猪感染链球菌后，耐药性是否会增强？

Does S. suis represent a danger for antibiotic resistance?

如前所述，该病在田间的发病率通常保持在5%以下。细菌耐药性增强，主要原因是我们为了预防疾病，而大量使用抗生素或做全群常规保健（在允许的情况下）。在一些国家，禁止在饲料中添加抗生素，因此有时会用这些抗生素进行饮水治疗。应对猪链球菌感染，我们使用抗生素，不一定会让这些菌株对用于治疗的常用药产生耐药性。这类感染的首选抗生素是β-内酰胺类抗生素。大多数致病菌株对此类药物敏感，这是由于耐药机制：它不是由β-内酰胺分子（β-内酰胺酶）的酶降解所介导的，而是改变分子量及/或降低其β-内酰胺靶蛋白【青霉素结合蛋白（PBP）】的结合青霉素的能力，通过这些方式来实现的。猪链球菌对青霉素和阿莫西林的耐药性增加，的确是由于其青霉素结合蛋白在染色体水平上发生了明显的累积性改变。这种抗性机制的结果是，可能需要数年时间才能形成某种抗性，如果形成，则耐药性的进展也会非常缓慢。另一重要方面，我们要不断检测农场菌株，从而确认这种假设。

As mentioned before, the incidence of the disease is usually kept under 5% in the field, but this is mainly due to the extensive and routine (where allowed) prophylactic and metaphylactic use of antibiotics. In some countries, where antibiotics in feed are banished, these are sometimes used in water. The problem of the antibiotic use for S. suis infections is not necessarily the development of resistance of such strains to the most frequently molecules used to treat S. suis-affected pigs. The antibiotics of choice for this type of infection are beta-lactams. Most strains able to cause disease are susceptible to such drugs and this is due to the mechanism of resistance: it is not mediated by enzymatic degradation of the beta-lactam molecules (beta-lactamases), but rather involves modifications in the form of altered molecular weight and/or a decrease in the penicillin-binding capacity of its beta-lactam target proteins: the penicillin- binding proteins (PBP). Indeed, an increase in resistance to penicillin and amoxicillin by S. suis is brought by distinct cumulative alterations in its PBPs which happen at the chromosomal level. The consequence of such mechanism of resistance is that it may take years to develop some kind of resistance and, if it develops, it progresses very slowly. On the other hand, it is important to keep testing field strains to confirm such a hypothesis.

值得注意的是，一些诊断实验室没有使用标准化方法来检测细菌耐药性，因此有时会观察到模棱两可的结果，例如：对青霉素敏感但对阿莫西林耐药，或对阿莫西林耐药但对阿莫西林克拉维酸敏感：这根本不可能是事实。如果观察到对β-内酰胺类抗生素有某种耐药性，建议将分离株送往独立实验室再次进行检测。从扁桃体分离出的一些菌株可能对β-内酰胺类抗生素不太敏感：这些菌株中的大多数没有囊膜和和毒性。此外，其中许多细菌甚至不属于猪链球菌。

It is important to note that some diagnostic laboratories do not use standardized methods to measure resistance, so equivocal results are sometimes observed, as for example: sensitivity to penicillin but resistance to amoxicillin or resistance to amoxicillin but susceptibility to amoxicillin with clavulanic acid: this is simply unlikely to be true. If some kind of resistance to beta-lactams is observed, it is recommended to send the isolate to an independent laboratory to repeat the test. Some strains isolated from tonsils may present lower level of susceptibility, event to beta-lactam antibiotics: most of these strains are non-encapsulated and non-virulent. In addition, many of these bacteria do not even belong to the Streptococcus suis species.

那么，我们能说对猪链球菌来讲，抗生素耐药性并不重要吗？应该谨记，一些猪用的抗生素对人类医学也很重要。此外，全世界猪链球菌对抗生素的耐药性数据令人担忧。农场菌株对许多不同的抗菌药物（如四环素和红霉素）高度耐药，即使它们仍然对β-内酰胺类药物敏感。的确，猪链球菌被视作抗生素耐药性的一个代表，并且存在向其他病原体传播耐药性的风险，且这一风险很高。这是因为，猪链球菌中有些可移动的遗传因子携带抗性基因，这些抗性基因不仅在猪链球菌菌株之间，而且也在链球菌与其他种类的细菌之间，频繁地转移。再次强调，我们必须持续监测所有猪病原菌的耐药性模式。

So, can we say that antibiotic resistance is not important for S. suis? It should be remembered that some of the antibiotics used are also of importance for human medicine. In addition, worldwide data from resistance of S. suis to antibiotics are alarming. Field strains are highly resistant to many different antimicrobials (such as tetracyclines and erythromycin), even if they are still susceptible to beta-lactams. Indeed, S. suis is considered a niche for antibiotic resistance and represents a high risk of transmission of resistance to other pathogens. This arises from mobile genetic elements in S. suis carrying resistance genes that are transferable at high frequency not only between S. suis strains but also to other bacterial species. Again, it is important to emphasize the need for continuous surveillance of resistance patterns in all pig pathogenic bacteria.

如何能不使用抗生素并能预防猪链球菌引起的疾病？

How to prevent disease caused by S. suis without using antibiotics?

限制使用抗生素后，一个后果就是断奶仔猪发病率高。在不使用抗生素的农场中，猪链球菌是最重要的关注点之一。每个人都有个疑问：我们如何才能预防猪链球菌病呢？大家也一致认为，控制应激和其他容易诱发疾病的因素（混合感染、环境和管理因素等），可以大大降低发病率。然而，只有这些往往还不够。我们还可以做些什么呢？

Restrictions in the use of antibiotics brought, among other consequences, an increase of clinical disease in post-weaned piglets. In farms where animals are raised without antibiotics, S. suis is one of the most important concern. The question everybody is asking: how can we prevent S. suis diseases? Everybody also agrees that controlling stress and predisposing factors (concomitant infections, environmental and management factors, etc.) may significantly help to reduce disease. However, this is frequently not enough. What else can be done?

为了治疗猪链球菌病，人们已经尝试了多种替代抗生素的方法。然而，大多数方法只做了体外实验，并没有做体内实验（表1）。到目前为止，还没有证明，有哪个活性化合物能够有效地控制体内的猪链球菌病。

There are many alternatives to antibiotics that have been tested for S. suis. However, most of them have been tested in vitro but not in vivo (Table 1). So far, no active compound has been clearly demonstrated as being effective to control S. suis disease in vivo.

表1: 杀灭猪链球菌的各种抗生素替代品

Table 1: Different products tested as an alternative to antibiotics to kill S. suis

The use of feed additives became also popular, based on the hypothesis of S. suis causing disease through the intestinal route, as discussed above. However, most available studies either have been tested in vitro or have not been published in peer-reviewed journals and lack the strict evaluation from the scientific community. Some examples are present in Table 2. Again, the use of these products become more and more popular, but there is no scientific proved data indicating any advantage to use them to control and prevent S. suis infections. More controlled and scientific research is indeed necessary.

表2: 控制猪链球菌感染而测试的几种饲料添加剂

Table 2: Feed additives tested to control S. suis infections

随着猪链球菌流行病学变得更加复杂（多菌株、多血清型），描述农场疾病控制和管理困难的报告很常见。一种合理的选择是使用疫苗。然而，到目前为止，还没有能够保护所有血清型/菌株的猪链球菌商品苗。许多研究评估了亚单位疫苗（蛋白质）甚至活苗，但得到的结果仍有争议。因此结果就是，兽医人员唯一的选择只能是使用细菌自家苗（整个细菌灭活）。自家苗使用的是从感染猪上分离出的主要致病菌株，疫苗由经认证的实验室生产。大多数已发表的研究使用的都是用研究实验室的参考菌株制作的自家苗，这是一种人工的 "自家苗"，并非由经认证的实验室生产。

As the complexity of S. suis epidemiology in swine increases (multiple strains, multiple serotypes), field reports describing difficulty in disease control and management are common. A logical alternative is the use of vaccines. However, so far, there is no commercial vaccine able to protect against all serotypes/strains of S. suis. Many research studies evaluated sub-unit vaccines (proteins) or even live vaccines, but controversial results have been obtained. The consequence is that the only alternative practitioners have in hands is the use of bacterins (killed whole bacteria), mostly autogenous vaccines. Autogenous vaccines are bacterins based on the predominant strain(s) recovered from diseased pigs in the affected farm and produced by accredited laboratories. Most published studies have been done with bacterins produced in research laboratories with reference strains, a kind of artificial “autogenous vaccine”, not produced by accredited laboratories.

对于自家苗的生产，第一步是选择菌种。与副猪嗜血杆菌不同，猪链球菌很容易分离。然而，在某些情况下，同一猪场内可能会从病猪上分离出不同的菌株。猪链球菌可能是次要的或主要的病原体：如前所述，混合感染、环境或管理问题可能刺激到定殖在扁桃体中的中等毒力菌株，从而诱发疾病。在这些情况下，我们最好集中精力减少以上诱发因素，因为猪链球菌病只是个结果，而并非真正的发病诱因。要明确诊断出来，引发感染的主要病原体就是猪链球菌，这并不容易。图3做了一个标准流程，可能帮我们做出决定，将某一特定菌株纳入自家苗。

For the production of an autogenous vaccine, the first step is the choice of the strain. Differently from Glaesserella (Haemophilus) parasuis, S. suis is easy to isolate. However, under certain circumstances, different strains may be isolated from diseased pigs within the same farm. S. suis may be either a secondary or primary pathogen: as mentioned, co-infections, environmental or management issues may help moderately virulent S. suis strains, normally located in tonsils, to induce disease. In these cases, it is better to concentrate the efforts to reduce predisposing factors, as S. suis disease is a consequence not really a cause of the health problem. Diagnosis of S. suis infection as primary pathogen is not easy. Figure 3 shows a standard procedure that may help on the decision to incorporate a given strain to an autogenous vaccine.

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