Penicillin belongs to the beta-lactam group of antibiotics. The lethal (bacteriocidal) effect occurs via an interaction between penicillins and the penicillin binding proteins (PBPs) found on the cell membrane. PBPs are enzymes (transpeptidases) involved in peptidoglycan cross-linking. Inactivation of these transpeptidases disrupts the normal cell wall peptidoglycan and induces cell lysis and death. Beta lactamases probably exsisted before the arrival of beta lactam antibiotics, but their role in bacteria are unclear. One thing is clear, however, these enzymes are found only in bacteria. It is believed that these enzymes have evolved from the conversion of PBPs through genetic transformation. The selection pressure for this may have been soil organisms producing beta-lactams. The resistance of ESBLs occur through inducible production of these hydrolytic enzymes.
Classes of ESBLs:
- Class A: TEM: This term from the parental enzyme found in the blood of a Greek patient (called Temoniera). This initial isolate was called TEM-1. This enzyme is encoded on a plasmid and is transposon mediated, allowing rapid spread to other Gram negative bacteria. These are ubiquitous to E. coli. SHV: This comes from SulpHydryl Variable, is expressed predominantly by Klebsiella pneumoniae. Since their discovery, TEM has 100 offspring and SHV about twenty.
- Class C: This contains hardly any variants. The main representative is AmpC chromosomally encoded by Citrobacter freundii, Enterobacter cloacae & Morganella morganii. These are inducible beta lactamases, and are highly active on first and second generation cephalosporins such as cefalexin.
- Class D: These are oxacillin-hydrolysing type enzymes (OXA) expressed by Pseudomonas aeruginosa (NLF). This is a family of at least 30 variants, some of which have an ESBL profile.
- Class B: These differ from the other 3 in many respects. They are structurally different as require Zn as an essential co-factor. They are metallo-beta-lactamases and confer MDR characteristics. These are active against carbapenems (and YES, imipenem resistant ESBLs have been described). These are the enzymes of greatest clinical concern.
- CTX-M: The so-called CTX-M enzymes are a relatively small family of plasmid-mediated ESBLs, which preferentially hydrolyse cefotaxime and are better inhibited by tazobactam than by sulbactam and clavulanate. These enzymes are not very closely related to TEM and SHV as they show only 40% identity with these enzymes. CTX-M has been detected in Salmonella typhimurium and E. coli. It seems that the serine residue at position 237 (present in CTX-M), has an important role in their extended spectrum of activity.
ESBLs vs IRTs:
In the early 1990s, beta-lactamases resistant to clavulanic acid and sulbactam inhibition (inhibitor-resistant TEM beta-lactamases: IRT) were discovered, exhibiting resistance at the clinical level to the beta-lactam–beta-lactamase inhibitor combinations ofamoxicillin–clavulanate, ticarcillin–clavulanate and ampicillin–sulbactam (but inhibition by tazobactam was retained), and subsequently to piperacillin–tazobactam (Tazocin). Despite the fact that IRTs are not real ESBLs (unlike TEM & SHV), they should be discussed with ESBLs. Therefore, they have been renamed with numerical TEM designations.There are at least 23 distinct IRT enzymes, primarily detected in France, and found mainly inclinical isolates of E. coli, but also in some strains of K. pneumoniae, Klebsiella oxytoca, P. mirabilis and Enterobacter cloacae. The sites of IRT amino acid substitutions are distinct from those of ESBL point mutations, occurring at a few specific amino-acid residues. However,recently, the TEM-50 enzyme, with common amino-acid substitutions to both ESBLs and IRTs, has been described, conferring slight resistance to oxyimino-cephalosporins (e.g ceftizoxime). Possibly, this newer enzyme demonstrates a new group of beta-lactamases with a more complex phenotype.
Epidemiology:
In 1983, just two years after the introduction of the oxyimino-beta-lactams (e.g. ceftazidime and cefotaxime) to the market, the first ESBLs was isolated in Germany from resistant Klebsiella pneumoniae strains. There have significant epidemics worldwide (for us it was the Stourbridge, UK one). Rates in Portual and Turkey reach 50%. The incidence is rising amongst the enterobacteriacae species. The selective pressure of the use and overuse of the oximinocephalosporins, which are widely prescribed for the treatment of serious Gram-negative nosocomial infections, has led to the isolation of a large number of ESBL enzymes worldwide, mainly from different genera of the Enterobacteriaceae. Strains expressing CTX-M have been isolated worldwide, numbering 29 enzymes, and have been associated with local outbreaks in Japan, South America, Eastern Europe and Spain. Recently, in Greece, analysis of six E. coli strains with the ESBL phenotype revealed a new CTX-M enzyme, conferring a lower level of resistance to ceftazidime compared with cefotaxime.