儿童肺炎支原体感染治疗策略优化研究

Mycoplasma pneumoniae is the most common pathogen of community-acquired pneumonia in pediatrics, and in recent years the global resistance rates to macrolide are rapidly increasing. Be concerned with side affect of tetracyclines and quinolones for children, azithromycin is still the first choice for the initial treatment of Mycoplasma pneumoniae infections regardless of the macrolides resistance. Clinical retrospective analysis showed that conventional dosing regimens may cause drug resistance in vivo and that the efficacy of treatment of resistant strains infections is not clear. The project will focus on the following profiles: first of all, we try to use the in vitro pharmacokinetic/pharmacodynamic (PK/PD) model with the detected drug concentration in human to simulate the in vivo process of azithromycin with Mycoplasma pneumoniae. Also we try to monitor resistance change in the route and special therapy and to obtain different regimen that can inhibit resistance of mycoplasma pneumoniae to azithromycin effectively though association analysis among drug concentration change, dynamic killing process and resistant mechanism. Secondly we try to establish a vitro PK/PD model of different azithromycin regimen, simulate a variety of dosage for the related PK/PD target, and then obtain an appropriate dosing regimen through Monte Carlo simulation. As we know this is the first time that the in vitro PK/PD model have been introduced into the study of Mycoplasma pneumoniae infections in pediatrics. It will be very useful to explore the better drug administration strategy both for macrolides-sensitive and macrolides-resistant Mycoplasma pneumoniae infections, reducing the growth rate of macrolide resistance and improving the clinical prognosis of drug-resistant strains infections.

肺炎支原体是儿童社区获得性肺炎最常见病原体，近年来全球范围内对大环内酯类耐药率迅速升高。由于儿童用药限制，无论是否耐药，阿奇霉素依然是肺炎支原体感染初始治疗的首选药物。临床回顾性分析结果显示，常规给药方案可能引起体内诱导耐药，且对于耐药株感染疗效不明。本研究拟借助既往建立的体外药动学/药效学（PK/PD）模型，首先模拟阿奇霉素作用于肺炎支原体的体内过程，采集多点样本以检测药物浓度经时变化、杀菌动态过程及耐药性变化，评价常用治疗方案与耐药产生的相关性及耐药机制。其次针对大环内酯类耐药肺炎支原体通过体外模型模拟不同给药方案，寻找相应指标靶值，再根据儿童中参数分布情况，使用蒙特卡洛模拟，计算不同给药方案的达标概率，筛选出最优的给药方案。本研究第一次将体外PK/PD模型引入儿童肺炎支原体感染研究，对于摸索肺炎支原体最佳给药策略，减少大环内酯类耐药率持续增长，改善耐药株感染临床预后具有重要临床意义。

肺炎支原体是儿童社区获得性肺炎最常见病原体，近年来全球范围内对大环内酯类耐药率迅速升高。由于儿童用药限制，无论是否耐药，阿奇霉素依然是肺炎支原体感染初始治疗的首选药物。该课题分离培养2017年到2019年上海某医院肺炎支原体临床株，并分析其分离情况、药敏、基因分型等特点。97.3%临床株对红霉素及阿奇霉素耐药，16元环大环内酯类药物MIC值较低。五位点MLVA分型方法具有较高的辨别力，更适用于区域性的研究，2019年M3-4-5-7-2菌株的显著增加，提示存在此类型菌株的扩散。体外固定浓度诱导敏感肺炎支原体菌株耐药，检测其药物敏感性变化及耐药相关基因的变化情况，使用不同大环内酯类药物诱导敏感菌株耐药所需时间不同，诱导菌株对麦迪霉素耐药耗时最长，诱导菌株对交沙霉素或罗红霉素耐药耗时较短；阿奇霉素固定浓度诱导敏感菌株耐药的耐药机制与自然产生的耐药菌株相同。对敏感菌株感染病例，建议临床首选麦迪霉素治疗有可能降低耐药率的发生，一旦发生耐药后可继续使用14及15元环类药物作为替代药物治疗。新喹诺酮类药物奈诺沙星对肺炎支原体临床株具有强大的抗微生物活性及杀菌效果，为临床应用奈诺沙星治疗耐药该病原体感染提供了支持性证据。鉴于喹诺酮类药物不推荐用于儿童，因此在大环内酯类药物对临床儿童耐药肺菌株感染治疗无效时，评估安全性且充分知情同意的情况后，奈诺沙星可作为替代治疗的一种选择。16元环大环内酯类药物有望成为治疗耐药菌株感染的潜在推荐药物，有效减缓14和15元环大环内酯类耐药株的增长，改善耐药株感染临床预后具有重要临床意义。