14 Chapter 1 Among the frequently encountered beta-lactamases are the extended spectrum betalactamases (ESBLs). This group comprises numerous variants (e.g., TEM, SHV, CTX-M, etc.), all of which possess the ability to hydrolyse the broader-spectrum cephalosporin antibiotics (David M. Livermore 2008). The escalating prevalence of ESBLs in the past two decades has significantly influenced the clinical use of cephalosporins (David M. Livermore et al. 2007). In certain countries, resistance due to ESBLs has reached alarming levels, necessitating the restriction of cephalosporins as the first-line treatment for common infections. Consequently, more broad-spectrum antibiotics like carbapenems and quinolones are employed. However, the efficacy of these broad-spectrum antibiotics may be limited as resistance to these agents rapidly emerges due to their widespread use. What is an “AmpC beta-lactamase”? The AmpC beta-lactamase is a bacterial enzyme that primarily targets specific betalactam antibiotics, especially cephalosporins (Jacoby 2009). It is prevalent among gramnegative bacteria, particularly in the Enterobacterales order. AmpC beta-lactamase production leads to resistance against commonly used beta-lactam antibiotics, and it is often unaffected by beta-lactamase inhibitors, distinguishing it from other ESBLs. The AmpC beta-lactamase belongs to molecular class C and is regulated by pathways involved in cell-wall degradation. Mutations in the regulatory gene ampR result in overexpression of ampC, causing broader resistance to cephalosporins, including thirdgeneration cephalosporins like ceftriaxone, cefotaxime, and ceftazidime. Additionally, mutations primarily in the ampD gene can lead to constitutive overexpression of ampC, resulting in long-lasting antibiotic resistance, particularly in species like Enterobacter cloacae complex and Citrobacter freundii (Kohlmann, Bähr, and Gatermann 2018). In most Enterobacterales, AmpC enzymes are inducible, but certain species like E. coli and Shigella spp. express ampC at low levels due to the absence of the ampR gene. However, mutations in the promoter/attenuator region of the ampC gene can lead to hyperproduction of the AmpC beta-lactamase (Caroff N, Espaze E, Gautreau D, Richet H 2000; Tracz et al. 2007). Figure 1 shows the sequence of the E. coli ATCC 25922 ampC promoter/attenuator region. Although most AmpC hyperproducers show relatively low resistance to third-generation cephalosporins, alterations in the AmpC beta-lactamase or changes in membrane permeability can contribute to increased resistance (Nordmann and Mammeri 2007; Martínez-Martínez 2008).
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