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French guidelines recommend reaching an amikacin concentration of ≥8 × MIC 1 h after beginning infusion (C1h), with MIC = 8 mg/L for probabilistic therapy. We aimed to elaborate a nomogram guiding clinicians in choosing the right first amikacin dose for ICU patients in septic shock. A total of 138 patients with 407 observations were prospectively recruited. A population pharmacokinetic model was built using a non-parametric, non-linear mixed-effects approach. The total body weight (TBW) influenced the central compartment volume, and the glomerular filtration rate (according to the CKD–EPI formula) influenced its clearance. A dosing nomogram was produced using Monte Carlo simulations of the amikacin amount needed to achieve a C1h ≥ 8 × MIC. The dosing nomogram recommended amikacin doses from 1700 mg to 4200 mg and from 28 mg/kg to 49 mg/kg depending on the patient's TBW and renal clearance. However, a Cthrough ≤ 2.5 mg/L 24 h and 48 h after an optimal dose of amikacin was obtained with probabilities of 0.20 and 0.81, respectively. Doses ≥ 30 mg/kg are required to achieve a C1h ≥ 8 × MIC with MIC = 8 mg/L. Targeting a MIC = 8 mg/L should depend on local ecology. [ABSTRACT FROM AUTHOR]

Midazolam is a benzodiazepine frequently used for sedation in patients hospitalized in the intensive care unit (ICU) for coronavirus disease 2019 (COVID‐19). This drug is primarily metabolized by cytochrome P450 3A (CYP3A) isoenzymes. Several studies have suggested that inflammation, frequently observed in these patients, could modulate CYP3A activity. The objective of this work was to study the impact of inflammation on midazolam pharmacokinetics in patients with COVID‐19. Forty‐eight patients hospitalized in the ICU for COVID‐19 and treated with midazolam administered by continuous infusion were included in this study. Midazolam and α‐hydroxymidazolam concentrations were measured and patient data, including the use of CYP3A inhibitors, were collected. Total and unbound concentrations of midazolam and α‐hydroxymidazolam were measured in plasma using a validated liquid‐chromatography coupled with mass spectrometry method. Inflammatory condition was evaluated by C‐reactive protein (CRP) level measurement. Both drug concentrations and CRP measurements were performed on 354 plasma samples. CRP elevation was significantly associated with the α‐hydroxymidazolam/midazolam plasma ratio decrease, whether for the unbound fraction or for the total fraction. Conversely, inflammation was not associated with protein binding modifications. Logically, α‐hydroxymidazolam/midazolam plasma ratio was significantly reduced when patients were treated with CYP3A inhibitors. In this study, we showed that inflammation probably reduces the metabolism of midazolam by CYP3A. These results suggest that molecules with narrow therapeutic margins and metabolized by CYP3A should be administrated with care in case of massive inflammatory situations. [ABSTRACT FROM AUTHOR]

Background: Amoxicillin is the first-line treatment for streptococcal or enterococcal infective endocarditis (IE) with a dose regimen adapted to weight.Objectives: Covariates influencing pharmacokinetics (PK) of amoxicillin were identified in order to develop a dosing nomogram based on identified covariates for individual adaptation.Patients and Methods: Patients treated with amoxicillin administered by continuous infusion for IE were included retrospectively. The population PK analysis was performed using the Pmetrics package for R (NPAG algorithm). Influence of weight, ideal weight, height, BMI, body surface area, glomerular filtration rate adapted to the body surface area and calculated by the CKD-EPI method (mL/min), additional ceftriaxone treatment and serum protein level on amoxicillin PK was tested. A nomogram was then developed to determine the daily dose needed to achieve a steady-state free plasma concentration above 4× MIC, 100% of the time, without exceeding a total plasma concentration of 80 mg/L.Results: A total of 160 patients were included. Population PK analysis was performed on 540 amoxicillin plasma concentrations. A two-compartment model best described amoxicillin PK and the glomerular filtration rate covariate significantly improved the model when included in the calculation of the elimination constant Ke.Conclusions: This work allowed the development of a dosing nomogram that can help to increase achievement of the PK/pharmacodynamic targets in IE treated with amoxicillin. [ABSTRACT FROM AUTHOR]

Introduction: Accidental cannabis poisoning after oral ingestion in infants is an emerging cause of intoxication with well-known clinical aspects but few data exist regarding the levels of cannabinoids in plasma and urine. Here, we present data on the concentrations of Δ-9-tetrahydrocannabinol (THC) and metabolites in plasma and/or urine in 10 infants after cannabis intoxication. Materials and methods: Cannabinoids were detected using an automated immunochemical method and quantified using liquid chromatography coupled with mass spectrometry. Results: Ten infants were admitted after cannabis poisoning. THC, THC-COOH and 11-OH-THC plasma levels ranged from 4.4 to 127 ng/mL, from 28 to 433 ng/mL and from 2 to 59.8 ng/mL, respectively. THC-COOH urine levels ranged from 748 to 5689 ng/mL. The most common symptoms were drowsiness, hypotonia, behavioural disorder and tachycardia. Discussion: No correlation between plasma concentrations and symptoms could be found, but the concentration of THC-COOH in the two patients who experienced seizures was higher than 3000 ng/mL. This series of cases of accidental intoxication in infants showed high THC and metabolites concentrations in urine and plasma. [ABSTRACT FROM AUTHOR]

Abstract: 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. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Self-injection of high-dose buprenorphine is responsible for well-described complications. In 2011, we have been alerted by unusual but serious cutaneous complication among injection buprenorphine users. A prospective data collection identified 30 cases of necrotic cutaneous lesions after injection of filtered buprenorphine solution, among which 25 cases occurred following injection of buprenorphine generics. The main goal of our study was to put forward particularities that could explain the cutaneous complications, by qualitatively and quantitatively confronting particles present in Subutex and generics solutions. We used the same protocol that injected-buprenorphine users: generic or subutex tablets were crushed in sterile water and filtered through 2 filters commonly used (cotton-pad and sterifilt). Solutions were analyzed by laser granulometry, flow cytometry and scanning electron microscopy. We have highlighted the wide variation of the quantity and the size of the particles present in solution between the two drugs after cotton-pad filtration. The proportion of particles <10 µm is systematically higher in the generic solutions than with Subutex. All of the insoluble particles found in generic solutions contain silica, whereas non- organic element was to be identified in the insoluble particles of Subutex. One skin biopsy obtained from one patient who developed a necrotic lesion after intravenous injection of filtrated solution of buprenorphine generic, shows non-organic elements. Identification of particles in situ enables us to confirm the presence of silica in the biopsy. Actually the monitoring of patient receiving generic of buprenorphine must be strengthened. [ABSTRACT FROM AUTHOR]

The influence of efavirenz, etravirine, raltegravir, and nevirapine administration on the pharmacokinetics of ritonavir-boosted darunavir was investigated using population pharmacokinetics analysis. The population was composed of 142 patients infected with HIV: darunavir plus nucleoside/nucleotide reverse transcriptase inhibitors (NRTI), 54 patients (group A); darunavir plus efavirenz ± NRTI, 4 patients (group B); darunavir plus etravirine ± NRTI, 5 patients (group C); darunavir plus nevirapine ± NRTI, 21 patients (group D); darunavir plus raltegravir ± NRTI, 38 patients (group E); and darunavir plus raltegravir and etravirine ± NRTI, 20 patients (group F). A significant increase in darunavir clearance in combination with nevirapine ( + 66%) and efavirenz ( + 235%) was observed. A significant decrease ( p < 0.05) in trough plasma concentration was observed in groups B and D compared with the other groups. Our study indicates that the combination of ritonavir-boosted darunavir and etravirine or raltegravir has no significant influence on the pharmacokinetics of darunavir in contrast to the combination of ritonavir-boosted darunavir and nevirapine or efavirenz, which involves an increase in darunavir clearance and a decrease in the plasma concentration of darunavir. [ABSTRACT FROM AUTHOR]

A letter to the editor is presented on a case of high metabolic N-oxidation of voriconazole in a patient with refractory aspergillosis.

A case study of 55-year-old patient who was diagnosed with extremely high blood concentration of acetone. It mentions that cerebrospinal fluid (CSF) was obtained at admission to assess for possible meningitis and a urine sample was obtained for toxicological screening. It presents information on observation of equal whole blood concentrations and plasma concentrations.

Abstract: The relationship between clearance of vancomycin administered by continuous infusion and the glomerular filtration rate (GFR) estimated by creatinine clearance (CLCr) was investigated in a large cohort of burn patients. Individual vancomycin clearance (CLVan) was estimated from the ratio between the rate of infusion and the plasma concentration at steady state for 70 patients (149 samples). The average value of CLVan (7.03±3.79L/h) was higher than normal values in non-burn patients. A significant relationship between CLVan versus CLCr was found (r =0.506; P <0.001): CLVan (L/h)=0.0205CLCr (mL/min)+3.47. From this result, a simple formula is proposed to adapt vancomycin dosage: rate of vancomycin continuous infusion (g/day)=[0.0205CLCr (mL/min)+3.47]×[target vancomycin concentration at steady state (mg/L)]×(24/1000). The limits of the predictive performance of this formula are discussed, since factors other than GFR can affect vancomycin elimination. This formula could help clinicians to define the optimum vancomycin dosage, particularly in patients with disturbed renal function. [Copyright &y& Elsevier]

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/m 2 ) 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 S treptococcus 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. [ABSTRACT FROM AUTHOR]