- Division of Infectious Diseases, Department of Internal Medicine, UTHealth McGovern Medical School, Houston, Texas, USA
Academic Editor: Wasim A. Dar
Received: March 29, 2018 | Accepted: October 16, 2018 | Published: November 2, 2018
OBM Transplantation 2018, Volume 2, Issue 4 doi:10.21926/obm.transplant.1804023
Recommended citation: Nigo M, Hasbun R, Vigil KJ. Bacterial Infections after Liver Transplantation: Updates in Post-Surgical Infections, Vancomycin-Resistant Enterococcus, and Multi-Drug Resistant Enterobacteriaceae. OBM Transplantation 2018;2(4):023; doi:10.21926/obm.transplant.1804023.
© 2018 by the authors. This is an open access article distributed under the conditions of the Creative Commons by Attribution License, which permits unrestricted use, distribution, and reproduction in any medium or format, provided the original work is correctly cited.
Since 1963, when the first liver transplantation was successfully performed, this life-saving procedure has been widely available in many countries . Despite its advances in technique and immunosuppressive strategies, post-liver transplant Infectious complications pose high morbidity and mortality [2,3,4]. Due to the complexity of its unique procedure and long operative time, immunocompromised status, metabolic abnormalities, and patient’s poor nutrition status and coagulopathy, liver transplant (LT) recipients have higher rates of infectious complications compared to heart and renal transplant recipients . The rate of infectious complications reaches up to 83%, being the vast majority of bacterial infections followed by fungal and viral infections [6,7,8,9,10]. The use of prophylaxis against cytomegalovirus and fungal infections has also contributed to the increase in the proportion of bacterial infections compared to other infectious etiologies [6,11].
The majority of infectious complications occur within four weeks after LT and are usually nosocomial or originate from the patient’s own flora . Donor-derived infections may also occur during this period . During the next post-LT period, which comprises the second to sixth months after the transplant, opportunistic infections might occur, depending on the patients’ risk and the intensity of immunosuppression. Six months after LT, bacterial infections are usually related to environmental exposures and late biliary complications .
There have been several review articles discussing bacterial infections in LT recipients [14,15,16,17,18,19]. In order to avoid redundancy, we will review bacterial infections with special emphasis on post-surgical infections, (e.g. biliary tract infections and liver abscesses), and multi-drug resistant pathogens frequently problematic in LT recipients, such as vancomycin-resistant Enterococcus (VRE) and multi-drug resistant (MDR) Enterobacteriaceae.
2. Post-Surgical Infections among Liver Transplant Recipients
During the first four weeks post-LT period, the most common infectious complications are related to post-surgical infections, including superficial infections, hepatobiliary tract infections, peritonitis, and liver/extra-hepatic abscesses [7,8,20,21,22]. These severe infections often lead to bloodstream infections resulting in high mortality in this vulnerable population [23,24]. Moreno et al evaluated a total of 3926 solid organ and hematopoietic stem cell transplant recipients in Spain and revealed that LT patients with bloodstream infections (BSIs) carried approximately three-fold higher mortality risk compared to kidney/heart transplant recipients with BSIs. The common source of bacteremia among overall transplant recipients was catheter-related, followed by intra-abdominal origin, which was almost exclusively seen in LT recipients .
Many studies have explored the risk factors for postsurgical infections among LT patients. Table 1 summarizes the risk factors from selected studies. Most of the studies have significant limitations due to the retrospective study design, small sample size, and the failure to effectively control all possible confounding factors in this complicated population [25,26,27,28,29]. A Brazilian study gathering 561 LT patients over a 9-year period (2002-2011) revealed that re-transplantation, the transfusion of more than two units of blood during the operation, hemodialysis, long cold ischemia time (more than 400 minutes) and CMV infection were independent risk factors for 60 days surgical site infections. No information regarding the site of infection was provided in this study . LT often requires multiple doses of surgical antibiotics prophylaxis for the prolonged operative time . Pre-existing coagulopathy often leads to heavy intraoperative bleeding which necessitates a large number of transfusions and may result in intra-abdominal hematomas susceptible to bacterial seeding. In addition, living donor liver transplant (LDLT) differs from deceased LT due to the unique procedure, which increases the risk for post-operative infections. The small-for-size donor grafts may lead to postoperative liver dysfunction with prolonged cholestasis and coagulopathy (known as smaller for size liver syndrome). Biliary leakage from the cut surface of the graft may subsequently lead to biloma formation and secondary infections. The surgical procedure for LDLT is technically more challenging and contributes to the higher incidence of complications such as biliary strictures [10,31,32]. Human immunodeficiency virus (HIV)-infected patients recently became considered as LT candidates. Several studies revealed LT recipients with HIV has similar overall mortality and graft loss especially in a modern era of potent antiretroviral treatment, compared to non-HIV infected recipients [33,34]. Of note, co-infection with hepatitis C has higher mortality and poor graft survival in this population . Among 109 consecutive HIV infected LT recipients between 1999 and 2010, forty patients (37%) experienced at least one infection during the first year post-transplant, and the majority were bacterial infections . Only four patients developed HIV related opportunistic infections with two candida esophagitis, one tuberculous lymphadenopathy, and one disseminated Mycobacterium avium infection.
Table 1 Larger Studies of Risk Factors for Infection after Liver Transplant
Type of study, Periods, and country
Jan 2002 to Dec 2011
Transfusion>2 units of blood during the procedure
Cold ischemia for > 400 minutes
543 patients were included.
No detail information of SSI was provided.
Aug 2003 to Sep 2005
Choledochojejunal or hepatojejunal Reconstruction
Previous history of liver/kidney transplant
More than four RBC transfusions
1222 patients from the Spain Registry.
Only 8.8 % SSI; lower than other studies.
Jan, 1999 to Dec, 2008
MELD score >30
ICU stay >48 h prior to transplant Intraoperative transfusion ≥15 units Retransplantation
227 consecutive LT patients.
Small number of biliary tract infections (1.7 %) and intra-abdominal infections (2.5%). Majority were bacteremia (7%), and pneumonia (3%).
SSI, Surgical site infection, RBC, Red blood cell, ICU, Intensive care units
2.1 Biliary Tract Infections and Cholangitis
The biliary tract is the “Achilles’ heel” of liver transplantation [38,39]. Despite the improvement in surgical techniques, biliary complications following LT remain a major cause of infection with an overall incidence of 5 – 25% [40,41,42]. Those complications are related to biliary strictures, leaks, stones or debris, and sphincter of Oddi dysfunction.
The type of biliary anastomosis during transplant is a well-known important factor associated with biliary complications. Two major types of anastomosis have been widely used; anastomosis of the biliary duct to a Roux-en-Y loop of the jejunum (choledochojejunostomy) and duct-to-duct anastomosis (choledochocholedochostomy). Choledochojejunostomy is generally recommended in patients with pre-existing biliary diseases, such as primary sclerosing cholangitis, prior biliary manipulation or surgeries, and for size mismatch between donor and recipient ducts [10,43]. However, choledochojejunostomy is associated with more intra-abdominal infections, especially fungal infections, compared to choledochocholedochostomy . Opening the jejunum increases the chance of contamination of the surgical field due to enteric organisms with a resultant increased risk of infection . In a previous study, intraoperative surveillance cultures from the peritoneum, fascia, explant, donor liver bile, and jejunal lumen were collected in 77 LT patients. Choledochojejunostomy, previous liver transplantation, and previous hepatobiliary surgery were significantly associated with detection of bacteria from the cultures . Interestingly, four out of 11 patients with positive surveillance cultures developed post-surgical infections within the first two weeks, and none of the patients with negative cultures developed infectious complications. Furthermore, three of the four patients had identical pathogens to the ones found in intraoperative cultures during the transplantation (Enterococci, Citrobacter, Enterobacter, and Pseudomonas). The late postoperative infections, more than three weeks after surgery, differed from the identified pathogen during operation . Moreover, Bubak et al described that five out of six patients who developed sepsis after liver biopsy had choledochojejunostomy for LT .
The association between bile leak, cholangitis and T-tube stents for biliary anastomosis is still controversial. Between 15-30% of cadaveric LT recipients with T-tube develop significant biliary complications. However, biliary stenosis frequently develops in patients without T-tube group [46,47,48]. The recent randomized trial from Spain suggested the selective use of T-tube based on the high incidence of biliary stricture in the patients with the biliary diameter less than 7mm without T-tube as well as the T-tube inherit complications after the removal . In addition to T-tube biliary reconstruction and Roux-en-Y anastomosis, ischemia/reperfusion injury, hepatic artery thrombosis (HAT), CMV infection and primary sclerosing cholangitis are also implicated risk factors for biliary complications .
2.2 Bile Leaks and Infected Biloma
Bile leaks have an incidence of 2 – 25% in post-LT, which is especially emphasized in living donor liver transplantation [43,50]. Those are divided into two categories, early (within 4 weeks transplant) and late . Early postoperative bile leaks are often due to ischemia from hepatic artery anastomosis, bleeding from the cut end of the bile ducts, and excessive tension on the ductal anastomosis. Late bile leaks are often related to elective or inadvertent removal of the T-tube.
Bilomas arise when bile ducts rupture into the intrahepatic parenchyma or free abdominal cavity due to bile duct necrosis, stricture or leaks, and result in intrahepatic or peri-hepatic bilious fluid collections. Most bilomas encountered in LT are outside the liver and usually in the perihepatic spaces . In a study evaluating 492 orthotropic liver transplants (OLT) recipients between 1994 and 2001, a total of 57 patients (11.5%) developed bilomas. Patients presented with fever (44%) and abdominal pain (40%). 28% of patients were diagnosed with bilomas within four weeks after transplantation. However, 14% were detected more than one year after transplantation. Risk factors were evaluated among 51 (12%) patients with infected bilomas; HAT (Odds ratio: OR 91), hepatic artery stenosis (OR 13), and Roux-en Y reconstruction (OR 6) were found to be independently associated . Safdar et al also described their experience of infected bilomas in 57 patients in Wisconsin. The most common pathogens were enterococci (37%) with a high incidence of vancomycin-resistant enterococci (VRE) (48% of enterococci cases), followed by coagulase-negative Staphylococcus (26%) and Candida species (26%). Furthermore, one or more new “superinfecting” pathogens were later detected in 95% of cases. There was complete resolution in 35 (61%) patients, 12 (21%) patients required re-transplantation and 20 (35 %) patients died. All patients underwent early diagnostic percutaneous aspiration and received more than four weeks of antimicrobial therapy . In the absence of re-transplantation, the optimal duration of antimicrobial therapy is unknown, but a prolonged antibiotic duration is almost often required .
2.3 Liver Abscess
Liver abscesses post-LT are a rare but life-threatening complication . It often occurs four weeks after transplantation and is frequently associated with the HAT [54,55]. In a retrospective study of 2,175 SOT patients from 1990 to 2000, 12 episodes of liver abscesses occurred in 10 (2.2%) out of 459 LT patients . Of note, eight out of 12 episodes were accompanied with HAT (overall cases of HAT were 13), which was preceded by hepatic abscesses in four cases . Stange et al. evaluated 30 patients (2.5%) who developed HAT among 1,250 LT recipients in Germany. One-third of HAT patients developed a liver abscess, and 50% of patients required re-transplantation . In an Iranian study of five cases of liver abscess among 560 LT recipients; three out of five patients had a bile duct anastomosis stricture (60%). Solitary abscess was seen in 60% of cases and was exclusively located in the right lobe . The management of abscesses includes both surgical interventions to correct the underlying process as well as antimicrobial therapy. The patient often requires multiple drainages and prolonged antimicrobial therapy. “Superinfection” is a common complication .
3. Multi-Drug Resistant Organisms (MDROs)
Prolonged waiting time and repeated and unavoidable exposures to both healthcare facility and antibiotics contribute increased risk for both colonization and infections due to MDROs. The rate of MDR bacteria and its species depend on the geographical locations or even facilities. For instance, in Spain, there is a higher rate of MDR gram-negative pathogens (Acinetobacter 8/11, Pseudomonas 26/35), but less MDR rate in gram positives (MRSA 5/13 and VRE 0/16) [57,58]. A trend shifting from gram-positive bacteria towards gram-negative pathogens has been observed in the U.S. study over several decades, after a previous global surge of S. aureus infections in the 1990s [11,15,59]. Routine prophylaxis for spontaneous bacterial peritonitis with quinolones might have contributed to this trend. More recently, MDROs are an emerging threat among the LT population. Carbapenem-resistant organisms have been reported in pre and post LT population . A prospective study from Brazil demonstrated that 18% of patients were colonized with carbapenem-resistant Enterobacteriaceae (CRE), and those patients had a higher incidence of CRE infections after transplant .
3.1 Vancomycin-Resistant Enterococcus (VRE)
Since VRE was first recognized in the 1980s after the introduction of cephalosporins, the prevalence has steadily increased. In the last 10 years, the prevalence of VRE among enterococcal bloodstream isolates in the United States was 27.8% [61,62]. Although Enterococcus faecium comprises only 10-20% of overall enterococcal infections, it is frequently identified as vancomycin-resistant; moreover, 80.7% of all bloodstream E. faecium isolates in the US were resistant to vancomycin in 2010 . VRE colonization often persists for months to years, and precede its invasive infections [63,64,65]. A meta-analysis estimated the prevalence of VRE colonization to be 15.6% among LT population in the U.S. and the colonized recipients carried 6.7 times higher risk of VRE infections in post-LT . VRE infections among LT recipients increase mortality up to nearly 60% [67,68]. Due to its intrinsic resistance and tolerance against antimicrobials, the therapeutic options are significantly limited and left significant challenges in its treatment.
Daptomycin (DAP) is a cyclic antimicrobial lipopeptide targeting the cell membrane in a calcium-dependent fashion. It is one of the few antibiotics exhibiting in vitro bactericidal activity against VRE. However, recent studies suggested that enterococci harboring higher DAP MIC (3-4 mcg/mL, CLSI breakpoint for susceptible is 4 mcg/mL) may already have a single mutation which abolishes its bactericidal activity . This finding is further supported by another retrospective study where DAP MICs of 3-4 mcg/mL, and immunosuppression were associated with microbiologic failure . An in vitro study comparing DAP (6, 8, 10, and 12 mg/kg/day) against VRE in a pharmacokinetic model demonstrated that 12mg/kg/day was required to sustain bactericidal activity and prevent the emergence of DAP-nonsusceptible strains . In order to overcome these problems, two strategies have often used. First is the use of a higher dose of DAP of 8 – 12 mg/kg/day, as opposed to the FDA, approved dosage of DAP (6 mg/kg for skin soft tissue infections). The efficacy of high-dose DAP therapy against VRE bacteremia was supported by several retrospective studies, and no significant safety concerns, such as CPK elevation, was observed [72,73]. The second approach to enhance its efficacy is to use combination therapy with ampicillin or ceftaroline . Despite the above strategies, DAP non-susceptible VRE has been an emerging issue, and a recent retrospective study in 14 LT recipients infected with DAP-nonsusceptible enterococci showed 71% of mortality with this recalcitrant pathogen .
The oxazolidinones class has two commercially available compounds, linezolid, and tedizolid. Both agents have intravenous and oral formulations. The oral formulations demonstrate great bioavailability in patients tolerating enteral nutrition. Linezolid is a bacteriostatic agent inhibiting protein synthesis by interacting with the A site of bacterial ribosomes. Linezolid is considered to be a valuable antibacterial agent for the treatment of VRE infections . Linezolid has been used as salvage therapy for bacteremic patients with VRE in a small, open-label study with a reported clinical cure rate of 78% . Another study of the compassionate use of linezolid for solid organ transplant recipients, including 50 liver transplant, showed 63% survival rates in this futile population . It also has good penetration to the biliary tract in post-transplant patients, which has potential benefit in biliary tract infections [78,79]. Hematologic and neurologic toxicities and lactic acidosis are the major side effects of linezolid as well as serotonin syndrome due to drug interactions. The former toxicities are considered due to mitochondrial toxicity. In LT recipients, a small study of 46 cases did not show significant adverse events related to linezolid, however, the median duration was only 11 days . Tedizolid was FDA approved in 2014 for the treatment of acute bacterial skin and skin structure infections (ABSSSIs). Several favorable advantages over linezolid are (i) its less mitochondrial toxicity that leads to myelosuppression and neuropathy , and (ii) its bactericidal profile against enterococci in non-immunocompromised models. However, in Phase III studies (ESTABLISH-1/2) for ABSSSIs, [82,83] this drug was used only for 6 days; thus, the toxicity of its prolonged use is questioned due to the paucity of clinical data. The efficacy of tedizolid in other sources of infections, such as bacteremia, is scarce . In ten linezolid-resistant Enterococcus isolates, tedizolid retained its in vitro activity with an average 4-8 fold lower MICs compared to linezolid . However, in vivo data is lacking.
Quinupristin/dalfopristin (Q/D) is a combination of quinupristin (streptogramin B) and dalfopristin (streptogramin A) that has in vitro bactericidal activity against E. faecium through the inhibition of protein synthesis. Importantly, Q/D has no activity against E. faecalis (due to intrinsic resistance). The data for its clinical use among LT patients are limited to case series of pediatric LT recipients and 12 adult cases among the case series of VRE infections with a success rate of 74% and 48%, respectively [86,87]. Additionally, Q/D has three important limitations: (i) its safety and tolerability profile with a high frequency of secondary effects (e.g., phlebitis, arthralgia, and myalgia) often resulting in treatment interruptions; (ii) many E. faecium carry the erm gene (B) which eliminates the bactericidal activity of Q/D . (iii) In cirrhotic patients, the mean values of the area under the curve of Q/D were approximately 2.8 and 1.5 times higher than in healthy volunteer . In addition, patients with hyperbilirubinemia had significantly higher exposure to quinupristin metabolites (up to a four-fold increase in AUC) due to the delayed elimination of the drug . Liver diseases were found to be a possible associated risk factor in 25 out of 50 patients who received Q/D and experienced significant arthralgia [90,91].
Tigecycline, a glycylcycline derivated from minocycline, but with a functional group substitution, has broad-spectrum activity against gram-positive cocci and gram-negative bacilli, including VRE. It is FDA approved for the treatment of complicated intra-abdominal infection, complicated skin and soft tissue infections and community-acquired pneumonia. However, there is a significant concern of its serum concentration and its bacteriostatic activity, which is a plausible explanation of high mortality among septic patients, resulting in a black-box warning by the FDA . In addition, phase 3 randomized clinical trials (RCT) comparing tigecycline and imipenem/cilastatin for hospital-acquired pneumonia demonstrated inferiority in tigecycline, mainly driven by the ventilator-associated pneumonia group . In order to achieve higher tissue/serum concentration of tigecycline, a higher dose (200mg IV loading followed by 100 mg every 12 hours) was investigated with improved outcome in VAP, but with higher side effects, especially gastrointestinal . On the other hand, tigecycline achieves high penetration in the biliary tract, making it an ideal option for the treatment of biliary tract infections . However, a recent small study of abdominal transplant recipients (LT:63%, Kidney: 22%) complicated with intra-abdominal infection (VRE was seen in 70% of cases) had higher mortality in the tigecycline group than the other comparators .
Oritavancin is a glycopeptide semisynthetic derivative of chloroeremomycin with the interesting property that it retains activity against VRE. This agent was FDA approved in 2014 for ABSSSIs after SOLO I/II studies demonstrated its non-inferiority to comparators [97,98]. This compound has in vitro activity against VRE isolates with an additional mechanism against secondary binding sites . This compound could be a theoretical option for the treatment of VRE infections; however, the suitable dosing and clinical data against this pathogen are undetermined.
3.2 Multi-Drug Resistant (MDR) Enterobacteriaceae
The prevalence of MDR gram-negative bacteria infections, including Enterobacteriaceae, has been increasing throughout the world. MDR Enterobacteriaceae infections have been recognized as major threats in the LT population, often leading to inappropriate initial empirical antimicrobial therapy, and carrying a high mortality rate, especially with bloodstream infections (BSIs) [57,60,100,101]. Additionally, LT recipients, compared to kidney and heart transplantation, have a higher incidence of MDR bacteremia . The emergence of carbapenem-resistant Enterobacteriaceae (CRE) infections are becoming a serious health care problem, and, indeed, solid organ transplantation (SOT) was one of the independent risk factors for CRE infection in New York City . The incidence in LT recipients varies widely among transplant centers, ranging from 3% to 23% with an increasing rate in recent studies [60,100,103]. Carriage of carbapenem-resistant Klebsiella at any point either pre-/post- LT seems the highest risk factor for the infection . Freire et al recently reported 36.8% of LT recipients who were infected or colonized with CRE prior to transplantation developed CRE infections in the post-transplant period . Carbapenem resistance can arise through the production of metallo-beta-lactamase or other mechanisms, such as KPCs or OXA-type carbapenemases. Alternatively, strains may express extended-spectrum beta-lactamases (ESBLs) or AmpC beta-lactamases in conjunction with loss or decreased expression of outer membrane porins. K. pneumoniae is one of the major pathogens producing carbapenemase and has spread throughout the world, especially sequence type 258 (ST258). A study from Pittsburg University identified 17 carbapenem-resistant K. pneumoniae bacteremic patients, and 80% of them were associated with liver or intestinal transplantation with frequent association with intra-abdominal abscesses. All but one strain of carbapenem-resistant Klebsiella spp. were ST258, KPC-2 producing strains . Infections with carbapenem-resistant Klebsiella infection or CRE are significant treatment challenges and often lead to a poor outcome, compared to carbapenem susceptible infections [29,100,106].
Polymyxin and colistin (polymyxin E) were originally introduced into clinical use in the 1950s. However, due to its significant side effects profile, these antimicrobials were not considered as therapeutic options for decades. As a desperate need for antimicrobial options against highly resistant organisms, the utility of these antimicrobials has been recently revisited. Although there is a little structural difference between those two compounds, a substantial difference of its pharmacokinetics exists. Polymyxin B is administered as an active antibacterial entity, whereas colistin is administered in the form of colistimethate, which requires conversion to colistin after its administration . As colistimethate is mainly excreted through the kidneys and has an unpredictable rate of conversion to an active molecule, there is a concern in attaining the optimal therapeutic serum concentration of active metabolites. In addition, the optimal dosage of those antibiotics is still undetermined. In order to attain possible synergistic effects, those compounds are often used with a second agent such as carbapenems, even when the MICs are above susceptible range against isolates. Mostardeiro et al evaluated nephrotoxicity among 92 transplant recipients that received polymixins, including eight LT recipients. Nephrotoxicity was reported in 36.2% of patients, and half of them required hemodialysis . Furthermore, in the last years, even these antimicrobials are facing resistance [109,110].
Tigecycline, as discussed above, has a broad-spectrum activity against gram-positive cocci and gram-negative bacilli, including CRE. Mouloudi et al described case series of LT recipients infected with CRE from various sources. Most of the patients were treated with tigecycline combined with other agents, such as colistin, and high ICU mortality was observed (60%) . In addition, high rate of polymicrobial infection/superinfection with Pseudomonas, intrinsically resistant against tigecycline, was observed and complicated the treatment strategy.
Fosfomycin is also considered as a salvage therapeutic option for CRE, especially in Europe as its intravenous formulation is not commercially available in many countries, including the U.S. Fosfomycin binds to the enzyme UDP-N-acetylglucosamine ennolpyruvyl transferase, inhibiting the formation of N-acetylmuramic acid, resulting in disruption of peptidoglycan assembly . It is a small hydrophilic molecule that achieves high levels of tissue penetration, including the central nervous system. Clinical use of this agent in LT is limited. A single case of a colistin resistant, carbapenem-resistant Klebsiella invasive infection in a LT patient was successfully treated with intravenous fosfomycin with other agents .
Recently introduced antimicrobial armamentarium for those carbapenem/multi-drug resistant organisms is ceftazidime-avibactam and imipenem-vaborbactam. Those new beta-lactam-beta-lactamase inhibitor combinations overcome beta-lactamase-mediated resistance to beta-lactam antibiotics. Older beta-lactamase inhibitors, such as clavulanic acid, tazobactam, and sulbactam do not inhibit class A carbapenemase . Avibactam has potent activity against KPC, Amp C, and Oxa-48, but not active against metallo-beta-lactamases. Ceftazidime-avibactam was approved by the U.S. FDA in February 2015 for complicated intra-abdominal infection and complicated urinary tract infections. More recently, a phase III study demonstrated its non-inferiority against meropenem in ventilator-associated pneumonia . However, noteworthy is that it is unknown if CRE were included in those studies, and the clinical utility among SOT recipients is yet to be determined. A recent small study evaluating the utility of ceftazidime-avibactam in bacteremic patients with carbapenem-resistant K. pneumoniae revealed better 90 days survival rate in univariate analysis compared to other options, although 30 days mortality did not differ . A study of CRE infections from Pittsburgh showed clinical successes at 30 days were 59% (22/37), and 23% (5/22) of the clinical successes had recurrent CRE infections within 90 days . Furthermore, the recent multicenter prospective observational study revealed a better outcome of 65% in patients with CRE infections treated with ceftazidime-avibactam, compared to the one treated with colistin . A study from MD Anderson in 2015 showed a high rate of isolates harboring metallo-beta-lactamases such as blaNDM (6/11, 55%) . Metallo-beta-lactamases, Ambler Class B, are resistant against new beta-lactamase inhibitors and other beta-lactams, except for aztreonam. However, the isolates harboring MBL are often accompanied with the production of ESBL, which abolishes the activity of aztreonam. With the understanding of the underlying mechanism of resistance, the intriguing combination of ceftazidime/avibactam and aztreonam has been proposed . The combination of ceftazidime/avibactam with aztreonam demonstrated a synergistic effect against metallo-beta-lactamase producing gram-negative pathogens, and successful use in a few cases [120,121]. Emerging resistance against avibactam has been reported . A single point mutation in SHV-1 and KPC-2 or various blaKPC-3 mutations conferred avibactam resistance [123,124]. Vaborbactam is the first boronic acid beta-lactamase inhibitor approved for by FDA in 11/2017. Boronates have a high affinity to serine proteases resulting in a covalent association between the catalytic serine and the boronate moiety. This is a novel mechanism compared to other clinically available beta-lactamase inhibitors . The combination remained its activity in 131/133 (98.5%) clinical KPC-producing Enterobacteriaceae strains from New York City .
Plazomicin was newly approved by FDA in 6/2018. This is a semisynthetic aminoglycoside which is designed to avoid enzymatic inactivation by common aminoglycoside-modifying enzymes . This antimicrobial compound has In vitro activity against gram-negative rods and some gram-positive cocci . The data of EPIC trial comparing plazomicin to meropenem in the patients with complicated UTIs due to drug-resistant Enterobacteriaceae revealed its non-inferiority and rapid clearance of bacteria than meropenem . Furthermore, plazomicin was associated with improved survival rates compared to colistin in the patients with carbapenem-resistant Enterobacteriaceae . No specific data are available in liver transplant populations.
Lastly, the management of MDROs is becoming more complex, in which infectious diseases specialists are of an utmost important role in this complicated group of patients. (Table 2 summarize the selected antibiotics for MDROs.) Early infectious diseases consultation has been shown to reduce all-cause mortality [131,132].
Bacterial infections have significant morbidity and mortality among the LT population, despite advances in technique and immunosuppressive strategy. Intra-abdominal infections are the main source of post-operative infections, which often requires surgical intervention and prolong antimicrobial therapy. BSIs in LT recipient lead three times higher mortality compared to the ones in other types of transplantation. Due to underlying morbidity and antimicrobial exposures pre and post LT, LT recipients carry a high risk for MDRO infections. VRE and MDR Enterobacteriaceae are often problematic in this population. Despite several new antibiotic armamentaria against those recalcitrant pathogens, better therapeutic options and strategies are still warranted.
M.N. wrote the manuscript. R.H and K.V. critically reviewed the manuscripts.
The authors have declared that no competing interests exist.
Table 2 Potential Antimicrobial Options for Multi-Drug Resistant Bacteria
1. Some animal models suggest bactericidal activity in vivo. 
2. Less active against P. aeruginosa, Proteus spp., Providencia spp., and Morganella spp.
3. Poor activities against Serratia spp., Providencia spp., and Morganella spp.
4. Less active against Pseudomonas spp., Morganella morganii, Acinetobacter spp. Enterobacter spp. Proteus vulgaris, Providencia spp. and Serratia spp.
6. Vaborbactam is a potent inhibitor of class A carbapenemase (e.g. KPC) and other class A (CTX-M, SHV, TEM) and class C beta-lactamases. However, class B and D carbapenemases are not inhibited. 
7. Meropenem exhibits bactericidal activity against susceptible isolates.  However, no data were found with the combination, especially against meropenem resistant strains.
C, Bactericidal, S, Bacteriostatic, U, Unknown, cSSSIs, Complicated skin and skin structure infections, uSSSIs, Uncomplicated skin and skin structure infections, BSIs, Bloodstream infections, cIAI, Complicated intra-abdominal infection, IE, Infective endocarditis, cUTI, Complicated UTI, Vancomycin-resistant Enterococcus faecium (VREF), CAP, Community-acquired pneumonia, CRE, Carbapenem-resistant Enterobacteriaceae, D-Ala D-Ala ,D-acyl-d-alanyl-d-alanine, D-Ala D-Lac, d-alanyl-d-lactate residues, Q/D, Quinupristin/dalfopristin
- Starzl TE, Marchioro TL, Kaulla KNV, Hermann G, Brittain RS, Waddell WR. Homotransplantation of the liver in humans. Surg Gynecol Obstet. 1963; 117: 659–676.
- Fulginiti VA, Scribner R, Groth CG, Putnam CW, Brettschneider L, Gilbert S, et al. Infections in recipients of liver homografts. N Engl J Med. 1968; 279: 619–626. [CrossRef]
- Moreno A, Cervera C, Gavaldá J, Rovira M, De La Cámara R, Jarque I, et al. Bloodstream infections among transplant recipients: results of a nationwide surveillance in Spain. Am J Transplant. 2007; 7: 2579–2586. [CrossRef]
- Schröter GPJ, Hoelscher M, Putnam CW, Porter KA, Hansbrough JF, Starzl TE. Infections complicating orthotopic liver transplantation. Arch Surg. 1976; 111: 1337–1347. [CrossRef]
- Singh N, Limaye AP. Infections in solid-organ transplant recipients. In: Mandell, Douglas, and Bennett’s principles and practice of infectious diseases. Philadelphia, PA: Saunders, 2014: 3440–3452.
- Kusne S, Dummer JS, Singh N, Iwatani S, Makowka L, Esquivel C, et al. Infections after liver transplantation. Medicine (Baltimore). 1988; 67: 132–143. [CrossRef]
- George DL, Arnow PM, Fox AS, Baker AL, Thistlethwaite JR, Emond JC, et al. Bacterial infection as a complication of liver transplantation: epidemiology and risk factors. Rev Infect Dis. 1991; 13: 387–396. [CrossRef]
- Paya CV, Hermans PE, Washington JA, Smith TF, Anhalt JP, Wiesner RH, et al. Incidence, distribution, and outcome of episodes of infection in 100 orthotopic liver transplantations. Mayo Clin Proc. 1989; 64: 555–564. [CrossRef]
- Song SH, Li XX, Wan QQ, Ye QF. Risk factors for mortality in liver transplant recipients with ESKAPE infection. Transplant Proc. 2014; 46: 3560–3563. [CrossRef]
- Abad CLR, Lahr BD, Razonable RR. Epidemiology and risk factors for infection after living donor liver transplantation. Liver Transplant. 2017; 23: 465–477. [CrossRef]
- Singh N, Wagener MM, Obman A, Cacciarelli TV, de Vera ME, Gayowski T. Bacteremias in liver transplant recipients: Shift toward gram-negative bacteria as predominant pathogens. Liver Transplant. 2004; 10: 844–849. [CrossRef]
- Mills JP, Wilck MB, Weikert BC, Porrett PM, Timko D, Alby K, et al. Successful treatment of a disseminated infection with extensively drug-resistant Klebsiella pneumoniae in a liver transplant recipient with a fosfomycin-based multidrug regimen. Transplant Infect Dis Off J Transplant Soc. 2016; 18: 777–781. [CrossRef]
- Fishman JA. Infection in solid-organ transplant recipients. N Engl J Med. 2007; 357: 2601–2614. [CrossRef]
- Kim SI. Bacterial infection after liver transplantation. World J Gastroenterol WJG. 2014; 20: 6211–6220. [CrossRef]
- Hand J, Patel G. Multidrug-resistant organisms in liver transplant: Mitigating risk and managing infections. Liver Transplant. 2016; 22: 1143–1153. [CrossRef]
- Hernandez MDP, Martin P, Simkins J. Infectious complications after liver transplantation. Gastroenterol Hepatol. 2015; 11: 741–753.
- Patel G, Huprikar S. Infectious complications after orthotopic liver transplantation. Semin Respir Crit Care Med. 2012; 33: 111–124. [CrossRef]
- Santoro-Lopes G, de Gouvêa EF. Multidrug-resistant bacterial infections after liver transplantation: An ever-growing challenge. World J Gastroenterol WJG. 2014; 20: 6201–6210. [CrossRef]
- Aguado JM, Silva JT, Fernández-Ruiz M, Cordero E, Fortún J, Gudiol C, et al. Management of multidrug resistant Gram-negative bacilli infections in solid organ transplant recipients: SET/GESITRA-SEIMC/REIPI recommendations. Transplant Rev. 2018; 32: 36–57. [CrossRef]
- Freire MP, Soares Oshiro ICV, Bonazzi PR, Guimarães T, Ramos Figueira ER, Bacchella T, et al. Surgical site infections in liver transplant recipients in the model for end-stage liver disease era: An analysis of the epidemiology, risk factors, and outcomes. Liver Transplant. 2013; 19: 1011–1019. [CrossRef]
- Hjortrup A, Rasmussen A, Hansen BA, Høiby N, Heslet L, Moesgaard F, et al. Early bacterial and fungal infections in liver transplantation after oral selective bowel decontamination. Transplant Proc. 1997; 29: 3106–3110. [CrossRef]
- Whiting JF, Rossi SJ, Hanto DW. Infectious complications after OKT3 induction in liver transplantation. Liver Transplant Surg. 1997; 3: 563–570. [CrossRef]
- Hashimoto M, Sugawara Y, Tamura S, Kaneko J, Matsui Y, Togashi J, et al. Bloodstream infection after living donor liver transplantation. Scand J Infect Dis. 2008; 40: 509–516. [CrossRef]
- Viehman JA, Clancy CJ, Clarke L, Shields RK, Silveira FP, Kwak EJ, et al. Surgical site infections after liver transplantation: Emergence of multidrug-resistant bacteria and implications for prophylaxis and treatment strategies. Transplantation. 2016; 100: 2107–2114. [CrossRef]
- Jeong S, Wang X, Wan P, Sha M, Zhang J, Xia L, et al. Risk factors and survival outcomes of biliary complications after adult-to-adult living donor liver transplantation. United Eur Gastroenterol J. 2017; 5: 997–1006. [CrossRef]
- Iida T, Kaido T, Yagi S, Yoshizawa A, Hata K, Mizumoto M, et al. Posttransplant bacteremia in adult living donor liver transplant recipients. Liver Transplant. 2010; 16: 1379–1385. [CrossRef]
- Bellier C, Bert F, Durand F, Retout S, Belghiti J, Mentré F, et al. Risk factors for Enterobacteriaceae bacteremia after liver transplantation. Transplant Int. 2008; 21: 755–763. [CrossRef]
- Hellinger WC, Crook JE, Heckman MG, Diehl NN, Shalev JA, Zubair AC, et al. Surgical site infection after liver transplantation: risk factors and association with graft loss or death. Transplantation. 2009; 87: 1387–1393. [CrossRef]
- Pereira MR, Scully BF, Pouch SM, Uhlemann A-C, Goudie S, Emond JE, et al. Risk factors and outcomes of carbapenem-resistant klebsiella pneumoniae infections in liver transplant recipients. Liver Transplant. 2015; 21: 1511–1519. [CrossRef]
- Asensio A, Ramos A, Cuervas-Mons V, Cordero E, Sánchez-Turrión V, Blanes M, et al. Effect of antibiotic prophylaxis on the risk of surgical site infection in orthotopic liver transplant. Liver Transplant. 2008; 14: 799–805. [CrossRef]
- Kiuchi T, Kasahara M, Uryuhara K, Inomata Y, Uemoto S, Asonuma K, et al. Impact of graft size mismatching on graft prognosis in liver transplantation from living donors. Transplantation. 1999; 67: 321–327. [CrossRef]
- Liu CL, Fan ST, Lo CM, Wei WI, Chan SC, Yong BH, et al. Operative outcomes of adult-to-adult right lobe live donor liver transplantation. Ann Surg. 2006; 243: 404–410. [CrossRef]
- Joshi D, Agarwal K. Role of liver transplantation in human immunodeficiency virus positive patients. World J Gastroenterol. 2015; 21: 12311–12321. [CrossRef]
- Vibert E, Duclos-Vallée J-C, Ghigna M-R, Hoti E, Salloum C, Guettier C, et al. Liver transplantation for hepatocellular carcinoma: The impact of human immunodeficiency virus infection. Hepatology. 2011; 53: 475–482. [CrossRef]
- Locke JE, Durand C, Reed RD, MacLennan P, Mehta S, Massie A, et al. Long-term outcomes after liver transplantation among human immunodeficiency virus infected recipients. Transplantation. 2016; 100: 141–146. [CrossRef]
- Teicher E, Boufassa F, Vittecoq D, Antonini T m., Tateo M-G, Coilly A, et al. Infectious complications after liver transplantation in human immunodeficiency virus-infected recipients. Transplant Infect Dis. 2015; 17: 662–670. [CrossRef]
- Sun H-Y, Cacciarelli TV, Singh N. Identifying a targeted population at high risk for infections after liver transplantation in the MELD era. Clin Transplant. 2011; 25: 420–425. [CrossRef]
- Chandrasekar PH, editor. Infections in the immunosuppressed patient: An Illustrated case-based approach. Oxford New York Auckland Cape Town: Oxford University Press, 2016. [CrossRef]
- de la Mora-Levy JG, Baron TH. Endoscopic management of the liver transplant patient. Liver Transplant. 2005; 11: 1007–1021. [CrossRef]
- Krok KL, Cárdenas A, Thuluvath PJ. Endoscopic management of biliary complications after liver transplantation. Clin Liver Dis. 2010; 14: 359–371. [CrossRef]
- Shamsaeefar A, Nikeghbalian S, Kazemi K, Motazedian N, Geramizadeh B, Malekhosseini SA. Thirteen-year evaluation of the management of biliary tract complication after deceased donor liver transplantation. Prog Transplant Aliso Viejo Calif. 2017; 27: 192–195. [CrossRef]
- Salahi H, Razmkon A, Mehdizadeh AR, Saberi-Firoozi M, Bahador A, Bagheri-Lankarani K, et al. Biliary tract complications after liver transplantation in a single center. Transplant Proc. 2005; 37: 3177–3178. [CrossRef]
- Ayoub WS, Esquivel CO, Martin P. Biliary complications following liver transplantation. Dig Dis Sci. 2010; 55: 1540–1546. [CrossRef]
- Arnow PM, Zachary KC, Thistlethwaite JR, Thompson KD, Bova JL, Newell KA. Pathogenesis of early operative site infections after orthotopic liver transplantation. Transplantation. 1998; 65: 1500–1503. [CrossRef]
- Bubak ME, Porayko MK, Krom RAF, Wiesner RH. Complications of liver biopsy in liver transplant patients: Increased sepsis associated with choledochojejunostomy. Hepatology. 1991; 14: 1063–1065. [CrossRef]
- Scatton O, Meunier B, Cherqui D, Boillot O, Sauvanet A, Boudjema K, et al. Randomized trial of choledochocholedochostomy with or without a T tube in orthotopic liver transplantation. Ann Surg. 2001; 233: 432–437. [CrossRef]
- Vougas V, Rela M, Gane E, Muiesan P, Melendez HV, Williams R, et al. A prospective randomised trial of bile duct reconstruction at liver transplantation: T tube or no T tube? Transplant Int. 1996; 9: 392–395. [CrossRef]
- López-Andújar R, Orón EM, Carregnato AF, Suárez FV, Herraiz AM, Rodríguez FSJ, et al. T-tube or no T-tube in cadaveric orthotopic liver transplantation: The eternal dilemma. Ann Surg. 2013; 258: 21–29. [CrossRef]
- Kochhar G, Parungao JM, Hanouneh IA, Parsi MA. Biliary complications following liver transplantation. World J Gastroenterol WJG. 2013; 19: 2841–2846. [CrossRef]
- Duailibi DF, Ribeiro MAF. Biliary complications following deceased and living donor liver transplantation: A review. Transplant Proc. 2010; 42: 517–520. [CrossRef]
- Thuluvath PJ, Pfau PR, Kimmey MB, Ginsberg GG. Biliary complications after liver transplantation: the role of endoscopy. Endoscopy. 2005; 37: 857–863. [CrossRef]
- Said A, Safdar N, Lucey MR, Knechtle SJ, D’Alessandro A, Musat A, et al. Infected bilomas in liver transplant recipients, incidence, risk factors and implications for prevention. Am J Transplant. 2004; 4: 574–582. [CrossRef]
- Nikeghbalian S, Salahi R, Salahi H, Bahador A, Kakaie F, Kazemi K, et al. Hepatic abscesses after liver transplant: 1997-2008. Exp Clin Transplant. 2009; 7: 256–260.
- Rabkin JM, Orloff SL, Corless CL, Benner KG, Flora KD, Rosen HR, et al. Hepatic allograft abscess with hepatic arterial thrombosis. Am J Surg. 1998; 175: 354–359. [CrossRef]
- Tachopoulou OA, Vogt DP, Henderson JM, Baker M, Keys TF. Hepatic abscess after liver transplantation: 1990-2000. Transplantation. 2003; 75: 79–83. [CrossRef]
- Stange BJ, Glanemann M, Nuessler NC, Settmacher U, Steinmüller T, Neuhaus P. Hepatic artery thrombosis after adult liver transplantation. Liver Transplant. 2003; 9: 612–620. [CrossRef]
- Bodro M, Sabé N, Tubau F, Lladó L, Baliellas C, Roca J, et al. Risk factors and outcomes of bacteremia caused by drug-resistant eskape pathogens in solid-organ transplant recipients. Transplant J. 2013; 96: 843–849. [CrossRef]
- Rodríguez-Baño J, Picón E, Gijón P, Hernández JR, Cisneros JM, Peña C, et al. Risk factors and prognosis of nosocomial bloodstream infections caused by extended-Spectrum-β-Lactamase-producing escherichia coli. J Clin Microbiol. 2010; 48: 1726–1731. [CrossRef]
- Wade JJ, Rolando N, Hayllar K, Philpott-Howard J, Casewell MW, Williams R. Bacterial and fungal infections after liver transplantation: An analysis of 284 patients. Hepatology. 1995; 21: 1328–1336. [CrossRef]
- Freire MP, Oshiro ICVS, Pierrotti LC, Bonazzi PR, de Oliveira LM, Song ATW, et al. Carbapenem-resistant enterobacteriaceae acquired before liver transplantation: Impact on recipient outcomes. Transplantation. 2017; 101: 811–820. [CrossRef]
- Patel G, Snydman DR, the AST Infectious Diseases Community of Practice. Vancomycin-resistant enterococcus infections in solid organ transplantation. Am J Transplant. 2013; 13: 59–67. [CrossRef]
- Arias CA, Mendes RE, Stilwell MG, Jones RN, Murray BE. Unmet needs and prospects for oritavancin in the management of vancomycin-resistant enterococcal infections. Clin Infect Dis. 2012; 54: S233–S238. [CrossRef]
- Patel R, Allen SL, Manahan JM, Wright AJ, Krom RAF, Wiesner RH, et al. Natural history of vancomycin-resistant enterococcal colonization in liver and kidney transplant recipients. Liver Transplant. 2001; 7: 27–31. [CrossRef]
- Olivier CN, Blake RK, Steed LL, Salgado CD. Risk of vancomycin-resistant Enterococcus (VRE) bloodstream infection among patients colonized with VRE. Infect Control Hosp Epidemiol. 2008; 29: 404–409. [CrossRef]
- Russell DL, Flood A, Zaroda TE, Acosta C, Riley MMS, Busuttil RW, et al. Outcomes of colonization with MRSA and VRE among liver transplant candidates and recipients. Am J Transplant. 2008; 8: 1737–1743. [CrossRef]
- Ziakas PD, Pliakos EE, Zervou FN, Knoll BM, Rice LB, Mylonakis E. MRSA and VRE colonization in solid organ transplantation: A Meta-analysis of published studies. Am J Transplant. 2014; 14: 1887–1894. [CrossRef]
- Newell KA, Millis JM, Arnow PM, Bruce DS, Woodle ES, Cronin DC, et al. Incidence and outcome of infection by vancomycin-resistant Enterococcus following orthotopic liver transplantation. Transplantation. 65: 439–442. [CrossRef]
- Papanicolaou GA, Meyers BR, Meyers J, Mendelson MH, Lou W, Emre S, et al. Nosocomial infections with vancomycin-resistant enterococcus faecium in liver transplant recipients: Risk factors for acquisition and mortality. Clin Infect Dis. 1996; 23: 760–766. [CrossRef]
- Munita JM, Panesso D, Diaz L, Tran TT, Reyes J, Wanger A, et al. Correlation between mutations in liaFSR of Enterococcus faecium and MIC of daptomycin: revisiting daptomycin breakpoints. Antimicrob Agents Chemother. 2012; 56: 4354–4359. [CrossRef]
- Shukla BS, Shelburne S, Reyes K, Kamboj M, Lewis JD, Rincon SL, et al. Influence of minimum inhibitory concentration in clinical outcomes of Enterococcus faecium bacteremia treated with daptomycin: Is it time to change the breakpoint? Clin Infect Dis. 2016; 62: 1514–1520. [CrossRef]
- Hall AD, Steed ME, Arias CA, Murray BE, Rybak MJ. Evaluation of standard- and high-dose daptomycin versus linezolid against vancomycin-resistant Enterococcus isolates in an in vitro pharmacokinetic/pharmacodynamic model with simulated endocardial vegetations. Antimicrob Agents Chemother. 2012; 56: 3174–3180. [CrossRef]
- Britt NS, Potter EM, Patel N, Steed ME. Comparative effectiveness and safety of standard-, medium-, and high-dose daptomycin strategies for the treatment of Vancomycin-resistant Enterococcal bacteremia among veterans affairs patients. Clin Infect Dis. 2017; 64: 605–613.
- Chuang Y-C, Lin H-Y, Chen P-Y, Lin C-Y, Wang J-T, Chen Y-C, et al. Effect of Daptomycin dose on the outcome of Vancomycin-resistant, Daptomycin-susceptible Enterococcus faecium bacteremia. Clin Infect Dis. 2017; 64: 1026–1034. [CrossRef]
- Smith JR, Barber KE, Raut A, Rybak MJ. β-Lactams enhance Daptomycin activity against Vancomycin-resistant Enterococcus faecalis and Enterococcus faecium in In Vitro Pharmacokinetic/Pharmacodynamic Models. Antimicrob Agents Chemother. 2015; 59: 2842–2848. [CrossRef]
- Lewis J d., Enfield K b., Cox H l., Mathers A j., Sifri C d. A single-center experience with infections due to daptomycin-nonsusceptible Enterococcus faecium in liver transplant recipients. Transplant Infect Dis. 2016; 18: 341–353. [CrossRef]
- Birmingham MC, Rayner CR, Meagher AK, Flavin SM, Batts DH, Schentag JJ. Linezolid for the treatment of multidrug-resistant, gram-positive infections: experience from a compassionate-use program. Clin Infect Dis. 2003; 36: 159–168. [CrossRef]
- Khoury JE, Fishman JA. Linezolid in the treatment of vancomycin‐resistant Enterococcus faecium in solid organ transplant recipients: report of a multicenter compassionate‐use trial. Transplant Infect Dis. 2003; 5: 121–125. [CrossRef]
- Pea F, Viale P, Lugano M, Baccarani U, Pavan F, Tavio M, et al. Biliary penetration and pharmacodynamic exposure of linezolid in liver transplant patients. J Antimicrob Chemother. 2009; 63: 167–169. [CrossRef]
- Pea F, Lugano M, Baccarani U, Della Rocca G, Viale P. Biliary pharmacodynamic exposure to linezolid in two liver transplant patients. J Antimicrob Chemother. 2014; 69: 567–568. [CrossRef]
- Radunz S, Juntermanns B, Kaiser G m., Treckmann J, Mathe Z, Paul A, et al. Efficacy and safety of linezolid in liver transplant patients. Transplant Infect Dis. 2011; 13: 353–358. [CrossRef]
- Lodise TP, Bidell MR, Flanagan SD, Zasowski EJ, Minassian SL, Prokocimer P. Characterization of the haematological profile of 21 days of tedizolid in healthy subjects. J Antimicrob Chemother. 2016; 71: 2553–2558. [CrossRef]
- Prokocimer P, De Anda C, Fang E, Mehra P, Das A. Tedizolid phosphate vs linezolid for treatment of acute bacterial skin and skin structure infections: the ESTABLISH-1 randomized trial. JAMA. 2013; 309: 559–569. [CrossRef]
- Moran GJ, Fang E, Corey GR, Das AF, De Anda C, Prokocimer P. Tedizolid for 6 days versus linezolid for 10 days for acute bacterial skin and skin-structure infections (ESTABLISH-2): a randomised, double-blind, phase 3, non-inferiority trial. Lancet Infect Dis. 2014; 14: 696–705. [CrossRef]
- Sudhindra P, Lee L, Wang G, Dhand A. Tedizolid for treatment of Enterococcal bacteremia. Open Forum Infect Dis. 2016; 3. [CrossRef]
- Barber KE, Smith JR, Raut A, Rybak MJ. Evaluation of tedizolid against Staphylococcus aureus and enterococci with reduced susceptibility to vancomycin, daptomycin or linezolid. J Antimicrob Chemother. 2016; 71: 152–155. [CrossRef]
- Verma A, Dhawan A, Philpott-Howard J, Rela M, Heaton N, Vergani GM, et al. Glycopeptide-resistant Enterococcus faecium infections in paediatric liver transplant recipients: safety and clinical efficacy of quinupristin/dalfopristin. J Antimicrob Chemother. 2001; 47: 105–108. [CrossRef]
- Winston DJ, Emmanouilides C, Kroeber A, Hindler J, Bruckner DA, Territo MC, et al. Quinupristin/Dalfopristin therapy for infections due to Vancomycin-resistant Enterococcus faecium. Clin Infect Dis. 2000; 30: 790–797. [CrossRef]
- López F, Culebras E, Betriú C, Rodríguez-Avial I, Gómez M, Picazo JJ. Antimicrobial susceptibility and macrolide resistance genes in Enterococcus faecium with reduced susceptibility to quinupristin-dalfopristin: level of quinupristin-dalfopristin resistance is not dependent on erm(B) attenuator region sequence. Diagn Microbiol Infect Dis. 2010; 66: 73–77. [CrossRef]
- Lamb HM, Figgitt DP, Faulds D. Quinupristin/dalfopristin: a review of its use in the management of serious gram-positive infections. Drugs. 1999; 58: 1061–1097. [CrossRef]
- Carver PL, Whang E, VandenBussche HL, Kauffman CA, Malani PN. Risk factors for arthralgias or myalgias associated with Quinupristin-Dalfopristin therapy. Pharmacother J Hum Pharmacol Drug Ther. 2003; 23: 159–164. [CrossRef]
- Linden PK, Bompart F, Gray S, Talbot GH. Hyperbilirubinemia during Quinupristin-Dalfopristin therapy in liver transplant recipients: Correlation with available liver biopsy results. Pharmacother J Hum Pharmacol Drug Ther. 2001; 21: 661–668. [CrossRef]
- Research C for DE and. Drug Safety and Availability - FDA Drug Safety Communication: FDA warns of increased risk of death with IV antibacterial Tygacil (tigecycline) and approves new Boxed Warning. Available at: https://www.fda.gov/drugs/drugsafety/ucm369580.htm. Accessed 11 February 2018.
- Freire AT, Melnyk V, Kim MJ, Datsenko O, Dzyublik O, Glumcher F, et al. Comparison of tigecycline with imipenem/cilastatin for the treatment of hospital-acquired pneumonia. Diagn Microbiol Infect Dis. 2010; 68: 140–151. [CrossRef]
- Ramirez J, Dartois N, Gandjini H, Yan JL, Korth-Bradley J, McGovern PC. Randomized phase 2 trial to evaluate the clinical efficacy of two high-dosage tigecycline regimens versus imipenem-cilastatin for treatment of hospital-acquired pneumonia. Antimicrob Agents Chemother. 2013; 57: 1756–1762. [CrossRef]
- Rodvold KA, Gotfried MH, Cwik M, Korth-Bradley JM, Dukart G, Ellis-Grosse EJ. Serum, tissue and body fluid concentrations of tigecycline after a single 100 mg dose. J Antimicrob Chemother. 2006; 58: 1221–1229. [CrossRef]
- Liebenstein T, Schulz LT, Viesselmann C, Bingen E, Musuuza J, Safdar N, et al. Effectiveness and safety of tigecycline compared with other broad-spectrum antimicrobials in abdominal solid organ transplant recipients with polymicrobial intraabdominal infections. Pharmacother J Hum Pharmacol Drug Ther. 2017; 37: 151–158. [CrossRef]
- Corey GR, Kabler H, Mehra P, Gupta S, Overcash JS, Porwal A, et al. Single-dose Oritavancin in the treatment of acute bacterial skin infections. N Engl J Med. 2014; 370: 2180–2190. [CrossRef]
- Corey GR, Good S, Jiang H, Moeck G, Wikler M, Green S, et al. Single-dose Oritavancin versus 7–10 days of Vancomycin in the treatment of Gram-positive acute bacterial skin and skin structure infections: The SOLO II Noninferiority study. Clin Infect Dis. 2015; 60: 254–262. [CrossRef]
- Patti GJ, Kim SJ, Yu T-Y, Dietrich E, Tanaka KSE, Parr TR, et al. Vancomycin and Oritavancin have different modes of action in Enterococcus faecium. J Mol Biol. 2009; 392: 1178–1191. [CrossRef]
- Kalpoe JS, Sonnenberg E, Factor SH, del Rio Martin J, Schiano T, Patel G, et al. Mortality associated with carbapenem-resistant Klebsiella pneumoniae infections in liver transplant recipients. Liver Transplant. 2012; 18: 468–474. [CrossRef]
- Linares L, Cervera C, Hoyo I, Sanclemente G, Marco F, Cofán F, et al. Klebsiella pneumoniae infection in solid organ transplant recipients: Epidemiology and antibiotic resistance. Transplant Proc. 2010; 42: 2941–2943. [CrossRef]
- Patel G, Huprikar S, Factor SH, Jenkins SG, Calfee DP. Outcomes of carbapenem-resistant Klebsiella pneumoniae infection and the impact of antimicrobial and adjunctive therapies. Infect Control Hosp Epidemiol. 2008; 29: 1099–1106. [CrossRef]
- Bergamasco M d., Barroso Barbosa M, de Oliveira Garcia D, Cipullo R, Moreira J c. m., Baia C, et al. Infection with Klebsiella pneumoniae carbapenemase (KPC)-producing K. pneumoniae in solid organ transplantation. Transplant Infect Dis. 2012; 14: 198–205. [CrossRef]
- Giannella M, Bartoletti M, Morelli MC, Tedeschi S, Cristini F, Tumietto F, et al. Risk factors for infection with Carbapenem-resistant klebsiella pneumoniae after liver transplantation: the importance of pre- and posttransplant colonization. Am J Transplant. 2015; 15: 1708–1715. [CrossRef]
- Clancy CJ, Chen L, Shields RK, Zhao Y, Cheng S, Chavda KD, et al. Epidemiology and molecular characterization of bacteremia due to carbapenem-resistant Klebsiella pneumoniae in transplant recipients. Am J Transplant. 2013; 13: 2619–2633. [CrossRef]
- Mouloudi E, Massa E, Papadopoulos S, Iosifidis E, Roilides I, Theodoridou T, et al. Bloodstream infections caused by carbapenemase-producing klebsiella pneumoniae among intensive care unit patients after orthotopic liver transplantation: Risk factors for infection and impact of resistance on outcomes. Transplant Proc. 2014; 46: 3216–3218. [CrossRef]
- Nation RL, Velkov T, Li J. Colistin and Polymyxin B: Peas in a Pod, or Chalk and Cheese? Clin Infect Dis. 2014; 59: 88–94. [CrossRef]
- Mostardeiro MM, Pereira CAP, Marra AR, Pestana JOM, Camargo LFA. Nephrotoxicity and efficacy assessment of Polymyxin use in 92 transplant patients. Antimicrob Agents Chemother. 2013; 57: 1442–1446. [CrossRef]
- Poirel L, Jayol A, Nordmann P. Polymyxins: antibacterial activity, susceptibility testing, and resistance mechanisms encoded by plasmids or chromosomes. Clin Microbiol Rev. 2017; 30: 557–596. [CrossRef]
- Monaco M, Giani T, Raffone M, Arena F, Garcia-Fernandez A, Pollini S, et al. Colistin resistance superimposed to endemic carbapenem-resistant Klebsiella pneumoniae: a rapidly evolving problem in Italy, November 2013 to April 2014. Eurosurveillance. 2014; 19: 20939. [CrossRef]
- Mouloudi E, Massa E, Piperidou M, Papadopoulos S, Iosifidis E, Roilides I, et al. Tigecycline for treatment of carbapenem-resistant klebsiella pneumoniae infections after liver transplantation in the intensive care unit: A 3-year study. Transplant Proc. 2014; 46: 3219–3221. [CrossRef]
- Parker S, Lipman J, Koulenti D, Dimopoulos G, Roberts JA. What is the relevance of fosfomycin pharmacokinetics in the treatment of serious infections in critically ill patients? A systematic review. Int J Antimicrob Agents. 2013; 42: 289–293. [CrossRef]
- Drawz SM, Bonomo RA. Three decades of β-Lactamase inhibitors. Clin Microbiol Rev. 2010; 23: 160–201. [CrossRef]
- Torres A, Zhong N, Pachl J, Timsit J-F, Kollef M, Chen Z, et al. Ceftazidime-avibactam versus meropenem in nosocomial pneumonia, including ventilator-associated pneumonia (REPROVE): a randomised, double-blind, phase 3 non-inferiority trial. Lancet Infect Dis. 2018; 18: 285–295. [CrossRef]
- Shields RK, Nguyen MH, Chen L, Press EG, Potoski BA, Marini RV, et al. Ceftazidime-Avibactam is superior to other treatment regimens against Carbapenem-resistant klebsiella pneumoniae bacteremia. Antimicrob Agents Chemother. 2017; 61: e00883-17. [CrossRef]
- Shields RK, Potoski BA, Haidar G, Hao B, Doi Y, Chen L, et al. Clinical outcomes, drug toxicity, and emergence of Ceftazidime-Avibactam resistance among patients treated for Carbapenem-resistant enterobacteriaceae infections. Clin Infect Dis. 2016; 63: 1615–1618. [CrossRef]
- van Duin D, Lok JJ, Earley M, Cober E, Richter SS, Perez F, et al. Colistin versus Ceftazidime-Avibactam in the treatment of infections due to Carbapenem-resistant enterobacteriaceae. Clin Infect Dis. 2018; 66: 163–171. [CrossRef]
- Aitken SL, Tarrand JJ, Deshpande LM, Tverdek FP, Jones AL, Shelburne SA, et al. High rates of nonsusceptibility to Ceftazidime-avibactam and identification of new delhi Metallo-β-lactamase production in enterobacteriaceae bloodstream infections at a major cancer center. Clin Infect Dis. 2016; 63: 954–958. [CrossRef]
- Marshall S, Hujer AM, Rojas LJ, Papp-Wallace KM, Humphries RM, Spellberg B, et al. Can Ceftazidime-Avibactam and Aztreonam overcome β-Lactam resistance conferred by Metallo-β-Lactamases in enterobacteriaceae? Antimicrob Agents Chemother. 2017; 61: e02243-16. [CrossRef]
- Jayol A, Nordmann P, Poirel L, Dubois V. Ceftazidime/avibactam alone or in combination with aztreonam against colistin-resistant and carbapenemase-producing Klebsiella pneumoniae. J Antimicrob Chemother. 2018; 73: 542–544. [CrossRef]
- Davido B, Fellous L, Lawrence C, Maxime V, Rottman M, Dinh A. Ceftazidime-Avibactam and Aztreonam, an interesting strategy to overcome β-Lactam resistance conferred by Metallo-β-Lactamases in enterobacteriaceae and pseudomonas aeruginosa. Antimicrob Agents Chemother. 2017; 61: e01008-17. [CrossRef]
- Shields RK, Nguyen MH, Press EG, Chen L, Kreiswirth BN, Clancy CJ. Emergence of Ceftazidime-Avibactam resistance and restoration of Carbapenem susceptibility in klebsiella pneumoniae carbapenemase-producing K pneumoniae: A case report and review of literature. Open Forum Infect Dis. 2017; 4: ofx101. [CrossRef]
- Papp-Wallace KM, Winkler ML, Taracila MA, Bonomo RA. Variants of β-Lactamase KPC-2 that are resistant to inhibition by Avibactam. Antimicrob Agents Chemother. 2015; 59: 3710–3717. [CrossRef]
- Shields RK, Chen L, Cheng S, Chavda KD, Press EG, Snyder A, et al. Emergence of Ceftazidime-Avibactam resistance due to Plasmid-Borne blaKPC-3 mutations during treatment of Carbapenem-resistant klebsiella pneumoniae infections. Antimicrob Agents Chemother. 2017; 61: e02097-16.
- Wong D, Duin D van. Novel Beta-lactamase inhibitors: Unlocking their potential in therapy. Drugs. 2017; 77: 615–628. [CrossRef]
- Lapuebla A, Abdallah M, Olafisoye O, Cortes C, Urban C, Quale J, et al. Activity of Meropenem combined with RPX7009, a novel β-Lactamase inhibitor, against Gram-negative clinical isolates in New York City. Antimicrob Agents Chemother. 2015; 59: 4856–4860. [CrossRef]
- Aggen JB, Armstrong ES, Goldblum AA, Dozzo P, Linsell MS, Gliedt MJ, et al. Synthesis and spectrum of the neoglycoside ACHN-490. Antimicrob Agents Chemother. 2010; 54: 4636–4642. [CrossRef]
- Walkty A, Adam H, Baxter M, Denisuik A, Lagacé-Wiens P, Karlowsky JA, et al. In Vitro activity of Plazomicin against 5,015 Gram-negative and Gram-positive clinical isolates obtained from patients in Canadian hospitals as part of the CANWARD study, 2011-2012. Antimicrob Agents Chemother. 2014; 58: 2554–2563. [CrossRef]
- Cloutier DJ, Komirenko AS, Cebrik DS, Keepers TR, Krause KM, Connolly LE, et al. Plazomicin Vs. Meropenem for complicated Urinary Tract Infection (cUTI) and Acute Pyelonephritis (AP): Diagnosis-specific results from the phase 3 EPIC study. Open Forum Infect Dis. 2017; 4: S532–S532. [CrossRef]
- McKinnell JA, Connolly LE, Pushkin R, Jubb AM, O’Keeffe B, Serio AW, et al. Improved outcomes with Plazomicin (PLZ) compared with Colistin (CST) in patients with bloodstream infections (BSI) caused by Carbapenem-resistant enterobacteriaceae (CRE): Results from the CARE study. Open Forum Infect Dis. 2017; 4: S531–S531. [CrossRef]
- Tissot F, Calandra T, Prod’hom G, Taffe P, Zanetti G, Greub G, et al. Mandatory infectious diseases consultation for MRSA bacteremia is associated with reduced mortality. J Infect. 2014; 69: 226–234. [CrossRef]
- Burnham JP, Olsen MA, Stwalley D, Kwon JH, Babcock HM, Kollef MH. Infectious diseases consultation reduces 30-day and 1-year all-cause mortality for multidrug-resistant organism infections. Open Forum Infect Dis. 2018; 5: ofy026. [CrossRef]
- Vernadakis S, Saner FH, Rath P-M, Kaiser GM, Mathe Z, Treckmann J, et al. Successful salvage therapy with daptomycin after linezolid and vancomycin failure in a liver transplant recipient with methicillin-resistant Staphylococcus aureus endocarditis. Transpl Infect Dis. 2009; 11: 346–348. [CrossRef]
- Flanagan S, Minassian SL, Morris D, Ponnuraj R, Marbury TC, Alcorn HW, et al. Pharmacokinetics of tedizolid in subjects with renal or hepatic impairment. Antimicrob Agents Chemother. 2014; 58: 6471–6476. [CrossRef]
- Grayson ML, Cosgrove SE, Crowe S, Hope W, McCarthy JS, Mills J, et al., editors. Kucers’ the use of antibiotics: A clinical review of antibacterial, antifungal, antiparasitic, and antiviral drugs, seventh edition - Three Volume Set. 7 edition. Boca Raton: CRC Press, 2017. [CrossRef]
- Manchandani P, Zhou J, Ledesma KR, Truong LD, Chow DS-L, Eriksen JL, et al. Characterization of polymyxin B biodistribution and disposition in an animal model. Antimicrob Agents Chemother. 2016; 60: 1029–1034. [CrossRef]
- Michalopoulos AS, Falagas ME. Colistin: recent data on pharmacodynamics properties and clinical efficacy in critically ill patients. Ann Intensive Care. 2011; 1: 30. [CrossRef]
- Dan JM, Mendler MH, Hemming AW, Aslam S. High-dose tigecycline and colistin for successful treatment of disseminated carbapenem-resistant Klebsiella pneumoniae infection in a liver transplant recipient. BMJ Case Rep. 2014; 2014.
- Patel SS, Balfour JA, Bryson HM. Fosfomycin tromethamine. Drugs. 1997; 53: 637–656. [CrossRef]
- Package Insert, AVYCAZ (ceftazidime and avibactam) for injection, for intravenous use. 2015; Available at: https://www.accessdata.fda.gov/drugsatfda_docs/label/2015/206494s001lbl.pdf. Accessed 23 August 2018.
- Package Insert, VABOMERETM (meropenem and vaborbactam) for injection, for intravenous use. 2017; Available at: https://www.accessdata.fda.gov/drugsatfda_docs/label/2017/209776lbl.pdf. Accessed 23 August 2018.
- Package Insert, ZEMDRI (plazomicin) injection, for intravenous use. 2018; Available at: https://www.accessdata.fda.gov/drugsatfda_docs/label/2018/210303Orig1s000lbl.pdf. Accessed 23 August 2018.
- Louie A, Liu W, Kulawy R, Drusano GL. In vivo pharmacodynamics of torezolid phosphate (TR-701), a new oxazolidinone antibiotic, against methicillin-susceptible and methicillin-resistant staphylococcus aureus strains in a mouse thigh infection model. Antimicrob Agents Chemother. 2011; 55: 3453–3460. [CrossRef]
- Karlowsky JA, Biedenbach DJ, Kazmierczak KM, Stone GG, Sahm DF. The activity of ceftazidime-avibactam against extended-spectrum and AmpC β-Lactamase-producing enterobacteriaceae collected in the INFORM global surveillance study in 2012-2014. Antimicrob Agents Chemother. 2016; 60: 2849-2857. [CrossRef]
- van Duin D, Bonomo RA. Ceftazidime/Avibactam and Ceftolozane/Tazobactam: Second-generation β-Lactam/β-Lactamase inhibitor combinations. Clin Infect Dis. 2016; 63: 234–241. [CrossRef]
- Lomovskaya O, Sun D, Rubio-Aparicio D, Nelson K, Tsivkovski R, Griffith DC, et al. Vaborbactam: Spectrum of Beta-Lactamase inhibition and impact of resistance mechanisms on activity in enterobacteriaceae. Antimicrob Agents Chemother. 2017; 61: e01443-17. [CrossRef]
- Inderlied CB, Lancero MG, Young LS. Bacteriostatic and bactericidal in-vitro activity of meropenem against clinical isolates, including Mycobacterium avium complex. J Antimicrob Chemother. 1989; 24 Suppl A: 85–99.