122例万古霉素致耳毒性的文献病例分析

Literature analysis of 122 cases of vancomycin-induced ototoxicity

目的 探讨万古霉素血清谷浓度与耳毒性的关系,为临床合理用药提供参考。方法 检索中国期刊全文数据库、维普中文期刊全文数据库、万方数据库,以“万古霉素”、“耳毒性”、“不良反应”、“听力损害”等为关键词,检索2000年1月~2021年12月期间关于万古霉素致耳毒性的个案报道及临床观察,最终纳入有效文献14篇,共涉及122例耳毒性患者。记录分析所有万古霉素致耳毒性患者性别与年龄分布情况、病原学检测结果、耳毒性的临床表现、成人耳毒性的发生情况、儿童万古霉素血清谷浓度及不良反应发生情况,比较儿童与成人耳毒性发生率。结果 122例万古霉素致耳毒性患者中,年龄≤30 d新生儿的耳毒性发生率最高,占52.46%(64/122),其次为31 d~18岁的儿童,占27.87%(34/122),最低为≥18岁的成人,占19.67%(24/122)。122例万古霉素致耳毒性患者中,原患疾病均为感染性疾病,疾病分型主要包括肺部感染72例、中枢神经系统感染24例、血流感染17例、皮肤软组织感染5例、腹膜炎2例、化脓性关节炎1例、骨髓炎1例。病原菌检测主要包括金黄色葡萄球菌(53.28%)、表皮葡萄球菌(15.57%)、溶血葡萄球菌(13.11%)、粪肠球菌(4.92%)、人葡萄球菌(3.28%)、鹑鸡肠球菌(3.28%)、腐生葡萄菌(1.64%)、缓症链球菌(1.64%)、屎肠球菌(1.64%)、无乳链球菌(1.64%)等。耳毒性包括前庭功能失调症状、耳锅功能障碍症状、听力损害等。3例成人出现头痛、眩晕、急剧动作时平衡失调等前庭功能失调症状,7例成人出现耳鸣、耳聋、耳部不适、耳痛、听力降低等耳锅功能障碍症状;64例新生儿、34例儿童、14例成人出现听力损害。其中6篇文献共纳入成人患者1093例,24例发生了耳毒性,5篇未按血清谷浓度分组检测不良反应,耳毒性发生率2.20%。其中8篇临床观察共纳入患儿1285例,发生不良反应230例,不良反应发生率为17.90%(230/1285)。不良反应主要包括听力损害(7.63%)、肝损害(9.65%)、肾损害(0.62%)。肝损害和听力损害的发生率明显高于肾损害,而肝损害和听力损害的发生率相近。万古霉素血清谷浓度<5 mg/L、5~10 mg/L、>10 mg/L患儿不良反应发生率分别为16.79%(133/792)、18.00%(56/311)、22.53%(41/182),比较差异无统计学意义(χ^(2)=3.315,P=0.191>0.05)。万古霉素血清谷浓度<5 mg/L、5~10 mg/L、>10 mg/L患儿听力损害发生率分别为6.69%(53/792)、6.75%(21/311)、13.19%(24/182),差异有统计学意义(χ^(2)=9.307,P=0.01<0.05)。万古霉素血清谷高浓度患儿听力损害发生率较高,且随用药剂量增加呈上升趋势。儿童耳毒性发生率7.63%高于成人的2.20%,差异有统计学意义(χ^(2)=35.788,P=0.000<0.05)。结论 儿童耳毒性发生率明显高于成人,成人耳毒性发生率较小;儿童应用万古霉素有较高的肝损害及听力损害,尤其是新生儿,患儿<5 mg/L、5~10 mg/L、>10 mg/L万古霉素血清谷浓度与听力损害显著相关。

Objective To investigate the relationship of vancomycin serum trough concentration and ototoxicity,so as to provide a reference for clinical rational drug use.Methods Searched the China National Knowledge Infrastructure,Chinese Scientific Journal Database,and Wanfang Database,using"vancomycin","ototoxicity","adverse reactions","hearing impairment"as keywords,and searched the case reports and clinical observations on vancomycin-induced ototoxicity from January 2000 to December 2021,and finally included 14 valid literatures,involving a total of 122 ototoxic patients.The gender and age distribution of all patients with vancomycin-induced ototoxicity,pathogenic test results,clinical manifestations of ototoxicity,occurrence of ototoxicity in adults,vancomycin serum trough concentration in children and occurrence of adverse reactions were recorded and analyzed,and the incidence of ototoxicity in children and adults were compared.Results Among the 122 patients with vancomycin-induced ototoxicity,the incidence of ototoxicity was highest in neonates aged≤30 d,accounting for 52.46%(64/122),followed by children aged 31 days-18 years,accounting for 27.87%(34/122),the lowest for adults≥18 years old,accounting for 19.67%(24/122).Among the 122 patients with vancomycin-induced ototoxicity,the original diseases were all infectious diseases,and the disease subtypes mainly included 72 cases of pulmonary infection,24 cases of central nervous system infection,17 cases of bloodstream infection,5 cases of skin soft tissue infection,2 cases of peritonitis,1 case of septic arthritis,and 1 case of osteomyelitis.Pathogen detection mainly included:Staphylococcus aureus(53.28%),Staphylococcus epidermidis(15.57%),Staphylococcus hemolyticus(13.11%),Enterococcus faecalis(4.92%),Staphylococcus hominis(3.28%),Enterococcus gallinarum(3.28%),Staphylococcus saprophyticus(1.64%),Streptococcus mitis(1.64%),Enterococcus faecium(1.64%),Streptococcus agalactiae(1.64%),etc.Ototoxicity includes symptoms of vestibular dysfunction,symptoms of ear pot dysfunction,and hearing impairment.Symptoms of vestibular dysfunction such as headache,vertigo,and balance disorders during sharp movements were observed in 3 adults,and symptoms of ear pot dysfunction such as tinnitus,deafness,ear discomfort,ear pain,and hearing reduction were observed in 7 adults;hearing impairment was observed in 64 neonates,34 children,and 14 adults.Among them,6 literatures included a total of 1093 adult patients,24 cases developed ototoxicity,Adverse reactions were not detected by serum trough concentration in 5 literatures,and the incidence of ototoxicity was 2.20%.Among them,8 clinical observations included 1285 children,230 cases of adverse reactions occurred,and the incidence of adverse reactions was 17.90%(230/1285).Adverse reactions mainly included hearing impairment(7.63%),liver damage(9.65%),and kidney damage(0.62%).The incidence of liver damage and hearing damage was significantly higher than that of kidney damage,while the incidence of liver damage and hearing impairment were similar.The incidence of adverse reactions in children with vancomycin serum trough concentration<5 mg/L,5-10 mg/L and>10 mg/L were 16.79%(133/792),18.00%(56/311),22.53%(41/182),and the difference was not statistically significant(χ^(2)=3.315,P=0.191>0.05).The incidence of hearing impairment in children with vancomycin serum trough concentration<5 mg/L,5-10 mg/L and>10 mg/L were 6.69%(53/792),6.75%(21/311),13.19%(24/182),and the difference was statistically significant(χ^(2)=9.307,P=0.01<0.05).The incidence of hearing impairment was higher in children with high vancomycin serum trough concentration and tended to increase with increasing dose of the drug.The incidence of ototoxicity 7.63%in children was higher than 2.20%in adults,and the difference was statistically significant(χ^(2)=35.788,P=0.000<0.05).Conclusion The incidence of ototoxicity in children is significantly higher than that in adults,and the incidence of ototoxicity in adults is low;Children treated with vancomycin have relatively high ratio of the liver damage and hearing impairment,especially neonates.There is significant correlation between vancomycin serum trough concentration(<5 mg/L,5-10 mg/L,>10 mg/L)and hearing impairment in children.