Trough Concentration Monitoring Research Articles

Mycophenolate Metabolite Trough Concentrations Are Not Well Correlated With Dosing or Adverse Outcomes in Pediatric Heart Transplant Recipients.

Although mycophenolate metabolite trough concentrations in serum are routinely obtained for pediatric orthotopic heart transplant (OHT) recipients, limited data support this practice. We sought to investigate the relationship of mycophenolic acid (MPA) and MPA glucuronide (MPAG) serum concentrations to dosing and adverse outcomes among pediatric OHT patients. This retrospective study included OHT recipients ages 0 to 21 years who received mycophenolate mofetil (MMF) with MPA and MPAG serum trough concentration monitoring. The primary outcome was the relationship between MPA and MPAG serum concentrations and dosing. Secondary outcomes included the relationship of adverse outcomes to either MPA and MPAG concentrations or dosing. A total of 98 patients with 1287 MPA and MPAG trough serum concentrations (each) were included. The median initial MMF dose was 40.3 mg/kg/day (IQR, 35.12-51.83) and 1164.4 mg/m2/day (IQR, 1080.77-1206.86). There was no correlation between either MPA or MPAG serum concentrations and mg/kg dosing, or mg/m2 dosing. When comparing the adverse effect of bone marrow suppression with no adverse effect, the median MPA serum trough concentration was 2 (IQR, 1.1-3.2) versus 1.6 (IQR, 0.8-2.5), p = 0.003. When comparing the adverse effect of infection with no adverse effect, median MPA serum trough concentration was 0.9 (IQR, 0.49-1.7) versus 1.6 (IQR, 0.8-2.5), p < 0.001. The clinical utility of this finding is of uncertain benefit. There was no association between MPAG serum concentrations and any adverse outcome (p = 0.053). We did not identify a correlation between mycophenolate serum trough concentrations and either adverse outcomes or dosing. Based on these results, we discourage routine monitoring of mycophenolate trough concentrations.

Vancomycin associated acute kidney injury in patients with infectious endocarditis: a large retrospective cohort study.

Background: Vancomycin remains the cornerstone antibiotic for the treatment of infective endocarditis (IE). Vancomycin has been associated with significant nephrotoxicity. However, vancomycin associated acute kidney injury (AKI) has not been evaluated in patients with IE. We conducted this large retrospective cohort study to reveal the incidence, risk factors, and prognosis of vancomycin-associated acute kidney injury (VA-AKI) in patients with IE. Methods: Adult patients diagnosed with IE and receiving vancomycin were included. The primary outcome was VA-AKI. Results: In total, 435 of the 600 patients were enrolled. Of these, 73.6% were male, and the median age was 52 years. The incidence of VA-AKI was 17.01% (74). Only 37.2% (162) of the patients received therapeutic monitoring of vancomycin, and 30 (18.5%) patients had reached the target vancomycin trough concentration. Multiple logistic regression analysis revealed that body mass index [odds ratio (OR) 1.088, 95% CI 1.004, 1.179], duration of vancomycin therapy (OR 1.030, 95% CI 1.003, 1.058), preexisting chronic kidney disease (OR 2.291, 95% CI 1.018, 5.516), admission to the intensive care unit (OR 2.291, 95% CI 1.289, 3.963) and concomitant radiocontrast agents (OR 2.085, 95% CI 1.093, 3.978) were independent risk factors for VA-AKI. Vancomycin variety (Lai Kexin vs. Wen Kexin, OR 0.498, 95% CI 0.281, 0.885) were determined to be an independent protective factor for VI-AKI. Receiver operator characteristic curve analysis revealed that duration of therapy longer than 10.75 days was associated with a significantly increased risk of VA-AKI (HR 1.927). Kidney function was fully or partially recovered in 73.0% (54) of patients with VA-AKI. Conclusion: The incidence of VA-AKI in patients with IE was slightly higher than in general adult patients. Concomitant contrast agents were the most alarmingly nephrotoxic in patients with IE, adding a 2-fold risk of VA-AKI. In patients with IE, a course of vancomycin therapy longer than 10.75 days was associated with a significantly increased risk of AKI. Thus, closer monitoring of kidney function and vancomycin trough concentrations was recommended in patients with concurrent contrast or courses of vancomycin longer than 10.75 days.

Real-life use of ceftobiprole for severe infections in a French intensive care unit

Ceftobiprole (CBP) is an anti-methicillin-resistant Staphylococcus aureus (MRSA) cephalosporin with a wide spectrum of activity. We aimed to describe our experience of real-life use of CBP for the treatment of severe infections of critically ill patients with multiple infected sites and related trough CBP concentrations.We performed a retrospective, observational, monocentric study in our intensive care unit (ICU) that included all patients treated with CBP for documented infections between January 2016 and December 2021. We collected demographic, clinical, and microbiological data. When available, we report the CBP trough concentrations. The primary endpoint was clinical cure at the end of treatment. The secondary endpoints were in-hospital mortality and documentation of the carriage of multidrug-resistant (MDR) bacteria not present before CBP treatment.Between January 2016 and December 2021, 47 patients were treated in the ICU with CBP. The main indication for treatment was pneumonia (51%) and most patients presented with associated bacteremia (72%). All infections were polymicrobial. A clinical cure was achieved for nearly 80% of the patients. Only five patients presented new carriage of MDR bacteria. In-hospital mortality was 32%. Out of 21 strains of Enterobacterales for which the MIC was available, 33% were considered to be resistant to CBP according to the EUCAST 2023 clinical breakpoint. Trough CBP concentrations were reported for 16 patients.In our real-life experience, treatment of ICU patients with CBP for polymicrobial severe infections resulted in most cases in a clinical cure. Monitoring of trough concentrations is critical, especially in cases of high MIC.

Does therapeutic drug monitoring (TDM) of trough concentrations suffice for optimizing preemptive therapy with ganciclovir of cytomegalovirus infections in non-renal solid organ transplant recipients?

The aim of this study is to explore the relationship between ganciclovir exposure and clinical efficacy and/or safety in non-renal solid organ transplant (SOT) recipients receiving preemptive therapy with ganciclovir/valganciclovir and undergoing therapeutic drug monitoring (TDM)-guided dosing optimization. Non-renal SOT recipients admitted to IRCCS Azienda Ospedaliero-Universitaria of Bologna receiving preemptive therapy with ganciclovir or valganciclovir for active cytomegalovirus (CMV) infection and who underwent at least one TDM were included. Desired ganciclovir Cmin range was set at 1-3mg/L, and average ganciclovir trough concentrations (Cmin ) were calculated for each patient. Reduced CMV viral load below the lower limit of quantification (LLQ) at 30 days and occurrence of myelotoxicity were selected as the primary outcome. Univariate analysis was performed by comparing patients with average Cmin below or above 1 or 3mg/L. Receiver operating characteristic (ROC) curve analysis was performed to identify the average ganciclovir Cmin cut-off predictive for clinical efficacy or toxicity. Twenty-nine out of 89 retrieved patients met the inclusion criteria, with a median (interquartile [IQR]) baseline CMV viral load of 27,163 copies/mL (IQR 13159.75-151340.25 copies/mL). Reduced CMV viral load below the LLQ at 30 days was found in 17 patients (58.6%). No difference was found in the primary outcome between patients showing average Cmin below or above 1mg/L (100.0%vs. 53.8%; p= .25) and/or 3mg/L (65.2%vs. 33.3%; p = .20). ROC analysis did not allow to identify an average Cmin cut-off predictive of clinical efficacy or toxicity. No clear relationship between ganciclovir Cmin and neither CMV eradication nor safety issues was identified.

Tacrolimus pharmacokinetics are influenced by CYP3A5, age, and concomitant fluconazole in pediatric kidney transplant patients.

Tacrolimus, the most common immunosuppressant for organ transplant, has a narrow therapeutic range and is metabolized by CYP3A4/5. Trough concentration monitoring and dosing adjustments are used to reach a therapeutic range. CYP3A5 intermediate and normal metabolizers (*1 allele carriers; IM/NM) demonstrate faster tacrolimus metabolism than poor metabolizers (PM). We analyzed the electronic health records of 93 patients aged <21 years for the first 8 weeks after a kidney transplant between January 2010 and December 2021. The target tacrolimus trough was 10-15 ng/mL in the first 4 weeks and 7-10 ng/mL in the next 4 weeks. Banked DNA was collected and genotyped for CYP3A5*3, *6, *7, and *8 alleles. We found that CYP3A5 IM/NM (n = 21) took longer than PM (n = 72) to reach the therapeutic range (7 vs. 4 days, p = 0.048). IM/NM had more dose adjustments (8 vs. 6, p = 0.025) and needed >150% of the required daily dose compared with PM. The concentration/dose ratio was influenced by age and concomitant fluconazole (p = 0.0003, p = 0.034, respectively) and the average daily dose decreases with age in CYP3A5 PM (p = 0.001). Tremors were more common in patients who ever had a trough concentration >15 ng/mL compared with those who never had a trough concentration >15 ng/mL (OR 3.31, 95% CI 1.03-8.98, p = 0.038). Using standard dosing, CYP3A5 IM/NM took longer to reach the goal range and require more dose adjustments and higher doses than PM. Preemptive genotyping could decrease the number of dose changes necessary to reach a therapeutic dose. We have implemented pre-transplant CYP3A5 testing at our institution.

Isavuconazonium or posaconazole for antifungal prophylaxis in patients with acute myeloid leukemia

Invasive fungal infection (IFI) prophylaxis is recommended in patients with acute myeloid leukemia (AML) during induction chemotherapy. Posaconazole (POSA) is the recommended agent of choice; however, this medication can be associated with QTc prolongation, hepatotoxicity, and drug-drug interactions. Furthermore, there is conflicting evidence for the role of isavuconazole (ISAV) in this setting as an alternative to POSA. The primary objective of this study was to evaluate the use of ISAV prophylaxis for primary IFI prevention in patients with AML undergoing induction. Additionally, the study investigated the use of ISAV trough concentration monitoring and compared these results to the efficacy of POSA therapeutic drug monitoring (TDM). Other secondary objectives included assessing the rates of toxicities associated with either prophylactic agent. This study analyzed the impact these toxicities had on patient outcomes by examining the need to hold or discontinue therapy. The final endpoint considered the efficacy associated with multiple dosing strategies employed at the study institution. Specifically, this included the use of loading doses or foregoing these when initiating prophylaxis. This was a retrospective, single-center, cohort study. Patients included in this study were adults with AML admitted to Duke University Hospital between June 30, 2016 and June 30, 2021, who received induction chemotherapy and primary IFI prophylaxis for at least 7 days. Exclusion criteria included patients who received concomitant antifungal agents and patients who received antifungal agents as secondary prophylaxis. 241 patients met inclusion criteria with 12 (4.98%) participants in the ISAV group and 229 (95.02%) participants in the POSA group. The IFI incidence in the POSA group was 14.5%, while the ISAV group did not have any occurrences of IFI. No significant difference was found in the rate of IFI occurrence between the two treatment groups (p = 0.3805). Furthermore, it was demonstrated that the use of a loading dose when initiating prophylaxis could impact rates of IFI for this patient population. Due to no difference in incidence, patient specific factors such as concomitant medications and baseline QTc should influence the choice between prophylactic agent.

Drug-drug interaction: decreased posaconazole trough concentrations during concomitant flucloxacillin treatment.

Posaconazole is used as prophylaxis of invasive fungal disease in immune-compromised haematological patients with prolonged neutropenia after intensive chemotherapy. During routine therapeutic drug monitoring of posaconazole, we repeatedly observed low posaconazole serum concentrations in patients that were concomitantly treated with flucloxacillin. A possible interaction between flucloxacillin and posaconazole was explored in this case series. Posaconazole trough serum concentrations during and before/after flucloxacillin treatment were collected from 10 patients. With a median concentration of 0.5 mg/L (IQR 0.3-0.6), the posaconazole trough serum concentration decreased by 47% during flucloxacillin treatment compared with the concentration before/after flucloxacillin treatment (0.9 mg/L, IQR 0.6-1.3). As a result, the posaconazole target trough concentration of ≥0.7 mg/L was only achieved in five out of nine patients during flucloxacillin treatment. Careful monitoring of posaconazole serum trough concentrations is recommended when concomitant use of flucloxacillin cannot be avoided.

Positive correlation between voriconazole trough concentrations and C-reactive protein levels in patients with chronic pulmonary aspergillosis: A retrospective cohort study

BackgroundVoriconazole (VRCZ) is the first-line treatment for chronic pulmonary aspergillosis (CPA). VRCZ trough concentration monitoring is recommended for adequate therapy because VRCZ concentrations vary widely. However, factors associated with variations in VRCZ concentrations, especially in the same patient at different time points, have not been identified. The objective of this study was to identify factors influencing VRCZ trough concentrations. Patients and methodsThis single-center retrospective study conducted at our institute between April 2014 and August 2016 included patients with CPA who received VRCZ. Patient trough concentrations were measured more than twice while the patients received the same dose using the same administration route (defined as one series). A step-wise method and multiple regression analysis were used to test the effects of patient characteristics on VRCZ trough concentrations. ResultsSixty-nine series in 49 patients were analyzed. VRCZ was administered orally in 59 series, intravenously in 7 series, and by dry syrup in 3 series. The median VRCZ trough concentration and the median variation in VRCZ concentrations were 1.68 and 0.99 μg/ml, respectively. In the simple regression analysis, creatinine, alkaline phosphatase, C-reactive protein (CRP), and creatinine clearance significantly correlated with VRCZ concentrations. Multiple regression analysis demonstrated a significant positive correlation between CRP and VRCZ concentration (P < 0.0001). ConclusionIn patients with CPA, VRCZ concentration correlated with CRP levels in the same patients receiving the same dose of VRCZ at different time points.

What Is the Best Vancomycin Therapeutic Drug Monitoring Parameter to Assess Efficacy? A Critical Review of Experimental Data and Assessment of the Need for Individual Patient Minimum Inhibitory Concentration Value

Therapeutic drug monitoring is recommended for the use of vancomycin, but a recent widely publicized US medical society consensus statement has changed the suggested optimal method(s) of dose adjustment. Specifically, 24 h area under the curve (AUC24)-based monitoring is has been recommended for vancomycin in preference to monitoring of trough concentrations. One reason cited for this change is the claim that AUC24 is a superior correlate to efficacy than trough (Cmin). Evidence from a number of retrospective analyses have been critically reviewed and determined to have weaknesses. This narrative review focuses on the experimental studies performed in vivo in animal models of infection and in vitro to determine the extent to which these data may provide a compelling distinction between pharmacokinetic/pharmacodynamics (PKPD) parameters that may translate to clinical use in therapeutic drug monitoring. Animal in vivo studies have been presented at conferences, but no original peer reviewed studies could be found that compare various PKPD parameters. These conference proceeding findings were supportive but unconvincing, even though they were favorably presented subsequently in review articles and clinical practice guidelines. In vitro data are somewhat conflicting, but the range of concentrations may play a role in the discrepancies found. It has been suggested that MIC may be assumed to have a value of 1 mg/L; however, it can be demonstrated that this assumption may lead to considerable discrepancy from results with an actual MIC value. The AUC24 parameter has been weighed against the percentage of time above the MIC (%T > MIC) as a comparative PKPD parameter, yet this may be an inappropriate comparison for vancomycin since all clinically useful dosing provides 100% T > MIC. Regardless, there is a distinction between clinical TDM parameters and PKPD parameters, so, in practice, the change to AUC24:MIC based on animal experiments and in vitro evidence for vancomycin may be premature.

941. Clinical Outcomes of Vancomycin Area-Under-the-Curve Monitoring: A Quasi-Experimental Study Interim Analysis

Abstract Background The 2020 Infectious Diseases Society of America vancomycin guidelines recommend the use of area-under-the-curve (AUC) monitoring instead of trough concentration monitoring. These guidelines changed due to evidence showing decreased rates of nephrotoxicity and lack of correlation between vancomycin troughs and patient treatment outcomes. Two common methodologies of calculating AUC exist in clinical practice, including two level kinetic calculations and Bayesian software programs. Previous studies used two levels for calculating the AUC. The purpose of this study is to evaluate if the same reduction in acute kidney injury (AKI) is achieved while using a Bayesian software program. Methods This retrospective quasi-experiment was performed at two sites within the same health system. The primary objective of this study was to assess the rate of AKI, as defined by the Acute Kidney Injury Network (AKIN) criteria, between patients receiving vancomycin dosed by trough monitoring as compared to AUC monitoring. Secondary objectives include mean daily dose of vancomycin, number of vancomycin levels, and severity of AKI. Patients were included in the study if they were 18 years or older, with at least one vancomycin concentration drawn. Patients were excluded if they had a baseline serum creatine greater than 2 mg/dL, received renal replacement therapy of any type, or received &amp;gt; 1 doses of vancomycin prior to admission. After screening for inclusion criteria, patients were matched 1:1 based on APACHE II score and vancomycin indication. Results One hundred and thirty patients met inclusion criteria at the interim analysis. Overall, baseline characteristics were similar between groups. No statistical difference was detected regarding the rate of acute kidney injury between the vancomycin trough group and AUC group (12% vs 14% p=0.971). The mean total daily doses of vancomycin were 1642 mg per day in the AUC group and 1838 mg per day in the trough group (p=0.08). Conclusion No statistical difference in rates of AKI were detected at the interim analysis, likely due to small sample size. Further data collection is ongoing to meet power and full results will be presented. Disclosures All Authors: No reported disclosures.

Linezolid-Associated Neuropathy in Patients with MDR/XDR Tuberculosis in Shenzhen, China.

ObjectiveLinezolid is one of the key drugs for the treatment of multidrug-resistant/extensively drug-resistant tuberculosis (MDR/XDR-TB). We aimed to describe the incorporation of the Michigan Neuropathy Screening Instrument (MNSI) and serum trough concentration as screening tools for neurotoxicity in the management of MDR/XDR-TB patients receiving a linezolid-based treatment regimen in Shenzhen, China.MethodsA total of 73 patients on a linezolid-containing anti–MDR/XDR-TB regimen were prospectively enrolled. The MNSI was used for peripheral neuropathy screening. Optic neuropathy was diagnosed by ophthalmologists. Serum trough concentration was recorded and its relationship with neuropathy analyzed.ResultsOf all patients, neuropathy was observed in 40% (29) during anti-TB treatment. Of these, 20 (69%) had peripheral neuritis, seven (24%) optic neuritis, and two (7%) both. Serum trough concentration >2 mg/L was observed in 17 (59%) patients with neuropathy and 13 (30%) patients without neuropathy. There was a significant statistical difference between the two groups (P=0.013). Time to onset of neuropathy from initiation of the linezolid-containing regimen was within 2 months for eight (28%) patients, 2–6 months for 18 (62%) patients, and >6 months for three (10%) patients. Sixteen (55%) patients were adjusted to a lower dose of 300 mg linezolid daily. Four (14%) patients had linezolid permanently removed from their regimen.ConclusionNeuropathy is a commonly reported adverse event associated with long-term use of linezolid. MNSI and serum trough–concentration monitoring can be adopted as simple screening tools for early detection of neuropathy to balance linezolid efficacy and tolerability.

Evaluation of Sirolimus Dosing in Neonates and Infants With Lymphatic Disorders: A Case Series.

Literature in pediatric patients suggests dosing sirolimus 1.6 mg/m2/day divided twice daily for lymphatic disorders with limited evidence available for dosing in neonates and infants. The objective of this research was to determine the sirolimus dose required to achieve therapeutic trough concentrations in infants with lymphatic disorders at Children's Hospital of Philadelphia. This retrospective review included patients <1 year of age at Children's Hospital of Philadelphia who were initiated on sirolimus for lymphatic disorder. Patients were included if they received at least 5 days of consecutive sirolimus therapy prior to trough concentration monitoring. Measures of central tendency and variability were used for statistical analysis. A total of 16 patients met criteria for inclusion. The median initial sirolimus dose was 1 mg/m2/day (IQR, 0.5-1.6 mg/m2/day). Fourteen patients (87.5%) achieved therapeutic trough concentrations on a median sirolimus dose of 0.5 mg/m2/day. Dosing frequency to achieve therapeutic trough concentrations included 1 patient (6.25%) on twice daily dosing, 12 patients (75%) on once daily dosing, and 1 patient (6.25%) requiring every 48-hour dosing. The median time to first therapeutic trough was 15.5 days (IQR, 5.5-18.5 days), and patients required a median of 1 dose adjustment. A median sirolimus dose to achieve therapeutic sirolimus trough concentrations in infants with lymphatic disorders was 0.5 mg/m2/day with a median of 1 dose adjustment. Sirolimus was well tolerated in the study population.

A machine learning model that emulates experts’ decision making in vancomycin initial dose planning

Vancomycin is a glycopeptide antibiotic that is a primary treatment for methicillin-resistant Staphylococcus aureus infections. To enhance its clinical effectiveness and prevent nephrotoxicity, therapeutic drug monitoring (TDM) of trough concentrations is recommended.Initial vancomycin dosing regimens are determined based on patient characteristics such as age, body weight, and renal function, and dosing strategies to achieve therapeutic concentration windows at initial TDM have been extensively studied. Although numerous dosing nomograms for specific populations have been developed, no comprehensive strategy exists for individually tailoring initial dosing regimens; therefore, decision making regarding initial dosing largely depends on each clinician's experience and expertise.In this study, we applied a machine-learning (ML) approach to integrate clinician knowledge into a predictive model for initial vancomycin dosing. A dataset of vancomycin initial dose plans defined by pharmacists experienced in vancomycin TDM (i.e., experts) was used to build the ML model. Although small training sets were used, we established a predictive model with a target attainment rate comparable to those of experts, another ML model, and commonly used vancomycin dosing software. Our strategy will help develop an expert-like predictive model that aids in decision making for initial vancomycin dosing, particularly in settings where dose planning consultations are unavailable.

Nebulized Antibiotics for Healthcare- and Ventilator-Associated Pneumonia.

Global emergence of multidrug-resistant and extensive drug-resistant gram-negative bacteria has increased the risk of treatment failure, especially for healthcare- or ventilator-associated pneumonia (HAP/VAP). Nebulization of antibiotics, by providing high intrapulmonary antibiotic concentrations, represents a promising approach to optimize the treatment of HAP/VAP due to multidrug-resistant and extensive drug-resistant gram-negative bacteria, while limiting systemic antibiotic exposure. Aminoglycosides and colistin methanesulfonate are the most common nebulized antibiotics. Although optimal nebulized drug dosing regimen is not clearly established, high antibiotic doses should be administered using vibrating-mesh nebulizer with optimized ventilator settings to ensure safe and effective intrapulmonary concentrations. When used preventively, nebulized antibiotics reduced the incidence of VAP without any effect on mortality. This approach is not yet recommended and large randomized controlled trials should be conducted to confirm its benefit and explore the impact on antibiotic selection pressure. Compared with high-dose intravenous administration, high-dose nebulized colistin methanesulfonate seems to be more effective and safer in the treatment of ventilator-associated tracheobronchitis and VAP caused by multidrug resistant and extensive-drug resistant gram-negative bacteria. Adjunctive nebulized aminoglycosides could increase the clinical cure rate and bacteriological eradication in patients suffering from HAP/VAP due to multidrug-resistant and extensive drug-resistant gram-negative bacteria. As nebulized aminoglycosides broadly diffuse in the systemic circulation of patients with extensive bronchopneumonia, monitoring of plasma trough concentrations is recommended during the period of nebulization. Large randomized controlled trials comparing high dose of nebulized colistin methanesulfonate to high dose of intravenous colistin methanesulfonate or to intravenous new β-lactams in HAP/VAP due to multidrug-resistant and extensive drug-resistant gram-negative bacteria are urgently needed.

The relationship of vancomycin 24-hour AUC and trough concentration.

Prior to the 2020 release of a joint consensus guideline on monitoring of vancomycin therapy for serious methicillin-resistant Staphylococcus aureus (MRSA) infections, clinicians had escalated vancomycin doses for 2 decades while targeting trough concentrations of 15 to 20 µg/mL, leading to an increased frequency of nephrotoxicity. For MRSA infections, the 2020 guideline recommends adjusting doses to achieve a 24-hour area under the concentration-time curve (AUC) of 400 to 600 µg · h/mL; however, monitoring of trough concentrations has been entrenched for 3 decades. Calculating dose regimens based on AUC will require obtaining an increased number of vancomycin serum concentrations and, possibly, advanced software. The aim of this investigation was to determine the relationship between AUC and trough concentration and the influence of dosing regimen on goal achievement. The relationship between trough concentration and AUC was explored through derivation of an equation based on a 1-compartment model and simulations. 24-hour AUC is related to dosing interval divided by half-life in a nonlinear fashion. The target trough concentration can be individualized to achieve a desired AUC range, and limiting use of large doses (>15-20 mg/kg) can protect against excessive 24-hour AUC with trough-only monitoring. After initially determining pharmacokinetic parameters, subsequent monitoring of AUC can be accomplished using trough concentrations only. Trough concentration may be used as a surrogate for AUC, although the acceptable target trough concentration will vary depending on dosing interval and elimination rate constant. This work included development of an AUC-trough equation to establish a patient-specific target for steady-state trough concentration.

Cystatin C and/or creatinine-based estimated glomerular filtration rate for prediction of vancomycin clearance in long-stay critically ill patients with persistent inflammation, immunosuppression and catabolism syndrome (PICS): a population pharmacokinetics analysis.

Persistent inflammation, immunosuppression and catabolism syndrome (PICS) in critically ill patients are associated with unreliable creatinine (Cr)-based estimated glomerular filtration rate (eGFR) and alteration in vancomycin clearance (CL) due to ongoing muscle wasting and renal dysfunction (RD). Currently, cystatin C (Cys) is of great interest for eGFR due to its muscle independence. Patients receiving intravenous vancomycin with trough concentration monitoring after intensive care unit stay ≥ 14days were retrospectively enrolled. Those with C-reactive protein > 30.0mg/L, lymphocytes count < 0.80 × 109, albumin < 30mg/L and weight loss > 10% were diagnosed with PICS. Impact of PICS on vancomycin trough achievement was analyzed. Plasma Cys and Cr levels with their eGFRs in RD were compared in patients with and without PICS. Furthermore, the performance of eGFRs in predicting vancomycin CL was quantificationally evaluated by population pharmacokinetics (PPK) analysis using the Phoenix NLME software. Of 69 enrolled patients, 32 (46.4%) were PICS. PICS was predictive of Cr-guided vancomycin supratherapeutic trough concentrations (OR = 5.26, P = 0.013). Significant elevation of Cys, not of Cr, was observed in patients with PICS suffering from RD (P = 0.022), causing substantial differences among eGFRs. Fifty-two and 17 patients were enrolled for the modeling group and validation group, respectively. A one-compartment PPK model with first-order elimination adequately described the data of 126 Ctrough. Prediction of vancomycin CL with Cys and Cr-based eGFR (CKD-EPIcys-cr) significantly reduced the interindividual variability of CL (from 75.6 to 28.5%). External validation with 34 Ctrough showed the robustness and accuracy of this model. This study showed the negative impact of PICS on Cr-guided vancomycin trough achievement. PPK model with CKD-EPIcys-cr can be used to optimize vancomycin dosage in patients with PICS.

Characterization of Therapeutic Drug Monitoring Practices of Voriconazole and Posaconazole at a Pediatric Hospital.

To characterize the voriconazole and posaconazole serum trough ordering practices in patients receiving prophylactic and treatment antifungal therapy. A retrospective chart review over a 6-year period of pediatric patients who received voriconazole and/or posaconazole for >24 hours. A total of 113 patients were included in this study and of these patients, 105 received voriconazole and 16 received posaconazole during the study period. Additionally, 167 trough levels were assessed in this study. Only 50% and 54% of levels were considered within goal recommendations for voriconazole and posaconazole, respectively. The median dose required to achieve goal trough concentration was dependent on drug, indication, and dosage form. Lastly, the most common adverse drug reactions (ADRs) were hepatoxicity, QTc prolongation, and CNS changes, which were in concordance with ADRs documented in the clinical trials for voriconazole and posaconazole. Approximately 20% of patients receiving either voriconazole or posaconazole died during the study period and the median trough in both groups was subtherapeutic. Increased monitoring of trough concentrations may be warranted to prevent death or breakthrough invasive fungal infections. Further studies are warranted for assessing the relationship between trough concentrations and treatment outcomes as well as relationship between dosing and achieving goal trough concentrations.

Maintenance Immunosuppression in Solid Organ Transplantation: Integrating Novel Pharmacodynamic Biomarkers to Inform Calcineurin Inhibitor Dose Selection.

Calcineurin inhibitors, the primary immunosuppressive therapy used to preventalloreactivity of transplanted organs, have a narrow therapeutic index. Currently, treatment is individualized based on clinical assessment of the risk of rejection or toxicity guided by trough concentration monitoring. Advances in immune monitoring have identified potential markers that may have value in understanding calcineurin inhibitor pharmacodynamics. Integration of these markers has the potential to complement therapeutic drug monitoring. Existing pharmacokinetic-pharmacodynamic (PK-PD) data is largely limited to correlation between the biomarker and trough concentrations at single time points. Immune related gene expression currently has the most evidence supporting PK-PD integration. Novel biomarker-based approaches to pharmacodynamic monitoring including development of enhanced PK-PD models are proposed to realize the full clinical benefit.

Volumetric absorptive microsampling and dried blood spot microsampling vs. conventional venous sampling for tacrolimus trough concentration monitoring

Objectives Monitoring tacrolimus blood concentrations is important for preventing allograft rejection in transplant patients. Our hospital offers dried blood spot (DBS) sampling, giving patients the opportunity to sample a drop of blood from a fingerprick at home, which can be sent to the laboratory by mail. In this study, both a volumetric absorptive microsampling (VAMS) device and DBS sampling were compared to venous whole blood (WB) sampling. Methods A total of 130 matched fingerprick VAMS, fingerprick DBS and venous WB samples were obtained from 107 different kidney transplant patients by trained phlebotomists for method comparison using Passing-Bablok regression. Bias was assessed using Bland-Altman. A multidisciplinary team pre-defined an acceptance limit requiring >80% of all matched samples within 15% of the mean of both samples. Sampling quality was evaluated for both VAMS and DBS samples. Results 32.3% of the VAMS samples and 6.2% of the DBS samples were of insufficient quality, leading to 88 matched samples fit for analysis. Passing-Bablok regression showed a significant difference between VAMS and WB, with a slope of 0.88 (95% CI 0.81-0.97) but not for DBS (slope 1.00; 95% CI 0.95-1.04). Both VAMS (after correction for the slope) and DBS showed no significant bias in Bland-Altman analysis. For VAMS and DBS, the acceptance limit was met for 83.0% and 96.6% of the samples, respectively. Conclusions VAMS sampling can replace WB sampling for tacrolimus trough concentration monitoring, but VAMS sampling is currently inferior to DBS sampling, both regarding sample quality and agreement with WB tacrolimus concentrations.

Value of venous thromboembolism prophylaxis by enoxaparin with anti-factor Xa trough concentration monitoring in surgical care.

Value of venous thromboembolism prophylaxis by enoxaparin with anti-factor Xa trough concentration monitoring in surgical care.