Carbapenem-resistant Enterobacteriaceae: a potential threat.

AFTER MORE THAN 7 DECADES OF ANTIBIOTIC USE, A REcurrent pattern of antimicrobial resistance spread is evident among certain bacterial pathogens. In this pattern, resistance occurs first among the most severely ill hospitalized patients, then spreads to involve other patients in the hospital, and ultimately reaches the community. These events are initially localized geographically; however, via spread from region to region, resistant bacterial strains eventually establish global endemicity. This pattern has been observed with penicillin-resistant staphylococci, methicillinresistant Staphylococcus aureus (MRSA), and extendedspectrum -lactamase (ESBL)–producing Enterobacteriaceae. In each case, adequate preventive measures to contain the spreadof resistantpathogenswerenot implemented in time. In this Commentary, we discuss the implications of a new resistance threat to public health: the global spread of carbapenem-resistant Enterobacteriaceae (CRE). Bacteria from the family Enterobacteriaceae are among the most common pathogens in humans, affecting all populations and causing syndromes ranging in severity from simple cystitis to pneumonia, peritonitis, bacteremia, and meningitis. Historically, these bacteria were susceptible to a wide range of antibiotics. During the past 25 years, however, multidrug resistance has emerged and become widespread, mediated primarily via acquired genes that code for ESBLs, other enzymes, and additional resistance mechanisms. In response to this broad-spectrum resistance, antibiotics from the carbapenem class have been established as the agents of last resort in treating these infections, and carbapenems have been increasingly used in recent decades as the only effective therapy. Yet during the past decade, carbapenem resistance in Enterobacteriaceae has emerged, and in recent years widespread outbreaks of CRE have been increasingly reported. Carbapenem-resistant Enterobacteriaceae differ from most other multidrug-resistant bacterial pathogens in that there is no reliable treatment. The spread of CRE has potentially devastating consequences for global public health and should be addressed with urgency by the international medical community and policy makers. Resistance to carbapenems in Enterobacteriaceae is generally caused by hydrolyzing enzymes. The most important among these are carbapenemases, primarily the serine -lactamase KPC and the metallo– -lactamase VIM. The genes coding for these enzymes are carried by plasmids that often carry other resistance factors as well, resulting in extensively drug-resistant (XDR) bacteria. Moreover, plasmids carrying resistance genes also may carry virulence factors, thus leading to severe infections. Since plasmids are readily transferred, these resistance genes can easily spread within species and even from species to species of Enterobacteriaceae. When such plasmids enter a rapidly disseminating bacterial strain, the result may be a widespread outbreak of a virulent XDR pathogen. Until recently, CRE were rare. During the past few years, however, the incidence has been increasing, with outbreaks reported in the northeastern United States and spread of CRE described in other countries as well. This dissemination is cause for concern. Since Enterobacteriaceae constitute normal human intestinal flora, the reservoir of potential spreaders, by fecal-oral and contact routes, extends to every individual. Carriage may persist for years, and therefore these XDR organisms may eventually spread to the healthy population in the community, with attendant long-term risk of infection to the carriers, similar to the current experience with ESBL-producing bacteria. These organisms are opportunistic pathogens, and once intestinal carriage is established individuals are at risk of infection under the right conditions. As these organisms become increasingly prevalent, treatment of health care–associated infections most likely will become more difficult or even impossible. These circumstances eventually may limit the ability to offer therapeutic interventions associated with a high risk of infection, such as solid organ and bone marrow transplantation and chemotherapy, and could make the hospital environment unsafe even to the general population undergoing simple and elective procedures. In addition, infections acquired in the community, even those occurring in young, healthy individuals, including such conditions as pyelonephritis and perforated appendicitis, may become untreatable and therefore life-threatening.