3.1.1 β-lactam resistance and ESBLs

The resistance genes for β-lactamases are located either on the bacterial chromosome or on plasmids, leading to both intrinsic and acquired resistance. The genes have mutated and evolved so that each one represents a ‘family’ of related genes. Two separate systems are used to classify β-lactamases: a structural scheme based on primary structure (Ambler, 1980; Hall and Barlow, 2005); and a functional scheme based on chemical reactivity and DNA sequence (Bush and Jacoby, 2005). The Ambler classification is based on classes A-D (Table 1), whereas the Bush‒Jacoby has numbered groups. This may seem complex but fortunately only a few subdivisions of the main classes of β-lactamases are widespread enough to mention specifically here in the context of surveillance.

Ambler DNA sequence classification of β-lactamases
Class Active site Selected examples
A Serine

Staphylococcal penicillinase

Broad-spectrum penicillinases, TEM and SHV

ESBLs e.g. CTX-TM, TEM-3 and SHV-2

Serine carbapenemases, e.g. KPC.

B Zinc Metallo-carbapenemases, e.g. IMP, NDM, VIM
C Serine Chromosomal cephalosporinases (some genes may be on plasmids), e.g. major families of plasmid-carried genes for AmpC such as CMY, LAT, FOX.
D Serine Oxacillinases - broad-spectrum not inhibited by clavulanate or tazobactam, e.g. OXA-1 and OXA-48 carbapenemase.
Table 1 Ambler DNA sequence classification of β-lactamases. Note that most ESBLs are in Class A and are derived from the two main types of broad-spectrum penicillinases ‒ TEM and SHV. Abbreviations: KPC – Klebsiella pneumoniae carbapenemase; IMP – Imipenemase metallo-beta-lactamase; NDM – New Delhi metallo-β-lactamase; VIM – Verona integron-encoded metallo-beta-lactamase; OXA – Oxacillin carbapenemases. © Professor Peter Hawkey, University of Birmingham (personal communication).

ESBL-producers among Enterobacterales are significant as they cannot be treated with the usual ‘workhorse’ antimicrobials ‒ amoxicillin and cephalosporins. They also tend to be MDR as several resistance genes may be carried on the same plasmid. This means that often no oral options are available because the majority of second- and third-line drugs to which the organisms are still susceptible can only be given intravenously. The presence of ESBL is also a driver of carbapenemase resistance as the choice of drug to treat them is usually a carbapenem.

ESBL-producers, mainly E. coli and Klebsiella, are also widely distributed in poultry, including those which have had little direct exposure to antimicrobials themselves. They are readily transmitted to humans via food consumption, for example by handling uncooked meat or consuming vegetables fertilised with animal manure; they can also be transferred in the other direction from humans to livestock (Subramanya et al., 2020; Uttapoln et al., 2019).

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Figure 4 Market day, Bahir Dar, Ethiopia
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ESBL-producers, mainly E. coli and Klebsiella, are widely distributed in poultry which is frequently on sale in markets and readily transmitted to humans, for example by handling uncooked meat or consuming vegetables fertilised with animal manure. The bacteria can also be transferred from humans to livestock.

Figure 4 Market day, Bahir Dar, Ethiopia

Cephalosporin hydrolysing enzymes of clinical and veterinary importance are shown in Table 2.

Group Notes
CTX-M ESBL: Found in E.coli and Klebsiella species; widespread and the predominant ESBL variants in many countries. The gene originated in an environmental organism, Kluyvera.(Class A)
TEM and SHV ESBL: Increasingly diverse with some being able to break down carbapenems as well as cephalosporins. They have been present in clinical isolates for many years which explains why the group is so diverse. (Class A).
AmpC Common in Enterobacterales. AmpC is not affected by inhibitors. Many species have the ampC gene on their chromosome but as this resistance is intrinsic it is not important for surveillance. The AmpC enzyme can, however, mask the presence of transmissible genes. Acquired plasmid-mediated ampC is of importance in a public health context, because unlike intrinsic ampC, it can be passed on to other bacteria. (Class C)

Table 2 Cephalosporin hydrolysing enzymes important in human and animal health

3.1 Gram-negative pathogens

3.1.2 Carbapenem resistance and carbapenemases