Optimization of Voriconazole Dosing Regimens Against Aspergillus Species and Candida Species in Pediatric Patients After Hematopoietic Cell Transplantation: A Theoretical Study Based on Pharmacokinetic/Pharmacodynamic Analysis.

This study aimed to optimize the dosing regimens of voriconazole (VRC) for pediatric patients after hematopoietic cell transplantation with different cytochrome P450 (CYP) 2C19 phenotypes and body weights, based on pharmacokinetic (PK)/pharmacodynamic (PD) analysis. The PK parameters of VRC were derived from previous literature. Combined with key factors affecting VRC, patients were categorized into 9 subgroups based on different CYP2C19 phenotypes (poor metabolizer/intermediate metabolizer, normal metabolizer, and rapid metabolizer/ultrarapid metabolizer) and typical body weights (15, 40, and 65 kg). Monte Carlo simulation was used to investigate dosing regimens for different groups. The area under the 24-hour free drug concentration-time curve to the minimum inhibitory concentration (MIC) > 25 was used as the target value for effective treatment. The probability of target achievement and the cumulative fraction of response were determined on the basis of the assumed MICs and MICs distribution frequency of Aspergillus species and Candida species. When the MIC was ≤1 mg/L, 4 mg/kg every 12 hours was sufficient for optimal effects in groups 1-3 and groups 5 and 6; however, 6 mg/kg every 12 hours was required for group 4, and 8 mg/kg every 12 hours was required for groups 7-9. In empirical treatment, lower (2-6 mg/kg every 12 hours) and higher (6-12 mg/kg every 12 hours) dosing regimens were recommended for Candida spp. and Aspergillus spp., respectively. Our findings will assist in selecting appropriate dosing regimens of VRC for pediatric patients after hematopoietic cell transplantation with different CYP2C19 phenotypes and body weights. Clinically, it is better to continuously adjust the dosing on the basis of the therapeutic drug monitoring.

Pharmacokinetic/pharmacodynamic analysis of high-dose tigecycline, by Monte Carlo simulation, in plasma and sputum of patients with hospital-acquired pneumonia.

WHAT IS KNOWN AND OBJECTIVE: To Investigate the pharmacokinetic/pharmacodynamic (PK/PD) parameters of high-dose tigecycline in plasma and sputum of patients with hospital-acquired pneumonia (HAP), and provide a therapeutic regimen of multidrug-resistant bacteria (MDRB) infections. METHODS: Blood/sputum samples were collected at intervals after tigecycline had reached a steady-state. Tigecycline concentrations in specimens were determined by high-performance liquid chromatography (HLPC), PK parameters were evaluated by WinNonlin software using a non-compartment model. The probability of target attainments (PTAs) at different minimal inhibitory concentrations (MICs) were calculated for achieving the PK/PD index with Crystal Ball software by 10,000-patient Monte Carlo Simulation. RESULTS: In plasma, the maximum concentration (Cmax ) and area under the concentration-time curve from 0 to 12 h (AUC0-12h ) were 2.21 ± 0.17 mg/L and 15.29 ± 1.13 h mg/L, respectively. In sputum, they were 2.48 ± 0.21 mg/L and 19.46 ± 1.82 h mg/L, respectively. The mean lung penetration rate was 127.27%. At the MIC ≤4 mg/L, the PTAs in plasma and sputum were 100.00%. When the MIC increased to 8 mg/L, the PTAs in plasma and sputum mostly were < 90.00% according to two criteria. WHAT IS NEW AND CONCLUSION: In this study, we explored PK/PD of high-dose tigecycline in plasma and sputum. From a PK/PD perspective, high-dose tigecycline had greater therapeutic outcomes in HAP treatment caused by MDRB. Antimicrobial-drug concentrations should be determined to optimize their clinical use.

Pharmacokinetic and pharmacodynamic analysis of cefoperazone/sulbactam for the treatment of pediatric sepsis by Monte Carlo simulation.

Pediatric sepsis syndrome is one of the most common reasons for pediatric intensive care unit hospitalization (PICU). Cefoperazone/sulbactam is a time-dependent beta-lactamase inhibitor combination which has been widely used in the treatment of sepsis. But the pharmacokinetic (PK) and pharmacodynamic (PD) data of cefoperazone/sulbactam are unknown in children with sepsis. The present work aimed to determine whether the usual dosing regimens of cefoperazone/sulbactam (1 hour infusion, 50 mg kg-1, every 12 hours) were suitable for these patients in PICU. A total of fourteen patients were enrolled and the PK parameters were estimated by non-compartmental analysis using WinNonlin software. The t1/2 and AUC0-12 of cefoperazone and sulbactam were 3.60 and 1.77 h, and 900.97 and 67.68 h µg mL-1, respectively. The Vd and CL of cefoperazone and sulbactam were 1.65 L and 5.16 L, and 17.41 mL min-1 and 122.62 mL min-1, respectively. The probability of target attainments (PTAs) of cefoperazone at different minimum inhibitory concentrations (MICs) based on the percentage time that concentrations exceed the minimum inhibitory concentration (% T > MIC) value were performed by Monte Carlo simulation and PTA was >90% at MICs ≤16 µg mL-1. The PK/PD profile of dosing regimens tested will assist in selecting the appropriate cefoperazone/sulbactam regimens for these patients. At a target of 80% T > MIC, the usual dosing regimens can provide good coverage for pathogens with MICs of ≤32 µg mL-1. The ratio between cefoperazone and sulbactam at 1 : 1 may be more suitable in pediatric sepsis. Individual dose and therapeutic drug monitoring in clinical practice will help achieve the best therapeutic effect while minimizing toxicity.

Pharmacokinetic/pharmacodynamic analysis of meropenem, by Monte Carlo simulation, in both plasma and cerebrospinal fluid in patients with cerebral hemorrhage after external ventricular drainage
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OBJECTIVE: Patients with cerebral hemorrhage are often prone to intracranial infection, and meropenem is recommended for treatment. But whether the widely used dosing regimen (1 g, 2-hour infusion, every 12 hours) is suitable for antibiotic therapy is still unclear. The purpose of this study was to perform pharmacokinetic/pharmacodynamic (PK/PD) analyses of meropenem in both plasma and cerebrospinal fluid (CSF) in these patients. MATERIALS AND METHODS: Ten patients were enrolled in the present study. The blood samples and CSF samples were taken at predetermined time points and determined by our previously developed HPLC method. Pharmacokinetic parameters were then calculated, and the probability of target attainment (PTA) was calculated by the time that drug concentrations were above the minimum inhibitory concentration (%T>MIC). RESULTS: The peak meropenem concentration (Cmax) of 17.79 ± 3.38 µg/mL in plasma was reached at 2 hours, and the area under the curve (AUC) was 46.95 ± 4.37 h×µg/mL. The Cmax of 6.51 ± 1.11 µg/mL in CSF was reached at 3.50 ± 0.53 hours, and the AUC was 24.53 ± 4.28 h×µg/mL. The average penetration rate of meropenem in these patients was 52.25%. In the case where the MIC value was ≤ 1 µg/mL and using 40%T>MIC as a PK/PD index, the PTA of meropenem in both plasma and CSF were able to provide good coverage with MIC ≤ 1 µg/mL. CONCLUSION: In conclusion, this is the first study on the PK/PD analysis of meropenem in both plasma and CSF in patients with cerebral hemorrhage. The results will assist in selecting appropriate dosing regimens of meropenem in these patients.

Pharmacokinetics and pharmacodynamics of linezolid in plasma/cerebrospinal fluid in patients with cerebral hemorrhage after lateral ventricular drainage by Monte Carlo simulation.

OBJECTIVE: We investigated the pharmacokinetic (PK) and pharmacodynamic (PD) parameters of linezolid in patients who had suffered cerebral hemorrhage after lateral ventricular drainage. MATERIALS AND METHODS: Ten patients with cerebral hemorrhage after lateral ventricular drainage with stroke-associated pneumonia who were given linezolid were enrolled. Plasma and cerebrospinal fluid (CSF) samples were taken at appropriate intervals after the first administration of linezolid and assayed by high-performance liquid chromatography (HPLC). Then, PK parameters were estimated, and a Monte Carlo simulation was used to calculate the probability of target attainments (PTAs) for linezolid achieving the PK/PD index at different minimal inhibitory concentrations (MICs). RESULTS: The maximum concentration of linezolid in plasma and CSF was reached at 1.00 h and 3.10 h, respectively. The average penetration of linezolid in CSF was 56.81%. If the area under the plasma concentration vs time curve from zero to the final sampling time (AUC0-24 h)/MIC ≥ 59.1 was applied as a parameter, the PTA of linezolid in plasma could provide good coverage (PTA ≥ 90%) only for pathogens with a MIC of ≤2 µg/mL, whereas it could be achieved in CSF with a MIC of ≤1 µg/mL. If %T > MIC ≥ 40% was applied as a parameter, the PTA of linezolid in plasma/CSF could provide good coverage if the MIC was ≤4 µg/mL. CONCLUSIONS: For patients with infection of the central nervous system and who are sensitive to the drug, the usual dosing regimens of linezolid can achieve a good therapeutic effect. However, for critically ill or drug-resistant patients, an increase in dose, the frequency of administration, or longer infusion may be needed to improve the curative effect.

Pharmacokinetic/Pharmacodynamic Analysis of Meropenem for the Treatment of Nosocomial Pneumonia in Intracerebral Hemorrhage Patients by Monte Carlo Simulation.

BACKGROUND: Nosocomial pneumonia (NP) is a frequent complication among patients with intracerebral hemorrhage (ICH). However, there are currently no pharmacokinetic (PK) and pharmacodynamic (PD) data to guide meropenem dosing in these patients. OBJECTIVE: To investigate the PK/PD properties of meropenem in these patients and whether the usual dosing regimens of meropenem (2-hour infusion, 1 g, every 8 hours) was suitable. METHODS: A total of 11 patients with a diagnosis of ICH complicated with NP were selected in the emergency internal medicine and treated with a 1-g/2-hours extended infusion model. The plasma concentrations of meropenem were determined by high-performance liquid chromatography. PK parameters were estimated by plasma concentration versus time profile using WinNonlin software. The probability of target attainments (PTAs) of meropenem at different minimum inhibitory concentrations (MICs) based on percentage time that concentrations were above the minimum inhibitory concentration (%T>MIC) value were performed by Monte Carlo simulation. RESULTS: The volume of distribution and total body clearance of meropenem were 55.55 L/kg and 22.89 L/h, respectively. Using 40%T>MIC, PTA was >90% at MICs ≤4 µg/mL. Using 80% or 100%T>MIC, PTA was >90% only at MICs ≤1 µg/mL. CONCLUSIONS: The PK/PD profile of dosing regimens tested will assist in selecting the appropriate meropenem regimens for these patients. At a target of 40%T>MIC, the usual dosing regimens can provide good coverage for pathogens with MICs of ≤4 µg/mL. However, when a higher target (80% or 100%) is desired for difficult-to-treat infections, larger doses, prolonged infusions, shorter intervals, and/or combination therapy may be required.