Estimating the fitness cost and benefit of cefixime resistance in Neisseria gonorrhoeae to inform prescription policy: A modelling study.
Estimating the fitness cost and benefit of cefixime resistance in Neisseria gonorrhoeae to inform prescription policy: A modelling study.
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DOI：
10.1371/journal.pmed.1002416
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发表时间：
2017-10
期刊：
影响因子：
15.8
通讯作者：
Didelot X
中科院分区：
文献类型：
--
作者：
Whittles LK;White PJ;Didelot X
淋病是英国最常见的细菌性性传播疾病之一。2015年记录的病例超过4.1万例，其中一半以上发生在男男性行为者(MSM)中。由于细菌对每一种一线抗生素都产生了耐药性，我们需要更好地了解抗生素耐药性的适合性好处和成本，以便为控制政策和规划提供信息。2005年至2010年，建议将头孢克新作为淋病的单剂治疗药物，在此期间，耐药性增加，随后下降。我们开发了一个随机分区模型，描述了英国男男性接触者中对头孢克肟敏感和对头孢克肟耐药的淋球菌菌株的自然历史和传播情况，并将其应用于2008至2015年间的诊断和处方数据。我们估计，无症状携带者在整个传播动态中起着关键作用，37%(95%可信区间CRI24%-52%)的感染保持无症状和未治疗，占继续传播的89%(95%CRI82%-93%)。在不使用头孢克肟的情况下，头孢克肟耐药性的适合性成本估计是这样的，即耐药菌株引起的继发感染数量仅为敏感菌株的大约一半，这不足以维持持久性。然而，我们估计83%(95%CRI 53%-99%)的头孢克肟耐药菌株治疗不成功，这代表了耐药的适合性好处。当31%(95%CRI26%-36%)的病例使用头孢克肟治疗时，这一益处足以抵消适应成本；当55%以上(95%CRI44%-66%)的病例使用头孢克肟治疗时，抗性品系比敏感品系具有净适合度优势。限制包括稀疏的数据导致关键模型参数的大间隔，以及复杂流行病学过程的建模中的必要假设。据我们所知，我们的研究提供了与淋球菌对临床相关抗生素的耐药性相关的适合性成本和收益的第一次估计。我们的发现对抗生素管理和公共卫生政策具有重要意义，特别是表明以前被废弃的抗生素可以再次用于治疗少数淋病病例，而不会增加耐药性水平。在一项模拟研究中，Xavier Didelot和他的同事解决了头孢克新耐药性对淋病治疗的影响。在英国，淋病是一种日益常见的性传播感染。近年来，淋病已经对许多抗生素产生了抗药性，以至于临床医生的治疗选择越来越少。目前推荐的治疗方法是两种抗生素的组合，这是有效的，但有令人担忧的迹象表明，情况可能并不总是如此。需要做出明智的决定来抗击耐药淋病，但目前由于缺乏对耐药性如何出现和传播的动态的了解，这一决定受到了阻碍。我们开发了一个数学模型，捕捉了2008至2015年间观察到的头孢克肟耐药动态。该模型包括了抵抗力的健康益处，以解释为什么头孢克肟在2010年之前被广泛使用时，抵抗力会增加。该模型还包括耐药性的适应成本，以解释为什么头孢克新耐药性自2010年以来有所下降。在推断了头孢克肟耐药性的适合性成本和益处后，我们能够预测如果重新引入头孢克肟会发生什么，并发现它可以用于治疗多达25%的淋病病例，而没有风险。头孢克辛此前曾因耐药性水平高而被放弃，但耐药性的适应成本如此之高，以至于耐药性水平后来下降，可以考虑重新引入来治疗少数病例。这项政策将降低对目前使用的其他抗生素产生抗药性的风险。可以进行类似的模拟研究，以调查淋病和其他细菌病原体对其他抗生素的耐药性的适合性成本和好处，为抗生素部署政策提供强有力的证据基础。在未来，可能会有一项政策，用一系列抗生素方案治疗淋病患者，这些方案将在个体患者水平上系统地随机进行。每种疗法的使用频率将由对每种疗法的适合性成本和抗药性的好处决定，一旦这些都被衡量出来。
Gonorrhoea is one of the most common bacterial sexually transmitted infections in England. Over 41,000 cases were recorded in 2015, more than half of which occurred in men who have sex with men (MSM). As the bacterium has developed resistance to each first-line antibiotic in turn, we need an improved understanding of fitness benefits and costs of antibiotic resistance to inform control policy and planning. Cefixime was recommended as a single-dose treatment for gonorrhoea from 2005 to 2010, during which time resistance increased, and subsequently declined. We developed a stochastic compartmental model representing the natural history and transmission of cefixime-sensitive and cefixime-resistant strains of Neisseria gonorrhoeae in MSM in England, which was applied to data on diagnoses and prescriptions between 2008 and 2015. We estimated that asymptomatic carriers play a crucial role in overall transmission dynamics, with 37% (95% credible interval CrI 24%–52%) of infections remaining asymptomatic and untreated, accounting for 89% (95% CrI 82%–93%) of onward transmission. The fitness cost of cefixime resistance in the absence of cefixime usage was estimated to be such that the number of secondary infections caused by resistant strains is only about half as much as for the susceptible strains, which is insufficient to maintain persistence. However, we estimated that treatment of cefixime-resistant strains with cefixime was unsuccessful in 83% (95% CrI 53%–99%) of cases, representing a fitness benefit of resistance. This benefit was large enough to counterbalance the fitness cost when 31% (95% CrI 26%–36%) of cases were treated with cefixime, and when more than 55% (95% CrI 44%–66%) of cases were treated with cefixime, the resistant strain had a net fitness advantage over the susceptible strain. Limitations include sparse data leading to large intervals on key model parameters and necessary assumptions in the modelling of a complex epidemiological process. Our study provides, to our knowledge, the first estimates of the fitness cost and benefit associated with resistance of the gonococcus to a clinically relevant antibiotic. Our findings have important implications for antibiotic stewardship and public health policies and, in particular, suggest that a previously abandoned antibiotic could be used again to treat a minority of gonorrhoea cases without raising resistance levels. In a modeling study, Xavier Didelot and colleagues address the implications of cefixime resistance for treatment of gonorrhea. Gonorrhoea is an increasingly common sexually transmitted infection in England. Gonorrhoea has become resistant to many antibiotics in recent years, to the extent that clinicians are running out of treatment options. The current recommended treatment is a combination of 2 antibiotics, which is effective, but there are worrying signs that it may not always be so. Informed decisions need to be made to fight antibiotic-resistant gonorrhoea, but this is currently hampered by a lack of understanding of the dynamics of how resistance emerges and spreads. We developed a mathematical model that captures the dynamics of cefixime resistance observed between 2008 and 2015. The model includes a fitness benefit of resistance, to explain why cefixime resistance increased when cefixime was widely used up until 2010. The model also includes a fitness cost of resistance, to explain why cefixime resistance decreased from 2010. Having inferred the fitness cost and benefit of cefixime resistance, we were able to predict what would happen if cefixime was reintroduced and found that it could be used to treat up to 25% of gonorrhoea cases without risk. Cefixime had previously been abandoned because of a high level of resistance, but the fitness cost of resistance is such that resistance levels have since dropped, and reintroduction could be considered to treat a minority of cases. This policy would reduce the risk of resistance developing to the other antibiotics currently used. Similar modelling studies could be carried out to investigate the fitness costs and benefits of resistance to other antibiotics in gonorrhoea and other bacterial pathogens, providing a strong evidence basis for antibiotic deployment policies. In the future, there could be a policy of treating patients with gonorrhoea with a range of antibiotic regimens that would be systematically randomized at the individual patient level. The frequency of use of each regimen would be determined by the fitness costs and benefits of resistance to each regimen, once these have been measured.
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