Pharmacokinetic and Pharmacodynamic Properties of Metronidazole in Pediatric Patients With Acute Appendicitis: A Prospective Study

2018 ◽  
Vol 8 (4) ◽  
pp. 297-302 ◽  
Author(s):  
Jason Child ◽  
Xinhui Chen ◽  
Rakesh D Mistry ◽  
Stig Somme ◽  
Christine MacBrayne ◽  
...  
Keyword(s):  
Pediatric Patients ◽  
Inhibitory Concentration ◽  
Area Under The Curve ◽  
Target Area ◽  
Postantibiotic Effect ◽  
Target Attainment ◽  
Once Daily ◽  
Pediatric Hospitals ◽  
Concentration Time ◽  
A Prospective Study

Abstract Background Metronidazole is traditionally dosed every 6–8 hours even though in adults it has a long half-life, concentration-dependent killing, and 3-hour postantibiotic effect. Based on this logic, some pediatric hospitals adopted once-daily dosing for appendicitis, despite limited pharmacokinetics-pharmacodynamics (PK/PD) in children. We studied pediatric patients with appendicitis given metronidazole once daily to determine whether this dosing would meet target area under the curve (AUC)/minimum inhibitory concentration (MIC) ratio of ≥70 for Bacteroides fragilis. Methods One hundred pediatric patients aged 4–17 years had an average of 3 blood draws per patient during the first 24 hours after a 30 mg/kg per dose of intravenous metronidazole. Concentrations of drug were determined using validated liquid chromatography and tandem mass spectrometry. A NONMEM model was constructed for determining PK, followed by Monte Carlo simulations to generate a population of plasma concentration-time AUC of metronidazole and hydroxy-metronidazole. Results Simulated AUC values met target attainment (AUC/MIC ratio of ≥70 to B fragilis MICs) for 96%–100% of all patients for an MIC of 2 mcg/mL. For MICs of 4 and 8 mcg/mL, target attainment ranged from 61% to 97% and 9% to 71%, respectively. Areas under the curve were similar to that of adults receiving 1000 mg and 1500 mg q24, or 500 mg q8 hours. Conclusions Metronidazole, 30 mg/kg per dose, once daily achieved AUC target attainment for B fragilis with an MIC of 2 mcg/mL or less in pediatric appendicitis patients. Based on this and studies in adults, there does not seem to be any PK/PD advantage of more frequent dosing in this population.

scholarly journals Optimization of Vancomycin Dosing to Achieve Target Area Under the Curve in Pediatrics

2021 ◽  
Vol 26 (7) ◽  
pp. 746-752
Author(s):  
Tyler E. Bosley ◽  
Robert J. Kuhn ◽  
Brian Gardner ◽  
Elizabeth B. Autry ◽  
Madeline Fuller ◽  
...  
Keyword(s):  
Acute Kidney Injury ◽  
Area Under Curve ◽  
Pediatric Patients ◽  
Inhibitory Concentration ◽  
Area Under The Curve ◽  
Kidney Injury ◽  
Target Area ◽  
Single Center ◽  
Age Cohorts ◽  
The Mean

OBJECTIVE Vancomycin dosing requirements to achieve a target area under curve/minimum inhibitory concentration (AUC/MIC) of 400 to 600 mg•hr/L have not been established in pediatrics. Dose modeling studies and recent guidelines suggest dosing higher than historical recommendations. This study examines dosing requirements to achieve target AUC/MIC in human pediatric patients. METHODS This retrospective study includes 77 patients, aged 1 month to 18 years, at a single center, who received at least 2 days of intravenous vancomycin with a pharmacokinetic monitoring note and calculated AUC/MIC. Dosing to achieve target AUC/MIC was evaluated by age and indication. Nephrotoxicity was also assessed. RESULTS The mean dose required to achieve target AUC/MIC for all patients was 67.7 mg/kg/day. Adjusting for age, the mean dose required to achieve target AUC/MIC of 400 to 600 mg•hr/L was found to be statistically significantly different among 3 age cohorts: 1 month to 5 years, 6 to 12 years, and 13 to 18 years [F(2,74) = 15.32, p < 0.001], with mean requirements of 79 ± 14.1, 65.6 ± 21.1, and 53.9 ± 17.1 mg/kg/day, respectively. Dosing requirements were also found to be statistically significantly different across indications [F(6,70) = 4.84, p < 0.001]. Acute kidney injury was identified in 5 patients (6.5%). CONCLUSIONS The vancomycin dose required to achieve target AUC/MIC in pediatrics was significantly higher in younger pediatric patients and ranged from 53.9 to 79 mg/kg/day, confirming recent guideline recommendations. Doses can be further adjusted for indication. Nephrotoxicity rates remain low compared with historical rates with single trough monitoring.

scholarly journals Pharmacokinetics of Daptomycin in Critically Ill Pediatric Patients

2018 ◽  
Vol 62 (6) ◽  
Author(s):  
Charalampos Antachopoulos ◽  
Stavroula Ilia ◽  
Paschalis Kadiltzoglou ◽  
Eirini Baira ◽  
Aristides Dokoumetzidis ◽  
...  
Keyword(s):  
Critically Ill ◽  
Drug Exposure ◽  
Pediatric Patients ◽  
Plasma Concentrations ◽  
Therapeutic Drug ◽  
Burn Patients ◽  
Time Curve ◽  
Once Daily ◽  
Concentration Time ◽  
Optimal Drug

ABSTRACT The pharmacokinetics of daptomycin (10 mg/kg once daily) was studied in 4 critically ill pediatric patients aged 8 to 14 yrs. The area under the concentration-time curve from time zero to infinity (AUC 0–∞ ) of plasma concentrations on day 1 ranged between 123.8 to 663.9 μg · h/ml, with lower values observed in septic and burn patients; clearance ranged from 15.1 to 80.7 ml/h/kg. Higher-than-recommended doses of daptomycin may be needed in septic children to ensure optimal drug exposure. Interpatient variability may suggest a role for therapeutic drug monitoring.

scholarly journals Vancomycin for Dialytic Therapy in Critically Ill Patients: Analysis of Its Reduction and the Factors Associated with Subtherapeutic Concentrations

2020 ◽  
Vol 17 (18) ◽  
pp. 6861
Author(s):  
Fernanda Moreira de Freitas ◽  
Welder Zamoner ◽  
Pamela Falbo dos Reis ◽  
André Luís Balbi ◽  
Daniela Ponce
Keyword(s):  
Acute Kidney Injury ◽  
Serum Concentration ◽  
Protective Factor ◽  
Bacterial Resistance ◽  
Inhibitory Concentration ◽  
Area Under The Curve ◽  
Kidney Injury ◽  
Factors Associated ◽  
Intermittent Haemodialysis ◽  
A Prospective Study

This study aimed to evaluate the reduction in vancomycin through intermittent haemodialysis (IHD) and prolonged haemodialysis (PHD) in acute kidney injury (AKI) patients with sepsis and to identify the variables associated with subtherapeutic concentrations. A prospective study was performed in patients admitted at an intensive care unit (ICU) of a Brazilian hospital. Blood samples were collected at the start of dialytic therapy, after 2 and 4 h of treatment and at the end of therapy to determine the serum concentration of vancomycin and thus perform pharmacokinetic evaluation and PK/PD modelling. Twenty-seven patients treated with IHD, 17 treated with PHD for 6 h and 11 treated with PHD for 10 h were included. The reduction in serum concentrations of vancomycin after 2 h of therapy was 26.65 ± 12.64% and at the end of dialysis was 45.78 ± 12.79%, higher in the 10-h PHD group, 57.70% (40, 48–64, 30%) (p = 0.037). The ratio of the area under the curve to minimal inhibitory concentration (AUC/MIC) at 24 h in the PHD group was significantly smaller than at 10 h (p = 0.047). In the logistic regression, PHD was a risk factor for an AUC/MIC ratio less than 400 (OR = 11.59, p = 0.033), while a higher serum concentration of vancomycin at T0 was a protective factor (OR = 0.791, p = 0.009). In conclusion, subtherapeutic concentrations of vancomycin in acute kidney injury (AKI) patients in dialysis were elevated and may be related to a higher risk of bacterial resistance and mortality, besides pointing out the necessity of additional doses of vancomycin during dialytic therapy, mainly in PHD.

scholarly journals Pharmacokinetic Variability and Target Attainment of Fluconazole in Critically Ill Patients

2021 ◽  
Vol 9 (10) ◽  
pp. 2068
Author(s):  
Ruth Van Daele ◽  
Joost Wauters ◽  
Katrien Lagrou ◽  
Raphaël Denooz ◽  
Marie-Pierre Hayette ◽  
...  
Keyword(s):  
Critically Ill ◽  
Trough Concentration ◽  
Critically Ill Patients ◽  
Inhibitory Concentration ◽  
Antifungal Drugs ◽  
Target Attainment ◽  
Augmented Renal Clearance ◽  
Time Curve ◽  
Concentration Time ◽  
Trough Concentrations

Background: Fluconazole is one of the oldest antifungal drugs. Previous studies have raised concerns considering variability in exposure and inadequate target attainment in critically ill patients. The current study aims to define variability and target attainment for fluconazole exposure in a large group of critically ill patients. Methods: In this pharmacokinetic study, daily plasma trough samples and, if possible, 24 h urine samples were collected to determine fluconazole concentration. A minimum target trough concentration of 10–15 mg/L was selected, corresponding to a free area under the concentration–time curve above the minimum inhibitory concentration (fAUC/MIC) of at least 100 for an MIC of 4 mg/L. Covariates that significantly influenced fluconazole exposure were identified. Results: In total, 288 plasma samples from 43 patients, with a median age of 66 years, were included. The median fluconazole trough concentration was 22.9 mg/L. A notable component of the measured concentrations was below the target trough concentrations (13% <10 mg/L and 27% <15 mg/L). The intra- and intersubject variability were 28.3% and 50.5%, respectively. The main covariates determining fluconazole exposure were the administered dose (mg/kg), augmented renal clearance, and renal replacement therapy. Conclusions: Fluconazole trough concentrations are variable in critically ill patients and a considerable number of these concentrations was below the predefined target trough concentrations.

Experience of once-daily aminoglycoside dosing using a target area under the concentration-time curve

1995 ◽  
Vol 25 (3) ◽  
pp. 230-235 ◽  
Author(s):  
M. L. Barclay ◽  
S. B. Duffully ◽  
E. J. Begg ◽  
R. C. Buttimore
Keyword(s):  
Target Area ◽  
Time Curve ◽  
Once Daily ◽  
Concentration Time

scholarly journals Population Pharmacokinetics of Vancomycin and Meropenem in Pediatric Extracorporeal Membrane Oxygenation Support

2021 ◽  
Vol 12 ◽  
Author(s):  
Brenda Zylbersztajn ◽  
Suzanne Parker ◽  
Daniel Navea ◽  
Giannina Izquierdo ◽  
Paula Ortiz ◽  
...  
Keyword(s):  
Pediatric Patients ◽  
Inhibitory Concentration ◽  
Area Under The Curve ◽  
Pediatric Intensive Care ◽  
Central Compartment ◽  
Pharmacokinetic Parameters ◽  
Median Dose ◽  
Dosing Interval ◽  
Infection Treatment ◽  
Extended Infusion

Objective: Describe primary pharmacokinetic/pharmacodynamic (PK/PD) parameters of vancomycin and meropenem in pediatric patients undergoing ECMO and analyze utilized dosing to reach PK/PD target.Design: Prospective, multicentric, population PK analysis.Setting: Two hospitals with pediatric intensive care unit.Patients: Pediatric patients (1 month - 15 years old) receiving vancomycin and meropenem for empiric or definitive infection treatment while ECMO support.Measurements and Main Results: Four serum concentration were obtained for patients receiving vancomycin (n = 9) and three for meropenem (n = 9). The PK/PD target for vancomycin was a ratio of the area under the curve to the minimal inhibitory concentration (AUC/MIC) of &gt;400, and for meropenem was 4 times above MIC for 50% of the dosing interval (fT50% &gt; 4xMIC). Pharmacokinetic modeling was performed using PMetrics 1.5.0. We included nine patients, with 11 PK profiles for each antimicrobial. The median age of patients was 4 years old (2 months - 13 years) and 45% were male. Creatinine clearance (CL) was 183 (30–550) ml/min/1.73 m2. The median dose was 13.6 (range 10–15) mg/kg every 6–12 h and 40 mg/kg every 8–12 h for vancomycin and meropenem, respectively. Two compartment models were fitted. Weight was included as a covariate on volume of the central compartment (Vc) for meropenem. Weight was included as a covariate on both Vc and clearance (CL) and serum creatinine was also included as a covariate on CL for vancomycin. The pharmacokinetic parameters CL and Vc were 0.139 ± 0.102 L/h/kg and 0.289 ± 0.295 L/kg for meropenem and 0.060 ± 0.055 L/h/kg and 0.419 ± 0.280 L/kg for vancomycin, respectively. Across each dosing interval 91% of patients achieved the PK/PD targets for adequate exposure for meropenem and 63.6% for vancomycin.Conclusion: Pharmacokinetic/pharmacodynamic objectives for vancomycin were achieved partially with conventional doses and higher dosing with extended infusion were needed in the case of meropenem.

scholarly journals Designing Fluoroquinolone Breakpoints for Streptococcus pneumoniae by Using Genetics instead of Pharmacokinetics-Pharmacodynamics

2004 ◽  
Vol 48 (9) ◽  
pp. 3630-3635 ◽  
Author(s):  
H. J. Smith ◽  
A. M. Noreddin ◽  
C. G. Siemens ◽  
K. N. Schurek ◽  
J. Greisman ◽  
...  
Keyword(s):  
Monte Carlo ◽  
Streptococcus Pneumoniae ◽  
Monte Carlo Simulations ◽  
Free Drug ◽  
Target Attainment ◽  
Time Curve ◽  
Once Daily ◽  
Concentration Time ◽  
Bacteriological Eradication ◽  
High Level

ABSTRACT We determined fluoroquinolone microbiological resistance breakpoints for Streptococcus pneumoniae by using genetic instead of pharmacokinetic-pharmacodynamic parameters. The proposed microbiological breakpoints define resistance as the MIC at which >50% of the isolates carry quinolone resistance-determining region mutations and/or, if data are available, when Monte Carlo simulations demonstrate a <90% chance of bacteriological eradication. The proposed microbiological resistant breakpoints are as follows (in micrograms per milliliter): gatifloxacin, >0.25; gemifloxacin, >0.03; levofloxacin, >1; and moxifloxacin, >0.12. Monte Carlo simulations of the once daily 400-mg doses of gatifloxacin and 750-mg doses levofloxacin demonstrated a high level of target attainment (free-drug area under the concentration-time curve from 0 to 24 h/MIC ratio of 30) by using these new genetically derived breakpoints.

Predictors of Purchasing a Hearing Aid After an Evaluation Period: A Prospective Study in Dutch Older Hearing Aid Candidates

2019 ◽  
Vol 28 (3S) ◽  
pp. 802-805 ◽  
Author(s):  
Marieke Pronk ◽  
Janine F. J. Meijerink ◽  
Sophia E. Kramer ◽  
Martijn W. Heymans ◽  
Jana Besser
Keyword(s):  
Help Seeking ◽  
Hearing Aid ◽  
Model Performance ◽  
Area Under The Curve ◽  
Secondary Data ◽  
Support Program ◽  
Evaluation Period ◽  
A Prospective Study ◽  
Study Participants ◽  
Baseline Covariates

Purpose The current study aimed to identify factors that distinguish between older (50+ years) hearing aid (HA) candidates who do and do not purchase HAs after having gone through an HA evaluation period (HAEP). Method Secondary data analysis of the SUpport PRogram trial was performed ( n = 267 older, 1st-time HA candidates). All SUpport PRogram participants started an HAEP shortly after study enrollment. Decision to purchase an HA by the end of the HAEP was the outcome of interest of the current study. Participants' baseline covariates (22 in total) were included as candidate predictors. Multivariable logistic regression modeling (backward selection and reclassification tables) was used. Results Of all candidate predictors, only pure-tone average (average of 1, 2, and 4 kHz) hearing loss emerged as a significant predictor (odds ratio = 1.03, 95% confidence interval [1.03, 1.17]). Model performance was weak (Nagelkerke R 2 = .04, area under the curve = 0.61). Conclusions These data suggest that, once HA candidates have decided to enter an HAEP, factors measured early in the help-seeking journey do not predict well who will and will not purchase an HA. Instead, factors that act during the HAEP may hold this predictive value. This should be examined.

Chrono-Pharmacological Study of Once Daily Curative Dose of a Low Molecular Weight Heparin (200IU antiXa/kg of Dalteparin) in Ten Healthy Volunteers

1995 ◽  
Vol 74 (02) ◽  
pp. 660-666 ◽  
Author(s):  
P Mismetti ◽  
J Reynaud ◽  
B Tardy-Poncet ◽  
S Laporte-Simitsidis ◽  
M Scully ◽  
...  
Keyword(s):  
Molecular Weight ◽  
Healthy Volunteers ◽  
Low Molecular Weight Heparin ◽  
Pharmacological Study ◽  
Area Under The Curve ◽  
Factor Xa ◽  
Similar Efficacy ◽  
Low Molecular Weight ◽  
Thrombin Time ◽  
Once Daily

SummaryLow molecular weight heparin (LMWH) is currently prescribed for the treatment of deep vein thrombosis at the dose of 100 IU antiXa/kg twice daily or at a dose of 175 IU antiXa/kg once daily with a similar efficacy. We decided to study the chrono-pharmacology of curative dose of LMWH once daily administrated according to the one previously described with unfractionated heparin (UFH).Ten healthy volunteers participated in an open three-period crossover study according to three 24 h cycles, separated by a wash-out interval lasting 7 days: one control cycle without injection, two cycles with subcutaneous injection of 200 IU antiXa/kg of Dalteparin (Fragmin®) at 8 a.m. or at 8 p.m. Parameters of heparin activity were analysed as maximal values and area under the curve.Activated partial thromboplastin time (APTT), thrombin time (TT), prothrombin time (PT) and tissue factor pathway inhibitor (TFPI) were higher after 8 p.m. injection than after 8 a.m. injection (p <0.05) while no chrono-pharmacological variation of anti factor Xa (AXa) activity was observed. Thus the biological anticoagulant effect of 200 IU antiXa/kg of Dalteparin seems to be higher after an evening injection than after a morning injection.A chrono-therapeutic approach with LMWH, as prescribed once daily, deserves further investigation since our results suggest that a preferential injection time may optimise the clinical efficacy of these LMWH.

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