Population Pharmacokinetics and Dosage Optimization of Teicoplanin in Children With Different Renal Functions

The glycopeptide antibacterial teicoplanin has become increasingly popular in the last decade with the rise in infections related to methicillin-resistant Staphylococcus aureus. Teicoplanin has 6 major and 4 minor components. It is predominantly (90%) bound to plasma proteins. Of the several methods available to measure concentrations in serum, fluorescence polarisation immunoassay has high reliability and specificity. Teicoplanin is not absorbed orally, but intravenous and intramuscular administration are well tolerated. Teicoplanin is eliminated predominantly by the kidneys and only 2 to 3% of an intravenously administered dose is metabolised. Total clearance is 11 ml/h/kg. Steady state is reached only slowly, 93% after 14 days of repeated administration. Elimination is triexponential, with half-lives of 0.4 to 1.0, 9.7 to 15.4 and 83 to 168 hours. Volumes of distribution are 0.07 to 0.11 (initial phase), 1.3 to 1.5 (distribution phase) and 0.9 to 1.6 (steady state) L/kg. A standard dosage regimen of 6 mg/kg every 12 hours for 3 doses, then daily, will produce therapeutic serum concentrations of > or = 10 mg/L in most patients. Higher dosages may be required in certain patients, for example intravenous drug abusers or those with burns, because of unpredictable clearance. Concentrations in bone reach 7 mg/L at 12 hours after a dose of teicoplanin 6 mg/kg, but reach only 3.5 mg/L in the cartilage. Doses of 10 mg/kg are necessary to achieve adequate bone concentrations. There is little penetration into cerebrospinal fluid or the aqueous or vitreous humour. In fat, concentrations may be subtherapeutic (0.5 to 5 mg/L) after a dose of 400mg. A single prophylactic dose of 12 mg/kg is sufficient to maintain therapeutic concentrations during cardiopulmonary bypass or burns surgery. High loading doses reduce the delay to attaining therapeutic concentrations. Premature neonates require a loading dose of 15 mg/kg and a maintenance dosage of 8 mg/kg daily to ensure therapeutic serum concentrations. Children need loading with 10 mg/kg every 12 hours for 3 doses followed by maintenance with 10 mg/kg/day. Clearance is reduced predictably in renal failure, and dosage adjustments can be based on the ratio of impaired clearance to normal clearance. In patients on haemodialysis, 3 loading doses of 6 mg/kg at 12-hour intervals followed by maintenance doses every 72 hours produced trough plasma concentrations of 8 mg/L in most patients at 48 hours. The monitoring of serum concentrations is not necessary to avoid toxicity, but can be helpful in certain patient groups to ensure therapeutic concentrations are present, especially in those not responding to treatment.

Early and effective antibiotic therapy is essential in the management of infection in critical illness. The loading dose is probably the most important dose and is a function of the volume of distribution of the drug and the desired plasma concentration but independent of renal function. Antibiotics are classified in a number of ways that have implications for dosing. Doses of hydrophilic agents such as β-lactams should be increased in the early stages of sepsis as the extravascular space increases. For lipophilic agents such as macrolides, the inflammatory process is less important, although factors such as obesity will affect dosing. Classification can also be based on pharmacodynamic properties. Concentration-dependent antibiotics such as aminoglycosides should be administered by extended interval regimens, which maximize bactericidal effect, minimize nephrotoxicity and allow time between doses for the post-antibiotic effect. The critical factor for time-dependent agents, such as β-lactams, is time above the MIC. Ideally administration of these agents should be continuous, although vascular access availability can restrict infusion time to between 4 and 6 h, which is probably adequate. As well as antibiotic factors, patient factors such as hepatic and renal failure will affect dosing. Hepatic failure will affect antibiotic metabolism, although it is most important in end-stage failure. Renal failure and support will affect drug elimination. Knowledge of these factors is essential. Patient safety and prevention of unnecessary harm is a weighty consideration in critical illness. To ensure effective treatment and minimize adverse effects, therapy should be reviewed daily and adjusted in the light of changes in patient organ function and underlying pathology.

中性粒细胞缺乏伴发热患者是一组特殊的疾病人群。由于免疫功能低下，炎症的症状和体征常不明显，病原菌及感染灶也不明确，发热可能是感染的唯一征象，如没有给予及时恰当的抗菌药物治疗，感染相关死亡率高。因此，充分认识中性粒细胞缺乏伴发热患者的相关风险、诊断方法以及如何合理使用抗菌药物，对于降低中性粒细胞缺乏伴发热的发生和死亡风险至关重要。 我国2012年《中国中性粒细胞缺乏伴发热患者抗菌药物临床应用指南》发布至今3年余，对临床诊疗发挥了很好的指导作用。期间国际上关于中性粒细胞缺乏伴发热的理念发生了一些重要的改变，我国在中性粒细胞缺乏伴发热的细菌流行病学调查及耐药菌监测方面也积累了大量临床研究和流行病学数据。因此，参考美国感染病学会（Infectious Diseases Society of America，IDSA）《发热和中性粒细胞缺乏患者治疗指南》（简称IDSA指南）[1]、第4届欧洲白血病感染会议（ECIL）《欧洲细菌耐药时代中性粒细胞减少症患者发热经验治疗指南》（简称ECIL-4经验治疗指南）[2]和《欧洲细菌耐药时代中性粒细胞减少症患者发热目标治疗指南》（简称ECIL-4目标治疗指南）[3]，结合国内流行病学资料、细菌耐药检测数据以及抗菌药物临床应用经验总结，中华医学会血液学分会和中国医师协会血液科医师分会对2012版指南进行修订。 一、定义 1．中性粒细胞缺乏：患者外周血中性粒细胞绝对计数（ANC） 21 d时感染的发生率明显增高。 中性粒细胞缺乏伴发热患者的临床表现不典型，感染部位不明显或难以发现，病原菌培养阳性率低。近期完成的中国血液病粒细胞缺乏伴发热患者的流行病学调查显示：①中心静脉置管（CVC）、消化道黏膜炎、既往90 d内暴露于广谱抗菌药物和中性粒细胞缺乏>7 d是中性粒细胞缺乏伴发热的危险因素。②在我国中性粒细胞缺乏伴发热患者中，能够明确感染部位者占54.7%，最常见的感染部位是肺，其后依次为上呼吸道、肛周、血流感染等。③能够明确感染微生物的比例为13.0%，致病菌以革兰阴性菌为主，占全部细菌总数的54.0%。④目前我国中性粒细胞缺乏患者感染的常见革兰阴性菌包括大肠埃希菌、肺炎克雷伯菌、铜绿假单胞菌、嗜麦芽窄食单胞菌、鲍曼不动杆菌；常见革兰阳性菌包括表皮葡萄球菌、肠球菌[包括耐万古霉素肠球菌（VRE）]、链球菌属、金黄色葡萄球菌[包括耐甲氧西林金黄色葡萄球菌（MRSA）]、凝固酶阴性葡萄球菌。⑤不同感染部位的致病菌谱有明显差异，如血流感染以大肠埃希菌、肺炎克雷伯菌、表皮葡萄球菌、铜绿假单胞菌和白色念珠菌为主，肺感染则以铜绿假单胞菌、嗜麦芽窄食单胞菌、黄曲霉和鲍曼不动杆菌为主[4]。 非发酵菌在革兰阴性菌中占较大比例。中国CHINET细菌耐药监测网的数据显示，2011–2014年在医院内分离的革兰阴性菌中非发酵菌所占比例波动于26.7%~37.7%[5]–[8]。中国粒细胞缺乏伴发热血液病患者的流行病学调查显示非发酵菌在革兰阴性菌中的检出比例为37.2%[4]。非发酵菌对常用抗菌药物的耐药发生率明显增高。近10年来鲍曼不动杆菌对碳青霉烯类耐药发生率从2005年的30％左右上升至2014年的62.4%[9]–[10]。2015年我国对亚胺培南耐药的鲍曼不动杆菌的检出率高达58.0%。非发酵菌耐药发生率的上升增加了临床抗菌治疗的难度。 尽管有相当一部分的中性粒细胞缺乏伴发热患者最终无法明确致病原，但考虑到这类患者的病情严重及死亡率较高，同时研究证实，尽早开始抗菌药物治疗可显著改善粒细胞缺乏伴发热患者的预后，所以强烈推荐这些患者尽早经验性应用抗菌药物治疗。 三、诊断 1．进行详细的病史询问和体格检查，以发现感染的高危部位和隐匿部位。但有相当一部分患者无法明确感染部位。 2．实验室检查：至少每3 d复查一次全血细胞计数、肝肾功能和电解质。建议进行降钙素原、C反应蛋白等感染相关指标的检查。 3．微生物学检查：至少同时行两套血培养检查，如果存在CVC，一套血标本从CVC的管腔采集，另一套从外周静脉采集。无CVC者，应采集不同部位静脉的两套血标本进行培养，采血量为每瓶10 ml。如果经验性抗菌药物治疗后患者仍持续发热，可以每隔2~3 d进行1次重复培养。同时根据临床表现，对可能出现感染部位进行相应的微生物学检查。建议中性粒细胞缺乏伴发热患者按照以下流程进行诊断（图1）。 图1 中性粒细胞缺乏伴发热患者的诊断流程 四、患者风险评估和耐药评估 患者危险度分层是中性粒细胞缺乏伴发热患者治疗开始前必要的工作，对于后续经验性选择抗菌药物至关重要。高危和低危的定义参照IDSA指南[1]标准（表1）。高危患者应首选住院接受经验性静脉抗菌药物治疗，不符合低危标准的患者在临床上均应参照高危患者指南进行治疗。 表1 中性粒细胞缺乏伴发热患者的危险度分层[1] 危险度 定义 高危 符合以下任何一项者 严重中性粒细胞缺乏（ 7 d 有以下任何一种临床合并症（包括但不限于）：①血流动力学不稳定；②口腔或胃肠道黏膜炎（吞咽困难）；③胃肠道症状（腹痛、恶心、呕吐、腹泻）；④新发的神经系统病变或精神症状；⑤血管内导管感染（尤其是导管腔道感染）；⑥新发的肺部浸润或低氧血症或有潜在的慢性肺部疾病 肝功能不全（转氨酶水平>5倍正常上限值）或肾功能不全（肌酐清除率 72 h >4周或病灶愈合、症状消失 金黄色葡萄球菌、铜绿假单胞菌或分枝杆菌所致导管相关性血流感染 首次血培养阴性后至少14 d 耐甲氧西林金黄色葡萄球菌血流感染（以糖肽类药物、达托霉素等治疗） 至少14 d，合并迁徙性病灶者适当延长 耐甲氧西林凝固酶阴性的葡萄球菌或肠球菌引起的血流感染 体温正常后持续治疗5~7 d 无法解释的发热患者 治疗持续至血细胞有明显恢复迹象，一般在ANC≥0.5×109/L时停药 注：有临床或微生物学感染证据患者的疗程取决于特定的微生物和感染部位。ANC：中性粒细胞绝对计数 八、抗菌药物预防用药的指征 对于高危患者，推荐预防性用药，可选择氟喹诺酮类药物、磺胺甲恶唑／甲氧苄氨嘧啶[15]，不建议预防性应用第三代头孢菌素。最佳的开始给药时间和给药持续时间尚无定论，推荐从中性粒细胞缺乏开始应用至ANC>0.5×109/L或出现明显的血细胞恢复证据。需要注意的是，长期预防性应用喹诺酮类药物可能导致革兰阳性球菌感染[16]，并可能导致细菌耐药性增加。对于低危患者，不推荐预防性应用抗菌药物。 不推荐常规使用抗菌药物预防导管相关血流感染。在插管前或应用CVC时，不推荐常规鼻腔给药或全身应用抗菌药物预防细菌定植或血流感染。 不推荐对自体造血干细胞移植患者预防性用药[17]。对于异基因造血干细胞移植患者，建议预防性用药以防止感染发生[18]。