Phage Therapy in Humans 人类的噬菌体疗法
During phage therapy, lytic phages are mainly applied to kill their bacterial hosts with no effect on human cells and no or minimal disturbance to the human microbiota relative to conventional antibiotics. Phage therapy is rapidly being revived, with encouraging effects in life-saving therapeutic use and multiple clinical trials. However, it is meeting obstacles with respect to regulations and policy issues for clinical use and implementation.81
在噬菌体疗法中，溶菌噬菌体主要用于杀死细菌宿主，对人体细胞没有影响，与传统抗生素相比，对人体微生物群没有或干扰极小。噬菌体疗法正在迅速复兴，在挽救生命的治疗和多项临床试验中取得了令人鼓舞的效果。然而，噬菌体疗法在临床使用和实施的法规和政策问题上遇到了障碍。 81
For clinical trials on phage therapy, phages should be sufficiently characterized and there must be selection of the right phage, human, and bacterium, and consideration of the right disease target for phage therapy. In addition, information on phage formulation, dosage, and efficacy is vital for effective therapy. For example, very specific phages are desired for monobacterial disease. However, this may be a limitation during polybacterial infections, unless the phage is provided in combination with antibiotics. This approach is relevant to patient safety because the removal of a single pathogen and the growth of other bacteria may threaten the patient’s life.82 In fact, phages with a broad host range may be more abundant than currently identified phages, although further investigations are required.83 Principally, all precautions, policies, and regulations for phage therapy need standardization, as is the case for antibiotics for human use.
对于噬菌体疗法的临床试验，噬菌体应具有充分的特征，必须选择合适的噬菌体、人类和细菌，并考虑噬菌体疗法的合适疾病靶点。此外，有关噬菌体配方、剂量和疗效的信息对于有效治疗也至关重要。例如，对于单细菌疾病，需要非常特异的噬菌体。然而，这在多细菌感染时可能会受到限制，除非噬菌体与抗生素联合使用。这种方法与病人的安全息息相关，因为去除单一病原体后，其他细菌的生长可能会威胁到病人的生命。 82 事实上，宿主范围广泛的噬菌体可能比目前发现的噬菌体数量更多，但还需要进一步调查。 83 就像人类使用抗生素一样，噬菌体疗法的所有预防措施、政策和法规也需要标准化。
The lack of validated and sufficiently controlled clinical trials presents a challenge for phage therapy for clinical use. Planning and designing pharmacological aspects and dosages are major activities to consider for clinical use.84 The dissemination of phages in the body may reduce their efficacy because phages require direct contact with bacteria at an optimum concentration to effectively act on the bacteria. Topical applications and many other methods are used to administer phages. Phage therapy can be given as monotherapy, combination therapy, or phage cocktails; however, the last of these provides broad-spectrum activity and a low risk of the development of resistance. More importantly, combination therapy largely elevates the challenge of diagnosing inflammatory effects, the potential for gene transfer, and phage resistance development for all phages in the cocktail.85 Another vital consideration to be addressed before any clinical trial is the onset of toxic shock, as phages are bactericidal.86
缺乏经过验证和充分控制的临床试验给噬菌体疗法的临床应用带来了挑战。规划和设计药理学方面和剂量是临床应用需要考虑的主要活动。噬菌体在体内的传播可能会降低其疗效，因为噬菌体需要以最佳浓度与细菌直接接触才能对细菌产生有效作用。噬菌体的局部应用和许多其他方法都可用于给药。噬菌体疗法可采用单一疗法、联合疗法或噬菌体鸡尾酒疗法，但最后一种疗法具有广谱活性，产生抗药性的风险较低。更重要的是，联合疗法在很大程度上提高了对鸡尾酒中所有噬菌体的炎症效应、潜在基因转移和噬菌体抗药性产生的诊断难度。 85 由于噬菌体具有杀菌作用，临床试验前需要考虑的另一个重要因素是中毒性休克的发生。 86
Clinical Trials Involving Phages
涉及噬菌体的临床试验
Clinical trials on phage therapy practices in Georgia and Poland were discussed by Kutter et al87 and are prominently mentioned in many studies in the literature, confirming the safety of phages in treating venous leg ulcers88 and their safety and efficacy in chronic otitis.89 Rhoads et al reported no adverse side effects in a patient with venous leg ulcers in a small phase I clinical trial on phage therapy.88 The efficacy and safety of anti-pseudomonal phages in late-stage recurrent otitis, which was mainly controlled by MDR P. aeroginosa, were demonstrated by Wright et al.89 Although phage therapy is incorporated in the health policies of Eastern European countries, the above-mentioned controlled clinical trials were among the first trials conducted in humans in the Western world. Currently, many clinical trials have been registered.88,89
Kutter 等人讨论了在格鲁吉亚和波兰进行的噬菌体疗法临床试验， 87 并在许多研究文献中重点提及，证实了噬菌体治疗静脉性腿部溃疡的安全性 88 以及治疗慢性中耳炎的安全性和有效性。 89 Rhoads 等人报告说，在一项关于噬菌体疗法的小型 I 期临床试验中，一名静脉腿部溃疡患者没有出现不良副作用。 88 Wright 等人证实了抗假单胞菌噬菌体对晚期复发性中耳炎（主要由 MDR 铜绿假单胞菌控制）的疗效和安全性。 89 尽管噬菌体疗法已被纳入东欧国家的卫生政策，但上述对照临床试验属于西方世界首次在人体中进行的试验。目前，许多临床试验已经注册。 88 89
Scientifically sound clinical trials are essential for phage therapy to be accepted by the Western clinical world. Although many observational phage therapy studies have been conducted and were effective, they have limitations owing to small sample sizes and poor control. In addition, despite the existence of promising case studies, strong clinical trial data are expected by regulators to prepare guidelines for phage therapy81 to be approved by the United States Food and Drug Administration (FDA).
科学合理的临床试验对于噬菌体疗法被西方临床界接受至关重要。虽然已经开展了许多观察性噬菌体疗法研究，而且效果显著，但由于样本量小、控制不力，这些研究存在局限性。此外，尽管存在有前景的病例研究，但监管机构仍希望获得强有力的临床试验数据，以便为噬菌体疗法制定指导方针，并获得美国食品药品管理局（FDA）的批准。
Determinants of Human Phage Therapy Trials
人类噬菌体疗法试验的决定因素
Virulent Genes
The pathogenicity and severity of a disease may increase when virulent genes are acquired from other virulent species, which may cause treatment failure.90 Phages can carry virulent genes that may increase the virulence and pathogenicity of bacteria during lysogenization. Phage virulent genes are detected in many human pathogens, including E. coli, P. aeroginosa, S. aureus, and S. pyogenes. Currently, not all phage-encoded virulent genes have been identified. Therefore, it is vital that the metagenome and each genome sequence are added to databases of bacterial virulent genes and antibiotic resistance genes to ensure safety.91,92
致病基因 从其他致病菌种获得致病基因后，疾病的致病性和严重程度可能会增加，从而导致治疗失败。噬菌体可携带毒力基因，在溶菌过程中可增加细菌的毒力和致病性。在大肠杆菌、绿脓杆菌、金黄色葡萄球菌和化脓性葡萄球菌等许多人类病原体中都检测到了噬菌体毒力基因。目前，并非所有噬菌体编码的毒力基因都已被确定。因此，将元基因组和每个基因组序列添加到细菌毒力基因和抗生素耐药基因数据库以确保安全至关重要。 9192
Transduction
Bacteria can acquire virulent and antibiotic-resistant genes through phage-mediated transduction. This can be mitigated by avoiding known transducing phages.93
转导 细菌可通过噬菌体介导的转导获得毒性基因和抗生素耐药基因。避免使用已知的转导噬菌体可以减少这种情况的发生。 93