Posaconazole in paediatric malignancy and haematopoietic stem cell transplant: dosing to achieve therapeutic concentration.

OBJECTIVES: Posaconazole is increasingly used for the treatment and prophylaxis of invasive fungal infections in immunocompromised children. We aimed to review evidence for paediatric posaconazole dosing regimens focusing on attainment of target concentrations and frequency of adverse effects. METHODS: In May 2023, the Cochrane, Embase, MEDLINE and PubMed databases were searched for articles reporting posaconazole dosing in children with malignancy or post-haematopoietic stem cell transplantation. Studies reporting the attainment of target serum concentrations were included. RESULTS: Overall, 24 studies were included. Eighteen studies of the oral suspension consistently reported poor attainment of target concentrations for prophylaxis (≥0.7 µg/mL, 12%-78%) despite high daily doses of 14-23 mg/kg/day (max. 1200 mg/day). Target attainment was significantly affected by gastric pH and food intake. Six studies of the delayed-release tablet (DRT) reported 58%-94% achieved concentrations ≥0.7 µg/mL, with the majority using lower doses of 4-12 mg/kg/day (max. 300 mg/day). Similarly, one study of powder for oral suspension found 67%-100% achieved target concentrations with a dose of 6 mg/kg/day (max. 300 mg/day). As expected, the IV formulation had high attainment of prophylaxis targets (81%-90%) with 6-10 mg/kg/day (max. 400 mg/day). All formulations were well tolerated, and no relationship between adverse effects and posaconazole concentrations was identified. CONCLUSIONS: The required posaconazole dose in immunocompromised children varies depending on the formulation. The IV infusion had the highest attainment of therapeutic concentration followed by the DRT and powder for suspension. By contrast, the oral suspension had low attainment of target concentrations despite higher daily doses.

Expanding the scope of the infectious diseases pharmacist in HCT: Beyond antimicrobial stewardship.

BACKGROUND: Infectious disease (ID) pharmacists and antimicrobial stewardship (AMS) programs are integral to the infection management of hematopoietic cell transplant (HCT) recipients demonstrating effective implementation of clinical pathways, de-escalation of empirical antibiotics for febrile neutropenia (FN), allergy assessments, and use of rapid diagnostic testing. The HCT procedure is complex, dynamic, and a high risk for infectious complications. Therefore, there is an important role for an ID and AMS pharmacist to collaborate with the primary treating team, with ongoing care, involving the optimal individual patient prophylactic, pre-emptive and treatment management of infections in this high-risk population. CONCLUSION: This review highlights key factors for consideration of ID/AMS Pharmacists in relation to HCT, including important aspects in the evaluation of infection risk prior to transplant, risk from donor sources, length of, and changes in immunosuppression, and potential drug-drug interactions from other essential supportive care therapies.

Density of antibiotic use and infectious complications in pediatric allogeneic hematopoietic cell transplantation.

BACKGROUND: Antibiotics, while an essential component of supportive care in allogeneic hematopoietic cell transplantation (allo-HCT), can have adverse effects and select for antibiotic resistance. Understanding of patterns of use will inform antimicrobial stewardship (AMS) interventions. METHODS: Retrospective, single-center cohort of children undergoing first allo-HCT (n = 125). Antibiotic prescription and infection data were included from the date conditioning was commenced until 30 days post allo-HCT. Antibiotic use was reported as length of therapy (LOT) (number of days a patient received an antibiotic) and days of therapy DOT (aggregating all antibiotics prescribed per day). Infections were classified as microbiologically documented infection (MDI) or clinically documented infections. RESULTS: At least one course of antibiotics was administered to 124 (99%) patients. The LOT was 636 per 1000 patient days and DOT was 959 per 1000 patient days. The median duration of cumulative antibiotic exposure per patient was 24 days (interquartile range [IQR] 20-30 days). There were 131 days of fever per 1000 patient days with patients febrile for a median of 4 days (IQR 1-7 days). Piperacillin-tazobactam was used for 116 (94%) of patients with an LOT of 532 per 1000 patient days. A total of 119 MDI episodes occurred in 74 (59%) patients, including blood stream infection in 30 (24%) and a proven/probable invasive fungal infection in 4 (3%). CONCLUSION: Pediatric HCT patients receive prolonged courses of broad-spectrum antibiotics relative to the frequency of fever and bacterial infections. This study has identified opportunities for AMS intervention to improve outcomes for our HCT patients.