120 Chapter 7 Introduction Escherichia coli is an important pathogen in both community and healthcare-associated infections (Weinstein, Gaynes, and Edwards 2005; J. D. D. Pitout 2012). In the past decades, a substantial increase in resistance to third-generation cephalosporin (3GC) antibiotics in E. coli has been observed worldwide, mainly caused by the production of extended-spectrum beta-lactamases (ESBLs) and AmpC beta-lactamases, restricting available treatment options for common infections (Jacoby 2009). AmpC betalactamases differ from ESBL as they hydrolyse not only broad-spectrum penicillins and cephalosporins, but also cephamycins. Moreover, AmpC beta-lactamases are not inhibited by ESBL-inhibitors like clavulanic acid, limiting antibiotic treatment options even further (Jacoby 2009). A widely used screening method for AmpC production is the use of susceptibility to cefoxitin (FOX), a member of the cephamycins (Martinez and Simonsen 2017). Although ampC beta-lactamase genes can be plasmid-encoded (plasmidmediated ampC, pampC), they are also encoded on the chromosomes of numerous Enterobacterales . E. coli naturally carries a chromosome-mediated ampC (campC) gene but, unlike most other Enterobacterales , this gene is non-inducible due to the absence of the ampR regulator gene (Jacoby 2009). Chromosomal AmpC production in E. coli is exclusively regulated by promoter and attenuator mechanisms. This results in constitutive low-level campC expression that still allows the use of 3GC antibiotics, such as cefotaxime (CTX), to treat E. coli infections (Jacoby 2009). However, various mutations in the promoter/attenuator region of E. coli may cause constitutive hyperexpression of campC, thereby increasing the minimum inhibitory concentrations (MICs) for broad-spectrum penicillins and cephalosporins and limiting appropriate treatment options (Tracz et al. 2005; 2007). A wide variety of promoter and attenuator mutations have been related to AmpC hyperproduction (Tracz et al. 2007). AmpC hyperproduction is primarily caused by alterations of the ampC promoter region, leading to a promoter sequence that more closely resembles the E. coli consensus σ70 promoter with a TTGACA −35 box separated by 17 bp from a TATAAT −10 box. These alterations can be divided into different variants associated with, for example, an alternate displaced promoter box, a promoter box mutation or an alternate spacer length due to insertions (Tracz et al. 2007). Furthermore, mutations of the attenuator sequence can lead to changes in the hairpin structure that strengthen the effect of promoter alterations on AmpC hyperproduction. In the study by Tracz et al. on FOX-resistant E. coli isolated from Canadian hospitals, 52 variants of
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