key: cord-0780755-sxwvwb90
authors: So, Miranda; Walti, Laura
title: Challenges of Antimicrobial Resistance and Stewardship in Solid Organ Transplant Patients
date: 2022-04-30
journal: Curr Infect Dis Rep
DOI: 10.1007/s11908-022-00778-1
sha: 8c22f3424ba434b856b2b43f82e6d48c3d5fedc7
doc_id: 780755
cord_uid: sxwvwb90

PURPOSE OF REVIEW: Without effective antimicrobials, patients cannot undergo transplant surgery safely or sustain immunosuppressive therapy. This review examines the burden of antimicrobial resistance in solid organ transplant recipients and identifies opportunities for antimicrobial stewardship. RECENT FINDINGS: Antimicrobial resistance has been identified to be the leading cause of death globally. Multidrug-resistant pathogens are associated with significant morbidity and mortality in transplant recipients. Methicillin-resistant S. aureus affects liver and lung recipients, causing bacteremia, pneumonia, and surgical site infections. Vancomycin-resistant enterococci is a nosocomial pathogen primarily causing bacteremia in liver recipients. Multidrug-resistant Gram-negative pathogens present urgent and serious threats to transplant recipients. Extended-spectrum beta-lactamase-producing E. coli and K. pneumoniae commonly cause bacteremia and intra-abdominal infections in liver and kidney recipients. Carbapenemase-producing Enterobacterales, mainly K. pneumoniae, are responsible for infections early-post transplant in liver, lung, kidney, and heart recipients. P. aeruginosa and A. baumannii continue to be critical threats. While there are new antimicrobial agents targeting resistant pathogens, judicious prescribing is crucial to minimize emerging resistance. The full implications of the COVID-19 global pandemic on antimicrobial resistance in transplant recipients remain to be understood. Currently, there are no established standards on the implementation of antimicrobial stewardship interventions, but strategies that leverage existing antimicrobial stewardship program structure while tailoring to the needs of transplant recipients may help to optimize antimicrobial use. SUMMARY: Clinicians caring for transplant recipients face unique challenges tackling emerging antimcirobial resistance. Coordinated antimicrobial stewardship interventions in collaboration with appropriate expertise in transplant and infectious diseases may mitigate against such threats.

Antimicrobials are life-saving medications that are essential to modern medicine. Antimicrobial resistance (AMR) is a global health threat that requires urgent multisectoral, multinational, and interdisciplinary action to addressthe so-called One Health approach [1, 2] . AMR has been described as the "silent pandemic," further exacerbated by antibiotics used to treat bacterial coinfections and secondary infections associated with the COVID-19 global pandemic [3] [4] [5] [6] . AMR disproportionately affects those who are most vulnerable, including immunocompromised patients and solid organ transplant (SOT) recipients [7] . Without effective antimicrobials, transplant surgery cannot be conducted safely, and antirejection immunosuppressants cannot be implemented, as untreatable infections will negate the life-saving purpose of organ transplantation [7] . This review briefly describes the epidemiology of AMR (among bacterial pathogens) from a global perspective, examines the burden of AMR in SOT recipients, and discusses the challenges in the wider context of the COVID-19 pandemic. It also highlights opportunities for antimicrobial stewardship initiatives in SOT patients to mitigate against the threats of AMR.

This review follows the international consensus published in 2012 for definitions of acquired resistance [8] . Multidrug resistance (MDR) is defined as nonsusceptibility to at least one agent in three or more antibiotic classes [8] . Extensively drug resistance (XDR) is defined as nonsusceptibility to at least one agent in all but two or fewer antibiotic classes (i.e., bacterial isolates remain susceptible to only one or two classes) [8] . Pandrug resistance (PDR) is defined as nonsusceptibility to all licensed, routinely available antibiotics [8] . Although these definitions have some limitations, they have been applied to the SOT population [9] .

Globally, AMR has been identified as a leading cause of death, with the highest burden in low-resource countries [10•] . There are notable regional differences in AMR rates and epidemiology, potentially associated with antibiotic use [7, 10•, 11, 12] . With concerted efforts, AMR rates for some pathogens such as methicillin-resistant Staphylococcus aureus (MRSA) and vancomycin-resistant enterococci (VRE) have stabilized, though primarily in high-income countries only, and not in low-resource settings [10•, 13, 14] . Globally, MRSA have shifted from healthcare settings to the community, whereas VRE remain primarily a nosocomial pathogen [15-18, 19••] . Furthermore, VRE with daptomycin-and linezolid-non-susceptibility have been described [20] . Vulnerable patients, such as those with frequent healthcare exposure due to immunocompromised state, are most at risk for contracting infections caused by MDR organisms [19••, 21, 22, 23••] . In contrast to MRSA and VRE, prevalence of MDR Gram-negative bacilli continues to rise and causes significant morbidity and mortality [24••] . Enterobacterales, mainly Escherichia coli and Klebsiella pneumoniae, are producers of betalactamases, such as cephalosporinases and cabapenemases, whereas non-fermenters such as Pseudomonas aeruginosa carry multiple mechanisms of resistance, and Acinetobacter baumannii resistance is conferred through carbapenemase (CRAB) [ 

Despite a decrease in MRSA infections between 2005 and 2016, they remain concerning for SOT patients [7, 26•] . MRSA infections are most common in liver and lung transplant recipients [26•, 27•, 28] , and the most common syndromes are bloodstream infections, pneumonia, surgical site infections, and intra-abdominal infections [29•] . In liver recipients with S. aureus bacteremia, the prevalence of MRSA ranged from 26.3 to 100% [28] . In a meta-analysis of 23 studies that evaluated infections of MRSA relative to colonization status, 17 (74%) pertained to liver recipients [30] . Pre-transplant, the pooled prevalence of MRSA colonization was 8.5% (95% CI 3.2-15.8%), compared to 9.4% (95% CI 3.0-18.5%) post-transplant [30] . MRSA colonization status was associated with increased risk of infections. The pooled risk ratio of infection was 5.5 (95% CI 2.36-12.90) from pre-transplant colonization and 10.56 (5.58-19.95 ) from post-transplant colonization [30] . In a recent single-center cohort study between 2008 and 2018 of 351 liver candidates, 5.4% (19/351) of the entire cohort were MRSA-positive, among whom two experienced infections [31] . In contrast, a single-center cohort of 369 pediatric SOT patients admitted between 2009 and 2014 found liver candidates to have the lowest risk of being colonized with MRSA (odds ratio 0.22, 95% CI 0.06-0.81), whereas lung candidates had the highest (odds ratio 18.7, 95% CI 1.9-182.3) [32] . Other risk factors for MRSA infections are summarized in Table 1 [26•, [33] [34] [35] [36] [37] .

Vancomycin-resistant enterococcus (VRE) infections have been decreasing between 2012 and 2017 [7, 29 •, 38] . A meta-analysis of VRE colonization status relative to infection rate in SOT patients estimated the pooled prevalence as 11.9% (95% CI 6.8-18.2) [30] . VRE colonization status was associated with infections, and liver recipients were the most commonly affected group [30] . Pre-transplant colonization was associated with VRE infection (risk ratio 6.65, 95% CI 2.54-17.41), as was post-transplant colonization (risk ratio 7.93, 95% CI 2.36-26.67) in a meta-analysis [30] . A singlecenter study of liver recipients identified 35% (123/351) of the entire cohort as VRE-positive, among whom 46% (57/123) experienced VRE infections [31] . A single-center cohort between 2008 and 2017 of 536 liver recipients reported 58 episodes of enterococcal bacteremia among 42 patients (7.8%), and VRE was the causative pathogen in 26 episodes (45%) [39] . Post-transplant dialysis and length of post-transplant hospitalization were associated with VRE bacteremia, with odds ratio 3.95 (95% CI 1.51-10.34) and 1.03 (95% CI 1.01-1.04), respectively [39] . A recent analysis of surgical site infections in liver transplant patients reported to the National Health Care Safety Network between 2015 and 2018 found prevalence of VRE to be 69.4% (84/121) among E. faecium isolates [40] . As VRE remains mainly a nosocomial pathogen, unit-level outbreaks affecting SOT patients have been described, with biofilm formation as a contributing factor [41] . VRE colonization status was not a risk factor for infections in non-liver recipients in a large single-center cohort study [42] . See Table 1 for a summary of risk factors for VRE infections.

Infections due to MDR Gram-negative bacilli (GNB), particularly extended-spectrum beta-lactamase (ESBL) and carbapenemase-producing Gram-negative pathogens, have been on the rise in the last decade and affecting SOT patients [ [23••] . In a five-center serial point-prevalence survey conducted in the USA, 154 patients were screened for CPE between 2019 and 2020, among whom 92 (60%) were SOT patients, and 7 (8%) recipients were colonized [51] . The average rate of infection is estimated to be 10% in liver, 5-10% in lung, and around 5% in kidney recipients, although sources of data are limited to small, single-center studies [ [52] . In a multicenter international cohort study of 60 SOT patients with CRE colonization and/or infection pre-transplant (30 liver and 17 heart recipients), KPC was the most commonly detected CRE organism [53] . Post-transplant infection occurred in 40% (24/60) of the patients, with 62% having surgical site infection and 46% having bacteremia [53] . In a single-center cohort of kidney recipients between 2017 and 2019, prevalence of early (90-day post-transplant) KPC infection was 10.4% (43/419), which included pneumonia, surgical site infections, urinary tract infections, and bacteremia [54] . Site of infection are generally related to the type of graft, potentially with secondary bacteremia [9, 23••] . For liver recipients, intra-abdominal infections such as abscesses, infected bilomas, hematomas, or biliary complications (cholangitis, biliary leakage) are common presentations [9] . Risk factors for CPE infections are summarized in Table 1 

The so-called difficult-to-treat resistant Pseudomonas aeruginosa remains a threat to SOT patients [7, 9, 46 ••, 55••]. Its mechanisms of resistance include efflux pump, plasmidencoded extended-spectrum beta-lactamases, inducible chromosomal cephalosporinase AmpC, carbapenemases (metallo-betalactamases, and oxacillinase), and inactivation of OprD porin [9, 56] . Lung recipients are at high risk of P. aeruginosa colonization, with prevalence estimated to be 28% pre-transplant and 38% post-transplant [57] . Patients with cystic fibrosis (CF) have pre-transplant and post-transplant colonization risks as high as 70%, and re-colonization by the same strain post-transplant was 53% in one study [58] [59] [60] [61] . For non-CF patients, colonization prevalence was reported to be 2.2% and 26% for pre-and post-transplant, respectively [59] . Pneumonia caused by MDR P. aeruginosa was reported in 33% of lung recipients early post-transplant in a retrospective study [62] , and complications such as fatal empyema have been described [63 •, 64] . SOT is a risk factor for antibioticresistant P. aeruginosa bloodstream infection [65] , which accounted for 37-63% of P. aeruginosa bacteremia in SOT patients [66, 67] . The incidence of P. aeruginosa bacteremia in liver recipients ranged from 0.5 to 14.4%, and carbapenemand quinolone-resistant P. aeruginosa was reported in 12.7% of patients, whereas the prevalence of XDR P. aeruginosa isolates was 9.3% [67] [68] [69] . Another study of abdominal transplant recipients with P. aeruginosa infections reported the prevalence of MDR isolates to be 46.3% (25/54) [70] . Risk factors for MDR or XDR P. aeruginosa infection are summarized in Table 1 [9] .

Carbapenem-resistant Acinetobacter baumannii (CRAB) is a critical threat in healthcare-associated infections [7] . Data describing the overall prevalence of CRAB colonization and infections in SOT patients are limited, and while geographical variation has been described, the prevalence in the USA appears to be low [9, 46••] . In a cohort of abdominal transplant recipients in China between 2013 and 2020, carbapenem-resistant Gram-negative pathogens were reported 10.5% (153/1452) of patients, and CRAB accounted for 31% (47/153) of the isolates [71] . A single-center study in Turkey of 41 SOT recipients with A. baumannii infections between 2011 and 2017 reported 58.5% and 41.5% of the isolates to be MDR and XDR, respectively [72] . In a cohort of lung recipients in South Korea between 2012 and 2016, 57% (55/96) had A. baumannii infections, and among those isolates, 93% (51/55) were MDR [73] . Risk factors for antibiotic-resistant A. baumannii infections are summarized in Table 1 [73, 74] .

In patients with CF, Burkholderia cepacia complex (BCC), particularly B. cenocepacia, are associated with accelerated pulmonary function decline [75, 76] . Pre-transplant colonization and infection with BCC is associated with posttransplant infection, chronic allograft dysfunction (CLAD), and poor survival outcomes compared to BCC-negative status [75, 76] . BCC tend to localize within macrophages, which may contribute to discordance between treatment response and in vitro susceptibility [75] . Resistance to aminoglycosides, fluoroquinolones, sulfamethoxazole-trimethoprim (SMX-TMP), ceftazidime, and meropenem necessitates combination therapy, including ceftazidime-avibactam [46••, 77] . Local epidemiology varies, with incidence of BCC in Canadian centers being higher than in the USA (7.2% vs. 4.5%) [75] . Facility outbreaks have been described, highlighting the risk of nosocomial transmission [75] . Similar to BCC, Stenotrophomonas maltophilia is a therapeutic challenge, with options for susceptible strains limited to SMX-TMP and levofloxacin, while potential alternatives for emerging resistance may include minocycline, levofloxacin, ceftazidime, or ceftazidime-avibactam [ 

Donor-derived infections are defined as any infection present in the donor that is transmitted to one or more recipient [78••] . There are several possible ways donors colonized or infected with MDR organisms may impact transplant recipients: acceptance for organ utilization, modification of peritransplant surgical antibiotic prophylaxis regimens targeting MDR organisms, and selection of empirical antibiotic regimens for donor-derived infections [ [87] . Isolation of resistant multidrug-resistant Gramnegative organisms from donor respiratory culture does not impact non-lung transplant recipient [88] .

Colonization and infections due to MDR organisms are associated with major impact on the outcomes of SOT recipients. However, in the absence of network-based, prospective registry data, the quality of available reports was limited by lack of standardized definitions to attribute morbidity and mortality to MDR organisms. Many were subject to bias due to retrospective, single-center design over varying study periods. For CPE infections, the reported mortality post-transplant rates varied. Driven by local epidemiology, depending on organ type, and infectious syndromes, the 1-year mortality ranged from less than 10% to over 80%, which was significantly higher than patients without CPE infections [23••, 43••, 52] . For ESBL-producing Gram-negative infections in liver and kidney transplant patients, bacteremia-related mortality was 26% [89] . Among patients with MRSA bacteremia, transplant status was not associated with higher 90-day mortality (adjusted odds ratio 0.74, 95% CI 0.44-1.25), but was associated with higher risk of septic shock and acute respiratory distress syndrome in a retrospective single-center study [90] . Others have reported higher long-term (1-year) mortality rate in lung recipients with MRSA infections compared with those who had methicillin-susceptible S. aureus infections [91] . Among heart transplant recipients, relative to those without infections, MDR pathogens and XDR pathogens infections were associated with 11-fold and 26-fold higher hazards of death, respectively [92•] . In a singlecenter study from 2011 to 2016, the most common MDR pathogens were ESBL-E. coli and K. pneumoniae, while P. aeruginosa and carbapenem-resistant K. pneumoniae were the most common XDR pathogens [92•] . In liver recipients, colonization and infection with MDR organisms were associated with increased risk of death (hazard ratio 2.57, p < 0.001) [31] . In kidney recipients, bacteremia due to P. aeruginosa, but not other MDR pathogens, was a significant risk factor for unfavorable outcome (defined as death, graft nephrectomy, or return to dialysis), adjusted OR 46.11 (95% CI 3.9-552.2) [50] . Others reported carbapenem-resistant K. pneumoniae infection to be an independent risk factor for 1-year mortality, OR 6.75 (95% CI 1.05-43.4) [54] .

SOT candidates and recipients have been affected by the direct risks of COVID-19 infection, as well as the secondary effects from the pandemic. Overall decrease in resources available at hospitals has led to reduction in non-urgent surgery and outpatient care, potentially adding to the negative impact on the mental status of SOT patients, contributing to decreased adherence to medical appointments [93] [94] [95] . Another potential impact has been a decrease in living and deceased organ donation worldwide, and its deleterious effect on transplant candidates' waitlist on morbidity and mortality [96] [97] [98] . Effects of the pandemic on AMR in general and subpopulations like SOT are difficult to predict. Increased antimicrobial use in COVID-19 patients could attribute to emergence of resistance [99, 100 •] . The overall prevalence of bacterial coinfection was estimated to be approximately 7%, and higher at 8.1% in critically ill patients, yet 70% of patients received antibiotics [5, 6, 101•] . As a result of efforts to tackle the pandemic, resources for infectious diseases, antimicrobial stewardship (AMS), and infection prevention and control were stretched to their limits. In spite of that, recent European and UK surveillance data reported a decrease in AMU over the last 2 years [102, 103] .

Severe COVID-19 infection with respiratory failure requiring prolonged mechanical ventilation or use of extracorporeal membrane oxygenation is associated with an increased risk of secondary infections and emergence of MDR pathogens [101•, 104, 105•] . Most studies addressing severely ill COVID-19 patients reported high rates of MDR pathogens [106•, 107] . Furthermore, COVID-19 patient unit-level outbreaks due to MDR pathogens have been reported [108] [109] [110] . In contrast, decline in MDR rates for the entire hospital was reported in an Italian hospital [111] . Lung transplantation has emerged as a long-term solution for COVID-19 patients with non-reversible lung fibrosis [112] [113] [114] . Since these patients have had heavy exposure to the healthcare environment and high pretransplant infection rates, MDR rates in this population is potentially higher than non-COVID lung recipients [112] . Although short-term outcome seems similar in the limited literature when compared to lung transplant for other indications, long-term data are missing and most studies did not specifically report on infections in the posttransplant period [112, 114] . The overall effect of the pandemic on AMR remains to be determined. Changes in the local epidemiology in healthcare settings could potentially lead to higher risks of acquisition of MDR pathogens among exposed individuals such as SOT recipients.

Antimicrobial stewardship (AMS) is defined as a coordinated set of interventions to improve and measure the appropriate use of antimicrobials by promoting the selection of the optimal antimicrobial regimen including dosing, duration of therapy, and route of administration [115•] . While new antimicrobials targeting MDR pathogens have become available in the last few years, clinicians are urged to be judicious in prescribing these agents to preserve their effectiveness [24 ••, 25••, 116] . Furthermore, global shortage of antimicrobials remains an ongoing challenge in healthcare [117] . Facing MDR and antimicrobial shortage, clinicians have had to resort to less desirable antimicrobials with worse adverse effects profile, such as polymixins or tigecycline [24••, 25••] . Clinicians may also need to mitigate complex interactions between immunosuppressants and antimicrobials, carefully balancing the need to treat an infection with the goal of minimizing negative impact on the allograft. For it would be extremely unfortunate for a patient, after receiving a life-saving/altering organ transplant, only to lose the allograft or worse, succumb to an infection caused by an antibiotic-resistant pathogen. To ensure sustainability of safe and effective antimicrobials for current and future patients, coherent actions to promote responsible use of antimicrobials under the auspices of quality improvement are crucial [118] .

Quality assurance programs from the US Center for Disease Prevention and Control (CDC), the Centers for Medicare and Medicaid, The Joint Commission, UK's National Institute for Health and Care Excellence, and Accreditation Canada, among others, have established quality standards for AMS programs across a wide spectrum of patient settings, including institutional and outpatient care [ 

Appoint a leader or co-leaders, such as a physician and pharmacist, responsible for program management and outcomes Reporting of AMS activities and key performance indicators that reflect interventions implemented in SOT patients

Appoint a pharmacist, ideally as the co-leader of the stewardship program, to lead implementation efforts to improve antibiotic use

Determine key performance indicators that are feasible, valid, and meaningful for local key stakeholders in SOT Ensure key performance indicators reflect interventions implemented in SOT patients

Implement interventions, such as prospective audit and feedback or preauthorization, to improve antibiotic use Priority interventions include prospective audit and feedback, preauthorization, and facility-specific treatment recommendations. 126] . A cross-sectional study of hospitals from 10 states in the USA evaluated the appropriateness of antimicrobial use in 1566 patients; immunocompromised patients (including SOT and stem cell transplant recipients) accounted for < 5% of the study cohort [126] .

In 2020, 91% of hospitals in the USA have met all core elements of AMS programs recommended by the CDC [127••] . Therefore, leveraging existing framework and building on AMS programs already in place may be an efficient use of resources to address the unique AMS needs of SOT patients. Potential "add-on" components may include adding expertise in SOT and transplant infectious diseases to the interdisciplinary AMS team, monitoring and reporting antimicrobial use in SOT care units, and investing in resources to engage SOT leadership and clinicians to become stakeholders in SOT-specific AMS interventions [19••] . Locally developed guidelines constitute a key AMS strategy; therefore, focusing on organ-specific guidelines tailored to the SOT program's epidemiology could be a reasonable starting point [19••, 115•] . Adjudication of adherence to surgical prophylaxis guidelines in transplant procedures is another reasonable intervention, focusing on organ-specific guidance [128, 129•] . Specific to the USA, the current National Healthcare Safety Network Antimicrobial Use Option Report does not include data from SOT care units for benchmarking, although this may change in the future. Potential interventions tailored to SOT patients within an existing hospital-based AMS program are summarized in Table 2 [19••, 119••]. Beyond the in-patient setting, antimicrobial prescribed in the ambulatory clinics, where SOT patients receive often life-long care and follow-up monitoring, presents a crucial opportunity to explore the next horizon of AMS in SOT patients.

Rising antimicrobial resistance, particularly among difficultto-treat Gram-negative pathogens, brings unique challenges to clinicians caring for SOT patients. While new antimicrobial agents targeting these pathogens have become available in recent years, without a coherent approach to ensure optimal and judicious use, they are at risk of losing their effectiveness due to emerging resistance. Antimicrobial stewardship programs tailored to the specific needs of SOT patients are important strategies to mitigate such threats to patient care.

Conflict of Interest Miranda So and Laura Walti do not have any conflict of interests to disclose.

This article does not contain any studies with human or animal subjects performed by any of the authors.

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Multidrug resistence prevalence in COVID Area

Impact of the COVID-19 pandemic on the incidence of multidrug-resistant bacterial infections in an acute care hospital in Brazil

Increased risk of acquisition of New Delhi metallo-beta-lactamase-producing carbapenem-resistant Enterobacterales (NDM-CRE) among a cohort of COVID-19 patients in a teaching hospital in Tuscany

Emerging co-pathogens: New Delhi metallo-beta-lactamase producing Enterobacterales infections in New York City COVID-19 patients

An outbreak of carbapenem-resistant Acinetobacter baumannii in a COVID-19 dedicated hospital

Reduction of multidrug-resistant (MDR) bacterial infections during the COVID-19 Pandemic: a retrospective study

Early outcomes after lung transplantation for severe COVID-19: a series of the first consecutive cases from four countries

Lung transplantation for patients with COVID-19

Lung transplantation for acute COVID-19: the Toronto Lung Transplant Program experience

Implementing an antibiotic stewardship program: guidelines by the Infectious Diseases Society of America and the Society for Healthcare Epidemiology of America

The GAIN Act legislation to combat antimicrobial resistance: where do we stand?

Shortage of essential antimicrobials: a major challenge to global health security

What is antimicrobial stewardship?

Core elements of antibiotic stewardship

Omnibus burden reduction (conditions of participation) final rule CMS-3346-F

• The Joint Commission. New antimicrobial stewardship standard. R3 Report Requirement

• The Joint Commission. Antimicrobial Stewardship in Ambulatory Health Care. R3 report requirement, rationale, reference

Foreword: 4th edition of the American Society of Transplantation Infectious Diseases Guidelines

Infection in organ transplantation

Current state of antimicrobial stewardship at solid organ and hematopoietic cell transplant centers in the United States

Assessment of the appropriateness of antimicrobial use in US hospitals

The AST ID Community of Practice. Surgical site infections: guidelines from the American Society of Transplantation Infectious Diseases Community of Practice

Eliminated routine postorthotopic liver transplant antibiotics in uncomplicated patients leads to equivalent safety outcomes