Assessing methods of measuring medication adherence in chronically ill children-a narrative review

Nonadherence in children who use long-term medication is a serious problem and assessing adherence is an important step to provide solutions to this problem. Medication adherence can be measured by several methods, including (a) self-report questionnaires or structured interviews, (b) therapeutic drug monitoring (TDM), (c) electronic devices, and (d) pick-up/refill rates. The objective of this narrative review is to provide an overview of the literature about methods for the measurement of medication adherence in chronically ill children and adolescents. Therefore, we conducted a literature search by using multiple databases. Four methods of monitoring medication adherence are presented for the most described chronic diseases: asthma, HIV/AIDS, epilepsy, diabetes mellitus and ADHD. First, 10 commonly used self-report questionnaires and structured interviews are described, including the main characteristics, (dis)advantages and their validation studies. Second, the use of TDM in pediatric trials for medication adherence measurement is discussed. New sampling methods (e.g. dried blood spot) and sampling matrices (e.g. hair, saliva and urine) have shown their benefits for TDM in children. Third, electronic devices to measure medication adherence in children are presented, being developed for several drug administration routes. Fourth, the analyses, advantages and disadvantages of pharmacy data are discussed. The usage of this data requires specific calculations and interpretations to assess adherence. As presented in this review, every adherence method has specific (dis)advantages. When deciding which adherence method is applicable, validity and generalizability should be taken into account. Combining multiple methods seems to offer the best solution in the daily clinical practice

Pregnancy related pharmacokinetics and antimicrobial prophylaxis during fetal surgery, cefazolin and clindamycin as examples

Antimicrobial prophylaxis during surgery aims to prevent post-operative site infections. For fetal surgery, this includes the fetal and amniotic compartments. Both are deep compartments as drug equilibrium with maternal blood is achieved relatively late. Despite prophylaxis, chorio-amnionitis or endometritis following ex utero intrapartum treatment or fetoscopy occur in 4.13% and 1.45% respectively of the interventions. This review summarizes the observations on two commonly administered antimicrobials (cefazolin, clindamycin) for surgical prophylaxis during pregnancy, with emphasis on the deep compartments. For both compounds, antimicrobial exposure is on target when we consider the maternal and fetal plasma compartment. In contrast, amniotic fluid concentrations-time profiles display a delayed and much more blunted pattern, behaving as deep compartment. For cefazolin, there are data that document further dilution in the setting of polyhydramnios. Along this deep compartment concept, there is some accumulation during repeated administration, modeled for cefazolin and observed for clindamycin. The relative underexposure to antimicrobials in amniotic fluid may be reflected in the pattern of maternal-fetal complications after fetal surgery, and suggest that antimicrobial prophylaxis practices for fetal surgery should be reconsidered. Further studies should be designed by a multidisciplinary team (fetal surgeons, clinical pharmacologists and microbiologists) to facilitate efficient evaluation of antimicrobial prophylaxis

Assessing methods of measuring medication adherence in chronically ill children-a narrative review

Nonadherence in children who use long-term medication is a serious problem and assessing adherence is an important step to provide solutions to this problem. Medication adherence can be measured by several methods, including (a) self-report questionnaires or structured interviews, (b) therapeutic drug monitoring (TDM), (c) electronic devices, and (d) pick-up/refill rates. The objective of this narrative review is to provide an overview of the literature about methods for the measurement of medication adherence in chronically ill children and adolescents. Therefore, we conducted a literature search by using multiple databases. Four methods of monitoring medication adherence are presented for the most described chronic diseases: asthma, HIV/AIDS, epilepsy, diabetes mellitus and ADHD. First, 10 commonly used self-report questionnaires and structured interviews are described, including the main characteristics, (dis)advantages and their validation studies. Second, the use of TDM in pediatric trials for medication adherence measurement is discussed. New sampling methods (e.g. dried blood spot) and sampling matrices (e.g. hair, saliva and urine) have shown their benefits for TDM in children. Third, electronic devices to measure medication adherence in children are presented, being developed for several drug administration routes. Fourth, the analyses, advantages and disadvantages of pharmacy data are discussed. The usage of this data requires specific calculations and interpretations to assess adherence. As presented in this review, every adherence method has specific (dis)advantages. When deciding which adherence method is applicable, validity and generalizability should be taken int

Clinical applications of population pharmacokinetic models of antibiotics: Challenges and perspectives

Because of increasing antimicrobial resistance and the shortage of new antibiotics, there is a growing need to optimize the use of old and new antibiotics. Modelling of the pharmacokinetic/pharmacodynamic (PK/PD) characteristics of antibiotics can support the optimization of dosing regimens. Antimicrobial efficacy is determined by susceptibility of the drug to the microorganism and exposure to the drug, which relies on the PK and the dose. Population PK models describe relationships between patients characteristics and drug exposure. This article highlights three clinical applications of these models applied to antibiotics: 1) dosing evaluation of old antibiotics, 2) setting clinical breakpoints and 3) dosing individualization using therapeutic drug monitoring (TDM). For each clinical application, challenges regarding interpretation are discussed. An important challenge is to improve the understanding of the interpretation of modelling results for good implementation of the dosing recommendations, clinical breakpoints and TDM advices. Therefore, also background information on PK/PD principles and approaches to analyse PK/PD data are provided

Simultaneous quantification of fentanyl, sufentanil, cefazolin, doxapram and keto-doxapram in plasma using liquid chromatography–tandem mass spectrometry

A simple and specific UPLC–MS/MS method was developed and validated for simultaneous quantification of fentanyl, sufentanil, cefazolin, doxapram and its active metabolite keto-doxapram. The internal standard was fentanyl-d5 for all analytes. Chromatographic separation was achieved with a reversed-phase Acquity UPLC HSS T3 column with a run-time of only 5.0 min per injected sample. Gradient elution was performed with a mobile phase consisting of ammonium acetate or formic acid in Milli-Q ultrapure water or in methanol with a total flow rate of 0.4 mL min−1. A plasma volume of only 50 μL was required to achieve adequate accuracy and precision. Calibration curves of all five analytes were linear. All analytes were stable for at least 48 h in the autosampler. The method was validated according to US Food and Drug Administration guidelines. This method allows quantification of fentanyl, sufentanil, cefazolin, doxapram and keto-doxapram, which is useful for research as we

A clinically relevant pharmacokinetic interaction between cyclosporine and imatinib

Purpose: Cyclosporine A (CsA) and imatinib are both CYP3A4 and P-glycoprotein substrates. Concomitant use after hematopoietic stem cell transplantation (HSCT) for chronic myeloid leukemia (CML) or Philadelphia chromosome-positive (Ph+) acute lymphatic leukemia (ALL) may therefore result in a pharmacokinetic interaction. Although case reports and a recent small study in children indeed suggested there is a relevant pharmacokinetic interaction, a larger study in adults is lacking. In this study, we assessed the presence and extent of this interaction in patients with CML or Ph+ ALL undergoing HSCT. Methods: From a large database containing data of all patients receiving HSCT in our center between 2005 and 2015, we selected 16 patients using this drug combination. The average dose-corrected CsA concentration was calculated before and after initiation of imatinib. Results: The average dose-corrected CsA concentration increased during imatinib use in all patients, on average by 94 % (p < 0.001). Based on measured drug con

The effectiveness of nitrofurantoin, fosfomycin and trimethoprim for the treatment of cystitis in relation to renal function

Objectives: We evaluated the effect of renal function on clinical failure rates of nitrofurantoin, fosfomycin and trimethoprim for the treatment of cystitis in primary care. Methods: Data were retrospectively obtained from 78 Dutch general practitioner (GP) practices between 2013 and 2019. Eligible episodes in patients (>11 years) were those requiring 5 days of nitrofurantoin (NF5), single-dose fosfomycin–trometamol (FT1), 3 days of trimethoprim (TMP3) for uncomplicated cystitis, or 7 days of nitrofurantoin (NF7) or trimethoprim (TMP7) for complicated cystitis. Clinical failure was defined as second antibiotic prescription for cystitis or pyelonephritis within 28 days post-prescription. Mixed effects regression analysis was used, with patient and GP practice as random effects and demography, comorbidity, and cystitis history as fixed effects. Results: Adjusted odds ratios (aORs) for clinical failure per 10mL/min decrease in estimated glomerular filtration rate (eGFR) were 1.05 (95% CI: 1.01–1.09) for NF5 (n = 24,591), 0.96 (95% CI: 0.92–1.01) for FT1 (n = 5359), 0.98 (95% CI: 0.89–1.08) for TMP3 (n = 1064), 1.05 (95% CI: 1.02–1.09) for NF7 (n = 10,628) and 1.02 (95% CI: 0.93–1.14) for TMP7 (n = 831). In uncomplicated cystitis and eGFR ≥60 mL/min, clinical failures occurred in 14.6% (1895/12 980) of NF5-treated, 20.7% (266/1283) of FT1-treated (aOR versus NF5 1.37, 95% CI 1.18–1.59) and 20.8% (66/318) of TMP3-treated patients (aOR 1.42, 95% CI 1.07–1.87 versus NF5). In uncomplicated cystitis and eGFR <60 mL/min, FT1 resulted in 16.0% (39/244) and NF5 in 23.3% clinical failures (110/472), aOR: 0.61, 95% CI: 0.39–0.95). Conclusions: In eGFR ≥60 mL/min treatment with fosfomycin or trimethoprim for uncomplicated cystitis was associated with more clinical failure than treatment with nitrofurantoin, while in eGFR <60 mL/min nitrofurantoin was associated with more clinical failure than fosfomycin–trometamol. Renal function, if known, should be considered in the clinical decision-making for cystitis treatment