From the Rady Children's Hospital San Diego, San Diego, CA.
University of California San Diego, La Jolla, CA.
Pediatr Infect Dis J. 2018 Nov;37(11):1130-1136. doi: 10.1097/INF.0000000000002170.
Drug-resistant Gram-negative bacteria are a growing threat to children; thus new antibiotics are needed to treat infections caused by these pathogens. Ceftolozane/tazobactam is active against many Gram-negative pathogens and is approved for treatment of complicated intra-abdominal and urinary tract infections in adults, but has not been evaluated in children.
This phase 1, noncomparative, open-label, multicenter study characterized the pharmacokinetics (by noncompartmental analysis), safety, and tolerability of single intravenous doses of ceftolozane/tazobactam in pediatric patients (birth [7 days postnatal] to < 18 years of age) with proven/suspected Gram-negative infection or receiving perioperative prophylaxis (clinicaltrials.gov NCT02266706). Patients were enrolled into 1 of 6 age groups to receive a single, age-based ceftolozane/tazobactam dose, with timed blood sample collection for determining plasma concentrations of ceftolozane and tazobactam. Safety and tolerability were also evaluated.
Thirty-seven patients received study drug; 34 were included in the pharmacokinetic population. Ceftolozane and tazobactam pharmacokinetic parameters were generally comparable for patients 3 months to < 18 years of age. Patients from birth (7 days postnatal) to < 3 months of age had lower clearance than older children, likely due to the immature renal function of these young infants. No deaths, study drug-related serious adverse events, or clinically significant laboratory abnormalities were observed after administration of ceftolozane/tazobactam.
The doses evaluated in this study yielded ceftolozane/tazobactam exposure levels generally comparable with those in adults. Single doses of ceftolozane/tazobactam were well-tolerated, and no safety concerns were identified. These data informed pharmacokinetic/pharmacodynamic models to derive pediatric dose recommendations for phase 2 ceftolozane/tazobactam clinical trials.
耐药革兰氏阴性菌对儿童的威胁日益增加；因此，需要新的抗生素来治疗这些病原体引起的感染。头孢他洛酯/他唑巴坦对许多革兰氏阴性病原体具有活性，已被批准用于治疗成人复杂性腹腔内和尿路感染，但尚未在儿童中进行评估。
这是一项 1 期、非对照、开放标签、多中心研究，旨在描述已确诊/疑似革兰氏阴性感染的儿科患者（出生后[出生后 7 天]至<18 岁）或接受围手术期预防用药时，单次静脉注射头孢他洛酯/他唑巴坦的药代动力学（非房室分析）、安全性和耐受性（clinicaltrials.gov NCT02266706）。患者分为 6 个年龄组中的 1 个，接受单次基于年龄的头孢他洛酯/他唑巴坦剂量，定时采集血样以测定头孢他洛酯和他唑巴坦的血浆浓度。还评估了安全性和耐受性。
37 名患者接受了研究药物；34 名患者纳入药代动力学人群。3 个月至<18 岁的患者头孢他洛酯和他唑巴坦的药代动力学参数通常相似。出生（出生后 7 天）至<3 个月的患者清除率低于年龄较大的儿童，这可能是由于这些婴儿的肾功能尚未成熟。给予头孢他洛酯/他唑巴坦后，未观察到死亡、与研究药物相关的严重不良事件或临床显著的实验室异常。
本研究评估的剂量产生的头孢他洛酯/他唑巴坦暴露水平与成人相当。单次给予头孢他洛酯/他唑巴坦耐受性良好，未发现安全性问题。这些数据为头孢他洛酯/他唑巴坦的药代动力学/药效学模型提供了信息，为 2 期头孢他洛酯/他唑巴坦临床试验提供了儿科剂量建议。
