As such, piglets are highly susceptible to Post-Weaning Diarrhea (PWD), a disorder that often affects pigs during the first 2 weeks of weaning and is characterized by sudden death or diarrhea and growth retardation in surviving piglets (2). on the use of critically important antimicrobials in food-producing animals and the prohibition of their use as growth promoters. As such, it is important now to begin the transition from these preventive/control measures to other, more sustainable, approaches. This review provides a quick synopsis of the currently approved and available therapies for PWD treatment while presenting an overview of novel antimicrobial strategies that are being explored for the control and treatment of this infection, including, prebiotics, probiotics, synbiotics, organic acids, bacteriophages, spray-dried plasma, antibodies, phytogenic substances, antisense oligonucleotides, and aptamers. Keywords: enteric colibacillosis, post-weaning diarrhea, gut microbiome, antibiotic therapy, zinc oxide, novel antimicrobial approaches Introduction Post-weaning period is a critical phase in the pig’s life because the immune system is immature, and the sow milk removal, and consequent interruption of nutritive intake of immunoglobulin present in the milk, increases pigs’ susceptibility to microbial infections, especially in the current lines of hyperprolific sows (1). As such, piglets are highly susceptible to Post-Weaning Diarrhea (PWD), a disorder that often affects pigs during the first 2 weeks of weaning and is characterized by sudden death or diarrhea and growth retardation in surviving piglets (2). PWD is one of the most serious threats to the swine industry worldwide, with episodes reaching mortality rates of 20 to 30% (2) and is associated with the proliferation of enterotoxigenic (ETEC) in the pig intestine Cyclosporin A (3). ETEC are gram-negative, flagellated bacilli and most pathogenic strains form smooth to mucoid colonies. Virulence factors include fimbriae, enterotoxins, endotoxins, and capsules. Fimbriae are the small hair-like structures on the bacterial surface that allow attachment to specific receptors on the surface of mucosal enterocytes of the small intestine, being crucial in the colonization process. Pathogenic strains also produce one or more enterotoxins, which are exotoxins elaborated locally in the small intestine that can have either local or systemic effects (1). There are 5 common, antigenically different fimbriae types found in pigs: F4 (K88), F5 (K99), F41, F6 (987P), and F18. The first 4 fimbriae types are responsible for mediating adhesion in neonates, while F18 is not Hexarelin Acetate associated with neonatal colibacillosis but is common in postweaning colibacillosis as is F4. It is also important to note that hemolysis is a common trait for pathogenic F4 and F18 isolates. Furthermore, the virulence of ETEC can also be characterized by the production of heat-labile toxins (LT), heat-stable toxin A (StA), heat-stable toxin B (StB), and verotoxin (shiga-like toxin, STX). The first three act locally interfering with electrolytes fluid increasing the fluid secretion to the lumen leading to diarrhea while verotoxin is responsible for the systemic vascular effects of edema disease (4). As an attempt to promote health and growth performance, different approaches have been used to prevent PWD, including mostly dietary supplementation, such as prebiotics and probiotics; genetic breeding for ETEC-resistant herds; administration of growth promotors; and vaccines (5, 6). It is important to highlight that growth promoters and zinc oxide (7), have been (or are being) banned from animal husbandry. Also, antibiotics use is now more restricted because of antimicrobial resistance observed in ETEC and potential consequences for human health (1). These restrictions are strongly affecting the control of PWD (8). This makes room for innovative, antibiotic-free, intervention/control strategies that can Cyclosporin A control ETEC infections. Antibiotics used to treat PWD Antibiotic therapy is required in many cases of enteric colibacillosis, being the main antimicrobials used for the treatment of enteric colibacillosis listed in Supplementary Table 1. According to Luppi, the choice of antibiotics for the treatment of PWD must consider several aspects (1): (i) the local of infection that must be located mainly in the small intestine; (ii) the empiric treatments based on the knowledge of the individual herd and local data on the resistance pattern; Cyclosporin A and (iii) the evaluation of the isolated strain’s antimicrobial susceptibility. However, as an outbreak of colibacillosis frequently requires quick actions, the use of antibiotics almost always precedes the results of the resistance pattern (1, 9). Also, it has been established the antibiotic should be administered to all animals exhibiting indicators referable to colibacillosis and ill pigs must be treated parenterally since they eat and drink very little. In practice when mortality happens, a metaphylactic approach is definitely applied wherein all animals in the pens are treated (1, 9C11). Of note that recommendations for the wise use of antimicrobials in veterinary medicine (2015/C/ 299/04) published in the official journal of the European Union considered the use of metaphylaxis and stated that antimicrobial metaphylaxis should be prescribed only when there is a real need.