Chapter 5 : β-Lactam Resistance in the 21st Century

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The β-lactamase community currently recognizes two major classification schemes based either on function or structure. Historically, these enzymes were separated according to biochemical activities, with classification based on hydrolysis of specific substrates and the sensitivity to selected inhibitors. After penicillin was used more frequently in post-World War II medicine, the incidence of penicillinase-producing increased in one British hospital from ≥8% in 1945 to almost 60% of clinical isolates in less than five years. Examples of apparent cause and effect relationships include the discovery of cephalosporin C and subsequent introduction of cephalosporin analogs, together with the introduction of broad-spectrum penicillins, such as ampicillin, leading to the identification of plasmid-encoded broad-spectrum penicillinases such as TEM-1. This ubiquitous β-lactamase among the , with the ability to hydrolyze not only many penicillins but also the early cephalosporins such as cephalothin, became the most prevalent plasmid-encoded enzyme in epidemiological surveys of the late 1970s and early 1980s. In the compilation shown, geographical areas reasonably close to each other sometimes exhibit different regional enzyme patterns. The level of β-lactam resistance produced by an enzyme is determined by a number of factors besides its intrinsic hydrolytic activity. β-Lactamases are ancient enzymes, widespread in the microbial world, that in recent years have coevolved with β-lactam antibiotics as aminopenicillins, cephalosporins, cephamycins, oxyimino-cephalosporins, monobactams, and carbapenems have been developed to target new pathogens or to overcome existing resistance.

Citation: Jacoby G, Bush K. 2005. β-Lactam Resistance in the 21st Century, p 53-65. In White D, Alekshun M, McDermott P (ed), Frontiers in Antimicrobial Resistance. ASM Press, Washington, DC. doi: 10.1128/9781555817572.ch5

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Bacterial Proteins
beta-Lactam Antibiotics
beta-Lactamase Inhibitors
Clavulanic acid
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Figure 1.

Effects of newly introduced β-lactam-containing agents on β-lactamase populations.

Citation: Jacoby G, Bush K. 2005. β-Lactam Resistance in the 21st Century, p 53-65. In White D, Alekshun M, McDermott P (ed), Frontiers in Antimicrobial Resistance. ASM Press, Washington, DC. doi: 10.1128/9781555817572.ch5
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Table 1

Functional groups of (3-lactamases based on Bush, Jacoby, and Medeiros scheme (16)

With exceptions for particular enzymes.

IC of clavulanic acid that were >10 µM were considered to be Clav( —). IC that were <1 µM were considered to be Clav(+). IC that were <1 µM for tazobactam are TZB (+).

ESBL, extended-spectrum β-lactamase.

IRTs, inhibitor-resistant TEM β-lactamases.

New group not included in reference 16. Note that functional group 4 enzymes are not included, as this group has not been fully characterized.

Citation: Jacoby G, Bush K. 2005. β-Lactam Resistance in the 21st Century, p 53-65. In White D, Alekshun M, McDermott P (ed), Frontiers in Antimicrobial Resistance. ASM Press, Washington, DC. doi: 10.1128/9781555817572.ch5
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Table 2

Known cassette-associated β-lactamase genes

Citation: Jacoby G, Bush K. 2005. β-Lactam Resistance in the 21st Century, p 53-65. In White D, Alekshun M, McDermott P (ed), Frontiers in Antimicrobial Resistance. ASM Press, Washington, DC. doi: 10.1128/9781555817572.ch5
Generic image for table
Table 3

Likely origin of some plasmid-mediated genes

Citation: Jacoby G, Bush K. 2005. β-Lactam Resistance in the 21st Century, p 53-65. In White D, Alekshun M, McDermott P (ed), Frontiers in Antimicrobial Resistance. ASM Press, Washington, DC. doi: 10.1128/9781555817572.ch5
Generic image for table
Table 4

Reported regional occurrence of plasmid-encoded β-lactamases or β-lactamase families

Includes Croatia, France, Greece, Italy, and Portugal.

Two different enzymes in geographically separated regions (141; Quinn and Queenan, personal communication).

Citation: Jacoby G, Bush K. 2005. β-Lactam Resistance in the 21st Century, p 53-65. In White D, Alekshun M, McDermott P (ed), Frontiers in Antimicrobial Resistance. ASM Press, Washington, DC. doi: 10.1128/9781555817572.ch5
Generic image for table
Table 5

Susceptibility (S) and resistance (R) breakpoints for dilutional or disk susceptibility testing and recommended screening parameters for ESBL detection by the CLSI and British Society for Antimicrobial Chemotherapy (BSAC)

For E. coli and Klebsiella spp. (2).

Citation: Jacoby G, Bush K. 2005. β-Lactam Resistance in the 21st Century, p 53-65. In White D, Alekshun M, McDermott P (ed), Frontiers in Antimicrobial Resistance. ASM Press, Washington, DC. doi: 10.1128/9781555817572.ch5

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