The past 10 years have brought a formidable challenge to the clinical arena, as carbapenems, until now the most reliable antibiotics against Klebsiella species, Escherichia coli, and other Enterobacteriaceae, are becoming increasingly ineffective.
Infections caused by carbapenem-resistant Enterobacteriaceae (CRE) pose a serious threat to hospitalized patients. Moreover, CRE often demonstrate resistance to many other classes of antibiotics, thus limiting our therapeutic options. Furthermore, few new antibiotics are in line to replace carbapenems. This public health crisis demands redefined and refocused efforts in the diagnosis, treatment, and control of infections in hospitalized patients.
Here, we present an overview of CRE and discuss avenues to escape a new era of untreatable infections.
INCREASED USE OF CARBAPENEMS AND EMERGENCE OF RESISTANCE
Developed in the 1980s, carbapenems are derivatives of thyanamycin. Imipenem and meropenem, the first members of the class, had a broad spectrum of antimicrobial activity that included coverage of Pseudomonas aeruginosa, adequately positioning them for the treatment of nosocomial infections. Back then, nearly all Enterobacteriaceae were susceptible to carbapenems.1
In the 1990s, Enterobacteriaceae started to develop resistance to cephalosporins—till then, the first-line antibiotics for these organisms—by acquiring extended-spectrum betalactamases, which inactivate those agents. Consequently, the use of cephalosporins had to be restricted, while carbapenems, which remained impervious to these enzymes, had to be used more.2 In pivotal international studies in the treatment of infections caused by strains of K pneumoniae that produced these inactivating enzymes, outcomes were better with carbapenems than with cephalosporins and fluoroquinolones.3,4
Ertapenem, a carbapenem without antipseudomonal activity and highly bound to protein, was released in 2001. Its prolonged half-life permitted once-daily dosing, which positioned it as an option for treating infections in community dwellers.5 Doripenem is the newest member of the class of carbapenems, and its spectrum of activity is similar to that of imipenem and meropenem and includes P aeruginosa.6 The use of carbapenems, measured in a representative sample of 35 university hospitals in the United States, increased by 59% between 2002 and 2006.7
In the early 2000s, carbapenem resistance in K pneumoniae and other Enterobacteriaceae was rare in North America. But then, after initial outbreaks occurred in hospitals in the Northeast (especially New York City), CRE began to spread throughout the United States. By 2009–2010, the National Healthcare Safety Network from the Centers for Disease Control and Prevention (CDC) revealed that 12.8% of K pneumoniae isolates associated with bloodstream infections were resistant to carbapenems.8
In March 2013, the CDC disclosed that 3.9% of short-stay acute-care hospitals and 17.8% of long-term acute-care hospitals reported at least one CRE health care-associated infection in 2012. CRE had extended to 42 states, and the proportion of Enterobacteriaceae that are CRE had increased fourfold over the past 10 years.9
Coinciding with the increased use of carbapenems, multiple factors and modifiers likely contributed to the dramatic increase in CRE. These include use of other antibiotics in humans and animals, their relative penetration and selective effect on the gut microbiota, case-mix and infection control practices in different health care settings, and travel patterns.