Effects, costs and implementation of monitoring kidney transplant patients' tacrolimus levels with dried blood spot sampling: A randomized controlled hybrid implementation trial.

AIMS: Dried blood spot (DBS) home sampling allows monitoring creatinine levels and tacrolimus trough levels as an alternative for blood sampling in the hospital, which is important in kidney transplant patient follow-up. This study aims to assess whether DBS home sampling results in decreased patient travel burden and lower societal costs. METHODS: In this single-centre randomized controlled hybrid implementation trial, adult kidney transplant patients were enrolled. The intervention group (n = 25) used DBS home sampling on top of usual care in the first 6 months after transplantation. The control group (n = 23) received usual care only. The primary endpoint was the number of outpatient visits. Other endpoints were costs per patient, patient satisfaction and implementation. RESULTS: There was no statistically significant difference in the average number of outpatient visits between the DBS group (11.2, standard deviation: 1.7) and the control group (10.9, standard deviation: 1.4; P = .48). Average costs per visit in the DBS group were not significantly different (€542, 95% confidence interval €316-990) compared to the control group (€533, 95% confidence interval €278-1093; P = .66). Most patients (n = 19/23, 82.6%) were willing to perform DBS home-sampling if this would reduce the number of hospital visits. Only 55.9% (n = 143/256) of the expected DBS samples were received and 1/5 analysed on time (n = 52/256). CONCLUSION: Adult kidney transplant patients are willing to perform DBS home sampling. However, to decrease patient travel burden and costs in post-transplant care, optimization of the logistical process concerning mailing and analysis of DBS samples is crucial.

Postmortem redistribution of cocaine and its metabolites, benzoylecgonine and ecgonine methyl ester in humans: Important variables that might be influencing the central blood / peripheral blood ratio.

INTRODUCTION: A big challenge in forensic toxicology is the correct interpretation of the results of quantitative analyses in postmortem cases. Postmortem drug concentrations not necessarily reflect the drug concentrations at the time of death, due to postmortem changes in drug concentrations caused by postmortem redistribution (PMR). Cardiac blood is more prone to PMR related concentration changes than peripheral blood. Because of this difference in susceptibility to PMR related concentration changes, the ratio of cardiac blood concentration/peripheral blood concentration (C/P) of a drug is an often-used marker of PMR. In this study, we investigated the relationship between different potentially significant variables and the C/P ratios of cocaine, benzoylecgonine (BE) and ecgonine methyl ester (EME) in humans. The aim was to elucidate the mechanisms involved in PMR of these substances and potentially provide guidelines aiding forensic toxicologists in the interpretation of postmortem quantitative results of cocaine and its metabolites. To differentiate between postmortem concentration changes due to redistribution versus degradation of cocaine, the relationships between these variables and metabolite/cocaine ratios were investigated as well. METHOD: Toxicological results of all postmortem cases that were positive for cocaine, BE and/or EME investigated by the Netherlands Forensic Institute between January 1st 2010 and July 31st 2020 were reviewed. The C/P ratios, BE/cocaine ratios and EME/cocaine ratios were determined for all selected cases. Cocaine, BE and/or EME were quantified in both femoral blood and cardiac blood in a total of 148 cases. Ratios were compared between subgroups by performing either a Mann-Whitney U test or a Kruskal-Wallis test followed by post-hoc Mann-Whitney U test. RESULTS: A statistically significant difference in C/P ratio of EME was observed between trauma and non-trauma cases with median C/P ratios of 2.03 and 1.57, respectively (p value=0.001). A statistically significant difference in EME/cocaine ratio was observed between the BMI subgroups 18.5 - 25.0 kg/m2 and> 25 kg/m2 with median EME/cocaine ratios of 3.79 and 1.58, respectively (p-value<0.001). CONCLUSION: Postmortem cocaine concentrations should be interpreted with caution, considering the occurrence of both PMR and postmortem degradation. When interpreting postmortem toxicological results in cocaine-related fatalities, it might prove useful to take the above-mentioned variables into account.

Postmortem redistribution of amphetamines and benzodiazepines in humans: Important variables that might be influencing the central blood / peripheral blood ratio.

INTRODUCTION: The primary objective of postmortem forensic toxicology is to determine if toxicological substances detected in bodily material of victims have contributed to the death of the victim. Interpretation of postmortem drug concentrations is hindered by the fact that time and site dependent variations in postmortem drug concentrations occur, as a result of postmortem redistribution (PMR). An often-used marker for the occurrence of PMR, is the cardiac blood concentration/peripheral blood concentration ratio (C/P ratio) of a drug. In this study, we investigated the relationship between 13 variables and the C/P ratios of amphetamines and benzodiazepines. METHOD: Toxicological results of all postmortem cases that were positive for amphetamines (amphetamine, MDMA, MDA) and/or benzodiazepines (diazepam, desmethyldiazepam, temazepam, oxazepam, midazolam, α-hydroxymidazolam) investigated by the Netherlands Forensic Institute between January 1 2010 and July 31 2020 were reviewed. A total of 112 amphetamine positive cases (224 paired specimen) and 179 benzodiazepine positive cases (358 paired specimen) were selected. The C/P ratios were determined for all selected cases. Ratios were compared between subgroups by performing either a Mann-Whitney U test or a Kruskal-Wallis test followed by post-hoc Mann-Whitney U test. RESULTS: After dividing cases in quartiles based on their amphetamine concentration in femoral blood, the amphetamine C/P ratio was significantly lower in cases with a high amphetamine concentration (quartile 4) compared to cases with a low amphetamine concentration (quartiles 1 and 2) with median C/P ratios of 1.6, 2.4 and 2.2, respectively (p-value<0.001 and p-value=0.001, respectively). The MDA C/P ratio was significantly higher in cases where trauma was the cause of death compared to cases where intoxication was the cause of death with median C/P ratios of 3.3 and 1.6, respectively (p-value<0.001). The MDA C/P ratio was also significantly lower in cases where resuscitation was attempted compared to cases where no resuscitation was attempted with median C/P ratios of 1.6 and 2.4, respectively (p-value=0.003). However, a significant dependency between the variables cause of death and attempted resuscitation was observed. No significant differences in benzodiazepine C/P ratios were observed between subgroups of any of the investigated variables. However, the low p-value of BMI suggests a potential difference in midazolam C/P ratio between BMI subgroups (p-value=0.027). CONCLUSION: When interpreting postmortem toxicological results, it might prove useful to take the above-mentioned variables into account.

Postmortem redistribution of morphine in humans: Important variables that might be influencing the central blood/peripheral blood ratio.

INTRODUCTION: In the field of forensic toxicology, many unexpected deaths are investigated as to whether toxicological substances may have caused or contributed to someone's death. One of the factors that makes interpretation of the results of quantitative analysis in postmortem toxicology challenging, is that measured postmortem drugs levels may vary according to the sampling site and the interval between death and specimen collection. These site- and time-dependent variations are caused by 'postmortem redistribution' (PMR). Literature shows that there are several factors that determine the degree of PMR, such as cell and tissue changes after death, decomposition and the physicochemical characteristics of drugs. Blood from peripheral sites seems to be less affected by PMR than cardiac blood. Therefore, the ratio of cardiac blood concentration/peripheral blood concentration (C/P) of a drug is often used as a marker of the extent of postmortem redistribution. In this study, we investigated the relationship between different potentially important variables and the C/P ratio of morphine in humans in order to provide new insights that might assist in the interpretation of quantitative results in forensic casework. METHOD: Toxicological results of all morphine positive postmortem cases investigated by the Netherlands Forensic Institute between January 1, 2010 and July 31, 2020 were reviewed. Morphine was quantified in both femoral and cardiac blood in a total of 103 cases. The C/P ratios were determined for all selected cases. To collect data for this study, all corresponding files were reviewed. C/P ratios were compared between subgroups by performing either a Mann-Whitney U test or a Kruskal-Wallis test, followed by a post-hoc Mann-Whitney U test. Bonferroni correction was performed to correct for the likelihood of a significant result by chance due to multiple testing. After Bonferroni correction, a p-value< 0.004 was considered statistically significant. RESULTS: The data suggests a relationship between grade of decomposition at autopsy, position of the corpse at discovery, route of administration, attempted resuscitation and the C/P ratio of morphine with p-values of 0.010, 0.026, 0.035 and 0.046, respectively. CONCLUSION: Grade of decomposition at autopsy, position of the corpse at discovery, route of administration and attempted resuscitation seem to be influencing the C/P ratio of morphine. Of these four variables, the route of administration seems to have the greatest impact.

Fosfomycin: Pharmacological, Clinical and Future Perspectives.

Fosfomycin is a bactericidal, low-molecular weight, broad-spectrum antibiotic, with putative activity against several bacteria, including multidrug-resistant Gram-negative bacteria, by irreversibly inhibiting an early stage in cell wall synthesis. Evidence suggests that fosfomycin has a synergistic effect when used in combination with other antimicrobial agents that act via a different mechanism of action, thereby allowing for reduced dosages and lower toxicity. Fosfomycin does not bind to plasma proteins and is cleared via the kidneys. Due to its extensive tissue penetration, fosfomycin may be indicated for infections of the CNS, soft tissues, bone, lungs, and abscesses. The oral bioavailability of fosfomycin tromethamine is <50%; therefore, oral administration of fosfomycin tromethamine is approved only as a 3-gram one-time dose for treating urinary tract infections. However, based on published PK parameters, PK/PD simulations have been performed for several multiple-dose regimens, which might lead to the future use of fosfomycin for treating complicated infections with multidrug-resistant bacteria. Because essential pharmacological information and knowledge regarding mechanisms of resistance are currently limited and/or controversial, further studies are urgently needed, and fosfomycin monotherapy should be avoided.