Carbapenem-Resistant Enterobacteriaceae in Solid Organ Transplantation: Management Principles

Abstract

Purpose of Review

Carbapenem-resistant Enterobacteriaceae (CRE) have emerged as a worldwide problem. Given their degree of immunosuppression and the level of contact with the healthcare system, solid organ transplant (SOT) recipients are at a disproportionately higher risk of acquisition, colonization, and infection with CRE, and outcomes from infection tend to be worse compared to non-transplant patients. Therapeutic options are limited for CRE infections although several newer agents have recently been approved for use. How well these agents perform in the setting of immunosuppression and SOT is unclear. We sought to review the epidemiology of CRE in SOT and the management principles.

Recent Findings

CRE infections are becoming an increasing problem in SOT, and donor-derived infections present a challenge in the peri-transplant period. Newer treatments for CRE are emerging that are less toxic and potentially more effective than prior CRE-active agents, but supportive clinical data are limited. Newer beta-lactamase inhibitors have good activity against KPC carbapenemases, but they lack activity against metallo-beta-lactamases (e.g., NDM). Promising data is emerging with newer agents that have activity against most carbapenemases, but, again, clinical data is needed. Combination therapy in addition to optimal pharmacokinetic and pharmacodynamics may go some way to improve outcomes against these difficult-to-treat organisms. Other novel therapies that prevent the emergence of resistance (oral beta-lactamase inhibitors) and eradication of resistant Gram-negative colonization (fecal microbiota transplant) may eventually become part of a bundle approach to reduce CRE infections in the future.

Summary

As in non-transplant patients, CRE infections in the transplant setting are challenging to treat and prevent. Infection prevention and control remains crucial to prevent widespread dissemination, and unique challenges exist with donor-derived CRE and how best to manage recipients in the peri-transplant period. Newer treatments are now in early-phase clinical studies, and in vitro activity data are supportive for several agents providing hope for improved outcomes with these typically difficult-to-treat and highly morbid infections in transplant recipients.

Introduction

It is well-established that infections caused by antimicrobial-resistant pathogens represent one of the greatest challenges to human health. Multidrug-resistant Gram-negative bacteria are of most concern, with reports of organisms causing infections that are resistant to all currently available antimicrobials. Carbapenems have been thought of as last-line therapy for multidrug-resistant Gram-negative bacteria, but with the emergence of carbapenemases worldwide, reliance on this antibiotic class is less secure. Patients who are immunocompromised, including solid organ transplant recipients, form one of the highest risk groups for acquisition and infection with carbapenem-resistant Gram-negative bacteria. Solid organ transplantation is an independent risk factor for the development of carbapenem-resistant Enterobacteriaceae (CRE) infection [1]. Transplant recipients have all the established risk factors for colonization and infection with resistant pathogens, such as recurrent exposure to broad-spectrum antimicrobials, extensive healthcare contact, longer length of hospital stays, exposure to the intensive care unit, and renal impairment [2, 3]. Infections typically occur early post-transplant, and sites of infection vary by organ transplant type [4]. Lung transplants are associated with pneumonias; liver transplant is associated with intra-abdominal infections and bacteremia; and the urinary tract is the most frequent source in kidney transplant recipients [5, 6]. Carbapenem resistance is problematic in non-fermenter Gram-negative bacteria, such as Pseudomonas and Acinetobacter, as well as Enterobacteriaceae, such as Klebsiella pneumoniae and Escherichia coli. This review will focus on CRE and its impact on solid organ transplantation, including management principles with regard to donor-derived CRE and newer treatment options of recipients with CRE infection.

Infection Prevention and Control of CRE in Solid Organ Transplantation

Adequately powered controlled studies are needed to define the best approach for management and control of CRE infection in SOT recipients. No standard guidelines exist for infection prevention in SOT, and centers implement a variety of different strategies [7]. While transmission of MDRO from donors to recipients is well-described, there are only few descriptions of confirmed horizontal transmission among hospitalized SOT recipients [8]. Horizontal transmission is a potentially significant risk, and, therefore, like for other patient groups, best-practice preventative strategies should be established and broadly adopted [2, 5, 9, 10]. The majority of the literature represents management of MDRO outbreaks, and eleven studies to date have tested the effect of infection prevention on CRE infection and/or colonization [10,11,12,13,14,15,16,17,18,19,20,21]. These studies form the basis of an updated guideline for infection prevention of CRE from the World Health Organization [11]. The majority of these studies assessed multi-modal strategies, including contact precautions, patient isolation and surveillance strategies, hand hygiene, antibiotic stewardship, and environmental cleaning. Unfortunately, heterogeneity in the design, intervention, and endpoints in these studies has precluded a comprehensive meta-analysis of pooled results. However, certain insights can be gleaned; six of 11 studies assessed strategies to improve hand hygiene compliance as part of an infection prevention bundle for CRE prevention and 5 of these 6 studies found reduced CRE infection rates with this intervention [10, 12, 14, 15, 17, 21]. Ten of 11 studies assessed the impact of active surveillance for CRE colonization in a combination of high-risk patients and close contacts [10, 12, 14,15,16,17,18, 20, 21]. Screening strategies varied and included longitudinal screening using rectal swabs of patients with known CRE to screening of patients for CRE development, as well as close contacts. Based on results that demonstrated a reduction in incidence of CRE after implementation of screening strategies, the WHO have made a strong recommendation that surveillance should be part of a multimodal strategy to prevent and control CRE health-care associated infections [11]. In addition, the majority of reports demonstrate a reduction in CRE with contact precautions and patient isolation strategies, which similarly form part of the strong recommendations put forward by the WHO. However, the optimal duration of patient isolation or screening post-CRE infection or colonization remains unknown, with some groups going so far as to recommend indefinite contact precautions [9]. A minority of studies assessed the role of environmental cleaning with two of three showing a decrease in CRE infection [10, 14, 17]. These studies could not conclude which agents were the best to use for cleaning purposes but did find that education of cleaning staff to be an important aspect of compliance with appropriate environmental cleaning. With respect to transplant recipients, acquisition of CRE from donors is a unique and significant risk, and it has been shown that hospitalization as short as two days is adequate for donor acquisition of a resistant organism that can be transmitted by transplantation [22, 23]. Communication gaps between facilities had been associated with adverse patient outcomes; therefore, inter-facility communication of CRE infection or colonization forms an essential strategy to reduce acquisition of CRE in these patients [24]. Collectively, these data support the use of multimodal approaches of infection prevention and control to prevent CRE infection and colonization. The relative contribution of any one intervention is difficult to ascertain from the existing literature, and guidelines strongly support a combination of measures [5, 11, 25]. Given the state of the current evidence and the limited number of available studies, it is perhaps not surprising that there are mixed levels of implementation across centers and countries when clinicians are surveyed [26]. Significant knowledge gaps regarding best practice remain and include optimal timing and methods of CRE screening, cost-effectiveness of screening in transplant cohorts, and the longitudinal dynamics of CRE colonization and risk factors for extended colonization.

Peri-Transplant Management and Donor-Derived CRE Infections

Multiple reports have illustrated the potentially devastating consequence of unrecognized transmission of CRE from donor to recipient typically due to the delays in laboratory processing coupled with the often urgent nature of organ procurement from a potential donor [27, 28••, 29,30,31,32,33]. Mularoni et al. described the experience of an Italian centre where 14% of 214 recipients received an organ from a CRE-infected or -colonized donor [32]. Errico et al. demonstrated that 3.4% of 588 lung and liver donors were colonized with CRE at the time of transplant [28••]. Of the recipients, 5% became CRE-colonized after transplant and occurred exclusively in lung recipients from donors with respiratory tract colonization and 1.9 and 5.3% of liver and lung recipients, respectively, developed CRE infection. Goldberg et al. described two recipients, each of a single lung from a donor whose colonization with a carbapenem-resistant Klebsiella pneumoniae (CRKP) was identified 48 h after successful donation, and, despite directed therapy, one of the recipients died of overwhelming and disseminated CRKP bacteremia [31]. Galvano et al. described a heart transplant recipient from a donor found to have colistin-resistant CRKP bacteremia, identified five days after donation. Despite optimization of multi-drug therapy, the patient developed disseminated infection leading to death [29]. As it stands, transplant institutions have varied guidelines about accepting organs from CRE-colonized or -infected donors. Physician acceptance varies based on infecting organism, type, or organ being transplanted and, in particular, differentiating between colonization versus infection. A survey of ID Physicians from the American Society of Transplantation Infectious Diseases Community of Practice found that only 10% of clinicians said they would accept an organ from a donor with CRE bacteremia [34].

These reports highlight the importance of optimal perioperative management where appropriate and directed therapy based on donor cultures is paramount. Mularoni et al. assessed the outcomes of 30 transplant recipients of organs from donors that were either colonized or infected with carbapenem-resistant organisms (CRO) [32]. The recipients were divided into low risk, defined as those receiving organs from donors where the CRO infection/colonization was of a non-transplanted organ, and high risk, defined as receiving an organ from a donor with either CRO bacteremia or infection/colonization of the transplanted organ. Of the 16/30 low-risk recipients, no CRO transmission occurred. Of the 14/30 high-risk recipients, eight received appropriate antibiotic therapy that was started in the first 6 days after transplantation and was continued for > 7 days. No transmission was reported for these eight patients. The remaining six patients received inappropriate therapy, or therapy was started > 7 days after transplantation or continued for < 7 days, and transmission occurred in four of these recipients. In the four recipients where transmission occurred, three developed infection, with one death related to overwhelming sepsis due to the transmitted CRE organism. The reported reasons for the inappropriate or delayed therapy in these six recipients were under-estimation of the risk and miscommunication of donor microbiology results.

Optimized communication between organ procurement agencies and transplanting centers must be prioritized to prevent delays in targeted therapy. The decision of whether to transplant an organ from a potential donor who is known to be colonized or infected with CRE requires careful consideration. The risk of transmission appears low for donors that have localized CRE infection or colonization of a non-transplanted organ [23, 32, 35]. The highest risk of transmission is in donors who have CRE bacteremia and infection or colonization of the transplanted organ, such as respiratory tract colonization in a lung donor or gastrointestinal tract colonization in a bowel or pancreas transplant [33]. With the advent of newer and more effective therapies with activity against CRE, as described in subsequent texts, recommendations may become more liberal with regard to accepting such donors.

Although the American Society of Transplantation Infectious Diseases Community of Practice does not routinely recommend antimicrobial therapy for recipients of allografts from donors with non-bacteremic, localized infection of other organs, a careful risk–benefit evaluation in the case of donor colonization or infection with CRE is recommended [36, 37]. A Working Group of the Israeli Society for Infectious Diseases recommended administering at least 48 h of active targeted therapy to the donor prior to transplantation in this setting, as well as at least three days of targeted therapy to the recipient, starting one hour before the transplant [35]. The Spanish Society of Transplant (SET), the Group for Study of Infection in Transplantation of the Spanish Society of Infectious Diseases and Clinical Microbiology (GESITRA_EIMC), and the Spanish Network for Research in Infectious Diseases (REIPI) recent guidelines for management of CRE in SOT recommend that recipients should receive a minimum of 7 days of effective antibiotics post-transplant and that consideration should be given to avoiding kidney donation from a patient with a CRE-related UTI or lung donation from a patient with CRE-related lower respiratory tract infection or any patient with a CRE bacteremia entirely [5]. Given reports of CRE infections occurring in recipients of organs from donors who were thought to only have localized infections of other organs, prophylactic targeted therapy to the recipient and donor, where feasible, is likely prudent [38].

New Antibiotics to Treat CRE Infections

Prospective clinical trials are still lacking to guide best practice in treatment of CRE infections. Established treatments often include polymyxins, tigecycline, aminoglycosides, and fosfomycin, often in combination; but, here, we will cover the newer antibiotic options.

Ceftazidime–Avibactam

The addition of avibactam, a diazabicyclooctane β-lactamase inhibitor, to ceftazidime improves the inhibitory activity of ceftazidime towards many resistant Gram-negative bacteria, including those producing classes A and C and some class D β-lactamases, including Klebsiella pneumoniae carbapenemases (KPCs) [39,40,41,42,43,44]. Unfortunately, ceftazidime–avibactam lacks meaningful activity against any of the class B metallo-beta-lactamases (MBLs) [43]. Castanheira et al. demonstrated that 99.3% of 456 Enterobacteriaceae isolates carrying blaKPC collected across US hospitals were susceptible to ceftazidime–avibactam, while de Jonge et al. similarly found 98.7% susceptibility in 609 carbapenem-resistant, non-MBL-producing isolates, the majority of which were KPC producing [40, 44]. Ceftazidime–avibactam is currently approved by the U.S. Food and Drug Administration (FDA) for the treatment of complicated urinary tract and intra-abdominal infections and hospital-acquired and ventilator-associated pneumonia.

Although limited to case reports and small series, the data supporting ceftazidime–avibactam efficacy in multidrug-resistant (MDR) Gram-negative infections in solid organ transplant recipients is accumulating [45]. Jacobs et al. detailed the case of a 47-year-old female who was administered ceftazidime–avibactam as part of a triple drug regimen for the treatment of a KPC3-producing K. pneumoniae intra-abdominal abscess and bacteremia post-kidney–pancreas transplant [46]. The patient ultimately succumbed to complications but successfully cleared the bacteremia while on combination therapy. Carmargo et al. described a 64-year-old female with KPC-producing K. pneumoniae successfully treated with ceftazidime–avibactam after multiple lines of therapy failed to resolve a peri-pancreatic collection after small bowel transplant [47]. Caravaca-Fontan et al. detailed a patient with recurrent KPC-producing K. pneumoniae urinary tract infection after kidney transplant successfully cured of recurrence after treatment with ceftazidime–avibactam [48]. In terms of larger case series, Shields et al. reported a single-center retrospective experience of 109 patients with carbapenem-resistant K. pneumoniae bacteremia (97% blaKPC), with 40 (36.7%) being solid organ transplant recipients [49]. They reported that the administration of ceftazidime–avibactam, either as monotherapy or as part of combination regimen, was associated significantly with clinical success and survival compared to alternative regimens. In an Italian series, Tumbarello et al. reviewed all cases of infections due to KPC-producing K. pneumoniae infection treated with ceftazidime–avibactam as salvage therapy where 35 of 138 patients were organ transplant recipients [50]. The majority of these patients were bacteremic; one third occurred in the ICU and all received ceftazidime–avibactam as part of a multidrug salvage regimen. In this cohort, treatment with ceftazidime–avibactam either as monotherapy or as part of a multidrug regimen was independently associated with survival compared to historical controls.

Emergence of resistance has been described in recipients of SOT receiving ceftazidime–avibactam [51, 52]. While wild-type blaKPC-3 and mutations in outer membrane porins have been described in sporadic cases of resistance, prolonged therapy with ceftazidime–avibactam has been linked to mutations in the blaKPC-3 gene [51, 53]. For this reason, the authors would recommend ensuring in vitro susceptibility has been determined prior to empiric therapy and consideration be given to repeat testing if infection seems to respond poorly to therapy. Other risk factors for development of resistance, including in SOT recipients, include obesity, renal replacement therapy, and treatment of pneumonia [41, 51, 52, 54, 55]. In general, ceftazidime–avibactam has been associated with lower rates of toxicity and adverse effects compared to comparator agents, including aminoglycosides, colistin, and tigecycline [56]. No specific risks to solid organ transplant recipients have been identified, and the body of evidence, albeit limited, supports the efficacy of this agent in this patient population as part of either single or combination therapy. Further work defining the pharmacokinetics/pharmacodynamics and optimized dosing of ceftazidime–avibactam in organ transplant recipients would still be welcomed [57,58,59].

Meropenem–Vaborbactam

Vaborbactam is a cyclic boronic acid pharmacophore β-lactamase inhibitor that has demonstrated potent in vitro inhibition of class A and C enzymes that, in combination, has increased the potency of meropenem > 64-fold [60, 61]. Meropenem–vaborbactam has no activity against MBLs or oxacillinases, but, it appears to have potent inhibitory activity against KPC-producing Enterobacteriaceae [60,61,62]. Meropenem–vaborbactam has been shown to have lower minimum inhibitory concentrations (MICs) than ceftazidime–avibactam against KPC-producing strains, and less than 25% of ceftazidime–avibactam-resistant strains are resistant to meropenem–vaborbactam [61]. While ceftazidime–avibactam resistance has been described in blaKPC-3-producing organisms, this vulnerability does not appear to exist for meropenem–vaborbactam [61, 63]. Meropenem–vaborbactam has received FDA approval for the treatment of complicated urinary tract infection and acute pyelonephritis based on a large, phase 3 clinical trial that demonstrated non-inferiority to piperacillin–tazobactam for these indications [64]. TANGO II, an open-label randomized control trial comparing meropenem–vaborbactam to best available therapy for known or suspected CRE infection, showed that patients randomized to meropenem–vaborbactam had increased clinical cure and trends towards decreased nephrotoxicity and mortality [65]. This trial was terminated prematurely by the Data Safety Monitoring Board, who deemed that randomization to the best available therapy arm would not be in the best interest of study participants. This trial did not exclude solid organ transplant recipients and analyzed 19 immunocompromised patients, although the exact number of solid organ transplant recipients was not reported.

Imipenem–Relebactam

Relebactam is a novel β-lactamase inhibitor, structurally similar to avibactam, with activity against class A (including KPC-type carbapenemases) and C β-lactamases. When combined with imipenem/cilastatin, relebactam significantly improves the spectrum of activity, reducing the MIC by up to 128-fold, including for isolates producing KPC enzymes [62, 66,67,68]. While early-phase data suggests that imipenem–relebactam is safe and well-tolerated, phase III clinical data is currently lacking [69].

Aztreonam–Avibactam

As described previously, the new beta-lactamase inhibitors are welcome news for the treatment of class A carbapenemases, such as KPC, but all are limited by their lack of activity against MBL enzymes. While KPC carbapenemases predominate globally, the prevalence of the more difficult to treat MBL-producing organisms is increasing. These carbapenemases render almost all antibiotics ineffective; however, when other beta-lactamases are not present, MBLs remain susceptible to the monobactam, aztreonam. This led to the innovative combination of aztreonam–avibactam. The avibactam can inhibit other class A, C, and some D beta-lactamases, which allows the aztreonam to be active against the MBL. Like other newer β-lactam/β-lactamase inhibitor combinations, significant aztreonam–avibactam potency towards MBL-negative Enterobacteriaceae has been demonstrated in vitro [70,71,72]. More excitingly, however, is that this combination has demonstrated improved activity against difficult-to-treat MBL-producing organisms, including IMP-, VIM-, and NDM-type MBLs [70, 73, 74]. Chew et al. showed that the addition of avibactam to aztreonam restored susceptibility of aztreonam in 98.6% of 70 carbapenem-resistant, dual-carbapenemase-producing (including MBL-producing) Enterobacteriaceae [73]. Marshall et al. demonstrated a significant reduction in ceftazidime/avibactam MIC in 21 ceftazidime/avibactam-resistant, MBL-producing Enterobacteriaceae with the addition of aztreonam to a multidrug regimen [75]. Shaw et al. recently detailed the experience of treating 10 patients, four of whom were solid organ transplant recipients, with NDM-1-producing K. pneumoniae as part of an outbreak with the combination of ceftazidime/avibactam and aztreonam [76•]. Evidence of synergy was demonstrated in vitro prior to therapy, and treatment was associated with a 60% success rate without adverse effects.

Other Agents

Early-phase studies have now been completed for several other new agents with promise against CRE infections; however, the inclusion of solid organ transplant recipients in these studies is limited. These include the new aminoglycoside, plazomicin, which is not degraded by the aminoglycoside-modifying enzymes and therefore has a greater spectrum of activity [77]. It is important to note however that plazomicin is not active against organisms that have a ribosomal methylase, which confers resistance to all aminoglycosides [78]. Ribosomal methylases have often been reported with NDM-type MBL-producing isolates [79]. The CARE trial, a randomized comparison of plazomicin to colistin as part of a multidrug regimen for CRE infections (where the majority were blood-stream infections), recruited a small number of patients but found that plazomycin was associated with improved survival and microbiological clearance compared to colistin [80]. Despite this, recruitment was difficult and small numbers of patients were enrolled, limiting the study’s statistical power. There is limited experience in transplant recipients, and nephrotoxicity remains a concern [81]. Another agent that is a modification of an existing class is the tetracycline derivative, eravacycline. Eravacycline is a modified tigecycline that can be administered orally or intravenously and has activity against CRE pathogens with a 1–2-fold lower MIC than tigecycline against these organisms [82]. Finally, a new and exciting agent in the pipeline is a siderophore cephalosporin known as cefiderocol. This antibiotic exploits the active iron uptake system of bacteria to reach its target and appears to have activity against KPC, OXA, and MBL-producing Enterobacteriaceae [83, 84]. We eagerly await clinical studies involving patients, and in particular transplant recipients, with CRE infections.

Combination Antimicrobial Therapy for CRE Infections

Combination antibiotic therapy has been associated with improved clinical and microbiological outcomes when treating KPC Enterobacteriaceae in patients with pneumonia and severe sepsis [85,86,87,88,89]. However, robust prospective clinical trial data have been limited, with recommendations based on retrospective series with significant clinical heterogeneity. Results of the AIDA trial, an open-label randomized trial comparing colistin monotherapy to colistin and infusional meropenem for the treatment of carbapenem-resistant, colistin-susceptible Gram-negative infections, were recently presented in the Lancet [90•]. In this cohort of 406 patients, combination therapy was not found to be superior to monotherapy. However, the majority of infections were caused by Acinetobacter baumannii, and there was a lack of therapeutic drug monitoring to ensure PK/PD targets were met. While numbers were too few to reach significance, there was a trend to fewer microbiological failures and deaths in those with Enterobacteriaceae infections who received combination therapy. Plans to compile results from the similarly designed Trial for the Treatment of Extensively Drug-Resistant Gram-negative Bacilli (NCT01597973) after completion of enrolment are described by the authors in an attempt to improve the power to detect a difference in the Enterobacteriaceae subgroup. While robust clinical data is currently lacking, evidence for antibiotic synergy has consistently been demonstrated in vitro for a wide range of combinations, including the newer agents described previously [66, 74, 75, 91,92,93]. Further studies evaluating the efficacy of combination therapy for CRE infections, including in transplant recipients, would be greatly welcomed.

Antimicrobial Pharmacokinetics Relevant to Solid Organ Transplant Recipients

Solid organ transplant recipients are vulnerable to sepsis and critical illness, increasing their risk for altered pharmacokinetics (PK) and antimicrobial failure [94,95,96]. β-lactams are hydrophilic, making them susceptible to the physiological effects of such critical illness, which include alterations in the volume of distribution (Vd) secondary to fluid resuscitation, perturbations in serum albumin, and capillary permeability [97,98,99]. Similarly, renal drug clearance may either be augmented or reduced, leading to either an increase or decrease in β-lactam clearance, respectively [97,98,99]. The efficacy of β-lactams is proportional to the time non-protein-bound drug spends above the MIC, with maximal bacterial killing and clinical efficacy occurring at target concentrations 4 × MIC [100, 101]. However, these correlations are based on animal models that used susceptible bacteria [99]. This work did not account for rising antimicrobial MICs and the profound physiological alterations that occur during critical illness and transplantation. Dose optimization of β-lactams via extended and continuous infusions has been an active area of research to assess their impact on patient outcomes; however, solid organ transplant recipients only form a small sub-group of these studies [95, 101,102,103].

Transplant recipients often require organ supports, including renal replacement therapy and extracorporeal membrane oxygenation (ECMO), both of which are associated with significant perturbations in the PK of β-lactam and other antibiotic classes. The circuitry of ECMO has been associated with antibiotic extraction, particularly affecting lipophilic and protein-bound drugs, while hemodilution increases the volume of distribution. However, the extent to which these changes affect β-lactam PK is less clear [104,105,106]. While limited evidence suggests that meropenem may achieve more favorable PK compared to piperacillin/tazobactam in the setting of ECMO, data to guide optimal therapy with any of the newer agents is scarce [104, 107].

Barriers to optimal antimicrobial PK vary between organs. For example, recipients undergoing lung transplant for cystic fibrosis (CF) experience significantly increased renal clearance compared to healthy controls [108]. Infection in the lung allografts also presents a significant PK barrier. Penetration of β-lactams into the pulmonary epithelial lining fluids (ELF) varies dramatically, with ceftazidime, meropenem, piperacillin, and imipenem reported to be 20, 30, 50, and 55%, respectively [99, 101, 109, 110]. Regarding the newer antimicrobials, ELF/plasma area under the curve (AUC) ratios improve when meropenem is combined with vaborbactam and when ceftazidime is combined with avibactam, while the ELF/plasma AUC ratio for ceftolozane/tazobactam appears to be about 48% [69, 111, 112]. Imipenem/cilastatin and relebactam have both been shown to have similar ELF/plasma AUC ratios of around of 55%. The penetrative potency into the pulmonary parenchyma in addition to strong anti-pseudomonal activity support these new agents as potentially important options for patients with difficult-to-treat pseudomonal respiratory tract infections [110].

In liver transplantation, significant physiological perturbations occur early post-transplant that influence antimicrobial PK, including rapid improvement in hepatic metabolic and synthetic function, volume status, and hemodynamics, particularly in cirrhotics [113]. Hepatic metabolic function continues to improve over time, including a normalization of albumin and restoration of hepatic allograft blood flow leading to a subsequent increase in hepatic drug clearance [114]. After heart transplant, changes in the cardiac index and stroke volume occur, theoretically increasing hepatic and renal blood flow. However, the real time effects of antibiotic drug clearance have not been quantified [114]. Early post-kidney transplant, cardiac index decreases, the effect of which is further exacerbated if an arteriovenous fistula remains in situ [115]. Despite significant physiological changes occurring in each organ type early post-transplant, the effects of antimicrobial PK in non-critically ill or septic organ transplants have not been determined. Further work is needed to clarify the differences that may compromise optimal therapeutic attainment and represent opportunities for organ-specific intervention. Furthermore, as laboratory resources and capacities expand to facilitate and support real-time therapeutic drug monitoring of antimicrobials, this will likely become a more integral component of antibiotic therapy, particularly for transplant recipients.

Future Perspectives

Colonization with CRE, which is a risk factor for subsequent invasive infection plus transmission to other patients, predominately occurs within the gut, and it would appear that gut dysbiosis, or disruption of the gut microbiome, increases the risk for colonization with multidrug-resistant bacteria [98, 116, 117]. In essence, a healthy gut microbiome can act to resist colonization with antimicrobial-resistant pathogens, also termed “colonization resistance.” [118] Disruption to the gut microbiome is common in transplantation due to recurrent exposures to antimicrobials, immunosuppression, and repeated contact with healthcare [119, 120]. This leads to the idea of gut microbiome protection or restoration as preventative strategies against gut dysbiosis.

In terms of gut microbiome protection, an exciting and novel approach has emerged with the advent of orally administered recombinant β-lactamase enzymes. Fifty percent of transplant recipients will experience a bacterial infection post-transplant with many receiving broad-spectrum antibiotics during the peri-transplant period, leading to antibiotic-induced dysbiosis and promotion of resistant bacterial overgrowth [121,122,123]. Recombinant oral β-lactamase enzymes have been developed that hydrolyze penicillins and cephalosporins but are not systemically absorbed and therefore only function within the gut [123, 124]. These agents are designed to be administered concurrently with intravenous beta-lactams, to protect the gut microbiome from the effects of systemic antibiotics. While in their infancy, these therapies present a particularly attractive strategy in transplant recipients who experience multiple infections requiring multiple courses of antimicrobials [124, 125, 126•].

In terms of gut microbiome restoration, microbiome-modulating therapy has been reported on to improve “colonization resistance” against drug-resistant bacteria. Wong et al. undertook a pooled analysis from 101 patients (18 studies) that underwent fecal microbiota transplantation (FMT) and found that 82% achieved decontamination or significant reduction in carriage of multidrug-resistant bacteria [127]. Based on favorable results with FMT in patients with C. difficile, interest in microbiome-modulating therapies is increasing [128,129,130,131]. As it stands, there is insufficient evidence to recommend FMT in transplant recipients as a strategy to either reduce carriage with multidrug-resistant bacteria or risk of subsequent infection, and there are significant theoretical risks in transplanting fecal flora into the immunocompromised. A number of trials are underway to examine whether carriage of MDR organisms in the gut can be reversed in hospitalized patients, including in solid organ transplantation (NCT02816437), the results of which are highly anticipated.

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Acknowledgements

Anton Y. Peleg acknowledges support from an Australian National Health and Medical Research Council Practitioner Fellowship.

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Olivia Smibert and Anoma Nellore declare that they have no conflict of interest.

Michael Satlin consulted for Shionogi and Achaogen and has received grant funding from Allergan and Merck. Anton Peleg has received research grant support through the investigator initiated research grant program from MSD.

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Smibert, O., Satlin, M.J., Nellore, A. et al. Carbapenem-Resistant Enterobacteriaceae in Solid Organ Transplantation: Management Principles. Curr Infect Dis Rep 21, 26 (2019). https://doi.org/10.1007/s11908-019-0679-4

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Keywords

  • CRE
  • CPE
  • Transplant
  • Treatment
  • Gram-negative bacteria