Invasive fungal infections (IFIs) are a significant cause of morbidity and mortality in de-novo acute myeloid leukemia patients receiving induction chemotherapy. Despite using posaconazole, a broad-spectrum antifungal, for IFI prophylaxis, the breakthrough IFI rate is high in the real-world setting. One of the reasons could be frequent suboptimal plasma posaconazole levels. In the present study, we evaluated if therapeutic drug monitoring (TDM) guided posaconazole prophylaxis can reduce the IFI rates in comparison to a historical cohort. We enrolled 90 patients, > / = 16 years of age, without baseline IFIs, planned for remission induction therapy. All patients were started on posaconazole suspension 200 mg TDS and the dose was increased in a stepwise manner if trough levels were found to be suboptimal (< 350 ng/ml for day 2 or < 700 ng/ml subsequently). The TDM based approach resulted in a significant decline in breakthrough IFI rates (18% versus 52%, P < 0.0001) A total of 69 patients (78%) required dose escalation. Thirty-one patients required change in antifungals due to either suboptimal levels, persistent fever, diarrhoea or vomiting. We could not demonstrate an exposure-response relationship but the difference in IFI rates in patients with a median posaconazole level > / = 700 ng/ml (0%) and < 700 ng/ml (21.6%) was clinically meaningful. Posaconazole levels were found to be significantly lower in patients on antacids and prokinetics. The incidence of posaconazole-related grade 3 toxicity was low (2.3%). Thus TDM-based dosing of posaconazole helps reduce breakthrough IFI rate and should be a part of posaconazole prophylaxis.
UNASSIGNED: The online version contains supplementary material available at 10.1007/s12288-023-01709-3.

Understanding the pharmacokinetics of gentamicin is essential in special populations, such as pediatric patients with acute lymphoblastic leukemia (ALL), in light of previous studies indicating that ALL patients have a lower volume of distribution than non-ALL patients. Furthermore, validation of such results is needed to ensure their clinical application. Accordingly, this single-center, retrospective, cross-sectional study compares the pharmacokinetic parameters of volume of distribution and clearance (Cl) of gentamicin between ALL and non-ALL patients. Inclusion criteria were pediatric patients aged between 1 and 14 years with or without ALL and receiving intravenous gentamicin for treatment courses > 72 h. Patients\' characteristics, such as age, sex, height, serum albumin, diagnosis, serum creatinine (Scr) concentration, dosing, and pharmacokinetic information, including peak and trough concentrations, were retrieved. The study scrutinized a total of 115 pediatric patients, comprising toddlers (15.7 %), children (76.5 %), and adolescents (7.8 %). All patients received gentamicin every 8 h, with an average dose of 2.50 (0.64) mg/kg. Patients were divided into two groups based on disease state, with 45.2 % (n = 52) in the non-ALL group and 54.8 % (n = 63) in the ALL group. Both groups had similar characteristics in terms of gender, weight, body surface area, and dose. The only significant covariates identified were weight and creatinine clearance (Clcr) for volume of distribution (Vd). A significant difference was found in Scr, Clcr, and blood urea nitrogen (BUN); however, no significant difference between ALL and non-ALL patients emerged in the volume of distribution or Cl. In conclusion, the study findings indicate that dosing requirements were similar between the two groups. Further prospective studies with larger sample sizes are warranted.

Background: Inflammatory bowel disease (IBD), encompassing ulcerative colitis and Crohn\'s disease, necessitates long-term medical therapy to manage symptoms and prevent complications. Therapeutic drug monitoring (TDM) has emerged as a strategy to optimize treatment efficacy, particularly with anti-tumour necrosis factor (anti-TNF) alpha drugs. This review explores the role of TDM for non-anti-TNF advanced therapies in IBD, focusing on vedolizumab, ustekinumab, tofacitinib, upadacitinib, risankizumab and ozanimod. Methods: The literature search, conducted through OVID (Medline) and PubMed, delves into proactive versus reactive TDM, timing of monitoring and methods for measuring drug levels and anti-drug antibodies. Results: While ustekinumab and vedolizumab exhibit exposure-response relationships, consensus on target levels and the role of TDM adjustments remains elusive. Limited data on risankizumab suggest a dose-dependent response, while for small molecule therapies (janus kinase inhibitors and ozanimod), the absence of real-world data and commercially available TDM tools pose challenges. Conclusion: At present, with the available data, there is a limited role for TDM in non-anti-TNF biologic and small-molecule therapies. This review underscores the need for further research to delineate the utility of TDM in guiding treatment decisions for these agents.

In this study, we assess healthcare providers\' adherence to therapeutic drug monitoring (TDM) guidelines for gentamicin in neonates. Conducted at the Maternity and Children\'s Hospital in Makkah, Saudi Arabia, from July 2020 to July 2022, it retrospectively analyzed the compliance of healthcare workers in managing neonates treated with gentamicin. Covering 410 neonates, primarily diagnosed with respiratory distress (56%) and sepsis (32%), the study revealed that while a majority of trough and peak levels conformed to guidelines, substantial deviations were noted in cases of respiratory distress. This underlines the necessity for targeted TDM strategies, particularly in managing respiratory distress in neonates, to ensure optimal treatment efficacy and safety. The findings urge stringent compliance with TDM guidelines, emphasizing personalized approaches in neonatal gentamicin therapy for improved healthcare outcomes.

Meropenem, linezolid, fluconazole, voriconazole, posaconazole, and vancomycin are six important antimicrobials used for severe infections in critically ill patients listed in special-grade antimicrobials in China. The six antimicrobials\' highly variable pharmacodynamics and pharmacokinetics in critically ill pediatric patients present significant challenges to clinicians in ensuring optimal therapeutic targets. Therefore, therapeutic drug monitoring of these antimicrobials in human plasma is necessary to obtain their plasma concentration. A rapid, simple, and sample-saving high-performance liquid chromatography-tandem mass spectrometry (HPLC-MS/MS) method was developed, which could simultaneously determine all six antimicrobials. It required only 10 μL of plasma and a one-step protein precipitation process. Chromatographic separation was achieved on a reversed-phase column (C18, 30 × 2.1 mm, 2.6 μm) via gradient elution using water and acetonitrile containing 0.1 % formic acid as mobile phase. The injection volume was 2 μL, and the total run time was only 2.5 min. Detection was done using a Triple Quad™ 4500MD tandem mass spectrometer coupled with an electrospray ionization (ESI) source in positive mode. The calibration curves ranged from 0.5 to 64 μg/mL for meropenem and fluconazole, 0.2-25.6 μg/mL for linezolid and voriconazole, 0.1-12.8 μg/mL for posaconazole and 1-128 μg/mL for vancomycin, with the coefficients of correlation all greater than 0.996. Furthermore, the method was validated rigorously according to the European Medicines Agency (EMA) guidelines, demonstrating excellent accuracy (from 93.0 % to 110.6 %) and precision (from 2.0 % to 12.8 %). Moreover, its applicability to various matrices (including serum, hemolytic plasma, and hyperlipidemic plasma) was evaluated. Thus, this method was successfully applied to routine therapeutic drug monitoring for critically ill pediatric patients and other patients in need.

UNASSIGNED: This study aimed to compare individual pharmacokinetic (PK) parameters of vancomycin with predicted values from five population PK models in patients with diabetic foot infections (DFIs).
UNASSIGNED: Patients with a diagnosis of DFI and an estimated glomerular filtration rate (eGFR) ≥ 30 mL/min were included in the study. Individual PK data was carried on by collecting three vancomycin serum concentrations in a steady-state condition. Five published population-based nomograms were assumed to predict PK parameters. Optimal vancomycin exposure was considered as a trough level of 15-20 mg/L or the area under the curve over 24 h/minimum inhibitory concentration (AUC24/MIC) ≥ 400.
UNASSIGNED: A total of 48 samples from 16 patients were analyzed. There was a statistically significant difference between the volume of distribution (Vd) obtained from population methods and the individual estimations (P ≤ 0.001 in Ambrose and Burton, P = 0.010 and 0.006 in Bauer and Burton revised models, respectively). AUC/MIC ≥ 400 was achieved in 68.7% of patients while 50% had a trough level of less than 15 mg/L.
UNASSIGNED: Vancomycin PK parameters, particularly individualized Vd, may not be predictable by population nomograms in patients with DFI and stable renal function. Moreover, the weak correlation between AUC24 values and trough concentrations underlines the starting practice of vancomycin AUC24-based monitoring and dosing in the clinical setting.

For several, also vital medications, such as immunosuppressants in solid organ and hematopoietic stem cell transplantation, therapeutic drug monitoring (TDM) remains the only strategy for fine-tuning the dosage to the individual patient. Especially in severe clinical complications, the intraindividual condition of the patient changes abruptly, and in addition, drug-drug interactions (DDIs) can significantly impact exposure, due to concomitant medication alterations. Therefore, a single TDM value can hardly be the sole basis for optimal timely dose adjustment. Moreover, every intraindividually varying situation that affects the drug exposure needs synoptic consideration for the earliest adjustment. To place the TDM value in the context of the patient\'s most detailed current condition and concomitant medications, the Individual Pharmacotherapy Management (IPM) was implemented in the posttransplant TDM of calcineurin inhibitors assessed by the in-house laboratory. The first strategic pillar are the defined patient scores from the electronic patient record. In this synopsis, the Summaries of Product Characteristics (SmPCs) of each drug from the updated medication list are reconciled for contraindication, dosing, adverse drug reactions (ADRs), and DDIs, accounting for defined medication scores as a second pillar. In parallel, IPM documents the resulting review of each TDM value chronologically in a separate electronic Excel file throughout each patient\'s transplant course. This longitudinal overview provides a further source of information at a glance. Thus, the applied two-arm concept of TDM and IPM ensures an individually tailored immunosuppression in the severely susceptible early phase of transplantation through digital interdisciplinary networking, with instructive and educative recommendations to the attending physicians in real-time. This concept of contextualizing a TDM value to the precise patient\'s condition and comedication was established at Halle University Hospital to ensure patient, graft, and drug safety.

Background: Extracorporeal therapies (ET) are increasingly used in pediatric settings as adjuvant therapeutic strategies for overwhelming inflammatory conditions. Although these treatments seem to be effective for removing inflammatory mediators, their influence on antimicrobials pharmacokinetic should not be neglected. Methods: A prospective observational study of children admitted to the pediatric intensive care unit (PICU) with a diagnosis of sepsis/septic shock. All critically ill children received hemoadsorption treatment with CytoSorb (CS) in combination with CKRT. Therapeutic drug monitoring has been performed on 10 critically ill children, testing four antimicrobial molecules: meropenem, ceftazidime, amikacin and levofloxacin. In order to evaluate the total and isolated CKRT and CS contributions to antibiotic removal, blood samples at each circuit point (post-hemofilter, post-CS and in the effluent line) were performed. Therefore, the clearance and mass Removal (MR) of the hemofilter and CS were calculated. Results: Our preliminary report describes a different impact of CS on these target drugs removal: CS clearance was low for amikacine (6-12%), moderate for ceftazidime (43%) and moderate to high for levofloxacine (52-72%). Higher MR and clearance were observed with CKRT compared to CS. To the best of our knowledge, this is the first report regarding pharmacokinetic dynamics in critically ill children treated with CKRT and CS for septic shock.

Clozapine is the most effective drug for treatment-resistant schizophrenia, and the dosage and concentration of clozapine in the treatment of mental illness vary greatly in different populations and are affected by many factors.
The serum clozapine concentration of 3734 psychiatric patients was detected, and data on daily dose, sex, age and other medical records were collected for statistical analysis.
The mean daily dose, mean serum concentration and mean C/D (concentration/dose) ratio of clozapine were 191.02 ± 113.47 mg/day, 326.15 ± 235.66 ng/mL and 1.94 ± 1.25 ng/mL per mg/day, respectively. There was difference in daily dose between sexes, and females had higher daily dose (p <0.01), higher serum clozapine concentrations (p < 0.01) and higher C/D ratios (p < 0.01). There were significant differences in daily dose (p < 0.001), serum drug concentration (p < 0.001) and C/D ratio (p < 0.001) among different age groups. The daily dose decreased with age (p for trend < 0.001), and the C/D ratio increased with age (p for trend < 0.001). Inpatients and outpatients had no difference in daily dose, but inpatients had higher serum concentration (p < 0.001) and C/D ratio (p < 0.001). There was no difference in daily dose among different occupations, but there were significant differences in serum concentration (p < 0.001) and C/D ratio (p < 0.001), and unemployed patients may have higher serum concentration and C/D ratio. Duration of disease, comorbidity, marital status, and psychotic type may influence the daily dose and serum concentration.
The effective daily dose and serum concentration of clozapine in the study area may be lower than recommended levels, and women have higher serum concentrations and slower metabolic rates. With increasing age, the daily dose decreases, and the metabolic rate slows. Inpatient status and occupation of patients may influence the serum concentration and metabolic rate of clozapine.

Objective: This study aimed to investigate the efficacy and tolerability of Lacosamide (LCM) in a pediatric population with epilepsy using LCM serum concentration and its correlation to the age of the participants and the dosage of the drug. Methods: Demographic and clinical data were collected from the medical records of children with epilepsy treated with LCM at Shamir Medical Center between February 2019 to September 2021, in whom medication blood levels were measured. Trough serum LCM concentration was measured in the biochemical laboratory using High-Performance Liquid Chromatography (HPLC) and correlated with the administered weight-based medication dosing and clinical report. Results: Forty-two children aged 10.43 ± 5.13 years (range: 1-18) were included in the study. The average daily dose of LCM was 306.62 ± 133.20 mg (range: 100-600). The average number of seizures per day was 3.53 ± 7.25 compared to 0.87 ± 1.40 before and after LCM treatment, respectively. The mean LCM serum concentration was 6.74 ± 3.27 mg/L. No statistically significant association was found between LCM serum levels and the clinical response (p = 0.58), as well as the correlation between LCM dosage and the change in seizure rate (p = 0.30). Our study did not find a correlation between LCM serum concentration and LCM dosage and the gender of the participants: males (n = 17) females (n = 23) (p = 0.31 and p = 0.94, respectively). A positive trend was found between age and LCM serum concentrations (r = 0.26, p = 0.09). Conclusion: Based on the data that has been obtained from our study, it appears that therapeutic drug monitoring for LCM may not be necessary. Nonetheless, further research in this area is needed in the light of the relatively small sample size of the study.