scholarly journals 1548. Characterizing Cefepime Neurotoxicity: Experience from a Tertiary Care Center Performing β-lactam Therapeutic Drug Monitoring

2019 ◽  
Vol 6 (Supplement_2) ◽  
pp. S565-S565
Author(s):  
Cara Nys ◽  
Natalie Hurst ◽  
Jiajun Liu ◽  
Kartikeya Cherabuddi ◽  
Nicole M Iovine ◽  
...  
Keyword(s):  
Renal Function ◽  
Trough Concentration ◽  
Additional Data ◽  
Care Center ◽  
Tertiary Care ◽  
Therapeutic Drug ◽  
High Likelihood ◽  
Serum Trough ◽  
Trough Concentrations ◽  
New Onset

Abstract Background Based on prior studies, elderly patients and those with renal dysfunction are prone to cefepime (CFP) toxicity. The toxicokinetics and toxicodynamics for CFP are not well established. Lamoth et al. reported a 50% probability of CFP neurotoxicity at a serum trough concentration of ≥22 mg/L, whereas Huwyler et al. observed CFP neurotoxicity when concentrations exceeded 35 mg/L. The objectives of this study were to quantify the incidence of CFP neurotoxicity and to assess the association between CFP concentrations and neurotoxicity. Methods We conducted a retrospective review between March 2016 and May 2018, of adult patients with serum CFP trough concentrations ≥25 mg/L. To be considered a CFP neurotoxicity case, patients were required to fulfill at least two of the NCI criteria for neurological toxicity such as, presence of new-onset confusion, delirium, or drowsiness. Following this, cases were classified as (1) high likelihood of toxicity (HLT) if they either had a neurology consult or EEG findings consistent with CFP toxicity and if their symptoms improved after discontinuation of CFP, (2) possible toxicity (PT) if neurology consult or EEG was absent or if we were unable to assess improvement after CFP was discontinued, or (3) nontoxicity (NT). Cases were independently reviewed by an ID pharmacist and physician. Additional data such as comorbidities, renal function, and use of anti-epileptics were collected. Results One hundred and forty-two patients were included in the analysis. Neurotoxicity (HLT+PT) related to CFP occurred in 18/142 (13%) patients; 67% (12/18) were considered HLT. The median age in the HLT cohort was 68 years (interquartile range [IQR], 57–74), with toxicity occurring a median of 6 days (IQR, 5–8) after starting CFP. At the time of neurotoxicity, HLT patients had diminished renal function with a median SCr of 1.6 mg/dL (IQR, 1.2–2.4) and a corresponding CrCl of 35.8 mL/minute (IQR, 19.2–50.9). The median CFP trough concentration in the HLT patients was 62 mg/L (IQR, 50–73) vs. 70mg/L (IQR, 41–115) in the PT and 42 mg/L (IQR, 31–61) in the NT groups. Conclusion Our data emphasize the need for careful dosing in older patients with renal insufficiency. Interestingly, our study reveals higher cefepime troughs (~3-fold higher) associated with neurotoxicity than previously reported. Disclosures All authors: No reported disclosures.

scholarly journals Vedolizumab Serum Trough Concentrations and Response to Dose Escalation in Inflammatory Bowel Disease

2020 ◽  
Vol 9 (10) ◽  
pp. 3142
Author(s):  
Byron P. Vaughn ◽  
Andres J. Yarur ◽  
Elliot Graziano ◽  
James P. Campbell ◽  
Abhik Bhattacharya ◽  
...  
Keyword(s):  
Dose Escalation ◽  
Trough Concentration ◽  
Clinical Remission ◽  
Clinical Status ◽  
Tertiary Care ◽  
Subsequent Response ◽  
Serum Trough ◽  
Receiver Operator Curve Analysis ◽  
Trough Concentrations ◽  
Tertiary Care Centers

Serum vedolizumab concentrations are associated with clinical response although, it is unknown if vedolizumab concentrations predict response to dose escalation. The aim of this study was to identify if vedolizumab trough concentrations predicted the response to vedolizumab dose escalation. We assessed a retrospective cohort of patients on maintenance vedolizumab dosing at five tertiary care centers with vedolizumab trough concentrations. Multivariate logistic regression was used to control for potential confounders of association of vedolizumab concentration and clinical status. Those who underwent a dose escalation were further examined to assess if vedolizumab trough concentration predicted the subsequent response. One hundred ninety-two patients were included. On multivariate analysis, vedolizumab trough concentration (p = 0.03) and the use of immunomodulator (p = 0.006) were associated with clinical remission. Receiver operator curve analysis identified a cut off of 7.4 μg/mL for clinical remission. Of the fifty-eight patients with dose escalated, 74% of those with a vedolizumab concentration <7.4 μg/mL responded versus 52% of those with a vedolizumab trough concentration ≥7.4 μg/mL (p = 0.08). After adjustment for relevant confounders, the odds ratio for response with vedolizumab concentration <7.4 μg/mL was 3.7 (95% CI, 1.1–13; p = 0.04). Vedolizumab trough concentration are associated with clinical status and can identify individuals likely to respond to dose escalation. However, a substantial portion of patients above the identified cut off still had a positive response. Vedolizumab trough concentration is a potentially helpful factor in determining the need for dose escalation in patients losing response.

scholarly journals Therapeutic Drug Monitoring of Voriconazole in Children from a Tertiary Care Center in China

2018 ◽  
Vol 62 (12) ◽  
Author(s):  
Lin Hu ◽  
Ting-ting Dai ◽  
Le Zou ◽  
Tao-ming Li ◽  
Xuan-sheng Ding ◽  
...  
Keyword(s):  
Therapeutic Drug Monitoring ◽  
Drug Monitoring ◽  
Care Center ◽  
Tertiary Care ◽  
Target Range ◽  
Therapeutic Drug ◽  
Affecting Factors ◽  
Administration Routes ◽  
Asian Children ◽  
Trough Concentrations

ABSTRACT Voriconazole is a broad-spectrum triazole antifungal and the first-line treatment for invasive aspergillosis (IA). The aim of this research was to study the dose adjustments of voriconazole as well as the affecting factors influencing voriconazole trough concentrations in Asian children to optimize its daily administration. Clinical data were analyzed of inpatients 2 to 14 years old who were subjected to voriconazole trough concentration monitoring from 1 June 2015 to 1 December 2017. A total of 138 voriconazole trough concentrations from 42 pediatric patients were included. Voriconazole trough concentrations at steady state ranged from 0.02 to 9.35 mg/liter, with high inter- and intraindividual variability. Only 50.0% of children achieved the target range (1.0 to 5.5 mg/liter) at initial dosing, while 35.7% of children were subtherapeutic, and 14.3% of children were supratherapeutic at initial dosing. There was no correlation between initial trough concentrations and initial dosing. A total of 28.6% of children (12/42) received an adjusted dose according to trough concentrations. Children <6, 6 to 12, and >12 years old required a median oral maintenance dose to achieve the target range of 11.1, 7.2, and 5.3 mg/kg twice daily, respectively (P = 0.043). The average doses required to achieved the target range were 7.7 mg/kg and 5.6 mg/kg, respectively, and were lower than the recommended dosage (P = 0.033 and 0.003, respectively). Affecting factors such as administration routes and coadministration with proton pump inhibitors (PPIs) explained 55.3% of the variability in voriconazole exposure. Therapeutic drug monitoring (TDM) of voriconazole could help to individualize antifungal therapy for children and provide guidelines for TDM and dosing optimization in Asian children.

scholarly journals Use of Therapeutic Drug Monitoring to Characterize Cefepime-Induced Neurotoxicity

2020 ◽  
Author(s):  
Veena Venugopalan ◽  
Cara Nys ◽  
Natalie Hurst ◽  
Yiqing Chen ◽  
Maria Bruzzone ◽  
...  
Keyword(s):  
Renal Function ◽  
Therapeutic Drug Monitoring ◽  
Trough Concentration ◽  
Drug Monitoring ◽  
Hospitalized Patients ◽  
Therapeutic Drug ◽  
Eeg Abnormalities ◽  
Increased Risk ◽  
Trough Concentrations ◽  
The Relationship

AbstractBackgroundThe incidence of cefepime-induced neurotoxicity (CIN) in hospitalized patients is highly variable. Although greater cefepime exposures incite neurotoxicity, data evaluating trough thresholds associated with CIN remains limited. The objectives of this study were to evaluate the incidence of CIN, assess the relationship between cefepime trough concentrations and CIN, investigate clinical factors associated with CIN, and describe electroencephalogram (EEG) abnormalities in CIN.MethodsThis was a retrospective study of adult patients who had received ≥ 5 days of cefepime with ≥ 1 trough concentration > 25 mg/L. Potential CIN cases were identified utilizing neurological symptoms, neurologist assessments, EEG findings and improvement of neurotoxicity after cefepime discontinuation.ResultsOne-hundred and forty-two patients were included. The incidence of CIN was 13% (18/142). The mean cefepime trough concentration in CIN patients was significantly greater than the non-neurotoxicity group (74.2 mg/L ± 41.1 vs. 46.6 mg/L ± 23, p=0.015). Lower renal function (creatinine clearance < 30 ml/min), greater time to therapeutic drug monitoring (TDM) (≥72 hours), and each 1 mg/mL rise in cefepime trough were independently associated with increased risk of CIN. Moderate generalized slowing of the background rhythm was the most common EEG pattern associated with CIN.ConclusionCefepime should be used cautiously in hospitalized patients due to the risk of neurotoxicity. Patients with greater renal function and those who had early cefepime TDM (≤ 72 hours) had lower risk of CIN.

scholarly journals Variability in Trough Total and Unbound Teicoplanin Concentrations and Achievement of Therapeutic Drug Monitoring Targets in Adult Patients with Hematological Malignancy

2017 ◽  
Vol 61 (6) ◽  
Author(s):  
Catherine J. Byrne ◽  
Jason A. Roberts ◽  
Brett McWhinney ◽  
Jerome P. Fennell ◽  
Philomena O'Byrne ◽  
...  
Keyword(s):  
Renal Function ◽  
Body Weight ◽  
Therapeutic Drug Monitoring ◽  
Creatinine Clearance ◽  
Trough Concentration ◽  
Drug Monitoring ◽  
Hematological Malignancy ◽  
Therapeutic Drug ◽  
Factors Associated ◽  
Trough Concentrations

ABSTRACT The objective of this study was to explore the following aspects of teicoplanin use in patients with hematological malignancy: early attainment of target trough concentrations with current high-dose teicoplanin regimens, variability in unbound teicoplanin fractions, factors associated with observed total and unbound trough concentrations, efficacy and toxicity, and renal function estimation. This was a single-center, prospective study. Samples for determination of trough concentrations were taken on days 3, 4, 7, and 10. Total and unbound teicoplanin concentrations were determined using validated high-performance liquid chromatography methods. Regression analyses were used to identify the factors associated with the trough concentration. Thirty teicoplanin-treated adults with hematological malignancy were recruited. Despite the use of dosages higher than the conventional dosages, the proportions of patients with a trough concentration of ≥20 mg/liter at 48 h and at 72 h were 16.7% and 37.9%, respectively. Renal function was significantly negatively associated with total trough concentrations at 48 h and 72 h (P < 0.05). For an average hematological malignancy patient (creatinine clearance = 70 ml/min), sequential loading doses of at least 12 mg/kg of body weight may be needed to achieve early adequate exposure. In the absence of measured creatinine clearance, estimates obtained using the Cockcroft-Gault (total body weight) equation could prove to be an acceptable surrogate. The unbound fractions of teicoplanin were highly variable (3.4 to 18.8%). Higher unbound fractions were observed in patients with low serum albumin concentrations. Teicoplanin was well tolerated. Teicoplanin loading doses higher than those in current use appear to be necessary. Increased dosing is needed in patients with increased renal function. The high variability in protein binding supports the contention for therapeutic drug monitoring of unbound teicoplanin concentrations. (This study has been registered with EudraCT under registration no. 2013-004535-72.)

scholarly journals Evaluating the Relationship between Vancomycin Trough Concentration and 24-Hour Area under the Concentration-Time Curve in Neonates

2018 ◽  
Vol 62 (4) ◽  
pp. e01647-17 ◽  
Author(s):  
Sheng-Hsuan Tseng ◽  
Chuan Poh Lim ◽  
Qi Chen ◽  
Cheng Cai Tang ◽  
Sing Teang Kong ◽  
...  
Keyword(s):  
Steady State ◽  
Trough Concentration ◽  
Therapeutic Drug ◽  
Population Pharmacokinetic ◽  
Time Curve ◽  
Content Type ◽  
Concentration Time ◽  
Vancomycin Trough ◽  
Trough Concentrations ◽  
The Relationship

ABSTRACT Bacterial sepsis is a major cause of morbidity and mortality in neonates, especially those involving methicillin-resistant Staphylococcus aureus (MRSA). Guidelines by the Infectious Diseases Society of America recommend the vancomycin 24-h area under the concentration-time curve to MIC ratio (AUC24/MIC) of >400 as the best predictor of successful treatment against MRSA infections when the MIC is ≤1 mg/liter. The relationship between steady-state vancomycin trough concentrations and AUC24 values (mg·h/liter) has not been studied in an Asian neonatal population. We conducted a retrospective chart review in Singapore hospitals and collected patient characteristics and therapeutic drug monitoring data from neonates on vancomycin therapy over a 5-year period. A one-compartment population pharmacokinetic model was built from the collected data, internally validated, and then used to assess the relationship between steady-state trough concentrations and AUC24. A Monte Carlo simulation sensitivity analysis was also conducted. A total of 76 neonates with 429 vancomycin concentrations were included for analysis. Median (interquartile range) was 30 weeks (28 to 36 weeks) for postmenstrual age (PMA) and 1,043 g (811 to 1,919 g) for weight at the initiation of treatment. Vancomycin clearance was predicted by weight, PMA, and serum creatinine. For MRSA isolates with a vancomycin MIC of ≤1, our major finding was that the minimum steady-state trough concentration range predictive of achieving an AUC24/MIC of >400 was 8 to 8.9 mg/liter. Steady-state troughs within 15 to 20 mg/liter are unlikely to be necessary to achieve an AUC24/MIC of >400, whereas troughs within 10 to 14.9 mg/liter may be more appropriate.

Improving the Identification of Patients at Risk of Postoperative Renal Failure after Cardiac Surgery

2006 ◽  
Vol 104 (1) ◽  
pp. 65-72 ◽  
Author(s):  
Duminda N. Wijeysundera ◽  
Keyvan Karkouti ◽  
W Scott Beattie ◽  
Vivek Rao ◽  
Joan Ivanov
Keyword(s):  
At Risk ◽  
Logistic Regression ◽  
Renal Function ◽  
Cardiac Surgery ◽  
Renal Insufficiency ◽  
Care Center ◽  
Tertiary Care ◽  
Receiver Operating Curve ◽  
Alternative Measure ◽  
Patients At Risk

Background Preoperative renal insufficiency is an important predictor of the need for postoperative renal replacement therapy (RRT). Serum creatinine (sCr) has a limited ability to identify patients with preoperative renal insufficiency because it varies with age, sex, and muscle mass. Calculated creatinine clearance (CrCl) is an alternative measure of renal function that may allow better estimation of renal reserve. Methods Data were prospectively collected for consecutive patients who underwent cardiac surgery requiring cardiopulmonary bypass at a tertiary care center. The relation between CrCl (Cockcroft-Gault equation) and RRT was initially described using descriptive statistics, logistic regression, and receiver operating curve analysis. Based on these analyses, preoperative renal insufficiency was defined as CrCl of 60 ml/min or less. Preoperative renal function was classified as moderate insufficiency (sCr &gt; 133 microM), mild insufficiency (100 microM &lt; sCr &lt; or = 133 microM), occult insufficiency (sCr &lt; or = 100 microM and CrCl &lt; or = 60 ml/min), or normal function (sCr &lt; or = 100 microM and CrCl &gt; 60 ml/min). The independent association of preoperative renal function with RRT was subsequently determined using multiple logistic regression. Results Of the 10,751 patients in the sample, 137 (1.2%) required postoperative RRT. Approximately 13% of patients with normal sCr had occult renal insufficiency. Occult renal insufficiency was independently associated with RRT (odds ratio, 2.80; 95% confidence interval, 1.39-5.33). The magnitude of this risk was similar to patients with mild renal insufficiency (P = 0.73). Conclusions The inclusion of a simple CrCl-based criterion in preoperative assessments may improve identification of patients at risk of needing postoperative RRT.

scholarly journals Are Vancomycin Trough Concentrations Adequate for Optimal Dosing?

2013 ◽  
Vol 58 (1) ◽  
pp. 309-316 ◽  
Author(s):  
Michael N. Neely ◽  
Gilmer Youn ◽  
Brenda Jones ◽  
Roger W. Jelliffe ◽  
George L. Drusano ◽  
...  
Keyword(s):  
Renal Function ◽  
Trough Concentration ◽  
Pharmacokinetic Data ◽  
Full Model ◽  
Full Data ◽  
Time Curve ◽  
Data Set ◽  
Content Type ◽  
Vancomycin Trough ◽  
Trough Concentrations

ABSTRACTThe current vancomycin therapeutic guidelines recommend the use of only trough concentrations to manage the dosing of adults withStaphylococcus aureusinfections. Both vancomycin efficacy and toxicity are likely to be related to the area under the plasma concentration-time curve (AUC). We assembled richly sampled vancomycin pharmacokinetic data from three studies comprising 47 adults with various levels of renal function. With Pmetrics, the nonparametric population modeling package for R, we compared AUCs estimated from models derived from trough-only and peak-trough depleted versions of the full data set and characterized the relationship between the vancomycin trough concentration and AUC. The trough-only and peak-trough depleted data sets underestimated the true AUCs compared to the full model by a mean (95% confidence interval) of 23% (11 to 33%;P= 0.0001) and 14% (7 to 19%;P< 0.0001), respectively. In contrast, using the full model as a Bayesian prior with trough-only data allowed 97% (93 to 102%;P= 0.23) accurate AUC estimation. On the basis of 5,000 profiles simulated from the full model, among adults with normal renal function and a therapeutic AUC of ≥400 mg · h/liter for an organism for which the vancomycin MIC is 1 mg/liter, approximately 60% are expected to have a trough concentration below the suggested minimum target of 15 mg/liter for serious infections, which could result in needlessly increased doses and a risk of toxicity. Our data indicate that adjustment of vancomycin doses on the basis of trough concentrations without a Bayesian tool results in poor achievement of maximally safe and effective drug exposures in plasma and that many adults can have an adequate vancomycin AUC with a trough concentration of <15 mg/liter.

scholarly journals Predictors of Voriconazole Trough Concentrations in Patients with Child–Pugh Class C Cirrhosis: A Prospective Study

Antibiotics ◽  
2021 ◽  
Vol 10 (9) ◽  
pp. 1130
Author(s):  
Yichang Zhao ◽  
Jingjing Hou ◽  
Yiwen Xiao ◽  
Feng Wang ◽  
Bikui Zhang ◽  
...  
Keyword(s):  
Trough Concentration ◽  
Multiple Linear Regression Model ◽  
Therapeutic Drug ◽  
Time Activity ◽  
Bivariate Correlation ◽  
Significant Difference ◽  
Daily Dose ◽  
Pugh Class ◽  
Trough Concentrations ◽  
Class C

This prospective observational study aimed to clinically describe voriconazole administrations and trough concentrations in patients with Child–Pugh class C and to investigate the variability of trough concentration. A total of 144 voriconazole trough concentrations from 43 Child–Pugh class C patients were analyzed. The majority of patients (62.8%) received adjustments. The repeated measured trough concentration was higher than the first and final ones generally (median, 4.33 vs. 2.99, 3.90 mg/L). Eight patients with ideal initial concentrations later got supratherapeutic with no adjusted daily dose, implying accumulation. There was a significant difference in concentrations among the six groups by daily dose (p = 0.006). The bivariate correlation analysis showed that sex, CYP2C19 genotyping, daily dose, prothrombin time activity, international normalized ratio, platelet, and Model for end-stage liver disease score were significant factors for concentration. Subsequently, the first four factors mentioned above entered into a stepwise multiple linear regression model (variance inflation factor <5), implying that CYP2C19 testing makes sense for precision medicine of Child–Pugh class C cirrhosis patients. The equation fits well and explains the 34.8% variety of concentrations (R2 = 0.348). In conclusion, it needs more cautious administration clinically due to no recommendation for Child–Pugh class C patients in the medication label. The adjustment of the administration regimen should be mainly based on the results of repeated therapeutic drug monitoring.

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