Objective: Liver dysfunction affects drug metabolism, including voriconazole, used for treating fungal infections. This study evaluated the effectiveness and safety of a voriconazole dosing regimen adjusted for liver dysfunction (VALID) compared to standard dosing.
Methods: The study included liver dysfunction patients hospitalized between January 2020 and December 2023. Patients were divided into the VALID group and a control group. Data on demographics, medication, liver and kidney function, and adverse events were collected. Propensity score matching was used to balance the groups. Voriconazole levels were measured using liquid chromatography.
Results: The study analyzed 182 patients with 375 voriconazole measurements—39 in the VALID group and 143 in the control group. After matching, both groups were similar in baseline characteristics. The VALID group had a significantly higher target trough concentration achievement (89.7% vs. 48.7%, P<0.0001) and lower initial voriconazole levels (2.46 mg/L vs. 4.13 mg/L, P=0.0004). The VALID group also had fewer adverse events (15.4% vs. 38.5%, P=0.02159). Efficacy between the two groups was similar (P=0.9132). Factors like CYP2C19 phenotype and liver function influenced voriconazole levels.
Conclusion: The VALID regimen improved target trough levels and reduced adverse events compared to standard dosing. These findings support individualized dosing for better voriconazole therapy in liver dysfunction patients. Further research is needed to confirm these results in larger studies.

Background: Although amikacin-induced ototoxicity is associated with cumulative exposure, the specific amount of exposure that may induce ototoxicity remains unknown.

Aims: This study aimed to clarify the relationship between amikacin exposure and ototoxicity.

Methods: This retrospective observational study included patients with non-tuberculous mycobacterial pulmonary disease. TDM data for amikacin, audiogram records, and patient characteristics were obtained from electronic medical records. Amikacin exposure was calculated from the TDM data, and the relationship between cumulative exposure and change from baseline in the audiogram was analyzed. The population pharmacokinetics/pharmacodynamics model was constructed using NONMEM version 7.5.0. This study was approved by our Ethics Committee.

Results: We enrolled 185 patients. Median amikacin dose and observation period were 500 (interquartile range [IQR]; 500–600) mg/day and 6.4 (IQR; 2.8–22.2) months, respectively. The patients underwent an average of five TDM measurements and four audiograms. Although the peak and trough amikacin concentrations were not significant predictors of ototoxicity, cumulative exposure was associated with audiogram changes. The estimated slope of audiogram change against cumulative amikacin exposure was 0.085 (95% confidence interval [CI]; 0.055–0.12) [dB* L/days/g/h] at 4000 Hz and 0.16 (95% CI; 0.11–0.21) [dB*L/days/g/h] at 8000 Hz. No hearing loss was observed at frequencies < 2000 Hz.

Conclusions: Ototoxicity was related to cumulative amikacin exposure of 117.6 [days*g*h/L], not to peak and trough amikacin concentrations.

Key Words: Amikacin, TDM, cumulative AUC, Ototoxicity.

Background: Fosfomycin-based combination therapy is a promising approach against difficult-to-treat Gram-negative bacteria (DT-GNB), but regimen selection remains challenging due to bacterial diversity and patient-specific side effects. Our in-house in vitro antibiotic combination testing (iACT) service identified effective fosfomycin-based combinations with high bactericidal activity within 24 hours, enabling tailored clinical implementation.

Aims: We assessed the side-effect profiles and clinical outcomes of iACT-guided fosfomycin-based combination therapy.

Methods: This prospective observational cohort study (2023-2025) included adult inpatients with DT-GNB infections. iACT was conducted using 96-well plates containing various antibiotics in mono, dual or triple combinations (>170 unique combinations) at clinically unbound concentrations. Bactericidal activity was defined as ≥3log10 CFU/mL reduction at 24 hours.

Results: Twenty-nine subjects who received iACT-guided fosfomycin-based combination therapy were evaluated. All 29 DT-GNB isolates were carbapenem-resistant. The most common bactericidal regimens were Fosfomycin+Aztreonam+Levofloxacin(7/29), Fosfomycin+Aztreonam+Meropenem(4/29) and Fosfomycin+Levofloxacin+Meropenem(3/29). Adverse effects occurred in 34.5%(10/29) of subjects, including hematologic (3), dermatologic(2), non-C. difficile-associated diarrhea(2), nausea/vomiting(1), hepatobiliary(1), and neurologic(1) events. All were well tolerated without regimen modifications, and no electrolyte imbalances were reported. Positive microbiological outcomes were achieved in 82.8%(24/29), with a 30-day all-cause mortality of 6.9%(2/29). Antibiotic TDM was performed in eight subjects receiving fosfomycin doses of 4–8g every 8h, except one hemodialysis patient who received an 8g load followed by 4g pre- and post-dialysis. Fosfomycin concentrations were observed to range from 13.61—1156.39 mg/L.

Conclusion: A two-pronged employing iACT-guided fosfomycin-based combination therapy for strain-specific treatment and TDM for real-time dose optimization can enhance clinical outcomes while minimizing toxicity in DT-GNB infections.

BACKGROUND
Sepsis is a life-threatening condition arising from a dysregulated immune response to infection, culminating in multi-organ dysfunction and often organ failure, with a high mortality rate. The liver is notably susceptible to these “toxic” insults early in sepsis, exacerbating systemic inflammation and driving multi-organ failure (MOF). Recent evidence identifies the HMGB1–Caspase-11 axis as a critical endogenous “toxin” pathway in sepsis-related inflammation and liver injury, yet effective interventions targeting this pathway remain elusive.

METHODS
Here, we developed DNAzyme-functionalized, pH-responsive glycyrrhizinic acid/zinc@polydopamine (GA/Zn@PDz) nanoparticles designed to release glycyrrhizinic acid and Zn²⁺ in weakly acidic conditions. These nanoparticles concurrently deliver a DNAzyme specifically targeting HMGB1, aiming to inhibit HMGB1-Caspase-11–mediated inflammation and pyroptosis via multiple mechanisms. By blocking this “endogenous toxin,” the system seeks to alleviate sepsis-induced liver injury and prevent progression toward MOF.

RESULTS
In vitro, GA/Zn@PDz nanoparticles displayed excellent cellular uptake and biostability, significantly reducing HMGB1 expression and inflammatory factor release. In a septic mouse model, GA/Zn@PDz prolonged survival, attenuated histopathological liver damage, and reduced inflammatory and coagulation markers. Importantly, safety evaluations demonstrated minimal adverse effects on healthy tissues, indicating good biocompatibility.

CONCLUSION
We successfully constructed a pH-responsive, DNAzyme-functionalized GA/Zn@PDz nanomaterial to counteract HMGB1, an endogenous “toxin,” in sepsis-induced liver injury. By effectively interfering with the HMGB1–Caspase-11 axis, this strategy suppresses toxic inflammation, alleviates multi-organ damage, and offers a promising new avenue for combined gene silencing and small-molecule therapy in sepsis management.

Background: Beta-lactam antibiotics are among the most prescribed antibiotics on the pediatric intensive care unit (PICU). For beta-lactam antibiotics, the unbound plasma concentrations above at least one to four times the minimum inhibitory concentration (MIC) for 100% of the dosing interval (100%ƒT>1-4×MIC) has been proposed as pharmacodynamic target to maximize bacteriological.

Aims: To determine the probability of target attainment of beta-lactam antibiotics in PICUs and to identify predictors and clinical outcomes associated with target nonattainment.

Methods: This prospective observational study was performed in two PICUs in the Netherlands. We enrolled pediatric patients treated with the following beta-lactam antibiotics: cefotaxime, ceftazidime, ceftriaxone, cefuroxime, flucloxacillin, and meropenem. Based on multiple samples within consecutive days of treatment, ƒT>MICECOFF and ƒT>4×MICECOFF were determined. Secondary endpoints were estimated regression models for examining the association of target nonattainment with patient characteristics and clinical outcomes.

Results: A total of 116 patients were included, of whom 27.6% achieved 100%ƒT>MICECOFF and 13.7% achieved 100%ƒT>4×MICECOFF. Regression analysis identified estimated glomerular filtration rate (eGFR)≥90mL/min./1.73m2 as risk factors for target nonattainment. In addition, no significant association between the 100%ƒT>MICECOFF target attainment and ICU length of stay (LOS) was found.

Conclusions: Plasma concentrations for beta-lactam antibiotics are frequently subtherapeutic in critically ill children (100%fT>MIC). We found an eGFR≥90mL/min./1.73m2 to be associated with target nonattainment, indicating kidney function should be taken into account when identifying individuals which may require higher dosages. These results may help identify subpopulations requiring higher dosages or continuous infusion in order to achieve adequate antibiotic exposure.

Key Words: Beta-lactams, Target-attainment

Background: A machine learning model for predicting vancomycin-associated acute kidney injury (AKI) based on the area under the concentration-time curve (AUC) at an early stage of administration has not been devised.

Aims: To construct a risk prediction model involving related risk factors such as concomitant drugs and comorbidities.

Methods: A multicenter, retrospective, cohort study was conducted among hospitalized patients treated with vancomycin at three hospitals between April 1, 2019 and March 31, 2024. Based on previous studies, 21 variables were included in the model building. After selecting important features, risk prediction models were built using eight machine learning algorithms. The performances of machine learning models were evaluated by using accuracy, precision, recall, and F1 scores.

Results: Five important features were selected: day 2 AUC, trough concentrations, and concomitant use of piperacillin/tazobactam, diuretics, or vasopressors. Among the evaluated machine learning models, Naïve Bayes and a random forest with class weights exhibited equal best prediction performances in terms of accuracy (97.4%, 95% CI 93.4%–99.3%), precision (83.3%), recall (62.5%), and F1 score (71.4%).

Conclusions: We constructed a machine learning-based risk prediction model for vancomycin-associated AKI at an early time of administration. Our results underscore the importance of considering both day 2 AUC and trough levels in the development of such risk prediction models. Furthermore, our findings contribute to the construction of machine learning-assisted population pharmacokinetic models for precise vancomycin dosing.

Key Words: vancomycin, acute kidney injury, machine learning, initial dosing design

Objectives: This study aimed to investigate the associated factors predicting 30-day mortality of carbapenem-resistant Gram-negative bacilli (CR-GNB) infections, with focus on polymyxin B AUCss,24h/MIC.
Methods: This prospective cohort study included patients with CR-GNB infections from January 2022 to January 2024. The primary outcome was 30-day mortality. Classification and regression tree (CART) analysis was used to calculate the AUCss,24h/MIC threshold for 30-day mortality. Multivariate analysis was conducted to assess risk factors affecting this outcome.
Results: We enrolled 107 patients, among which 30-day mortality occurred in 31 (29.0%) cases. The CART-derived AUCss,24h/MIC breakpoint was 51.3, and patients in the below-breakpoint group had 3.4-fold higher 30-day mortality than those in the above-breakpoint group (58.1% vs 17.1%, P < 0.001). On multivariate analysis, polymyxin B AUCss,24h/MIC of ≥ 51.3 (aOR 0.08, P = 0.001) predicted a lower risk for 30-day mortality. This survival benefit of AUCss,24h/MIC target attainment remained stable in patients with high risk of mortality or carbapenem-resistant Acinetobacter baumannii infections.
Conclusions: Polymyxin B AUCss,24h/MIC of ≥ 51.3 independently predicted lower 30-day mortality in treating CR-GNB infections. Future studies are required to confirm the reliability of AUCss,24h/MIC target in randomized controlled trials.
Keywords: polymyxin B; carbapenem-resistant gram-negative bacilli; 30-day mortality; predictors; AUCss,24h/MIC