Chuhui Wang

Introduction: Carbapenem-resistant organisms (CROs) threaten critically ill patients, requiring model-informed ceftazidime-avibactam (CAZ-AVI) dosing by renal function and renal replacement therapy (RRT) status. Materials and Methods: Thirty-three patients were prospectively enrolled at one center (18 RRT; 15 non-RRT). RRT settings were recorded. Samples were collected at 0, 1, 2, 4, 6, and 8 h after first-dose and steady-state infusions. Population pharmacokinetic modeling used NONMEM. Monte Carlo simulations evaluated joint probability of target attainment (PTA) for minimum inhibitory concentration (MIC)-directed therapy and pathogen-specific cumulative fraction of response (CFR) for empirical therapy using BRICS MIC distributions under two targets: (1) CAZ 100% fT > MIC and AVI 100% fT > 1 mg/L; and (2) CAZ 50% fT > 4MIC and AVI 50% fT > 1 mg/L. Robust model-informed regimens required joint PTA ≥ 90% under both targets for MIC-directed therapy and CFR ≥ 90% under both for empirical therapy; lower values were exploratory. Results: We analyzed 211 blood samples (120 RRT; 91 non-RRT). Creatinine clearance (CrCL) was retained in the final non-RRT models, whereas no covariate was retained in the final RRT models. RRT-model clearance (CL)/volume of distribution (V_d) estimates were 2.03 L/h/17.0 L for CAZ and 1.77 L/h/14.0 L for AVI; non-RRT estimates were 3.36 L/h/20.5 L and 4.27 L/h/16.0 L, respectively. At MICs ≤ 8 mg/L, robust model-informed regimens included 2000/500 mg q6h for augmented renal clearance and 2000/500 mg q12h during RRT. For CFR-based empirical therapy during RRT, robust model-informed regimens were 2000/500 mg q12h for carbapenem-resistant Klebsiella pneumoniae (CRKP) and 2000/500 mg q8h for carbapenem-resistant Pseudomonas aeruginosa (CRPA). Conclusion: Our study describes the pharmacokinetics of CAZ-AVI in critically ill patients and provides model-informed dosing regimens stratified by renal function and RRT status for both empirical and targeted therapy. Larger, multicenter prospective studies are warranted to validate these findings.

Thrombocytopenia can cause substantial morbidity and mortality in critically ill patients. There are multiple etiology factors and various mechanisms associated with thrombocytopenia, of which drug-induced thrombocytopenia (DITP) deserves attention. Herein, we describe a case of severe thrombocytopenia during intensive care unit (ICU) hospitalization that was probable to be associated with vancomycin. In addition, clinical studies evaluating thrombocytopenia caused by vancomycin were systematically reviewed and 6 studies with acceptable quality were included and analyzed. By revealing the process of identifying this case of DITP and reviewing relevant clinical studies, a risk alert of vancomycin related severe hematotoxicity should be focused on.

Purpose: Voriconazole (VRC) is an antifungal agent which is used for treatment and prophylaxis of invasive fungal infections. The common clinical adverse reactions mainly include central nervous system (CNS) toxicity and abnormal liver function. These adverse reactions limit the clinical use of voriconazole to a certain extent. Therefore, the aim of this study was to analyze the risk factors of voriconazole neurotoxic side effects and to determine the plasma trough concentration (C_min) threshold of voriconazole-induced CNS toxicity, so as to improve the safety of voriconazole treatment. Patients and Methods: This study retrospectively collected the clinical data of 165 patients who received voriconazole and underwent therapeutic drug monitoring (TDM). CNS toxicity was defined using the National Cancer Institute (NCI) criteria, logistic regression was used to analyze the risk factors of CNS toxicity, classification and Regression tree (CART) model was used to determine the C_min threshold for CNS toxicity. Results: Voriconazole-related CNS toxicity occurred during treatment in 34 of 165 patients (20.6%) and the median time from administration to onset of CNS toxicity was 6 days (range, 2– 19 days). The overall incidence of CNS toxicity was 20.6% (34/165), including visual disturbances in 4.8% (8/165) and nervous system disorders in 15.8% (26/165). C_min significantly affects the occurrence of CNS toxicity and the threshold of C_min for voriconazole CNS toxicity was determined to be 4.85 mg/L, when C_min > 4.85 mg/L and ≤ 4.85 mg/L, the incidence of CNS was 32.9% and 11.6%, respectively. Conclusion: Voriconazole trough concentration of C_min is an independent risk factor for CNS toxicity, and the threshold of C_min for CNS toxicity is 4.85mg/L. TDM should be routinely performed in patients with clinical use of voriconazole to reduce the occurrence of CNS toxicity of voriconazole.

The dosage regimen of vancomycin, teicoplanin and daptomycin remains controversial for critically ill patients undergoing continuous renal replacement therapy (CRRT). Monte Carlo simulation was applied to identify the optimal regimens of antimicrobial agents in patients with methicillin-resistant Staphylococcus aureus (MRSA) infections based on the mechanisms of different CRRT modalities on drug clearance. The optimal vancomycin dosage for patients received a CRRT doses ≤ 30 mL/kg/h was 20 mg/kg loading dose followed by 500 mg every 8 h, while 1 g every 12 h was appropriate when 35 mL/kg/h was prescribed. The optimal teicoplanin dosage under a CRRT dose ≤ 25 mL/kg/h was four loading doses of 10 mg/kg every 12 h followed by 10 mg/kg every 48 h, 8 mg/kg every 24 h and 6 mg/kg every 24 h for continuous veno-venous hemofiltration, continuous veno-venous hemodialysis and continuous veno-venous hemodiafiltration, respectively. When the CRRT dose increased to 30–35 mL/kg/h, the teicoplanin dosage should be increased by 30%. The recommended regimen for daptomycin was 6–8 mg/kg every 24 h under a CRRT dose ≤ 25 mL/kg/h, while 8–10 mg/kg every 24 h was optimal under 30–35 mg/kg/h. The CRRT dose has an impact on probability of target attainment and CRRT modality only influences teicoplanin.

The optimal dose of vancomycin in critically ill patients receiving continuous venovenous hemofiltration (CVVH) remains unclear. The objective of this study was to identify factors that significantly affect pharmacokinetic profiles and to further investigate the optimal dosage regimens for critically ill patients undergoing CVVH based on population pharmacokinetics and pharmacodynamic analysis. A prospective population pharmacokinetic analysis was performed at the surgical intensive care unit in a level A tertiary hospital. We included 11 critically ill patients undergoing CVVH and receiving intravenous vancomycin. Serial blood samples were collected from each patient, with a total of 131 vancomycin concentrations analyzed. Nonlinear mixed effects models were developed using NONMEM software. Monte Carlo Simulation was used to optimize vancomycin dosage regimens. A two-compartment model with first-order elimination was sufficient to characterize vancomycin pharmacokinetics for CVVH patients. The population typical vancomycin clearance (CL) was 1.15 L/h and the central volume of distribution was 16.9 L. CL was significantly correlated with ultrafiltration rate (UFR) and albumin level. For patients with normal albumin and UFR between 20 and 35 mL/kg/h, the recommended dosage regimen was 10 mg/kg qd. When UFR was between 35 and 40 mL/kg/h, the recommended dosage regimen was 5 mg/kg q8h. For patients with hypoalbuminemia and UFR between 20 and 25 mL/kg/h, the recommended dosage regimen was 5 mg/kg q8h. When UFR was between 25 and 40 mL/kg/h, the recommended dosage regimen was 10 mg/kg q12h. We recommend clinicians choosing the optimal initial vancomycin dosage regimens for critically ill patients undergoing CVVH based on these two covariates.

Patients with augmented renal clearance (ARC) have been described as having low vancomycin concentration. However, the pharmacokinetic model that best describes vancomycin in patients with ARC has not been clarified. The purpose of this study is to determine the pharmacokinetic of vancomycin in Chinese adults and the recommend dosage for patients with different renal function, including patients with ARC. We retrospectively collected 424 vancomycin serum concentrations from 209 Chinese patients and performed a population pharmacokinetic model using NONMEM 7.4.4. The final model indicated that the clearance rate of vancomycin increased together with the creatinine clearance, and exhibited a nearly saturated curve at higher creatinine clearance. The estimated clearance of vancomycin was between 3.46 and 5.58 L/h in patients with ARC, with 5.58 being the maximum theoretical value. The central volume of distribution increased by more than three times in patients admitted to Intensive Care Unit. Monte Carlo simulations were conducted to explore the probability of reaching the target therapeutic range (24-h area under the curve: 400–650 mg·h/L, trough concentration: 10–20 mg/L) when various dose regimens were administered. The simulations indicated that dose should increase together with the creatinine clearance until 180 mL/min. These findings may contribute to improving the efficacy and safety of vancomycin in patients with ARC.

Malignant hyperthermia (MH) is a rare life-threatening response that triggered by exposure to specific anesthetics commonly used during surgery interventions. Dantrolene is a well-known drug which used as first-line therapy for MH. A 14-year-old Chinese boy with a mutation in RYR1 whose muscle biopsy diagnosis was central core disease (CCD) occurred MH after cervical spine surgery underwent general anesthesia without volatile anesthetics or succinylcholine. The MH crisis treatment workflow was started and intravenous dantrolene was used soon which combined with sequent continuous veno-venous hemofiltration (CVVH) and plasma exchange (PE) therapy. We explored the pharmacokinetics of dantrolene during the treatment and the results showed that a one-compartment model with first-order absorption and elimination was sufficient to characterize dantrolene pharmacokinetics. The clearance estimate for dantrolene was 0.43 mL/(min*kg) and volume of distribution was 0.61 L/kg. The clearance of dantrolene was significantly affected by CVVH and PE.

What is known and objective The antibiotic concentration in abdominal drainage fluid is very important for the treatment of patients with severe acute pancreatitis (SAP). Previous studies show that quinolones and carbapenems have high abdominal tissue levels, whereas aminoglycosides fail to penetrate into abdominal tissue in sufficient concentrations. However, there are limited data with respect to vancomycin. This case aims to investigate the penetration of vancomycin to abdominal drainage fluid in a 44‐year‐old SAP patient. Case summary We report a case of a 44‐year‐old female with SAP, on treatment of vancomycin. The time courses of vancomycin concentration in plasma and abdominal drainage fluid of the patient were described. Simultaneous measurement of abdominal drainage fluid and serum concentrations demonstrated that vancomycin can rapidly penetrate into abdominal tissue in acceptable amounts. What is new and conclusion This case demonstrated that it took about 30 minutes for vancomycin to get from plasma to abdominal drainage fluid and about 76% of vancomycin could move into abdominal drainage fluid for SAP patients.

Antibiotic concentration in pancreas tissue is very important for the treatment of severe acute pancreatitis (SAP) with infection. We report a case of a 44-year-old female with SAP on treatment of vancomycin. The time courses of vancomycin concentration in serum and pancreas tissue of the patient was described. This case demonstrated that it took about 30 minutes for vancomycin to get through from serum to pancreas tissue and about 76% of vancomycin could move into pancreas tissue for SAP patients.