Antibiotic resistance and extended spectrum beta-lactamases: Types, epidemiology and treatment (2024)

2.1. Interference with cell wall synthesis

Beta-lactam antibiotics like penicillin and cephalosporin impede enzymes that are responsible for the formation of peptidoglycan layer (Benton et al., 2007).

2.2. Inhibition of protein synthesis

Oxazolidinones, the newest class of antibiotics, interact with the A site of the bacterial ribosome where they should interfere with the placement of the aminoacyl-tRNA. Tetracyclines interfere with protein synthesis by binding to 30S subunit of ribosome, thereby weakening the ribosome-tRNA interaction. Macrolides bind to the 50S ribosomal subunit and inhibit the elongation of nascent polypeptide chains. Chloramphenicol binds to the 50S ribosomal subunit blocking peptidyl transferase reaction. Aminoglycosides inhibit initiation of protein synthesis and bind to the 30S ribosomal subunit (Leach et al., 2007).

2.3. Interference with nucleic acid synthesis

Rifampicin interferes with a DNA-directed RNA polymerase. Quinolones inhibit DNA synthesis with interference of type II topoisomerase, DNA gyrase and type IV topoisomerase during replication cycle causing double strand break (Strohl, 1997).

2.4. Inhibition of a metabolic pathway

Sulfonamides (e.g. sulfamethoxazole) and trimethoprim each block the key steps in the folate synthesis, which is a cofactor in the biosynthesis of nucleotides, the building blocks of DNA and RNA (Strohl, 1997).

2.5. Disorganizing of the cell membrane

The primary site of action is the cytoplasmic membrane of Gram-positive bacteria, or the inner membrane of Gram-negative bacteria. It is hypothesized that polymyxins exert their inhibitory effects by increasing bacterial membrane permeability, causing leakage of bacterial content. The cyclic lipopeptide daptomycin displays rapid bactericidal activity by binding to the cytoplasmic membrane in a calcium-dependent manner and oligomerizing in the membrane, leading to an efflux of potassium from the bacterial cell and cell death (Straus and Hanco*ck, 2006). Antibiotic resistant versus antimicrobial activity mechanism is shown in Fig. 1.

3.1. Antibiotic inactivation

3.2. Antibiotic inactivation by group transfer

The most diverse family of resistant enzymes is the group of transferases. These enzymes inactivate antibiotics (aminoglycosides, chloramphenicol, streptogramin, macrolides or rifampicin) by chemical substitution (adenylyl, phosphoryl or acetyl groups are added to the periphery of the antibiotic molecule). The modified antibiotics are impaired in their binding to a target. Chemical strategies include O-acetylation and N-acetylation (Blanchard, 2004; Schwarz et al., 2004), O-phosphorylation (Matsuoka and Sasaki, 2004), O-nucleotidylation (Brisson-Noel et al., 1988), O-ribosylation, O-glycosylation, and thiol transfer. These covalent modification strategies all require a co-substrate such as ATP, acetyl-CoA, NAD⁺, UDP-glucose, or glutathione for their activity and consequently these processes are restricted to the cytoplasm.

3.3. Antibiotic resistance via target modification

The second major resistance mechanism is the modification of the antibiotic target site so that the antibiotic is impotent to bind properly. However, it is possible for mutational changes to occur in the target that reduce susceptibility to inhibition while retaining cellular function (Spratt, 1994).

4.1. Antibiotic resistance via mutations

There is a substantial number of biochemical mechanisms of antibiotic resistance that are based on mutational events, like the mutations of the sequences of genes encoding the target of certain antibiotics (e.g. resistance to rifampicin and fluoroquinolones is caused by mutations in the genes encoding the targets of these molecules, RpoB and DNA-topoisomerases, respectively) (Ruiz, 2003). The variation in the expression of antibiotic uptake or of the efflux systems may also be modified by mutation (e.g. the reduced expression or absence of the OprD porin of Pseudomonas aeruginosa reduces the permeability of the cell wall to carbapenems) (Wolter et al., 2004).

4.2. Antibiotic resistance via horizontal gene transfer

A principal mechanism for the spread of antibiotic resistance is by horizontal transfer of genetic material. Antibiotic resistance genes may be transferred by different mechanisms of conjugation, transformation or transduction. Over the last 15years, β-lactamase enzymes that have an extended spectrum of activity (ESBL) against the majority of β-lactams, including cephalosporins but not carbapenemases, have evolved. One of these, CTX-M-15, initially found in E. coli but now found in other members of Enterobacteriaceae and frequently associated with a specific lineage, uropathogenic clone ST131 (Bush and Fisher, 2011; Woodford et al., 2011), has spread worldwide. It is often located on highly mobile IncFII plasmids and associated with mobile genetic element IS26. The risk of infection is particularly high in individuals in association with prolonged hospitalization, catheterization, nursing home residency, previous antibiotic treatment, underlying renal or liver pathology, and travel to high-risk areas (Nordmann et al., 2011).

5.1. SHV type

The SHV family of β-lactamases appears to be derived from Klebsiella spp. The progenitor of the SHV class of enzymes, SHV-1, is universally found in K. pneumoniae. In many strains of K. pneumoniae, the gene encoding SHV-1, or its apparent precursor, LEN-1, resides within the bacterial chromosome too; it may be that the gene for SHV-1 β-lactamase evolved as a chromosomal gene in Klebsiella and was later incorporated into a plasmid which has spread to other enterobacteria species. SHV-1 confers resistance to broad-spectrum penicillins such as ampicillin, tigecycline and piperacillin but not to the oxyimino substituted cephalosporins (Livermore, 1995). The SHV-1 β-lactamase is responsible for up to 20% of the plasmid-mediated ampicillin resistance in K. pneumoniae species (Tzouvelekis and Bonomo, 1999).

5.2. TEM type

TEM-1, first reported from an E. coli isolate in 1965, has substrate and inhibition profiles similar to those of SHV-1 (Datta and Kontomichalou, 1965). TEM-1 is capable of hydrolyzing penicillins and first generation cephalosporins but is unable to attack the oxyimino cephalosporin. The first TEM variant with increased activity against extended spectrum cephalosporins was TEM-3 (Soughakoff et al., 1988; Sirot et al., 1987). TEM-2 the first derivative of TEM-1, had a single amino acid substitution from the original β-lactamase (Barthelemy et al., 1985). This caused a shift in the isoelectric point from a pI of 5.4–5.6, but it did not change the substrate profile. TEM-3, originally reported in 1989, was the first TEM-type β-lactamase that displayed the ESBL phenotype (Soughakoff et al., 1988). In retrospect, TEM-3 may not have been the first TEM-type ESBL. Klebsiella oxytoca, harboring a plasmid carrying a gene encoding ceftazidime resistance, was first isolated in Liverpool, England, in 1982 (Du Bois et al., 1995). The responsible β-lactamase was what is now called TEM-12. Interestingly, the strain came from a neonatal unit which had been stricken by an outbreak of K. oxytoca producing TEM-1 (Du Bois et al., 1995). This is a good example of the emergence of ESBLs as a response to the selective pressure induced by extended-spectrum cephalosporins.

5.3. CTX type

A new family of β-lactamases that preferentially hydrolyzes cefotaxime has arisen. It has been found in isolates of Salmonella enterica serovar, Typhimurium, E. coli mainly and some other species of Enterobacteriaceae (Gazouli et al., 1998; Knothe et al., 1983). These are not very closely related to TEM or SHV β-lactamases (Tzouvelekis et al., 2000). In addition to the rapid hydrolysis of cefotaxime, another unique feature of these enzymes is that they are better inhibited by the β-lactamase inhibitor tazobactam than by sulbactam and clavulanate (Bradford et al., 1998; Ma et al., 1998).

CTX-M β-lactamases are found exclusively in the functional group 2 (Bush and Jacoby, 2010) and thought to originate from chromosomal ESBL genes found in Kluyvera spp. (Bush and Jacoby, 2012), an opportunistic pathogen of the Enterobacteriaceae found in the environment. The first CTX-M proteins were discovered in the late 1980s and today more than 100 variants have been sequenced (Bonnet, 2004). Based on their amino acid sequences, they can be divided into five groups (CTX-M group 1, 2, 8, 9, and 25) (Bonnet, 2004).

The origin of the CTX-M enzymes is different from that of TEM and SHV ESBLs. While SHV-ESBLs and TEM-ESBLs were generated by amino acid substitutions of their parent enzymes, CTX-M ESBLs were acquired by the horizontal gene transfer from other bacteria using genetic apparatuses such as conjugative plasmid or transposon. The gene sequences encoding CTX-M enzymes show a high similarity to those of β-lactamases of Kluyvera species. In addition, the gene sequences adjacent to the CTX-M genes of Enterobacteriaceae are also similar to those surrounding the β-lactamase genes on the chromosomes of Kluyvera species (Olson et al., 2005; Humeniuk et al., 2002; Poirel et al., 2002).

Kinetic studies have shown that the CTX-M-type β-lactamases hydrolyze cephalothin or cephaloridine better than benzyl penicillin and they preferentially hydrolyze cefotaxime over ceftazidime (Tzouvelekis et al., 2000; Bradford et al., 1998). Although there is some hydrolysis of ceftazidime by these enzymes, it is usually not enough to provide clinical resistance to organisms in which they reside. It has been suggested that the serine residue at position 237, which is present in all of the CTX-M enzymes, plays an important role in the extended-spectrum activity of the CTX-M-type β-lactamases (Tzouvelekis et al., 2000). Although it has been shown not to be essential, the Arg-276 residue lies in a position equivalent to Arg-244 in TEM- or SHV-type ESBLs, as suggested by molecular modeling, and may also play a role in the hydrolysis of oxyimino cephalosporins (Gazouli et al., 1998). Recent crystallographic data for the Toho-1 enzyme suggested that there was increased flexibility of the interacting β 3 strands and ω loop of this enzyme in comparison to other class A β-lactamases. Furthermore, the lack of hydrogen bonds in the vicinity of the ω loop could account for the extended-spectrum phenotype (Ibuka et al., 1999).

5.4. OXA type

The OXA-type β-lactamases are so named because of their oxacillin-hydrolyzing abilities. These β-lactamases are characterized by hydrolysis rates for cloxacillin and oxacillin greater than 50% as that for benzyl penicillin (Bush et al., 1995). They predominantly occur in P. aeruginosa (Weldhagen et al., 2003) but have been detected in many other Gram-negative bacteria. In fact, the most common OXA-type β-lactamase, OXA-1 has been found in 1–10% of E. coli isolates (Livermore, 1995). The OXA-type ESBLs were originally discovered in P. aeruginosa isolates from a single hospital in Ankara, Turkey. In France, a novel derivative of OXA-10 (numbered OXA-28) was found in a P. aeruginosa isolate (Poirel et al., 2001). A novel ESBL (OXA-18) and an extended-spectrum derivative of the narrow spectrum OXA-13 β-lactamase (numbered OXA-19) have also been discovered in France in P. aeruginosa isolates (Philippon et al., 1997). The evolution of ESBL OXA-type β-lactamases from parent enzymes with narrower spectra has many parallels with the evolution of SHV- and TEM-type ESBLs. Unfortunately there are very few epidemiologic data on the geographical spread of OXA-type ESBLs (Philippon et al., 1997).

5.5. PER type

The PER-type ESBLs share only around 25–27% hom*ology with known TEM- and SHV-type ESBLs (Bauernfeind et al., 1996). PER-1 β-lactamase efficiently hydrolyzes penicillins and cephalosporins and is susceptible to clavulanic acid inhibition. PER-1 was first detected in P. aeruginosa (Neuhauser et al., 2003), and later in S. enterica serovar Typhimurium and Acinetobacter isolates as well (Vahaboglu et al., 2001). In Turkey, as many as 46% of nosocomial isolates of Acinetobacter spp. and 11% of P. aeruginosa were found to produce PER-1 (Vahaboglu et al., 1997). PER-2, which shares 86% hom*ology to PER-1, has been detected in S. enterica serovar Typhimurium, E. coli, K. pneumoniae, Proteus mirabilis, and Vibrio cholerae O1 El Tor (Petroni et al., 2002).

5.6. GES type

GES-1 was initially described in a K. pneumoniae isolate from a neonatal patient just transferred to France from French Guiana (Poirel et al., 2000). GES-1 has hydrolytic activity against penicillins and extended-spectrum cephalosporins, but not against cephamycins or carbapenems, and is inhibited by β-lactamase inhibitors. These enzymatic properties resemble those of other class A ESBLs; thus, GES-1 was recognized as a member of ESBLs.

5.7. VEB-1, BES-1, and other ESBL type

Other unusual enzymes having ESBL have also been described (e.g. BES-1, CME-1, VE-B-1, PER, SFO-1, and GES-1) (Bradford, 2001). These novel enzymes are found infrequently, details of these enzymes are reviewed elsewhere (Naas et al., 2008).

6.1. Phenotypic detection

The US Clinical and Laboratory Standards Institute (CLSI) and the UK Health Protection Agency (HPA) have published guidelines for ESBL detection in Enterobacteriaceae specifically for E. coli, Klebsiella spp., and Proteus spp. (CLSI, 2002; HPA, 2008). The HPA guidelines also include other species, such as Salmonella spp. These guidelines are based on the principle that most ESBLs hydrolyze third-generation cephalosporins although they are inhibited by clavulanate, and recommend initial screening with either 8mg/L (CLSI) or 1mg/L (HPA) of cefpodoxime, 1mg/L each of cefotaxime, ceftazidime, ceftriaxone, or aztreonam, followed by confirmatory tests (including the E-test ESBL strips) with both cefotaxime and ceftazidime in combination with clavulanate at a concentration of 4μg/mL. Automated systems that use similar detection principles have proved to be popular in clinical laboratories, especially those in North America and certain European countries (Spanu et al., 2006). If clinical laboratories adhere to the published guidelines for detecting ESBLs, the CLSI and HPA published methods show high sensitivity of up to 94% and specificity of 98% for detecting ESBLs in E. coli, Klebsiella spp. and Proteus spp. (Wiegand et al., 2007).

6.2. Genotypic detection

The determination of whether a specific ESBL present in a clinical isolate is related to TEM and SHV enzymes is a complicated process because point mutations around the active sites of the TEM and SHV sequences have led to amino acid changes that increase the spectrum of activity of the parent enzymes, such as in TEM1, TEM2, and SHV1 (Bradford, 2001). The molecular method commonly used is the PCR amplification of the bla_TEM and bla_SHV genes with oligonucleotide primers, followed by sequencing. Sequencing is essential to discriminate between the non-ESBL parent enzymes (e.g. TEM1, TEM2, or SHV1) and different variants of TEM or SHV ESBLs (e.g. TEM3, SHV2, etc.) (Bradford, 2001).

The PCR amplification of CTX-M-specific products without sequencing, in an isolate that produces an ESBL, usually provides sufficient evidence that a bla_CTX-M gene is responsible for this phenotype. This is unlike TEM and SHV types of ESBLs. Several recent studies have described various molecular approaches for the rapid screening of ESBL-positive organisms for the presence of different bla_CTX-M genes. This involved a PCR assay that used four sets of primers to amplify group specific CTX-M β-lactamase genes (Pitout et al., 2004), amplification of a universal DNA fragment specific for most of the different groups of CTX-M β lactamases (Batchelor et al., 2005), duplex PCR (Pitout et al., 2007), multiplex PCR (Woodford et al., 2006), real-time PCR (Birkett et al., 2007), pyrosequencing (Naas et al., 2007), and reverse-line hybridization (Ensor et al., 2007). Molecular techniques undoubtedly have the potential to play an essential part in the laboratory setting for the screening, tracking, and monitoring of the spread of large number of organisms producing CTX-M enzymes from the community and hospital settings in real time.

Table 1

Epidemiology of ESBL producing organisms.

Peer review under responsibility of King Saud University.

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