Carbapenem-resistant Enterobacteriaceae: A menace to our most vulnerable patients
ABSTRACTThe emergence of carbapenem-resistant Enterobacteriaceae (CRE) highlights the importance of effective antibiotics to maintain the safety of our health care system. Clinicians will encounter CRE as a cause of difficult-to-treat and often fatal infections in hospitalized patients. We review the mechanisms of carbapenem resistance, the dissemination and clinical impact of these resistant organisms, and challenges to their detection, treatment, and control.
KEY POINTS
- The utility of carbapenems is being undermined by the emergence of resistance in Enterobacteriaceae and other bacteria.
- The clinical impact of CRE falls on elderly patients exposed to these organisms in hospitals and long-term care facilities. In this vulnerable group, invasive infections with CRE exact a high death rate.
- Long-term care facilities play an important role in the transmission dynamics of CRE.
- Tigecycline and colistin are treatments of last resort against infections caused by CRE. Their use in combination with other agents, especially carbapenems, may improve outcomes and needs to be explored further.
- Early detection of CRE in the microbiology laboratory is key to guiding infection control and treatment decisions and supporting surveillance efforts.
POWERFUL ENZYMES THAT TRAVEL FAR
Bacterial acquisition of carbapenemases, enzymes that inactivate carbapenems, is crucial to the emergence of CRE. The enzyme in the sentinel carbapenem-resistant K pneumoniae isolate found in 1996 in North Carolina was designated K pneumoniae carbapenemase (KPC-1). This mechanism also conferred resistance to all cephalosporins, aztreonam, and beta-lactamase inhibitors such as clavulanic acid and tazobactam.10
KPC-2 (later determined to be identical to KPC-1) was found in K pneumoniae from Baltimore, and KPC-3 caused an early outbreak in New York City.11,12 To date, 12 additional variants of blaKPC, the gene encoding for the KPC enzyme, have been described.13
The genes encoding carbapenemases are usually found on plasmids or other common mobile genetic elements.14 These genetic elements allow the organism to acquire genes conferring resistance to other classes of antimicrobials, such as aminoglycoside-modifying enzymes and fluoroquinolone-resistance determinants, and beta-lactamases.15,16 The result is that CRE isolates are increasingly multidrug-resistant (ie, resistant to three or more classes of antimicrobials), extensively drug-resistant (ie, resistant to all but one or two classes), or pandrug-resistant (ie, resistant to all available classes of antibiotics).17 Thus, up to 98% of KPC-producing K pneumoniae are resistant to trimethoprim-sulfamethoxazole, 90% are resistant to fluoroquinolones, and 60% are resistant to gentamicin or amikacin.15
The mobility of these genetic elements has also allowed for dispersion into diverse Enterobacteriaceae such as E coli, Klebsiella oxytoca, Enterobacter, Serratia, and Salmonella species. Furthermore, KPC has been described in non-Enterobacteriaceae such as Acinetobacter baumannii and P aeruginosa.
Extending globally, KPC is now endemic in the Mediterranean basin, including Israel, Greece, and Italy; in South America, especially Colombia, Argentina, and Brazil; and in China.18 Most interesting is the intercontinental transfer of these strains: it has been documented that the index patient with KPC-producing K pneumoniae in Medellin, Colombia, came from Israel to undergo liver transplantation.19 Likewise, KPC-producing K pneumoniae in France and Israel could be linked epidemiologically and genetically to the predominant US strain.20,21
Even more explosive has been the surge of another carbapenemase, the Ambler Class B New Delhi metallo-beta-lactamase, or NDM-1. Initially reported in a urinary isolate of K pneumoniae from a Swedish patient who had been hospitalized in New Delhi in 2008, NDM-1 was soon found throughout India, in Pakistan, and in the United Kingdom.22 Interestingly, several of the UK patients with NDM-1-harboring bacteria had received organ transplants in the Indian subcontinent. Reports from elsewhere in Europe, Australia, and Africa followed suit, usually with a connection to the Indian subcontinent epicenter. In contrast, several other cases in Europe were traced to the Balkans, where there appears to be another focus of NDM-1.23
Penetration of NDM-1 into North America has begun, with cases and outbreaks reported in several US and Canadian regions, and in a military medical facility in Afghanistan. In several of these instances, there has been a documented link with travel and hospitalizations overseas.24–27 However, no such link with travel could be established in a recent outbreak in Ontario.27
In addition, resistance to carbapenems may result from other enzymes (Table 1), or from combinations of changes in outer membrane porins and the production of extended spectrum beta-lactamases or other cephalosporinases.28
