE colonization in LT recipients include hospitalization, paracentesis, previous endoscopic retrograde cholangio-pancreatography, and anti-anaerobic antibiotic therapy. VRE post-LT colonization was associated with increased all-cause 90-day mortality [108], but specific information regarding VRE-infection-related mortality was scarce.
VRE infections are usually preceded by VRE colonization, with a 6.7 times higher risk of infection for VRE-carriers [63,109]. As VRE are part of the intestinal microbiota, they mostly cause SSI or organ/space infections in LT recipients, including biliary tract infections and intra-abdominal abscesses, often associated with BSIs [110].
Cohort studies mostly describe increased morbidity and mortality in VRE-colonized LT-recipients. A 2014 meta-analysis by Ziakas et al. [63] indicated a pooled prevalence for VRE colonization before and after SOT of 11.9% and 16.2%, respectively. LT-specific pooled analysis found a 16% post-LT VRE colonization prevalence [63]. However, the current prevalence is probably higher than these estimates, as trends suggest that over the last decade, VRE-colonization increased both in the general hospitalized population and in LT recipients.
Epidemiology of VRE-colonization and infections in LT-recipient is summarized in Table 6.
A recent retrospective cohort study by Chiang et al. [66] showed that among 343 LT recipients treated between 2014 and 2017, 68 (20%) had pre-LT VRE colonization and, among the remaining 275 LT recipients, 20 (9.8%) acquired VRE post-transplant. Six (2%) patients developed an invasive VRE infection, five in the VRE-colonized group and one in the non-VRE-colonized group (5.7% vs. 0.4%). Mortality at 2 years was 13% in VREcolonized versus 7% in non-colonized recipients (p = 0.085).  A study conducted in the USA [67] found a rate of 27% pre-LT VRE colonization. Post-LT VRE infection developed in 5% of recipients pre-LT VRE colonized and no infections developed in the non-colonized group. A study conducted in South Korea [65] reported a rate of 23% colonized by VRE pre-LT and 20% who acquired VRE post-LT. Post-LT VRE infection developed in 9% patients and the authors recorded a higher risk of mortality in LT recipients who acquired VRE post-LT.

Post-LT VRE SSI
In our cohort, 39 (10.9%) LT recipients treated between 2010 and 2020 were pre-LT VRE colonized [112]. After receiving a VRE target prophylaxis, four (10.2%) pre-LT VRE colonized patients developed a VRE infection (three BSIs and one SSI) within 30 days post-LT. Among non-VRE pre-LT colonized patients, only one patient (0.3%) developed a BSI. However, a cohort from Iran [111] did not find an association between VRE-colonization and increased mortality or longer hospital stay.

Methicillin-Resistant Staphylococcus aureus (MRSA)
The incidence of early post-LT infection by MRSA, once a major cause of early post-LT infections [36,37,69], decreased during the last two decades [39]. The main risk factor for post-LT MRSA infection is pre-or post-LT MRSA nasal colonization [69], with an increased risk of 15.6 times compared to non-colonized recipients (odds ratio 15.6; 95% CI 6.6-36.9) [113]. However, common infection control procedures decreased MRSA colonization in the LT setting [114]. Other risk factors for MRSA infection are prolonged ICU stay and/or invasive mechanical ventilation and cytomegalovirus primary infection [37,115,116]. As MRSA usual colonization sites are nose and skin, in LT recipients, it most commonly causes lung and BSIs, including catheter-related BSIs. Post-LT MRSA infection survival varies in different settings and depending on the site of infection, ranging from 6% in catheter-related bacteremia to as high as 60% in complicated MRSA bacteremia and septic shock [37,68]. Epidemiological studies of MRSA-colonization and infections in LT-recipient are summarized in Table 7.
A Chinese cohort [76]  In a Japanese cohort [117] of living donor LT recipients, 13% were colonized by MRSA and 5.7% of LT patients developed a MRSA BSI.

Donor-Derived MDR Bacterial Infection
Bacterial donor-derived infections (DDI) represent one third of donors transmitting infections in SOT, with 65% of them due to Gram-negative bacteria [118]. In this setting, the transmission of MDRO from donor to recipient is a known risk [119], with growing interest due to the global increment of MDRO-colonization and the more frequent procurement of marginal livers to increase access to this procedure. Whilst LT recipients with non-MDRO infected donors do not usually have serious infective complications if a specific antimicrobial treatment is provided [120], the use of livers from MDRO-infected donors can have worse outcomes [121]. In the case of MDRO infection, therapeutic options are limited, absent, or have diminished efficacy. Furthermore, particularly virulent bacteria that are also prone to become MDR, such as S. aureus and P. aeruginosa, can lead more frequently to invasive infections threatening the survival of the graft and the recipient [122][123][124][125]. Special attention should be paid to potential MDRO organ infection from geographical regions with high prevalence of MDRO colonization. The risk of MDRO donor colonization/infection increased with the duration of terminal donor hospitalization, with 20% of donors MDRO colonized by day 10, and 33% of donors MDRO colonized by day 15 [7]. Risk factors for MDRO donor colonization/infections include hepatitis C viremia, dialysis, prior hematopoietic cell transplant, and exposure to antibiotics with a narrow Gram-negative spectrum [7].
Colonization by MDRO is not a contraindication for organ procurement, according to the European Guide to the Quality and Safety of Organ for Fransplantation [126], as long as the colonized tissue remains sealed from the rest of the body and particularly from the transplanted organ. The guidelines from the American Society of Transplantation Infectious Diseases Community of Practice are more cautious; although MDRO colonization is not a considered an absolute contraindication for organ procurement, a careful discussion for riskbenefit assessment and an outlined plan for peri-transplant antibiotics are required [127].
Guidelines recommendations are reflected in a reduction in the number of organs transplanted per donor and in a higher match run at which organs are accepted in donors with MDR Gram-negative bacteria [6].
The literature on MDRO DDI is sparse, also because the rate of donor-to-recipient transmission is low. The few data available suggest that 8-15% of LT recipients of MDROcolonized or infected donors develop a MDRO-DDI [128,129], even if underreporting of cases is highly likely [130].
A retrospective Italian cohort study [128], involving 30 SOT recipients of organs with a carbapenem-resistant Gram-negative bacteria infection or colonization between 2012 and 2013, reported three cases of SOT recipient infection (10%), of whom two were LT recipients and one CR-KP colonization. In the first case, the LT recipient was a 22-year-old girl who developed an intra-abdominal CR-KP-purulent collection, which was successfully treated with surgical drainage and a 7-day course of colistin and tigecycline. The second case was a 50-year-old man who developed an abdominal CR-KP SSI, which was resolved with peri-hepatic drainage.
In a large Chinese cohort study [129] of 724 SOT, of whom 240 were LT, studied between 2015 and 2020, 68 donors had MDRO infections. DDI was registered from 10 (14.7%) donors, transmitted to 22 recipients, 4 (18.1%) of whom died. Among the 22 infected recipients, 6 were LT recipients, 1 died, while the other 5 survived with normal graft function. The causing organism of these six DDIs were two VRE, one CRAB, one Enterobacter aerogenes, and one CR-KP. Unfortunately, this study did not use uniform SOT DDI definitions.
Another USA cohort showed that among 182 patients who underwent LT in 2015 and 2016 [121], 22 had an MDRO-positive donor and the increment in the hazard of post-LT infections associated with MDRO on donor culture was 3.8 (95% CI 0. 98-14.43), but only one probable MDRO DDI was detected.
Concerning MRSA, we found only single case studies reported in the literature [122]. Three case reports [122,124] described MRSA transmission from a donor with infective endocarditis to a LT recipient, despite a documented pre-LT bacteremia clearance. Finally, Obed et al. [125] described a living donor-derived Panton-Valentine Leucocidine-positive MRSA transmission that most likely was the causative agent of a hemorrhagic necrotizing pneumonia that was fatal to a LT-recipient. Epidemiological studies of DDI in LT-recipient are summarized in Table 8.

Post-LT MDR Bacterial Infection Prevention
The most effective way to tackle MDRO infections is to reduce and/or prevent MDRO colonization. General operator infection control measures, such as reinforcement of hand hygiene and alcoholic hand solution monitoring, associated with antimicrobial stewardship, are fundamental to reduce the incidence of all the MDRO for patients undergoing LT, especially during ICU stay. Even though few LT-specific studies are available for MDROinfection control, for the purposes of this review, we generalized data from studies on SOT recipients or inpatients admitted to ICU. Surveillance cultures and carrier isolation were proven to be effective for CRE and MRSA [131], while their efficacy and cost-effectiveness are still controversial for ESBLE and VRE [132], especially in high prevalence settings. Water and environmental decontamination are particularly important for non-fermentative saprophytic bacteria, including P. aeruginosa and CRAB [133][134][135][136].
Antimicrobial prophylaxis is administered at transplantation to reduce SSI incidence. The most common causative pathogens are skin and intestinal flora. There is no widely accepted antibiotic prophylaxis for LT, as there is not enough evidence to prefer a single antibiotic regimen. When selecting antibiotics, it is necessary to evaluate local bacterial prevalence, resistance patterns, and patient and donor characteristics. The most commonly used and accepted LT prophylaxis regimens include third-generation cephalosporin plus ampicillin, piperacillin-tazobactam, or amoxicillin-clavulanate [137]. Similarly, optimal antibacterial prophylaxis duration is not well defined, but recently, 24 h prophylaxis was proven to be non-inferior to seventy-two-hour prophylaxis in a randomized-controlled trial [138].
Furthermore, to minimize the impact of donor-transmitted bacteria following SOT, prompt inter-facility communication, antibiotic prophylaxis based on in vitro susceptibility testing, and careful infection control practices are essential [127]. MDRO bacteraemic donors should receive effective antimicrobial therapy for 24-48 h prior to procurement and recipients of these organs should receive a 7-to-14-day course of antibiotics targeting the donor isolate [70,127,139].

ESBL-Producing Enterobacteriacaeae
Contact precautions for ESBLE colonization and/or infection are recommended in non-endemic areas, while the role of these measures in endemic regions is still debated [70]. Active surveillance for ESBLE among asymptomatic SOT before surgery is considered good practice, but no data are published regarding how many transplant centers follow this recent recommendation [140].
Intestinal decolonization is not recommended [141]. Studies reported the development of tobramycin-and colistin-resistance by Gram-negative bacilli after attempted intestinal decolonization with orally administered colistin [142,143].
The role of perioperative prophylaxis targeted on ESBLE-colonization remains uncertain. The 2019 guidelines from the American Society of Transplantation Infectious Diseases Community of Practice [70] did not recommended target prophylaxis.
Nevertheless, after these guidelines, a paper by Logre et al. [45] reported a higher incidence of ESBLE infections after LT among ESBLE carriers comparing inactive versus active ESBLE prophylaxis. Of the 11 patients who received inactive ESBLE prophylaxis, 63.6% developed an infection, compared to 29.8% of the 57 patients who received an active ESBLE prophylaxis. Although this difference was statistically significant (29.8% vs. 63.6%, p = 0.04), the study had several limitations: its retrospective nature, the small sample size, and the imbalance between the two prophylaxis groups. Despite these study limitations, recent guidelines by European Society of Clinical Microbiology and Infectious Diseases (ESCMID) [140] provided a conditional recommendation for the use of target perioperative antibiotic prophylaxis in LT patients colonized by ESBLE, especially in areas with more than 10% of ESBLE prevalence.

Carbapenem-Resistant Enterobacteriaceae
The Center for Disease Control and Prevention (CDC) CRE prevention and control toolkit 2015 recommendations include: healthcare worker education, contact precautions, patient and staff cohorting, chlorhexidine bathing, targeted screening of contacts and active surveillance, optimization of hand hygiene, environmental cleaning, minimized use of indwelling devices, implementation of antimicrobial stewardship, and inter-facility communication [131].
The role of intestinal decolonization and fecal microbiota transplantation for eradication of CRE carriage in SOT recipients is under investigation and remains unclear due to the lack of studies addressing this issue. However, the ESCMID-European Committee on Infection Control (EUCIC) clinical guidelines regarding decolonization of MDR Gram-negative bacteria carriers do not recommend routine decolonization of CRE [141].
When the donor is found colonized or infected with CRE after LT, prompt communication regarding donor cultures and early targeted pre-emptive therapy are essential. On the other hand, if the donor is found to be infected or colonized with CRE prior to transplantation, its suitability for organ donation should be carefully considered, particularly if the infection concerns the liver or is a BSI [70].
A recent review and the European guidelines highlight how the evidence for target prophylaxis for CRE in pre-LT colonized patients is still scarce [140,144]. A recent study suggested the use of risk prediction models for infection and mortality in order to en-able better targeting interventions for CRE infection after transplant [93] rather than a target prophylaxis.

MDR, XDR and PDR Non-Fermenting Gram-Negative Bacilli
Contact precautions, improved compliance with hand hygiene, and cohorting are recommended in the settings of MDR P. aeruginosa, CRAB, and other non-fermenting Gram negative bacilli [70]. For these organisms, environmental control, deep cleaning, and care of indwelling devices are of particular importance, as they are saprophytic bacteria [133]. These organisms can also colonize devices used for respiratory therapy or diagnostic procedures (e.g., bronchoscopes). Thus, proper disinfection and possibly sterilization are required, and workers using and processing reusable equipment should be properly trained [145].
In addition to the above-mentioned measures, daily chlorhexidine bathing, active rectal and groin screening can be useful infection control bundles to curtail CRAB outbreaks [133][134][135][136].

Vancomycin-Resistant Enterococci
Among infection prevention measures for VRE, the only one found to be beneficial in a recent meta-analysis was hand hygiene after patient encounters [132]. Furthermore, this meta-analysis raised concerns about the quality and limitations of the published infection control studies on VRE.
VRE-targeted LT surgical prophylaxis is not recommended by international guidelines [146]. A study by Sarwar et al. [147] reported that among 27 VRE-colonized patients that underwent LT, 25 received surgical prophylaxis with daptomycin. Notably, none of the 25 patients that received daptomycin developed a VRE infection during the post-transplant period, whilst 2 patients, who did not receive daptomycin, developed VRE bacteraemia.

Methycillin-Resistant Staphylococcus aureus (MRSA)
Infection control strategies such as surveillance cultures to detect nasal colonization and decolonization with intranasal mupirocin, the use of cohorting, and contact isolation measures are widely used and related to a decrement of MRSA infection in the general population [148].
Data consistent with the general population are also available for the LT setting. A retrospective study conducted by Singh et al. [114] from 1996 to 2004 showed how the application of these strategies since 2000 reduced the rate of post-LT new acquisition of S. aureus nasal colonization from 45.6% to 9.9%. A concomitant decrement of post-LT S. aureus infections from 40.4% to 4.1% was also observed, with recipients acquiring S. aureus post-LT significatively more at risk of S. aureus infection vs. non-carriers and patients colonized before LT. Although this study did not focus specifically on MRSA, these data support the use of the above-mentioned MRSA infection control strategies in LT recipients.

Summary and Future Perspective
The prevalence of, and risk factors associated with, MDRO colonization and infection in LT candidates/recipients vary widely according to specific pathogens. As MDRO infections profoundly impact LT recipients' morbidity and mortality, preventive measures are essential. The implementation of infection control and antimicrobial stewardship measures is the keystone for the reduction in MDRO-colonization prevalence. Regarding DDI, the development of standardized definitions of donor-derived MDRO infections are fundamental as centralized reporting mechanisms, with the goal to reduce underreporting of cases. Development and maintenance of updated local and regional guidelines and protocols are necessary to face MDRO infections in LT. Further studies of the epidemiology of LT associated infections, preventive measures of DDI, and the efficacy of a LT surgical antimicrobial prophylaxis tailored to the candidate's colonization are required. Funding: This research received no external funding.

Data Availability Statement:
The data presented in this study are available on request from the corresponding author.

Conflicts of Interest:
The authors declare no conflict of interest.