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Valentina Gracchi - One of the best experts on this subject based on the ideXlab platform.
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Flucloxacillin decreases tacrolimus blood trough levels: a single-center retrospective cohort study
European Journal of Clinical Pharmacology, 2020Co-Authors: Herman Veenhof, Hugo M. Schouw, Martine T. P. Besouw, Daan J. Touw, Valentina GracchiAbstract:Purpose Tacrolimus and everolimus are widely used to prevent allograft rejection. Both are metabolized by the hepatic cytochrome P450 (CYP) enzyme CYP3A4 and are substrate for P-glycoprotein (P-gp). Drugs influencing the activity or expression of CYP enzymes and P-gp can cause clinically relevant changes in the metabolism of immunosuppressants. Several case reports have reported that Flucloxacillin appeared to decrease levels of drugs metabolized by CYP3A4 and P-gp. The magnitude of this decrease has not been reported yet. Methods In this single-center retrospective cohort study, we compared the tacrolimus and everolimus blood trough levels (corrected for the dose) before, during, and after Flucloxacillin treatment in eleven transplant patients (tacrolimus n = 11 patients, everolimus n = 1 patient, Flucloxacillin n = 11 patients). Results The median tacrolimus blood trough level decreased by 37.5% (interquartile range, IQR 26.4–49.7%) during Flucloxacillin treatment. After discontinuation of Flucloxacillin, the tacrolimus blood trough levels increased by a median of 33.7% (IQR 22.5–51.4%). A Wilcoxon signed-rank test showed statistically significantly lower tacrolimus trough levels during treatment with Flucloxacillin compared with before ( p = 0.009) and after Flucloxacillin treatment ( p = 0.010). In the only available case with concomitant everolimus and Flucloxacillin treatment, the same pattern was observed. Conclusions Flucloxacillin decreases tacrolimus trough levels, possibly through a CYP3A4 and/or P-gp-inducing effect. It is strongly recommended to closely monitor tacrolimus and everolimus trough levels during Flucloxacillin treatment and up to 2 weeks after discontinuation of Flucloxacillin.
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Flucloxacillin decreases tacrolimus blood trough levels a single center retrospective cohort study
European Journal of Clinical Pharmacology, 2020Co-Authors: Herman Veenhof, Hugo M. Schouw, Martine T. P. Besouw, Daan J. Touw, Valentina GracchiAbstract:Tacrolimus and everolimus are widely used to prevent allograft rejection. Both are metabolized by the hepatic cytochrome P450 (CYP) enzyme CYP3A4 and are substrate for P-glycoprotein (P-gp). Drugs influencing the activity or expression of CYP enzymes and P-gp can cause clinically relevant changes in the metabolism of immunosuppressants. Several case reports have reported that Flucloxacillin appeared to decrease levels of drugs metabolized by CYP3A4 and P-gp. The magnitude of this decrease has not been reported yet. In this single-center retrospective cohort study, we compared the tacrolimus and everolimus blood trough levels (corrected for the dose) before, during, and after Flucloxacillin treatment in eleven transplant patients (tacrolimus n = 11 patients, everolimus n = 1 patient, Flucloxacillin n = 11 patients). The median tacrolimus blood trough level decreased by 37.5% (interquartile range, IQR 26.4–49.7%) during Flucloxacillin treatment. After discontinuation of Flucloxacillin, the tacrolimus blood trough levels increased by a median of 33.7% (IQR 22.5–51.4%). A Wilcoxon signed-rank test showed statistically significantly lower tacrolimus trough levels during treatment with Flucloxacillin compared with before (p = 0.009) and after Flucloxacillin treatment (p = 0.010). In the only available case with concomitant everolimus and Flucloxacillin treatment, the same pattern was observed. Flucloxacillin decreases tacrolimus trough levels, possibly through a CYP3A4 and/or P-gp-inducing effect. It is strongly recommended to closely monitor tacrolimus and everolimus trough levels during Flucloxacillin treatment and up to 2 weeks after discontinuation of Flucloxacillin.
Ann K Daly - One of the best experts on this subject based on the ideXlab platform.
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human leukocyte antigen hla b 57 01 restricted activation of drug specific t cells provides the immunological basis for Flucloxacillin induced liver injury
Hepatology, 2013Co-Authors: Manal Monshi, Ann K Daly, Lee Faulkner, Andrew Gibson, Rosalind E Jenkins, John Farrell, Caroline Earnshaw, Ana Alfirevic, Karin Cederbrant, Neil FrenchAbstract:The role of the adaptive immune system in adverse drug reactions that target the liver has not been defined. For Flucloxacillin, a delay in the reaction onset and identification of human leukocyte antigen (HLA)-B*57:01 as a susceptibility factor are indicative of an immune pathogenesis. Thus, we characterize Flucloxacillin-responsive CD4+ and CD8+ T cells from patients with liver injury and show that naive CD45RA+CD8+ T cells from volunteers expressing HLA-B*57:01 are activated with Flucloxacillin when dendritic cells present the drug antigen. T-cell clones expressing CCR4 and CCR9 migrated toward CCL17 and CCL 25, and secreted interferon-gamma (IFN-γ), T helper (Th)2 cytokines, perforin, granzyme B, and FasL following drug stimulation. Flucloxacillin bound covalently to selective lysine residues on albumin in a time-dependent manner and the level of binding correlated directly with the stimulation of clones. Activation of CD8+ clones with Flucloxacillin was processing-dependent and restricted by HLA-B*57:01 and the closely related HLA-B*58:01. Clones displayed additional reactivity against β-lactam antibiotics including oxacillin, cloxacillin, and dicloxacillin, but not abacavir or nitroso sulfamethoxazole. Conclusion: This work defines the immune basis for Flucloxacillin-induced liver injury and links the genetic association to the iatrogenic disease. (HEPATOLOGY 2013;)
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a role for the pregnane x receptor in Flucloxacillin induced liver injury
Hepatology, 2010Co-Authors: Elise Andrews, Martin Armstrong, Jonathan Tugwood, Daniel Swan, Philip Glaves, Munir Pirmohamed, Guruprasad P Aithal, Matthew Wright, Christopher P Day, Ann K DalyAbstract:Drug-induced liver injury (DILI) due to Flucloxacillin is a rare but serious complication of treatment. There is some evidence that Flucloxacillin is a human pregnane X receptor (PXR) agonist. This study was designed to investigate the relevance of PXR to Flucloxacillin toxicity and to identify genes changing in expression in response to Flucloxacillin. Changes in gene expression in human hepatocytes after treatment with 500 μM Flucloxacillin for 72 hours were examined by expression microarray analysis. The ability of Flucloxacillin to act as a PXR agonist was investigated with reporter gene experiments. Flucloxacillin DILI cases (n = 51), drug-exposed controls without toxicity (n = 64), and community controls (n = 90) were genotyped for three common PXR polymorphisms. Luciferase reporter assays were used to assess the significance of a promoter region PXR polymorphism. Seventy-two probe sets representing 50 different genes showed significant changes in expression of 1.2-fold or higher. Most genes showing changes greater than 3-fold were known to be rifampicin-responsive, and this suggested a PXR-dependent mode of regulation. Using a luciferase-everted repeat separated by 6 base pairs element construct, we confirmed that Flucloxacillin was a PXR agonist. We found a difference in the distribution of a PXR polymorphism (rs3814055; C-25385T) between Flucloxacillin DILI cases and controls with the CC genotype associated with an increased risk of disease (odds ratio = 3.37, 95% confidence interval = 1.55-7.30, P = 0.0023). Reporter gene experiments showed lower promoter activity for the C allele than the T allele. Conclusion: Flucloxacillin is a PXR agonist at pharmacologically relevant concentrations, and a functionally significant upstream PXR polymorphism is a risk factor for Flucloxacillin-induced DILI. Hepatology 2010
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hla b 5701 genotype is a major determinant of drug induced liver injury due to Flucloxacillin
Nature Genetics, 2009Co-Authors: Ann K Daly, Peter T Donaldson, Pallav Bhatnagar, Yufeng Shen, Itsik Peer, Aris Floratos, Mark J Daly, David Goldstein, Sally John, Matthew R NelsonAbstract:Ann Daly and colleagues report results of a genome-wide association study to identify common variants associated with drug-induced liver injury due to Flucloxacillin. They show that carriers of the HLA-B*5701 allele in the MHC region are at 80-fold increased risk of developing this severe adverse drug reaction. Drug-induced liver injury (DILI) is an important cause of serious liver disease. The antimicrobial agent Flucloxacillin is a common cause of DILI, but the genetic basis for susceptibility remains unclear. We conducted a genome-wide association (GWA) study using 866,399 markers in 51 cases of Flucloxacillin DILI and 282 controls matched for sex and ancestry. The GWA showed an association peak in the major histocompatibility complex (MHC) region with the strongest association (P = 8.7 × 10−33) seen for rs2395029[G], a marker in complete linkage disequilibrium (LD) with HLA-B*5701. Further MHC genotyping, which included 64 Flucloxacillin-tolerant controls, confirmed the association with HLA-B*5701 (OR = 80.6, P = 9.0 × 10−19). The association was replicated in a second cohort of 23 cases. In HLA-B*5701 carrier cases, rs10937275 in ST6GAL1 on chromosome 3 also showed genome-wide significance (OR = 4.1, P = 1.4 × 10−8). These findings provide new insights into the mechanism of Flucloxacillin DILI and have the potential to substantially improve diagnosis of this serious disease.
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hla b 5701 genotype is a major determinant of drug induced liver injury due to Flucloxacillin
Nature Genetics, 2009Co-Authors: Ann K Daly, Peter T Donaldson, Pallav Bhatnagar, Yufeng Shen, Itsik Peer, Aris Floratos, Mark J Daly, David Goldstein, Sally John, Matthew R NelsonAbstract:Drug-induced liver injury (DILI) is an important cause of serious liver disease. The antimicrobial agent Flucloxacillin is a common cause of DILI, but the genetic basis for susceptibility remains unclear. We conducted a genome-wide association (GWA) study using 866,399 markers in 51 cases of Flucloxacillin DILI and 282 controls matched for sex and ancestry. The GWA showed an association peak in the major histocompatibility complex (MHC) region with the strongest association (P = 8.7 x 10(-33)) seen for rs2395029[G], a marker in complete linkage disequilibrium (LD) with HLA-B*5701. Further MHC genotyping, which included 64 Flucloxacillin-tolerant controls, confirmed the association with HLA-B*5701 (OR = 80.6, P = 9.0 x 10(-19)). The association was replicated in a second cohort of 23 cases. In HLA-B*5701 carrier cases, rs10937275 in ST6GAL1 on chromosome 3 also showed genome-wide significance (OR = 4.1, P = 1.4 x 10(-8)). These findings provide new insights into the mechanism of Flucloxacillin DILI and have the potential to substantially improve diagnosis of this serious disease.
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Flucloxacillin induced liver injury
Toxicology, 2008Co-Authors: Elise Andrews, Ann K DalyAbstract:Flucloxacillin is a common cause of drug-induced liver injury in Europe, affecting in the region of 8.5 in every 100,000 first time users of the drug. The mechanism by which the drug causes the liver injury is currently unknown but it is believed to be influenced by a combination of genetic and environmental factors. This review summarises what is currently known about the disposition of Flucloxacillin in the liver, considers potential mechanisms by which Flucloxacillin may cause the liver injury, and suggests candidate genes which could determine individual susceptibility to Flucloxacillin-induced liver injury.
Jeffrey Lipman - One of the best experts on this subject based on the ideXlab platform.
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optimization of Flucloxacillin dosing regimens in critically ill patients using population pharmacokinetic modelling of total and unbound concentrations
Journal of Antimicrobial Chemotherapy, 2020Co-Authors: Marta Ulldemolins, Jeffrey Lipman, Roger J M Bruggemann, Nynke G L Jager, Reinier M Van Hest, Jiao Xie, Gloria WongAbstract:BACKGROUND: Initial appropriate anti-infective therapy is associated with improved outcomes in patients with severe infections. In critically ill patients, altered pharmacokinetic (PK) behaviour is common and known to influence the achievement of PK/pharmacodynamic targets. OBJECTIVES: To describe population PK and optimized dosing regimens for Flucloxacillin in critically ill patients. METHODS: First, we developed a population PK model, estimated between-patient variability (BPV) and identified covariates that could explain BPV through non-linear mixed-effects analysis, using total and unbound concentrations obtained from 35 adult critically ill patients treated with intermittent Flucloxacillin. Second, we validated the model using external datasets from two different countries. Finally, frequently prescribed dosing regimens were evaluated using Monte Carlo simulations. RESULTS: A two-compartment model with non-linear protein binding was developed and validated. BPV of the maximum binding capacity decreased from 42.2% to 30.4% and BPV of unbound clearance decreased from 88.1% to 71.6% upon inclusion of serum albumin concentrations and estimated glomerular filtration rate (eGFR; by CKD-EPI equation), respectively. PTA (target of 100%fT>MIC) was 91% for patients with eGFR of 33 mL/min and 1 g q6h, 87% for patients with eGFR of 96 mL/min and 2 g q4h and 71% for patients with eGFR of 153 mL/min and 2 g q4h. CONCLUSIONS: For patients with high creatinine clearance who are infected with moderately susceptible pathogens, therapeutic drug monitoring is advised since there is a risk of underexposure to Flucloxacillin. Due to the non-linear protein binding of Flucloxacillin and the high prevalence of hypoalbuminaemia in critically ill patients, dose adjustments should be based on unbound concentrations.
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low Flucloxacillin concentrations in a patient with central nervous system infection the need for plasma and cerebrospinal fluid drug monitoring in the icu
Annals of Pharmacotherapy, 2014Co-Authors: Mohd H Abdulaziz, Jeffrey Lipman, Craig Mcdonald, Brett Mcwhinney, Jacobus P J Ungerer, Jason A RobertsAbstract:Objective: To report the difficulty in achieving and maintaining target antibiotic exposure in critically ill patients with deep-seeded infections. Case Summary: We present a case of a 36-year-old man who was admitted to the intensive care unit with diffuse central nervous system and peripheral methicillin-sensitive Staphylococcus aureus infection (minimum inhibitory concentration; MIC, 1 µg/mL). Owing to the complicated nature of the infection, sequential concentrations of free Flucloxacillin were measured in plasma and cerebrospinal fluid (CSF) and used to direct antibiotic dosing. Unsurprisingly, the trough plasma concentrations of Flucloxacillin were below the MIC (0.2-0.4 µg/mL), and the corresponding CSF concentrations were undetectable (<0.1 µg/mL) with standard intermittent bolus dosing of 2 g every 4 hours. By administering Flucloxacillin by continuous infusion (CI) and increasing the dose to 20 g daily, the plasma (2.2-5.7 µg/mL) and CSF (0.1 µg/mL) levels were increased, albeit lower than the p...
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Flucloxacillin dosing in critically ill patients with hypoalbuminaemia special emphasis on unbound pharmacokinetics
Journal of Antimicrobial Chemotherapy, 2010Co-Authors: Marta Ulldemolins, Jason A Roberts, Steven C Wallis, Jordi Rello, Jeffrey LipmanAbstract:Objectives: To describe the total and unbound plasma concentration –time profiles for highly protein-bound Flucloxacillin (95%–97% protein binding) in critically ill patients with hypoalbuminaemia and without severe renal dysfunction, and to use population pharmacokinetic modelling and Monte Carlo simulations to assess the probability of target attainment against an MIC distribution. Patients and methods: Ten patients with hypoalbuminaemia and receiving Flucloxacillin as part of therapy were enrolled. Sixty-seven total, 67 unbound plasma and 10 urine samples were collected and analysed. Population pharmacokinetic modelling of unbound plasma data and Monte Carlo simulations were then undertaken with NONMEM w . Non-compartmental pharmacokinetic analysis was performed for total plasma concentrations. Results: Total Flucloxacillin V was increased in critically ill patients with hypoalbuminaemia 2-fold compared with healthy volunteer data. Unbound Flucloxacillin concentrations after 2 g bolus fell below 1 mg/L 4 h after the end of the infusion, providing evidence that standard dosing would be insufficient for the treatment of methicillin-susceptible Staphylococcus aureus (MSSA) (MIC ¼2 mg/L). Monte Carlo simulations suggest that continuous infusion of 8 g/24 h Flucloxacillin would enable 100% successful attainment of the pharmacodynamic target, 50% f T. MIC. For more aggressive targets (4 –5× MIC for 100% f T. MIC), continuous infusion of higher doses (i.e. 12 g/24 h) would be required. Conclusions: Administration of standard doses by intermittent bolus is likely to result in underdosing, and continuous infusion of higher doses is more likely to achieve pharmacokinetic –pharmacodynamic targets for the treatment of infections caused by the most common wild type of MSSA. Our data emphasize the importance of using unbound concentrations for determining dosage regimens for highly bound antibiotics.
Daan J. Touw - One of the best experts on this subject based on the ideXlab platform.
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Flucloxacillin decreases tacrolimus blood trough levels: a single-center retrospective cohort study
European Journal of Clinical Pharmacology, 2020Co-Authors: Herman Veenhof, Hugo M. Schouw, Martine T. P. Besouw, Daan J. Touw, Valentina GracchiAbstract:Purpose Tacrolimus and everolimus are widely used to prevent allograft rejection. Both are metabolized by the hepatic cytochrome P450 (CYP) enzyme CYP3A4 and are substrate for P-glycoprotein (P-gp). Drugs influencing the activity or expression of CYP enzymes and P-gp can cause clinically relevant changes in the metabolism of immunosuppressants. Several case reports have reported that Flucloxacillin appeared to decrease levels of drugs metabolized by CYP3A4 and P-gp. The magnitude of this decrease has not been reported yet. Methods In this single-center retrospective cohort study, we compared the tacrolimus and everolimus blood trough levels (corrected for the dose) before, during, and after Flucloxacillin treatment in eleven transplant patients (tacrolimus n = 11 patients, everolimus n = 1 patient, Flucloxacillin n = 11 patients). Results The median tacrolimus blood trough level decreased by 37.5% (interquartile range, IQR 26.4–49.7%) during Flucloxacillin treatment. After discontinuation of Flucloxacillin, the tacrolimus blood trough levels increased by a median of 33.7% (IQR 22.5–51.4%). A Wilcoxon signed-rank test showed statistically significantly lower tacrolimus trough levels during treatment with Flucloxacillin compared with before ( p = 0.009) and after Flucloxacillin treatment ( p = 0.010). In the only available case with concomitant everolimus and Flucloxacillin treatment, the same pattern was observed. Conclusions Flucloxacillin decreases tacrolimus trough levels, possibly through a CYP3A4 and/or P-gp-inducing effect. It is strongly recommended to closely monitor tacrolimus and everolimus trough levels during Flucloxacillin treatment and up to 2 weeks after discontinuation of Flucloxacillin.
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Flucloxacillin decreases tacrolimus blood trough levels a single center retrospective cohort study
European Journal of Clinical Pharmacology, 2020Co-Authors: Herman Veenhof, Hugo M. Schouw, Martine T. P. Besouw, Daan J. Touw, Valentina GracchiAbstract:Tacrolimus and everolimus are widely used to prevent allograft rejection. Both are metabolized by the hepatic cytochrome P450 (CYP) enzyme CYP3A4 and are substrate for P-glycoprotein (P-gp). Drugs influencing the activity or expression of CYP enzymes and P-gp can cause clinically relevant changes in the metabolism of immunosuppressants. Several case reports have reported that Flucloxacillin appeared to decrease levels of drugs metabolized by CYP3A4 and P-gp. The magnitude of this decrease has not been reported yet. In this single-center retrospective cohort study, we compared the tacrolimus and everolimus blood trough levels (corrected for the dose) before, during, and after Flucloxacillin treatment in eleven transplant patients (tacrolimus n = 11 patients, everolimus n = 1 patient, Flucloxacillin n = 11 patients). The median tacrolimus blood trough level decreased by 37.5% (interquartile range, IQR 26.4–49.7%) during Flucloxacillin treatment. After discontinuation of Flucloxacillin, the tacrolimus blood trough levels increased by a median of 33.7% (IQR 22.5–51.4%). A Wilcoxon signed-rank test showed statistically significantly lower tacrolimus trough levels during treatment with Flucloxacillin compared with before (p = 0.009) and after Flucloxacillin treatment (p = 0.010). In the only available case with concomitant everolimus and Flucloxacillin treatment, the same pattern was observed. Flucloxacillin decreases tacrolimus trough levels, possibly through a CYP3A4 and/or P-gp-inducing effect. It is strongly recommended to closely monitor tacrolimus and everolimus trough levels during Flucloxacillin treatment and up to 2 weeks after discontinuation of Flucloxacillin.
Evan J. Begg - One of the best experts on this subject based on the ideXlab platform.
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Probenecid and food effects on Flucloxacillin pharmacokinetics and pharmacodynamics in healthy volunteers.
The Journal of infection, 2019Co-Authors: Richard J. Everts, John D. Turnidge, Ronald Begg, Sharon J. Gardiner, Mei Zhang, Stephen T. Chambers, Evan J. BeggAbstract:Summary Objectives To measure the effect of probenecid, fasting and fed, on Flucloxacillin pharmacokinetic and pharmacodynamic endpoints. Methods Flucloxacillin 1000 mg orally was given to 11 volunteers alone while fasting (‘Flucloxacillin alone’), and with probenecid 500 mg orally while fasting (‘probenecid fasting’) and with food (‘probenecid fed’). Flucloxacillin pharmacokinetic and pharmacodynamic endpoints were compared. Results Probenecid, fasting and fed, increased free plasma Flucloxacillin area under the concentration-time curve (zero to infinity) ∼1.65-fold (p 80% for Flucloxacillin plus probenecid (fasting or fed) and Conclusions Probenecid increased Flucloxacillin exposure, with predicted pharmacodynamic effects greater than pharmacokinetic effects because of the altered shape of the concentration-time curve. Probenecid may improve the applicability of oral Flucloxacillin regimens.
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total Flucloxacillin plasma concentrations poorly reflect unbound concentrations in hospitalized patients with staphylococcus aureus bacteraemia
British Journal of Clinical Pharmacology, 2018Co-Authors: Paul K L Chin, Sharon J. Gardiner, Mei Zhang, Stephen T. Chambers, Philip G Drennan, Simon C Dalton, Evan J. BeggAbstract:AIMS Flucloxacillin dosing may be guided by measurement of its total plasma concentrations. Flucloxacillin is highly protein bound with fraction unbound in plasma (fu ) of around 0.04 in healthy individuals. The utility of measuring unbound Flucloxacillin concentrations for patients outside the intensive care unit (ICU) is not established. We aimed to compare Flucloxacillin fu in non-ICU hospitalised patients against healthy volunteers, and to examine the performance of a published model for predicting unbound concentrations, using total Flucloxacillin and plasma albumin concentrations. METHODS Data from 12 healthy volunteers (248 samples) and 47 hospitalized patients (61 samples) were examined. Plasma Flucloxacillin concentrations were measured using a validated liquid chromatography-tandem mass spectrometry method. Flucloxacillin fu for the two groups was compared using a generalized estimating equation model to account for clustered observations. The performance of the single protein binding site prediction model in hospitalized patients was compared with measured unbound concentrations using Bland-Altman plots. RESULTS The median (range) Flucloxacillin fu for healthy (median albumin 45 g l-1 ) and hospitalized individuals (median albumin 30 g l-1 ) were 0.04 (0.02-0.07) and 0.10 (0.05-0.37), respectively (P < 0.0001). The prediction model underpredicted unbound Flucloxacillin concentrations with a mean bias (95% limits of agreement) of -54% (-137%, +30%). CONCLUSIONS The Flucloxacillin fu values observed in our cohort of hospitalized patients had a wide range and were greater than those of healthy individuals. Unbound Flucloxacillin plasma concentrations were predicted poorly by the model. Instead, unbound concentrations should be measured to guide dosing.
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in healthy volunteers taking Flucloxacillin with food does not compromise effective plasma concentrations in most circumstances
PLOS ONE, 2018Co-Authors: Sharon J. Gardiner, Richard J. Everts, Ronald Begg, Mei Zhang, Stephen T. Chambers, Philip G Drennan, Jared Green, Heather Isenman, Evan J. BeggAbstract:It is usually recommended that Flucloxacillin is given on an empty stomach. The aim of this study was to compare total and free Flucloxacillin concentrations after oral Flucloxacillin, given with and without food, based on contemporary pharmacokinetic and pharmacodynamic targets. Flucloxacillin 1000 mg orally was given to 12 volunteers, after a standardised breakfast and while fasting, on two separate occasions. Flucloxacillin concentrations over 12 hours were measured by liquid chromatography-tandem mass spectrometry. Pharmacokinetic parameters, and pharmacodynamic endpoints related to target concentration achievement, were compared in the fed and fasting states. For free Flucloxacillin, the fed/fasting area under the concentration-time curve from zero to infinity (AUC0-∞) ratio was 0.80 (p<0.01, 90% CI 0.70-0.92), the peak concentraton (Cmax) ratio 0.51 (p<0.001, 0.42-0.62) and the time to peak concentration (Tmax) ratio 2.2 (p<0.001, 1.87-2.55). The ratios for total Flucloxacillin concentrations were similar. The mean (90% CI) fed/fasting ratios of free concentrations exceeded for 30%, 50% and 70% of the first 6 hours post-dose were 0.74 (0.63-0.87, fed inferior p<0.01), 0.95 (0.81-1.11, bioequivalent) and 1.15 (0.97-1.36, fed non-inferior), respectively. Results for 8 hours post-dose and those predicted for steady state were similar. Comparison of probability of target attainments for fed versus fasting across a range of minimum inhibitory concentrations (MICs) were in line with these results. Overall, this study shows that food reduced the AUC0-∞ and Cmax, and prolonged the Tmax of both free and total Flucloxacillin concentrations compared with the fasting state, but achievement of free concentration targets associated with efficacy was in most circumstances equivalent. These results suggest that taking Flucloxacillin with food is unlikely to compromise efficacy in most circumstances.
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Curves of geometric mean concentrations for the whole group.
2018Co-Authors: Sharon J. Gardiner, Richard J. Everts, Ronald Begg, Mei Zhang, Stephen T. Chambers, Philip G Drennan, Jared K. Green, Heather L. Isenman, Evan J. BeggAbstract:(a) Total Flucloxacillin concentrations, and (b) free Flucloxacillin concentrations in the fed (■) and fasting state (●). Error bars are not shown since statistics were performed on paired differences.
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Free Flucloxacillin concentrations (geometric means) exceeded for 30%, 50% and 70% of 6- and 8-hour dose intervals in the fed and fasting states.
2018Co-Authors: Sharon J. Gardiner, Richard J. Everts, Ronald Begg, Mei Zhang, Stephen T. Chambers, Philip G Drennan, Jared K. Green, Heather L. Isenman, Evan J. BeggAbstract:The ratio fed/fasting (geometric mean ± 90% CI) following 1000 mg oral Flucloxacillin is also provided based on raw data, and modelled to steady-state.