167 Summary and general discussion blaDHA, or blaACC, appear to have varying impacts on the hydrolysis of different betalactam antibiotics (Philippon, Arlet, and Jacoby 2002). Additionally, mutations in the ampC promoter/attenuator region can lead to varying levels of resistance, and studies have even identified mutations in the ampC gene sequence that result in changes in the active site and higher resistance levels (Tracz et al. 2007; Nordmann, Poirel, and Nordmann 2007). Furthermore, other mechanisms affecting membrane permeability, such as efflux pumps and porins, have been observed in conjunction with AmpCmediated resistance, leading to more extensive resistance patterns (Goessens et al. 2013). Variations in gene and/or plasmid copy number have also been proposed as contributing factors to differences in phenotypes (Kurpiel and Hanson 2012). In Chapter 8 of this thesis, the sequencing depth of chromosomal housekeeping genes is compared to plasmid-encoded scaffolds carrying the blaCMY-2 gene. The ratio between these two components serves as an estimate of the plasmid copy number. Interestingly, isolates with elevated minimal inhibitory concentrations for cefotaxime, ceftazidime, and piperacillin-tazobactam exhibited higher estimated plasmid copy numbers. This finding suggests a potential association between plasmid copy number and increased resistance rates to beta-lactamase inhibitor combinations. However, further research is necessary to validate and expand upon these initial findings. In summary, the emergence of AmpC-mediated resistance represents a significant challenge in combating antibiotic resistance. The investigation conducted in Chapter 8 sheds light on the potential role of plasmid copy number in influencing resistance rates to beta-lactamase inhibitor combinations. Additional studies are needed to corroborate these findings and enhance our understanding of the underlying mechanisms involved. Future perspectives The exploration of AmpC-mediated resistance in this thesis has provided valuable insights into its intricacies. However, the depth of this topic reveals a multitude of variants and mechanisms, leading to intriguing questions and avenues for future research. One important aspect to consider is the clinical relevance of AmpC-mediated resistance and its lower prevalence compared to ESBL-mediated resistance in humans. The prevalence of CTX-M types, such as blaCTX-M, is significantly higher than that of CMY- or DHA-type ampC genes. Further investigation is needed to understand the reasons behind this disparity, such as the potential role of specific vectors in the 9
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