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: Ensuring adequate antibiotic exposure for central nervous system (CNS) infections remains a
dilemma. Standard dosing regimens are suboptimal for CNS infections, particularly for carbapenem-
resistant infections.

Aims: We describe the first case of TDM-guided high-dose ceftazidime-avibactam therapy at 15g/day, exceeding conventional dosing recommendations, to treat Klebsiella pneumoniae Carbapenemase (KPC)-producing Klebsiella pneumoniae brain abscess.

Methods: Ceftazidime and avibactam concentrations in plasma and brain abscess were assayed using liquid
chromatography tandem mass spectrometry (LCMS). Free drug concentrations in plasma were estimated using published protein binding values.

Results: A 55 year-old, 53.6kg, male developed KPC-producing Klebsiella pneumoniae left basal ganglial
abscess [ceftazidime-avibactam minimum inhibitory concentration (MIC) 1/4 mg/L]. IV ceftazidime-avibactam 2.5g q8h, IV Levofloxacin 750mg q24h and IV Fosfomycin 8g q8h were initiated based on in vitro antibiotic combination testing results. His free ceftazidime and avibactam trough levels in the plasma were 22.6 mg/L and 4.5 mg/L respectively. Assuming 32% avibactam CNS penetration 6 , his CNS avibactam level was estimated to be 3mg/L, which was inadequate. Hence, ceftazidime-avibactam was increased to 2.5g q4h (each dose infused over 3h) and maintained for 5 weeks. Weekly trough concentrations ranged between 63.7 to 104.8 mg/L (ceftazidime) and 8.9 to 16.1 mg/L (avibactam). After 3 weeks of high-dose-therapy, brain abscess was aspirated. This sample showed no bacterial growth and yielded ceftazidime concentration of 57 mg/g; avibactam concentration of 8.6 mg/g. The patient completed therapy without major adverse events.

Conclusion: TDM enabled safe use of ultra-high-dose antibiotics.

Keywords: central nervous system infection, carbapenem-resistant infection, beta-lactam, ceftazidime-avibactam

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: TDM for linezolid plays a crucial role in optimizing treatment outcomes in multidrug-resistant tuberculosis (MDR-TB) while minimizing toxicity. In contrast to plasma pharmacokinetics (PK), hair analysis provides a non-invasive method to assess long-term drug accumulation and adherence.

Aims: To assess hair's potential as a matrix for long-term drug monitoring, we compared plasma PK parameters (AUC, Cmax, Cmin) with hair concentrations of linezolid in Indian MDR-TB patients.

Methods: With the approval of the human ethics committee, plasma PK analysis was performed on 92 patients with MDR-TB, while hair drug concentrations were assessed on 90 patients. The quantification of plasma and hair samples was conducted using UPLC-MS. Plasma PK parameters and hair concentrations of the drugs were evaluated using non-compartmental analysis, and Spearman's correlation was applied for an assessment of their relationship.

Results: Hair drug concentrations correlated significantly with plasma AUC (ρ = 0.81, P = 0.02), indicating that hair drug levels reliably reflect plasma exposure. Based on these findings, hair analysis may serve as a non-invasive method for long-term adherence monitoring and TDM in MDR-TB patients.

Conclusion: It is clear that plasma PK correlates strongly with hair drug concentrations, which is supportive of the potential for hair as a complementary biomatrix for long-term TDM in MDR-TB prevention and treatment. Incorporating hair analysis in clinical practice could aid in adherence monitoring and individualized dosing strategies for optimizing treatment outcomes.

Key Words: Linezolid, MDR-TB,TDM, LC-MS/MS

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.

Backround: Ganciclovir (GCV) is a nucleoside analogue used for the systemic treatment and prevention of infections caused by DNA viruses belonging to the Herpesviridae family. Severe manifestations of diseases caused by these viruses occur in patients with weakened immunity due to factors such as chemotherapy, acquired immunodeficiency from HIV infection, or immunosuppressive therapy following organ transplants. This drug is characterized by high inter- and intra-individual variability.

Aims: The aim of this work was to develop sensitive and rapid analytical method for the determination of ganciclovir and to evaluate the importance of therapeutic monitoring of ganciclovir in patients after lung transplantation.

Methods: An LC-MS/MS method was developed for the determination of GCV using electrospray ionization on an Agilent 1290 Triple Quad 6470 system. The internal standard used was isotopically labeled ganciclovir-d5. The analysis was performed on an Eclipse Plus C18 column using a gradient of mobile phases (A – water with buffer (5%), B – acetonitrile with buffer (5%)). The method was successfully validated. For sample preparation, only protein precipitation with acetonitrile was used.

Results: Patients after lung transplantation are always prophylactically administered by valganciclovir, and ganciclovir is given in the case of a confirmed infection. Levels were determined in 60 lung transplant patients. In more than 80% of cases, optimal serum levels of ganciclovir were not achieved with the initial dosing regimen.

Conclusions: The results demonstrated that therapeutic drug monitoring (TDM) is essential for all lung transplant patients to establish individualized optimal pharmacotherapy.

Key Words: ganciclovir, LC-MS, lung transplantation

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