1. Introduction 1.介绍
The discovery of antibiotics was a revolution in medicine, as they have saved countless lives. However, their indiscriminate use has led to the emergence of multi-drug resistant (MDR) bacteria. This problem is now a major global threat and poses a serious challenge in the search for alternative therapies against MDR bacteria [1]. A key factor determining the high rate of MDR spread is the irrational use of antibiotics [2]. The World Health Organization describes the rational application of a drug as when patients receive an appropriate drug for the appropriate indications in the doses personally and individually required for an indicated period of time, implying the lowest cost and with suitable information available, among other measures [3]. The problem of antibiotic resistance causes serious health and economic losses to society worldwide [4]. For example, in the European Union, 25,000 patients die each year due to infections caused by MDR bacteria, with an associated economic cost to society of about 1.5 billion annually [5]. In addition, the COVID-19 pandemic has led to an increase in antibiotic prescription, exacerbating the prospects for antimicrobial resistance [6,7,8].
抗生素的发现是医学上的一场革命，因为它们挽救了无数人的生命。然而，它们的滥用导致了多重耐药（MDR）细菌的出现。这个问题现在是一个主要的全球性威胁，并在寻找针对MDR细菌的替代疗法方面构成了严峻的挑战[ 1]。决定MDR高传播率的一个关键因素是抗生素的不合理使用[ 2]。世界卫生组织将药物的合理应用描述为当患者在指定的时间段内以个人和个人所需的剂量接受适当适应症的适当药物时，这意味着最低的成本和可用的适当信息，以及其他措施[ 3]。抗生素耐药性问题给全世界社会造成严重的健康和经济损失[ 4]。 例如，在欧盟，每年有25，000名患者因MDR细菌引起的感染而死亡，每年给社会带来约15亿美元的相关经济成本[ 5]。此外，COVID-19大流行导致抗生素处方增加，加剧了抗生素耐药性的前景[ 6，7，8]。
The agro-food industry plays a crucial role in the emergence of MDR bacteria. In developed countries, livestock farming accounts for about 50–80% of total antibiotic use [9,10]. Moreover, the highest rates of antibiotic resistance are detected in tetracycline, sulfonamide, and penicillin, antibiotics commonly used in the animal feed industry [11,12]. Different factors seem to play a role in the prevalence of MDR microorganisms. Farm size has been associated with higher rates of antimicrobial resistance, which may be related to differences in farm management (hygiene and feeding practices). Antibiotic usage in farms contaminates water with MDR microorganisms that even reach wild species, where the existence of these microorganisms has also been evidenced [12]. Antimicrobials in animal production play an important role in MDR bacteria in humans. Most of the antimicrobials used in food-producing animals are closely related or identical to human antimicrobials. Extensive usage of antibiotics in the food industry can increase the spread of MDR bacteria that can reach humans through food or other routes [13]. Antibiotics in livestock are not exclusively treatments for bacterial infections but have also been widely used as growth-promoting factors since 1951 [9,14]. Indiscriminate use of antibiotics has been linked to higher levels of antibiotic-resistance genes that are also transferred to bacteria infecting humans. Denmark banned Avopracine in 1995, one of the antibiotics used as a growth promoter in livestock, followed by the EU five years later, banning 11 antibiotics for growth promotion. Therefore, nowadays antibiotics usage in the EU varies greatly among EU members, with Italy and Spain leading the way [9].
农业食品工业在MDR细菌的出现中起着关键作用。在发达国家，畜牧业占抗生素总使用量的50-80%[ 9，10]。此外，在四环素、磺胺和青霉素中检测到最高的抗生素耐药性，这些抗生素通常用于动物饲料行业[ 11，12]。不同的因素似乎在MDR微生物的流行中起作用。农场规模与较高的抗菌素耐药性有关，这可能与农场管理（卫生和饲养习惯）的差异有关。农场中抗生素的使用会使水受到MDR微生物的污染，这些微生物甚至会到达野生物种，这些微生物的存在也已得到证明[ 12]。动物生产中的抗菌剂在人类MDR细菌中起着重要作用。用于食用动物的大多数抗菌剂与人类抗菌剂密切相关或相同。 在食品工业中广泛使用抗生素会增加MDR细菌的传播，这些细菌可以通过食物或其他途径到达人类[ 13]。抗生素在牲畜中不仅是细菌感染的治疗方法，而且自1951年以来也被广泛用作生长促进因子[ 9，14]。滥用抗生素与较高水平的抗药性基因有关，这些基因也转移到感染人类的细菌中。丹麦在1995年禁止了阿伏拉辛，这是一种在牲畜中用作生长促进剂的抗生素，欧盟在5年后紧随其后，禁止了11种用于生长促进的抗生素。因此，目前欧盟成员国之间的抗生素使用情况差异很大，意大利和西班牙领先[ 9]。
Despite the fact that companion animals are not linked to the human food chain, they can also act as reservoirs of MDR bacteria [15], and their proximity to humans makes them a potential focus for cross-transmission of zoonotic bacteria, including MDR strains that pose a potential threat to human health [11,16]. Nowadays, the range of species that can be considered as companion animals has increased significantly, including a wide diversity of species (rodents, guinea pigs, reptiles, etc.). This increases the likelihood of human contact with microorganisms and thus the possibility of transfer of dangerous pathogens [16]. Social concern for health care has grown in recent decades, especially in urban areas. Due to their easy availability, the most commonly used antimicrobials in companion animals are human antibiotics, which increases the emergence of MDR strains [6,17], and they become potential reservoirs. Due to the increase in MDR strains that can affect humans, which is caused by misuse of human antimicrobials in animals [11], it has become necessary to investigate new alternatives to animal-only antibiotics. Here, we propose bacteriophages (phages), viruses that infect bacteria, as a promising tool against MDR bacteria and as an alternative treatment in the fight against pathogenic bacteria.
尽管伴侣动物与人类食物链没有联系，但它们也可以作为MDR细菌的宿主[ 15]，并且它们与人类的接近使它们成为人畜共患病细菌交叉传播的潜在焦点，包括对人类健康构成潜在威胁的MDR菌株[ 11，16]。如今，可被视为伴侣动物的物种范围已显着增加，包括各种各样的物种（啮齿动物，豚鼠，爬行动物等）。这增加了人类与微生物接触的可能性，从而增加了危险病原体转移的可能性[ 16]。近几十年来，社会对卫生保健的关注有所增加，特别是在城市地区。由于其易于获得，伴侣动物中最常用的抗菌剂是人用抗生素，这增加了MDR菌株的出现[ 6，17]，并且它们成为潜在的储库。 由于在动物中滥用人用抗菌药物导致可影响人类的MDR菌株增加[ 11]，因此有必要研究仅限动物的抗生素的新替代品。在这里，我们提出噬菌体（噬菌体），感染细菌的病毒，作为一个有前途的工具，对MDR细菌和作为一种替代治疗在打击病原菌。