31 AmpC beta-lactamases: epidemiology, infection control and treatment with beta-lactamase inhibitor combinations (such as amoxicillin-clavulanic acid) and third-generation cephalosporins are in most cases ineffective. Often it will be necessary to switch to a carbapenem or another group of antibiotics, such as quinolones. In some cases, the MIC values of third-generation cephalosporins are still below the resistance breakpoint in Enterobacterales with campC genes. Nonetheless, resistance to these agents can still occur due to derepression during treatment. Based on the study by Kohlmann et al, the risk of derepression appears to be different per species. Enterobacter cloacae complex isolates have a greater chance of developing resistance than Morganella morgagnii (Kohlmann, Bähr, and Gatermann 2018). That is why a distinction can be made per campC expressing species as to whether or not third-generation cephalosporins can be safely used when treating infections with AmpC producing Enterobacterales with low cephalosporin MIC values. A fourth-generation cephalosporin such as cefepime could be an alternative, but is currently used only to a limited extent in the Netherlands (Tamma et al. 2019). Beta-lactamase inhibitors such as tazobactam and avibactam may also be an alternative therapy. In the Merino-II study, no significant difference was seen in clinical outcomes between the treatment with carbapenems and piperacillintazobactam, although microbiological failure occurred significantly more often in the piperacillin-tazobactam group (Stewart et al. 2021). Clinical comparative studies have mainly been performed with therapeutics that need parenteral administration. Data on oral treatment with 3rd generation cephalosporins (e.g., ceftibuten) of infections with chromosomal AmpC-producing Enterobacterales are scarce, although a recent study of a new oral combination preparation (e.g. ceftibuten/VNRX-7145) shows effectiveness in urinary tract infections (Karlowsky, Hackel, and Sahm 2022). As this new combination drug is not yet available in the Netherlands, oral treatment with, for example, quinolones or trimethoprim-sulfamethoxazole will depend on the resistance pattern and (local) antibiotic guidelines. It is unknown if Enterobacterales containing pampC genes can be treated similarly, when measured MICs are below breakpoint level. Comparative clinical studies such as with chromosomal AmpC are lacking. The NVMM guideline “Laboratory detection of high resistant microorganisms (BRMO)” recommends blocking the result for the antibiotic in question, reporting it as resistant, warning of unclear therapeutic effect, or prescribing only in consultation with a clinical microbiologist or infectious disease specialist (J.A.J.W Kluytmans et al. 2021). Future studies on the optimal treatment of Enterobacterales containing different plasmids AmpC variants are needed. 2
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