Susceptibility breakpoints and target values for therapeutic drug monitoring of voriconazole and Aspergillus fumigatus in an in vitro pharmacokinetic/pharmacodynamic model--authors' response

Abstract Background Central nervous system (CNS) infections caused by carbapenem-resistant Enterobacterales (CRE) and Difficult-to-treat resistant (DTR)-P. aeruginosa (PA) present a therapeutic dilemma. Therapies are limited due to antibiotic resistance and inadequate CNS diffusion. Intraventricular polymyxins are utilized in this setting despite a lack in pharmacokinetic data after CNS injection. We describe the utilization of intravenous and intrathecal polymyxin E [colistimethate (CMS)] therapeutic drug monitoring (TDM) in 3 cases of post-neurosurgical meningitis. Methods Bacterial identification and susceptibility testing were performed using MicroScan. TDM was employed by dosing CMS at 125,000 IU (i.e., 4.1 mg CBA or 10 mg) administered via external ventricular drain twice daily and 4.5 MIU (133.2 CBA or 360 mg) CMS administered over 30 minutes IV twice daily. Four pairs of CSF and blood samples were collected for each patient (Table 1). Samples were placed on ice to minimize in-vitro conversion of CMS to Colistin. Colistin binding in plasma and CSF was measured using ultracentrifugation. Concentrations of CMS and Colistin in CSF and human plasma were determined by liquid chromatography/mass spectrometry. Patients A, B and C received 20, 15, and 12 doses of CMS, respectively, prior to TDM. Results Bacterial cultures revealed DTR PA, blaKPCE. cloacae and blaOXA-48K. pneumoniae for patients A, B and C, respectively. Colistin minimum inhibitory concentrations (MIC) were 0.5 µg/ml, 0.125 µg/ml, and 0.125 µg/ml, respectively. The measured CSF and plasma concentrations of CMS, Colistin, and binding are shown in Table 1. Clinical resolution and microbiological cure were attained in all patients. Therapeutic Drug Monitoring of Unchanged CMS and Formed Colistin in CSF samples for patient A, B, and C Therapeutic Drug Monitoring of Unchanged CMS and Formed Colistin in Plasma Samples for patient A, B, and C Conclusion Favorable concentrations of formed Colistin and CMS in CSF were achieved in 3 patients with complicated CNS infection. To the best of our knowledge, this is the first study to report the binding of Colistin in CSF in humans. A TDM method was effectively applied to demonstrate that Colistin achieves and maintains the PK/PD target (fAUC/MIC) [ratio of area under the plasma concentration curve of unbound drug to MIC] that best correlates with killing activity. Overall, our results support intraventricular polymyxins for treating DTR Gram-negative CNS infections. Disclosures Robert A. Bonomo, MD, entasis (Research Grant or Support)Merck (Grant/Research Support)NIH (Grant/Research Support)VA Merit Award (Grant/Research Support)VenatoRx (Grant/Research Support)

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A Non-Invasive Method for Detection of Antihypertensive Drugs in Biological Fluids: The Salivary Therapeutic Drug Monitoring

Frontiers in Pharmacology ◽

10.3389/fphar.2021.755184 ◽

2022 ◽

Vol 12 ◽

Author(s):

Valeria Avataneo ◽

Elvira Fanelli ◽

Amedeo De Nicolò ◽

Franco Rabbia ◽

Alice Palermiti ◽

...

Keyword(s):

Therapeutic Drug Monitoring ◽

Drug Monitoring ◽

Antihypertensive Drugs ◽

Biological Fluids ◽

Real Life ◽

European Medicines Agency ◽

Therapeutic Drug ◽

Hypertensive Patients ◽

Non Invasive ◽

Target Values

Objectives: Arterial hypertension is still the most frequent cause of cardiovascular and cerebrovascular morbidity and mortality. Antihypertensive treatment has proved effective in reduction of cardiovascular risk. Nevertheless, lifestyle interventions and pharmacological therapy in some cases are ineffective in reaching blood pressure target values, despite full dose and poly-pharmacological treatment. Poor adherence to medications is an important cause of treatment failure. Different methods to assess therapeutic adherence are currently available: Therapeutic drug monitoring in biological fluids has previously demonstrated its efficacy and reliability. Plasma and urine have been already used for this purpose, but they may be affected by some practical limitations. Saliva may represent a feasible alternative.Methods: Fourteen antihypertensive drugs and two metabolites were simultaneously tested in plasma, urine, and saliva. Tested molecules included: atenolol, nebivolol, clonidine, ramipril, olmesartan, telmisartan, valsartan, amlodipine, nifedipine, doxazosin, chlorthalidone, hydrochlorothiazide, indapamide, sacubitril, ramiprilat, and sacubitrilat. Therapeutic drug monitoring was performed using ultra-high performance liquid chromatography, coupled to tandem mass spectrometry (UHPLC-MS/MS). The method has been preliminarily evaluated in a cohort of hypertensive patients.Results: The method has been validated according to US Food and Drug Administration (FDA) and European Medicines Agency (EMA) guidelines. The application on a cohort of 32 hypertensive patients has demonstrated sensibility and specificity of 98% and 98.1%, respectively, with a good feasibility in real-life clinical practice.Conclusion: Saliva may represent a feasible biological sample for therapeutic drug monitoring by non-invasive collection, prompt availability, and potential accessibility also in out-of-clinic settings.

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In vitro evaluation of an intravenous microdialysis catheter for therapeutic drug monitoring of gentamicin and vancomycin

Pharmacology Research & Perspectives ◽

10.1002/prp2.483 ◽

2019 ◽

Vol 7 (4) ◽

Cited By ~ 1

Author(s):

Jackelien E. van der Mast ◽

Maarten W. Nijsten ◽

Jan‐Willem C. Alffenaar ◽

Daan J. Touw ◽

Wouter Bult

Keyword(s):

Therapeutic Drug Monitoring ◽

Drug Monitoring ◽

Therapeutic Drug ◽

Microdialysis Catheter ◽

In Vitro Evaluation ◽

Intravenous Microdialysis

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Therapeutic drug monitoring of infliximab: performance evaluation of three commercial ELISA kits

Clinical Chemistry and Laboratory Medicine (CCLM) ◽

10.1515/cclm-2015-0987 ◽

2016 ◽

Vol 54 (7) ◽

Cited By ~ 16

Author(s):

Ellen M.H. Schmitz ◽

Daan van de Kerkhof ◽

Dörte Hamann ◽

Joost L.J. van Dongen ◽

Philip H.M. Kuijper ◽

...

Keyword(s):

Performance Evaluation ◽

Therapeutic Drug Monitoring ◽

The Netherlands ◽

Drug Monitoring ◽

Processing System ◽

Therapeutic Drug ◽

Treatment Groups ◽

Therapeutic Consequences ◽

Target Values ◽

Automated Processing

AbstractTherapeutic drug monitoring (TDM) of infliximab (IFX, RemicadeThe kits of Theradiag (Lisa Tracker Infliximab), Progenika (Promonitor IFX) and apDia (Infliximab ELISA) were implemented on an automated processing system. Imprecision was determined by triplicate measurements of patient samples on five days. Agreement was evaluated by analysis of 30 patient samples and four spiked samples by the selected ELISA kits and the in-house IFX ELISA of Sanquin Diagnostics (Amsterdam, The Netherlands). Therapeutic consequences were evaluated by dividing patients into four treatment groups using cut-off levels of 1, 3 and 7 μg/mL and determining assay concordance.Within-run and between-run imprecision were acceptable (≤12% and ≤17%, respectively) within the quantification range of the selected ELISA kits. The apDia assay had the best precision and agreement to target values. Statistically significant differences were found between all assays except between Sanquin Diagnostics and the Lisa Tracker assay. The Promonitor assay measured the lowest IFX concentrations, the apDia assay the highest. When patients were classified in four treatment categories, 70% concordance was achieved.Although all assays are suitable for TDM, significant differences were observed in both imprecision and agreement. Therapeutic consequences were acceptable when patients were divided in treatment categories, but this could be improved by assay standardization.

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