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G Model IJMM-50480; No. of Pages 9 ARTICLE IN PRESS International Journal of Medical Microbiology xxx (2010) xxx–xxx Contents lists available at ScienceDirect International Journal of Medical Microbiology journal homepage: www.elsevier.de/ijmm Mini Review Resistance to cephalosporins and carbapenems in Gram-negative bacterial pathogens Yvonne Pfeifer, Angela Cullik, Wolfgang Witte ∗ Robert Koch-Institute, Nosocomial Infections, Wernigerode Branch, Burgstr. 37, 38855 Wernigerode, Germany a r t i c l e Keywords: Antibiotic resistance Enterobacteriaceae ESBL Carbapenemases i n f o a b s t r a c t During the past 15 years, emergence and dissemination of -lactam resistance in nosocomial Enterobacteriaceae, Pseudomonas aeruginosa and Acinetobacter baumannii, became a serious problem worldwide. Especially the increasing resistance to 3rd and 4th generation cephalosporins and carbapenems is of particular concern. Gram-negative bacteria pursue various molecular strategies for development of resistance to these antibiotics: (a) generation of extended-spectrum -lactamases (ESBL) according to the original definition due to extension of the spectrum of already widely disseminated plasmid-encoded -lactamases by amino acid substitution; (b) acquisition of genes encoding ESBL from environmental bacteria as, for instance the CTX-M-type -lactamases from Kluyvera spp.; (c) high-level expression of chromosome-encoded -lactamase (bla) genes as blaOXA or blaampC genes due to modifications in regulatory genes, mutations of the -lactamase promoter sequence as well as integration of insertion sequences containing an efficient promoter for intrinsic bla genes; (d) mobilization of bla genes by incorporation in integrons and horizontal transfer into other Gram-negative species such as the transfer of the ampC gene from Citrobacter freundii to Klebsiella spp.; (e) dissemination of plasmid-mediated carbapenemases as KPC and metallo--lactamases, e.g. VIM and IMP; (f) non-expression of porin genes and/or efflux pump-based antibiotic resistance. This mini-review summarizes the historical emergence of -lactam resistance and -lactamases as major resistance mechanism in enteric bacteria, and also highlights recent developments such as multidrug- and carbapenem resistance. © 2010 Elsevier GmbH. All rights reserved. Introduction Gram-negative bacteria possess resistance mechanisms affecting antibiotics of different classes such as tetracyclines, aminoglycosides, and cotrimoxazole. However, broad-spectrum resistance to -lactams and to fluorquinolones are today of the utmost significance. Ciprofloxacin is a very popular fluorquinolone for treatment of nosocomial infections, e.g. urinary tract infections. The frequent resistance to ciprofloxacin in Enterobacteriaceae is due to mutations in target genes. In recent years, a new resistance mechanism is increasingly observed. The plasmid-mediated qnr genes code for pentapeptide-repeat proteins protecting the type II topoisomerase from quinolones. This qnr mechanism causes low-level resistance to fluorquinolones but favours and complements additional resistance mechanisms (Martinez-Martinez et al., 2008). Because of its occurrence and transferability in many enterobacterial species the analysis of dissemination of qnr genes demands attention. ∗ Corresponding author. Tel.: +49 3943 679 246; fax: +49 3943 679 317. E-mail address: [email protected] (W. Witte). Besides fluorquinolones, -lactam antibiotics are most frequently applied in treatment of bacterial infections. The large number of natural, semisynthetic and synthetic -lactam antibiotics can be subdivided into 6 different structural subtypes: (i) penams (e.g. benzylpenicillin, ampicillin); (ii) cephems which include classical cephalosporins, 2nd generation cephalosporins (e.g. cefotiam, cefuroxime), and also representatives of 3rd generation cephalosporins (e.g. cefotaxime, ceftazidime); (iii) cephamycins as 7-␣-methoxy cephalosporins (e.g. cefoxitin); (iv) monobactams as monocyclic molecules (e.g. aztreonam); (v) penems with a 2,3-double bond in the fused thiazoline ring (e.g. faropenem); and (vi) carbapenems (e.g. imipenem) with an unsaturated fused 5membered ring differing from penem structure by possession of a carbon atom at position 1. In the early 1950s, enteric bacteria that mediated resistance to the first penicillins attracted attention. In general, resistance of bacteria against -lactam antibiotics relies on 3 basic principles: 1438-4221/$ – see front matter © 2010 Elsevier GmbH. All rights reserved. doi:10.1016/j.ijmm.2010.04.005 Please cite this article in press as: Pfeifer, Y., et al., Resistance to cephalosporins and carbapenems in Gram-negative bacterial pathogens. Int. J. Med. Microbiol. (2010), doi:10.1016/j.ijmm.2010.04.005 G Model IJMM-50480; 2 No. of Pages 9 ARTICLE IN PRESS Y. Pfeifer et al. / International Journal of Medical Microbiology xxx (2010) xxx–xxx Fig. 1. Proportion of invasive isolates of Escherichia coli with resistance to third-generation cephalosporins in 2008 (http://www.rivm.nl/earss/). * These countries did not report any data or reported less than 10 isolates. (i) possession of an altered or acquired penicillin binding protein (PBP) with low affinity for -lactams (e.g. PBP2a in methicillinresistant Staphylococcus aureus); (ii) efflux pumps that additionally use -lactams as substrates (e.g. the mex system in Pseudomonas aeruginosa); (iii) -lactamases which cleave the amide bond of the -lactam ring, thus inactivating the antibiotic agent. The introduction of 3rd generation cephalosporins, which started with cefotaxime 30 years ago, was a milestone in antimicrobial chemotherapy. Undoubtedly as a consequence of selective pressure exerted by these new cephalosporins, resistance in enterobacterial species emerged a few years later. At that time, 2 main causes were specified: • expansion of the substrate spectrum of broad-spectrum TEMtype and SHV-type -lactamases which were already widely disseminated due to plasmid location of these genes (Jarlier et al., 1988; Sirot et al., 1988), • constitutive high-level expression of the intrinsic ampC gene, coding for a cephamycinase (cefoxitin as phenotypical indicator substrate) in species with an efficient ampC promoter such as Fig. 2. Proportion of invasive isolates of Klebsiella pneumoniae resistant to carbapenems in 2008 (http://www.rivm.nl/earss/). * These countries did not report any data or reported less than 10 isolates. Please cite this article in press as: Pfeifer, Y., et al., Resistance to cephalosporins and carbapenems in Gram-negative bacterial pathogens. Int. J. Med. Microbiol. (2010), doi:10.1016/j.ijmm.2010.04.005 ARTICLE IN PRESS G Model IJMM-50480; No. of Pages 9 Y. Pfeifer et al. / International Journal of Medical Microbiology xxx (2010) xxx–xxx 3 Table 1 Modified classification scheme of -lactamases (according to Ambler, 1980). -lactamase-class -lactamases Important examples Broad-spectrum -lactamases TEM-1, TEM-2 SHV-1, SHV-11 ESBL TEM-type TEM-3, TEM-52 ESBL SHV-type SHV-5, SHV-12 ESBL CTX-M-type CTX-M-1, CTX-M-15 Carbapenemases KPC, GES, SME AmpC cephamycinases (chromosomal-encoded) AmpC Enterobacter spp. Citrobacter spp. cephamycins (cefoxitin), 3rd gen. cephalosporins AmpC cephamycinases (plasmid-encoded) CMY, DHA, MOX FOX, ACC, Enterobacteriaceae cephamycins (cefoxitin), 3rd gen. cephalosporins Broad-spectrum -lactamases OXA-1, OXA-9 ESBL OXA-type OXA-2, OXA-10 penicillins, 3rd gen. cephalosporins Carbapenemases; Carbapenemases OXA-48; OXA-23,-24,-58 ampicillin, imipenem; all -lactamsc Metallo--lactamases (Carbapenemases) VIM IMP A Serine--lactamases C D Metallo--lactamases a b c B Preferential occurrence Important phenotypical resistance traitsa ampicillin, cephalotin Enterobacteriaceae and nonfermentersb penicillins, 3rd gen. cephalosporins all -Lactamsc Enterobacteriaceae; A. baumannii Enterobacteriaceae and nonfermenters oxacillin, ampicillin cephalotin all -lactamsc Characteristical resistances that are partially used used for diagnostic purposes; Broad-spectrum -lactamase TEM-1 frequently occurs in nonfermenters (P. aeruginosa, A. baumannii); Broad hydrolytic spectrum including carbapenems. Citrobacter freundii, Enterobacter cloacae, and Serratia marcescens (Sanders and Sanders, 1988). Since the early 1990s, further -lactamase-related resistance mechanisms were discovered. Particularly significant was the mobilisation of genes coding for enzymes with ESBL activity from the environmental bacterial genus Kluyvera which led to the rise of the CTX-M enzyme family in Enterobacteriaceae (Bonnet, 2004). Cephalosporin resistance in E. coli can also be mediated by hyperproduction of AmpC -lactamase caused by promoter mutations increasing the ampC transcription rate (Caroff et al., 2000). The introduction of carbapenems in antimicrobial chemotherapy resulted in emergence of carbapenem hydrolyzing -lactamases (carbapenemases); first in P. aeruginosa and Acinetobacter spp., later in Enterobacteriaceae (Bush, 1998). At present, various -lactamases are widespread in nearly every Gramnegative pathogenic species. Often, these enzymes are responsible for therapy failure because of mediating multidrug-resistance. The prevalence rates of -lactam resistance in Gramnegative pathogens vary significantly in European countries. Figs. 1 and 2 display the frequency of resistance to 3rd generation cephalosporins in invasive E. coli as well as the frequency of carbapenem resistance in invasive Klebsiella pneumoniae, respectively (EARSS data, http://www.rivm.nl/earss/). A general view of the multitudinous number of -lactamases is given by classification schemes: Already in 1980, Ambler (1980) recognized that there are 2 major groups of enzymes: one with serine in its active site (class A), and another one which needs a bivalent cation, preferentially zinc for hydrolysis (class B, metallo-lactamases). The group of serine--lactamases was expanded with recognition of class C enzymes (Jaurin and Grundström, 1981) and class D enzymes (Ouellette et al., 1987). In 1995 Bush, Jacoby and Medeiros proposed another functional classification scheme of beta-lactamases which became widely used (Bush et al., 1995). Table 1 displays the basic principle of -lactamase classification according to Ambler. Resistance to cephalosporins: the “classical” ESBL The major cause of 3rd generation cephalosporin resistance in Enterobacteriaceae are ESBL enzymes of Ambler class A. Of special relevance are variants of broad-spectrum -lactamases TEM-1, TEM-2, and SHV-1 that are generated by mutations which extend their substrate specificity to 3rd and 4th generation cephalosporins, in particular to cefotaxime, ceftriaxone, and ceftazidime. These lactamases exhibit a wide range of amino acid substitutions leading to extended substrate specificity. These mutations affect the recognition of substrates and the rates of formation and hydrolysis of the acyl–enzyme complex. There is sufficient evidence that class A -lactamases perform several conformational changes induced by substrate binding and substrate reaction. In parallel, most substrates undergo chemical rearrangements triggered by the enzyme attack which can lead to more complex kinetics. The interplay of both processes finally results in extended substrate spectrum and in different rates of hydrolysis for different cephalosporins (for summary see also Raquet et al., 1995; Page, 2008). At present, 174 TEM-1 and TEM-2 variants and 119 SHV-1 variants have been recorded (http://www.lahey.org/Studies on 5th of May 2010, not yet released types are excluded). The first ESBL types were described in Central Europe and France during the 1980s (Paterson and Bonomo, 2005). At this time ESBL were most often associated with nosocomial outbreaks in intensive care units due to particular strains of K. pneumoniae. This situation changed when ESBL emerged in E. coli leading to a complex epidemiological situation which involves different clones of E. coli, a variety of ESBL and different genetic elements carrying blaESBL genes, respectively (Pitout et al., 2005; Rodriguez-Bano et al., 2004; Branger et al., 2005; Machado et al., 2005; Jeong et al., 2004). Please cite this article in press as: Pfeifer, Y., et al., Resistance to cephalosporins and carbapenems in Gram-negative bacterial pathogens. Int. J. Med. Microbiol. (2010), doi:10.1016/j.ijmm.2010.04.005 ARTICLE IN PRESS G Model IJMM-50480; No. of Pages 9 4 Y. Pfeifer et al. / International Journal of Medical Microbiology xxx (2010) xxx–xxx Table 3 Frequency of ESBL types in nosocomial E. coli from Germany. Table 2 Classification and evolution of CTX-M-type ESBL. CTX-M group CTX-M-1-type ESBL Probable natural reservoir and precursor gene Selected examples of CTX-M types in Enterobacteriaceae K. ascorbata kluA1-11 genes → CTX-M-1 → CTX-M-3 → CTX-M-15a → CTX-M-23a → CTX-M-28a → CTX-M-32a → CTX-M-54a → CTX-M-58a CTX-M-2-type ESBL K. ascorbata kluA1-11 genes → CTX-M-2 → CTX-M-35a → CTX-M-42a CTX-M-9-type ESBL K. georgiana kluG1 gene → CTX-M-14 → CTX-M-16a → CTX-M-19a → CTX-M-27a CTX-M-8-type ESBL K. georgiana kluG1 gene → CTX-M-8 → CTX-M-40 → CTX-M-63 CTX-M-25-type ESBL K. georgiana kluG1 gene → CTX-M-25 → CTX-M-26 → CTX-M-41 2004 2008 No. of strains No. of hospitals TEM type SHV type CTX-M type n = 49 n = 29 n=7 n=2 n = 40 (81%) No. of strains No. of hospitals TEM type SHV type CTX-M type n = 154 n = 150 n=6 n=3 n = 143 (93%) CTX-M-1 CTX-M-2 CTX-M-3 CTX-M-9 CTX-M-14 CTX-M-15 n = 10 n=2 n=7 n=7 n=2 n = 11 (27.5%) CTX-M-1 CTX-M-2 CTX-M-3 CTX-M-9 CTX-M-14 CTX-M-15 n = 50 n=4 n=1 n=2 n = 10 n = 76 (53%) Other types of ESBL of Ambler class A enzymes are naturally able to hydrolyze 3rd generation cephalosporins and/or several carbapenems such as CTX-M, VEB, GES and IBC, PER, TLA, BES, and SFO (for summary see also Paterson and Bonomo, 2005). Although a number of genetic mechanisms have apparently been involved in the assimilation of blaCTX-M genes, insertion sequences ISEcp1 and ISCR1 in association with class 1 integron structures have obviously played a prominent role in these processes (Bonnet, 2004; Eckert et al., 2004; Poirel et al., 2005). The incorporation of a blaCTX-M gene in E. coli or Klebsiella spp. results in cefotaxime resistance. Expansion of the hydrolytic spectrum to ceftazidime is due to mutations which mainly affect the -loop of the enzymes (Poirel et al., 2002; Cartelle et al., 2004; Novais et al., 2008). New CTX-M types possessing an extended substrate spectrum can result from convergent evolution within each blaCTX-M subgroup. This is evident for different genetic surroundings of the blaCTX-M-14 gene in E. coli from the same hospital setting (Navarro et al., 2007). Furthermore, this can be facilitated in mutator strains (Stepanova et al., 2008). A brief overview about origin, dissemination, and expansion of substrate spectrum of CTX-M enzymes is given in Table 2. Recent emergence and origin of CTX-M-type ESBL Dissemination of CTX-M genes The description of the first CTX-M-type ESBL, namely CTXM-1, goes back to the late 1980s. Thereafter, new variants have been increasingly reported. At present, 95 variants are assigned in the Lahey clinic database. They are clustered into five lineages or subgroups according to amino acid sequence similarities. Each subgroup has a natural ancestor represented by a chromosomal gene of the different environmental Kluyvera species, especially K. ascorbata and K. georgiana (Bonnet, 2004). Very likely, the heterogeneity of CTX-M types among clinical, enterobacterial isolates reflects that blaCTX-M genes have been captured from different sources within the genus Kluyvera by multiple events (Barlow et al., 2008). In general, spread of antibiotic resistance genes like blaCTX-M is facilitated by 3 major strategies: (a) clonal dissemination of the bacterial strain which has acquired resistance genes; (b) spread of a particular plasmid and/or transposon between a variety of different strains; and (c) translocation of resistance genes between different mobile genetic elements. At first sight, one would assume that the European-wide rise of CTX-M-type ESBL is based on dissemination of particular mobile genetic elements and/or plasmids. However, a more detailed analysis of the genetic environment of blaCTX-M genes indicates that this is rather due to a series of independent events. The blaCTX-M-15 a CTX-M types mediating ceftazidime resistance by mutations expanding the substrate spectrum. Fig. 3. Examples for the genetic environment of blaCTX-M in different plasmids harboured by nosocomial E. coli isolates (Cullik et al., 2010). Please cite this article in press as: Pfeifer, Y., et al., Resistance to cephalosporins and carbapenems in Gram-negative bacterial pathogens. Int. J. Med. Microbiol. (2010), doi:10.1016/j.ijmm.2010.04.005 G Model IJMM-50480; No. of Pages 9 ARTICLE IN PRESS Y. Pfeifer et al. / International Journal of Medical Microbiology xxx (2010) xxx–xxx gene which became prevalent in Europe was supposed to be originated from the related, plasmid-encoded blaCTX-M-3 gene which had spread in Poland recently. The Polish blaCTX-M-3 gene, however, is located in a different distance from ISEcp1 than blaCTX-M-15 in isolates from UK, France, Turkey, Canada, and India (overview by Livermore et al., 2007). Although blaCTX-M-15 containing E. coli have firstly been described in India, there is no real evidence for spreading to UK and France later on. Further more, it remains unclear why CTX-M-group 9 enzymes (CTX-M-14, CTX-M-16, CTXM-19, CTX-M-27) are predominant in Spain and group 1 enzymes (CTX-M-1, CTX-M-3, CTX-M-15) in most of the other European countries (Livermore et al., 2007). For E. coli from nosocomial infections in Germany, an increase of the proportion of CTX-M-15 has been observed (Table 3). In this study, ESBL types of phenotypically ESBL-positive E. coli from blood cultures, wound infections and tracheal secretions, isolated in different hospitals throughout Germany were determined by PCR and sequencing (Pfeifer et al., 2010a). A wide dissemination of one particular blaCTX-M-15 containing E. coli strain belonging to serotype O25 ST131 in hospitals and in the community had been reported for England and Wales from 2003 to 2005 (Woodford et al., 2004). Interhospital spread of an E. coli strain expressing blaCTX-M-15 has also been observed in France (Leflon-Guibout et al., 2004). Plasmid hospitalism was described for a 90-kb blaCTX-M-15 -containing IncFII plasmid in a Lebanese hospital (Kanj et al., 2008). In 2006, ESBL-producing E. coli from a German university hospital were analysed. For 21 of the 22 corresponding isolates, a large potpourri of CTX-M-type ESBL were detected, representing CTX-M groups 1 (blaCTX-M-1, blaCTX-M-3 , blaCTX-M-15 ) and 9 (blaCTX-M-9, blaCTX-M-14 , blaCTX-M-65 ). Additionally, blaCTX-M-1 and blaCTX-M-15 were found to be associated with plasmids of different incompatibility groups (IncN, IncI1, IncFII). The analysis of their genetic environment indicated the integration of an IS26/CTX-M element into different plasmids. Because of their similar genetic neighbourhood (Fig. 3) either hot spots for IS integration or exchange of a particular larger blaCTX-M containing module can be supposed (Cullik et al., 2010). 5 Resistance to cephalosporins: AmpC -lactamases The ampC gene which is contained in the chromosome of nearly all enterobacterial species besides Klebsiella spp. and Proteus spp. is regulated by a complex mechanism (Fig. 4). Beta-lactam antibiotics like cefoxitin induce ampC expression by binding to transpeptidases (penicillin-binding proteins) resulting in a balance shift to murein degradation (Jacobs et al., 1997). The degradation products (anhydro-muropeptides) are transferred into the cytoplasm mediated by the AmpD porin (Normark, 1995). Function of these degradation products in cytoplasm is the activation of the transcriptional regulator AmpR causing increased promoter activity. The AmpD amidase counteracts this activation by further degradation of muropeptides. Different ampD gene mutations lead to a functional loss of AmpD and cause constitutive high-level ampC expression. Another reason for a permanent ampC expression are specific ampR mutations that reduce the ability of AmpR binding the UDP-muropeptide repressor (Kuga et al., 2000). For E. coli, there are 2 options to confer broad-spectrum cephalosporin resistance mediated by AmpC enzymes: - high-level expression of the intrinsic E. coli ampC gene by generation of more efficient promoter structures; and - acquisition of plasmid-borne ampC originating from other enteric species. Chromosomal AmpC ˇ-lactamases and cephalosporin resistance in E. coli In cephalosporin-susceptible E. coli wild-type strains, the ampC expression is on a low level because of degenerated promoter boxes. A mutation at position −42 of the ampC promoter sequence associated with a mutation at position −18 generates 2 new alternative promoter boxes which result in high-level expression of chromosomal E. coli ampC and mediating cephalosporin resistance (Caroff et al., 2000). Furthermore, mutations with in the −10 and −35 ampC promoter boxes as well as insertions of nucleotides Fig. 4. Regulation of ampC in Enterobacteriaceae (according to Wiegand, 2003). Please cite this article in press as: Pfeifer, Y., et al., Resistance to cephalosporins and carbapenems in Gram-negative bacterial pathogens. Int. J. Med. Microbiol. (2010), doi:10.1016/j.ijmm.2010.04.005 G Model IJMM-50480; No. of Pages 9 6 ARTICLE IN PRESS Y. Pfeifer et al. / International Journal of Medical Microbiology xxx (2010) xxx–xxx Fig. 5. Examples for mutations in the Escherichia coli ampC promoter sequence generating a new (108/04) or more efficient (67/04; 99/04) promoter in clinical isolates from nosocomial blood stream infections in a German hospital (Pfeifer and Witte, 2007). * E. coli wild-type ampC promoter sequence; underlined, ampC promoter boxes, single nucleotide polymorphisms (SNPs) and start codon ATG. Table 4 Examples for plasmid-mediated AmpC -lactamases in Enterobacteriaceae. AmpC-type -lactamases Likely origin Country and year Species References CMY-1 MIR-1 BIL-1 CMY-2 MOX-1 FOX-1 DHA-1 ACC-1 Aeromonas hydrophila Enterobacter cloacae Citrobacter freundii Citrobacter freundii Aeromonas hydrophila Aeromonas caviae Morganella morganii Hafnia alvei South Korea, 1988 USA, 1988 Pakistan, 1989 Greece, 1990 Japan, 1991 Argentina, 1989 Saudi Arabia, 1992 Germany 1997 K. pneumoniae K. pneumoniae E. coli K. pneumoniae K. pneumoniae K. pneumoniae Salmonella enteriditis K. pneumoniae Bauernfeind et al. (1989) Jacoby and Tran (1999) Payne et al. (1992) Bauernfeind et al. (1996) Horii et al. (1993) Gonzalez et al. (1994) Gaillot et al. (1997) Bauernfeind et al. (1999) between these promoter boxes increase the promoter activity and entail in high-level ampC expression as described previously (Siu et al., 2003). Examples of the promoter region of ampC found in clinical isolates of E. coli are displayed in Fig. 5. Plasmid-mediated AmpC ˇ-lactamases and cephalosporin resistance Constitutive expression of plasmid-located ampC genes mediates resistance to broad-spectrum cephalosporins in species without own ampC gene (e.g. Klebsiella spp.) or in species with low-level expression of the intrinsic ampC gene (e.g. E. coli). Starting point was the mobilisation of chromosomal ampC genes from different enteric bacteria (such as C. freundii and E. cloacae) and horizontal transfer in other species (Philippon et al., 2002). Only a few mobilization events are likely, e.g. the C. freundii ampC gene seems to have been mobilized only one time not long ago (Barlow and Hall, 2002a). The first plasmid-borne ampC gene, namely CMY-1, was already reported in 1989 (Bauernfeind et al., 1989), followed by MIR-1 and CMY-2 (Papanicolaou et al., 1990). Until today, a number of other types like MOX-1, FOX-1, DHA-1, and ACC-1 were described (Table 4). A closer look at the phylogeny of ampC genes, based on Bayesian phylogenetic inference, revealed that plasmidborne AmpC -lactamases, e.g. the C. freundii ampC differ from their ancestors only by a few mutations (overview see also Jacoby, 2009). However, the amino acid-sequence similarities of AmpC enzymes from different ancestors are small. At present, the CMY and DHA -lactamases are most frequent AmpC in E. coli and K. pneumoniae, and a further dissemination and frequency rate is to be expected. Resistance to carbapenems: class A carbapenemases Four different groups of class A enzymes exerting carbapenemase activity became recently known: (i) SME: nearly exclusively associated with S. marcescens with 3 variants described so far (Queenan et al., 2000, 2006); (ii) IMI (NUC-A): preferentially in E. cloacae (from the United States, France, and Argentina). Although flanked by tpnA of Tn5O3, it is not known whether blaIMI is mobile (Rasmussen et al., 1996); (iii) GES (named after first detection in K. pneumoniae from Guiana): sixteen variants are known so far; there are indications for integron location. GES enzymes were mainly found in P. aeruginosa, but also in K. pneumoniae and E. coli from both North America and Asia (Poirel et al., 2000a). (iv) KPC (acronym for K. pneumoniae carbapenemase): ten variants are known so far. KPC-2 and KPC-3 are the most frequent variants worldwide. The blaKPC genes are located on the novel tn3-based transposon tn4401 (Naas et al., 2008). KPC-2 was first described in a carbapenem-resistant K. pneumoniae in North Carolina in 2001 (Yigit et al., 2001). Furthermore KPC2 was reported in isolates of Salmonella enterica in the USA (Miriagou et al., 2003), K. oxytoca (Yigit et al., 2003), P. aeruginosa (Villegas et al., 2007), and E. cloacae (Bratu et al., 2005). KPC-3 was frequently detected in nosocomial K. pneumoniae in the North East of the USA and in Israel (Bratu et al., 2005; Shiri et al., 2009). Until today, KPC-producing K. pneumoniae have also been observed in Europe (Naas et al., 2005) and in Finland (Österblad et al., 2009), South America (Villegas et al., 2006), China (Cai et al., 2008), and Germany (Wendt, 2008). Resistance to carbapenems: class D -lactamases (OXA) According to the original definition, OXA -lactamases were named for their ability to hydrolyse oxacillin. Also included are several oxacillinases with an extended hydrolysis spectrum for cephalosporins caused by amino acid substitutions (Naas and Nordmann, 1999; Bush, 1988). Most of these OXA-type ESBL derive from OXA-10 (e.g. OXA-11, OXA-14, OXA-16, OXA-17) or in a subcluster from OXA-15 (e.g. OXA-19, OXA-28). OXA2 derivatives are rarer (Walther-Rasmussen and Hoiby, 2006). The OXA carbapenemases are a number of different class D OXA enzymes such as OXA-23-like, OXA-24-like, OXA-48, OXA-51-like, and OXA-58-like (Walther-Rasmussen and Hoiby, 2006). Initially, OXA-beta-lactamases were reported from P. aeruginosa but until now, these carbapenemases have been detected in many other Gram-negative bacteria including Enterobacteriaceae. The natural Please cite this article in press as: Pfeifer, Y., et al., Resistance to cephalosporins and carbapenems in Gram-negative bacterial pathogens. Int. J. Med. Microbiol. (2010), doi:10.1016/j.ijmm.2010.04.005 G Model IJMM-50480; No. of Pages 9 ARTICLE IN PRESS Y. Pfeifer et al. / International Journal of Medical Microbiology xxx (2010) xxx–xxx 7 Table 5 Intrinsic and acquired metallo--lactamases (according to Bebrone, 2007). Subclass Metallo-enzyme Bacterial species Year of first description B1, intrinsic BcII CcrA BlaB IND-1 EBR-1 SFB-1 SLB-1 Bacillus cereus Bacillus fragilis Elizabethkingia meningoseptica Chryseobacterium indologenes Empedobacter brevis Shewanella frigdimarina Shewanella livingstonens 1966 1990 1998 1999 2002 2005 2005 B1, acquired IMP-1 VIM-1 IMP-2 VIM-2 SPM-1 GIM-1 SIM-1 P. aeruginosa, S. marcescens A. baumannii, P. aeruginosa S. marcescens, A. baumannii P. aeruginosa, A. baumannii P. aeruginosa P. aeruginosa A. baumannii 1994 1999 2000 2000 2002 2004 2005 B2, intrinsic CphA ImiS Sfh-1 Aeromonas hydrophila Aeromonas veronii Serratia fonticola 1991 1996 2003 B3, intrinsic GOB-1 FEZ-1 THIN-3 Mbl1b CAU-1 BJP-1 Elizabethkingia meningoseptica Legionella gormanii Janthinobacterium lividum Caulobacter crescentus Caulobacter vibrioides Bradyrhizobium japonicum 2000 2000 2001 2001 2002 2006 reservoir of blaOXA genes is most probably in environmental bacteria e.g. Ralstonia spp., Burkholderia spp. as well as in deep cold see microflora such as Shewanella spp. (Heritier et al., 2004). The big family of OXA carbapenemases is very diverse and blaOXA genes are located on both chromosomes and plasmids. A study based on Bayesian phylogeny of blaOXA genes revealed that this diversity results mainly from ancient events as well as the mobilization from chromosomes to plasmids occurred millions of years ago (Barlow and Hall, 2002b). Chromosomal-encoded blaOXA genes play a particular role in antibiotic resistance of Acinetobacter baumannii. OXA-51-like lactamases in this species are strongly associated with the 3 major epidemic lineages (“European” clones I, II, and III as defined by AFLP; Evans et al., 2008). The blaOXA-51-like genes are of special interest because they seem to be ubiquitous in A. baumannii. Insertion of ISAba1 upstream blaOXA-51-like provides a strong promoter resulting in enhanced gene expression and carbapenem resistance (Merkier and Centron, 2006; Turton et al., 2006). The wide geographical dissemination of OXA carbapenemases is obviously associated with travelling of patients. In Germany, 2 outbreaks of infections with multiresistant A. baumannii were recorded in 2007, in total 16 patients and 9 patients, respectively; unfortunately, associated with a number of fatal outcomes. Plasmid-borne OXA-58 was identified in the first and OXA-23 in the second outbreak. For both events, an acquisition of the epidemic strain by the index patient in a hospital abroad was likely (Pfeifer et al., 2010b). Resistance to carbapenems: class B metallo--lactamases (MBL) MBL belong to a superfamily of enzymes with wide catalytic diversity [(oxydoreductases, glyoxylases, phosphoryl cholinesterase (for review see Bebrone, 2007)]. These enzymes are basically able to hydrolyse all -lactam antibiotics except monobactams. Based on DNA sequence alignments of the genes, MBL are classified into 3 subclasses: B1, B2, and B3 (Garau et al., 2004). Although there is a low degree of similarity between the determinants of the subclasses, this grouping is supported by crystallographic analysis of the corresponding enzymes. The ability of MBL production has not only been detected in Gram- negative bacterial pathogens, but also in a surprising number of environmental bacteria. An overview is shown in Table 5. Especially subclass B1 MBL genes (intrinsic or acquired) were found in many bacterial species. Recently the new MBL enzyme NDM-1 was identified in K. pneumoniae (Dongeun et al., 2009). In contrast, subclass 2 enzymes were mostly identified in different Aeromonas species (Walsh et al., 1996). Subclass B3 enzymes are intrinsic in a number of different environmental species from which some of them can come out as nosocomial pathogen in immunocompromized patients (e.g. S. maltophilia; Walsh et al., 1994, 2005). Dissemination of acquired subclass B1 MBL The most frequent MBL acquired by Gram-negative bacterial pathogens are of IMP and VIM type. These enzymes were originally described in P. aeruginosa and A. baumannii, but today they are also spread in Enterobacteriaceae (Poirel et al., 2000b; Tortola et al., 2005). For VIM-type enzymes, 12 allelic variants are known so far (Walsh et al., 2005). The emergence of different VIM and IMP subtypes in different geographical areas suggests that the corresponding genes have been captured independently from (unknown) natural reservoirs. This view is supported by reports on more rarely acquired MBL: SPM-1 in South America (Toleman et al., 2002), GIM-1 in Germany (Castanheira et al., 2004), and SIM-1 in Korea (Lee et al., 2005). The genetic determinants for these acquired MBL are in most cases incorporated in type 1 or type 3 integrons located on large plasmids or the chromosome. For blaSPM-1 , an association with the ISCR44 element has been described. These insertion elements are able to mobilize long stretches of adjacent DNA, most probably by rolling circle replications. ISCR elements have also been described for P. aeruginosa with blaIMP-1 and blaVIM-1 (Toleman et al., 2006). Carbapenemase-producing, multidrug-resistant K. pneumoniae, the forerunner of an end of the antibiotic era? In K. pneumoniae, there is a variety of mechanisms to elude the effect of carbapenems: (a) AmpC production plus porin loss; (b) production of a “classical” ESBL plus porin loss; (c) production of carbapenemases such as KPC or OXA; as well as (d) production of Please cite this article in press as: Pfeifer, Y., et al., Resistance to cephalosporins and carbapenems in Gram-negative bacterial pathogens. Int. J. Med. Microbiol. (2010), doi:10.1016/j.ijmm.2010.04.005 G Model IJMM-50480; 8 No. of Pages 9 ARTICLE IN PRESS Y. Pfeifer et al. / International Journal of Medical Microbiology xxx (2010) xxx–xxx acquired MBL (Jacoby et al., 2004). Multidrug-resistant K. pneumoniae have been described from many parts of the world such as Greece, the Near East, the United States (Deshpande et al., 2006). This development is reflected by 3 examples from Germany (Pfeifer and Witte, 2008; Wendt, 2008): (i) a cluster of infections (n = 4) in 2 German hospitals associated with K. pneumoniae producing a combination of 3 enzymes (VIM-1, CMY-4, CTX-M-9) in each strain and conferring resistance to all available antibiotics but colistin, (ii) a cluster of infections (n = 5) in 2 German hospitals with multidrug-resistant K. oxytoca containing blaVIM-1 , qnrB2, and deletions in porin genes ompK35/36 resulting in a translational stop, (iii) a cluster of infections with KPC-2-producing K. pneumoniae and E. coli in Germany conferring resistance to all antibiotics except colistin. Infections with carbapenem-resistant Enterobacteriaceae are still rare in many European countries (see also Fig. 2). 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