We conducted this multicenter retrospective study to evaluate the prevalence, clinical patterns, and risk factors for tigecycline-induced liver injury, which is a type of drug-induced liver injury (DILI). Inpatients receiving intravenous tigecycline for ≥7 days were included. Patient information was collected to assess possible DILIs. The pattern and severity of tigecycline DILI were evaluated. A multivariable logistic regression model was used to identify the independent risk factors associated with tigecycline DILI. A total of 986 patients were identified and 397 patients were included in this study. The prevalence of tigecycline DILI was 10.3% (95% confidence interval [CI] = 7.51-13.7%). The most common type of tigecycline DILI was cholestatic, with mild severity observed in most cases. Abnormal baseline alanine aminotransferase levels (odds ratio [OR] = 3.11, 95% CI = 1.55-6.24, P = 0.001), intensive care unit admission (OR = 2.63, 95% CI = 1.32-5.36, P = 0.006), and treatment length (in weeks) (OR = 1.25, 95% CI = 1.05-1.49, P = 0.011) were independent risk factors for tigecycline DILI. Our results indicate that the prevalence of tigecycline DILI is high, and that the patients at risk should receive special attention.

Background: Vancomycin dosing is difficult in critically ill patients receiving continuous renal replacement therapy (CRRT). Previous population pharmacokinetic (PopPK) models seldom consider the effect of residual diuresis, a significant factor of elimination, and thus have poor external utility. This study aimed to build a PopPK model of vancomycin that incorporates daily urine volume to better describe the elimination of vancomycin in these patients.Methods: We performed a multicenter retrospective study that included critically ill patients who received intermittent intravenous vancomycin and CRRT. The PopPK model was developed using the NONMEM program. Goodness-of-fit plots and bootstrap analysis were employed to evaluate the final model. Monte Carlo simulation was performed to explore the optimal dosage regimen with a target area under the curve of ≥400 mg/L h and 400–600 mg/L h.Results: Overall, 113 observations available from 71 patients were included in the PopPK model. The pharmacokinetics could be well illustrated by a one-compartment model with first-order elimination, with the 24-h urine volume as a significant covariate of clearance. The final typical clearance was 1.05 L/h, and the mean volume of distribution was 69.0 L. For patients with anuria or oliguria, a maintenance dosage regimen of 750 mg q12h is recommended.Conclusion: Vancomycin pharmacokinetics in critically ill patients receiving CRRT were well described by the developed PopPK model, which incorporates 24-h urine volume as a covariate. This study will help to better understand vancomycin elimination and benefit precision dosing in these patients.

Background: Pembrolizumab is superior to chemotherapy as a first-line treatment for patients with mismatch-repair-deficient (dMMR) or microsatellite-instability-high (MSI-H) advanced or metastatic colorectal cancer (CRC), with a significant long-term survival benefit according to the KEYNOTE-177 trial. The current study aimed to determine whether pembrolizumab is a cost-effective treatment for patients with dMMR/MSI-H advanced or metastatic CRC in China. Methods: A partitioned survival model (PSM) was developed to simulate patients with dMMR/MSI-H advanced or metastatic CRC based on progression-free survival (PFS), progressive disease (PD) and death. The model was designed using a lifetime horizon, a 6-week cycle, and a 5% discount rate. The patients in the model had metastatic dMMR/MSI-H CRC and had not previously received treatment; these characteristics were similar to those of patients in KEYNOTE-177, a phase 3, open-label randomized clinical trial. The health outcomes and utilities were based on the KEYNOTE-177 trial and published data, respectively. Costs were calculated based on local charges (2022) and published literature. A treatment was deemed cost-effective in China if the incremental cost-effectiveness ratio (ICER) value was less than U.S.$38,142.56 per quality-adjusted life-year (QALY). The robustness of the results was assessed via one-way deterministic and probabilistic sensitivity analyses. Results: Baseline analysis revealed that pembrolizumab provided an additional 2.58 QALYs (3.00 life-year) at an incremental cost of U.S.$78,286.04, resulting in an ICER of U.S.$30,330.15 per QALY, which was below the willingness-to-pay threshold of U.S.$38,142.56 per QALY. When the patient assistance program (PAP) was considered, the ICER became U.S.$1,730.67 per QALY, manifesting absolute cost-effectiveness. The results of sensitivity analyses demonstrated that pembrolizumab was cost-effective in most cases. Conclusions: Pembrolizumab is a cost-effective first-line treatment for dMMR/MSI-H advanced or metastatic CRC patients in China, especially considering the PAP.

Introduction: Recent studies suggested the potential benefits of extended infusion times to optimize the treatment efficacy of ceftazidime/avibactam, which indicated that the current pharmacokinetic/pharmacodynamic (PK/PD) target may not be sufficient, especially for severe infections. The purpose of this study is to assess the adequacy of dosing strategies and infusion durations of ceftazidime/avibactam when applying higher PK/PD targets. Methods: This study utilized published PK parameters to conduct Monte Carlo simulations. Different dosages including the recommended regimen based on renal function were simulated and evaluated by the probability of target attainment (PTA) and cumulative fraction of response (CFR). Different PK/PD targets were set for ceftazidime and avibactam. MIC distributions from various sources were used to calculate the CFR. Results: Multiple PK/PD targets have been set in this study, All recommended dosage could easily achieve the target of 50%fT ≥ MIC (ceftazidime) and 50%fT ≥ C_{T=1.0 mg/L} (avibactam). However, for severe infection patients with normal renal function and augmented renal clearance at the recommended dosage (2000 mg/500 mg, every 8 hours), the infusion duration needs to be extended to 3 hours and 4 hours to achieve the targets of 100%fT ≥ MIC and 100%fT ≥ C_{T=1.0 mg/L}. Only continuous infusion at higher dosages achieved 100%fT ≥ 4×MIC and 100%fT ≥ C_{T=4.0 mg/L} targets to all currently recommended regimens. According to the varying MIC distributions, higher concentrations are needed for Pseudomonas aeruginosa, with the attainment rates vary across different regions. Conclusion: The current recommended dosing regimen of ceftazidime/avibactam is insufficient for severe infection patients, and continuous infusion is suggested.