51 Development of an algorithm to discriminate between plasmid- and chromosomal-mediated AmpC Introduction Escherichia coli is an important pathogen in both community and healthcare-associated infections (Weinstein, Gaynes, and Edwards 2005; J. D. D. Pitout 2012). ESBL-producing E. coli have spread worldwide, restricting available treatment options. Although to a lesser degree, acquired AmpC beta-lactamases in E. coli are also emerging as a potential threat to the activity of broad-spectrum penicillins and third-generation cephalosporins (3GCs). Acquired AmpC beta-lactamases are encoded on plasmids and hence transferable between species. The prevalence of plasmid-mediated AmpC (pAmpC) beta-lactamases in E. coli clinical isolates reported in the literature varies between 0.06% and 10.1% (Jørgensen et al. 2010; Ding et al. 2008); however, variance in prevalence is likely to be influenced by diagnostic strategies used in these studies, and there are also regional differences in prevalence. In the Netherlands, a country with low levels of antimicrobial resistance, a pAmpC prevalence between 0.6% and 1.3% was found in E. coli isolates recovered from faecal samples in the community (E. Ascelijn Reuland et al. 2015; Van Hoek et al. 2015). Recently, Harris et al.7 described pAmpC as the second most common group (17.1%) of 3GC-hydrolysing beta-lactamases in E. coli bloodstream infections in Australia, New Zealand and Singapore. Different types of plasmid-mediated ampC (pampC) genes have been detected in Enterobacterales, with blaCMY-2 as the most common AmpC-encoding resistance gene (Harris et al. 2018). Other, less frequently isolated AmpC beta-lactamase genes are other varieties of blaCMY, as well as blaDHA, blaACT, blaACC, blaMIR, blaMOX, blaFOX and blaCFE. Depending on the type of pAmpC beta-lactamase, the hydrolysing capability might vary (Jacoby 2009; Philippon, Arlet, and Jacoby 2002). E. coli naturally carries a chromosomal-mediated ampC (campC) gene, but unlike in other Enterobacterales this gene is non-inducible (Jacoby 2009). In E. coli AmpC production is regulated by promoter and attenuator mechanisms resulting in constitutive low-level ampC expression and hence allows the use of beta-lactam antibiotics to treat these E. coli infections in the absence of other resistance mechanisms. Various mutations in the promoter/attenuator region of E. coli may cause constitutive hyperexpression of campC. These E. coli strains may then become resistant to cephamycins, broadspectrum penicillins or even 3GCs, making it difficult to differentiate these strains phenotypically from pAmpC enzyme production. In contrast to hyperexpressed campC genes, pampC genes are capable of spreading this resistance mechanism to other bacteria within a hospital setting by horizontal gene transfer (San Millan 2018; Rozwandowicz et al. 2018). This poses a greater threat to 4
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