Matthieu Grégoire

Simultaneous determination of ceftaroline, daptomycin, linezolid and rifampicin concentrations in human plasma by on-line solid phase extraction coupled to high-performance liquid chromatography–tandem mass spectrometry

Methicillin-resistant Staphylococcus aureus infection is a serious clinical problem worldwide. Ceftaroline, daptomycin, linezolid in combination with rifampicin are particularly used in this indication. To allow monitoring of these antibiotics, an on-line solid phase extraction coupled to high-performance liquid chromatography-tandem mass spectrometry assay requiring a 100 μL aliquot of human plasma has been developed. Besides, significance of 25-O-desacetylrifampicin concentrations was evaluated. Sample pre-treatment is limited to protein precipitation with methanol. After centrifugation 10 μL of supernatant are injected into the chromatographic system, which consists of an on-line solid phase extraction followed by a separation on a phenyl-hexyl column and detected by a tandem mass spectrometer. Plasma drug concentrations were determined by multiple reaction monitoring in positive ion mode, and assay performance was evaluated. 25-O-Desacetylrifampicin activity, was compared to rifampicin using a microbiological method. Sample preparation using methanol precipitation followed by solid-phase extraction yielded good recovery and ionization efficiency, with chromatographic separation achieved within 3 min per sample. Within-run and between-run precisions ranged respectively from 1.22% to 9.35% and from 1.61% to 9.36%. Lower limits of quantification were 0.04 mg/L for linezolid, 0.1mg/L for rifampicin, 0.2mg/L for ceftaroline and 0.5mg/L for daptomycin. It appears that 25-O-desacetylrifampicin displays a substantial intrinsic bactericidal activity against S. aureus. This assay provides simple, rapid, sensitive and accurate quantification of the four antibiotic drugs and one metabolite and can be routinely used to monitor drug concentration in methicillin-resistant S. aureus infected patients.

Influence of nevirapine administration on the pharmacokinetics of dolutegravir in patients infected with HIV-1

OBJECTIVES The metabolic pathways of dolutegravir and nevirapine suggest a potential pharmacokinetic interaction between these drugs. The objective of this study was to investigate the influence of nevirapine administration on the pharmacokinetics of dolutegravir in patients infected with HIV-1. PATIENTS AND METHODS This study was an investigator-initiated trial registered at ClinicalTrials.gov under identifier NCT02067767. Dolutegravir (50 mg once daily) was added to the antiretroviral regimen (400 mg of nevirapine once daily + 600/300 mg of abacavir/lamivudine once daily) in 10 adult patients for 5 days. After discontinuation of nevirapine, the combination of dolutegravir + abacavir/lamivudine was continued. Full pharmacokinetic profiles were assessed on the day of nevirapine discontinuation and 2 weeks after discontinuation of nevirapine. The pharmacokinetic parameters of dolutegravir were calculated by non-compartmental analysis. The log-transformed values of these parameters were compared between periods with and without nevirapine co-administration. RESULTS The co-administration of nevirapine led to a significant decrease (P < 0.05) in the area under the plasma concentration-time curve for dolutegravir from the time the dose was administered until the end of the dosing interval (-19%, P = 0.011), as well as decreases in trough plasma concentration (-34%, P = 0.018) and terminal half-life (-15%, P = 0.039), and a significant increase (P < 0.05) in apparent oral clearance for dolutegravir (+23%, P = 0.011). CONCLUSIONS The decrease in dolutegravir exposure in combination with nevirapine suggests that the metabolism of dolutegravir is induced by nevirapine. According to therapeutic drug monitoring for dolutegravir, some patients may need a higher dose than 50 mg of dolutegravir once daily to maintain the therapeutic plasma concentration throughout the dosing interval.

Evaluation of a Methotrexate Chemiluminescent Microparticle Immunoassay Comparison to Fluorescence Polarization Immunoassay and Liquid Chromatography–Tandem Mass Spectrometry

OBJECTIVES For most laboratories, methotrexate (MTX) concentrations are routinely monitored by fluorescence polarization immunoassay (FPIA). In anticipation of an announced withdrawal of the FPIA reagent on the Abbott TDxFLx (Abbott Diagnostics, Abbott Park, IL), we have evaluated a new reagent kit developed by Abbott on the Architect i1000, based on chemiluminescent microparticle immunoassay (CMIA). METHODS Precision, inaccuracy, and selectivity were assessed. Interassay variability was established using 75 plasma patient samples treated with MTX and analyzed by two methods: FPIA and liquid chromatography-tandem mass spectrometry (LC-MS/MS). RESULTS FOR MTX,: the intraday inaccuracy was between -6.37% and +3.52%, while interday performance was between -3.70% and 7.90%. Intraday and interday imprecision was less than 2.65% and less than 2.22%, respectively. The correlation coefficient between CMIA and FPIA or LC-MS/MS was 0.9969 and 0.9985, respectively. CONCLUSIONS These results comparing CMIA vs FPIA and LC-MS/MS indicate that CMIA is a suitable alternative to the FPIA method.

Comparison Between an Automated and Manual Extraction for the Determination of Immunosuppressive Drugs Whole Blood Concentrations by Liquid Chromatography Tandem Mass Spectrometry.

The whole blood extraction for liquid chromatography tandem mass spectrometry (LC‐MS/MS) of simultaneous quantification of cyclosporine A (Cys A), tacrolimus (Tacrs), sirolimus (Siros), and everolimus (Evers) is still performed manually in many laboratories. The analytical results obtained with an automated method using a liquid handler versus a classical manual preparation were compared.

Prophylactic cefazolin concentrations in morbidly obese patients undergoing sleeve gastrectomy: do we achieve targets?

Morbid obesity is known to increase the risk of surgical site infections. Optimal concentrations of prophylactic antibacterial drugs are required. Using Monte Carlo simulations, the aim of this work was to build a population pharmacokinetics model for a morbidly obese population to assess a 4000-mg dose of cefazolin recommended by the guidelines and to propose new administration schemes. One hundred and seventeen morbidly obese patients (mean body mass index, 46.95 kg/m2) received 4000 mg of cefazolin intravenously before sleeve gastrectomy. Using population pharmacokinetics modelling and Monte Carlo simulations, probabilities of target attainment (PTAs) (subcutaneous tissue concentration of cefazolin above the minimum inhibitory concentration (MIC) throughout the surgical procedure was targeted) were determined. For Staphylococcus spp. and Streptococcus spp., which are the most frequent species isolated from post-surgical infections in bariatric surgery (MIC usually ≤2 mg/L), PTA remains greater than 0.9 until 2 h after administration of 4000 mg of cefazolin. For MIC up to 4 mg/L, efficient prophylaxis was checked until 1 h after the initial administration. A 3000-mg regimen followed by a continuous infusion (1000 mg/h) achieves these two targets until 4 h after the loading dose. A 2000-mg and a 3000-mg regimen do not achieve sufficient concentrations. According to the duration of surgery and MIC values, an initial administration of 4000 mg should be sufficient, but for extended surgeries continuous infusion can be considered.

Cannabis and anticancer drugs: societal usage and expected pharmacological interactions – a review

Cannabis is a plant that has been used for centuries to relieve a wide range of symptoms. Since the 1960s, interest in medical research into this plant has grown steadily. Already very popular for recreational use, a growing number of consumers not accustomed to using cannabis for psychoactive purposes have begun to use it as an alternative or complement to mainstream pharmaceutical medicines. The principal unsubstantiated or ‘social’ uses of cannabis are based mainly on data that is at best controversial, but usually not scientifically proven. The aim of this review was to identify the scientific basis and reasons that lead patients with cancer to consume cannabis, and also to identify whether there is a risk of interaction between cannabis and anticancer medicines through drug transporters (P‐glycoprotein and other ATP‐binding cassette superfamily members) Cytochromes P450 (3A, 1A, 2B, 2C, 2D families…) and glucuronyl transferases.

Difference between plasma and red blood cell acetone distribution during the first 60 h of a massive intoxication

After a first episode of acetone intoxication six months earlier (1 L of acetone with plasma concentration at hospital admission of 3.7 g/L), a 55-year-old patient was hospitalized in intensive care because of coma (Glasgow Coma Scale [GCS] 3). He was currently prescribed quetiapine, levodopa, propranol, oxazepam, and domperidone for a Parkinsons disease associated with vestibular disorders and depressive syndrome. Brain CT-scan was non-contributory and an acute kidney injury (serum creatinine of 153 mmol/L on day 1) was not felt to be related to circulatory failure (heart rate 70/min, blood pressure 100/60mmHg) but could have been an artifact due to interference of acetone with the creatinine dosage method (Jaffe reaction colorimetric kit, Roche, Basel, Switzerland). The blood pH was 7.36 with serum bicarbonate of 24.9mmol/L. The patient was maintained on mechanical ventilation, slowly aroused and extubation was possible on day 4. He was discharged at his baseline neurological status and GCS 15. Plasma, whole blood, urine, and CSF samples were taken during hospitalization. CSF was obtained at admission to assess for possible meningitis and a urine sample was obtained for toxicological screening. Acetone quantification was done in head-space gas chromatography coupled with flame ionization detection Agilent 7890A GC system (Agilent, Palo Alto, CA). Pharmacokinetics parameters were calculated using a non-compartmental analysis [1]. Acetone plasma concentration at hospital admission was of 4.4 g/L (Figure 1). Maximum concentrations of acetone in whole blood, CSF and urine were of 2.49 g/L, 3.44 g/L and 2.36 g/L respectively (Figure 1). Calculated terminal half-life was 17 h. Pharmacokinetics of acetone is presented in Figure 1. Whole blood concentrations were equal to plasma concentrations 60 h after intake.

Pharmacokinetics of Tedizolid in an Obese Patient after Bariatric Surgery

ABSTRACT An obese woman was treated with oral tedizolid 200 mg once daily for pseudoarthrosis 10 years after Roux-en-Y bypass surgery. Total plasma peak concentration was 2.12 mg/liter 3 h after intake, and area under the concentration-time curve from 0 to 24 h (AUC0–24) was 28.3 mg/liter · h. The AUC0–24/MIC ratio for unbound concentrations and for sensitive Staphylococcus and Streptococcus strains was ≥10.8, higher than the target ratio of 3. These results support the use of tedizolid without adjustment after bariatric surgery.

Stability and Compatibility of Antibiotics in Peritoneal Dialysis Solutions Applied to Automated Peritoneal Dialysis in The Pediatric Population

♦ Objectives: Assess the stability of several antibiotics in peritoneal dialysis (PD) solutions under common conditions of use in pediatrics, particularly in automated PD. ♦ Methods: Amoxicillin, cefazolin, cefepime, ceftazidime, imipenem, cotrimoxazole, tobramycin, vancomycin, and the association of ceftazidime + vancomycin and ceftazidime + tobramycin, were tested in 3 different PD solutions: bicarbonate/lactate solution with 2 glucose concentrations (Physioneal 1.36 and 3.86%; Baxter Healthcare Corporation, Deerfield, IL, USA) and an icodextrin-containing solution (Extraneal; Baxter Healthcare Corporation, Deerfield, IL, USA). Concentrations were those recommended in guidelines for the treatment of peritonitis in pediatrics. Physioneal bags were incubated at 37°C for 24 hours, whereas Extraneal bags were stored 12 hours at room temperature (22 ± 2°C) and then 12 hours at 37°C. Drug concentrations were determined using high performance liquid chromatography (HPLC). Each measure was taken in triplicate. Stability of antibiotics was defined as less than 10% degradation of the drug over time. ♦ Results: Cefazolin, cotrimoxazole, tobramycin, and vancomycin were stable under studied conditions. Ceftazidime was stable 24 hours in icodextrin, 12 hours in Physioneal 1.36% and 6 hours in Physioneal 3.86%. The association of tobramycin or vancomycin did not influence the stability of ceftazidime. Cefepime and amoxicillin were stable 6 h, 4 h, and 8 h in Physioneal 1.36%, 3.86% and Extraneal, respectively. The stability of imipenem was very low: 2 h in Physioneal and 6 h in Extraneal. Moreover, an increasingly yellow coloration was observed with the use of imipenem, whereas no color change or precipitation occurred in other bags. ♦ Conclusion: Cefazolin, tobramycin, cotrimoxazole, and vancomycin are stable in PD solutions up to 24 hours and can be administered in the PD bag for the treatment of peritonitis, even in automated PD under studied conditions. However, amoxicillin, cefepime, ceftazidime, and imipenem must be used with caution due to their lack of stability.