3.2. Phage Therapy in Companion Animals
3.2.伴侣动物中的噬菌体治疗
Currently, societal concern for companion animal health has increased considerably. This has led to a misuse of antimicrobials to treat infections in companion animals and to an increase in MDR strains [6,17]. However, this societal concern also boosts research into new alternatives for the treatment of infections in companion animals.
目前，社会对伴侣动物健康的关注大大增加。这导致滥用抗菌剂治疗伴侣动物感染，并导致MDR菌株增加[ 6，17]。然而，这种社会关注也促进了对伴侣动物感染治疗新替代方案的研究。
A recent study conducted in the United Kingdom provides insight into the views of veterinarians and pet owners on the use of phage therapy in companion animals. Despite the limited sample size (n = 20), the study gives an indication of the possible acceptance of phage therapy in these groups. In this study, veterinarians acknowledge their difficulties in finding antibiotics to treat infections and the need for an alternative. The results of the study showed that 75% of the participants would agree with the use of phage therapy for the treatment of infections in companion animals after a brief explanation of what phages are and how phage therapy works. Although veterinarians were more familiar with the concept, pet owners would trust the veterinarians’ advice. This would explain why there were no significant differences between the two groups [84].
最近在英国进行的一项研究深入了解了兽医和宠物主人对伴侣动物使用噬菌体治疗的看法。尽管样本量有限（n = 20），但该研究表明这些组可能接受噬菌体治疗。在这项研究中，兽医承认他们在寻找抗生素治疗感染方面遇到了困难，并且需要一种替代品。研究结果显示，在简要解释了什么是噬菌体疗法以及噬菌体疗法如何工作后，75%的参与者同意使用噬菌体疗法治疗伴侣动物的感染。虽然兽医更熟悉这个概念，但宠物主人会相信兽医的建议。这就解释了为什么两组之间没有显著差异[ 84]。
Animals traditionally used as models, such as mice, rats, or hamsters, are also considered pets. Therefore, there are many studies on phage therapy using these animals obtained during research on phage-based treatments for humans. For example, a murine model of chronic Pseudomonas aeruginosa lung infection was performed to test the efficacy of phage PELP20, demonstrating its potential for phage therapy [60]. Phage therapy has also been tested against MDR A. baumannii infections in murine models, showing an increased survival rate of animals when treated with the phage φkm18p [61]. There are also examples of phage therapy for septicemia caused by S. aureus in mice, where phage S13’ significantly reduced the severity of infection [62]. Rabbits have also been considered as animal models for testing phage therapy. A cocktail of three virulent phages against Vibrio cholerae has been tested in both mice and rabbits to prevent the severe dehydrating disease caused by this pathogen. Oral administration of the phage cocktail against V. cholerae reduced pathogen colonization of the intestinal tract, preventing choleric diarrhea [63]. However, these examples all focused on human medicine.
传统上用作模型的动物，如小鼠，大鼠或仓鼠，也被认为是宠物。因此，有许多关于使用这些动物的噬菌体治疗的研究，这些动物是在对人类进行基于噬菌体的治疗的研究期间获得的。例如，进行慢性铜绿假单胞菌肺部感染的鼠模型以测试噬菌体PELP 20的功效，证明其用于噬菌体治疗的潜力[ 60]。噬菌体疗法也已经针对MDR A进行了测试。在鼠模型中的鲍曼不动杆菌感染，显示当用噬菌体φ km18 p处理时动物的存活率增加[ 61]。也有噬菌体治疗由沙门氏菌引起的败血症的例子。在小鼠中，噬菌体S13’显著降低了感染的严重程度[ 62]。兔也被认为是测试噬菌体疗法的动物模型。三种抗霍乱弧菌的强毒疫苗的混合物已经在小鼠和兔子身上进行了试验，以预防由这种病原体引起的严重脱水病。 口服给予抗霍乱弧菌的噬菌体混合物减少了肠道的病原体定植，预防了胆汁性腹泻[ 63]。不过，这些例子都是针对人类医学的。
In 2010, the first report of a veterinary clinical trial of a phage-based treatment of infection was published. Ten dogs with chronic P. aeruginosa otitis were treated with a cocktail of six phages active against P. aeruginosa. The phage preparation was applied directly to the ear canal and massaged for deeper penetration. After 48 h, P. aeruginosa counts decreased by 67% (p < 0.001), and clinical signs of infection were reduced by 31.1% (p < 0.0001) with no adverse events detected. These results suggest the potential of phage therapy in the veterinary setting [64]. A further study focused on phage therapy against P. aeruginosa, a major cause of urinary tract and wound infection, isolated and characterized P. aeruginosa phages with different lytic activity against 22 P. aeruginosa isolates. A phage cocktail composed of Pbuna-virus PB1-like phages showed an inhibitory effect on the emergence of phage-resistant variants [65].
2010年，发表了第一份关于基于噬菌体的感染治疗的兽医临床试验报告。10只患有慢性铜绿假单胞菌耳炎的狗用六种抗铜绿假单胞菌的活性物质的混合物治疗。将噬菌体制剂直接应用于耳道并按摩以更深地渗透。48小时后，铜绿假单胞菌计数减少67%（p < 0.001），感染的临床体征减少31.1%（p < 0.0001），未检测到不良事件。这些结果表明了噬菌体治疗在兽医环境中的潜力[ 64]。进一步的研究集中于针对铜绿假单胞菌（尿路和伤口感染的主要原因）的噬菌体治疗，分离并表征了对22种铜绿假单胞菌分离株具有不同裂解活性的铜绿假单胞菌。由Pbuna病毒PB1样噬菌体组成的噬菌体混合物显示出对噬菌体抗性变体出现的抑制作用[ 65]。
Phage therapy has been tested to treat other bacterial infections in humans. Extraintestinal pathogenic E. coli are bacteria that colonize the human and canine gastrointestinal tract asymptomatically but can cause significant pathology when they infect distal tissues, especially in immunosuppressed patients. MDR in a clonal group of these bacteria, ST131, is increasing worldwide. The HP3 phage was tested in immunosuppressed mice infected with two strains of ST131. Mice treated with the phage showed a significant reduction (p = 0.03) of colony-forming units in the liver and kidney. In this case, the phages were administered parenterally [33].
噬菌体疗法已被测试用于治疗人类的其他细菌感染。肠外致病性E.大肠杆菌是无症状地定殖于人和犬胃肠道的细菌，但当它们感染远端组织时，特别是在免疫抑制患者中，可引起显著的病理学。这些细菌的克隆群ST 131的MDR在全球范围内正在增加。在用两种ST 131菌株感染的免疫抑制小鼠中测试HP3噬菌体。用噬菌体处理的小鼠显示肝脏和肾脏中的集落形成单位显著减少（p = 0.03）。在这种情况下，胃肠外给药[ 33]。
There are more dog infections for which phage therapy has been proposed as a treatment. Staphylococcus pseudointermedius causes several diseases in canines, such as urinary tract infections, otitis externa, pyodermal infections, respiratory infections, and reproductive tract infections. Given the high prevalence of methicillin-resistant S. pseudointermedius strains, phage therapy is presented as a potentially successful alternative to treat these infections in canines [85] also due to the promising data shown in humans [86]. Several phages have been isolated against S. pseudointermedius. In addition, the potential use of staphylococcal endolysins against S. pseudointermedius to treat infections caused by this pathogen has also been proposed [85].
有更多的狗感染，噬菌体疗法已被提出作为一种治疗方法。假中间葡萄球菌在犬科动物中引起几种疾病，如尿路感染、外耳炎、脓皮病感染、呼吸道感染和生殖道感染。鉴于耐甲氧西林沙门氏菌的高流行率。由于pseudointermedius菌株，噬菌体疗法被认为是治疗犬中这些感染的潜在成功替代方案[ 85]，这也是由于在人类中显示的有希望的数据[ 86]。已分离出几种抗S.伪中间体此外，葡萄球菌内溶素的潜在用途对S。还提出了pseudointermedius来治疗由该病原体引起的感染[ 85]。
Uropathogenic E. coli causes urinary tract infections in dogs and cats. An in vitro assay identified five promising phages, four T4-type phages and one with morphological similarity to temperate P2-type phages. This work showed environmental isolation of phages that may be useful in treating canine and feline urinary tract infections [66].
肾盂肾炎大肠大肠杆菌导致狗和猫的尿路感染。一项体外试验确定了五个有前途的拟南芥，四个T4型拟南芥和一个形态相似的温带P2型拟南芥。这项工作表明，环境隔离可能有助于治疗犬和猫的尿路感染[ 66]。
Phage therapy has also been tested for equine diseases. Equine keratitis can be caused by many bacterial species. P. aeruginosa is one of them and can cause corneal corruption that can lead to blindness in some cases. Antimicrobial therapy makes its treatment challenging. In one study, a phage cocktail with Myoviridae and Podoviridae phages demonstrated complete prevention of equine keratitis as well as suppression of this infection, making phage therapy an important candidate for equine keratitis [67].
噬菌体疗法也已被测试用于马疾病。马角膜炎可由许多细菌引起。铜绿假单胞菌是其中之一，可导致角膜腐败，在某些情况下可导致失明。抗微生物治疗使其治疗具有挑战性。在一项研究中，具有肌尾病毒科和短尾病毒科的噬菌体混合物证明完全预防马角膜炎以及抑制这种感染，使得噬菌体疗法成为马角膜炎的重要候选物[ 67]。
Reptiles are also part of the wide variety of animals considered as pets. Salmonellosis associated with reptiles as exotic pets has been a growing problem in recent years, caused by poor hygiene after handling reptiles. Because of this potential harm to human health, antibiotic treatment has been tried in reptiles without consistent success and leading to an increase in drug-resistant strains. Phage therapy represents an alternative for the treatment of reptiles. In particular, the phage Felix O1 has been successfully tested in bearded dragons [68].
近年来，以爬行动物作为宠物饲养的案例越来越多，但随之而来的一大问题是与爬行动物相关的沙门氏菌病。由于饲养者在处理爬行动物后卫生习惯不佳，导致沙门氏菌病的发病率上升。针对这一潜在的人类健康危害，兽医曾尝试使用抗生素治疗爬行动物，但效果并不理想，反而导致耐药菌株的增加。噬菌体疗法为爬行动物治疗提供了另一种选择。研究表明，噬菌体 Felix O1 在治疗宠物鬃狮蜥方面取得了成功。