CN114601840A - 一种联合用药,用于治疗卡氏肺孢子虫肺炎 - Google Patents
一种联合用药,用于治疗卡氏肺孢子虫肺炎 Download PDFInfo
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- CN114601840A CN114601840A CN202011444225.8A CN202011444225A CN114601840A CN 114601840 A CN114601840 A CN 114601840A CN 202011444225 A CN202011444225 A CN 202011444225A CN 114601840 A CN114601840 A CN 114601840A
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- sulfamethoxazole
- clindamycin
- pneumocystis carinii
- carinii pneumonia
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Abstract
本发明属于制药领域，更具体地，本发明公开了一种联合用药，用于治疗卡氏肺孢子虫肺炎(Pneumocystis pneumonia,PCP)。
Description
技术领域
本发明属于制药领域，更具体地，本发明公开了一种联合用药，用于治疗卡氏肺孢子虫肺炎(Pneumocystis pneumonia,PCP)。
背景技术
卡氏肺孢子虫肺炎(Pneumocystis pneumonia,简称PCP，在本专利中用PCP代替)是HIV和非HIV相关免疫缺陷患者中常见的机会感染之一。尤其是实体器官移植患者，PCP的总发生率在5-15％之间。其影响因素包括术后预防措施、移植器官类型及免疫抑制方案等。PCP可导致患者出现干咳、高热、气促等症状，严重者可导致低氧血症、呼吸衰竭或ARDS。非HIV的PCP肺炎患者的症状及进展比HIV-PCP快，病情更为严重，通常以严重低氧血症为主。有研究提示非HIV感染患者的PCP的死亡率高达30％–60％。随着实体器官移植数量的与日俱增，如何能更有效的治疗实体器官移植术后重症PCP，便日益成为亟待解决的问题。
目前，针对实体器官移植术后的PCP，一线治疗仍为复方磺胺甲噁唑，其标准剂量为15-20mg/公斤体重/天甲氧苄啶(TMP)和75-100mg/公斤体重/天磺胺甲恶唑(SMX)。但这是基于上世纪七八十年代的一些小型、非对照的观察性研究所得出的结论(Lau WK,YoungLS:Trimethoprim-sulfamethoxazole treatment of Pneumocystis carinii pneumoniain adults.N Engl J Med 1976,295(13):716-718，Winston DJ,Lau WK,Gale RP,YoungLS:Trimethoprim-sulfamethoxazole for the treatment of Pneumocystis cariniipneumonia.Ann Intern Med 1980,92(6):762-769)。因此，在缺乏随机对照研究的情况下，目前尚未确定复方磺胺甲噁唑治疗实体器官移植术后PCP的最佳剂量。此外，该标准剂量由于其药物剂量偏大，较易产生药物不良反应，导致临床使用时依从性较低，从而降低了疗效。为了减少复方磺胺甲噁唑的不良反应、增加药物使用的依从性，有研究使用中剂量(10mg/kg/d TMP)、降阶梯剂量或低剂量(4-10mg/公斤体重/天TMP)来治疗实体器官移植术后的PCP。但这些给药方案的治疗效果仍存在争议。另一方面，复方磺胺甲噁唑是通过作用于二氢叶酸合成酶和还原酶，双重阻断细菌叶酸合成的第一、第二步，从而干扰了细菌蛋白合成。而目前已有研究提示卡氏肺孢子虫存在二氢叶酸合成酶和还原酶的基因突变，尤其是使用复方磺胺甲噁唑预防PCP的患者中，这种突变更易发生，从而导致对于复方磺胺甲噁唑的耐药性产生。一般而言，当复方磺胺甲噁唑治疗PCP失败时，可采用阿托伐醌、氨苯砜及克林霉素-伯氨喹等作为二线替代方案。但是这些治疗方案的治疗效果尚无法达到复方磺胺甲噁唑的疗效(Kosaka M,Ushiki A,Ikuyama Y,Hirai K,Matsuo A,Hachiya T,HanaokaM:A Four-Center Retrospective Study of the Efficacy and Toxicity of Low-DoseTrimethoprim-Sulfamethoxazole for the Treatment of Pneumocystis Pneumonia inPatients without HIV Infection.Antimicrob Agents Chemother 2017,61(12).Schmidt JJ,Lueck C,Ziesing S,Stoll M,Haller H,Gottlieb J,Eder M,Welte T,Hoeper MM,Scherag A et al:Clinical course,treatment and outcome ofPneumocystis pneumonia in immunocompromised adults:a retrospective analysisover 17years.Crit Care 2018,22(1):307.)。
对于重症PCP而言，伯氨喹联合克林霉素被认为是最有效的二线治疗方案。但伯氨喹的毒性反应明显，包括急性胰腺炎、血糖波动、骨髓抑制、肾功能不全和电解质紊乱等(Nickel P,Schurmann M,Albrecht H,Schindler R,Budde K,Westhoff T,Millward J,Suttorp N,Reinke P,Schurmann D:Clindamycin-primaquine for pneumocystisjiroveci pneumonia in renal transplant patients.Infection 2014,42(6):981-989.Benfield T,Atzori C,Miller RF,Helweg-Larsen J:Second-line salvagetreatment of AIDS-associated Pneumocystis jirovecii pneumonia:a case seriesand systematic review.J Acquir Immune Defic Syndr 2008,48(1):63-67.)。因此，能找到一个既能保持或提高复方磺胺甲噁唑疗效，又能通过减少复方磺胺甲噁唑剂量来降低不良反应，是摆在面前急需解决的临床问题。
发明内容
为了实现本发明的目的，本发明公开了磺胺类药物和林可霉素类药物联合使用在制备药物中的用途，所述药物用于治疗卡氏肺孢子虫肺炎。
具体的，本发明中所述的磺胺类药物为中效磺胺类药物复方磺胺甲噁唑。作为优选的方案，本发明所述的林可霉素类药物为林可霉素、克林霉素、克林霉素磷酸酯之一。
作为优选的方案，本发明所述的林可霉素类药物为克林霉素。
作为优选的方案，本发明所述的磺胺类药物为复方磺胺甲噁唑，林可霉素类药物为克林霉素。
作为优选的方案，本发明所述的复方磺胺甲噁唑的用量按磺胺甲噁唑计为0.02克/公斤体重/天至0.06克/公斤体重/天，克林霉素的用量为0.3克/6小时至0.6克/6小时.
更优选的方案，本发明所述的复方磺胺甲噁唑的用量按磺胺甲噁唑计为0.03克/公斤体重/天，克林霉素的用量为0.6克/6小时
上述两种药物可以同时或续贯给药。
作为优选的方案，本发明所述的所述卡氏肺孢子虫肺炎为实体器官移植术后卡氏肺孢子虫肺炎。
更优选的方案，本发明所述的实体器官移植后卡氏肺孢子虫肺炎为肾移植术后卡氏肺孢子虫肺炎，最优选为肾移植书后严重卡氏肺孢子虫肺炎。
本发明还公开了一种药物组合物，含有磺胺甲噁唑、甲氧苄啶和克林霉素，用于制备治疗卡氏肺孢子虫肺炎的药物。
上述药物组合物一般含有赋形剂如淀粉、糖(如蔗糖、葡萄糖、麦芽糖)、某些类型的明胶、硬脂酸或其盐、硬脂酸镁或硬脂酸钙、滑石粉、植物脂肪或油、乙二醇或其他已知赋形剂，也可以含有芳香剂和着色剂或其他成分。包含上述赋形剂或\和其他成分的组合物通过本领域已知的常规方法制备，可以为片剂、胶囊或其他形式，方便口服给药。
本发明的申请人将磺胺类药物和林可霉素类药物联合使用能加速患者氧合的改善、缩短住院时间、减少住院费用，从而减少不良反应率，提高了磺胺药的完成率，从而总体可以提高磺胺类药物复方磺胺甲噁唑疗效；同时可以通过减少其剂量来降低不良反应，达到治疗PCP，尤其是实体器官移植术后的PCP,特别是肾移植术后的PCP，尤其适用于治疗肾移植术后的重症PCP的目的。
附图说明
图1：1A干预6天后，两组方案的P/F绝对值变化，1B干预3天后，两组方案的P/F相对值变化(P/F比值为动脉血气分析中的血氧分压值(mmHg)与吸入气体中氧气的浓度(％)；连续线条为联合治疗组CT组，虚线为标准复方磺胺甲噁唑组T组，以下同；
图1显示联合治疗方案能更快、更显著的改善患者的氧合情况；
图2：联合治疗组一例重症PCP患者在入院时的胸部CT影像(2A)提示双肺弥漫性渗出明显；在联合治疗7天后复查胸部CT(2B)提示双肺渗出明显减少；
图3：标准复方磺胺甲噁唑组一例重症PCP患者在入院时的胸部CT影像(3A)，治疗5天后复查提示双肺渗出明显增加(3B)，再经过16天治疗，双肺渗出才出现明显吸收(3C)；
图2与图3说明联合治疗方案能更快的改善肺部病变；
图4：两组患者的乳酸脱氢酶(LDH)变化情况，显示无差异；
图5：两组患者的C反应蛋白(CRP)变化趋势，显示无差异；
图6：两组患者的降钙素原(PCT)变化趋势，显示无差异；
图7：两组患者的肌酐(Cr)变化趋势，显示无差异；
图8：两组患者的总胆红素(TB)变化趋势，显示无差异；
图9：两组患者的血小板(Plt)变化趋势，显示无差异；
图10：两组患者的血红蛋白(Hb)变化趋势，显示无差异；
图11：两组患者的白细胞(WBC)计数变化趋势，显示无差异；
图12：两组患者的血清钾离子含量(K+)变化趋势，显示无差异。
具体实施方式
以下实施例是对本发明进行进一步的说明，不应理解为是对本发明的限制。
复方磺胺甲噁唑(山东新华制药，规格磺胺甲噁唑0.4g,甲氧苄啶80mg)
克林霉素(江苏九旭药业、规格0.6g/支)
患者队列：回顾性收集20例同种异体肾移植术后重症PCP的患者，其中10例接受标准剂量复方磺胺甲噁唑治疗(按磺胺甲噁唑计0.05克/公斤体重/天)，10例接受联合治疗(克林霉素0.6克/6小时，复方磺胺甲噁唑(按磺胺甲噁唑计0.03克/公斤体重/天))。
患者入组标准：
·器官移植术后，考虑到临床实际情况，以肾移植术后患者为主
·年龄大于18岁
·除外孕妇、终末期状态(如肿瘤晚期、严重器官功能不全等)
·PCP的诊断标准
1.肺泡灌洗NGS明确肺孢子阳性；
2.临床表现有发热、气促、干咳；P/F<300；
3.胸部CT检查可见双肺从肺门开始的弥漫性网状结节样间质浸润，或呈磨玻璃状阴影。
患者排除标准：
·年龄小于18岁
·妊娠妇女
·既往有明确复方磺胺甲噁唑或克林霉素过敏史
·不同意全面、积极的生命支持治疗
·肿瘤晚期、严重器官功能不全
给药方案：复方磺胺甲噁唑为口服或鼻饲，克林霉素为静脉滴注。标准治疗组，复方磺胺甲噁唑的剂量按磺胺甲噁唑计相当于0.05克/公斤体重/天；联合治疗组，克林霉素剂量为0.6克/6小时，复方磺胺甲噁唑剂量按磺胺甲噁唑计相当于0.03克/公斤体重/天。
临床检测：所有患者在治疗前后均定期随访动脉血气、血常规、肝肾功能、血电解质、C反应蛋白等；每5-7天随访一次胸部CT。
各项指标：主要的观察指标包括P/F比值的绝对值及相对变化度、机械通气使用率、住院存活率、不良反应率及复方磺胺甲噁唑完成度等。
结果：
两组患者的不良反应发生情况比较见表1：
表1
从上表可以看出，联合治疗组患者的不良反应发生率更少(40％vs 80％)，两组患者血小板、白细胞、肌酐、总胆红素每日的变化无统计学差异。因发生不良反应而需要减少复方磺胺甲噁唑用量，从而降低了标准治疗组的复方磺胺甲噁唑完成度，使得联合治疗组的复方磺胺甲噁唑完成度较高(8/10 vs 2/10)。
从图1和图2的结果可以看出：经过不同的治疗方法干预，从第6天起，联合治疗组的P/F比值大于300，至干预后第7天，联合治疗组的P/F比值显著高于标准治疗组(341vs269.29，P＝0.033)。此外，从干预后第4天起，联合治疗组的P/F变化度就显著高于标准治疗组，P/F比值的改善更快，更明显。
两组患者的治疗后结局见表2：
表2两组患者的治疗结局比较
| 标准治疗 | 联合治疗 | P | |
| 住院死亡率(％) | 20 | 0 | 0.474 |
| 高流量氧疗时间(h) | 166.3 | 110.86 | 0.475 |
| 无创正压通气(％) | 3(30％) | 2(20％) | 1.0 |
| 无创正压通气时间(h) | 10.10 | 25.7 | 0.740 |
| 有创机械通气率(％) | 3(30％) | 0(0％) | 0.211 |
| 体外膜肺氧合治疗率(％) | 1(10％) | 0(0％) | 1.00 |
| 肾脏替代治疗率(％) | 0(0％) | 1(10％) | 1.00 |
| 纵膈气肿发生率(％) | 5(50％) | 0(0％) | 0.033 |
| 住院时间(天) | 45 | 24 | 0.011 |
| 住ICU时间(天) | 23 | 12 | 0.008 |
| 二重感染(n) | 8 | 0 | 0.001 |
| 细菌感染 | 4 | 0 | 0.087 |
| 真菌感染 | 3 | 0 | 0.211 |
| 病毒感染 | 5 | 0 | 0.033 |
| P/F比值达到300mmHg所需时间(天) | 10 | 5 | 0.109 |
| 住院费用(元) | 255712 | 109656 | 0.014 |
从上表可以看出，联合治疗组有创机械通气使用率更低(0％VS 30％)，发生纵隔气肿的概率更低更少(0vs 50％P＝0.033)。联合治疗组的患者发生二重感染比例更低(0％vs 80％,P＝0.001)。同时，联合治疗组的住ICU时间更短(12天vs 23天P＝0.008),住院时间更短(24天vs 45天P＝0.011)，住院费用更少(109656元vs 255712元P＝0.014)。标准治疗组中有1例患者使用ECMO，而联合治疗组的患者无人使用ECMO。
最终，两组患者的住院存活率分别为联合治疗组100％，标准治疗组80％。
Claims (11)
1.磺胺类药物和克林霉素类药物联合使用在制备药物中的用途，所述药物用于治疗卡氏肺孢子虫肺炎。
2.如权利要求1所述的用途，其特征在于，所述的磺胺类药物为中效磺胺类药物复方磺胺甲噁唑。
3.如权利要求1所述的用途，其特征在于，所述的林可霉素类药物为林可霉素、克林霉素、克林霉素磷酸酯之一。
4.如权利要求3所述的用途，其特征在于，所述的林可霉素类药物为克林霉素。
5.如权利要求2或4所述的用途，其特征在于，所述的磺胺类药物为复方磺胺甲噁唑，林可霉素类药物为克林霉素。
6.如权利要求5所述的用途，其特征在于，所述的复方磺胺甲噁唑的用量按磺胺甲噁唑计为0.02克/公斤体重/天至0.06克/公斤体重/天，克林霉素的用量为0.3克/6小时至0.6克/6小时。
7.如权利要求6所述的用途，其特征在于，所述的复方磺胺甲噁唑的用量按磺胺甲噁唑计为0.03克/公斤体重/天，克林霉素的用量为0.6克/6小时。
8.一种药物组合物，含有磺胺甲噁唑、甲氧苄啶和克林霉素，用于制备治疗卡氏肺孢子虫肺炎的药物。
9.如权利要求1或权利要求8所述的用途，其特征在于，所述卡氏肺孢子虫肺炎为实体器官移植术后卡氏肺孢子虫肺炎。
10.如权利要求9所述的用途，其特征在于，所述实体器官移植术后卡氏肺孢子虫肺炎为肾移植术后卡氏肺孢子虫肺炎。
11.如权利要求10所述的用途，其特征在于，所述肾移植术后卡氏肺孢子虫肺炎为肾移植术后重症卡氏肺孢子虫肺炎。
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