Multidrug-resistant gram-negative infections in transplant and oncology patients

Common mechanisms of gram-negative resistance

Gram-negative organisms are divided into the Enterobacteriaceae (e.g., Escherichia coli, Klebsiella species, Enterobacter cloacae ) and the glucose nonfermenting gram-negative organisms ( Pseudomonas aeruginosa , Acinetobacter baumannii , Stenotrophomonas maltophilia ). Drug resistance in Enterobacteriaceae is often due to the production of β-lactamases. Common β-lactamases include extended-spectrum β-lactamases (ESBLs), AmpC β-lactamases, and carbapenemases. ESBLs and carbapenemases are generally plasmid mediated, whereas Amp C β-lactamases can either be plasmid mediated or chromosomally mediated.

Common ESBL genes include bla _TEM , bla _CTX-M-type , and bla _SHV , and the associated enzymes result in the hydrolysis of penicillins, cephalosporins, and aztreonam. SHV and the widely spread TEM enzyme were among the first to be recognized from this group; however, CTX-M enzymes are now rapidly becoming a common mechanism of bacterial resistance in many parts of the world. Mechanisms of AmpC β-lactamase resistance in Enterobacteriaceae are divided into three categories: (1) inducible resistance by chromosomally encoded ampC genes (e.g., E. cloacae , Citrobacter freundii, Serratia marcescens ), (2) noninducible chromosomal resistance owing to promoter and/or attenuator mutations (e.g.; E. coli , Shigella spp.); or (3) plasmid-mediated resistance (e.g., E. coli , Klebsiella pneumoniae , Salmonella spp.). Common carbapenemase genes include bla _KPC , bla _NDM , and bla _OXA-48-like . Plasmids that carry ESBL and carbapenemase genes also frequently encode fluoroquinolone resistance, trimethoprim-sulfamethoxazole resistance, and aminoglycoside resistance.

Resistance mechanisms common to P. aeruginosa include OprD porins, hyperproduction of AmpC β-lactamases, upregulation of efflux pumps, and mutations in penicillin-binding proteins, with the minority producing carbapenemases. Drug resistance in Actinobacter baumannii is generally the result of the production of carbapenemases such as OXA-23-like, OXA-40-like, OXA-58-like, and OXA-143-like carbapenemases.

Epidemiology and risk factors

Hematopoietic stem cell transplant recipients.

Patients undergoing allogenic hematopoietic stem cell transplant (HSCT) are at particular risk for invasive infections with gram-negative enteric pathogens. This may be related to conditioning therapy, intestinal graft-versus-host disease, or a prolonged need for parenteral nutrition, all of which can damage the gut epithelium and allow greater translocation of enteric pathogens, resulting in bloodstream infections (BSIs).

A multicenter observational study evaluated the risk factors associated with 848 episodes of multidrug-resistant gram-negative (MDRGN) BSIs in children after HSCT in the United States between 2004 and 2008 and 2011 and 2014. All positive blood culture results between days −10 and +365 surrounding allogenic HSCT were included. Approximately 53% of patients had at least one episode of a gram-negative rod (GNR) BSI; the most frequent pathogens implicated were Klebsiella spp. (26%), Enterobacter spp. (17%), Pseudomonas spp. (16%), E. coli (13%), Stenotrophomonas spp. (7%), and Citrobacter spp. (2%). Approximately 15% of GNR BSIs were caused by organisms resistant to three or more classes of antibiotics. Age older than 16 years and more than one BSI event were risk factors for infection with a resistant organism.

A large study from 65 institutions across 25 countries in Europe, Asia, and Australia was conducted by the European Bone Marrow Transplantation Group to study antibiotic resistance among patients of all ages undergoing autologous or allogenic HSCT. The study results showed that 13% percent of the study participants were 18 years of age or younger. Enterobacteriaceae were significantly more resistant to fluoroquinolones compared with non-Enterobacteriaceae (57% vs. 31%), whereas carbapenem resistance (51% vs. 8%), and multidrug-resistance (47% vs. 32%) was more common in non–lactose-fermenting GNRs, which include P. aeruginosa and A. baumannii. Rates of resistance against all classes of antibiotics were significantly higher in allogenic versus autologous HSCT recipients. In general, GNR resistance in children mirrored proportions in adults, except for fluoroquinolones and antipseudomonal β-lactam/β-lactamase inhibitor combination drugs, for which resistance was higher in adults.

Heart and lung transplant recipients

Infections are a leading cause of death in pediatric heart transplant patients, especially in the first year after transplant, with more than half of infections caused by bacterial pathogens. The Pediatric Heart Transplant Study, a prospectively maintained multiinstitutional research database in the United States, studied bacterial infections in children younger than 18 years less than 1 month, 1 to 6 months and more than 6 months after transplant. Among the GNRs, P. aeruginosa was the most common cause of infection at all time points and was especially more likely to occur in patients with cardiac devices or nosocomial infections. Other important GNRs, regardless of the time point, included Enterobacter spp. (5%), Klebsiella spp. (5%), and E. coli (5%). Data regarding antibiotic resistance were not collected; however, the investigators noted that 2% to 5% of the infections in the first month after transplant were due to organisms commonly resistant to first-line antibiotic agents (e.g., Serratia spp., Citrobacter spp., Stenotrophomonas spp., and Acinetobacter spp.).

Data from a study in adults receiving a solid organ transplant (SOT) showed a steady increase in MDRGN infections (5% in 2007-2008 to 39% in 2014-2015). This was largely driven by an increase in ESBL Enterobacteriaceae. A study in Italy showed that Klebsiella spp., A. baumannii, and P. aeruginosa (49%, 44%, and 31%, respectively) caused the majority of carbapenem-resistant infections. Infection with carbapenem-resistant organisms was more common in patients with a history of lung or heart transplant.

Data are limited in the pediatric lung transplant population to estimate determinants of MDRGN infections. Data from adult lung transplant recipients without underlying cystic fibrosis indicated that P. aeruginosa and Enterobacter spp. were the most common MDRGNs (20% and 19%%, respectively). Any previous exposure to broad-spectrum antibiotics, the presence of a tracheostomy, and an intensive care unit (ICU) stay longer than 14 days were associated with MDRGN bacterial acquisition. Prior colonization with MDRGN bacteria in donors or recipients was not associated with MDRGN infections or worse survival after transplant. Similar results were observed in a cohort of adult cystic fibrosis lung transplant recipients colonized with pan-resistant bacteria, including P. aeruginosa, S. maltophilia, and Burkholderia cepacian .

Liver and intestinal transplant recipients

Children undergoing liver transplants are at high risk of MDGN infections. However, limited data exist regarding the epidemiology of multidrug resistance in this population. In a single-center study of U.S. adults between 2010 and 2014 who received a liver transplant, 53% of bacterial infections were found to be MDR. Among the Enterobacteriaceae, 55% were found to be MDR and 82% were resistant to antibiotics that were used for bacterial prophylaxis.

Among children undergoing intestinal transplants, a U.S. single-center study of BSIs within the first year after transplant showed that almost 24% of the Klebsiella spp. were MDR. Similarly, another U.S.-based study including both adults and children showed that despite use of prophylactic therapy based on individual bacterial resistance patterns, 45% of subsequent infectious episodes were due to MDR organisms. A Spanish study of both children and adults who received an intestinal transplant showed that the most common GNRs isolated were P. aeruginosa, E. coli, and A. baumanni , with 65%, 50% and 100% of respective isolates being MDR.

Renal transplant recipients

A systematic review including both pediatric and adult studies showed that 10% of renal transplant recipients develop urinary tract infections (UTIs) with ESBL-producing Enterobacteriaceae . In a Canadian study enrolling adult renal transplant patients, most UTIs were caused by antibiotic-resistant E. coli or K. pneumoniae ; 5% of isolates were ESBL-producing. Furthermore, resistance to trimethoprim-sulfamethoxazole or fluoroquinolones occurred in 52% and 21%, respectively, of isolated microorganisms. Another study in adult renal transplant recipients showed that although infection with carbapenem-resistant Enterobacteriaceae (CRE) occurred in only 1% of patients, it was associated with higher mortality (30% vs. 10%) and a higher rate of recurrence (50% vs. 22%) compared with patients with more susceptible isolates.

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