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The reversibility of bacterial resistance to antibiotics is poorly understood. Therefore, the aim of this study was to determine, over a period of five years, the effect of fluoroquinolone (FQ) use in primary care on the development and gradual decay of Escherichia coli resistance to FQ. In this matched case–control study, we linked three sources of secondary data of the Health Service of the Autonomous Province of Bolzano, Italy. Cases were all those with an FQ-resistant E. coli (QREC)-positive culture from any site during a 2016 hospital stay. Data were analyzed using conditional logistic regression. A total of 409 cases were matched to 993 controls (FQ-sensitive E. coli) by the date of the first isolate. Patients taking one or more courses of FQ were at higher risk of QREC colonization/infection. The risk was highest during the first year after FQ was taken (OR 2.67, 95%CI 1.92–3.70, p < 0.0001), decreased during the second year (OR 1.54, 95%CI 1.09–2.17, p = 0.015) and became undetectable afterwards (OR 1.09, 95%CI 0.80–1.48, p = 0.997). In the first year, the risk of resistance was highest after greater cumulative exposure to FQs. Moreover, older age, male sex, longer hospital stays, chronic obstructive pulmonary disease (COPD) and diabetes mellitus were independent risk factors for QREC colonization/infection. A single FQ course significantly increases the risk of QREC colonization/infection for no less than two years. This risk is higher in cases of multiple courses, longer hospital stays, COPD and diabetes; in males; and in older patients. These findings may inform public campaigns and courses directed to prescribers to promote rational antibiotic use.
Epithelial-to-mesenchymal transition (EMT) is discussed to be centrally involved in invasion, stemness, and drug resistance. Experimental models to evaluate this process in its biological complexity are limited. To shed light on EMT impact and test drug response more reliably, we use a lung tumor test system based on a decellularized intestinal matrix showing more in vivo-like proliferation levels and enhanced expression of clinical markers and carcinogenesis-related genes. In our models, we found evidence for a correlation of EMT with drug resistance in primary and secondary resistant cells harboring KRAS\(^{G12C}\) or EGFR mutations, which was simulated in silico based on an optimized signaling network topology. Notably, drug resistance did not correlate with EMT status in KRAS-mutated patient-derived xenograft (PDX) cell lines, and drug efficacy was not affected by EMT induction via TGF-β. To investigate further determinants of drug response, we tested several drugs in combination with a KRAS\(^{G12C}\) inhibitor in KRAS\(^{G12C}\) mutant HCC44 models, which, besides EMT, display mutations in P53, LKB1, KEAP1, and high c-MYC expression. We identified an aurora-kinase A (AURKA) inhibitor as the most promising candidate. In our network, AURKA is a centrally linked hub to EMT, proliferation, apoptosis, LKB1, and c-MYC. This exemplifies our systemic analysis approach for clinical translation of biomarker signatures.