## 2 Overview of Chemo-Mechanical Disinfection and Current Intracanal Medications  
Endodontic treatment involves a chemo-mechanical approach to eliminate the infected tissues and disinfect the root dentin [15]. In a single-visit treatment appointment, the infected tissues are removed using rotary file systems called \"intracanal instrumentation.\" Around 35% of the intracanal walls may remain intact after the instrumentation, reflecting in remaining infected tissues [16]. This scenario mandates combining the mechanical instrumentation and irrigation of the canals, using a sodium hypochlorite (NaOCI) solution [17]. NaOCI irrigation is not only helpful to disinfect the canals, but also to eliminate endotoxins produced by the putative endodontic pathogens [1, 18]. Free chlorine in NaOCl irrigation can dissolve necrotic tissues by breaking down proteins into amino acids [19]. Consistent exchange and the use of a large volume of irrigation are recommended to maintain the antibacterial effectiveness of NaOCl [20].  
Although robust bacterial reduction was gained, using instrumentation and irrigation, efficient disinfection of the root canal system is still not reached. As mentioned earlier, specific anatomic landmarks and the complexity of the formed biofilms may limit this chemo-mechanical approach's effectiveness [3, 21, 22]. _E. faecalis_ can penetrate dental tubules to a deep extent, escaping from instrumentation and irrigation [23]. Another approach used to increase bacteria reduction is the use of antibacterial intracanal medications. These medications are applied inside the root canal and left to act between the two visits to increase the endodontic treatment's success rate [24, 25].  
Calcium hydroxide (Ca(OH)\({}_{2}\)) is the most commonly used intracanal medication in endodontic treatment. Ca(OH)\({}_{2}\) reduces the bacterial content via the cell layer's damage by direct contact and increasing the pH [26]. Even though it has a wide range of antibacterial activity, calcium hydroxide is not effective against _E. faecalis_[7, 8]. Its proton pump enables _E. faecalis_ to resist high pH [8] and grow in the presence of calcium hydroxide [7]. Moreover, _E. faecalis_ can invade tubules and bind to collagen [6], depending on environmental signals to regulate its genetic expression [9]. Therefore, two-visit appointments with calcium hydroxide as intracanal medication does not show better periapical healing results, as _E. faecalis_ can be recovered after the treatment [10, 11].  
Chlorexidine (CHX) at 2% was found more effective against _E. faecalis_ than Ca(OH)\({}_{2}\)[12]. However, there is no further bacterial reduction when compared to chemo-mechanical instrumentation. In this context, the use of antibiotics as intracanal medications is recommended. However, antibiotics' diffusion through the root canal may not be sufficient to inactivate bacteria [27]. Several investigations found that antibiotics could not fully eradicate pathogens inside the root canal system [13, 14]. In addition, bacterial resistance development following the use of antibiotics is a rising concern among dentists. In the United States alone, around 2 million individuals are affected by infectious disease owing to bacterial resistance, resulting in 20,000 deaths annually [28]. Therefore, more efforts should be directed to explore and design other approaches that replace antibiotic use in targeting dental pathogens.