1,721,007 research outputs found
An innovative population pharmacokinetic/pharmacodynamic strategy for attaining aggressive joint PK/PD target of continuous infusion ceftazidime/avibactam against KPC- and OXA-48- producing Enterobacterales and preventing resistance development in critically ill patients
No full textObjectives Ceftazidime/avibactam is a key antibiotic for carbapenemase-producing Enterobacterales (CPE) Gram-negative infections, but current dosing may be suboptimal to grant activity. This study explores the population pharmacokinetics/pharmacodynamics (PK/PD) of continuous infusion (CI) ceftazidime/avibactam for maximizing treatment efficacy in critically ill patients.Methods A retrospective analysis of adult patients receiving CI ceftazidime/avibactam and therapeutic drug monitoring (TDM) of both compounds was performed. Population PK/PD modelling identified the most accurate method for estimating ceftazidime/avibactam clearance based on kidney function and Monte Carlo simulations investigated the relationship between various CI dosing regimens and aggressive joint PK/PD target attainment of ceftazidime/avibactam.Results The European Kidney Function Consortium (EKFC) equation best described kidney function for ceftazidime/avibactam clearance. The findings challenge the current approach of only reducing the ceftazidime/avibactam dose based on kidney function by identifying dose adjustments in patients with augmented kidney function. Our CI ceftazidime/avibactam dosing strategies, adjusted by TDM, showed promise for achieving optimal aggressive joint PK/PD targets and potentially improving clinical/microbiological outcomes against KPC- and OXA-48-producing Enterobacterales. The risk of neurotoxicity associated with these strategies appears acceptable.Conclusions This study suggests that adjusting ceftazidime/avibactam dosing regimen based solely on eCLcr might be suboptimal for critically ill patients. Higher daily doses delivered by CI and adjusted based on TDM have the potential to improve aggressive joint PK/PD target attainment and potentially clinical/microbiological outcomes. Further investigations are warranted to confirm these findings and establish optimal TDM-guided dosing strategies for ceftazidime/avibactam in clinical practice
Reappraisal of Linezolid Dosing in Renal Impairment to Improve Safety
No full textLinezolid is administered as a fixed dose to all patients despite evidence of increased exposure and myelosuppression in renal impairment. The objectives of these studies were to assess the risk of thrombocytopenia with standard-dose linezolid in renal impairment and to identify an alternate dosing strategy. In Study 1, data from adult patients receiving linezolid for ≥ 10 days were retrospectively reviewed to determine the frequency of thrombocytopenia in patients with and without renal impairment. Time-to-event analyses were performed using Cox proportional hazards models. In Study 2, population pharmacokinetic modeling was employed to build covariate-structured models using an independent dataset of linezolid concentrations obtained during routine therapeutic drug monitoring (TDM). Monte Carlo simulations were performed to identify linezolid dosing regimens that maximize attainment of therapeutic trough concentrations (2-8 mg/L) across various renal function groups. Toxicity analysis (Study 1) included 341 patients, 133 (39.0%) with renal impairment. Thrombocytopenia occurred more frequently among patients with renal impairment (42.9% vs 16.8%, p < 0.001), and renal impairment was independently-associated with this toxicity in multivariable analysis (aHR 2.37, 95% CI 1.52 - 3.68). Pharmacokinetic analyses (Study 2) included 1309 linezolid concentrations from 603 adult patients. Age, body surface area, and estimated glomerular filtration rate (eGFR) were identified as covariates of linezolid clearance. Linezolid dose reductions improved the probability of achieving optimal exposures in simulated patients with eGFR < 60 mL/min. Thrombocytopenia occurs more frequently in patients with renal impairment receiving standard linezolid doses. Linezolid dose reduction and trough-based TDM is predicted to mitigate this treatment-limiting toxicity
Pharmacokinetics and Pharmacodynamics of Continuous Infusion Meropenem in Overweight, Obese, and Morbidly Obese Patients with Stable and Unstable Kidney Function: A Step Toward Dose Optimization for the Treatment of Severe Gram-Negative Bacterial Infections
No full textBACKGROUND:
Meropenem is an anti-Gram-negative antimicrobial, the time-dependent activity of which may be maximized through administration by continuous infusion.
OBJECTIVES:
The objectives of this study were to characterize the pharmacokinetics of continuous infusion meropenem in relation to body size and Cockcroft-Gault estimated creatinine clearance (CLCR) in overweight and obese patients with stable and unstable kidney function with the intent of creating a nomogram for optimal dosing.
PATIENTS AND METHODS:
Patients from a single institution with a body mass index ≥25 kg/m(2) receiving meropenem by continuous infusion with measurement of meropenem steady-state concentrations (C ss) were identified. Individual Bayesian estimates of meropenem volume of distribution of the central compartment (V c) and clearance (CL) were calculated and relationships to body size descriptors and CLCR estimated using these body size descriptors were defined by regression. Kidney function stability was defined based on median absolute deviation, stratification by the ratio of maximum to minimum serum creatinine (SCr) and individual patient-level regression of SCr over time. The influence of kidney function stability on meropenem CL estimation by CLCR was tested.
RESULTS:
A total of 375 patients (77.9 % male) with 846 C ss values (62.4 % of patients with ≥2 measurements) were identified. The median daily dose of meropenem and frequency of infusion bag changes were 2000 mg/day and four times per day, respectively. The meropenem C ss values were ≥16, ≥8, ≥4, and ≥2 mg/L for 41.1, 76.1, 97.4, and 99.9 % of observations, respectively. The median (range) age, weight, and BMI were 66 (24-90) years, 90 (70-250) kg, and 30.8 (25.1-81.6) kg/m(2), respectively. The mean [standard deviation (SD)] serum creatinine at baseline was 1.57 (1.37) mg/dL. The mean (SD) V c was 28.1 (1.36) L and not related to body size, while CL was 8.85 (6.40) L/h and best related to CLCR estimated using adjusted body weight (ABW). The meropenem CL to CLCR relationship was not significantly impacted by the presence or absence of kidney function stability. The user-friendly dosing nomogram based on CLCR estimated using ABW showed that optimal drug exposure [Css ≥ minimum inhibitory concentration (MIC)] may be obtained even against multi-drug resistant (MDR) pathogens when considering dosages up to 1250 mg every 6 h by continuous infusion.
CONCLUSIONS:
Meropenem CL is best estimated using CLCR with ABW in patients with a BMI ≥25 kg/m(2) and this relationship is not altered by unstable kidney function. Application of our dosing nomogram may improve the care of overweight and obese patients with severe MDR Gram-negative infections treated with meropenem by continuous infusion
Levofloxacin dosing regimen in severely morbidly obese patients (BMI ≥40 kg/m2) should be guided by creatinine clearance estimates based on ideal body weight and optimized by therapeutic drug monitoring
No full textBACKGROUND:
Levofloxacin is a commonly prescribed antimicrobial where recommendations exist to reduce doses for renal impairment but not to increase doses for augmented renal function. Morbidly obese patients are increasing in prevalence, and represent a population that can have augmented renal function requiring higher-than-standard doses.
OBJECTIVE:
The current investigation was performed to characterize the pharmacokinetics (PK) and evaluate the influence of alternate body size descriptors and renal function as predictors of levofloxacin clearance (CL) and the area under the curve over 24 h (AUC24).
METHODS:
A database of patients undergoing levofloxacin therapeutic drug monitoring (TDM) were queried to identify patients ≥18 years of age with a body mass index ≥40 kg/m(2). A maximum a posteriori probability Bayesian approach using a two-compartment linear PK model was used to estimate individual PK parameters and AUC24.
RESULTS:
A total of 394 concentration-time data points (peaks and trough) from 68 patients between 98 and 250 kg were evaluated. The median (5th, 95th percentile) daily dose and AUC24 was 1,000 (250, 1,500) mg and 90.7 (44.4, 228) mg·h/L, respectively. Levofloxacin CL was significantly (p 90 % probability of achieving an AUC24 of 50-150 mg·h/L in morbidly obese patients. Subsequent application of TDM and integration with pathogen-specific information could then be applied to tailor the levofloxacin regimen.
CONCLUSIONS:
The proposed approach serves as a relevant alternative to the current fixed-dosing paradigm of levofloxacin in the morbidly obese
Linezolid Population Pharmacokinetics to Improve Dosing in Cardiosurgical Patients: Factoring a New Drug-Drug Interaction Pathway
No full textLinezolid-induced myelosuppresion is likely in cardiosurgical patients due to reduced kidney function and potential drug-drug interactions. We show through population modeling and simulation that lower doses than the standard coupled with therapeutic drug monitoring are necessary in this vulnerable population.Background Linezolid-induced myelosuppression limits optimal therapy in cardiosurgical patients with deep-seated infections at current doses. Methods Adult patients who received a cardiac surgery intervention and linezolid for a documented or presumed serious gram-positive infection were evaluated. Therapeutic monitoring data, dosing, concomitant medications, and other pertinent laboratory data were collected retrospectively. A population pharmacokinetic model was constructed to identify covariates and test potential drug-drug interactions that may account for interpatient variability. Simulations from the final model identified doses that achieve a target therapeutic trough concentration of 2-8 mg/L. Results This study included 150 patients (79.3% male) with sepsis and hospital-acquired pneumonia in 71.7% as the primary indication. The population had a median (minimum-maximum) age, body weight, and estimated glomerular filtration rate (eGFR) of 66 (30-85) years, 76 (45-130) kg, and 46.8 (4.9-153.7) mL/minute, respectively. The standard linezolid dosage regimen achieved the therapeutic range in only 54.7% of patients. Lower-than-standard doses were necessary in the majority of patients (77%). A 2-compartment Michaelis-Menten clearance model with weight, kidney function, and the number of interacting drugs identified as covariates that best fit the concentration-time data was used. Cyclosporine had the greatest effect on lowering the maximum elimination rate (V-max) of linezolid. Empiric linezolid doses of 300-450 mg every 12 hours based on eGFR and the number of interacting medications are suggested by this analysis. Conclusions Lower empiric linezolid doses in cardiosurgical patients may avoid toxicities. Confirmatory studies are necessary to verify these potential drug interactions
Balancing the scales: achieving the optimal beta-lactam to beta-lactamase inhibitor ratio with continuous infusion piperacillin/tazobactam against extended spectrum beta-lactamase producing Enterobacterales
Full text linkPiperacillin/tazobactam (TZP) is administered intravenously in a fixed ratio (8:1) with the potential for inadequate tazobactam exposure to ensure piperacillin activity against Enterobacterales. Adult patients receiving continuous infusion (CI) of TZP and therapeutic drug monitoring (TDM) of both agents were evaluated. Demographic variables and other pertinent laboratory data were collected retrospectively. A population pharmacokinetic approach was used to select the best kidney function model predictive of TZP clearance (CL). The probability of target attainment (PTA), cumulative fraction of response (CFR) and the ratio between piperacillin and tazobactam were computed to identify optimal dosage regimens by continuous infusion across kidney function. This study included 257 critically ill patients (79.3% male) with intra-abdominal, bloodstream, and hospital-acquired pneumonia infections in 89.5% as the primary indication. The median (min-max range) age, body weight, and estimated glomerular filtration rate (eGFR) were 66 (23-93) years, 75 (39-310) kg, and 79.2 (6.4-234) mL/min, respectively. Doses of up to 22.5 g/day were used to optimize TZP based on TDM. The 2021 chronic kidney disease epidemiology equation in mL/min best modeled TZP CL. The ratio of piperacillin:tazobactam increased from 6:1 to 10:1 between an eGFR of <20 mL/min and >120 mL/min. At conventional doses, the PTA is below 90% when eGFR is ≥100 mL/min. Daily doses of 18 g/day and 22.5 g/day by CI are expected to achieve a >80% CFR when eGFR is 100-120 mL/min and >120-160 mL/min, respectively. Inadequate piperacillin and tazobactam exposure is likely in patients with eGFR ≥ 100 mL/min. Dose regimen adjustments informed by TDM should be evaluated in this specific population
Population Pharmacokinetics and Dosing Considerations for the Use of Linezolid in Overweight and Obese Adult Patients
No full textBACKGROUND:
Linezolid is an anti-Gram-positive antimicrobial agent used at a fixed dose of 600 mg every 12 h.
OBJECTIVES:
The objective of this study was to assess the population pharmacokinetics and pharmacodynamics of linezolid in a retrospective cohort of overweight and obese hospitalized patients.
PATIENTS AND METHODS:
Population pharmacokinetic and Monte Carlo simulations were conducted to assess the probability of target attainment (PTA) of an area under the concentration-time curve from time zero to 24 h (AUC24)/minimum inhibitory concentration (MIC) ratio > 100, defined as the pharmacodynamic target of efficacy, with incremental candidate dosages. Maximum permissible doses were defined as those causing a ≤ 25% of probability of a linezolid trough of > 8.06 mg/L, associated with thrombocytopenia. The cumulative fraction of response was calculated for the permissible linezolid doses by testing the PTA against the MIC distributions of a large collection of Staphylococci and Enterococci.
RESULTS:
A total of 352 trough (minimum) and 293 peak (maximum) linezolid concentrations from 112 patients were included. The final mixed-saturative model accounted for 88% of drug concentrations variability over time, and estimated creatinine clearance [by means of the Chronic Kidney Diseases Epidemiology formula (CrCLCKD-EPI)] was the only covariate that improved the model fit. Dose reduction to 450 mg every 12 h may be optimal for patients with coagulase-negative staphylococcal infections and a CrCLCKD-EPI < 130 mL/min/1.73 m2. Dose escalation to 450 mg every 8 h may be optimal for patients with a CrCLCKD-EPI ≥ 60 mL/min/1.73 m2. Escalation to 600 mg every 8 h should not be recommended due to an unacceptable high risk of thrombocytopenia. Patients with CrCLCKD-EPI ≥ 130 mL/min/1.73 m2 and/or co-medication with P-glycoprotein modulators require therapeutic drug monitoring to optimize linezolid doses.
CONCLUSIONS:
Dosage adjustments of linezolid in this population should be based on CrCLCKD-EPI estimates, rather than on body size descriptors
Pragmatic options for dose optimization of ceftazidime/avibactam with aztreonam in complex patients
No full textAvibactam is a β-lactamase inhibitor that is combined with aztreonam against Enterobacterales co-expressing serine- and metallo-β-lactamases (MBL). Optimal dosing of aztreonam with avibactam is not well-defined in critically ill patients and contingent on ceftazidime/avibactam product labelling
High-Dose Micafungin for Preterm Neonates and Infants with Invasive and Central Nervous System Candidiasis
Full text linkHigh doses of micafungin are advocated in neonates with systemic candidiasis but limited pharmacokinetic (PK) and safety data are available to support their use. Eighteen preterm neonates and infants with systemic candidiasis, 3 with meningitis, were treated for at least 14 days with 8 to 15 mg/kg/day of intravenous micafungin. Plasma concentrations (4 measurements) were determined after the third dose and cerebrospinal-fluid (CSF) concentrations were also obtained in three patients. Population PK analyses were used to identify the optimal model and further validated using external data (n=5). The safety of micafungin was assessed through liver and kidney function biomarkers. The mean (standard deviation) age and weight at administration was 2.33 (1.98) months and 3.24 (1.61) kg, respectively. The optimal PK model was one that scaled plasma clearance to weight and the transaminase ratio. The CSF was sampled in three patients with observed concentrations between 0.80-1.80 mg/L. The model predicted mean (SD) micafungin AUC24 values is 336 (165) h•mg/L with a 10 mg/kg/day dosage. Eighteen of the 23 subjects (78.2%) had clinical resolution of their infection but five had neurologic impairments. Among transaminases, alkaline phosphatase measurements were significantly higher post-treatment with a geometric mean ratio [90% confidence interval] of 1.17 [1.01, 1.37]. Furthermore, marked elevations in gamma-glutamyl transferase (GGT) was observed in three patients treated with 10-15 mg/kg/day doses and improvement in GGT was noted after dose reduction. Higher weight-based doses of micafungin are generally well tolerated in neonates and infants and achieve pharmacokinetic profiles predictive of effect
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