中国科技论文统计源期刊　中文核心期刊  
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WHO《西太平洋地区医学索引》来源期刊  
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医药导报
医药导报, 2017, 36(10): 1204-1205
doi: 10.3870/j.issn.1004-0781.2017.10.029
头孢哌酮/舒巴坦致粒细胞缺乏1例
钟晗1,, 郑毅隽2, 陈璋璋3,
1.上海交通大学医学院附属仁济医院药学部,上海 200127
2.复旦大学附属中山医院外科监护室,上海 200032
3.复旦大学附属中山医院药剂科,上海 200032

作者简介 钟晗(1985-),女,湖南醴陵人,主管药师,硕士,从事临床药学工作。电话:021-68383427,E-mail:hannahzhong22@gmail.com。

通信作者 陈璋璋(1977-),女,浙江平阳人,副主任药师,硕士,从事临床药学工作。电话:021-64041990-2482,E-mail:chen.zhangzhang@zs-hospital.sh.cn。
中图分类号: R978.11     文献标识码: B     文章编号: 1004-0781(2017)10-1204-02
摘要:

关键词: 头孢哌酮/舒巴坦 ; 白细胞减少 ; 粒细胞缺乏

Abstract:
1 病例介绍

患者,男,43岁。因高处坠落致截瘫3 d,于2015年12月14日入院,临床诊断为颈椎骨折、脊髓损伤、截瘫。2015年12月16日行颈5前路椎体次全切除减压+植骨融合+内固定术。入院后患者反复发热,每日体温峰值(Tmax)为38~39 ℃。先后予注射用头孢替安2 g,q12h,静脉滴注(2015年12月16日—2015年12月18日),注射用甲泼尼龙琥珀酸钠500 mg,qd,静脉滴注(2015年12月17日—2015年12月20日),注射用头孢他啶2 g,q12h,静脉滴注(2015年12月20日—2015年12月21日),注射用美罗培南1 g,q8h,静脉滴注(2015年12月21日—2015年12月28日),注射用万古霉素1 g ,q8h,静脉滴注(2015年12月21日—2015年12月31日)治疗,患者体温未下降。2015年12月23日患者血常规:白细胞计数(WBC)10.88×109·L-1,中性粒细胞百分比(N%)83.3%,中性粒细胞数(N)9.1×109·L-1,红细胞计数(RBC)3.22×1012·L-1,血红蛋白(Hb)96 g·L-1,血小板计数(PLT)169×109·L-1。因血培养示泛耐药鲍曼不动杆菌生长,根据药敏结果从2015年12月30日开始予静脉滴注头孢哌酮/舒巴坦钠(商品名:舒普深,辉瑞制药有限公司,批号:M83987)3 g,q6h,鼻胃管饲盐酸米诺环素(商品名:美满霉素,惠氏制药有限公司,批号:L52082)100 mg,bid。2016年1月1日(用药3 d后),患者体温下降,Tmax 37.4 ℃,血常规:WBC 3.64×109·L-1,N% 66.4%,N 2.4×109·L-1,RBC 3.08×1012·L-1,Hb 95 g·L-1,PLT 201×109·L-1。2016年1月4日(用药6 d后),患者出现粒细胞缺乏伴发热,Tmax 38.8 ℃,血常规:WBC 0.91×109·L-1,N% 32.9%,N 0.3×109·L-1 ,RBC 2.94×1012·L-1,Hb 87 g·L-1,PLT 160×109·L-1,肝肾功能正常。2016年1月5日(用药7 d后),考虑抗菌药物导致粒细胞缺乏,停用米诺环素胶囊,并予重组人粒细胞刺激因子注射液100 μg,qd,皮下注射。2016年1月7日(停米诺环素2 d后),Tmax 38.1 ℃,血常规:WBC 2.36×109·L-1,N 0.5×109·L-1,RBC 2.77×1012·L-1,Hb 80 g·L-1,PLT 128×109·L-1;患者粒细胞缺乏改善不明显,遂停用头孢哌酮/舒巴坦。其后,患者粒细胞缺乏逐渐改善。2016年1月8日(停头孢哌酮/舒巴坦1 d后),Tmax 37.5 ℃,血常规:WBC 3.34×109·L-1,N 1.3×109·L-1,RBC 2.45×1012·L-1,Hb 73 g·L-1,PLT 137×109·L-1;血培养结果显示阴性。2016年1月9日(停头孢哌酮/舒巴坦2 d后)血常规:WBC6.39×109·L-1,N 3.9×109·L-1,RBC 2.58×1012·L-1,Hb 75 g·L-1,PLT 144×109·L-1。住院期间患者未再使用其他抗菌药物,并于2016年1月11日停用重组人粒细胞刺激因子注射液。血常规(2016年1月18日):WBC 8.37×109·L-1,N 7.2×109·L-1,RBC 2.43×1012·L-1,Hb 72 g·L-1,PLT 165×109·L-1,2016年1月20日患者生命体征平稳,予以出院。停用头孢哌酮/舒巴坦后未再发生粒细胞缺乏。

2 讨论

本例患者使用头孢哌酮/舒巴坦和米诺环素6 d后出现粒细胞缺乏伴发热。停用米诺环素2 d,同时给予重组人粒细胞刺激因子注射液2 d后,粒细胞缺乏伴发热症状无明显改善。停用头孢哌酮/舒巴坦,继续给予重组人粒细胞刺激因子注射液2 d,患者粒细胞缺乏明显改善。该患者粒细胞缺乏伴发热症状的出现及改善与头孢哌酮/舒巴坦开始使用和停药有时间相关性。患者既往无甲状腺功能亢进史,无恶性肿瘤史。合并用药中肠内营养乳剂、注射用盐酸氨溴索、注射用胸腺法新、氯化钾缓释片均为长期用药,说明书和文献报道中未见致中性粒细胞减少或缺乏不良反应,近期用药维生素K1注射液也无相关报道。且以上药物在粒细胞缺乏治疗过程中未更改。盐酸米诺环素胶囊长期用药可能导致粒细胞减少[1],研究表明米诺环素致粒细胞缺乏与自身免疫相关,往往攻击成熟的细胞,而不是影响粒细胞生成,且与肝损伤同时出现[2-3]。该患者虽然不能完全排除粒细胞缺乏与米诺环素的相关性,但患者仅使用米诺环素6 d,停用该药后粒细胞缺乏未明显改善,且不伴有肝功能损伤,与文献报道的长期使用米诺环素致粒细胞缺乏不符,故该患者米诺环素致粒细胞缺乏的可能性较小。头孢哌酮/舒巴坦较常见的不良反应有发热、寒战、头痛、中性粒细胞轻微减少等[1] ,该患者粒细胞缺乏伴发热符合头孢哌酮钠/舒巴坦已知的不良反应。根据国家药品不良反应监测中心制订的药品不良反应因果关系判断标准,该患者粒细胞缺乏可能与头孢哌酮/舒巴坦有关。

急性粒细胞缺乏是指外周血中性粒细胞的绝对计数<0.5×109·L-1,大于70%的案例可归因于药物[4-5]。除了化疗药物外,导致粒细胞缺乏的常见药物有抗甲状腺药、安乃近、磺胺甲基异唑/甲氧苄啶、卡马西平和柳氮磺砒啶[5]。β-内酰胺导致粒细胞缺乏较罕见,常发生在用药2周后,停药1周内恢复。机制尚未明确,研究表明可能与药物的免疫介导反应或直接的血液学毒性反应有关[6]。MURPHY等[7]报道头孢呋辛导致白细胞减少症患者产生IgG抗体,ROUVEIX等[8]报道在怀疑β-内酰胺导致的粒细胞缺乏患者中,在发生粒细胞缺乏后2 d检测到β-内酰胺抗体,并且在恢复后抗体消失。这些抗体会导致大量外周血中的粒细胞或髓前体细胞迅速的破坏[4]。而β-内酰胺类抗菌药物对骨髓的直接毒性也有报道,NEFTEL等[9]报道β-内酰胺类抗菌药物会导致粒细胞前体缺乏分化的髓系元素,HAUSER等[10]报道使用头孢他啶1周后会使集落刺激因子活力和白细胞介素-6水平下降,这两种细胞因子都与造血功能有关。这种直接的毒性作用与药物剂量相关[7]。该患者头孢哌酮/舒巴坦导致粒细胞缺乏发生在用药后6 d,可能与该药的使用剂量较大相关,用到每日最大剂量12 g,从而导致剂量相关的直接毒性。由于未对患者抗体水平进行监测,不明确是否有免疫反应的影响。停用头孢哌酮/舒巴坦2 d后,患者白细胞数和中性粒细胞数恢复正常,与既往报道相符。

需要警惕的是,有研究报道在发生β-内酰胺类抗菌药物导致的白细胞减少时,如换用同类其他抗菌药物,会导致不良反应的再激发[7]。因此,对于该类患者,在以后使用其他β-内酰胺类抗菌药物时需谨慎,尽量使用其他类型的抗菌药物。

本例报告头孢哌酮/舒巴坦致粒细胞缺乏非常罕见,尽管药物不良反应机制尚不明确,但提示临床使用β-内酰胺类抗生素治疗时,尤其对那些接受长疗程、高剂量治疗的患者,需仔细监测白细胞和粒细胞计数。如发生可疑的β-内酰胺类抗菌药物导致的白细胞减少,甚至粒细胞缺乏时,应该及时停药,并进行相关的对症处理。

The authors have declared that no competing interests exist.
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关键词（key words）
头孢哌酮/舒巴坦
白细胞减少
粒细胞缺乏
作者
钟晗
郑毅隽
陈璋璋