中国循证儿科杂志 ›› 2022, Vol. 17 ›› Issue (1): 10-15.

• 论著 • 上一篇    下一篇

口服复方新诺明治疗新生儿耐药肠杆菌败血症9例病例系列报告

刘仕祺,杜娟,杨子馨,李耿,陈璐,齐宇洁,黑明燕   

  1. 国家儿童医学中心首都医科大学附属北京儿童医院新生儿中心北京,100045
  • 收稿日期:2021-12-15 修回日期:2022-01-13 出版日期:2022-02-25 发布日期:2022-02-25
  • 通讯作者: 齐宇洁,黑明燕

9 cases of neonatal drugresistant Enterobacteriaceae treated with oral SMZco: A case series report

LIU Shiqi, DU Juan, YANG Zixin, LI Geng, CHEN Lu, QI Yujie, HEI Mingyan   

  • Received:2021-12-15 Revised:2022-01-13 Online:2022-02-25 Published:2022-02-25
  • Contact: QI Yujie, email: qiyj0805@yeah.net; HEI Mingyan, email: heimingyan@bch.com.cn

摘要: 背景:超说明书用药的情况在新生儿科非常普遍,基于耐药肠杆菌(CRE)败血症存在抗生素选择受限,复方新诺明(SMZco)可口服且其口服制剂的生物利用度较高,但说明书不建议在2月龄以下的婴儿中使用。 目的:总结口服SMZco治疗新生儿CRE败血症的经验和临床疗效。 设计:病例系列报告。 方法:通过医院药物管理系统,检索并申领同时符合以下条件的SMZco病历,2018年1月至2021年6月在首都医科大学附属北京儿童医院新生儿中心住院、入院时日龄≤28 d或矫正胎龄≤44 周、住院期间CRE败血症诊断明确的病例,经新生儿医生、药师和儿科感染科会诊认为应用SMZco获益明显,不良反应可控;患儿家长接受医生建议,签署口服SMZco用药知情同意书。参考>2月龄儿童SMZco推荐剂量,观察用药期间过敏反应、胆红素脑病表现,每周监测血常规和肝肾功能。采集人口学信息,手术或深静脉置管史,有创通气时间,临床表现,标本培养阳性时间,菌种,药敏试验结果,口服SMZco时日龄、剂量,口服SMZco前后WBC、PLT和CRP,口服SMZco后不良反应和临床结局。 主要结局指标:好转出院和不良事件发生。 结果:9例口服SMZco的婴儿纳入分析,男5例,女4例;6例患儿的CRE败血症发生在手术后,8例有深静脉置管史;机械通气时间(793±381)h。标本类型:PICC管端和伤口分泌物各1例,单纯血2例,单纯痰3例、血+痰和血+脑脊液各1例。9例均接受>2周静脉广谱抗菌药物治疗; 2例符合中枢神经系统感染诊断。获得CRE阳性培养结果为在我院住院39(23.5,49)d时,其中8例为肺炎克雷伯菌,1例为大肠埃希菌,均能产生超广谱β内酰胺酶,对碳青霉烯类抗菌药物耐药;对阿米卡星耐药3例、敏感6例,对庆大霉素耐药5例、敏感4例,对环丙沙星耐药6例、敏感3例,对氯霉素中介2例、敏感7例,对四环素耐药3例、敏感5例、中介1例,对SMZco和替加环素均敏感。口服SMZco日龄为49(38,70.5)d;3例为停用静脉抗生素后的序贯口服SMZco;6例为联合碳青霉烯类或三代头孢菌素治疗;口服SMZco的剂量以磺胺甲恶唑含量计为40~60 mg·kg-1·d-1。3例自动出院未完成疗程;6例按计划完成SMZco疗程的患儿应用SMZco的平均时间为(24.3±11.6)d,其中1例病原标本为深部痰、SMZco应用10 d,余5例疗程均>2周。9例患儿临床症状均得到改善,用药后WBC、PLT均恢复正常,7例CRP降至正常,2例自动出院前CRP亦明显下降。9例均未发生过敏反应,无胆红素脑病表现,未出现溶血性贫血、PLT减少,3例仅ALT有2.2~3.5倍的升高,对症治疗后均降至正常,肾功能均正常。 结论:对于有明确培养和药敏结果的新生儿CRE感染,在充分应用强广谱抗生素治疗仍不能取得满意疗效的情况下,可考虑联合口服SMZco抗感染治疗,但需严格遵守超说明书用药和家长书面知情告知流程,密切监测不良反应。

关键词: 复方新诺明, 婴儿, 新生, 耐药肠杆菌, 败血症, 抗菌药物

Abstract: Background: Offlabel drug use is common in neonates. Appropriate and effective administration of antibiotics for Carbapenemresistant Enterobacteriaceae (CRE) infection in neonates is challenging. Sulfamethoxazole compound (SMZco) can be taken orally with high bioavailability, however, it is not recommended to be used in infants under 2 months. Objective: To summarize the experience and therapeutic effect of oral SMZco for the CRE septicemia in newborns. Design: Case series report. Methods: Through the hospital drug management system, SMZco medical records that meet the following criteria were collected: a. Patients were hospitalized in NICU of Beijing Children's Hospital, Capital Medical University from January 2018 to June 2021; b. The age on admission was ≤ 28 d or the corrected age was ≤ 44 weeks; c. The CRE septicemia was confirmed by positive blood culture results and clinical manifestations. The oral SMZco as a combined use of medications was administered when the pros and cons were thoroughly discussed by neonatal physicians and clinical pharmacists, and formal written consents were signed by parents. The dose of SMZco was referred to that for children above 2 months old. Signs of allergy and manifestations of bilirubin encephalopathy had been closely watched during the treatment. Complete blood counting and renohepatofunction were monitored weekly. The following information was collected: demographic characteristics, history of surgical intervention or long line catheterization, ventilation time, time interval between blood drawing and culture positive, species of the positive culture results together with the drug sensitivity test, age of starting SMZco administration, dosage of SMZco, WBC, PLT and CRP before and after SMZco treatment, adverse reactions and clinical outcomes. Main outcome measures: Discharge after improvement. Results: A total of 9 newborns with CRE septicemia were enrolled, among which 5 were males, 6 received surgery intervention before CRE septicemia was confirmed, and 8 had history of long line catheterization. The average gestational age was (31.0 ± 4.4) weeks, ventilation time was (793±381)h . Specimens for the positive CRE cultures were blood (2 cases), tracheal bronchial secretion (3 cases), tip of PICC (1 case), surgical wound swab (1 case), blood and tracheal bronchial secretion (1 case) and blood+cerebrospinal fluid (1 case). Before the administration of SMZco, all cases were treated with broadspectrum antibiotics for more than 2 weeks. There were 2 cases of CRE meningitis. The medium time of positive CRE culture was 39 (23.5,49) d of hospitalization before or after being transferred to our center. Among the 9 cases, 8 were Klebsiella pneumoniae and 1 was Escherichia coli, all of which produced extendedspectrum βlactamases. Analysis of antimicrobial susceptibility assay revealed resistance to Amikacin (3 cases), Gentamicin (6 cases), Ciprofloxacin (7 cases), and Tetracycline (3 cases). All were sensitive to SMZco and Tegacyclin. SMZco treatment was initiated at 49(38,70.5) days of life for patients, and the dose of SMZ was 4060 mg·kg-1·d-1. There were 6 cases treated with oral SMZco in combination of intravenous carbapenems or thirdgeneration cephalosporins, while 3 cases were with oral SMZco only. Six out of nine patients completed the SMZco course of (24.3 ± 11.6) days, while three out of nine patients did not complete the required SMZco course due to their discharge against medical advice. Among the 6 patients with complete SMZco course, 1 was treated for 10 d (tracheal bronchial secretion positive), and the other 5 were treated for more than 2 weeks. All patients presented improved clinical symptoms and inflammatory markers after the starting of SMZco. All patients had normalization of WBC and PLT, 7 patients had normalization of CRP and other 2 patients had dramatically improved CRP before discharge against medical advice. No allergy was found, nor signs of bilirubin encephalopathy or hemolytic anemia or thrombocytopenia. There were 3 patients (33.3%) with an ALT elevation 2.23.5 times of normal value, which was normalized after symptomatic intervention. All patients had normal renal function during SMZco treatment. Conclusion: For neonates who had culture confirmed CRE septicemia, under the instruction of drug sensitivity results, a combined use of oral SMZco is a choice to treat the CRE infection when the treatment response of strong broad spectrum antibiotics is negative. However, it is necessary to strictly follow the procedures of offlabel drug use, parent consenting, and close monitoring of side effects.

Key words: SMZco, Infant, Newborn, Drug-resistant Enterobacteriaceae, Septicemia, Antibiotics