Therapeutic drug monitoring of liposomal amphotericin B in children. Are we there yet? A systematic review.

INTRODUCTION: Therapeutic drug monitoring (TDM) is a tool that supports personalized dosing, but its role for liposomal amphotericin B (L-amb) is unclear. This systematic review assessed the evidence for L-amb TDM in children. OBJECTIVES: To evaluate the concentration-efficacy relationship, concentration-toxicity relationship and pharmacokinetic/pharmacodynamic (PK/PD) variability of L-amb in children. METHODS: We systematically reviewed PubMed and Embase databases following PRISMA guidelines. Eligible studies included L-amb PK/PD studies in children aged 0-18 years. Review articles, case series of 600 mg·h/L for nephrotoxicity. L-amb doses of 2.5-10 mg/kg/day were reported to achieve Cmax/MIC > 25 using an MIC of 1 mg/L. CONCLUSIONS: While significant PK variability was observed in children, evidence to support routine L-amb TDM was limited. Further studies on efficacy and toxicity benefits are required before routine TDM of L-amb can be recommended.

Why hospital-based healthcare professionals do not report adverse drug reactions: a mixed methods study using the Theoretical Domains Framework.

PURPOSE: Adverse drug reaction (ADR) underreporting is highly prevalent across the world. This study aimed to identify factors associated with ADR reporting and map these to a behavioural change framework to help inform future interventions designed to improve ADR underreporting. METHODS: A mixed methods survey was distributed to healthcare professionals at a tertiary hospital in Sydney, Australia. Quantitative data was analysed using logistic regression to identify factors that predict ADR reporting. Qualitative data was evaluated using content analysis. These were then integrated and mapped to the 14 domains within the Theoretical Domains Framework (TDF) to identify target areas relevant for improving ADR reporting. RESULTS: One hundred thirty-three healthcare professionals completed the survey. Knowing how to report ADRs (OR 4.56, 95%CI 1.95-10.7), having been trained on ADR reporting (OR 2.72, 95%CI 1.29-5.77), and encountering ADRs as part of clinical practice (OR 10.3, 95%CI 3.59-29.4) were significant predictors of reporting an ADR. Content analysis identified three categories: modifying the ADR reporting process, enabling clinicians to report ADRs, and creating a positive ADR reporting culture. After data integration, the three target TDF domains were knowledge, environmental context/resources, and beliefs about consequences. CONCLUSION: Future interventions designed to improve ADR reporting should address these target domains to instigate behaviour change in healthcare professionals' reporting of ADRs.

LInezolid Monitoring to MInimise Toxicity (LIMMIT1): A multicentre retrospective review of patients receiving linezolid therapy and the impact of therapeutic drug monitoring.

BACKGROUND: Linezolid is a broad-spectrum antimicrobial with limited use due to toxicity. This study aimed to evaluate linezolid toxicity in a large multicentre cohort. Secondary objectives were to identify factors contributing to toxicity, including the impact of therapeutic drug monitoring (TDM). METHODS: Patients administered linezolid between January 2017 and December 2019 were retrospectively reviewed. Data were collected on patient characteristics, linezolid therapy and outcomes. Descriptive statistics were performed on all patients, and statistical comparisons were undertaken between those who did and did not experience linezolid toxicity. A multivariable logistic regression model was constructed to identify any covariates that correlated with toxicity. RESULTS: Linezolid was administered to 1050 patients; of these, 381 did not meet the inclusion criteria and 47 were excluded as therapy ceased for non-toxicity reasons. There were 105 of 622 (16.9%) patients assessed to have linezolid toxicity. Patients who experienced toxicity displayed a higher baseline creatinine (96.5 µmol/L vs. 79 µmol/L; P = 0.025), lower baseline platelet count (225 × 109/L vs. 278.5 × 109/L; P = 0.002) and received a longer course (median 21 vs. 14 days; P < 0.001) than those who did not. Linezolid TDM was performed in 144 patients (23%). Multivariable logistic regression demonstrated that TDM-guided appropriate dose adjustment significantly reduced the odds of linezolid toxicity (aOR = 0.45; 95% CI 0.21-0.96; P = 0.038) and a treatment duration > 28 days was no longer significantly associated with toxicity. CONCLUSIONS: This study confirmed that linezolid treatment-limiting toxicity remains a problem and suggests that TDM-guided dose optimisation may reduce the risk of toxicity and facilitate prolonged courses beyond 28 days.