Saturable elimination of piperacillin in critically ill patients: implications for continuous infusion.

The study aimed to evaluate saturation of piperacillin elimination in critically ill adult patients. Seventeen critically ill adult patients received continuous and intermittent infusion of piperacillin/tazobactam. Piperacillin plasma concentrations (n = 217) were analysed using population pharmacokinetic (PopPK) modelling. Post-hoc simulations were performed to evaluate the type I error rate associated with the study. Unseen data were used to validate the final model. The mean error (ME) and root mean square error (RMSE) were calculated as a measure of bias and imprecision, respectively. A PopPK model with parallel linear and non-linear elimination best fitted the data. The median and 95% confidence interval (CI) for the model parameters drug clearance (CL), volume of central compartment (V), volume of peripheral compartment (Vp) and intercompartmental clearance (Q) were 9 (7.69-11) L/h, 6.18 (4.93-11.2) L, 11.17 (7.26-12) L and 15.61 (12.66-23.8) L/h, respectively. The Michaelis-Menten constant (Km) and the maximum elimination rate for Michaelis-Menten elimination (Vmax) were estimated without population variability in the model to avoid overfitting and inflation of the type I error rate. The population estimates for Km and Vmax were 37.09 mg/L and 353.57 mg/h, respectively. The bias (ME) was -20.8 (95% CI -26.2 to -15.4) mg/L, whilst imprecision (RMSE) was 49.2 (95% CI 41.2-56) mg/L. In conclusion, piperacillin elimination is (partially) saturable. Moreover, the population estimate for Km lies within the therapeutic window and therefore saturation of elimination should be accounted for when defining optimum dosing regimens for piperacillin in critically ill patients.

Measuring antibiotics in exhaled air in critically ill, non-ventilated patients: A feasibility and proof of concept study.

PURPOSE: Measurement of antibiotic concentrations is increasingly used to optimize antibiotic therapy. Plasma samples are typically used for this, but other matrices such as exhaled air could be an alternative. MATERIALS AND METHODS: We studied 11 spontaneously breathing intensive care unit patients receiving either piperacillin/tazobactam or meropenem. Patients exhaled in the ExaBreath® device, from which the antibiotic was extracted. The presence of antibiotics was also determined in the condensate found in the device and in the plasma. RESULTS: Piperacillin or meropenem could be detected in the filter in 9 patients and in the condensate in 10. Seven patients completed the procedure as prescribed. In these patients the median quantity of piperacillin in the filter was 3083 pg/filter (range 988-203,895 pg/filter), and 45 pg (range 6-126 pg) in the condensate; meropenem quantity was 21,168 pg/filter, but the quantity in the condensate was below the lower limit of quantification. There was no correlation between the concentrations in the plasma and quantities detected in the filter or condensate. CONCLUSIONS: Piperacillin and meropenem can be detected and quantified in exhaled air of non-ventilated intensive care unit patients; these quantities did not correlate with plasma concentrations of these drugs.

Hair cortisol in relation to job stress and depressive symptoms.

BACKGROUND: Measurement of hair cortisol concentration (HCC) may be used as a biomarker for chronic stress. However, the association between stress and HCC has rarely been investigated in a working population. AIMS: To explore associations between (i) HCC and various stress measures and (ii) HCC and symptoms of depression in Belgian workers. METHODS: Hair samples were collected from workers in two production companies and cortisol content was determined by liquid chromatography tandem mass spectrometry. Participants completed a questionnaire including socio-demographics, health behaviours and standardized measures for assessing stress. RESULTS: After excluding those workers suffering from a psychiatric or neuroendocrine disease and those treated with glucocorticoids, there were a total of 102 workers with both questionnaire, cortisol results and anthropometric measures. Median HCC was 5.73 pg/mg hair (interquartile range = 4.52-9.06). No significant associations were found between cortisol and the standardized measures related to several work psychosocial risk factors. A significantly lower mean HCC was found in shift workers compared with dayworkers, adjusted for age. Additionally, a significant higher mean HCC was found in workers with symptoms of depression compared with those without symptoms of depression, after adjustment for age. CONCLUSIONS: HCC showed a limited applicability as a biomarker for job stress in this sample, although the results suggest this method may be a suitable marker for detecting early symptoms of depression. Further research is needed to investigate the applicability of HCC in the working environment and within job stress research.

How appropriate is therapeutic drug monitoring for lithium? Data from the Belgian external quality assessment scheme.

BACKGROUND: Lithium remains a mainstay in the management of mood disorders. As with many psychotropic drugs, lithium treatment requires continuous observation for adverse effects and strict monitoring of serum concentrations. The present study aimed to assess the appropriateness of lithium assays used by Belgian laboratories, and to evaluate acceptability of their clinical interpretations. METHODS: Nine in-house serum samples spiked with predetermined concentrations of lithium were distributed to 114 participants in the Belgian external quality assessment scheme. Laboratories were requested to report the assay technique, lithium measurements and interpretations with regard to measured concentrations. Inter/intramethod imprecision and bias were reported and acceptability of clinical interpretations was assessed. The intramethod variability was evaluated by selecting methods used by 6 laboratories or more. Flame photometry (IL 943) was considered as the reference method. RESULTS: Laboratories returned assay results using colorimetry (69.3%), ion selective electrode (15.8%), flame photometry (8.8%), atomic absorption spectroscopy (5.2%) or mass spectrometry (0.9%). Lithium concentrations were systematically higher when measured with the Vitros assay (median bias: 4.0%), and were associated with consecutive biased interpretations. In contrast, the Thermo Scientific Infinity assay showed a significant negative bias (median bias: 9.4%). 36.0% of laboratories reported numerical values below their manufacturer cut-off for the blank sample; 16.6% of these laboratories detected residual lithium concentrations. CONCLUSIONS: The present study revealed assay-related differences in lithium measurements and their interpretations. Overall, there appeared to be a need to continue EQA of therapeutic drug monitoring for lithium in Belgium.

Roadside drug testing: comparison of two legal approaches in Belgium.

BACKGROUND: Internationally, urine on-site testing has been used for detecting drivers under the influence of drugs (DUID) but more and more countries, such as Belgium, are switching to oral fluid screening. OBJECTIVE: To compare the previous (published in 1999) and current (published 2009) enforcement procedures of DUID in Belgium. The two evaluated procedures differ in the way the drivers are screened by the police (signs of impairment versus signs of recent drug use), the matrix for screening (urine versus oral fluid) and the analytical cut-off concentrations in plasma. METHODS: Data on positive screening and confirmation results were gathered from 1st April 2008 to 30th September 2010, when urine screening (Dipro Druglab panels test) was performed; and from 1st October 2010 to 31st March 2013, when an on-site oral fluid test (Securetec Drugwipe 5(+)) was used. RESULTS: Approximately 4100 data sets related to urine screening and 3900 data sets related to oral fluid screening were studied. Eighty-eight percent of positive urine on-site tests yielded positive results in plasma for cannabis, 21% for cocaine, 20% for amphetamines and 7% for opiates. Sixty-six percent of the positive oral fluid on-site tests yielded positive results in plasma for cannabis, 30% for cocaine, 28% for amphetamines and 8% for opiates. For cannabis, opiates and amphetamines more negative results in plasma were observed in the period of urine screening. CONCLUSIONS: The percentage of plasma samples of tested drivers, in which none of the positive screened target drugs were present in a concentration above the legal cut-off value, has decreased from 17% to 8% since the introduction of the current legislation involving oral fluid screening.

Stability of generic brands of meropenem reconstituted in isotonic saline.

BACKGROUND: Meropenem is a relatively unstable compound when dissolved. Currently, all available data have been derived from tests on the original product from Astrazeneca, and it is unsure if these data can be extrapolated to the stability of other commercially available vials. The aim of this study was therefore to assess the stability of four different brands of meropenem to be used as a prolonged or continuous infusion. METHODS: Commercially available meropenem vials were reconstituted and mixed with 0.9% sodium chloride to produce solutions with concentrations of 10.20 and 40 mg/mL in polypropylene syringes, which were kept at 25 °C. Samples were taken immediately after preparation and up to 12 hours. Solutions retaining >90% of the initial concentration were considered stable. RESULTS: The stability was concentration-dependent. At 25 °C, all 10 and 20 mg/mL solutions were stable for 12 hours in 0.9% sodium chloride, while the 40 mg/mL solutions were stable for a maximum of 8 hours. Stability of the different vials of meropenem was comparable for the time period tested (related samples Friedman's two way of analysis of variance by ranks, P=0.282). CONCLUSION: All tested commercially available vials of meropenem in a concentration of 10 and 20 mg/mL were stable for 12 hours at 25 °C when diluted in 0.9% sodium chloride. The 40 mg/mL solutions were stable for a maximum of 8 hours. This report is the first to show equivalent stability between different commercially available vials of meropenem.

Therapeutic drug monitoring-based dose optimisation of piperacillin and meropenem: a randomised controlled trial.

PURPOSE: There is variability in the pharmacokinetics (PK) of antibiotics (AB) in critically ill patients. Therapeutic drug monitoring (TDM) could overcome this variability and increase PK target attainment. The objective of this study was to analyse the effect of a dose-adaption strategy based on daily TDM on target attainment. METHODS: This was a prospective, partially blinded, and randomised controlled trial in patients with normal kidney function treated with meropenem (MEM) or piperacillin/tazobactam (PTZ). The intervention group underwent daily TDM, with dose adjustment when necessary. The predefined PK/pharmacodynamic (PK/PD) target was 100% fT>4MIC [percentage of time during a dosing interval that the free (f) drug concentration exceeded 4 times the MIC]. The control group received conventional treatment. The primary endpoint was the proportion of patients that reached 100% fT>4MIC and 100 % fT>MIC at 72 h. RESULTS: Forty-one patients (median age 56 years) were included in the study. Pneumonia was the primary infectious diagnosis. At baseline, 100% fT>4MIC was achieved in 21% of the PTZ patients and in none of the MEM patients; 100% fT>MIC was achieved in 71% of the PTZ patients and 46 % of the MEM patients. Of the patients in the intervention group, 76 % needed dose adaptation, and five required an additional increase. At 72 h, target attainment rates for 100% fT>4MIC and 100% fT>MIC were higher in the intervention group: 58 vs. 16%, p = 0.007 and 95 vs. 68%, p = 0.045, respectively. CONCLUSIONS: Among critically ill patients with normal kidney function, a strategy of dose adaptation based on daily TDM led to an increase in PK/PD target attainment compared to conventional dosing.

Methadone-related fatalities: review in the Ghent district between 1978-2008.

Previous research demonstrated that Methadone Maintenance Programs (MMP) and Methadone Maintenance Treatment/Therapy (MMT) could significantly reduce the mortality risk. However, in current forensic practice, methadone ingestion can still directly or indirectly be involved in fatalities. The objectives of this study were twofold. Firstly, referring to the wide range of blood levels reported in methadone-related fatalities, we aimed to provide insight into the interpretation of a quantitative post-mortem blood concentration. Secondly, to examine and discuss possible causes, mechanisms and manners of death. During a 30-year-period, all medico-legal files at the Department of Forensic Medicine (Ghent University) were searched through, to investigate whether methadone was involved in the fatal outcome. A significant increase in the methadone-related fatalities was found since 1995, which has also been noticed in other studies. In our study (n=48), the most frequent cause of death was intoxication: only one was due to a pure methadone intoxication, whereas in all other fatal intoxications, a poly-drug intoxication was found. In this study, cardiopulmonary failure, induced by depression of the vital centres in the brainstem, was--as expected--the most important mechanism of death. When we considered the post-mortem blood levels in our study group, we observed a wide range, namely between 0.10 and 4.13 microg/ml (median: 0.54 microg/ml, mean: 0.81 microg/ml, SD: 0.14). This was in line with previous reports, although the extreme values differed. We conclude that the interpretation of post-mortem methadone blood levels is still hazardous due to e.g. difficulties to assess the individual tolerance level, the variety of surviving periods after ingestion, interfering post-mortem redistribution and the combined ingestion of methadone with other drugs. Therefore, a close collaboration between the forensic pathologist and toxicologist is recommended in order to provide a well-grounded conclusion.

[Cannabis and driving: the situation in Europe]. / Cannabis et conduite automobile: la situation en Europe.

In Europe, three million people consume cannabis every day. Investigations showed that more than two thirds of drug users drive after having smoked cannabis. Epidemiological studies show that between 0.5% and 8.2% of the general driving population is positive for cannabis. For drivers wounded or deceased as a result of an accident, the percentage varies respectively from 3.3% to 10% and from 2.2% to 8.4%. Finally, very high percentages are found in the studies which analysed the presence of drugs in drivers suspected of driving under the influence of drugs: more than 50% in Austria, Belgium, Germany, Switzerland and the United Kingdom. Six European countries adopted an analytical or 'per se' legislation and the cut-offs vary between 0.3 and 2 ng/mL THC. In the Netherlands, experimental studies carried out after administration of cannabis clearly showed the impairing effects, in particular in the event of simultaneous consumption of cannabis and alcohol. Various research projects financed by the European Union studied the epidemiologic aspects (IMMORTAL), detection by psychotechnical tests (CERTIFIED) and roadside drug detection (ROSITA and ROSITA-2).

Workplace drug testing in Europe.

Not much information is available on workplace drug testing (WDT) in Europe. There is no specific legislation and there are no generally accepted guidelines. Many companies establish a drug policy with little or no provisions for drug testing. Often, testing is performed on-site by occupational physicians, with little or no quality control, no systematic confirmation of positives, no chain of custody and no adulteration testing. In some parts of Europe, e.g. in the United Kingdom and some Scandinavian countries, WDT is increasing in importance, but it is not as widespread as in USA. The most frequently performed tests are amphetamines, cannabinoids, cocaine, opiates and alcohol. The percentage of positives is variable, but seems to decrease with the years following the introduction of WDT. Cannabis is the drug that is most frequently found.Recently, the European Workplace Drug Testing Society (EWDTS) was founded, with the aims to ensure that WDT in Europe is performed to a defined quality standard and in a legally secured way and to provide an independent forum for all aspects of WDT.A working group in the United Kingdom has recently finalised the United Kingdom laboratory guidelines for legally defensible WDT and discussions are under way with the EWDTS to establish common guidelines. Many efforts will be needed to establish WDT as an accepted part of a company policy on drugs: establishing and maintaining the confidence in the results of the laboratory, establishing the legal status of WDT, preserving the privacy and rights of the employees, proving the cost-effectiveness of WDT in a European context, finding a balance between strict guidelines and enough flexibility to tailor testing to the changing needs. It is hoped that the exchange of experience between different countries will contribute to reaching these goals.

Development and validation of a high-performance liquid chromatographic method for the determination of gamma-hydroxybutyric acid in rat plasma.

A method for the determination of gamma-hydroxybutyric acid (GHB) in rat plasma was developed using solid-phase extraction (SPE) and high-performance liquid chromatography (HPLC) with UV detection. GHB was isolated from plasma using strong anion-exchange SPE columns. The chromatographic separation was performed on a C18 Aqua column. The lower limit of quantification was 10 microg/ml using 60 microl of plasma. The linearity of the calibration curves was satisfactory as indicated by correlation coefficients of >0.990. The within-day and between-day precision were <10% (n=24), the accuracy was nearly 101%. Plasma concentrations in rats after GHB infusion determined by HPLC-UV were compared with the corresponding concentrations determined with a validated gas chromatographic-mass spectrometric method by orthogonal distance regression. A good correlation was observed and a t-test indicated no significant differences from 0 and 1 for the intercept and slope, respectively.

Automated flow cytometric analysis of cerebrospinal fluid.

BACKGROUND: Recently, the UF-100 (Sysmex Corporation) flow cytometer was developed to automate urinalysis. We evaluated the use of flow cytometry in the analysis of cerebrospinal fluid (CSF). METHODS: UF-100 data were correlated with microscopy and biochemical data for 256 CSF samples. Microbiological analysis was performed in 144 suspected cases of meningitis. RESULTS: Good agreement was obtained between UF-100 and microscopy data for erythrocytes (r = 0.919) and leukocytes (r = 0.886). In some cases, however, incorrect classification of lymphocytes by the UF-100 led to underestimation of the leukocyte count. UF-100 bacterial count positively correlated (P < 0.001) with UF-100 leukocyte count (r = 0.666), CSF total protein (r = 0.754), and CSF lactate concentrations (r = 0.641), and negatively correlated with CSF glucose concentration (r = -0.405; P < 0.001). UF-100 bacterial counts were unreliable in hemorrhagic samples and in samples collected by ventricular drainage where interference by blood platelets and cell debris was observed. Another major problem was the UF-100 "bacterial" background signal in sterile CSF samples. Cryptococcus neoformans yeast cells and cholesterol crystals in craniopharyngioma were detected by the flow cytometer. CONCLUSIONS: Flow cytometry of CSF with the UF-100 offers a rapid and reliable leukocytes and erythrocyte count. Additional settings offered by the instrument may be useful in the diagnosis of neurological disorders.

Ethical issues in pharmacoepidemiological research in Belgium.

PURPOSE: To illustrate the ethical issues faced in pharmacoepidemiological research in Belgium. METHODS: The experience with three studies is described. The studies concern the use of drugs for euthanasia in medical practice, cytomegalovirus infection in single solid organ transplants and a comparison of benzodiazepine use in the general population and in acute self-poisoning. RESULTS: With some creativity, it was possible to meet the requirements of the ethics committees and the law on computer databases, e.g. by bringing data validation closer to the data entry process, by assuring anonymity in mailing procedures, or by deleting identification labels as soon as they are no longer necessary. CONCLUSIONS: The existing juridical vacuum has not really impeded pharmacoepidemiological research.

2-oxo-3-hydroxy-LSD: an important LSD metabolite?

Recently, certain studies have indicated that 2-oxo-3-hydroxy-LSD is present in urine at much higher concentrations than LSD. We determined LSD and 2-oxo-3-hydroxy-LSD in urine by GC-MS (Hewlett Packard 5970) after solid phase extraction on SPEC.PLUS MP1 disks (3 mL, 30 mg, Ansys, Irvine, CA, USA), using the method recommended for amphetamines and derivatisation with BSTFA. For 2-oxo-3-hydroxy-LSD-bis-TMS, the ions with m/z of 309 and 499 were used as quantification and confirmation ion respectively. In four samples containing between 561 and 7007 pg/mL of LSD, 2-oxo-3-hydroxy-LSD concentrations between 8021 and 28466 pg/mL were found, i.e. 4 to 41 times higher than the LSD concentrations. 2-oxo-3-hydroxy-LSD does not seem to be conjugated. These results indicate that 2-oxo-3-hydroxy-LSD, is present in urine in much higher concentrations than LSD, which could facilitate confirmation of positive screenings and increase detection times.

Evaluation of the diagnostic performance of the Boehringer Mannheim CEDIA LSD assay.

The precision and the diagnostic performance of the Boehringer Mannheim CEDIA DAU LSD assay was evaluated. The assay was performed in the semi-quantitative mode on a Hitachi 917 analyzer. Within-run coefficients of variation (CVs) of the semiquantitative values for 0.25 and 1.0 ng/mL were 11.2 and 6.2%, respectively. Day-to-day CVs for the same concentrations were 12.6 and 8.6%. We analyzed 318 urine samples by CEDIA, DPC Coat-A-Count RIA and Behring EMIT II. Confirmation was performed by GC-MS, after extraction on Bond Elut Certify columns. Two hundred sixty-three samples were negative by all methods. Twenty-five samples were positive by all immunoassays, 19 of which were confirmed by gas chromatography-mass spectrometry (GC-MS). One sample was falsely negative by CEDIA. Three samples were positive by EMIT and CEDIA, but negative by RIA and GC-MS. Twenty-six samples were positive by EMIT alone, but they were not confirmed by GC-MS. The LSD CEDIA assay seems to be less specific than DPC RIA but more specific than the EMIT LSD assay.