Minor extended-spectrum β-lactamases

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Uncontrollable dissemination of extended-spec-trum b-lactamases (ESBLs) on mobile genetic elements is worrisome. Owing to the highly adap-tive nature of ESBL genes, numerous variants have emerged and have been disseminated world-wide; therefore, their nomenclature and defini-tion are changing [1,2]. However, this article will refer to the classical definition of the term ESBL, according to which, ESBL is an enzyme that is able to hydrolyze oxyimino-cephalosporins but not cephamycins or carbapenems and is inhibited by clavulanic acid [2].

Currently, there are two popular classifica-tion schemes for b-lactamases: one is based on its molecular structure identity, the Ambler scheme; the other is the functional classification scheme. The Ambler scheme divides b-lactamases into four classes: class A, class C and class D rep-resent serine enzymes, whereas class B represents metallo-enzymes [3]. The functional classification scheme, originally proposed in 1995 by Bush et al., divides b-lactamases into three groups with various subgroups [4]. Typically, Group 1 enzymes are the chromosomal cephalosporinases represented in Ambler class C, and Group 3 enzymes are the metallo-enzymes represented in Ambler class B. Group 2 enzymes are organ-ized into 12 subgroups from 2a to 2f. ESBLs are classified under Group 2be in the functional classification scheme. In Group 2be, there are enzymes from large TEM and SHV families as

well as minor ESBLs. This article is focused on three emerging families of ESBLs: CTX-M, PER and VEB of Group 2be.

CTX-M-typeThe CTX-M-1 enzyme was first described on a highly cefotaxime-resistant Escherichia coli strain (MIC 128 mg/l) isolated from an ear exudate from a newborn child in Germany [5]. Subsequently, the CTX-M-2 enzyme was reported from cefotaxime-resistant Salmonella enterica serovar Typhimurium strains isolated from clinical speci-mens from patients suffering from meningitis, septicemia or enteritis in Argentina [6]. Since then, the CTX-M enzymes have formed a rapidly growing family of ESBLs distributed both over a wide geographic area and among a wide range of clinical bacteria, particularly members of the Enterobacteriaceae [7].

CTX-M ESBLs are found in many regions worldwide, including South America (Argentina and Brazil), the Far East (Japan, China, Korea, Taiwan, Vietnam and India), Eastern Europe (Poland, Latvia, Russia, Greece, Hungary, Bulgaria, Romania and Turkey) and Western Europe (France, Germany, Spain and the UK) [7,8]. While endemic situations are domi-nant in most European countries, Asia and South America, the USA sporadically reports CTX-M-producing isolates [9,10]. However, an increasing number of recent reports from the

Esragul Akinci1 and Haluk Vahaboglu†2

1Ankara Numune Egitim ve Araştırma Hastanesi, Enf. Hst & Klin. Mikr. Klinigi, Ankara 06100, Turkey 2Kocaeli Universitesi, Tip Fakultesi Enf. Hst & Klin. Mikr. Dept, Kocaeli 41380, Turkey †Author for correspondence:[email protected]

Over the last few decades, various extended-spectrum b-lactamases (ESBLs), which are remotely related to the classical TEM and SHV families, have emerged. Among these, CTX-M, VEB and PER variants are of particular interest due to their widespread dissemination. This article will focus on these emerging ESBLs. CTX-M was first identified from an Escherichia coli strain in Germany and since then, a rapidly growing family of ESBLs has formed worldwide. There are now more than 90 CTX-M variants. VEB-1 ESBL is widespread in Southeast Asia. It was first identified in an E. coli strain isolated from a Vietnamese boy in 1996. After the initial discovery, it spread to other species. PER-1, now reported from various continents, was restricted to Turkish hospitals for years after the first identification in a strain of Pseudomonas aeruginosa in 1993. The worldwide dissemination of ESBLs is a healthcare crisis that deserves special attention.

Keywords: b-lactamase • Acinetobacter • antimicrobial drug resistance • Escherichia coli • Pseudomonas aeruginosa

Minor extended-spectrum b-lactamasesExpert Rev. Anti Infect. Ther. 8(11), 1251–1258 (2010)

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USA have shown that CTX-M-producing isolates are widely distributed [11]. There are now more than 90 CTX-M vari-ants. Some of the enzymes are only found in specific countries, whereas some of them, such as CTX-M-15, have been detected worldwide [8,9,12].

CTX-M-type enzymes have been found predomi-nantly in the Enterobacteriaceae, most prevalently E. coli, Salmonella typhimurium, Klebsiella pneumoniae and Proteus mirabilis [13]. They have also been reported in the other spe-cies, such as Vibrio cholerae, Citrobacter freundii, Serratia marc-escens, Morganella morganii, Enterobacter aerogenes, Aeromonas hydrophila and Shigella flexneri [7].

CTX-M b-lactamases originated from the Kluyvera spp. of environmental bacteria. The bla

CTX-M genes have been described

or presumed to be natural and chromosomal in the species Kluyvera cryocrescens (bla

KLUC-1), Kluyvera ascorbata (bla

KLUA) and

Kluyvera georgiana (blaKLUG-1

) [7,14–16]. CTX-M ESBLs have 40% or less similarity with TEM and SHV-type ESBLs [10,13].

In clinical strains, CTX-M-encoding genes are mostly located on transferable plasmids [13]. The bla

TEM-1 gene often coexists on

the same plasmid and associations with blaTEM-2

, blaOXA-1

and bla

SVH genes are probable [7]. These plasmids can also carry genes

for resistance to other antibiotics, including amino glycosides, fluoro quinolones, chloramphenicol, sulfonamides and tetra-cyclines [7,9]. Different genetic elements may be involved in the mobilization and transfer of bla

CTX-M genes. Insertion sequences,

especially ISEcp1 and the class I integron-associated Orf513, appear to be involved in the mobilization of bla

CTX-M genes

[7,9,13,17–19]. Other elements, such as IS10 and IS26, may also play a role in the mobilization of bla

CTX-M genes [7,20,21]. One study,

interestingly, found phage-related sequences adjacent to blaCTX-M-10

genes, which suggested that transduction might be a possible mechanism for b-lactamase gene transfer [22].

CTX-M-type enzymes confer resistance to penicillins, extended-spectrum cephalosporins and monobactams. They are inhibited by clavulanate, sulbactam and tazobactam. CTX-M b-lactamases are less effective against penicillins than TEM and SHV and the highest hydrolytic activity is obtained against nar-row-spectrum cephalosporins [7]. Characteristically, the CTX-M enzymes hydrolyze cefotaxime more efficiently than ceftazidime, and MIC levels of cefotaxime are usually several-fold higher than ceftazidime [10,13]. Although the MIC of ceftazidime increases, it often remains in the 2–8 µg/ml range and it has been sug-gested that patients infected with CTX-M-producing isolates in this MIC range to ceftazidime may be successfully treated with it [10,23,24]. Low hydrolytic activity against ceftazidime might be used to distinguish CTX-M enzymes from TEM and SHV enzymes. However, certain types of CTX-M enzymes also inacti-vate ceftazidime and confer resistance to this agent [10,25–27]. The emergence of these variants suggests that the CTX-M enzymes are evolving and have activity against ceftazidime [7]. CTX-M ESBLs are also very active against cefepime and MICs are higher than in other ESBLs. Thus, cefepime MIC levels may be useful for predicting the presence of CTX-M enzymes [28]. Cefepime cannot be used if the MIC exceeds 8 mg/l, which predicts the presence

of CTX-M b-lactamases. However, cefepime may be used if the MIC is less than or equal to 1 mg/l, which indicates the absence of a CTX-M enzyme [28].

The CTX-M ESBLs are inhibited by b-lactamase inhibi-tors. Tazobactam exhibits the greatest inhibitory effect, while sulbactam is the least active [10,29–31]. The level of resistance to b-lactam plus b-lactam inhibitor combinations depends on the amount of enzyme produced. Generally, with combinations of clavulanate and amoxicillin or ticarcillin, susceptibility or a low level of resistance is observed. Resistance to piperacillin is usually blocked by tazobactam [7].

CTX-M-producing isolates play a role in nosocomial infec-tions. However, in contrast to SHV and TEM ESBLs, CTX-M enzymes also emerge in community-acquired infections; the dra-matic increase in these infections has exacerbated public-health concerns [9,23,32]. In community-acquired infections, E. coli is the most common CTX-M ESBL-producing pathogen (especially CTX-M15). Most of these infections are urinary tract infec-tions, but bacteremia and gastroenteritis have also been reported [8,23,32,33]. Recent reports have shown that community-acquired bloodstream infections caused by CTX-M-producing E. coli may be a serious threat to public health [34,35]. The widespread use of cephalosporins and fluoroquinolones has been proposed as a fac-tor contributing to the emergence of CTX-M ESBL-producing bacteria in the community setting [23].

The causes of the increase in community-acquired infections with CTX-M-producing isolates are not yet clear. Antibiotic over-use, hospital cross-infection, animals, the food chain, trade and human migration seem to have contributed to the recent dissemi-nation of ESBLs outside of hospitals [8,12]. CTX-M ESBL genes have been detected in food-producing animals [36,37]. This may pose a human health hazard and resistance may be transferred by close contact, consumption of animal meat, or through the transfer of resistant genes from bacteria of animal origin to bacte-ria infecting humans [36]. These resistant genes can also be found in commensal microorganisms, which may serve as a reservoir. A dramatic increase in fecal carriage of CTX-M ESBL-producing isolates has been detected and the results denote the significance of the intestinal tract as a reservoir. It also indicates the increasing trend toward the endemic nature of these isolates [38].

The simultaneous observation of CTX-M enzymes in noso-comial and community strains from multiple geographic locations is consistent with their emergence from a widespread reservoir, owing to independent genetic events, such as the mobilization of bla

CTX-M genes from the chromosomes of environmental Kluyvera

bacteria [7]. CTX-M ESBLs are implicated in small, countrywide or international outbreaks. Several cases of outbreaks of noso-comial infections caused by bacteria expressing CTX-M ESBLs have been described [13]. The dissemination of these enzymes involves plasmid transfer or clonal spread, but they also involve mobile elements, such as ISEcp1 and orf513 [8–12].

CTX-M-producing bacteria are multiresistant. In addition to penicillins and cephalosporins, they also show resistance to aminoglycosides, fluoroquinolones, tetracyclines and sulfona-mides [8–11,13,32–34]. Therapeutic options in hospitalized patients

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infected with CTX-M-producing organisms are limited to carba-penems. Some non-b-lactam antibiotics, such as tigecycline, also have good activity against ESBL-positive bacteria [39]. According to susceptibility test results, aminoglycosides and fluoroquino-lones may be alternative therapeutic agents. Although, patients infected with CTX-M-producing isolates sensitive to ceftazi-dime were successfully treated with this agent, these data need to be confirmed with more studies [23,24]. Because of the inocu-lum effect, these isolates may be resistant to ceftazidime in vivo. Therefore, the use of ceftazidime can lead to therapeutic failure. In community-acquired infections, choices are more limited and include oral b-lactam/b-lactamase inhibitor combinations, fosfo-mycin or nitrofurantoin for urinary tract infections, oral fluoro-quinolones and trimethoprim–sulfamethoxazole, if the isolates are susceptible [9]. If this emerging public-health threat is ignored, clinicians may be forced, in future, to use carbapenems as the first choice for empirical treatment of serious community-acquired urinary tract infections [40].

VEB-typeThe bla

VEB-1 (Vietnamese extended-spectrum b-lactamase) gene

was first identified in an E. coli strain isolated from pus from a 4-month-old Vietnamese boy in 1996 [41]. It was located on a plasmid and an integron. Antibiotic susceptibility tests revealed high-level resistance to amino-, carboxy- and ureido-penicil-lins, oxyimino-cephalosporins, chloramphenicol, tetracycline, trimethoprim–sulfamethoxazole and aminoglycosides. In disk diffusion tests, the typical synergistic effect between ceftazi-dime or aztreonam and clavulanic acid was observed along with an unusual synergy between cefoxitin and cefuroxime. Kinetic parameters of VEB-1 showed a very high hydrolytic activity against extended-spectrum cephalosporins, except for ceftazi-dime and aztreonam, while the activity against penicillins was much lower [41].

After the initial discovery of VEB-1 b-lactamase, it spread to other species and the bla

VEB-1 gene was identified in other

Gram-negative bacteria including Pseudomonas aeruginosa, Klebsiella pneumoniae, Acinetobacter baumannii, Proteus mira bilis, Enterobacter cloacae, Citrobacter freundii, Providencia stuartii, Enterobacter sakazakii and Alcaligenes xylosoxidans [41–50]. VEB-1 b-lactamase is widespread in Southeast Asia. Several reports from Thailand and Vietnam have been published [42,48,49,51]. It has also been reported from other regions of the world, including France, Belgium, the UK, Bulgaria, Argentina, Iran, Kuwait, Algeria, China, Korea and India [43–47,50,52–59].

Protein sequence ana lysis showed that VEB-1 is a class A b-lactamase, having very low levels of homology with other b-lactamases. It has less than 20% amino acid identity with most known class A enzymes. The highest percentage of amino acid identity was 38% with PER-1 and PER-2 [41]. In addition, VEB-1 shares significant sequence identity with cblA and cepA, found in Bacteroides spp. [41]. Several VEB-1-like b-lactamases have been identified to date. They are VEB-1a, VEB-1b and VEB-2–7 [60,101]. All are minor variants of VEB-1, sharing similar amino acid identity. Thus, the hydrolytic activity of VEB-1-like

ESBL (kinetic data is not present for VEB-7 in the literature) is expected to be identical to that reported for VEB-1 b-lactamase, which confers high-level resistance to ceftazidime, cefotaxime and aztreonam [43,60].

In most instances, blaVEB-1

is located on a gene cassette, which is presented on a class 1 integron [41]. The bla

VEB-1 and bla

GES-1

gene cassettes are the only class A ESBL gene cassettes that are part of a class 1 integron [41,42]. The bla

VEB-1 gene was associated

mostly with IS1999 and rarely with an additional IS2000 element in P. aeruginosa isolates, whereas IS1999 was only very rarely associated with bla

VEB-1 in Enterobacteriaceae [61,62]. The asso-

ciation between IS1999 and the Pant

promoter enhances blaVEB-1

expression by about 60% in P. aeruginosa, but not in E. coli [62]. An increase in b-lactamase expression may change bacteria from being susceptible to being intermediate or resistant.

The location of the blaVEB-1

gene on a transferable plasmid deter-mines the threat of spread among other species. Epidemiological ana lysis indicated that bla

VEB-1 has spread among various entero-

bacterial species [41,42,48]. Its dissemination is not due to a single strain or a single plasmid type [42]. Most of the bla

VEB-1-positive

isolates had a self-conjugative plasmid [41,42,48]. It is indicated that the spread of bla

VEB-1 is due to the transfer of different plas-

mids and class 1 integrons and rarely to clonally related strains [42]. Researchers in Vietnam found a large transferable plasmid carrying a bla

VEB-1 gene in K. pneumoniae and E. coli isolates at

the same time from the same patient, indicating a horizontal gene transfer [41].

Nosocomial infections and outbreaks involving isolates with VEB-1 b-lactamase have been described in several countries, including France, Belgium, Korea and China [42,43,45–47,58,59]. In France, in 2003–2004, a nationwide outbreak emerged with clon-ally related A. baumannii isolates producing VEB-1 b-lactamase [45–47]. In these multiresistant strains, the bla

VEB-1 gene was identi-

fied on the chromosome and was part of an integron [45,47]. Most affected were intensive care units and medical wards [46,47]. Inter-hospital spread was associated with patient transfer [47]. Previous treatment with third-generation cephalosporins was identified as the only risk factor for A. baumannii acquisition [46]. The national alert enabled early control of new clusters and demonstrated the usefulness of early warning about antimicrobial drug resist-ance [47]. Intercountry spread of VEB-1-producing A. baumannii isolates was also illustrated. In Belgium, from December 2003 to March 2005, three hospitals located close to the French border, and one in the Brussels area, reported isolation of six VEB-1-positive A. baumannii isolates compatible with a French epidemic clone [53]. Restricted use of broad-spectrum antibiotics and strict hygiene measures are very important means for the prevention of the spread of ESBL-producing isolates [42].

PER-typePER-1 was first identified in a clinical P. aeruginosa strain (RNL-1) isolated from the urinary tract of a hospitalized patient who was transferred from a University hospital in Ankara, Turkey, to France [63]. RNL-1 was resistant to oxyimino-cephalosporins, which was reversible by clavulanate. An ESBL gene, named

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blaPER-1

, was cloned encoding a pI 5.4 class A ESBL that is remotely related to the classical TEM and SHV type enzymes (27% iden-tity) [64]. Initial experiments suggested a chromosomal location for bla

PER-1 [63]; however, studies on further isolates from Ankara

showed that blaPER-1

is encoded on conjugative plasmids larger than 154 kbp [65]. Resistance profiles of transconjugates were typical of class A ESBLs with high MICs for oxyimino-cephalosporins that are reversed by clavulanate. Interestingly, tazobactam was not such a successful inhibitor [65]. Kinetic studies with purified enzyme showed that PER-1 had strong hydrolytic activity against amoxi-cillin, ticarcillin, cephalothin and extended-spectrum cepha-losporins, and interestingly clavulanic acid, sulbactam, imipenem and cephamycins were inhibitors [63].

In 1994, PER-1-producing Salmonella were isolated in Istanbul, Turkey, from the CNS fluid of four neonatal meningitis cases, three of whom died [66]. All four neonates were born in the same hospital over a 4-month period, which pointed to a possible gastro intestinal carriage state of an ESBL-producing S. typhimu-rium isolate among hospital workers. Interestingly, the authors found, through a telephone survey among university hospitals in Istanbul, another ESBL-producing Salmonella isolate, which was subsequently shown to also be a PER-1 producer. This second hospital was located on the other side of Bosphorus, Turkey, and a link between the cases has not been documented. A retrospective study revealed the existence of a nosocomial PER-1-producing S. typhimurium outbreak in both hospitals and documented the clonality of the isolates [67].

In 1996, and later in 2006, two multicenter studies performed with contributions from university hospitals from distinct regions showed that PER-1 is stably widespread among nosocomial Acinetobacter spp. and P. aeruginosa isolates in Turkish hospitals [68,69]. PER-1 was identified as widespread and multifocal in Northern Italy among P. aeruginosa and among members of the Enterobacteriaceae [70–73]. Subsequent studies reported PER-1 from other European countries [53,74,75] and from the Asian continent [73,76].

Studies showed that the blaPER-1

gene is transposon associ-ated in both nonfermenter hosts and in Salmonella spp. [77]. In P. aeruginosa, P. stuartii and A. baumannii, bla

PER-1 was a part

of the IS4 family composite transposon, whereas in Salmonella spp. and A. baumannii, the transposon was not retained in a composite form.

Soon after the first identification of PER-1 in P. aeruginosa and the revelation of the fact that it is widespread in Turkish hospitals, PER-2 (86% amino acid identity with PER-1) was identified in a S. typhimurium strain from Argentina [78]. To date, PER-2 is restricted to South America, more specifically to Argentina, and is spreading among the members of the Enterobacteriaceae [79–81]. Currently, six PER-type enzymes are reported; PER-1, PER-3, PER-4 and PER-5 cluster together by single amino acid replace-ments, whereas PER-2 and PER-6 are located outside by 86% identity to the PER-1 amino acid sequence [82]. PER-6 was iden-tified in an Aeromonas allosaccharophila environmental isolate, whereas PER-3, PER-4 and PER-5 were identified in Aeromonas punctata, Proteus vulgaris and A. baumannii, respectively, according to GeneBank data.

PER-type ESBLs are evolving and disseminating worldwide and, most importantly, the occurrence of PER-type ESBLs in hospitals pose significant health problems to patients [83].

Expert commentary & five-year view“Gram-negative bacteria combat antibiotics predominantly by three mechanisms: first is the up- or downregulation of efflux/porin barriers, which prevents the antibiotics from accessing targets; second is the mutational modification of targets, which reduces the antibiotics’ affinity for their targets; and third is the enzymatic inactivation of antibiotics. The first two mecha-nisms depend on modifications of already existing structures in the bacteria and might be sorted under the evolutionary term ‘adaptive mutation.’ This is a weapon that a microorganism uses immediately to survive antibiotic pressure. It appears readily and, once the pressure diminishes, it reverts [84–86]. By contrast, enzy-matic inactivation of antibiotics, as is the case with b-lactamases, often depends on the acquisition of extrinsic determinants. This type of resistance arrives after a complex adaptation process of the extrinsic gene to the host, defined as ‘cost of fitness.’ Once a host has paid that cost, eliminating the fitted resistant determi-nant is difficult and requires time. Both of these methods, the mutational alteration of existing structures and the acquisition of extrinsic genes, are adaptive machinery that bacteria use to respond to changing environmental conditions.”

This is an ordinary introductory paragraph of a discussion on the b-lactamase problem. How should we decode this para-graph? Does it intend to imply that microorganisms can plan, sense changes in their environment and take appropriate counter measures? In our example, do microorganisms sense b-lactam antibiotics in their environment and acquire suitable resistance genes or appropriately mutate existing genes? Almost 900 b-lacta-mases have been identified. Have all these enzymes evolved on purpose, or are they the consequences of random events, as Luria and Delbrück suggested in 1943 [87]?

The authors believe that all these mutations or genetic acquisi-tions are unpredictable and constitutional errors of bacterial biol-ogy. These and even more mutations have occurred under forces driven by DNA replication and repair errors since such organisms first appeared. The authors believe that bla genes existed and were attempting to disseminate among bacteria since Lucy (lived 3.2 million years ago).

From the authors’ viewpoint, the critical question is: what prevented the dissemination of these mutant organisms or bla genes prior to the wide and extensive consumption of germ-killing compounds?

The answer, according to the authors, is obviously competition between the susceptible counterparts sharing the same micro-environment and its limited resources with mutants. Mankind disturbed this balance in the microenvironment. We must see that the concept the antibiotic market’s actors and opinion leaders propound depends exclusively on destroying the resist-ant bacteria by consuming new, expensive and highly efficient antibiotics, which, put another way, also means destroying the susceptible counterparts and degenerating the natural balance

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more and more. We must leave this concept and try to restore the natural balance. The authors assert that this is the only safe way to combat resistant microorganisms in terms of b-lactamases and b-lactam antibiotics.

One last point is that we must all understand that research-ing resistant genes and mechanisms, and even the epidemiol-ogy of resistance, is different from managing healthcare and setting healthcare policies. Research on resistance issues has evolved during the past few decades to the genetic level, and is currently progressing even more deeply. One consequence of such a technical level is the prominence of basic research sci-entists in this area. The technical level these scientists provide has improved our understanding of resistance genes’ kinetics, which is invaluable; however, we must cautiously interpret the

conclusions regarding antibiotic and healthcare policies drawn by scientists who lack medical knowledge and are unfamiliar with infectious diseases.

The authors believe that the future of infectious diseases largely depends on our conceptual behavior on the resistance issue and on prioritizing ‘prevention’ over ‘killing’.

Financial & competing interests disclosureThe authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

No writing assistance was utilized in the production of this manuscript.

ReferencesPapers of special note have been highlighted as:• of interest•• of considerable interest

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2 Livermore DM. Defining an extended-spectrum b-lactamase. Clin. Microbiol. Infect. 14(Suppl. 1), 3–10 (2008).

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Key issues

• CTX-M extended-spectrum b-lactamases (ESBLs) are widespread throughout the world and have been found predominantly in the Enterobacteriaceae, most prevalently Escherichia coli, Salmonella typhimurium, Klebsiella pneumoniae and Proteus mirabilis.

• CTX-M b-lactamases originated from the Kluyvera spp. of environmental bacteria and blaCTX-M

genes are mostly located on transferable plasmids. Different genetic elements, especially ISEcp1 and the class I integron-associated Orf513, also appear to be involved in the mobilization of bla

CTX-M genes.

• In contrast to SHV and TEM ESBLs, CTX-M enzymes also emerge in community-acquired infections and the dramatic increase in these infections exacerbates public health concerns. In community-acquired infections, E. coli is the most common CTX-M ESBL-producing pathogen (especially CTX-M15) and most of the infections are urinary tract infections.

• VEB-1 b-lactamase is widespread in Southeast Asia. However, nationwide outbreaks and intercountry spread involving isolates with VEB-1 b-lactamase were also reported in Europe.

• PER-1 is widespread in various countries in the Old world while PER-2 is disseminating countrywide in South America.

• Class A ESBLs are now a global health threat; dissemination is unpreventable but might be curtailed by infection control measures and, particularly, by globally applied antibiotic restriction policies.


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CTX-M)

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