**1. Introduction**

*Escherichia coli* is the best-known member of the normal microbiota of the human intestine and a versatile gastrointestinal pathogen. *E. coli* infection is a major global problem in the clinical and community setting. The prevalence of *E. coli* among clinical specimens varies from country to country and even among two different institutions in the same country and continuously changes over time [1–4]. More and more people die each year from hospital infections caused by multidrugresistant *E. coli* [5].

According to the WHO, *E. coli* is considered a global critical pathogen that possesses the highest priority for research, discovery, and development of new antibiotics [6]. When antibiotics are consumed during bacterial infection treatment, the resistance of the commensal *E. coli* is developed after exposure [7]. Undeniably, commensal *E. coli* is one of the main reservoirs for antibiotic resistance transmission to other pathogenic bacteria through plasmid exchange, for example (**Figure 1**) [8–10].

Via contact with livestock or a contaminated natural environment, humans can be exposed to viable commensal antibiotic-resistant *E. coli* [11].

Indiscriminate use of antimicrobials and antibiotic overuse has led to the treacherous resistance rates in recent years, creating a very complicated therapeutic challenge that threatens to return clinicians and patients to a "pre-antibiotic era". Furthermore, mobile genetic elements (plasmids, bacteriophages) carrying antibiotic resistance genes (ARGs) play a major role in transferring resistance to both human and nonhuman, contribute to the spread of antimicrobial-resistant organisms, and increases the risk factor of infections and diseases in both animals and humans [12].

This chapter will discuss various mechanisms, epidemiology, vaccines, and novel approaches to combat *E. coli* antibiotic resistance.
