Simultaneous determination of oxacillin and cloxacillin in plasma and CSF using turbulent flow liquid chromatography coupled to high-resolution mass spectrometry: Application in therapeutic drug monitoring.

Cloxacillin and oxacillin are group M penicillins. The therapeutic monitoring of plasma concentrations of these antibiotics and those of their hydroxymethylated metabolites is of great clinical interest, especially in the choice of an adequate dosage allowing an effective treatment while limiting the occurrence of undesirable effects and the development of bacterial resistance. In this context, we conducted this work aiming at developing and validating a method allowing the determination of cloxacillin and oxacillin as well as the identification of their active metabolites in different biological matrices (CSF and plasma) using turbulent flow liquid chromatography coupled to high-resolution mass spectrometry. To do this, we carried out several optimisation tests. Subsequently, we validated our method according to the latest bioanalytical validation recommendations of the European Medicines Agency. The validation results showed that our method is specific and sensitive. We obtained good linearity in the range 0.5 to 100 µg/mL with correlation coefficients above 0.995. The lower limit of quantification was 0.5 µg/mL for each analyte. The method was found to be accurate with repeatability and reproducibility coefficients of variation below 15 %. Our method is also accurate with bias values below 15 %. Recovery values ranged from 87 % to 95 %. Finally, we were able to apply our method to the therapeutic monitoring of the analysed molecules and to identify their active metabolites. Our results suggest that LC-MS shows superiority in the therapeutic monitoring of these antibiotics due to the superiority of specificity shown by this method. This assay method can be routinely used for the daily plasma assays of patients treated with these antibiotics in the context of therapeutic monitoring.

What to Do with the New Antibiotics?

Multidrug-resistant Gram-negative bacteria-related infections have become a real public health problem and have exposed the risk of a therapeutic impasse. In recent years, many new antibiotics have been introduced to enrich the therapeutic armamentarium. Among these new molecules, some are mainly of interest for the treatment of the multidrug-resistant infections associated with Pseudomonas aeruginosa (ceftolozane/tazobactam and imipenem/relebactam); others are for carbapenem-resistant infections associated with Enterobacterales (ceftazidime/avibactam, meropenem/vaborbactam); and finally, there are others that are effective on the majority of multidrug-resistant Gram-negative bacilli (cefiderocol). Most international guidelines recommend these new antibiotics in the treatment of microbiologically documented infections. However, given the significant morbidity and mortality of these infections, particularly in the case of inadequate therapy, it is important to consider the place of these antibiotics in probabilistic treatment. Knowledge of the risk factors for multidrug-resistant Gram-negative bacilli (local ecology, prior colonization, failure of prior antibiotic therapy, and source of infection) seems necessary in order to optimize antibiotic prescriptions. In this review, we will assess these different antibiotics according to the epidemiological data.

Therapeutic Drug Monitoring of Sputum Voriconazole in Pulmonary Aspergillosis.

Voriconazole is one of the most used antifungal azoles against pulmonary aspergillosis. Therapeutic drug monitoring (TDM) of the voriconazole concentration in plasma is recommended in clinical practice guidelines to prevent treatment failure and toxicity. The aim of this study was to evaluate the feasibility and utility of TDM of the voriconazole concentration in the sputum of patients treated for pulmonary aspergillosis. Fifty sputum and 31 plasma samples were analysed with high-performance tandem mass spectrometry (HPLC-MS/MS) in 24 patients included in the study. The voriconazole concentration was simultaneously assessed in the plasma and sputum in 22 samples. The correlation between the sputum and plasma levels was estimated with a univariate linear regression model, and the observed R2 was 0.86. We determined the following equation, Csputum = 0.45 (Cplasma) + 0.21, which could predict the voriconazole concentration in plasma from sputum. TDM of the voriconazole concentration in sputum is an easy, non-invasive and accurate method with which to evaluate voriconazole exposure in patients with pulmonary aspergillosis.

[Therapeutic drug monitoring of antidepressants: Why venlafaxine is the most monitored drug? A review of literature]. / Suivi thérapeutique pharmacologique des antidépresseurs : pourquoi la venlafaxine est le médicament le plus surveillé ? Une revue de la littérature.

Venlafaxine is the third most frequently prescribed antidepressant in France the last decade, with about 400,000 daily doses. Therapeutic drug monitoring (TDM) of this medication, by measuring the active moiety venlafaxine (V) and O-desmethylvenlafaxine (ODV), is recommended (level of recommendation 2). However, this antidepressant seems to be the one for which clinicians most often use TDM, much more frequently than escitalopram, which is more prescribed and for which TDM is also recommended. The main goal of this review is to provide an update on the TDM of venlafaxine: its therapeutic interval, its level of recommendation and the origin of its "success". From the literature does not enable to define a therapeutic interval for the active moiety V+ODV, that is to say a steady-state trough concentration allowing a clinical response without toxicity. Nevertheless, a target concentration from 100 to 400µg/L is certainly relevant for the majority of patients without any pharmacodynamic resistance ; though a greater concentration could result in an earlier response or could be required for a clinical response in a minority of patients. A patient with no clinical response despite a concentration greater than 1000µg/L should be proposed another antidepressant. Measurement of the ODV/V ratio is also a useful tool, values below 0.3 usually reflecting a slow metabolizer phenotype for cytochrome P-450 2D6, which is more at risk of adverse effects. Research for this phenotype probably explains many prescriptions for TDM.

How to optimize administration of cefoxitin for the treatment of extended spectrum producing Enterobacteriaceae-related infection?

Pharmacological and clinical data regarding cefoxitin for the treatment of ESBL-producing Enterobacteriaceae-related infections are limited. We performed a multicentric prospective cohort study to evaluate continuous/prolonged, or intermittent infusion of cefoxitin. We assessed the plasma concentration as a function of the duration of infusion and then performed a simulation of the percentage of patients who would reach the PK/PD targets, set at 100% ƒT> MIC or 100% ƒT>4 MIC. Eighty-one patients were included. All patients were treated with 6 gr./day. MICs to cefoxitin ranged from 0.5 to 64 mg/L. Sixteen (19.7%) patients were infected with strains with cefoxitin MICs ≥ 8 mg/L. In all patients infected with strains with MICs ≤ 6 mg/L, PK/PD objectives (100% ƒT> MIC) were achieved with prolonged or continuous infusion. In contrast, when MICs were 8 mg/L only, continuous infusion was sufficient to achieve the PK/PD objectives (100% ƒT> MIC). Extended infusion of cefoxitin is necessary for the treatment of non-UTI ESBL-related infections.

Interest of adjusting urine cannabinoids to creatinine level to monitor cannabis cessation therapy in heavy smokers with psychiatric disorders.

Up to 25% of hospitalized patients in a psychiatric department exhibit troubles linked to cannabis use. Weaning patients with psychiatric disorders off drugs of abuse requires specific care to improve their clinical outcome. The present study aims to develop a predictive model of urinary excretion of creatinine-normalized cannabinoids (UCNC ) and to determine UCNC thresholds corresponding to the widely used cut-offs of 20 ng/mL and 50 ng/mL for cannabinoids. One hundred thirty-two patients with 452 urine samples were included between 2013 and 2017. Urinary cannabinoids and UCNC elimination curves were computed for each patient. Using a mono-exponential mixed effect model with 88 samples from 26 subjects exhibiting at least 3 decreasing UCNC in a row, the average calculated elimination rate constant was 0.0108 ± 0.0026 h-1 , corresponding to a mean elimination half-life of 64 ± 12 hours. The use of UCNC is of particular interest because of a high inter- and intra-individual variability of urinary creatinine concentration (from 0.06 to 3.81 mg/mL). Moreover, UCNC allows for the detection of diluted or concentrated urine specimens that may lead to false positive (FP) or false negative (FN) results. Receiver operator characteristic (ROC) curves were used to assess UCNC thresholds of 32.4 and 124.7 ng/mg that provide a strong discrimination between positive and negative samples for cannabinoids cut-offs of 20 and 50 ng/mL respectively. The developed model and the defined UCNC thresholds allowed for the accurate prediction of the time needed to reach a negative UCNC result that could be used by clinicians to optimize clinical care.

The right blood collection tube for therapeutic drug monitoring and toxicology screening procedures: Standard tubes, gel or mechanical separator?

Stability data of toxics or drugs in gel-based or mechanical separation blood collection tubes are lacking, especially for therapeutic drug monitoring and clinical toxicology procedures. According to ISO 15189 accreditation standard, laboratories need to master the entire preanalytical process including the stability of analytes in a specific tube. Here we explored the impact of BD PST™ II and Barricor™ separator tubes on the stability of 167 therapeutic compounds and common drugs of abuse in plasma samples using LC-MS/MS. Forty drugs were significantly affected by the use of PST™ II tubes, including antidepressants (11/26), neuroleptics (9/13), cardiovascular drugs (5/26), anxiolytics and hypnotics (4/25) and some drugs of abuse (5/26). Six compounds exhibited significant reduction by the mechanical Barricor™ tubes. Ten drugs exhibited low (<85%) but non-significant recoveries due to inter-assay variability. Besides, a logP > 3.3 was determined as a cut-off value to predict a potential lack of stability in PST™ II gel tubes with an 86.4% sensitivity and a 61.4% specificity. As a consequence, determination of drugs with a logP > 3.3 should be carried out with caution in plasma samples withdrawn on PST™ II. The study showed the Barricor™ and non-gel tubes cause less drug interference and are recommended for the drugs studied.