Management of multidrug resistant Gram-negative bacilli infections in solid organ transplant recipients: SET/GESITRA-SEIMC/REIPI recommendations☆
Introduction
The expectancy and quality of life among patients undergoing solid organ transplantation (SOT) have significantly improved over the previous decades. These advances have stemmed from the development of more potent and safer immunosuppressive drugs and the implementation of clinical guidelines that have made possible to optimize prophylaxis strategies against the main opportunistic microorganisms. However, a major threat to this improvement has emerged from the progressive increase in the incidence of post-transplant infectious complications due to multidrug resistant (MDR) Gram-negative bacilli (GNB) [1]. These include non-fermenting GNB such as Pseudomonas aeruginosa, Burkholderia spp., Stenotrophomonas spp. or carbapenem-resistant Acinetobacter baumannii (CRAB), as well as extended-spectrum β-lactamases (ESBL) and carbapenem-resistant Enterobacteriaceae (CRE), with a special role played by carbapenem-resistant Klebsiella pneumoniae (CRKP) [2], [3]. SOT recipients are particularly vulnerable to developing infections by MDR GNB as they usually face prolonged exposure to the healthcare environment, have frequent requirements for invasive diagnostic and therapeutic procedures, and are commonly exposed to broad-spectrum antibiotics [2], [4], [5]. Long-term post-transplant immunosuppression not only plays a relevant role in enhancing susceptibility to infection, but also in determining the prognosis of such complication through its deleterious effect on the host immune response. On the other hand, the limited therapeutic armamentarium available against these microorganisms often entail the use of potentially nephrotoxic agents, which represents an additional risk for kidney transplant (KT) recipients and other transplant populations with preexisting renal impairment or other concomitant nephrotoxic therapies (i.e., calcineurin inhibitors). Therefore, the therapeutic approach to infections due to MDR GNB in SOT recipients turns out to be particularly challenging as compared to other groups of patients.
In recent years there has been an increase in the simultaneous resistance to multiple antimicrobials in a number of Gram-positive and Gram-negative microorganisms, thus notably limiting the therapeutic alternatives for the infections produced by these pathogens. Although infections produced by Gram-positive microorganisms such as methicillin-resistant Staphylococcus aureus (MRSA) and glycopeptide-resistant Enterococcus spp. (VRE) are frequent in some healthcare settings, newer anti-Gram-positive bacterial agents with excellent in vitro activity and favorable pharmacokinetics and safety profiles are becoming increasingly available [6], [7], [8]. However, the problem with MDR GNB is more worrisome, since some of them have developed mechanisms of resistance against most of, if not virtually all, available antimicrobials. Moreover, it is foreseeable a relative paucity of promising anti-Gram-negative bacterial agents in the pipeline over the next years. Enterobacteriaceae, P. aeruginosa and A. baumannii constitute the GNB in which such therapeutic challenges are more often observed in daily clinical practice and, therefore, the present recommendations will be exclusively focused on them.
Although the resistance of these microorganisms to different antimicrobials may be explained by the selection of chromosomal mutations, the most commonly involved mechanism is by far the acquisition of exogenous genes located in mobile genetic elements (plasmids, transposons). Among these genes, the pivotal role is played by those that code for the production of ESBL, AmpC β-lactamases and carbapenemases [9].
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ESBL. These enzymes can hydrolyze and, therefore, provide resistance to penicillins, aztreonam and all generations of cephalosporins, except for cephamycins (i.e, cefoxitin, cefotetan or cefmetazole). Besides cephamycins, ESBL do not hydrolyze carbapenems, and are inhibited by β-lactamase inhibitors such as clavulanic acid, tazobactam, sulbactam and avibactam. The ESBL-encoding genes can be located in plasmids, thus facilitating horizontal spread from one bacterium to another. There are multiple types of ESBL with agent-specific hydrolysis capacities. In addition to Enterobacteriaceae, ESBL can also be produced by P. aeruginosa and Acinetobacter spp. [10].
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AmpC-type β-lactamases. These enzymes are cephalosporinases encoded on the chromosome of many Enterobacteriaceae and other GNB such as P. aeruginosa and Acinetobacter spp. which confer resistance to first- and second-generation cephalosporins and cefoxitin, as well as to most penicillins and β-lactam/β-lactamase inhibitor combinations (BLBLI). In many Enterobacteriaceae (including Citrobacter freundii, Enterobacter cloacae and Serratia marcescens) and P. aeruginosa, AmpC-type β-lactamases are constitutively expressed at low level, but may be induced under exposure to β-lactams through mutations in regulator genes. The resulting AmpC overproduction may confer additional resistance to third- and fifth-generation cephalosporins, while remaining susceptible to fourth-generation cephalosporins. Genes coding for these enzymes can be also located in mobile plasmids, with the potential for dissemination to other bacteria. Nevertheless, in overall terms AmpC-type β-lactamases are less frequently found in plasmids than ESBL [11].
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Carbapenemases. These enzymes constitute a diverse group characterized by their disparate ability to hydrolyze carbapenems (ertapenem, imipenem, meropenem, doripenem) and confer, in most cases, in vitro resistance to this class of antimicrobials. Carbapenemases fundamentally belong to three different classes according to Ambler's molecular classification: i) class A, mainly KPC-type enzymes; ii) class B or metallo-β-lactamases (MBLs), mainly VIM-, IMP- and NDM-type enzymes; and iii) class D, mainly OXA-48 group. Although most of the carbapenemases also hydrolyze the remaining classes of β-lactams, some of them exerts no significant activity against broad-spectrum cephalosporins (such as cefotaxime and ceftazidime) and aztreonam (i.e., OXA-48-group carbapenemases) while others do not hydrolyze aztreonam (i.e., MBLs). Horizontal transfer via plasmids is the most common mode of dissemination. Carbapenemase producers are mainly identified among K. pneumoniae and Escherichia coli isolates, with a relatively lower contribution to the resistance mechanisms in P. aeruginosa and A. baumannii [12].
Although the term “MDR” literally stands for resistance to more than one antimicrobial, there are currently multiple well-established definitions for MDR, extensive drug-resistant (XDR) and pandrug-resistant (PDR) bacteria, which describe the different patterns of acquired resistance observed in drug-resistant bacteria involved in healthcare-related infections. The present recommendations will use the consensus definitions jointly proposed by the European Center for Disease Prevention and Control (ECDC) and the Centers for Disease Control and Prevention (CDC). This document establishes standardized international terminology to describe acquired resistance profiles in Enterobacteriaceae (excluding Salmonella and Shigella), P. aeruginosa and Acinetobacter spp. Of note, such epidemiologically significant antimicrobial categories do not take into account the intrinsic resistance patterns shown by the different microorganisms (Table 1) [13].
In these consensus definitions for MDR, XDR and PDR bacteria, the different antimicrobial classes are distributed into categories depending on whether they are prescribed against Enterobacteriaceae, P. aeruginosa or Acinetobacter spp. (Table 2) [13].
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MDR. Taking into account the antimicrobial categories specifically established for Enterobacteriaceae, P. aeruginosa and Acinetobacter spp., a microorganism is considered MDR when it shows acquired non- susceptibility (intermediate or resistant) to at least one agent in 3 or more antimicrobial categories (listed in Table 2).
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XDR. A microorganism is considered XDR when it shows acquired non-susceptibility to at least one agent in all but one or two antimicrobial categories (listed in Table 2) (i.e. bacterial isolate remains susceptible to only one or two of the indicated categories for each group of microorganisms).
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PDR. A microorganism is considered PDR when it shows acquired non-susceptibility to all agents in all antimicrobial categories (listed in Table 2).
To ensure that the above definitions are correctly applied, bacterial isolates should be tested against all or nearly all antimicrobial agents within each category. Although these definitions do not necessarily correlate with the presence of the most frequent resistance mechanisms found in Enterobacteriaceae (i.e., ESBL, AmpC-type β-lactamases or carbapenemases), according to these criteria, all isolates of this group harboring such mechanisms must be considered, at least, as MDR.
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Liver transplantation (LT): Infectious complications due to MDR GNB are associated to significant morbidity and mortality among LT recipients [4], [14]. In this group of patients the rate of infection due to ESBL-producing Enterobacteriaceae ranges from 5.5% to 7%, with K. pneumoniae and E. coli as the most common species identified. The incidence of infections by CRE, particularly CRKP, ranges from 6% to 12.9% in some settings. Infection usually occurs at the early post-transplant period (mean of 12–24 days after the transplant procedure). More than half of the cases have an intra-abdominal origin, such as abscesses, infected bilomas, hematomas or biliary complications (i.e., cholangitis, recurrent cholangitis or biliary leakage). Healthcare-associated pneumonia (HCAP) or urinary tract infection (UTI) are other complications that may be caused by CRKP. Skin and soft tissue infections are less common, although cases of necrotizing infection (necrotizing fasciitis or myonecrosis) have been occasionally reported [15]. The mortality of LT recipients diagnosed with infection due to CRKP has been shown to be up to five times higher than that observed for carbapenem-susceptible isolates (CSKP) [16], [17].
In certain series MDR microorganisms are involved in more than half of the cases of GNB bloodstream infection (BSI) in LT recipients (15). The prevalence of this antimicrobial phenotype, however, varies according to the species involved (62.5% for A. baumannii, 54.8% for Enterobacteriaceae, 54.2% for S. maltophilia and 51.5% for Pseudomonas spp.) [18].
On the other hand HCAP, including ventilator-associated pneumonia (VAP), is the most common complication associated with CRAB and MDR P. aeruginosa in LT receptors [19], [20], [21].
Finally, superinfection by MDR GNB in cases of tertiary peritonitis after LT is not uncommon.
Risk factors include pre-transplant fecal carriage of ESBL-producing isolates, surgical reintervention, and a high MELD score (listed in Table 4). All-cause mortality is around 30% and reaches 41% in the presence of BSI [22], [23].
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KT: The urinary tract is the source for most of the post-transplant infections, including BSI, among KT recipients, frequently in form of uncomplicated cystitis (although acute graft pyelonephritis comprises up to one-tenth of the cases). Recurrent UTI represents a common problem that requires ruling out the presence of structural abnormalities such as vesicoureteral reflux, ureterovesical junction stenosis or neurogenic bladder. Infection of renal cysts in KT recipients with underlying renal polycystic disease may also explain UTI recurrence.
In KT recipients, ESBL-producing E. coli accounts for up to 12% of infections, particularly in the presence of simultaneous pancreas transplantation, post-transplant requirement of renal replacement therapy, previous use of antibiotics, or urinary tract obstruction or instrumentation [21]. About 70% of the complications caused by ESBL-producing or AmpC-hyperproducing GNB are UTI, although other potential infection sources include the surgical site (SSI), the kidney cell or the presence of lymphocele or urinary fistulas [24].
CRKP may be responsible for UTI after KT, associated or not with BSI and recurrent episodes [25], [26]. In addition, this microorganism is commonly involved in intra-abdominal infections related to the surgical procedure such as collections, abscesses or hematomas. Similarly to observe among LT recipients, attributable mortality is higher in infections caused by CRKP in comparison to susceptible counterparts.
With regards to MDR P. aeruginosa, the most common clinical manifestations in KT recipients are UTI and HCAP, often complicated by the development of associated BSI [21], [27].
Similarly, CRAB constitutes a not uncommon cause of HCAP, particularly in form of VAP, and is responsible for up to 3% of all the episodes of BSI after KT [19], [20].
Risk factors generally associated with MDR GNB infection in KT recipients include age older than 50 years, hepatitis C virus (HCV) infection, renal replacement therapy after transplantation and surgical reintervention, kidney-pancreas transplantation and post-transplant nephrostomy [14], [15], [18], [21], [24] (listed in Table 4).
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Heart transplantation (HT): HCAP and UTI are the main forms of bacterial infection after HT. The incidence of pneumonia is highest in the first months after transplantation. The most common causative agents are MDR P. aeruginosa, CRAB and MDR S. maltophilia, and associate BSI is also frequent [28].
The incidence of mediastinitis and sternal surgical wound infection after HT is close to 2.5%. Although most episodes are due to Staphylococcus spp., an increasing number of cases of mediastinitis caused by ESBL-producing E. coli [29] or non-fermenting GNB has been reported in recent years [30].
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Lung Transplantation (LuT): Colonization of the respiratory tract by MDR P. aeruginosa during pre-transplant period is especially common in LuT recipients with cystic fibrosis, with a prevalence > 50% that may increase up to 75% after transplantation [5]. On the other hand, P. aeruginosa is the leading cause of HCAP after LuT, accounting for up to 25% of cases [31]. It has been suggested that P. aeruginosa colonization and infection may play a role in the pathogenesis of bronchiolitis obliterans syndrome (BOS) and in the risk of developing bronchovascular fistula, complications that negatively impact medium- and long-term prognosis [32], [33].
Most infections due to CRAB are associated to epidemic outbreaks. HCAP is the most common complication, but UTI, catheter-related BSI and SSI have been also reported [31]. Infectious complications caused by this pathogen frequently entail a high mortality rate among LuT recipients [34].
Burkholderia spp. has been associated with various complications after LuT, such as chronic lung infections, mediastinal abscesses, pleural effusion or chest wall infection [35]. In this group of patients, mediastinitis is also a common complication.
> 50% of all episodes of GNB BSI in LuT are produced by strains with a MDR phenotype, which may account for up to 100% of B. cepacia isolates in this setting [36].
Overall, infections caused by MDR GNB result in a significantly higher attributable mortality than those due to susceptible microorganisms. One study identified the inadequacy of empirical antibiotic treatment and the inability to identify the primary source of infection as risk factors for mortality associated with BSI due to ESBL-producing E. coli in non-transplanted patients [37]. Other authors have reported a higher risk of death associated with CRKP infection among LT and LuT recipients [16], [38]. It has also been shown that patients with CRAB infection after SOT had a longer hospital stay and an increased risk of graft loss and death compared to patients without any infection or those with infection due to carbapenem-susceptible A. baumannii [19], [20], [39]. Infection due to MDR P. aeruginosa was associated with higher mortality in LT recipients, reaching 38% in case of BSI [21], [40]. Such poorer outcomes are mainly driven by increased odds for inappropriateness of empirical antimicrobial therapy and clinical failure of targeted therapy, even when antimicrobial agents with in vitro activity are used [4].
Section snippets
What are the risk factors for developing ESBL-producing Enterobacteriaceae infections after SOT?
Studies performed in Spain have estimated that approximately 20% of infections in SOT recipients are caused by MDR bacteria, from which 75% are due to ESBL-producing Enterobacteriaceae [41]. > 20% of all E. coli isolated in urine cultures of SOT recipients with a diagnosis of UTI are ESBL-producing Enterobacteriaceae [42]. KT recipients are significantly at risk [42]. Different period comparison has confirmed that the incidence of the infections produced by these microorganisms is increasing [43]
What are the risk factors for developing CPE infections after SOT?
Approximately 3 to 10% of all SOT recipients in areas where CPE are endemic develop an infection by these microorganisms. The infection site frequently correlates with the type of transplant performed. Mortality rates associated with CPE infections in SOT recipients are close to 40% [124]. Therefore, it is very important to know the risk factors for developing infections by these microorganisms (listed in Table 4).
Several studies have evaluated the risk factors for developing a CPE infection.
What are the risk factors for developing MDR P. aeruginosa infections after SOT?
The incidence of infections produced by MDR P. aeruginosa strains is higher in SOT recipients than in the general population. Almost 50% of all P. aeruginosa BSI in SOT recipients are caused by MDR strains [18], [27]. The risk of infection is higher in LuT, since more than half of the cystic fibrosis patients that are candidates for LuT are colonized by MDR strains, and up to 75% will subsequently be colonized after transplantation [32].
The risk of developing MDR P. aeruginosa infections
What are the risk factors for developing MDR A. baumannii infections after SOT?
A. baumannii infection in SOT recipients is above all a healthcare-associated infection. Its incidence varies widely depending on the center's epidemiological data, ranging from 8% to 50% [18], [41], [185], [229], [230], [231], [232], [233]. A. baumannii infections are more prevalent among transplant recipients than among other non-transplanted patients admitted to the ICU after undergoing surgery [34].
Although SOT recipients frequently have infections caused by MDR microorganisms, data in this
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The authors have no conflicts of interest to disclose.
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Funding sources: J.T.S. holds a research contract from the Fundación para la Formación e Investigación de los Profesionales de la Salud de Extremadura (FundeSalud), Instituto de Salud Carlos III. M.F.R. holds a clinical research contract “Juan Rodés” (JR14/00036) from the Spanish Ministry of Economy and Competitiveness, Instituto de Salud Carlos III.
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Spanish Renal Disease Network (RedInRen, RD16/0009/0006).
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Spanish Renal Disease Network (RedInRen, RD16/0009/0030).