Molecular diversity of extended-spectrum β-lactamases and carbapenemases, and antimicrobial resistance

Sawa et al. Journal of Intensive Care (2020) 8:13 https://doi.org/10.1186/s40560-020-0429-6 REVIEW Open Access Molecular diversity of extended-spectrum β-lactamases and carbapenemases, and antimicrobial resistance Teiji Sawa1* , Kunihiko Kooguchi2 and Kiyoshi Moriyama3 Abstract Along with the recent spread of multidrug-resistant bacteria, outbreaks of extended-spectrum β-lactamase (ESBL) and carbapenemase-producing bacteria present a serious challenge to clinicians. β-lactam antibiotics are the most frequently used antibacterial agents and ESBLs, and carbapenemases confer resistance not only to carbapenem antibiotics but also to penicillin and cephem antibiotics. The mechanism of β-lactam resistance involves an efflux pump, reduced permeability, altered transpeptidases, and inactivation by β-lactamases. Horizontal gene transfer is the most common mechanism associated with the spread of extended-spectrum β-lactam- and carbapenem resistance among pathogenic bacterial species. Along with the increase in antimicrobial resistance, many different types of ESBLs and carbapenemases have emerged with different enzymatic characteristics. For example, carbapenemases are represented across classes A to D of the Ambler classification system. Because bacteria harboring different types of ESBLs and carbapenemases require specific therapeutic strategies, it is essential for clinicians to understand the characteristics of infecting pathogens. In this review, we summarize the current knowledge on carbapenem resistance by ESBLs and carbapenemases, such as class A carbapenemases, class C extended-spectrum AmpC (ESAC), carbapenem-hydrolyzing class D β-lactamases (CHDLs), and class B metallo-βlactamases, with the aim of aiding critical care clinicians in their therapeutic decision making. Keywords: β-Lactam, β-Lactamase, Carbapenemase, Classification, Multidrug resistance Background Among the recent spread of multidrug-resistant bacteria, outbreaks of extended-spectrum β-lactam- and carbapenemresistant bacteria are a serious problem not only making treatment difficult but also worsening the prognosis of infected patients [1]. β-lactam antibiotics are the most frequently used antibacterial agents, and extendedspectrum β-lactams and carbapenems have been developed as specific drugs to treat bacterial species resistant to penicillins and cephems [2]. Bacterial resistance to carbapenems incorporates not only carbapenem antibiotics but also resistance to penicillin and cephem antibiotics. Therefore, resistance to carbapenems presents a significant threat to patients who are immunocompromised and are therefore susceptible to infections caused by * Correspondence: 1 Department of Anesthesiology, School of Medicine, Kyoto Prefectural University of Medicine, 465 Kajii-cho, Kamigyo, Kyoto 602-8566, Japan Full list of author information is available at the end of the article multidrug-resistant bacteria all over the world [3]. The mechanism of resistance to extended-spectrum βlactams and carbapenems involves an efflux pump, reduced permeability, altered transpeptidases, and inactivation by β-lactamases. Horizontal gene transfer is the most common mechanism associated with the spread of antimicrobial resistance across pathogenic bacterial species, such as carbapenemase-producing Enterobacteriaceae (CPE) [4, 5]. In various bacterial species, novel extended-spectrum β-lactamases (ESBLs) or carbapenemases with different structures or characteristic features are reported each year. Various ESBLs and carbapenemases have been reported in the Enterobacteriaceae including Enterobacter, Klebsiella, Escherichia coli [6, 7], and other opportunistic species such as Serratia, Acinetobacter, and Pseudomonas [8]. In addition, the genetic elements by which drug-resistant genes horizontally move across bacterial species have been studied among these bacterial species. © The Author(s). 2020 Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated. Sawa et al. Journal of Intensive Care (2020) 8:13 As one typical example, Pseudomonas aeruginosa, one of the major causative agents of infection in immunocompromised individuals, displays resistance to various antibacterial agents. Its resistance mechanism is, in part, derived from the organism’s natural resistance, but is also acquired through horizontal gene transfer and/or mutations within its DNA. P. aeruginosa is naturally resistant to β-lactam antibiotics, such as penicillin and cephem, and aminoglycoside antibiotics. Since the 1990s, P. aeruginosa strains have emerged that have acquired resistance to broad-spectrum penicillins, thirdgeneration cephems, carbapenems, anti-P. aeruginosa aminoglycosides, and new quinolones [9, 10]. Among these multidrug-resistant P. aeruginosa (MDRP), one of the major clinical concerns is the spread of P. aeruginosa strains that harbor a carbapenemase because β-lactam antibiotics including carbapenems are the most frequently used antibacterial agents. An anti-methicillin-resistant Staphylococcus aureus (MRSA) drug, albekacin sulfate, a monobactam aztreonam, and polypeptide colistin appear to be effective against MDRP, but the emergence of resistant strains has also been reported including extensively drug-resistant P. aeruginosa (XDRP) and pandrug-resistant P. aeruginosa (PDRP) [10, 11]. To date, many different types of ESBLs and carbapenemases have emerged with different enzymatic characteristics [1]. Because the specific therapeutic strategy is dependent on the type of ESBL and carbapenemase, it is vital for clinicians to understand the characteristics of ESBLs and carbapenemases [12]; however, in practice, the complex biology associated with ESBLs and carbapenemases presents significant challenges in the effective control of infections. In this review, we summarize antimicrobial resistance by ESBLs and carbapenemases, with Page 2 of 13 the aim of collating the current knowledge in this field to aid therapeutic decision making by critical care clinicians. β-Lactam antibiotics, penicillin-binding protein (PBP), and β-lactamase We will begin by reiterating the mechanism of action of β-lactam antibiotics. The main constituent of the cell wall formed in the outer membrane layer of eubacteria is peptidoglycan, which is a macromolecular structure consisting of peptide and sugar (Fig. 1). This peptidoglycan structure confers resistance to osmotic pressure and retains cell morphology and strength. It is also the (...truncated)