AgResearch Grasslands, Private Bag 11008, Palmerston North 4442, New Zealand.
Vet Parasitol. 2013 Nov 15;198(1-2):145-53. doi: 10.1016/j.vetpar.2013.08.022. Epub 2013 Aug 29.
The rotation of different anthelmintic classes, on an approximately annual basis, has been widely promoted and adopted as a strategy to delay the development of anthelmintic resistance in nematode parasites. Part of the rationale for recommending this practice was the expectation that resistant genotype worms have a lower ecological fitness than susceptible worms, at least in the early stages of selection, and so reversion towards susceptibility could be expected in those years when an alternative class of anthelmintic was used. The routine use of combination anthelmintics might be expected to negate this opportunity for reversion because multiple classes of anthelmintic would be used simultaneously. A simulation model was used to investigate whether the optimal strategy for use of multiple drug classes (i.e. an annual rotation of two classes of anthelmintic or continuous use of two classes in combination) changed with the size of the fitness cost associated with resistance. Model simulations were run in which the fitness cost associated with each resistance gene was varied from 0% to 15% and the rate at which resistance developed was compared for each of the drug-use strategies. Other factors evaluated were the initial frequency of the resistance genes and the proportion of the population not exposed to treatment (i.e. in refugia). Increasing the proportion of the population in refugia always slowed the development of resistance, as did using combinations in preference to an annual rotation. As the fitness cost associated with resistance increased, resistance developed more slowly and this was more pronounced when a combination was used compared to a rotation. If the fitness cost was sufficiently high then resistance did not develop (i.e. the resistance gene frequency declined over time) and this occurred at lower fitness costs when a combination was used. The results, therefore, indicate that the optimal drug-use strategy to maximise the benefit of any fitness cost associated with resistance is the use of combinations of different anthelmintic classes. Manual calculations confirmed that, within the model, the only resistant genotypes capable of surviving treatment with a combination are those carrying multiple resistance genes. These individuals are less fit, resulting in the worm population surviving treatment having a lower overall ecological fitness. This is a previously unreported perspective on the use of combination anthelmintics and strengthens the argument that any new class of anthelmintic, for which resistance genes can be expected to be rare, should be brought to market in combination.
不同驱虫药类别的轮换，大约每年一次，已被广泛推广和采用，作为延缓线虫寄生虫对驱虫药产生抗药性的策略。推荐这种做法的部分依据是，预期具有抗性基因型的蠕虫比敏感型蠕虫的生态适应性更低，至少在选择的早期阶段是这样，因此，在使用替代类驱虫药的那一年，可能会出现对敏感性的逆转。常规使用联合驱虫药可能会消除这种逆转的机会，因为会同时使用多种类别的驱虫药。使用模拟模型来研究是否最佳的多药类策略（即每年轮换两种驱虫药类或连续使用两种驱虫药类的联合用药）随着与抗药性相关的适应性成本的大小而改变。模拟模型的模拟运行中，每种抗性基因相关的适应性成本从 0%变化到 15%，并比较了每种药物使用策略的抗性发展速度。评估的其他因素包括抗性基因的初始频率和未暴露于治疗的人群比例（即避难所）。增加避难所中的人群比例总是会减缓抗药性的发展，这与使用组合药物而不是每年轮换药物的情况一样。随着与抗药性相关的适应性成本增加，抗药性的发展速度越慢，当使用组合药物时，这种情况更为明显。如果适应性成本足够高，那么抗药性就不会发展（即抗性基因频率随着时间的推移而下降），当使用组合药物时，这种情况发生的成本更低。因此，结果表明，使用不同驱虫药类别的组合药物最大化任何与抗药性相关的适应性成本的最佳药物使用策略是使用组合药物。模型内的手动计算证实，在模型中，唯一能够在组合药物治疗下存活的抗性基因型是携带多个抗性基因的个体。这些个体适应性较低，导致接受治疗的蠕虫种群的整体生态适应性降低。这是对联合驱虫药使用的一个以前未被报道的观点，并加强了这样的论点，即任何新的驱虫药类别，如果预期抗性基因很少，都应该与其他药物联合推向市场。
