scholarly journals Clinical Applicability of Monitoring Antihypertensive Drug Levels in Blood

Hypertension ◽  
2020 ◽  
Vol 76 (1) ◽  
pp. 80-86 ◽  
Author(s):  
Laura E.J. Peeters ◽  
Lida Feyz ◽  
Eric Boersma ◽  
Joost Daemen ◽  
Teun van Gelder ◽  
...  
Keyword(s):  
Antihypertensive Drugs ◽  
Limit Of Detection ◽  
Plasma Concentrations ◽  
False Negative ◽  
Therapeutic Drug ◽  
Model Parameters ◽  
Time Interval ◽  
Drug Levels ◽  
Clinical Applicability ◽  
Drug Concentrations

Dried blood spot (DBS) analysis is a novel analytical method for therapeutic drug monitoring to identify nonadherence to antihypertensive drugs. This study was conducted to evaluate the clinical applicability of measuring drug concentrations of 8 antihypertensive drugs, using DBS and venipuncture. Furthermore, this study aimed to provide more insight into the between-patient variability in drug concentrations. False-negative values from DBS compared with a venipuncture were determined to assess drug adherence. A generalized estimating equation was used to estimate the model parameters, including sex, dose, age, weight, and the time interval, between drug intake and sampling, on the C plasma (drug concentration in plasma). No false-negative values were found when measuring nonadherence using DBS compared with venipuncture. A high variability in C plasma between patients was observed, especially at peak concentrations with a fold change reaching from 2.3 to 35.2. The time of intake was significantly related to the height of the C plasma in 7 of the 8 measured drugs with a P <0.05, but the influence of dose, weight, age, and sex on drug levels differed largely between the measured drugs. DBS is a reliable and convenient method to assess nonadherence to antihypertensive drugs in clinical practice. The C plasma of the 8 antihypertensive drugs in this study show a large interindividual difference, and therefore, low plasma concentrations do not necessarily mean nonadherence. Nonadherence can only be confirmed if drug levels are undetectable, that is, values below the lower limit of detection.

Therapeutic Drug Monitoring of Imatinib and Impact on Clinical Decision Making.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 4820-4820 ◽  
Author(s):  
Carolyn Blasdel ◽  
Yanfeng Wang ◽  
Theodore Lagattuta ◽  
Brian Druker ◽  
Laurie Letvak ◽  
...  
Keyword(s):  
Decision Making ◽  
Drug Monitoring ◽  
Dose Adjustment ◽  
Clinical Decision Making ◽  
Plasma Concentrations ◽  
Clinical Decision ◽  
Therapeutic Drug ◽  
Dose Increase ◽  
Qrt Pcr ◽  
Drug Concentrations

Abstract OBJECTIVES: Imatinib (IM) has demonstrated durable clinical efficacy in the majority of chronic myeloid leukemia (CML) patients. Optimal response may be influenced by multiple innate and external factors, some of which may be controlled by monitoring plasma concentrations of the drug. This abstract reports 6 cases where analyzing plasma IM trough concentrations (Cmin) in patients treated with three commonly used IM doses (400, 600, and 800 mg daily) influenced clinical decision making. METHODS: IM trough blood samples were collected at a time before that day’s IM dosing. Plasma concentrations of IM were determined by a validated LC/MS/MS method. RESULTS: In large population studies of CML patients enrolled in Phase I, II, and III clinical trials, the mean Cmin levels of IM at 400 mg qd, 600 mg qd, and 400 mg bid doses were: 981 (±543, 55%, n=394), 1572 (±1032, 66%, n=14), and 3479 (±1264, 36%, n=14) ng/mL, respectively. Large inter-patient variability was shown at all three doses. Of the 6 cases detailed in the table below, 4 (ID 1, 3, 4, and 5) had dose reduction due to tolerability concerns with subsequent improvement of symptoms following dose adjustment. One patient (ID 2) had a dose increase because of a poor qRT-PCR response. Another (ID 6) had a dose increase due to low plasma IM exposure resulting from drug-drug interaction with phenytoin, a known inducer of CYP3A4 (the major metabolizing isozyme for IM). After dose adjustment, all six patients showed good clinical response to IM treatment. The new mean Cmin value in these patients was 2000 (±471) ng/mL, representing a 24% coefficient of variability. CONCLUSIONS: Although the data is limited, IM drug monitoring proved useful in managing tolerability, lack of efficacy, adherence or potential drug interactions that modulate imatinib drug concentrations. More prospective studies are needed to demonstrate the value of IM drug monitoring in routine clinical practice. Patient ID Age, Sex CML Stage IM Daily Dose 1st Cmin (ng/mL) Reason for Dose Change New Dosing Regimen New Cmin (ng/mL) CP, chronic phase1 1 54, f CP 200 mg bid, Jan 03 3048, Sep 05 transfusion-dependent, anemia, Sep 05 300 mg, Oct 05 2130, Jan 06 2 9, f CP 300 mg, Jan 05 not done qRT-PCR 0.016, Jan 06 400 mg, Jan 06 2341, Jul 06 3 13, f CP 300 mg bid, May 05; 700 mg, Aug 05; 600 mg, Sep 05 1966, Feb 06 nausea, fatigue, arthralgias, myalgia, ongoing 400 mg, Mar 06 1222, May 06 4 67, f CP 400 mg, Feb 05 not done myelosuppression, Mar 05 200 mg, Mar 05 1928, May 06 5 53, f CP 400 mg, Apr 03; 600 mg, May 03; 800 mg, Jul 04 not done inflammatory pulmonary reaction with shortness of breath; dose held, Mar 05 400 mg, Oct 05 2378, May 06 6 73, m CP 350 mg, on phenytoin, Apr 99 35, Jun 99 stopped phenytoin, Jul 99 500 mg, Jul 99 not done; qRT-PCR negative, Jul 06

scholarly journals Therapeutic Drug Monitoring of Piperacillin-Tazobactam Using Spent Dialysate Effluent in Patients Receiving Continuous Venovenous Hemodialysis

2010 ◽  
Vol 55 (2) ◽  
pp. 557-560 ◽  
Author(s):  
Michael J. Connor ◽  
Charbel Salem ◽  
Seth R. Bauer ◽  
Christina L. Hofmann ◽  
Joseph Groszek ◽  
...  
Keyword(s):  
Therapeutic Drug Monitoring ◽  
Drug Monitoring ◽  
Kidney Injury ◽  
Therapeutic Drug ◽  
Plasma Drug ◽  
Drug Dosing ◽  
Drug Levels ◽  
Drug Concentrations ◽  
Continuous Venovenous Hemodialysis ◽  
Dosing Strategies

ABSTRACTSepsis and multisystem organ failure are common diagnoses affecting nearly three-quarters of a million Americans annually. Infection is the leading cause of death in acute kidney injury, and the majority of critically ill patients who receive continuous dialysis also receive antibiotics. Dialysis equipment and prescriptions have gradually changed over time, raising concern that current drug dosing recommendations in the literature may result in underdosing of antibiotics. Our research group directed its attention toward antibiotic dosing strategies in patients with acute renal failure (ARF), and we sought data confirming that patients receiving continuous dialysis and antibiotics actually were achieving therapeutic plasma drug levels during treatment. In the course of those investigations, we explored “fast-track” strategies to estimate plasma drug concentrations. As most antimicrobial antibiotics are small molecules and should pass freely through modern high-flux hemodialyzer filters, we hypothesized that continuous renal replacement therapy (CRRT) effluent could be used as the medium for drug concentration measurement by reverse-phase high-pressure liquid chromatography (HPLC). Here we present the first data demonstrating this approach for piperacillin-tazobactam. Paired blood and dialysate trough-peak-trough samples were drawn from 19 patients receiving piperacillin-tazobactam and continuous venovenous hemodialysis (CVVHD). Total, free, and dialysate drug concentrations were measured by HPLC. Dialysate drug levels predicted plasma free drug levels well (r2= 0.91 and 0.92 for piperacillin and tazobactam, respectively) in all patients. These data suggest a strategy for therapeutic drug monitoring that minimizes blood loss from phlebotomy and simplifies analytic procedures.

scholarly journals Real-life isoniazid and rifampicin plasma concentrations in children: a tool for therapeutic drug monitoring of tuberculosis

2021 ◽  
Vol 21 (1) ◽  
Author(s):  
Chiara Tersigni ◽  
Giulia Boiardi ◽  
Lorenzo Tofani ◽  
Elisabetta Venturini ◽  
Carlotta Montagnani ◽  
...  
Keyword(s):  
Plasma Concentration ◽  
Therapeutic Drug Monitoring ◽  
Drug Monitoring ◽  
Venous Blood ◽  
Plasma Concentrations ◽  
Age Groups ◽  
Real Life ◽  
Therapeutic Drug ◽  
Blood Samples ◽  
Drug Concentrations

Abstract Background Low plasma levels of first-line antitubercular drugs can be counted among the main causes of poor response to antitubercular therapy, and therapeutic drug monitoring has been proposed as a method to promote tailored treatments for both child and adult patients. The main aim of the study was to evaluate serum concentrations of isoniazid (INH) and rifampicin (RIF) and to investigate reasons for sub-therapeutic plasma concentrations in order to fix dosages. Methods Children with TB were prospectively enrolled from January to August 2019. Two venous blood samples were collected (the first at least 15 days after the beginning of antitubercular treatment, and the second between 1 and 8 weeks later). Plasma concentrations were determined by a validated high-performance liquid chromatography method. Results In all, 45 children were included. Seventy blood samples for INH plasma concentration were collected between 120 and 240 min after drug intake. Adjusting for dose (mg/kg/day) and time of INH administration, when considering three different age groups (≤ 2 years, 2–12 years, > 12 years), a statistically significant lower INH plasma concentration was observed in younger children compared to the older age groups in the multivariate analysis (p < 0.001 and p < 0.001). A total of 68 blood samples were evaluated for RIF concentrations. Both for INH and RIF a statistically significant lower plasma concentration was also observed in adolescents (p < 0.001). Fifteen children (15/45, 33%) presented drug concentrations under the referral therapeutic range. Conclusions Based on our findings, monitoring patients’ drug plasma concentrations in children under 2 years of age and in adolescents can make treatment more patient-tailored.

scholarly journals Current therapeutic applications and pharmacokinetic modulations of ivermectin

2019 ◽  
Vol 12 (8) ◽  
pp. 1204-1211 ◽  
Author(s):  
Khan Sharun ◽  
T. S. Shyamkumar ◽  
V. A. Aneesha ◽  
Kuldeep Dhama ◽  
Abhijit Motiram Pawde ◽  
...  
Keyword(s):  
Sustained Release ◽  
Plasma Concentrations ◽  
Oral Route ◽  
Research Trend ◽  
Therapeutic Drug ◽  
Parasitic Diseases ◽  
Therapeutic Applications ◽  
Drug Concentrations ◽  
Wonder Drug ◽  
Long Acting

Ivermectin is considered to be a wonder drug due to its broad-spectrum antiparasitic activity against both ectoparasites and endoparasites (under class of endectocide) and has multiple applications in both veterinary and human medicine. In particular, ivermectin is commonly used in the treatment of different kinds of infections and infestations. By altering the vehicles used in the formulations, the pharmacokinetic properties of different ivermectin preparations can be altered. Since its development, various vehicles have been evaluated to assess the efficacy, safety, and therapeutic systemic concentrations of ivermectin in different species. A subcutaneous route of administration is preferred over a topical or an oral route for ivermectin due to superior bioavailability. Different formulations of ivermectin have been developed over the years, such as stabilized aqueous formulations, osmotic pumps, controlled release capsules, silicone carriers, zein microspheres, biodegradable microparticulate drug delivery systems, lipid nanocapsules, solid lipid nanoparticles, sustained-release ivermectin varnish, sustained-release ivermectin-loaded solid dispersion suspension, and biodegradable subcutaneous implants. However, several reports of ivermectin resistance have been identified in different parts of the world over the past few years. Continuous use of suboptimal formulations or sub-therapeutic plasma concentrations may predispose an individual to resistance toward ivermectin. The current research trend is focused toward the need for developing ivermectin formulations that are stable, effective, and safe and that reduce the number of doses required for complete clinical cure in different parasitic diseases. Therefore, single-dose long-acting preparations of ivermectin that provide effective therapeutic drug concentrations need to be developed and commercialized, which may revolutionize drug therapy and prophylaxis against various parasitic diseases in the near future. The present review highlights the current advances in pharmacokinetic modulation of ivermectin formulations and their potent therapeutic applications, issues related to emergence of ivermectin resistance, and future trends of ivermectin usage. Keywords: ivermectin, ivermectin resistance, pharmacokinetic modulation, therapeutic applications.

scholarly journals Interest of Dosing of Ibrutinib in B-Cell Lymphoid Malignancies: Data from a Real-Life, Phase 4 Study

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 3960-3960
Author(s):  
Anne Calleja ◽  
Sandra De Barros ◽  
Camille Vinson ◽  
Caroline Protin ◽  
Lucie Oberic ◽  
...  
Keyword(s):  
Adverse Events ◽  
B Cell ◽  
Conflicts Of Interest ◽  
Plasma Concentrations ◽  
Real Life ◽  
Therapeutic Drug ◽  
Therapeutic Effects ◽  
Lymphoid Malignancies ◽  
Oncology Nurse ◽  
Drug Concentrations

Abstract Introduction: Therapeutic drug monitoring (TDM) entails the measurement of drug concentrations and the individualization of drug dosages or schedules to maximize therapeutic effects and minimize toxicity. Ibrutinib (IBR), the first-in-class inhibitor of BTK (Bruton tyrosine kinase) is approved for the therapy of relapsed/refractory chronic lymphocytic leukemia (R/R CLL), mantle cell lymphoma (MCL) and Waldenström's disease (WM), at the dose of 420-560mg/d. Drug-drug interactions (DDI), older age, liver diseases have been reported to impact PK parameters of ibrutinib, but dosing is not yet part of clinical practice, despite TDM of imatinib and other kinase inhibitors is routinely used in chronic myeloid leukemia. In this study, we sought to determine whether TDM of ibrutinib should be proposed for patients, in a preliminary cohort of 73 patients included in the PK-e3i trial (NCT02824159). Methods: Serial plasma PK samples were collected at steady-state after one month of therapy in 73 patients: before intake (residual concentration), and then at time 0.5-1-2-4-6h. Key PK parameters for ibrutinib and its metabolite DHD-ibrutinib were calculated: Cmax, Cmin, tmax,AUC24h. Analysis of DDI was made by an oncology pharmacist in 49/73 patients. Treatment-related adverse events were monitored by phonecalls given by an oncology nurse (AMA procedure) and during consultations with hematologist (at least twice a month the first 6 months, then monthly until 12 months, then every 3 months), and severity graded according CTCAE version 4 scale. Efficacy of therapy in CLL patients was assessed with an "effect marker" to demonstrate biological efficacy, the redistribution hyperlymphocytosis seen in 70% of patients the first month of therapy. Results: we reported very similar PK results for ibrutinib as compared to pivotal phase 1 trials in CLL and other B-cell lymphoid malignancies (Advani RH, J Clin Oncol 2013, Byrd JC, New Engl J Med 2013). Mean peak plasma concentrations were observed 1-2h after dosing, Cmax and AUC results showing an important inter-patient heterogeneity. Median Cmax was 150ng/ml (8.2-596ng/ml), and median AUC24h was 412.4 ng h/mL ((32.2-2906 ng h/mL). According to published phase I trials, complete or near complete BTK occupancy was observed in patients with AUCs exceeding 160 ng h/mL, suggesting ibrutinib dose might have been supramaximal in 67 of our patients. Adverse events the first 3 months were seen in 96% (grade 1), 63% (grade 2), 25% (grade 3) and 6.5% (grade 4), respectively. We plotted AUC results for the total cohort of 73 patients (Figure 1), and for 49 patients with adverse events monitoring available at 3 months (9/49 needed drug dose reduction due to toxicity) (Figure 2), both emphasizing the absence of correlations between AUC levels and toxicities. We next splited up toxicities into 10 sub-groups (bleeding, cardiac, liver, muscle, joint, skin, infection, gastro-intestinal, hematologic, neurologic disorders). Again, we could not identify a specific organ toxicity associated with a significant increase of Cmax or AUC24h, nor we could identify a specific DDI signature explaining side effects in our patents (data not shown: 13/49 had CYP3A4 inhibitors, 25/49 had pgp inhibitors). In 45 CLL patients with PK parameters and lymphocyte counts available after one month of therapy, we made the intriguing observation that lower Cmax correlated with the lack of observable, transient hyperlymphocytosis (a class-effect of ibrutinib, correlating with PFS in the Resonate trial) (Figure 3). Altogether, our data did not find any positive correlation between high ibrutinib exposure and efficacy or safety profile. Conclusions: our preliminary results suggested that higher Cmax and AUC24h did not correlate neither to efficacy nor to classical toxicities reported with ibrutinib intake. On one hand, we think that dosing intra-cellular concentrations could be more reliable than in plasma. On the other hand, we could consider TDM of ibrutinib in the context of a clinical trial reducing the doses of drug over time, to limit clinical and financial toxicity of this highly efficient drug. Disclosures No relevant conflicts of interest to declare.

scholarly journals Developing a Nationwide Infrastructure for Therapeutic Drug Monitoring of Targeted Oral Anticancer Drugs: The ON-TARGET Study Protocol

Cancers ◽  
2021 ◽  
Vol 13 (24) ◽  
pp. 6281
Author(s):  
Anna Mc Laughlin ◽  
Eduard Schmulenson ◽  
Olga Teplytska ◽  
Sebastian Zimmermann ◽  
Patrick Opitz ◽  
...  
Keyword(s):  
Therapeutic Drug Monitoring ◽  
Anticancer Drugs ◽  
Drug Monitoring ◽  
Drug Exposure ◽  
Plasma Concentrations ◽  
Blood Sampling ◽  
Therapeutic Drug ◽  
Study Phase ◽  
Blood Samples ◽  
Drug Concentrations

Exposure-efficacy and/or exposure-toxicity relationships have been identified for up to 80% of oral anticancer drugs (OADs). Usually, OADs are administered at fixed doses despite their high interindividual pharmacokinetic variability resulting in large differences in drug exposure. Consequently, a substantial proportion of patients receive a suboptimal dose. Therapeutic Drug Monitoring (TDM), i.e., dosing based on measured drug concentrations, may be used to improve treatment outcomes. The prospective, multicenter, non-interventional ON-TARGET study (DRKS00025325) aims to investigate the potential of routine TDM to reduce adverse drug reactions in renal cell carcinoma patients receiving axitinib or cabozantinib. Furthermore, the feasibility of using volumetric absorptive microsampling (VAMS), a minimally invasive and easy to handle blood sampling technique, for sample collection is examined. During routine visits, blood samples are collected and sent to bioanalytical laboratories. Venous and VAMS blood samples are collected in the first study phase to facilitate home-based capillary blood sampling in the second study phase. Within one week, the drug plasma concentrations are measured, interpreted, and reported back to the physician. Patients report their drug intake and toxicity using PRO-CTCAE-based questionnaires in dedicated diaries. Ultimately, the ON-TARGET study aims to develop a nationwide infrastructure for TDM for oral anticancer drugs.

scholarly journals Therapeutic Drug Monitoring in the Treatment of Active Tuberculosis

2011 ◽  
Vol 18 (4) ◽  
pp. 225-229 ◽  
Author(s):  
Aylin Babalik ◽  
Sharyn Mannix ◽  
Denis Francis ◽  
Dick Menzies
Keyword(s):  
Therapeutic Drug Monitoring ◽  
Drug Monitoring ◽  
Therapeutic Benefit ◽  
Active Tuberculosis ◽  
Therapeutic Drug ◽  
Smear Microscopy ◽  
Retrospective Case ◽  
Drug Levels ◽  
Drug Concentrations ◽  
Culture Conversion

Therapeutic drug monitoring ensures optimal dosing while aiming to reduce toxicity. However, due to the high costs and complexity of testing, therapeutic drug monitoring is not routinely used in the treatment of individuals with active tuberculosis, despite the efficacy demonstrated in several randomized trials. This study reviewed data spanning five years regarding the frequency of finding low drug levels in patients with tuberculosis, the dosing adjustments that were required to achieve adequate levels and the factors associated with low drug levels.BACKGROUND: Therapeutic drug monitoring (TDM) is used to optimize dosing that maximizes therapeutic benefit while minimizing toxicity. In the treatment of active tuberculosis (TB), TDM is not routine, yet low levels of anti-TB drugs can be associated with poorer treatment outcomes.METHODS: In a retrospective case control study, patients with active TB in whom TDM was performed were considered cases and compared with controls who did not undergo TDM, and matched according to year of diagnosis and the results of direct smear microscopy. Medical records were reviewed to abstract demographic, clinical, radiographic and microbiological data including time until smear and culture conversion.RESULTS: In total, 20 patients were identified in whom TDM was performed, of whom 17 (87%) had at least one low drug concentration. Overall, 27 of 45 (60%) initial drug concentrations were low and resulted in an increased drug dosage. Low drug levels were found in 13 of 15 (87%) isoniazid, four of five (80%) rifabutin and eight of 12 (67%) rifampin measurements, but in only two of 13 (15%) pyrazinamide measurements. Within cases only, the 17 patients with low serum drug levels were significantly more likely to have comorbid illnesses, be smear positive, have lower serum albumin levels and had nonsignificantly longer time to culture conversion, compared with the three cases in whom all drug levels were within therapeutic ranges.CONCLUSIONS: TB drug levels were frequently below clinically acceptable levels in patients with active TB, particularly in those with HIV infection or other comorbidities. TDM is potentially useful for the treatment of active TB, but is currently underused.

Evaluation of Therapeutic Drug Monitoring in a Long-Term Care Facility: A Pilot Project

1988 ◽  
Vol 22 (7-8) ◽  
pp. 594-596 ◽  
Author(s):  
Frank Pucino ◽  
Peggy J. Baumgart ◽  
Gordon L. Strommen ◽  
Inger-Lise Silbergleit ◽  
Dave Forbes ◽  
...  
Keyword(s):  
Therapeutic Drug Monitoring ◽  
Drug Monitoring ◽  
Long Term Care ◽  
Care Facility ◽  
Therapeutic Drug ◽  
Term Care ◽  
Drug Levels ◽  
Long Term Care Facility ◽  
Drug Concentrations

The need for a therapeutic drug monitoring service was evaluated in a 150-bed long-term care facility. Thirty blood samples from 28 residents (mean age 87.9 years) were assayed to determine trough drug concentrations. All subjects were examined to determine pharmacodynamic effect. Pharmacokinetic consultations were written for serum drug concentrations outside accepted ranges. Fifty percent (15 of 30) of serum drug levels measured were subtherapeutic; the remaining levels were in the normal therapeutic range. Based on this sample data, it could be concluded that a minimum of 32 percent and as many as 68 percent of serum drug levels would be subtherapeutic following drug analysis in similar nursing home populations. Of 12 consultations, recommendations for seven (58 percent) were accepted by the subject's primary care physicians. Four of the consultations (33 percent) resulted in dosage modifications. These results support the need for further study.

Plasma concentrations resulting from continuous infusion of meropenem in a community-based outpatient program: A case series

2020 ◽  
Vol 77 (24) ◽  
pp. 2074-2080
Author(s):  
Amy Legg ◽  
Melanie Halford ◽  
Kate McCarthy
Keyword(s):  
Continuous Infusion ◽  
Drug Exposure ◽  
Plasma Concentrations ◽  
Case Series ◽  
Infectious Complications ◽  
Antimicrobial Treatment ◽  
Therapeutic Drug ◽  
Community Based ◽  
Drug Concentrations ◽  
Tertiary Center

Abstract Purpose Traditionally meropenem has been considered too unstable in solution for continuous infusion. However, in the era of increasing antimicrobial resistance, use of meropenem is becoming more frequently required, and the ability to facilitate its administration via community-based programs would be beneficial. There are some reassuring data about meropenem stability in solution, but data about actual drug exposure in patients and subsequent clinical outcomes are lacking. Summary Here we present a case series of 4 patients at a single tertiary center who received meropenem via continuous infusion coordinated through an outpatient parenteral antimicrobial treatment (OPAT) program. We provide plasma drug concentrations achieved and report on the patients’ clinical progress. All patients achieved drug concentrations of at least 2 times the minimum inhibitory concentration (MIC) while receiving meropenem via continuous infusion and had resolution of their infectious complications. No adverse effects of meropenem continuous infusion were noted. Conclusion Meropenem continuous infusion along with therapeutic drug monitoring was used successfully in a community-based program. Due to interpatient pharmacokinetic variability, we consider meropenem concentration monitoring compulsory during continuous-infusion meropenem therapy.

scholarly journals Continuous versus intermittent infusion of cefotaxime in critically ill patients: a randomized controlled trial comparing plasma concentrations

2019 ◽  
Author(s):  
Heleen Aardema ◽  
Wouter Bult ◽  
Kai van Hateren ◽  
Willem Dieperink ◽  
Daan J Touw ◽  
...  
Keyword(s):  
Critical Care ◽  
Critically Ill ◽  
Critically Ill Patients ◽  
Plasma Concentrations ◽  
Prolonged Treatment ◽  
Therapeutic Drug ◽  
Drug Concentrations ◽  
Pharmacodynamic Profile ◽  
Continuous Dosing ◽  
Critical Care Patients

Abstract Background In critical care patients, reaching optimal β-lactam concentrations poses challenges, as infections are caused more often by microorganisms associated with higher MICs, and critically ill patients typically have an unpredictable pharmacokinetic/pharmacodynamic profile. Conventional intermittent dosing frequently yields inadequate drug concentrations, while continuous dosing might result in better target attainment. Few studies address cefotaxime concentrations in this population. Objectives To assess total and unbound serum levels of cefotaxime and an active metabolite, desacetylcefotaxime, in critically ill patients treated with either continuously or intermittently dosed cefotaxime. Methods Adult critical care patients with indication for treatment with cefotaxime were randomized to treatment with either intermittent dosing (1 g every 6 h) or continuous dosing (4 g/24 h, after a loading dose of 1 g). We defined a preset target of reaching and maintaining a total cefotaxime concentration of 4 mg/L from 1 h after start of treatment. CCMO trial registration number NL50809.042.14, Clinicaltrials.gov NCT02560207. Results Twenty-nine and 30 patients, respectively, were included in the continuous dosing group and the intermittent dosing group. A total of 642 samples were available for analysis. In the continuous dosing arm, 89.3% met our preset target, compared with 50% in the intermittent dosing arm. Patients not reaching this target had a significantly higher creatinine clearance on the day of admission. Conclusions These results support the application of a continuous dosing strategy of β-lactams in critical care patients and the practice of therapeutic drug monitoring in a subset of patients with higher renal clearance and need for prolonged treatment for further optimization, where using total cefotaxime concentrations should suffice.

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