Carbapenemases in Enterobacteriaceae: the magnitude of a worldwide concern
Authors: J.M. Rolain, G. Cornaglia
Journal: Clinical Microbiology and Infection (2014)

Although carbapenemases in Enterobacteriaceae were relatively rare a decade ago, their emergence and rapid spread is now an alarming worldwide problem, for both the scientific and public health communities [1Canton R Akova M Carmeli Y et al.Rapid evolution and spread of carbapenemases among Enterobacteriaceae in Europe.Clin Microbiol Infect. 2012; 18: 413-431Abstract Full Text Full Text PDF PubMed Scopus (670) Google Scholar]. In the present theme issue, we provide an overview of the different factors that probably explain the spread and success of the main carbapenemase producers, and the current knowledge on epidemiology, genetics, diagnostics, prevention and surveillance, and treatment. In the first review of this issue, the classification, phylogenetic aspects and different genetic platforms associated with carbapenemases in Gram-negative bacteria are reviewed [2Diene SM Rolain JM Carbapenemase genes and genetic platforms in Gram-negative bacilli: Enterobacteriaceae, Pseudomonas and Acinetobacter species.Clin Microbiol Infect. 2014; 20: 831-838Abstract Full Text Full Text PDF PubMed Scopus (141) Google Scholar]. Carbapenemases are mainly found in Amber classes A, B, and D, with KPC, NDM and OXA-48 being the most frequently encountered in Enterobacteriaceae, respectively [2Diene SM Rolain JM Carbapenemase genes and genetic platforms in Gram-negative bacilli: Enterobacteriaceae, Pseudomonas and Acinetobacter species.Clin Microbiol Infect. 2014; 20: 831-838Abstract Full Text Full Text PDF PubMed Scopus (141) Google Scholar]. Interestingly, this study shows very large diversity and long-lasting phylogenetic evolution, with notable variation in the mean GC content and percentages of identity for the different carbapenemase-encoding genes. Moreover, these genes can be found chromosomally or on mobile genetic elements such as transposons, integrons, and plasmids, the latter being widely associated with the worldwide spread in Enterobacteriaceae. These mobile genetic elements frequently contain other antibiotic resistance genes, leading to rapid evolution towards multidrug-resistant bacteria. The magnitude of the problem is probably underestimated, as new antibiotic resistance genes may emerge at any time, as was the case for NDM-1 [3Rolain JM Canton R Cornaglia G Emergence of antibiotic resistance: need for a new paradigm.Clin Microbiol Infect. 2012; 18: 615-616Abstract Full Text Full Text PDF PubMed Scopus (43) Google Scholar]. In the second review, by Poirel et al. [4Nordmann P Poirel L The difficult-to-control spread of carbapenemase producers in Enterobacteriaceae worldwide.Clin Microbiol Infect. 2014; 20: 821-830Abstract Full Text Full Text PDF PubMed Scopus (490) Google Scholar], the current epidemiology of carbapenemases in Enterobacteriaceae demonstrates that carbapenemase producers have spread all over the world, and that the situation is becoming worrying in some countries, especially in the USA, Greece, Israel and Italy for KPC carbapenemases, in the Indian subcontinent for NDM carbapenemases, and in North Africa and Turkey for OXA-48 [4Nordmann P Poirel L The difficult-to-control spread of carbapenemase producers in Enterobacteriaceae worldwide.Clin Microbiol Infect. 2014; 20: 821-830Abstract Full Text Full Text PDF PubMed Scopus (490) Google Scholar]. NDM and OXA-48 enzymes have been identified in both nosocomial and community-acquired Escherichia coli and Klebsiella pneumoniae, whereas KPC producers are mainly nosocomial K. pneumoniae isolates. Rapid detection and identification of these genes is critical for the implementation of health control policies, but detection is complicated by the low enzymatic activity of some enzymes (mainly OXA-48). The third review, by Hrabak et al. [5Hrabak J Chudackova E Papagiannitsis CC Detection of carbapenemases in Enterobacteriaceae: a challenge for diagnostic microbiological laboratories.Clin Microbiol Infect. 2014; 20: 839-853Abstract Full Text Full Text PDF PubMed Scopus (159) Google Scholar], summarizes the current screening methods and laboratory diagnosis methods for carbapenemase detection and identification. Carbapenemase producers can be screened by using faecal or rectal swabs, which are streaked onto commercial cultivation media for detection of isolates with reduced susceptibility to carbapenems. Confirmation of carbapenemase activity can be achieved with phenotypic tests (Modified Hodge test, inhibition by chelating agents, combined disk methods, colorimetric assays, and matrix-assisted laser desorption ionization time-of-flight mass spectrometry) or with molecular tests (PCR, real-time PCR, microarrays, and genome sequencing) [5Hrabak J Chudackova E Papagiannitsis CC Detection of carbapenemases in Enterobacteriaceae: a challenge for diagnostic microbiological laboratories.Clin Microbiol Infect. 2014; 20: 839-853Abstract Full Text Full Text PDF PubMed Scopus (159) Google Scholar]. Because there are only limited therapeutic options for the treatment of infections caused by carbapenemase producers, infection prevention remains one of the critical approaches for preventing the spread of such organisms, and strategies for this are reviewed by Savard et al. [6Savard P Perl TM Combating the carbapenemases in Enterobacteriaceae: a battle that infection prevention should not lose.Clin Microbiol Infect. 2014; 20: 854-861Abstract Full Text Full Text PDF PubMed Scopus (31) Google Scholar]. Prevention practices are critical, because infections caused by carbapenemase producers are associated with high rates of morbidity and mortality, prolonged hospital stays, and overall increased healthcare costs [6Savard P Perl TM Combating the carbapenemases in Enterobacteriaceae: a battle that infection prevention should not lose.Clin Microbiol Infect. 2014; 20: 854-861Abstract Full Text Full Text PDF PubMed Scopus (31) Google Scholar]. Thus, it seems reasonable to conduct epidemiological surveys to identify carriers who act as reservoir for transmission to others, in order to implement contact isolation and cohorting for prevention of transmission. Moreover, epidemiological studies for surveillance of the magnitude of the problem at local, national and international levels are also warranted to prevent pandemic diffusion of new multidrug-resistant clones [6Savard P Perl TM Combating the carbapenemases in Enterobacteriaceae: a battle that infection prevention should not lose.Clin Microbiol Infect. 2014; 20: 854-861Abstract Full Text Full Text PDF PubMed Scopus (31) Google Scholar]. Finally, the review from Tzouvelekis et al. [7Tzouvelekis LS Markogiannakis A Piperaki E Souli M Daikos GL Treating infections caused by carbapenemase-producing Enterobacteriaceae.Clin Microbiol Infect. 2014; 20: 862-872Abstract Full Text Full Text PDF PubMed Scopus (267) Google Scholar] provides a meta-analysis based on 20 clinical studies on the treatment of infections caused by carbapenemase-producing Enterobacteriaceae. Treatment of infections caused by carbapenemase producers is challenging, because only a few antibiotics (including colistin, tigecycline, and aminoglycosides) may remain effective, and resistance to these compounds has also recently emerged in Enterobacteriaceae. Treatment with a single effective antibiotic is associated with an unacceptably high mortality rate, and combination regimens should be the rule to obtain a clear survival benefit [7Tzouvelekis LS Markogiannakis A Piperaki E Souli M Daikos GL Treating infections caused by carbapenemase-producing Enterobacteriaceae.Clin Microbiol Infect. 2014; 20: 862-872Abstract Full Text Full Text PDF PubMed Scopus (267) Google Scholar]. In conclusion, carbapenemases now represent an unrelenting threat to human health worldwide, and will constitute one of the most challenging problems confronting containment of infectious diseases in the years to come. The authors declare no conflict of interest.