Microdialysis sampling to monitor target-site vancomycin concentrations in septic infants: a feasible way to close the knowledge gap.

This work is dedicated to the memory of Hartmut Derendorf (1953-2020), a pioneer of modern pharmacokinetics and valued mentor of this project. OBJECTIVES: Septic infants/neonates need effective antibiotic exposure, but dosing recommendations are challenging as the pharmacokinetics in this age are highly variable. For vancomycin, which is used as a standard treatment, comprehensive pharmacokinetic knowledge especially at the infection site is lacking. Hence, an exploratory clinical study was conducted to assess the feasibility and safety of microdialysis sampling for vancomycin monitoring at the target site. METHODS: Nine infants/neonates with therapeutic indications for vancomycin treatment were administered 15 mg/kg as 1-hour infusions every 8-24 hours. Microdialysis catheters were implanted in the subcutaneous interstitial space fluid of the lateral thigh. Samples were collected every 30 minutes over 24 hours, followed by retrodialysis for catheter calibration. Prior in vitro investigations have evaluated impact factors on relative recovery and retrodialysis. RESULTS: In vitro investigations showed the applicability of microdialysis for vancomycin monitoring. Microdialysis sampling was well tolerated in all infants/neonates (23-255 days) without major bleeding or other adverse events. Pharmacokinetic profiles were obtained and showed plausible vancomycin concentration-time courses. CONCLUSIONS: Microdialysis as a minimally invasive technique for continuous longer-term sampling is feasible and safe in infants/neonates. Interstitial space fluid profiles were plausible and showed substantial interpatient variation. Hence, a larger microdialysis trial is warranted to further characterise the pharmacokinetics and variability of vancomycin at the target site and ultimately improve vancomycin dosing in these vulnerable patients.

Drug combinations and impact of experimental conditions on relative recovery in in vitro microdialysis investigations.

The need for pharmacokinetic knowledge about antibiotics directly at the site of infection, typically the interstitial space fluid (ISF) of tissues, is gaining acceptance for effective and safe treatment. One option to acquire such data is the microdialysis technique employing a catheter with a semipermeable membrane inserted directly in the ISF. A prerequisite is catheter calibration, e.g. via retrodialysis, yielding a conversion factor from measured to true ISF concentrations, termed relative recovery. This value can be influenced by various factors. The present investigation assessed the impact of three of them on relative recovery using seven drugs: (I) drug combinations/order, (II) air in the microdialysis system, (III) flow rate changes inherent when using common in vivo microdialysis pumps. All experiments were performed in a standardised in vitro microdialysis system. (I) Relative recovery of single antibiotics (linezolid, meropenem, cefazolin, metronidazole, tigecycline) was determined in microdialysis and retrodialysis settings and compared with values using either antibiotic or antibiotic+analgesic (acetaminophen and metamizole) combinations or single drugs with reversed microdialysis order. For assessing these factors for lower relative recovery values (as in in vivo), these were mimicked by increasing the flow rate for linezolid. (II) For the impact of air, linezolid relative recovery of freshly carbonated solutions was compared to degassed ones in microdialysis and retrodialysis settings. For each condition in (I) and (II), summary statistics of relative recovery were calculated and for the impact of the factors a linear mixed-effect model developed. (III) From samples taken during an automatic flush sequence (15 µL/min) of an in vivo pump and afterwards switching to the flow rate of 1 and 2 µL/min for 120 min, the time necessary for relative recovery to reach equilibrium was determined. (I) High relative recovery values (flow rate 2 µL/min: ≥84%; flow rate 5 µL/min: ≥65%) were observed for all investigated single drugs. Intra- and intercatheter variability ranged from 0.3%-11% and 3%-25%, respectively. Based on these values and on the statistical model, the impact of drug combination versus single drug as well as of reversed order was small with changes in relative recovery of smaller equal 9%. (II) Compared to degassed solutions, relative recovery in carbonated solutions was 23% and 19% lower (relative reduction) in the microdialysis and retrodialysis setting, respectively, with increased intercatheter variability (up to 37%). (III) As expected, relative recovery increased after the flush sequence and was constant 10-15 min after the switch to the typical 1 and 2 µL/min flow rate. Given the intercatheter variability, combinations and the order of drugs showed minor but clinically negligible impact on relative recovery. In contrast, air in the microdialysis catheter/system caused falsely low and inconsistent relative recovery values and must be avoided when performing a trial. Also changes in flow rate at the end of pump flush sequence impacted relative recovery. Hence, a sufficient equilibration time of 10-15 min prior to sampling should be implemented in sampling protocols. In vitro microdialysis presents a highly valuable complementary platform to clinical microdialysis studies impacting the design, sampling schedule and data analysis of such trials to gain knowledge of target-site pharmacokinetics for contributing to better informed decisions in the individual patient/special populations in future.

Quality of compounded hydrocortisone capsules used in the treatment of children.

OBJECTIVES: Due to the lack of paediatric-licensed formulations, children are often treated with individualized pharmacy-compounded adult medication. An international web-based survey about the types of medication in children with adrenal insufficiency (AI) revealed that the majority of paediatric physicians are using pharmacy-compounded medication to treat children with AI. Observations of loss of therapy control in children with congenital adrenal hyperplasia with compounded hydrocortisone capsules and regained control after prescribing a new hydrocortisone batch led to this 'real world' evaluation of pharmacy-compounded paediatric hydrocortisone capsules. METHODS: Capsule samples were collected randomly from volunteering parents of treated children suffering from congenital adrenal hyperplasia from all over Germany. Analysis of net mass and hydrocortisone content by high-performance liquid chromatography with ultraviolet (HPLC-UV) detection method was performed based on the European Pharmacopeia. RESULTS: In a total of 61 batches that were sent, 5 batches could not be analysed because of missing dose information, insufficient number of capsules or were not possible to be evaluated. Fifty-six batches containing 1125 capsules were evaluated. 21.4% of the batches revealed insufficiency in uniformity of net mass or drug content and additional 3.6% failed because they did not contain the labelled drug. CONCLUSIONS: Compounded medication is a possible cause of variation of steroid doses in children with adrenal insufficiency or congenital adrenal hyperplasia, putting these vulnerable patients at risk of poor disease control and adrenal crisis. These data may apply to other individualized compounded oral medication as well, emphasizing the need for development of licensed paediatric formulations approved by regulatory authorities.