Voriconazole therapeutic drug monitoring including analysis of CYP2C19 phenotype in immunocompromised pediatric patients with invasive fungal infections.

PURPOSE: Therapeutic drug monitoring (TDM) of voriconazole (VCZ) should be mandatory for all pediatric patients with invasive fungal infections (IFIs). The narrow therapeutic index, inter-individual variability in VCZ pharmacokinetics, and genetic polymorphisms cause achieving therapeutic concentration during therapy to be challenging in this population. METHODS: The study included 44 children suffering from IFIs treated with VCZ. Trough concentrations (Ctrough) of VCZ ware determined by the HPLC-FLD method. Identification of the CYP2C19*2 and CYP2C19*17 genetic polymorphisms was performed by PCR-RFLP. The correlation between polymorphisms and VCZ Ctrough was analyzed. Moreover, the effect of factors such as dose, age, sex, route of administration, and drug interactions was investigated. RESULTS: VCZ was administered orally and intravenously at a median maintenance dosage of 14.7 mg/kg/day for a median of 10 days. The VCZ Ctrough was highly variable and ranged from 0.1 to 6.8 mg/L. Only 45% of children reached the therapeutic range. There was no significant association between Ctrough and dosage, age, sex, route of administration, and concomitant medications. The frequencies of variant phenotype normal (NM), intermediate (IM), rapid (RM) and ultrarapid metabolizers (UM) were 41%, 18%, 28%, and 13%, respectively. Ctrough of VCZ were significantly higher in NM and IM groups compared with RM, and UM groups. CONCLUSION: The Ctrough of VCZ is characterized by inter-individual variability and a low rate of patients reaching the therapeutic range. The significant association exists in children between VCZ Ctrough and CYPC19 phenotype. The combination of repeated TDM and genotyping is necessary to ensure effective treatment.

No difference in laxity, proprioception and neuromuscular control after suture-tape augmented ACL repair of acute proximal avulsions versus ACL reconstruction using hamstring autografts in young, active population.

Purpose: The purpose of this study is to compare results of suture-tape augmented anterior cruciate ligament (ACL) repair (internal bracing [IB]) and ACL reconstruction (ACLR) with hamstring autograft in terms of laxity, proprioception and neuromuscular control. The hypothesis was that with strict indications IB may provide better results in proprioception and neuromuscular control. Methods: Patients with unilateral ACL injury treated with IB or ACLR with hamstring autograft were enroled in this retrospective study. Anterior tibial translation (ATT) in 30° and 90° of flexion was measured with Rolimeter. The joint position sense (JPS) test was performed in 30° and 60° of flexion using Biodex System 4Pro. The time-synchronized motion capture system and surface electromyography set were used during dynamic tasks to assess knee valgus and semitendinosus (ST) and biceps femoris (BF) activities. Comparisons between both techniques and operated versus contralateral healthy knees were performed. Results: The study groups involved 28 patients after ACLR (21.8 ± 4.8 years) and 20 patients after IB (25.8 ± 10.5 years) with the average follow-up 30 ± 18 and 28 ± 15 months, respectively. The ATT did not differ significantly between operated groups. In 30° of flexion ATT for ACLR was significantly higher in operated than in contralateral knee (5.8 ± 2.4 mm vs. 4.3 ± 1.3 mm, p < 0.001). The JPS test and dynamic knee valgus presented no significant differences. The ACLR group presented significantly higher ST (p = 0.048) and BF (p = 0.012) activity comparing operated to contralateral knee in dynamic tasks. Conclusion: Suture-tape augmented ACL repair and ACLR with hamstring autograft yield similar results in terms of laxity, proprioception and neuromuscular control. Level of Evidence: Level III: Retrospective comparative study.