5例患儿服用小剂量利奈唑胺问题的处置与分析

彭静, 李思婵, 徐华

华中科技大学同济医学院附属武汉儿童医院(武汉市妇幼保健院)药学部,武汉 430016

通信作者徐华,女,主任药师,学士,主要研究方向:医院药学。电话:027-82433315,E-mail:1437060144@qq.com。

作者简介彭静(1982-),女,湖北武汉人,副主任药师,硕士,主要研究方向:临床药学。 ORCID:0000-0002-6965-4913。电话:027-82433462,E-mail:pengjing2008@sina.com。

基金资助: 中国药学会全国医药经济信息网科技传播创新工程2018年重点项目(CMEI2018KPYJ00106)

中图分类号: R978.1 文献标识码: B 文章编号: 1004-0781(2021)02-0262-03

摘要:

目的介绍利奈唑胺片分剂量的方法,分析其科学性,为患儿临床精准用药提供药学服务。方法采用先分劈储存,临用时固体药品液体化的方法,处置临床5例患儿服用小剂量利奈唑胺片的问题。结果临床药师运用药学专业知识,科学合理地解决了利奈唑胺片分剂量问题,使患儿服用利奈唑胺片剂量尽可能精确、经济,并获得了较好的治疗效果。结论临床药师在解决临床个性化药物治疗相关问题时能根据药品的性质、处方特点和用药需要,采用合理的药学技术正确处置片剂分剂量问题,以保证药品稳定,服用安全有效;利奈唑胺片剂分剂量为权衡利大于弊时的无奈之举,亟待开展片剂临时调配处方的研究。

关键词: 利奈唑胺 ; 新生儿 ; 分剂量

Abstract:

开放科学(资源服务)标识码(OSID)

利奈唑胺是第一个应用于临床的新型唑烷酮类抗生素,2000年在美国首次上市^[1]。由于该药作用机制独特,与其他药物无交叉耐药性,在临床对耐药革兰阳性菌感染的治疗有一定优势。利奈唑胺在美国被批准用于治疗耐万古霉素屎肠球菌感染、医院内获得性肺炎(hospital acquired pneumonia,HAP)、社区获得性肺炎(community-acquired pneumonia,CAP)、非复杂性的皮肤及软组织感染、复杂性的皮肤和软组织感染(包括未并发骨髓炎的糖尿病足部感染)^[2]。

在新生儿使用利奈唑胺抗感染过程中,如何精确口服利奈唑胺剂量,临床医生往往难于把握,临床药师运用药学相关专业知识,科学合理地帮助临床医师解决患儿精确分剂量的实际问题。笔者对5例新生儿口服利奈唑胺抗感染治疗实例进行分析,报道如下。

1 患儿口服利奈唑胺片相关问题的提出

1.1 临床资料

2017年8月1日—2019年4月1日,我院新生儿内科5例患儿欲使用口服利奈唑胺片剂,每次剂量10 mg·kg^-1,q8h,抗感染治疗。利奈唑胺片(商品名:斯沃,辉瑞制药有限公司,注册证号:H20060289,规格:每片600 mg),患儿无法整片吞服。5例患儿资料见表1。

表1 5例患儿临床资料

序号	性别	入院时年龄/d	体质量/ kg	住院时间/d	与用药相关诊断	利奈唑胺使用情况	单次剂量/ mg
1	女	12	2.49	44	大病灶肺炎、新生儿脓毒血症	住院期间口服,出院带药口服	24
2	男	27	6.74	46	无乳链球菌感染、新生儿化脓	住院静脉滴注,出院带药口服	60
					性脑膜炎、新生儿脓毒血症
3	女	17	4.64	46	化脓性脑膜炎	住院静脉滴注,出院带药口服	46
4	男	11	3.64	25	新生儿化脓性脑膜炎	住院期间口服,出院带药口服	36
5	女	21	5.06	32	新生儿肺炎、新生儿化脓性脑	住院期间口服,出院带药口服	50
					膜炎(无乳链球菌)

表1 5例患儿临床资料

1.2 存在问题

临床药师针对患儿情况,首先提出以下问题:患儿是否一定要使用利奈唑胺片治疗(市场无液体制剂或更小剂量规格药品供应,无可替代药品,且可替代药品亦无液体制剂或更小剂量规格)。上述5例患儿中4例为新生儿化脓性脑膜炎,前期抗感染治疗有效,出院时复查脑脊液尚未完全恢复正常;另有1例患儿肺脓肿形成,给予美罗培南及万古霉素治疗7 d后病情有进展,改用利奈唑胺注射液治疗22 d后患儿体温恢复正常,复查胸部X线片及炎症指标较前有明显改善,但是患儿肺部CT提示双肺肺炎并部分空腔形成。5例患儿均未达到停药标准,后续选择改用利奈唑胺口服序贯治疗能为患儿减少治疗费用,缩短住院时间,符合合理用药应遵循的安全性、有效性、经济性和适当性原则。目前国内市售的利奈唑胺制剂仅有片剂和注射剂。因此,上述患儿只能采用利奈唑胺片分剂量的方法来实现口服序贯治疗。

2 利奈唑胺片分剂量的处置方法

2.1 利奈唑胺片精确分剂量方案的提出

临床药师通过检索相关文献^{[3,4,5,6,7,8,9,10,11,12,13]},根据药品的性质、患儿用药特点和药物经济学原则,建议采用先分劈储存,临用时再固体药品液体化的方法。例如,患儿每次服用利奈唑胺50 mg:采用切药器分劈方法将药片分成1/2片,采用遮光包装袋密闭在15~30 ℃条件下保存,临用时取出1/2片研磨成细盐状粉末后放入遮光瓶子中,然后分2次加入纯化水共60 mL,加入第1份纯化水后,用力振摇瓶子使瓶内粉末全部湿润,再加入另一半纯化水,用力振摇瓶子使溶液混合均匀。配制后每毫升混悬液内含利奈唑胺5 mg。服用前,振摇瓶子,使溶液混匀,使用10 mL一次性无菌溶药注射器按比例抽取所需体积药液,操作时应注意个人、器具、环境清洁卫生。配制的混悬液密闭后在15~30 ℃条件下保存,可供患儿服用6次,即2 d内使用,多余药液可弃去。药师、医师和护士共同讨论后认为上述方法是在权衡利弊的情况下最好的解决方案。

2.2 利奈唑胺片精确分剂量的实施

与患儿家长充分沟通,并取得同意后,医师按照患儿体质量换算用药剂量,护士在临床药师指导下临时调配口服溶液,临床药师在患儿住院治疗期间及时评估疗效,监测药品不良反应,加强药学监护。患儿出院时需继续服用利奈唑胺片,对家长进行该药物特殊使用和储存方法说明及用药教育。

2.3 利奈唑胺片服药问题解决的效果观察

5例患儿按上述方法口服利奈唑胺片后病情好转,服药期间耐受性良好,未出现明显不适反应。

3 讨论

3.1 利奈唑胺片是否适合分劈或者磨粉仍缺乏相关研究资料

利奈唑胺片为白色或类白色的薄膜衣片,椭圆形,长轴和短轴均>6 mm,且为非缓释剂型。从药剂学的角度分析,直径>6 mm片剂,不管有无刻痕,切药器的分劈效果优于其他分劈方法,尽量使用切药器,但是1/4片或以下的剂量不推荐分劈^[3,4]。与分劈药片法比较,磨粉法能将药品分隔更均匀,但是磨粉法又存在剂量准确度差、容易吸潮、稳定性不确定、交叉污染等风险。综上所述,按照上述患儿的单次服药用量需要将利奈唑胺片分成10~25份,不太适合直接使用分劈和磨粉的方法分剂量。

3.2 利奈唑胺片分剂量方法的依据来源

固体药品液体化作为儿童的给药方式,可弥补固体药品分剂量时存在的很多不足,因此被很多医院采用,成为小儿药品临时调配的推荐方式^[4]。目前,国内口服溶剂型药品的临时调配有两种方法:①将药片研磨成粉后放入量杯中,加入适量水制成溶液,按比例抽取所需体积药液服用,该法适用于易溶于水且在水中稳定的药物^[7];②对于不溶于水或微溶于水的药品,通常需要加入助悬剂制备成混悬剂;同时可加入抗氧剂以增加稳定性,加入糖浆或其他矫味剂以改善口感,加入防腐剂以抑制微生物生长^[5,6]。处方设计可以参考《英国药典》《美国药典》《马丁代尔药物大典》等权威书籍或可靠商业产品等。若没有适宜的处方可供选择,则需要药师在可靠的科学原理基础上设计、制作处方。制作处方时应主要注重考虑制剂的稳定性;制剂的存储、包装及有效期;制作过程中添加的赋形剂与药物间的相互作用及潜在的毒性等^[7,8]。笔者检索文献发现关于利奈唑胺口服溶剂型临时调配的报道不多,仅获知利奈唑胺具有水溶性^[9],在pH值为1~7.5、37 ℃时溶解度8 mg·mL^-1[10]。利奈唑胺水溶液稳定性较差,在生产和存贮过程中不可避免出现有关物质增加的现象,储存时间短^[11]。在乳酸钠、0.9%氯化钠注射液、5%葡萄糖注射液和10%葡萄糖注射液中,25 ℃时,利奈唑胺的保质期为34 d。随着pH值和温度升高,稳定性会下降^[12]。《美国药典》指出临时调配的不含防腐剂的药物水溶液,如果没有稳定性信息,溶液在密封、避光容器中,在冰箱中储藏,时间可为14 d(易分解的原料药或成分除外)^[13]。因此为提高剂量准确度,确保溶液稳定性,建议采用先分劈储存,临用时再固体药品液体化的方法。今后笔者将开展片剂临时调配处方的研究,对处方的准确性、稳定性和制剂储存条件、微生物污染以及药动学和药物不良反应进行深入研究,为儿童个性化用药提供参考依据。

3.3 片剂分剂量的无奈和解决措施

儿童是用药的特殊群体,医生需要根据儿童的体质量、年龄或体表面积计算给药剂量,但由于适宜儿童的药品规格缺乏,为满足不同年龄段患儿需求,分剂量用药在儿科临床中不可避免^[14,15],特别是新生儿,其剂量甚至为成人剂量的几十分之一。临床药师在新生儿内科常常被问及关于口服片剂分剂量的问题,由于片剂分剂量使用在我国药品法规中并没有作明确的说明,也没有相关的操作规范可以参考,片剂分剂量往往是在权衡利大于弊时的无奈之举。新生儿正处于生长发育旺盛期,各器官发育不完善,不论何种片剂分剂量方法在新生儿用药中都存在风险,临床应尽量避免使用需分剂量的口服片剂药物,以确保儿童用药安全有效。同时,国家应采取相应的激励措施,促使药品生产企业研发适合儿童,尤其是婴幼儿的剂型;在药品说明书中标明药品是否可以分剂量或分剂量方法。

参考文献

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Linezolid: the first oxazolidinone antimicrobial

2003

... 利奈唑胺是第一个应用于临床的新型唑烷酮类抗生素,2000年在美国首次上市^[1].由于该药作用机制独特,与其他药物无交叉耐药性,在临床对耐药革兰阳性菌感染的治疗有一定优势.利奈唑胺在美国被批准用于治疗耐万古霉素屎肠球菌感染、医院内获得性肺炎(hospital acquired pneumonia,HAP)、社区获得性肺炎(community-acquired pneumonia,CAP)、非复杂性的皮肤及软组织感染、复杂性的皮肤和软组织感染(包括未并发骨髓炎的糖尿病足部感染)^[2]. ...

Population pharmacokinetics of linezolid in patients treated in a compassionate use program

2003

Tablet-splitting:a common yet not so innocent practice

2011

... 临床药师通过检索相关文献^{[3,4,5,6,7,8,9,10,11,12,13]},根据药品的性质、患儿用药特点和药物经济学原则,建议采用先分劈储存,临用时再固体药品液体化的方法.例如,患儿每次服用利奈唑胺50 mg:采用切药器分劈方法将药片分成1/2片,采用遮光包装袋密闭在15~30 ℃条件下保存,临用时取出1/2片研磨成细盐状粉末后放入遮光瓶子中,然后分2次加入纯化水共60 mL,加入第1份纯化水后,用力振摇瓶子使瓶内粉末全部湿润,再加入另一半纯化水,用力振摇瓶子使溶液混合均匀.配制后每毫升混悬液内含利奈唑胺5 mg.服用前,振摇瓶子,使溶液混匀,使用10 mL一次性无菌溶药注射器按比例抽取所需体积药液,操作时应注意个人、器具、环境清洁卫生.配制的混悬液密闭后在15~30 ℃条件下保存,可供患儿服用6次,即2 d内使用,多余药液可弃去.药师、医师和护士共同讨论后认为上述方法是在权衡利弊的情况下最好的解决方案. ...

... 利奈唑胺片为白色或类白色的薄膜衣片,椭圆形,长轴和短轴均>6 mm,且为非缓释剂型.从药剂学的角度分析,直径>6 mm片剂,不管有无刻痕,切药器的分劈效果优于其他分劈方法,尽量使用切药器,但是1/4片或以下的剂量不推荐分劈^[3,4].与分劈药片法比较,磨粉法能将药品分隔更均匀,但是磨粉法又存在剂量准确度差、容易吸潮、稳定性不确定、交叉污染等风险.综上所述,按照上述患儿的单次服药用量需要将利奈唑胺片分成10~25份,不太适合直接使用分劈和磨粉的方法分剂量. ...

分劈药片的剂量准确性考察

2013

... 固体药品液体化作为儿童的给药方式,可弥补固体药品分剂量时存在的很多不足,因此被很多医院采用,成为小儿药品临时调配的推荐方式^[4].目前,国内口服溶剂型药品的临时调配有两种方法:①将药片研磨成粉后放入量杯中,加入适量水制成溶液,按比例抽取所需体积药液服用,该法适用于易溶于水且在水中稳定的药物^[7];②对于不溶于水或微溶于水的药品,通常需要加入助悬剂制备成混悬剂;同时可加入抗氧剂以增加稳定性,加入糖浆或其他矫味剂以改善口感,加入防腐剂以抑制微生物生长^[5,6].处方设计可以参考《英国药典》《美国药典》《马丁代尔药物大典》等权威书籍或可靠商业产品等.若没有适宜的处方可供选择,则需要药师在可靠的科学原理基础上设计、制作处方.制作处方时应主要注重考虑制剂的稳定性;制剂的存储、包装及有效期;制作过程中添加的赋形剂与药物间的相互作用及潜在的毒性等^[7,8].笔者检索文献发现关于利奈唑胺口服溶剂型临时调配的报道不多,仅获知利奈唑胺具有水溶性^[9],在pH值为1~7.5、37 ℃时溶解度8 mg·mL^-1[10].利奈唑胺水溶液稳定性较差,在生产和存贮过程中不可避免出现有关物质增加的现象,储存时间短^[11].在乳酸钠、0.9%氯化钠注射液、5%葡萄糖注射液和10%葡萄糖注射液中,25 ℃时,利奈唑胺的保质期为34 d.随着pH值和温度升高,稳定性会下降^[12].《美国药典》指出临时调配的不含防腐剂的药物水溶液,如果没有稳定性信息,溶液在密封、避光容器中,在冰箱中储藏,时间可为14 d(易分解的原料药或成分除外)^[13].因此为提高剂量准确度,确保溶液稳定性,建议采用先分劈储存,临用时再固体药品液体化的方法.今后笔者将开展片剂临时调配处方的研究,对处方的准确性、稳定性和制剂储存条件、微生物污染以及药动学和药物不良反应进行深入研究,为儿童个性化用药提供参考依据. ...

儿科用药药品分剂量的策略及实例分析

2012

1例儿童抗癫痫药物分剂量案例分析

2017

医院药剂科临时调配药物的使用现状与合法性分析

2012

... [7,8].笔者检索文献发现关于利奈唑胺口服溶剂型临时调配的报道不多,仅获知利奈唑胺具有水溶性^[9],在pH值为1~7.5、37 ℃时溶解度8 mg·mL^-1[10].利奈唑胺水溶液稳定性较差,在生产和存贮过程中不可避免出现有关物质增加的现象,储存时间短^[11].在乳酸钠、0.9%氯化钠注射液、5%葡萄糖注射液和10%葡萄糖注射液中,25 ℃时,利奈唑胺的保质期为34 d.随着pH值和温度升高,稳定性会下降^[12].《美国药典》指出临时调配的不含防腐剂的药物水溶液,如果没有稳定性信息,溶液在密封、避光容器中,在冰箱中储藏,时间可为14 d(易分解的原料药或成分除外)^[13].因此为提高剂量准确度,确保溶液稳定性,建议采用先分劈储存,临用时再固体药品液体化的方法.今后笔者将开展片剂临时调配处方的研究,对处方的准确性、稳定性和制剂储存条件、微生物污染以及药动学和药物不良反应进行深入研究,为儿童个性化用药提供参考依据. ...

Stability considerations in liquid dosage forms extemporaneously prepared from commercially available products

2006

新型()唑烷酮类抗生素利奈唑胺

2008

BDDCS applied to over 900 drugs

2011

一种利奈唑胺干混悬剂及其制备方法:CN201710381562.9 A

2018

Evaluation of the stability of linezolid in aqueous solution and commonly used intravenous fluids

2017

Extemporaneous drug formulations

2008

国内13家儿童医院片剂分剂量问卷调查与儿童适宜规格的建议

2015

... 儿童是用药的特殊群体,医生需要根据儿童的体质量、年龄或体表面积计算给药剂量,但由于适宜儿童的药品规格缺乏,为满足不同年龄段患儿需求,分剂量用药在儿科临床中不可避免^[14,15],特别是新生儿,其剂量甚至为成人剂量的几十分之一.临床药师在新生儿内科常常被问及关于口服片剂分剂量的问题,由于片剂分剂量使用在我国药品法规中并没有作明确的说明,也没有相关的操作规范可以参考,片剂分剂量往往是在权衡利大于弊时的无奈之举.新生儿正处于生长发育旺盛期,各器官发育不完善,不论何种片剂分剂量方法在新生儿用药中都存在风险,临床应尽量避免使用需分剂量的口服片剂药物,以确保儿童用药安全有效.同时,国家应采取相应的激励措施,促使药品生产企业研发适合儿童,尤其是婴幼儿的剂型;在药品说明书中标明药品是否可以分剂量或分剂量方法. ...

儿科门诊患者家庭用药管理现状分析

2019