Resistance-minimizing strategies for introducing a novel antibiotic for gonorrhea treatment: a mathematical modeling study.
Resistance-minimizing strategies for introducing a novel antibiotic for gonorrhea treatment: a mathematical modeling study.
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引入新型抗生素治疗淋病的耐药性最小化策略：数学模型研究。
DOI：
10.1101/2023.02.14.23285710
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发表时间：
2023
期刊：
影响因子：
--
通讯作者：
Grad,YH
中科院分区：
文献类型：
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作者：
Reichert,E;Yaesoubi,R;Rönn,MM;Gift,TL;Salomon,JA;Grad,YH
背景淋病是一种高度流行的性传播感染，由于淋病奈瑟菌对抗生素耐药性的增加，淋病是一个紧迫的公共卫生问题。在美国，只有头孢曲松仍是推荐的治疗药物。随着新的抗淋球菌抗生素被批准的前景，我们的目的是评估如何部署一种新药，以最大限度地提高其临床上有用的lifesty.MethodsWe使用了一个房室模型的淋病传播在美国人口的男性与男性发生性关系（MSM），比较战略引入一种新的抗生素淋病治疗。MSM人群被分为三个性活动组（低，中，高）的特点是每年的合作伙伴的变化率。测试的四种引入策略是：（1）随机50-50分配，其中每个寻求治疗的感染个体有50%的概率接受药物A（当前药物;头孢曲松类抗生素）或药物B（2）当前药物和新抗生素的联合治疗;（3）储备策略，即新抗生素被储备，直到当前治疗达到5%的耐药阈值流行率;（4）逐渐转换，或逐渐引入新药，直到达到随机50-50分配。关注的主要结局是对每种药物（新药和当前的头孢曲松类抗生素）的耐药率达到5%的时间;探索了主要结局对新抗生素性质的敏感性，特别是治疗后出现耐药的概率和耐药的适应性成本。次要结果包括每种药物达到1%耐药阈值的时间，以及人群水平的患病率，平均和范围年发病率，以及淋球菌感染事件的累积数量。随机50-50分配策略为19.2年，联合治疗策略为19.9年。储备策略在探索的参数空间下对减轻抗生素耐药性的作用一直较差，并且随着从头耐药性出现的概率降低以及与耐药性相关的适应性成本增加，储备策略越来越优于其他策略。联合治疗倾向于延长抗生素耐药性的发展，并最大限度地减少每年淋球菌感染的数量（在基线模型条件下，联合治疗每年平均感染事件数为178641 [范围177 998-181 731]，储备策略为180084 [178 011-184 405]）。 一旦对关键参数（即，新抗生素出现耐药性的可能性和耐药性的健康成本）进行了可靠的估计，就应该重新审视这些分析。
BackgroundGonorrhoea is a highly prevalent sexually transmitted infection and an urgent public health concern because of increasing antibiotic resistance inNeisseria gonorrhoeae. Only ceftriaxone remains as the recommended treatment in the USA. With the prospect of new anti-gonococcal antibiotics being approved, we aimed to evaluate how to deploy a new drug to maximise its clinically useful lifespan.MethodsWe used a compartmental model of gonorrhoea transmission in a US population of men who have sex with men (MSM) to compare strategies for introducing a new antibiotic for gonorrhoea treatment. The MSM population was stratified into three sexual activity groups (low, intermediate, and high) characterised by annual rates of partner change. The four introduction strategies tested were: (1) random 50–50 allocation, where each treatment-seeking infected individual had a 50% probability of receiving either drug A (current drug; a ceftriaxone-like antibiotic) or drug B (a new antibiotic), effective at time 0; (2) combination therapy of both the current drug and the new antibiotic; (3) reserve strategy, by which the new antibiotic was held in reserve until the current therapy reached a 5% threshold prevalence of resistance; and (4) gradual switch, or the gradual introduction of the new drug until random 50–50 allocation was reached. The primary outcome of interest was the time until 5% prevalence of resistance to each of the drugs (the new drug and the current ceftriaxone-like antibiotic); sensitivity of the primary outcome to the properties of the new antibiotic, specifically the probability of resistance emergence after treatment and the fitness costs of resistance, was explored. Secondary outcomes included the time to a 1% resistance threshold for each drug, as well as population-level prevalence, mean and range annual incidence, and the cumulative number of incident gonococcal infections.FindingsUnder baseline model conditions, a 5% prevalence of resistance to each of drugs A and B was reached within 13·9 years with the reserve strategy, 18·2 years with the gradual switch strategy, 19·2 years with the random 50–50 allocation strategy, and 19·9 years with the combination therapy strategy. The reserve strategy was consistently inferior for mitigating antibiotic resistance under the parameter space explored and was increasingly outperformed by the other strategies as the probability of de novo resistance emergence decreased and as the fitness costs associated with resistance increased. Combination therapy tended to prolong the development of antibiotic resistance and minimise the number of annual gonococcal infections (under baseline model conditions, mean number of incident infections per year 178 641 [range 177 998–181 731] with combination therapy, 180 084 [178 011–184 405] with the reserve strategy).InterpretationOur study argues for rapid introduction of new anti-gonococcal antibiotics, recognising that the feasibility of each strategy must incorporate cost, safety, and other practical concerns. The analyses should be revisited once robust estimates of key parameters—ie, the likelihood of emergence of resistance and fitness costs of resistance for the new antibiotic—are available.FundingUS Centers for Disease Control and Prevention, National Institute of Allergy and Infectious Diseases.