Background: Critically ill patients often have altered pharmacokinetics that complicate achieving adequate meropenem exposure. Therapeutic drug monitoring (TDM) can guide dosing and improve outcomes by ensuring appropriate PK/PD targets.

Aims: This study evaluates the achievement of pharmacokinetic/pharmacodynamic (PK/PD) targets for meropenem and identifies factors associated with failing to meet these targets in ICU patients.

Methods: We retrospectively studied ICU patients who had meropenem TDM from September 2022 to December 2024. Patients with incomplete data or invalid assays were excluded. We collected demographic, laboratory (creatinine, estimated glomerular filtration rate (eGFR)), therapeutic (dose, administration mode), vasopressor, renal replacement therapy (RRT), and microbiological data. The PK/PD targets (ƒCmin(or ƒCss)≥4×MIC; Cmin(or Css)<16mg/L) were assessed using the first TDM. Patients were categorized as below-target, on-target, or above-target. Univariate and multivariable regressions were performed.

Results: Eighty-four patients were included: 51.2% had documented MIC, 19.0% had no MIC, and 29.8% were treated empirically. Only 39.3% were on-target, while 60.7% were off-target (31.0% below, 29.8% above). Median Cmin|Css was 9.75μg/mL[3.88-17.40], with median dose of 4g/24h[3.0-6.0]. Higher dose (OR=1.84; 95%CI [1.23-2.75]; p=0.003) and prolonged/continuous infusion (OR=6.09; 95%CI [1.12-33.14]; p=0.036) increased the risk of above-target exposure, whereas higher eGFR (OR=0.96; 95%CI [0.94-0.98]; p=0.003) reduced it. RRT (OR=0.147; 95%CI [0.03-0.82]; p=0.029) decreased risk of below-target exposure.

Conclusions: About two-thirds of ICU patients had meropenem exposures outside recommended PK/PD targets at first TDM. Higher doses and prolonged/continuous infusions may increase above-target risk, underscoring the need for early TDM to optimize dosing.

Background: To explore the effect factors of serum voriconazole (VRC) trough concentration (Cmin) in adults with pulmonary aspergillosis, and to provide evidence for the safe and effective use of VRC in clinic.

Methods: HPLC-UV was used to detect the Cmin of VRC . Waters symmetry C18 column (4.6 mm×250 mm, 5 μm) was used. The mobile phase was acetonitrile/water (V/V=41:59). The flow rate was 1.0 mL•min-1 and the detecting wave length was 256 nm. The column temperature was 30 ℃, and the sample size was 80 μL. A total of 545 adults with pulmonary aspergillosis were collected, and the relationship between the Cmin of VRC and clinical efficacy was analyzed, as well as the the influencing factors.

Results: The method was specific, simple, accurate and low-cost, which is suitable for routine determination of Cmin in clinical patients. In the monitored 545 adults, the Cmin of VRC was significant different among individuals, and the average Cmin was 3.59±2.10 mg•L-1. Among them, 545 cases (76.3%) were in the effective range (0.5~5.0 mg•L-1). Univariate linear regression analysis showed that CRP, albumin, direct bilirubin, and serum creatinine were related to the Cmin of VRC. Multivariate regression linear analysis showed that CRP, albumin, and the use of proton pump inhibitors (PPIs) were significantly correlated with the Cmin of VRC.

Conclusions: The Cmin of VRC in adults with pulmonary aspergillosis is susceptible to a variety of factors, such as CRP and albumin. The serum concentration of VRC should be monitored individually to ensure its safety.

Background and Aims: Augmented renal clearance (ARC) and febrile neutropenia (FN) elevate the clearance of drugs excreted primarily by glomerular filtration. This study aimed to evaluate the influence of ARC and FN on dose-normalized trough concentration (C/D) and clearance of teicoplanin (TEIC) by comparing C/D between ARC and non-ARC patients as well as C/D and clearance between FN and non-FN patients.

Methods: This retrospective, single-center, observational cohort study enrolled 309 patients who received an intravenous injection of TEIC. Of the 94 patients who met the selection criteria, 25 satisfied the definition of ARC and 31 the definition of FN. ARC was defined as an estimated glomerular filtration rate ≥ 96.5 mL/min/1.73 m2 using the CKD-EPI formula. FN was defined as an axillary temperature ≥ 37.5°C and neutrophil count < 500/μL. TEIC clearance was estimated using a population pharmacokinetic model for Japanese adult patients with Bayesian estimation.

Results: Compared to the non-ARC group (n = 69), the ARC group (n = 25) had significantly lower first trough concentration (p = 0.014) and lower C/D (p = 0.009). In contrast, the FN (n =31) and non-FN groups (n = 63) did not differ significantly in the first trough concentration, C/D, or clearance. Forced entry multiple regression analysis identified only ARC as the independent factor associated with C/D (p = 0.001).

Conclusions: A higher TEIC loading dose may be required for patients with ARC, regardless of the presence or absence of FN.

Keywords: Teicoplanin, augmented renal clearance, febrile neutropenia

Background: Cycloserine (Cs) is a crucial anti-drug-resistant tuberculosis medication with significant clinical efficacy. However, its clinical application is limited by neuropsychiatric-related adverse reactions (ADRs).

Aims: Develop a prediction model that accurate identification of high-risk populations for Cs-related neuropsychiatric ADRs.

Methods: This study retrospectively evaluated the peak plasma concentration (Cmax) of Cs and Cs-related neuropsychiatric ADRs, and analyzed the risk factors of developing neuropsychiatric ADRs. A multivariable ordinal logistic regression model was built to predict the incidence of neuropsychiatric ADRs.

Results: This study enrolled a total of 136 participants, with a cumulative incidence of neuropsychiatric ADRs of 12.5% (17/136). Patients with ADRs had significantly higher Cs Cmax (26.50 mg/L vs. 18.11 mg/L, P=0.0003). The incidence of ADRs increased with higher Cs exposure, particularly when Cmax exceeded 30 mg/L. ROC analysis demonstrated the strong predictive value of Cmax for neuropsychiatric ADRs (AUC=0.726, 95%CI: 0.6118-0.8396). Notably, the predictive efficacy of the logistic regression model significantly improved after incorporating drinking history as a covariate, achieving a final predictive accuracy of 87.6%. The model demonstrated good calibration (Hosmer-Lemeshow test p=0.563).

Conclusions: Cs Cmax serves as a critical indicator for predicting Cs-related psychiatric ADRs, with higher Cmax correlating with an increased likelihood of psychiatric ADRs. Dynamic monitoring of Cs Cmax combined with drinking history assessment in clinical practice enables accurate identification of high-risk populations for psychiatric ADRs, thereby providing a scientific basis for developing individualized medication regimens and implementing early interventions.

Keywords: Cycloserine, peak plasma concentration, neuropsychiatric-related adverse reactions

Background
Meropenem, a broad-spectrum beta‐lactam antibiotic, is increasingly used amid rising antimicrobial resistance. Its variable pharmacokinetics and limited heat stability challenge maintaining therapeutic plasma levels in OPAT, though TDM may mitigate this. Clinicians often use convenience sampling from vascular access devices (PIVC, PICC, CVC) instead of venepuncture from TDM, though evidence questions its reliability. This study evaluates reliability of meropenem TDM via PICC sampling.

Aims
Assess whether meropenem TDM via convenience sampling from PICC lines yields reliable plasma concentrations, potentially improving OPAT availability for meropenem therapy and patient comfort.

Methods
A benchtop experiment was conducted using Bard polyurethane PICCs modified to varying lengths. Human plasma was spiked with meropenem to a target concentration of 20 mg/L. Samples were collected directly (no line) and after passage through segments of 5 cm, 10 cm, 25 cm, and 55 cm. Meropenem concentrations were measured via a validated UHPLC-MS/MS method over a 0.2–100 mg/L range. This process was repeated in triplicate.

Results
The assay performed reliably within a calibration range from LLOQ 0.2 mg/L to ULOQ 100 mg/L. Meropenem concentrations in plasma remained consistent across varying PICC lengths. Sample 0 (no PICC) had a mean concentration of 18.5 mg/L Sample 1 (shortest) had a mean concentration of 19.1 mg/L, Sample 2 showed 19.0 mg/L, Sample 3 19.0 mg/L, and Sample 4 (longest) 19.4 mg/L.

Conclusions
Convenience sampling via PICC reliably reflects meropenem plasma concentrations, supporting its use for TDM in OPAT. Further clinical studies are warranted.

Keywords: meropenem, TDM, OPAT, PICC, convenience sampling, pharmacokinetics.

Background: Immunocompromised patients are susceptible to opportunistic infections. Rifabutin and isavuconazole are commonly used as alternative agents for mycobacterial and fungal infections, respectively. Compared to rifampin and voriconazole, rifabutin has moderate enzyme induction, and isavuconazole exhibits less enzyme inhibition. Co-administration may increase rifabutin and decrease isavuconazole exposure, but the extent remains unclear. This combination is contraindicated in the isavuconazonium Canadian product labeling.

Aims: This study reviews patients receiving rifabutin and isavuconazole concurrently in a medical center, analyzing plasma drug concentrations to assess interaction effects.

Methods: Adult patients treated with rifabutin and isavuconazole concurrently between November 2022 and December 2024 were included if therapeutic drug monitoring (TDM) was performed. Medical history and associated laboratory data were collected via a retrospective chart review.

Results: Six patients underwent TDM while on both medications (mean age 74.2 ± 12.4 years). None had hepatic dysfunction or received other medications which may affect rifabutin and isavuconazole concentrations. Two dialysis patients received reduced rifabutin doses and had lower concentrations. Most patients maintained rifabutin peak concentrations within the therapeutic range (0.3–0.9 mcg/mL) during concurrent use. One patient showed a decrease in isavuconazole trough concentration (4.9 to 2.1 mcg/mL) after rifabutin initiation but remained within therapeutic levels (2–5 mcg/mL). Another patient with severe diarrhea had subtherapeutic concentrations of both drugs.

Conclusions: Rifabutin and isavuconazole co-administration demonstrated a pharmacokinetic interaction but did not significantly impact achieving therapeutic drug levels. Standard dosing appeared safe, though TDM is recommended for dialysis patients or those with severe diarrhea.

Keywords: Rifabutin, Isavuconazole, Drug-interaction, Pharmacokinetics

Background: Amikacin is widely used in critically ill paediatric patients but presents dosing challenges due to developmental pharmacokinetics (PK) variations. Factors such as age, body weight, organ maturation, and concurrent therapies profoundly impact therapeutic efficacy.

Aims: This study aimed to characterize current prescribing practices, determine the PK parameters of amikacin, and identify factors influencing serum levels in critically ill paediatric patients.

Methods: A retrospective analysis was performed from January 2022 through December 2023 on patients admitted to the Paediatric Intensive Care Unit who received intravenous amikacin. Trough and peak concentrations were obtained at the third dose. The elimination rate constant (Ke), volume of distribution (Vd), and clearance (CL) were estimated using a one-compartment model based on both concentrations. Clinical and laboratory data were collected to identify the factors affecting PK parameters.

Results: Of 214 patients, the mean dose administered was 14.06±2.11mg/kg/day over an average duration of 7.8±3.95days. The mean Ke was 0.14±0.26hr⁻¹, the mean Vd was 0.59±0.30L/kg, and the mean clearance (CL) was 0.08±0.03L/kg/hr. Nearly a quarter (24.3%) of Cmax values and 7.5% of Cmin values fell outside the therapeutic range. Notably, Vd significantly associated with age, creatinine clearance, alkaline phosphatase, and alanine aminotransferase levels, while CL was significantly associated with age, dose, and creatinine clearance.

Conclusion: A substantial proportion of critically ill paediatric patients do not achieve optimal amikacin levels with current dosing. Further refinement of amikacin dosing in this population is warranted, and the development of a pharmacometrics model is needed to optimize treatment outcomes and minimize toxicity.

Background: Multidrug-resistant tuberculosis (MDR-TB), characterized by resistance to isoniazid and rifampicin, poses a significant threat as it is not effectively treated with standard first-line therapies. The urgent need for new anti-TB drugs and strategies has driven research into novel synthetic compounds with potential efficacy against Mycobacterium tuberculosis.

Aims: To synthesize and characterize a novel series of 5,6-dihydropyridazine-1(4H)-carbohydrazides and its analogs and evaluate their in vitro anti-tuberculosis activity against Mycobacterium tuberculosis H37Rv strain. Additionally, their toxicological safety was assessed in preclinical models to predict their suitability for oral administration.

Methods:The in vitro anti-tuberculosis activity was evaluated using the resazurin microtiter assay against M. tuberculosis H37Rv strain. Toxicological assessments included genotoxicity studies, a 14-day acute oral toxicity study, a 90-day repeated oral toxicity study, and a 6-month chronic toxicity study in Wistar rats.

Results:The synthesized compounds exhibited significant anti-tuberculosis activity, suggesting their potential as lead compounds for further development. Genotoxicity studies showed no mutagenic or genotoxic effects at concentrations up to 5000 µg/plate. In acute toxicity studies, the NOAEL was determined to be 5 g/kg bw. The 90-day toxicity study indicated a safe basis for long-term evaluation. The 6-month chronic toxicity study established a no observed effect level (NOEL) of 1,000 mg/kg bw/d. No fetal abnormalities related to the test compounds were observed in the developmental toxicity study.

Conclusions:These findings suggest that these compounds may serve as promising candidates for further development as potential anti-TB agents.

Key Words: Carbohydrazides, tuberculosis, MDR-TB, toxicity, drug development.

Background: Vancomycin is a narrow therapeutic index drug primarily eliminated through renal excretion. Serum creatinine is commonly used to estimate renal clearance, but it may be overestimated in sarcopenic conditions, particularly in critically ill patients. Sarcopenic conditions can be assessed by evaluating muscle strength using the Medical Research Council Sum Score (MRC-SS).

Aims: The study aimed to investigate the association between muscle strength and vancomycin renal clearance in critically ill patients.

Methods: Patients in the intensive care unit (ICU) at Seoul National University Hospital in 2024, without renal diseases and with at least one vancomycin trough concentration and an MRC-SS, were included. Patients were classified into two categories based on MRC-SS: normal muscle strength (MRC-SS ≥ 36) and muscle weakness (MRC-SS < 36). The correlation between vancomycin trough concentrations and serum creatinine levels was analyzed using Spearman’s rank correlation coefficients in both groups.

Results: A total of 28 patients were identified, with 12 in the normal strength group and 16 in the muscle weakness group. The serum creatinine levels (mean ± standard deviation) were 0.79 ± 0.28 mg/dL in the normal muscle strength group and 0.61 ± 0.22 mg/dL in the muscle weakness group, respectively. Vancomycin trough level was moderately correlated with serum creatinine levels in patients with normal muscle strength (ρ = 0.412, p = 0.008), but not in those with muscle weakness (ρ = 0.118, p = 0.428).

Conclusions: Serum creatinine may not accurately reflect vancomycin renal clearance in sarcopenic conditions among critically ill patients.

Keywords: Vancomycin, Sarcopenia