Continuous Evolution: Perspective on the Epidemiology of Carbapenemase Resistance Among Enterobacterales and Other Gram-Negative Bacteria

Abstract

The global emergence of carbapenemase-producing bacteria capable of hydrolyzing the once effective carbapenem antibiotics is considered a contemporary public health concern. Carbapenemase enzymes, once constrained to isolates of Klebsiella pneumoniae, are now routinely reported in different bacteria within the Enterobacterales order of bacteria, creating the acronym CRE which now defines Carbapenem-Resistant Enterobacterales. CRE harboring different types of enzymes, including the most prevalent types KPC, VIM, IMP, NDM, and OXA-48, are now routinely reported and more importantly, are now frequently present in many infections world-wide. Defining and updating the contemporary epidemiology of both the US and global burden of carbapenem-resistant infections is now more important than ever. This review describes the global distribution and continued evolution of carbapenemases which continue to spread at alarming rates. Informed understanding of the current epidemiology of CRE, coupled with advances in antibiotic options, and the use rapid diagnostics offers the potential for rapid identification and management of carbapenem-resistant infections.

Keywords: Carbapenem-resistant enterobacterales (CRE); Enterobacterales; Epidemiology; Global.

Fig. 1

CRE reported cases, Centers for Disease Control as of 2017, reported by geographic US state reporting [55]. CRE defined by 2015 CDC case definition for CRE; resistant to imipenem, meropenem, doripenem, or ertapenem OR documentation that isolates possess a carbapenemase gene. Reference Source CDC [56]

Fig. 2

Carbapenem resistance from Central Line–Associated Bloodstream Infections (CLABSIs). Figure adapted from Sievert et al. [32]; values represent percent carbapenem resistant for respective bacteria isolated from postive blood cultures representative of CLABSI infection. Carbapenem resistance, as defined in this report, included all applicable pathogens with a result of I or R to imipenem, meropenem, or doripenem. 2006–2007 Klebsiella data inclusive of K. pneumoniae isolates only. Carbapenem resistance rates by pathogen differ depending on the site of infection [33][34]. Rates for P. aeruginosa and A. baumannii are lower for bloodstream infections that have been reported from other types of infections [e.g., ventilator-associated pneumonia (VAP)] [32][34] Thus, it is likely that studies reporting bloodstream and CLABSI infections may under-report true prevalence of carbapenem resistance rates

Fig. 3

Prevalence of carbapenem-resistant Gram-negative infections in the United States. Adapted from Cai et al. [38]. In the US, overall carbapenem resistance among the 4 selected pathogens (E. coli, K. pneumoniae, P. aeruginosa, A. baumannii) was 4.5% out of 292,742 isolates tested

Fig. 4

Global distribution of Carbapenemase-producing bacteria: global distribution of carbapenemases in Enterobacteriaceae, by country and region. ^aKPCs are endemic in some US states; ^bOXA mainly refers to OXA-48, except in India, where it refers to OXA-181. IMP active on imipenem metallo-β-lactamase, KPC Klebsiella pneumoniae carbapenemase, NDM New Delhi metallo-β-lactamase, OXA oxacillinase-type carbapenem-hydrolyzing β-lactamase, VIM Verona integron-encoded metallo-β-lactamase. Reprinted with permission from: Logan, K., Weinstein, R. The epidemiology of carbapenem-resistant Enterobacteriacae: the impact and evolution of a global menace. J of Infect Disease. 2017;215(S1):S28–36. https://doi.org/10.1093/infdis/jiw282. (12)

Fig. 5

Countries in which carbapenemase genes have been described are shown. Countries shown in red boxes represents cases in which outbreaks involving carbapenemase genes have been described. Figure of Europe adapted from [12, 12, 12, 12]