Background: Itraconazole is a triazole antifungal metabolized by CYP3A4. Drug interactions resulting in increased metabolism can lead to subtherapeutic concentrations and treatment failure. Flucloxacillin is known to induce CYP450 enzymes, and the impact on voriconazole, a CYP2C19 substrate, is particularly marked; however, the interaction continues to be disputed. Case reports (posaconazole, isavuconazole) and case series (tacrolimus) suggest CYP3A4 substrates are affected. There are currently no reports about the interaction affecting itraconazole.

Aims: To describe the impact of concurrent flucloxacillin therapy on itraconazole concentrations and provide evidence for this clinically significant drug interaction.

Methods: We identified three patients receiving concurrent itraconazole and flucloxacillin, with itraconazole concentrations available pre-, during and post-flucloxacillin treatment. All patients had methicillin-sensitive Staphylococcus aureus infections requiring flucloxacillin. Itraconazole trough concentrations were measured regularly and analysed in relation to dose adjustments.

Results: Two patients had therapeutic itraconazole concentrations (500-1000ng/mL) before flucloxacillin, however all demonstrated subtherapeutic concentrations despite standard or increased dosing during co-treatment. Similar to voriconazole, a notable impact on itraconazole concentrations became apparent approximately one week after flucloxacillin initiation. The interaction occurred independently of the flucloxacillin administration route. One case exhibited undetectable itraconazole concentrations despite standard dosing. The interaction was consistent across different formulations (Sporanox, Lozanoc).

Conclusion: This case series provides evidence that flucloxacillin significantly reduces itraconazole concentrations through CYP3A4 induction. An alternative anti-staphylococcal agent, such as cefazolin, is recommended as metabolic induction affects most alternative antifungal agents.

Keywords: itraconazole, flucloxacillin, drug interaction, CYP3A4, therapeutic drug monitoring, antifungal

Background: HIV infection triggers oxidative stress by producing reactive oxygen species (ROS), neutralized by antioxidant molecules, such as glutathione. Both ROS and antioxidants could influence the expression of genes encoding enzymes and transporters involved in systemic and intracellular antiretroviral drug pharmacokinetics, with a potential effect on the clinical outcome of people with HIV (PWH). No studies investigating the role of oxidative stress and antioxidant molecules in affecting antiretroviral drug exposure are present.

Aims: To quantify antioxidant molecules, evaluating their impact on plasma and intracellular (PBMCS) drug exposure.

Methods: Plasma and PBMCS drug concentrations and mitochondrial and cytosol oxidative stress biomarker levels were evaluated through liquid chromatography.

Results: 25 PWH with a median age of 42.5 years and BMI of 23.3 kg/m² were analyzed. BIC/TAF/FTC (48%) and RPV/TAF/FTC (40%) were the most frequent antiretroviral therapies, whereas PWH in dual therapy were mostly given DTG/3TC (80%). Three different patterns were identified: associations between antioxidant molecules and a) only systemic (i.e. cytosol n-acetylcysteine with DTG plasma levels), b) only intracellular (i.e. mitochondrial s-adenosylmethionine with intracellular BIC exposure) and c) both systemic and intracellular antiretroviral drug concentrations (i.e. mitochondrial glycine and FTC plasma-PBMCS concentrations or mitochondrial glutathione and RPV plasma-PBMCS).

Conclusions: This is the first study showing the potential role of oxidative stress-related factors impacting on systemic and/or intracellular antiretroviral drug exposures. Overall, mitochondrial oxidant molecules seem to regulate the intracellular antiretroviral concentrations compared to cytosol biomarkers. The clinical relevance of these different associations is currently under evaluation.

Keywords: antioxidants, ros, haart, antiretroviral treatment

Background
Tedizolid (TZD) is a novel oxazolidinone anti-MRSA agent that primarily binds to plasma albumin. Approximately 90% of TZD is protein-bound, leaving about 10% unbound. As albumin levels decrease due to pathological conditions, the unbound fraction (fuB) of TZD is hypothesized to increase.

Aims
This study aimed to quantitatively evaluate TZD protein binding by modeling the relationship between bound (Cb) and unbound (Cu) concentrations using both clinical and in vitro data.

Methods
A total of 93 plasma samples were analyzed from six healthy adults and five patients. Additionally, 72 in vitro samples were prepared by adding TZD to albumin solutions. TZD concentrations were measured using high-performance liquid chromatography. Nonlinear mixed-effects modeling was used to compare linear and nonlinear binding models. This study was approved by the ethics committees of Toyama University Hospital and Nihon University.

Results
Both clinical and in vitro analyses indicated that the relationship between Cb and Cu was best described by a linear model. For clinical data, the model was Cb = Slope × Cu, while for in vitro data, it was Cb = Slope × Alb × Cu. The estimated Slope was 5.64 (clinical) and 0.00406 L/µmol (in vitro). fuB was 0.15 in clinical samples and 0.40 in vitro.

Conclusion
TZD exhibited linear plasma protein binding at clinically relevant concentrations. The 2.7-fold higher fuB in vitro suggests additional plasma protein binding, indicating that TZD also binds to proteins other than albumin.

Keywords
Unbound concentration, NONMEM, Pharmacokinetics, Protein binding, Tedizolid

Background: The application of high-dose amikacin is currently challenging due to the lack of effective tools guiding TDM.

Aims: This study aimed to develop a popPK model and evaluate the performance of Bayesian forecasting for model-based TDM.

Methods: The dataset-1 from critically ill patients receiving high-dose amikacin was applied for popPK modeling with the help of NONMEM7.5. The developed model would be externally validated by dataset-2 from patients in the same department. The study investigated the performance to predict peak concentrations in dataset-2 of the Bayesian estimation using a midpoint level of the same dosing interval. The time after dose needed to achieve a trough concentration of 2.5mg/L (required dosing interval) by Bayesian 2-level estimation (peak, mid) was compared to those of Bayesian 1-level ones (mid).

Results: The dataset-1 and dataset-2 included 140 patients (283 concentrations) and 121 patients (231 concentrations), respectively. A two-compartment model was established with Cockcroft-Gault creatinine clearance, length of ICU stay, and weight as covariates for PK parameters. Regarding external validation, the developed model showed rBias values between predicted and observed concentrations of 18.4% and 2.42% for priori and posterior predictions, respectively. Bayesian forecasting exhibited good performance when comparing forecast-peak concentrations to observations, with rBias of 6.8% and rRMSE of 29.9%. No significant difference was found in the required dosing interval estimated by Bayesian forecasting using 1-level or 2-level in which 70.7% agreement was observed.

Conclusions: Implementing a midpoint TDM with Bayesian forecasting is satisfactory to guide amikacin dosing.

Key Words: popPK, amikacin, ICU, TDM, Bayesian

Background: Voriconazole is widely used to prevent fungal infections in patients receiving a hematopoietic stem cell transplantation (HSCT). The drug shows highly variable pharmacokinetics, and TDM is used to guide dosing. Voriconazole is extensively metabolized by CYP2C19. Both genetic variation and inflammation have been shown to influence CYP2C19-activity. Together these factors can lead to phenoconversion. However, both factors are currently disregarded and not incorporated into hematologic guidelines.

Aim: Here, we investigated the effect of CYP2C19 drug metabolizer phenotypes in HSCT patients receiving voriconazole in absence and presence of inflammation. Moreover, the influence of inflammation on target attainment and the association between inflammation and CYP2C19 activity was explored.

Methods: We analyzed CYP2C19 metabolizer phenotypes of 126 HSCT patients from the Biobank Hematologische Ziekten (LUMC) receiving voriconazole in the absence and presence of inflammation defined as CRP >10 mg/L .

Results: Higher (dose-corrected) voriconazole concentrations were observed during inflammation (LMM p=<2e-16, effect size of phenotype β=-5.99e-02 mg/L per mg voriconazole; CRP β=1.54e-03 mg/L). During inflammation, the frequency of supra-therapeutic levels of voriconazole increased, while the frequency of sub-therapeutic levels decreased (χ2-test p=0.0080). Finally, a subgroup analysis of 25 patients with longitudinal follow-up including data prior- during, and post-inflammation, showed that voriconazole levels changed in parallel to inflammatory status.

Conclusions: Our data confirm the combined effect of inflammation and CYP2C19 genotype on voriconazole metabolism, and suggest TDM to prevent supra-therapeutic voriconazole levels during inflammation is most beneficial in CYP2C19 IMs and RMs.

Key: Voriconazole, CYP2C19, Inflammation, phenoconversion, TDM, HSCT

Background
Model-informed precision dosing(MIPD) is now the preferred method for vancomycin TDM. However, its impact on reducing vancomycin-associated acute-kidney-injury (AKI) and attainment of area under the curve (AUC) targets has not been specifically examined in a real-world, paediatric ICU setting where resourcing for the MIPD service is limited.

Aim
To assess the impact of real-world vancomycin MIPD implementation on vancomycin-associated AKI rates and therapeutic target attainment in critically ill children.

Methods
Vancomycin courses from patients admitted to a paediatric ICU (2020-2022) were retrospectively reviewed. All courses with at least 2 doses and ≥ 1 vancomycin concentration were included. From January 2020 to June 2021, vancomycin dosing was determined solely by trough concentration monitoring. From July 2021, MIPD was increasingly used to guide vancomycin dosing by targeting a 24-hour AUC of 400-600mg·h/L. AKI severity was determined by modified KDIGO criteria. Due to resource constraints MIPD was generally not applied a priori and was not applied for all courses.

Results
In total, 648 vancomycin courses were identified. The average patient age was 3.9 years (range; 1.5 days - 19.1 years). The median (range 100 – 1838 mg·h/L) AUC24 was 452mg·h/L in 2020, 411.97mg·h/L in 2021, and 388mg·h/L in 2022. The vancomycin-associated AKI rate was 13% in 2020, 12% in 2021 and 9% in 2022 (p = 0.4). Severe AKI reduced from 8.6% in 2020, 7.8% in 2021, to 3.7% in 2022 (p = 0.4).

Conclusion
There was a non-significant trend towards a reduction in vancomycin-associated AKI with the implementation of MIPD.

Background: Itraconazole is commonly prescribed for antifungal prophylaxis in transplant recipients. Two capsule formulations (Lozanoc® and Sporanox®) are available with a suggested 2:1 bioavailability ratio, but this relationship has not been confirmed in complex patients.

Aims: To compare the relative bioavailability between Lozanoc® and Sporanox® in transplant recipients and identify factors influencing itraconazole concentrations.

Methods: We constructed a relational database using retrospective therapeutic drug monitoring (TDM) data from transplant recipients at St. Vincent's Hospital Sydney (2016-2024). Trough concentrations, administration data, and patient characteristics were analysed when both formulations were administered at 200mg twice daily. Generalized linear mixed models (GLMMs) were used to account for repeated measurements within patients and to identify factors influencing dose-normalized concentrations over time.

Results: We included 362 trough concentrations from 103 patients in analyses. The mean first concentration ratio (Lozanoc®/Sporanox®) was 1.06, suggesting similar initial bioavailability despite the expected 2:1 ratio. The weighted mean concentration normalized to dose ratio was 1.85. GLMM analysis revealed Lozanoc® concentration increased significantly over time (0.069 ng·mL⁻¹/mg daily), while Sporanox® decreased (-0.054 ng·mL⁻¹/mg daily). H2 antagonists and food/fluid intake symptoms reduced Sporanox® concentrations but had less impact on Lozanoc®.

Conclusions: The theoretical 2:1 bioavailability ratio between formulations does not apply in complex patients, particularly early post-transplant. These findings highlight the importance of TDM for both formulations and suggest current dosing equivalence recommendations need reconsideration in this context.

Keywords: itraconazole, bioavailability, transplant, therapeutic drug monitoring, antifungal, 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: tigecycline is widely used in critically ill infected patients for its good antibacterial activity. COVID-19 has a great impact on the physiological function of patients.

Aims: to investigate the effect of COVID-19 on tigecycline plasma concentrations and PK/PD compliance rates in critically ill infected patients.

Methods: 90 critically ill patients with/without COVID-19 treated with tigecycline were retrospectively analyzed. Patients were divided into high and low dose groups.The trough concentration, medium concentration, peak concentration and area under the curve (Cmin, C1/2t, Cmax, AUC0-24) after the fourth administration were collected. The PK/PD compliance rate at different infection sites was calculated, and the adverse reactions were observed.

Results: The total compliance rates of Cmax, AUC0-24 and PK/PD in COVID-19 group were significantly higher than those in non-COVID-19 group (P<0.05). There were 24 cases of adverse reactions in the COVID-19 group, including 16 cases in the high-dose group and 8 cases in the low-dose group; there were 13 cases of adverse reactions in the non-COVID-19 group, 8 cases in the high-dose group and 5 cases in the low-dose group. The incidence of adverse reactions in the COVID-19 group was higher than that in the non-COVID-19 group (P<0.05).

Conclusions: Tigecycline peak concentrations and PK/PD compliance rates were significantly increased in critically ill patients with COVID-19, as well as the incidence of adverse reactions. More attention to plasma concentrations and adverse reactions were needed when using tigecycline.

Keywords: Tigecycline; COVID-19; plasma concentrations; PK/PD

Background: In pediatric patients, vancomycin plays a pivotal role in combating infections, necessitating precise therapeutic drug monitoring to ensure efficacy and safety. The adoption of model-informed precision dosing (MIPD) has demonstrated potential in optimizing dosing strategies based on the area under the concentration-time curve (AUC24h).

Aims: To evalute predictive performance of population pharmacokinetic models using only trough concentrations to estimate AUC24h.

Methods: Predictive performance of 23 vancomycin population pharmacokinetic models was retrospectively evaluated in two cohorts; (A) 21 subjects with PNA<50 days, (B) 124 subjects with PNA≥50 days. Multiple scenarios were investigated using; (a) peak and trough concentration, (b) using either peak or (c) trough concentration solely, (d) covariate information (a priori). The median AUC24h per subject across all models was used as ‘true’ AUC24h.

Results: For both cohorts, relative root mean square error (rRMSE) for the AUC24h precision using only trough concentrations was similar to the rRMSE using both a peak and trough sample. For cohort A, the model by Chen, Colin, and Mehrotra showed best trough-based performance with the lowest relative Bias (rBias) (-3.3% and -2.6%) and rRMSE (6.8% and 7.3%). For cohort B, the models from Alsultan and Lv illustrated the lowest rBias (1.75% and -5.4%) and rRMSE (16.6% and 15.1%).

Conclusions: This study illustrates that trough concentration-based AUC24h estimation is a feasible approach in vancomycin MIPD. These findings endorse the selected models for advanced MIPD vancomycin therapy in pediatrics, though further investigation into clinical outcomes is recommended.

Key Words: Vancomycin, External evaluation, Population pharmacokinetics, AUC, Pediatrics

Background: Gentamicin is the empirical therapy of choice for sepsis in newborns, with dosing of 4mg/kg every 24 – 36 hours, depending on premenstrual age.

Aims: To investigate the therapeutic drug monitoring (TDM) outcomes of the current IV Gentamicin regimen in treating infections among neonates.

Methods: This retrospective cohort study was conducted in HSIP. Patient demographic and clinical data were collected from the TDM request forms for all neonates admitted to the neonatal ward from January 2020 – December 2022. Through and peak levels were measured on the third dose of therapy. The therapeutic ranges for trough and peak levels were <1.0 mg/L and >5.0 mg/L, respectively. Elevated serum creatinine was defined as serum creatinine level (SCr) >71 μmol/L. Multivariable logistic regression was performed to identify the risk factors of acquiring toxic trough levels.

Results: A total of 227 patients were included in the final analysis. The total number of patients achieving the targeted peak level was 74.90%. More than half of the patients (52.0%) experienced toxic trough levels. The mean serum trough and peak levels (standard deviation) were 1.23 (1.11) mg/L and 7.31 (3.93) mg/L respectively. The risk factor associated with toxic trough level was elevated serum creatinine with OR 2.55, 95% confidence interval [1.19,5.46], p=0.016).

Conclusion: The current gentamicin regimen resulted in an alarming proportion of patients having toxic trough levels, particularly with elevated SCr. The study findings underscore the need to optimize the dosing regimen to minimize toxicity in neonates

Keywords: gentamicin, neonate, creatinine, therapeutic drug monitoring

Background: Pseudomonas aeruginosa has a large armamentarium of resistance mechanisms, enabling resistance emergence against almost all antibiotics in monotherapy.

Aims: To evaluate regimens of meropenem (MER) and ciprofloxacin (CIP), alone and combined, against isogenic P. aeruginosa strains with different resistance mechanisms in a dynamic hollow fibre infection model (HFIM) and develop a mechanism-based mathematical model (MBM) accounting for the resistance mechanisms.

Methods: Four isogenic strains were used: PAOD1 (spontaneous oprD mutation/loss of porin OprD), PAΔADmexR (ampD knock-out/AmpC overexpression and mexR knockout/MexAB-OprM overexpression), PAOD1ΔmexR and PAOD1ΔAD (other combinations of the resistance mechanisms). Regimens were: MER continuous infusion (CI, 6g/day, 12g/day additionally against MER-resistant strains), CIP intermittent infusions (400mg, 8-hourly as 1-h infusions), and both combinations. The HFIM was run for 240h. MBM was performed.

Results: All monotherapies resulted in regrowth with amplification of resistant subpopulations. The combination regimens suppressed total and resistant counts of PAOD1, PAΔADmexR and PAOD1ΔAD. Against PAOD1ΔmexR, MER 6g + CIP performed synergistically from 24h-120h, while MER 12g + CIP was synergistic from 24h-192h. MER-resistant counts emerged from 72h and 168h for the respective combination regimens; CIP-resistant colonies emerged from 216h with the low-dose combination only. An MBM with subpopulation synergy was developed that described the bacterial response to antibiotic based on the resistance mechanisms for all mono- and combination therapies.

Conclusions: Combination regimens enhanced bacterial killing and suppressed regrowth and resistance overall. An MBM accounting for different resistance mechanisms well-described the impact of double mutations and combination therapies on bacterial response.

Keywords: mathematical modelling, combination, pharmacodynamics, genomics

Background: Amikacin and gentamicin are key aminoglycosides against multidrug-resistant infections, with trough monitoring used to minimize toxicity. These target recommendations vary due to outdated pharmacokinetic data and differing dosing strategies across patient populations. This inconsistency is compounded by differences in dosing strategies based on monotherapy or synergistic therapy.

Aims: This scoping review examines trough targets and their clinical implications, aiming to reconcile pharmacokinetic and clinical evidence to enhance the precision of amikacin and gentamicin trough monitoring in practice.

Methods: Search on PubMed and EMBASE were conducted from inception till 01/10/2024 using keywords that encompassed “aminoglycosides”, “therapeutic drug monitoring”, “ototoxicity” and “nephrotoxicity”. Articles reporting the trough levels with pharmacokinetic parameters and/or patient-related clinical outcomes (adults) were included.

Results: A total of 22 clinical studies were identified. For the context of this study, extended interval dosing of aminoglycosides is considered over the traditional multiple-daily doses. Intravenous amikacin (15mg/kg/dose) achieving an optimal trough of <5mg/L, and gentamicin (7mg/kg/dose) achieving an optimal trough of <1mg/L; both levels were associated with reduced nephrotoxicity and ototoxicity while maintaining efficacy. Higher doses respectively, often exceed the toxicity threshold. Extending dosing intervals, rather than dose reduction, in renal-impaired patients can help achieve target peak concentration for optimal killing effect while minimizing toxicity.

Conclusion:
Optimal trough targets for amikacin (<5mg/L) and gentamicin (<1mg/L) at recommended doses reduce toxicity while preserving efficacy. Extending dosing intervals, rather than dose reduction, is a key strategy to mitigate toxicity, particularly in renal-impaired patients.

Keywords:
Aminoglycosides, Amikacin, Gentamicin, therapeutic drug monitoring, trough targets, infections

Background: With rising antimicrobial resistance, beta-lactam dosing regimens recommended by literature may no longer be relevant. HDBL exceeding conventional recommendations (ECR) may increasingly be necessary to ensure adequate tissue penetration and clinical success.

Aims: We evaluated safety of HBDL in patients without renal impairment.

Methods: Adult patients (≥16 years old) with creatinine clearance ≥50mL/min, who received HDBL ECR, and underwent therapeutic drug monitoring (TDM) in Singapore General Hospital from 2016 to 2024 were included. Safety outcome includes adverse drug reaction (hepatotoxicity, neurotoxicity, diarrhea and death within 30 days of HDBL initiation).

Results: Sixteen patients (median age 45 years [IQR:32-59]) were included. Majority were Chinese (62.5%) and male (68.8%). Most (87.5%) were on culture-directed therapy for multi-drug resistant organisms; 25% had body mass index >30kg/m². Median daily urine and extrarenal output were 2680mL [IQR:1930-3050mL] and 640mL [IQR:110-1295mL] respectively. Nine (56.3%) patients had inadequate beta-lactam levels on conventional beta-lactam dosing regimen and require HDBL. A total of 20 beta-lactam levels were drawn while patients were on HDBL (i.e. total daily dose of 8-24g for meropenem, 10-15g for ceftazidime-avibactam, 8-12g for cefepime, 27g for piperacillin-tazobactam, 12-24g for ceftolozane-tazobactam). There were eight meropenem levels (median trough (MT):17.4mg/L [IQR:10.4-25.1mg/L]); 5 ceftazidime-avibactam levels (ceftazidime MT:57.2mg/L [IQR:37.2-78.5mg/L]; avibactam MT:7.9mg/L [IQR:4.9-10.5mg/L]); 3 cefepime levels (cefepime MT:41.3mg/L [IQR:36.4-60.7mg/L]); 2 piperacillin-tazobactam levels (piperacillin trough range (TR) 28.2-125mg/L; tazobactam TR 6.1-60mg/L); 2 ceftolozane-tazobactam levels (ceftolozane TR 33.4-70.8mg/L; tazobactam TR 2.3-9.5mg/L). None developed adverse concerns.

Conclusions: TDM-guided HDBL ECR is safe.

Keywords: Augmented clearance, Therapeutic drug monitoring, High-dose, Beta-lactam, Safety

Background: Linezolid is an antibiotic of increasing clinical importance. Drug interactions affecting linezolid pharmacokinetics are not well characterized.

Aims: To describe a pharmacokinetic interaction between linezolid and moxifloxacin observed in a clinical case.

Methods: Serial blood samples and 24h urine were collected from a healthy 69-year-old male receiving TDM-guided linezolid (300 mg daily) for prosthetic joint infection under three conditions: (1) linezolid with moxifloxacin, (2) linezolid after moxifloxacin cessation, and (3) linezolid with moxifloxacin recommenced. Plasma concentrations were determined using LC-MS/MS. Non-compartmental pharmacokinetic analysis was used to determine AUC0-24 and total/renal clearances.

Results: Moxifloxacin co-administration increased linezolid exposure by approximately 40-70% (AUC0-24 76 h*mg/L with moxifloxacin, 106 h*mg/L rechallenge vs. 131 h*mg/L without). Peak concentrations were elevated with a modest prolongation of elimination half-life. The effect was reproducible upon moxifloxacin rechallenge. Absolute renal clearance was reduced with moxifloxacin (1.2 L/h with moxifloxacin, 1.0 L/h rechallenge vs. 1.4 L/h without).

Discussion: This case provides compelling evidence for a clinically significant interaction between linezolid and moxifloxacin, a commonly used combination in mycobacterial and nocardia infections. The mechanism remains undetermined. This interaction has important clinical implications, as increased linezolid exposure may lead to concentration-dependent adverse effects.

Conclusion: Clinicians should be aware of possible increased linezolid exposure when co-administered with moxifloxacin. Therapeutic drug monitoring of linezolid is indicated, especially in patients with risk factors for toxicity. Further investigation is warranted to elucidate the mechanism and determine if this interaction occurs with other fluoroquinolones.

Keywords: linezolid, moxifloxacin, drug interaction, therapeutic drug monitoring

Background: Due to an epidemic of vancomycin-resistant Staphylococcus haemolyticus infections in neonatology, daptomycin is increasingly used in this population in probabilistic treatment. Little is known about daptomycin exposure in this context.

Aim: We report on a case series of patients who benefited from therapeutic drug monitoring (TDM) of daptomycin in our hospital between oct2024 and Jan2025.

Method: Neonates suspected of having a low-susceptibility to vancomycin, daptomycin-susceptible infection were treated with daptomycin 6 mg/kg/12h, in 1h infusions. Trough (Cmin) and 1h post-infusion (Cmax) plasma concentrations were measured by LC-MS/MS whereas AUC0-24h (=AUC0-12h*2) were approximated by trapezoidal method (no pop-PK-model available in neonates). The PK-PD targets were Cmin<24.3µg/mL for toxicity and AUC/MIC>666µg.h/mL for efficacy.

Results: Fifteen neonates benefited from TDM (4♀, 11♂), one child was treated for 2 separate infectious episodes. S.haemolyticus was identified in 9 cases with an MIC of 0.25mg/L (no germ found in the other 7 cases). Median [min-max] Cmax was 36.7µg/mL [12.4-60.6] (n=10). Median Cmin was 14.9µg/mL [4.8-41.9], 4/16 were above the recommended threshold. Median AUC0-24h was 541.6µg.h/mL [206.4-1134] (n=10). The PK-PD target for efficacy was achieved in 9 patients but can’t be evaluated for the others. No adverse events attributable to daptomycin were identified during treatment or up to the end of hospitalization. Daptomycin was never discontinued for lack of efficacy, two children died unrelated to the infection.

Conclusion: Daptomycin was safely used in children, but the appropriateness of the dosing regimen still needs to be assessed to ensure PK-PD target attainment.

Keywords: daptomycin, neonates, exposure

Background: Multidrug resistance in bacteria poses a significant threat to global health, creating an urgent need for new sources of antibiotics. Nut grass or Cyperus rotundus L., a typical Asian medicinal herbal remedy, is gaining increasing attention in the scientific community as a potential source of antimicrobial agents.

Methods: In this study, endophytic fungi in this plant were isolated, macro- and micrologically identified, and assessed for their antibacterial properties on Gram-positive and Gram-negative bacteria.

Results: Consequently, seven types of endophytic fungi with potential antibacterial activities were obtained from Vietnamese Cyperus rotundus L. These endophytic strains could inhibit Gram-positive bacteria, including Bacillus subtilis, Methicillin-susceptible Staphylococcus aureus (MSSA), and Methicillin-resistant Staphylococcus aureus (MRSA). In particular, the most potent fungus could effectively inhibit MRSA, Escherichia coli, and Pseudomonas aeruginosa. Furthermore, a significant impact of the culture medium on the biomass's antibacterial activity was observed, and the Potato Dextrose Agar (PDA) and Czapek-Dox (Cz) media were shown to be the most appropriate culture media.

Conclusions: Altogether, endophytic fungi isolated from Cyperus rotundus L. were shown to be a promising source for antibiotics to tackle the problem of antibiotic resistance.

Background: Therapeutic drug monitoring of Ganciclovir is routinely performed using trough concentration (C0), while no studies found a clear relationship with efficacy. Besides, area under the curve (AUC) is increasingly used in therapeutic drug monitoring of ganciclovir.

Aims: The aim of this study was to explore the variation of pharmacokinetics indices and target attainment of GCV in transplantation.

Methods: Transplanted patients who received ganciclovir/valganciclovir and had C0 and AUC0-24h performed between 2022 and 2025 were retrospectively included in the study. Pharmacokinetic variability was assessed using AUC0-24h/C0 linear regression, inter- and intra-patients dose-adjusted coefficient of variation for C0 and AUC0-24h and percentage of patients reaching the therapeutic range (C0=1-2µg/mL, AUC0-24h=40-60µg.h/mL).

Results: Thirty-one transplanted patients (8 children/23 adults, 6 universal prophylaxis/20 preemptive therapy/5 curative treatment) contributed to 54 occasions. A poor AUC0-24h/C0 correlation was found (adults: r²=0,44, children: r²=0,55). A high (CV=144%) and mild (CV=41%) interindividual variability were found for C0/D and AUC0-24h/D, respectively. A mild (CV=56%) and low (CV=20%) interindividual variability were found for C0/D and AUC0-24h/D, respectively. Ten percent of adults had AUC0-24h within the range (41% for C0) while 45% of children had AUC0-24h within the range (0% for C0).

Conclusions: C0 does not seem to be the best parameter to monitor ganciclovir treatment and could be replaced by the estimation of AUC for a more precise therapy. Further studies are needed to better define the relationship between AUC0-24h and ganciclovir pharmacodynamics/clinical outcomes.

Key words: area under the curve, trough concentration, cytomegalovirus, antivirals, pharmacokinetics.

Background: The Area-Under-the-Curve/Minimum Inhibitory Concentration(AUC/MIC)-based vancomycin TDM has been recommended over trough-based TDM for neonates. However, this recommendation was based on extrapolations from pediatric and pharmacokinetic models. Neonates have unique pharmacokinetic differences due to their immature renal function and rapidly changing fluid status.

Aims: This study aims to compare the (1)percentage of patients attaining subtherapeutic, therapeutic and supra-therapeutic targets; (2)dose required for target attainment (AUC 400-600, assuming MIC 1, or trough 10-20mg/L); (3)culture-directed treatment efficacy (microbiological resolution, clinical efficacy) using vancomycin trough-vs. AUC/MIC-based TDM.

Methods: This was a single-center, retrospective observational study conducted at KK Women’s and Children’s Hospital, Singapore(KKH) from January 2020 to December 2024. Neonates [post-menstrual age(PMA) <45 weeks] who received intravenous vancomycin, with at least two vancomycin serum concentrations obtained during steady state, were included. Neonates with acute kidney injury, on dialysis or extracorporeal membrane oxygenation(ECMO) are excluded. Using Adult and Pediatric Kinetics(APK©) software, 24-hour AUC was determined using a one-compartmental model.

Results: Of the 22 neonates included, a larger proportion of patients achieved therapeutic targets when the AUC/MIC-based method (40.9%) was used, compared to the trough-based method (22.7%, p=0.2). This resulted in lower adjusted doses of vancomycin when AUC/MIC-based TDM was used(p=0.03). Almost all patients attained clinical improvement and microbiological clearance regardless of whether their serum vancomycin concentrations were therapeutic at initial steady state (95%). Two patients (9%) developed acute kidney injury after vancomycin therapy.

Conclusions: AUC/MIC-based vancomycin TDM resulted a larger proportion of neonates achieving therapeutic targets with potentially lower adjusted doses of vancomycin.

Background: Posaconazole (PSCZ) is a triazole antifungal agent for the prevention of invasive fungal infections in patients undergoing hematopoietic stem cell transplantation and with hematological malignancies. When the serum concentration is low, there is a possibility of breakthrough infection, insufficient therapeutic effect, or induction of resistant bacteria. When the serum concentration is high, there is a possibility of adverse events such as hypokalemia.

Aims: We investigated the factors affecting the PSCZ serum concentration.

Methods: 39 patients with hematological malignancies were studied. PSCZ serum concentration was determined by HPLC-UV. Univariate and multivariate analyses were used to investigate the factors affecting significantly trough concentration. Genetic polymorphisms of transporters affecting the pharmacokinetics of PSCZ were analyzed.

Results: Patients with diarrhea or a higher PSCZ-glucuronic rate showed low blood concentrations. Based on Spearman's rank correlation coefficient, trough serum concentration was positively correlated with age and total bilirubin and negatively correlated with metabolic rate and diarrhea. From multiple regression analysis, the similar results were obtained.
In patients with a homozygous mutant for SNPs in MRP2 C3972T or two homozygous variants of SNPs in ‘MDR1 T3435C, MDR1 T1236C, BCRP G34A’, the PSCZ serum concentration was significantly higher, suggesting the possible lower activity of both the inhibition of gastrointestinal absorption and hepatic-biliary excretion of PSCZ.

Conclusions: In order to achieve safe and effective treatments in patients receiving posaconazole, we recommend that TDM be performed taking into account the age, liver function and the occurrence of diarrhea.

Key Words: Posaconazole, diarrhea, glucuronic metabolism, genetic polymorphism of transporters, hypokalemia

Background: Nirmatrelvir/ritonavir is an antiviral regimen for patients at high risk for severe COVID-19, but it poses significant risks of drug-drug interactions (DDIs), primarily due to ritonavir’s potent inhibition of cytochrome-P450 3A4.

Aims: This study aimed to assess the impact of nirmatrelvir/ritonavir-related DDIs and evaluate an expert-driven approach for their management.

Methods: We conducted a retrospective observational study of all pharmacology expert opinions regarding nirmatrelvir/ritonavir-related DDIs, between February 2022 and December 2024. Data on patient demographic and clinical characteristics, concomitant medications, and expert recommendations were systematically collected and analyzed.

Results: Among 455 patients (median age 75 years), 6% received an expert recommendation of contraindication to Nirmatrelvir/ritonavir prescription due to unmanageable DDIs or severe renal impairment. Of the 429 eligible patients, 86.7% had at least one clinically significant DDI, with a median of eight concomitant medications per patient. The most frequent DDIs involved statins (17.7%), immunosuppressants (12.0%), and direct oral anticoagulants (10.5%). Expert recommendations included continuing therapy without modification (76%), temporary interruption (14%), dosage adjustment (6%), or changing treatment (3%). Close clinical monitoring was advised for 8%, and therapeutic drug monitoring for 6%. The majority of requests in 2022 came from hospital specialists (71%), whereas general practitioners accounted for 45% in 2023 and 50% in 2024.

Conclusions: A specialized pharmacology service can effectively support safe prescribing of nirmatrelvir/ritonavir in a high-risk, predominantly older and polypharmacy-prone population. Our service has expanded beyond tertiary centers, enhancing access for a wider range of healthcare professionals and ensuring safer treatment management.

Keywords: nirmatrelvir/ritonavir, drug-drug interaction

Background: Pseudomonas aeruginosa (Pa) isolates from the ST235-clone are high-risk as they are often extensively drug-resistant and prevalent in endemics. Innovative personalised treatment for the pathogen and patients is needed to optimise patient outcomes.

Aims: To investigate ceftolozane/tazobactam (C/T) and meropenem (MER), in monotherapy and combination, against ST235-clone Pa isolates using the dynamic in vitro hollow-fibre infection model (HFIM), quantitative and systems pharmacology (QSP) modelling, whole genome sequencing (WGS) and Monte Carlo simulations (MCS).

Methods: Three multidrug-resistant isolates from hospitalised patients were investigated in 240-h HFIM studies (n=1-2 replicates; inoculum ~106.8 CFU/mL) against intermittent C/T (1.5/0.5g 3h infusion 8-hourly, t1/2=2h) and continuous infusion MER (6g/day). Quantified total viable and resistant bacterial counts were QSP modelled. Whole genome sequencing and MCS were performed.

Results: All MER and 2 of 3 C/T monotherapy treatments failed and amplified resistance. The combination performed successfully against all isolates. The model, informed by the resistance mechanisms present, well-described antibacterial effects of the monotherapy and combination regimens, without estimating strain-specific drug effect parameters. MCS predicted the combination would supress regrowth against all isolates for 95% of simulated patients.

Conclusions: The combination of C/T and MER enhanced bacterial killing, consistently suppressing regrowth and resistance against all tested isolates. The QSP model is the first model to characterise the different bacterial responses to an antibiotic combination, only by the resistance mechanisms present and their complex interplay; representing an initial step towards pathogen-specific personalised medicine. MCS predicted the likely effectiveness of tested regimens for patients with normal renal function.

Background: Adequate antibiotic exposure is crucial when managing multidrug-resistant infections. HDNBLBLI may improve tissue penetration, clinical outcomes and prevent further resistance development. However, there is limited data on HDNBLBLI usage exceeding literature recommendations (ELR).

Aims: We evaluated safety and efficacy of HDNBLBLI.

Methods: Adult patients (≥16 years) receiving ceftazidime-avibactam or ceftolozane-tazobactam ELR, who underwent therapeutic drug monitoring (TDM) in Singapore General Hospital from 2020 to 2025 were included. Primary efficacy outcome was achieving personalized therapeutic unbound serum BLBLI targets (PT). Secondary efficacy outcome was 30-day infection-related mortality (IRM) after HDNBLBLI initiation. Safety outcomes included adverse drug reaction from HDNBLBLI usage (hepatotoxicity, neurotoxicity, diarrhea).

Results: There were 21 patients (median age 58 years [IQR:55-64]); 33% were bacteremic. Most were on culture-directed HDNBLBLI for multi-drug resistant organisms (carbapenem-resistant Enterobacterales [47.6%], Pseudomonas aeruginosa [23.8%], Acinetobacter baumannii [14.3%]) - Ceftazidime MIC 0.5-4mg/L; Ceftolozane MIC 4-8mg/L. Most patients had soft tissue infection and pneumonia (28.6% each). 61.9% patients had renal impairment (9 hemodialysis [HD]; 4 continuous renal replacement therapy [CRRT]). Majority (80.9%) received ceftazidime-avibactam: Ceftazidime-avibactam daily doses [DD] were 10-15g (normal renal function [NRF]), 2.5-7.5g (HD) and 7.5g (CRRT); Ceftazidime (median peak 92.7mg/L [IQR:72.5-113.5mg/L]; median trough 53.2mg/L [IQR:34.6-66.2mg/L]), Avibactam (median peak 19.4mg/L [IQR:13.1-27.4mg/L]; median trough 11.6mg/L [IQR:5.7-14.7mg/L]). Ceftolozane-tazobactam DD were 12-24g (NRF), 2.25g (HD) and 12g (CRRT); Ceftolozane (peak 52.6-218.9mg/L; trough 33.4-114.8mg/L); Tazobactam (peak 12.9-86.3mg/L; trough 2.3-41.1mg/L). Most (85.7%) patients achieved PT. None developed adverse reactions or IRM.

Conclusions: TDM-guided HDNBLBLI is safe and efficacious.

Keywords: Ceftazidime-avibactam, Ceftolozane-tazobactam, Beta-lactam, Beta-lactamase inhibitor, High-dose therapy, Multidrug resistance

Background
It is inadequate to direct evaluation of meropenem pharmacokinetic targets and clinical efficacy. This study aimed to investigate the predictors of meropenem clinical effectiveness and to optimize dosing regimens precisely in the Department of Respiratory and Intensive Care Unit (RICU).
Methods
Patients with severe pneumonia using meropenem in RICU were included. Blood samples were assayed using two-dimensional high-performance liquid chromatography. Logistic regression analysis was conducted to identify predictors of efficacy. Population pharmacokinetics analysis was performed to optimize dosing regimens.
Results
396 meropenem concentrations from 111 patients were measured. The joint predictor of total protein, platelet, Cpeak, and APACHE Ⅱ score had a good predictive performance on the clinical efficacy (P <0.001). Model-based simulation suggested to administer 2000 mg of meropenem every 8 hours at a 2-hour infusion for the patient with a minimum inhibitory concentration (MIC) of 8 mg/L and a creatinine clearance (CrCL) of 30 ml/min, or at 3-hour infusion for the patient with a MIC of 4 mg/L and a CrCL of 60 ml/min, respectively, which could achieve a probability of target attainment (PTA), with 100% of the time between doses at which the free fraction concentration remains above MIC (%fT>MIC) ≥ 80%. And only at specific MICs and pharmacodynamic targets, did PTAs of the prolonged infusion be significantly different (P <0.05).
Conclusion
High Cpeak caused potential unfavorable outcomes. 2000 mg of meropenem every 8 hours with 2-hour or 3-hour infusion was recommended for patients with severe pneumonia in RICU. The benefits of prolonged infusion were limited.

Background: Renal impairment, either acute kidney injury (AKI) or chronic end-stage renal failure (ESRF), is common among septic patients. While renal dose adjustment recommendations exist for beta-lactams, they may not be relevant due to rising antimicrobial resistance and technological advancements in RRT.

Aims: We evaluated safety of HDBL exceeding literature recommendations (ELR), in patients requiring RRT.

Methods: Adult patients (≥16 years old) who required RRT, and received therapeutic drug monitoring (TDM)-guided HDBL ELR in Singapore General Hospital were recruited from 2016 to 2025. Safety outcomes included adverse drug reaction (hepatotoxicity, neurotoxicity, diarrhea and death within 30 days of HDBL initiation).

Results: Thirty-eight patients (median age 59 years [IQR:55.3-73]) were included. Majority were Chinese (57.9%) and male (63.2%). Patients required RRT due to AKI (50%) or ESRF (50%). Most (52.6%) had residual urine and/or extrarenal output >500mL daily; 47.4% were on culture-directed therapy for multi-drug resistant organisms; 34.1% had body mass index >30kg/m². Forty-three beta-lactam levels were drawn: 20 meropenem (median trough [MT]:25.2mg/L [IQR:19.7-28mg/L]; daily dose (DD) 2g for peritoneal dialysis [PD] and hemodialysis [HD], 4-8g for continuous renal replacement therapy [CRRT]); 11 ceftazidime-avibactam (ceftazidime MT:53.2mg/L [IQR:39.8-63.8mg/L]; avibactam MT:14.2mg/L [IQR:11.1-17.8mg/L]; DD 7.5g [CRRT], 2.5-7.5g [HD]); 5 aztreonam (MT:143.6mg/L [IQR:99-181.6mg/L]; DD 6g [PD], 3-8g [HD]); 3 piperacillin-tazobactam (piperacillin trough range 126.7-140.2mg/L, tazobactam trough 32mg/L; DD 13.5g [HD]); 2 cefepime (DD 2g [HD]); 2 ceftolozane-tazobactam (trough 114.8/41.1mg/L; DD 2.25g [HD], 12g [CRRT]). None developed safety concerns.

Conclusions: TDM-guided HDBL ELR is safe for patients requiring RRT.

Keywords: Dialysis, High-dose, Beta-lactam, Safety

Background
Beta-lactam therapeutic drug monitoring (TDM) is recommended for critically ill patients and those with less susceptible organisms but evidence for non-critically ill patients with lower pharmacokinetic variations, is limited.

Aims
To evaluate the need for beta-lactam TDM in the Asian population with sepsis.

Methods
An observational study at Tan Tock Seng Hospital from January 2022 to August 2023 assessed patients with Gram-negative bacteraemia receiving empiric piperacillin-tazobactam or meropenem. Minimum inhibitory concentrations (MIC) were determined using gradient-diffusion tests. The MIC¬90 of Gram-negative bacteria from a historic cohort (Oct 2022 – Dec 2023) was extracted to represent antibiotic susceptibility from other specimen sources. Therapeutic concentration was defined as an fCmin/MIC≥1.

Results
Out of 293 eligible participants, 68 were enrolled with 16.0% critically ill. Median age was 67, inter-quartile range (IQR) 57-74 years. 30-day mortality of 7.4%. Median MIC of the bacteraemia isolates to meropenem was 0.032, IQR 0.032-0.064 mg/L and to piperacillin-tazobactam was 2, IQR 1-4 mg/L. Overall, median fCmin/MIC was 17.51, IQR 2.88-57.57 with 8% (n=6) with fCmin/MIC<1. Comparisons using MIC90 data and Clinical and Laboratory Standards Institute (CLSI) and European Committee on Antimicrobial Susceptibility and Testing (EUCAST) breakpoints showed that up to 44% and 3.1% in those receiving piperacillin-tazobactam and meropenem respectively will achieve Cmin/MIC<1.

Conclusion
Asian patients with Gram-negative bacteraemia have a low risk of sub-therapeutic levels of piperacillin-tazobactam and meropenem. Significant risks arise when considering other sources of sepsis. Further studies are needed to identify who would benefit from beta-lactam TDM in this population.

Beta-lactam, TDM, Asian

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
Elderly patients with tuberculosis (TB) are at increased risk of adverse reactions to anti-TB drugs. With the growing number of elderly population and rising TB incidence in advanced age, managing anti-TB therapy in older adults presents unique challenges compared to younger patients.

Aims
This study aims to characterize the pharmacokinetics of four first-line anti-TB drugs in elderly Thai patients with active TB.

Methods
Twenty elderly TB patients receiving isoniazid (INH), rifampicin (RIF), ethambutol (EMB), and pyrazinamide (PZA) for at least four weeks underwent serial blood sampling at pre-dose (0) and 1, 2, 4, 6, 8, and 12 hours post-dose. Drug concentrations were quantified using a fully validated LC-MS/MS method, and pharmacokinetic parameters were analyzed via non-compartmental analysis. Adverse reactions were also assessed.

Results
INH reached peak plasma concentration (Cmax) in 1 hour with an apparent oral clearance (CL/F) of 0.48 L/hr/kg. RIF, EMB, and PZA had a median Tmax of 2 hours, with CL/F values of 0.25, 0.58, and 0.05 L/hr/kg, respectively. Considerable inter-individual variability was observed in drug plasma concentrations. Adverse reactions were reported in 30% of patients, including mild maculopapular rash (20%), mild transaminitis (5%), and asymptomatic drug-induced liver injury (5%).

Conclusions
This study provides pharmacokinetic data on first-line antituberculosis drugs in elderly Thai patients. Given the variability in drug exposure, therapeutic drug monitoring is recommended to optimize efficacy and minimize complications.

Keywords
Pharmacokinetics, Antituberculosis drugs, Elderly, Therapeutic Drug Monitoring

Background
Coagulase-negative staphylococci (CoNS) are commonly found on human skin and can cause hospital-acquired bloodstream infections, typically treated with vancomycin. Vancomycin dosing for methicillin-resistant Staphylococcus aureus (MRSA) infections was traditionally based on maintaining trough concentrations (Ctrough) between 10–20 mg/L. However, current recommendations emphasize targeting a 24-hour area under the curve to minimum inhibitory concentration (AUC24/MIC) ratio of 400–600 mg.h/L. There are no specific guidelines for vancomycin dosing in CoNS infections.

Aim
To investigate relationships between Ctrough, treatment outcomes, and nephrotoxicity in patients with CoNS infections.

Methods
Data were retrieved for adult patients treated at Srinagarind Hospital, Thailand between 2010 and 2023. Treatment outcomes, including 30-day mortality, early clinical response (ECR), and clinical response at the end of therapy (CRend), as well as vancomycin trough concentrations and nephrotoxicity were analyzed.

Results
Fifty-one patients met the study criteria. Ctrough levels were higher in the mortality group (n=6) (32.11 mg/L vs 18.64 mg/L, p = 0.010) and in patients with nephrotoxicity (n=12) (30.71 mg/L vs 18.64 mg/L, p = 0.013). No correlation was observed between Ctrough and ECR or CRend. There was no correlation between achieving vancomycin Ctrough 10-20 mg/L and treatment outcomes or nephrotoxicity.

Conclusion
Vancomycin levels positively correlated with mortality and nephrotoxicity in CoNS-infected patients but not clinical response. Maintaining Ctrough 10-20 mg/L may not ensure therapeutic effects. Due to the small sample size, conclusions on optimal CoNS dosing cannot be made and further research is required to determine an optimal AUC24/MIC ratio.

Keywords
vancomycin,CoNS,PKPD,TDM

Objectives:To explore the relationship between ganciclovir trough concentration and clinical efficacy/safety in patients with pulmonary cytomegalovirus (CMV) infection, and to evaluate the target value for therapeutic drug monitoring (TDM) in predicting efficacy or toxicity.

Methods: An observational study was conducted from Jan 2021 to Dec 2023 on patients with CMV lung infection. TDM was performed to collect target trough concentrations, and clinical outcomes and adverse events (AEs) were assessed. Multiple regression and binary logistic regression analyses were used to identify factors influencing trough concentrations and clinical efficacy. Receiver operating characteristic (ROC) curve analysis was employed to determine trough concentration cutoffs for predicting toxicity.

Results: Among 149 patients, only 19.22% achieved the target trough concentration range of 2-4 μg/ml. Factors such as diabetes, organ transplantation, and elevated hemoglobin levels decreased trough concentrations, while elevated blood creatinine and continuous renal replacement therapy (CRRT) increased them. Factors influencing clinical efficacy included organ transplantation, duration of ganciclovir administration, and albumin levels. ROC analysis identified ganciclovir trough concentration cutoffs of 0.985 μg/ml (AUC=0.600) for decreased hemoglobin and 0.995 μg/ml (AUC=0.701) for elevated blood creatinine.

Conclusions: No association was observed between ganciclovir trough concentration and clinical efficacy. However, thresholds for ganciclovir trough concentrations causing decreased hemoglobin and increased blood creatinine levels were identified. Renal replacement therapy was associated with elevated trough concentrations. These findings highlight the importance of TDM for ganciclovir and suggest the need to reconsider the target concentration range.

Keywords: Ganciclovir, Cytomegalovirus, Lung infection, therapeutic drug monitoring, trough concentration

Background: Limited information is available regarding the pharmacokinetic parameters of intravenous vancomycin (VCM) in peritoneal dialysis patients.

Aims: This study aimed to investigate the pharmacokinetic parameters of VCM in Japanese peritoneal dialysis patients.

Methods: This study included peritoneal dialysis patients who received intravenous VCM at Sakai City Medical Center from January 2022 to December 2024. Patients undergoing hemodialysis or without serial serum VCM concentration measurements were excluded. Patient data (age, sex, renal function, VCM administration history, and serum VCM concentrations) were extracted from medical records, and pharmacokinetic parameters were calculated.

Results: Seven patients were included. The initial VCM dose was 21.6 ± 2.2 mg/kg, and the administration interval from the second dose was 52.5 ± 13.0 hours. Pharmacokinetic parameters were calculated based on serum concentration measurements, assuming a distribution volume of 1.07 L/kg. The mean elimination rate constant was 0.00583 ± 0.00132 hr⁻¹, mean clearance was 6.58 ± 1.48 mL/min, and the mean half-life was 127.9 ± 29.7 hours. The AUC was 529.9 [277.3–1147.9] mg·hr/mL, with 61.1% (11/19) within the target range of 400 < AUC < 600.

Conclusion: VCM was administered approximately every 48 hours. Frequent serum concentration monitoring may have contributed to stable VCM administration. Larger studies are needed to confirm these results.

Key Words: vancomycin, pharmacokinetic parameters, peritoneal dialysis

Background: Vancomycin is the first-line treatment for methicillin-resistant Staphylococcus aureus (MRSA) infections, and achieving the recommended AUC24H/MIC target is crucial for optimal clinical outcomes.

Aims: This study is a sub-analysis of a larger pharmacokinetic study population and focuses on vancomycin pharmacokinetics/pharmacodynamics (PK/PD) and treatment outcomes in paediatric patients with MRSA infections.

Methods: A retrospective cohort analysis was conducted in 23 children admitted to a tertiary paediatric hospital between January 2022 and December 2023. Data were collected from pharmacokinetic and medical records. PK parameters were estimated using established equations. Clinical outcomes were assessed based on clinical and microbiological parameters at the end of treatment.

Results: Among 23 paediatric patients with MRSA infections, two cases (8.7%) were non-responders. The initial vancomycin dose used was 58.40mg/kg/day (IQR: 15.00). The majority of patients (73.9%) had a vancomycin minimum inhibitory concentration (MIC) of ≤1mg/L. Sub-therapeutic pre-levels were observed in 82.6% of patients, with a median level of 8.40mg/L (IQR: 5.22). Additionally, 87% had a sub-therapeutic 24 hours-area under the curve (AUC24H), with a median value of 313.45mg·h/L (IQR: 181.58), while 52.2% had a sub-therapeutic AUC24H/MIC, with a median value of 286.05mg.h/L (IQR: 341.14). To achieve the target AUC24H of 426.30mg·h/L (IQR: 129.62), patients required a median dose of 66.67mg/kg/day (IQR: 18.61).

Conclusion: A large proportion of paediatric MRSA patients received sub-therapeutic vancomycin dosing, failing to meet the AUC24H/MIC targets. Optimized dosing and individualized TDM are needed to improve outcomes, warranting further research in a larger study population.

Keywords: MRSA, vancomycin, therapeutic drug monitoring

Background: The clinical application of antimicrobial therapeutic drug monitoring (TDM) improves achievement of pharmacokinetic/pharmocodynamic targets while minimising toxicity. However, literature describing complex drug interactions and unexpected drug disposition in polymicrobial infections remains scarce

Aim: To describe a case where TDM played a critical role in identifying and managing multiple unexpected drug disposition scenarios, including a possible novel drug-drug interaction between voriconazole and piperacillin/tazobactam.

Methods: A 54-year-old man with gastrointestinal graft-versus-host-disease post allogeneic stem cell transplant for high-risk myelofibrosis developed resistant polymicrobial infections of the blood stream, psoas abscess and prosthetic hip joint. Pathogens isolated included Lomentospora prolificans, Morganella morganii, vancomycin-resistant Enterococcus and AmpC beta-lactamase Escherichia coli. Treatment initially comprised of voriconazole, linezolid and piperacillin/tazobactam. Intensive TDM was performed, targeting trough concentrations between 2-5 mg/L for voriconazole, 2-7 mg/L for linezolid, and 4× minimum inhibitory concentrations for beta-lactam agents.

Results: TDM revealed persistently subtherapeutic trough voriconazole concentrations (mean 0.5mg/L) despite dose escalation to 1500mg/day (triple standard dose) during piperacillin/tazobactam treatment. A subsequent switch to cefepime improved voriconazole concentrations (mean 2.3mg/L). Linezolid concentrations were initially subtherapeutic (mean 1.1mg/L), requiring double standard dosing, suggesting CYP2J2 induction by a pathophysiological mechanism. Dose adjustments maintained antimicrobial concentrations within target ranges, contributing to treatment success without toxicity.

Conclusions: Proactive TDM represents a valuable clinical tool for antimicrobial stewardship by enabling swift detection of drug disposition anomalies, and antimicrobial optimization. The interaction identified here between voriconazole and piperacillin/tazobactam, putatively mediated through CYP450 enzyme induction, has important implications for beta-lactam selection in patients requiring triazole antifungals.

Background
Vancomycin is essential for treating severe Gram-positive infections in adult critically ill patients, but its narrow therapeutic index requires therapeutic drug monitoring (TDM) to optimize efficacy and minimize toxicity. The debate between trough concentration (Cmin)-based dosing and area under the curve (AUC)-based dosing remains unresolved, impacting mortality, nephrotoxicity, and clinical outcomes.

Aims
This meta-analysis evaluates the impact of TDM on mortality, nephrotoxicity, and clinical cure rates in adult critically ill patients receiving vancomycin.

Methods
A systematic search in PubMed, Scopus, Google Scholar, ProQuest, and Cochrane Library identified nine studies assessing vancomycin TDM in adult critically ill patients. These included three studies each for mortality, nephrotoxicity, and clinical cure rates.

Results
TDM significantly reduced mortality in three studies (N = 11,587 vs. 11,150; RR 0.84 [95% CI: 0.79, 0.89]). Subgroup analysis of Cmin <15 mg/L vs. Cmin >15 mg/L (N = 11,737) showed improved survival with lower trough levels (RR 0.65 [95% CI: 0.54, 0.78]). Nephrotoxicity risk (N = 156 vs. 150) showed no significant difference (RR 0.83 [95% CI: 0.48, 1.44]). Clinical cure rates (N = 22 vs. 48) comparing AUC <400 vs. >400 mg·h/L found no clear benefit (RR 1.80 [95% CI: 0.41, 7.98]).

Conclusions
This meta-analysis confirms TDM significantly reduces mortality, especially with Cmin <15 mg/L, challenging high-trough strategies. However, nephrotoxicity and clinical cure rates were not significantly impacted, supporting a shift to AUC-based dosing. Further randomized trials are needed to refine vancomycin TDM protocols.

Keywords
vancomycin, therapeutic drug monitoring, critically ill, sepsis, AUC, mortality

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: Clindamycin is commonly used for treatment of both methicillin susceptible and resistant S. aureus (MSSA, MRSA). Recurrent infections are often attributed to small colony variants (SCV), which tolerate otherwise inhibitory antibiotic concentrations.
Methods: To expose MSSA to a mean pediatric free clindamycin 24-h area under the concentration-time curve (AUC) of 7.2 mcg*h/mL reported after standard dosing, we inoculated 10⁵ CFU/mL into broth with clindamycin 0.3 mcg/mL, and 0.5, 2, and 4 times AUC. We quantified CFU on standard agar and agar containing clindamycin at the MIC (0.25 mcg/mL) over 21 days. We identified SCVs phenotypically based on size and slow growth.
Results: All concentrations of clindamycin initially inhibited growth relative to clindamycin-free control. This inhibition was sustained at 2x and 4x AUC, but rebound growth appeared by day 6 in the 0.5x and 1x AUC flasks. Emergence of SCV phenotypes comprising 39-52% of the population occurred by day 8 in all conditions. With low dose clindamycin, the entire population had converted to SCVs by day 14 (0.5x AUC) or day 17 (1x AUC). These SCVs grew on clindamycin agar and randomly selected colonies had MICs that had become resistant per CLSI criteria.
Conclusions: Inadequate dosing and exposure of clindamycin in humans in the treatment of MSSA may promote growth of tolerant and/or resistant SCV with subsequent treatment failure or recurrence following cessation of therapy. We are conducting further experiments to optimize dosing and exposure of clindamycin to reduce the emergence of SCVs.

Keywords: Pharmacokinetics, pharmacodynamics, clindamycin, MSSA, SCV, resistance

Background: Continuous infusion (CI) of vancomycin has been proposed as a method to enhance therapeutic drug levels while minimizing nephrotoxicity compared to intermittent infusion (IntI). However, data on the clinical significance of CI in Japan remain limited.

Aims: This study presents a scoping review along with a case series analysis to assess the significance of CI in Bayesian-assisted, area under the concentration-time curve (AUC)-guided vancomycin dosing.

Methods: A scoping review was conducted using PubMed, Web of Science, and the Cochrane Library to identify studies published between 2018 and 2024. Additionally, a retrospective analysis was performed on 15 patients treated with CI at Kumamoto University Hospital, examining demographics, nephrotoxicity incidence, and mortality rates.

Results: The review identified 10 studies, including one randomized controlled trial. Many studies relied solely on trough concentrations as a surrogate for AUC estimation in IntI regimens without Bayesian assistance. CI target exposure levels varied, with only a few studies adhering to the recommended AUC range of 400–600 μg·h/mL. In the case series, four patients with high creatinine clearance required dose adjustments and achieved therapeutic targets without nephrotoxicity or mortality. Among the remaining 11 patients, only 45.1% reached therapeutic targets, while 54.5% experienced nephrotoxicity.

Conclusions: The findings highlight the need for further research to refine dosing strategies and clarify the advantages of CI compared to Bayesian-assisted IntI. However, CI may be particularly beneficial for patients requiring higher doses (≥3–4 g/day), as it could improve target attainment while mitigating nephrotoxicity risks.

Key Words: Vancomycin,Continuous infusion,Scoping review,Case series,Nephrotoxicity

Background: Isavuconazole is a new azole antifungal drug, which is used for invasive aspergillosis and mucormycosis.

Aims: This study intends to promote individualized drug administration in clinical practice by reviewing the effect of drug-drug interactions on the pharmacokinetics of isavuconazole.

Methods The literature concerning the interactions of isavuconazole was systematically retrieved from three
retrieval platforms, PUBMED, EMBASE, and the Cochrane Library, using the search terms: "isavuconazole" or “isavuconazonium” or “Cresemba” and "interact*”, or “cotreatment”, or “coadministration”, or “combination”, or “concomitant”. Then conduct screening according to the inclusion and exclusion criteria.

Results Eleven studies involving 24 drugs were included in this study. Rifampicin, flucloxacillin, and phenobarbital decreased the exposure of isavuconazole. Ketoconazole and ritonavir significantly increased the exposure of isavuconazole. Esomeprazole, letermovir, midazolam,estradiol/norethisterone, atorvastatin, digoxin, metformin, methotrexate, bupropion, repaglinide, dextromethorphan, caffeine, methadone, warfarin, cyclosporine, tacrolimus, sirolimus, prednisone, and mycophenolate mofetil had no significant effects on the exposure of isavuconazole. However, in the interaction studies of the latter 17 drugs in healthy volunteers, a single dose of concomitant drug was given, which cannot well represent clinical patients. Therefore, these drugs still need to be used with caution.

Conclusions :At present, few reports exist on drugs that alter the pharmacokinetics of isavuconazole. However, many interactions still need to be explored on the basis of the metabolic characteristics of isavuconazole. For clinical patients who are taking isavuconazole in combination with CYP3A4/5, uridine diphosphate glucuronosyltransferase inhibitors or inducers, therapeutic drug monitoring is recommended.

Keywords: isavuconazole; drug-drug interaction; pharmacokinetics

Objective: To evaluate the impact of pharmacist involvement in blood sample quality assessment on the interpretation of vancomycin (VAN) plasma concentrations.
Methods: A retrospective data conducted at Wuhan No. 1 hospital, analyzing data from patients treated with VAN and monitored for plasma concentration between January and December 2022. Key metrics included the distribution and proportion of unqualified samples, departmental distribution, differences in sample quality before and after re-evaluation, and the distribution of VAN plasma concentrations.
Results: The study involved 92 patients and 177 samples from 20 related departments, with 162 samples undergoing VAN plasma concentration monitoring. Among these, 36.42% (59/162) fell within the therapeutic window of 10-20 mg/L, while 22.84% (37/162) were below 10 mg/L and 30.86% (50/162) exceeded 20 mg/L. Overall, 115 samples (64.97%) were qualified, and 62 (35.03%) were unqualified. Of the unqualified samples, 15 were identified during initial evaluation, and 47 were identified during the re-evaluation. After standardized education and retesting, 44 samples showed a significant difference in concentration before and after retesting (P<0.05). The largest difference was observed in samples collected post-administration, with a mean difference of approximately -16.5 mg/L.
Conclusion: Under a sample-centered management mode, pharmacist involvement in pre- and post-analytical evaluation significantly improved the reliability of VAN therapeutic drug monitoring (TDM) data, demonstrating its clinical applicability.
Key words: Vancomycin therapeutic drug monitoring; Sample Quality Assessment; Pharmacist involvement; Pre- and post-analytical evaluation; Plasma Concentration Interpretation

Background: Imipenem and meropenem, carbapenem antibiotics with nephrotoxic potential, have unpredictable outcomes in critically ill patients due to variable PK/PD parameters. No prior research combined relevant factors to prevent associated AKI and death.

Aims: To improve AKI and death risk factor identification in patients on these drugs via machine learning with PK parameters, optimizing therapy safety and prognosis.

Methods: A total of 157 patients treated with imipenem and 160 patients treated with meropenem from May 2021 to November 2023 were sampled. Elimination phase and trough concentrations of the study population were measured by UPLC-MS/MS. PK/PD parameters of the patients were calculated by nonlinear mixed-effects model. Twelve machine learning algorithms constructed prediction models. SHAP values and performance indicators evaluated variable significance and model efficacy.

Results: Decision tree model and extreme random tree model showed the highest efficiency in identifying AKI induced by imipenem and meropenem, respectively. SHAP analysis showed that CREA and drug clearance weights were relatively high in two major categories of clinical indicators and pharmacokinetic parameters. Extreme random tree model showed robust performance with respect to mortality risk outcomes in the imipenem and meropenem treatment groups. SHAP analysis showed that CRRT, age, and CL were key predictors of death in the imipenem group, and CL, TP, and ALB were key predictors of death in the meropenem group.

Conclusions: This study offers a basis for AKI risk assessment and prognosis in treatment, guides individualized strategies, and shows machine learning's clinical value.

Keywords: machine learning, PK/PD, imipenem and meropenem, AKI, death.

Background: Therapeutic Drug Monitoring (TDM) of vancomycin is essential for optimizing efficacy and minimizing toxicity, particularly in renal impairment patients. The role of pharmacists in monitoring vancomycin levels and adjusting doses.

Aims: To evaluate the impact of pharmacist-led TDM on vancomycin monitoring and dosing appropriateness in empiric and documented therapy across different renal function groups.

Methods: A retrospective study was conducted on 347 hospitalized patients. Patients were categorized based on renal function. Pharmacists monitored vancomycin levels and provided recommendations to physicians. The proportion of patients achieving target therapeutic levels was compared across groups, and the influence of renal function impairment on drug levels was analyzed.

Results: Among 347 patients with 782 prescriptions. Mean age of 59.78 ± 17.30 years. ICU admissions accounted for 27.67%. Renal function distribution included 40.35% normal, 35.73% CKD, and 23.92% ESRD. Empiric treatment was indicated in 74.04% of cases. Vancomycin levels were within the target in 25.96%, below target in 32.35%, and above target in 41.69%. Patients with normal renal function had subtherapeutic levels in 45.80% (p < 0.001), while CKD and ESRD groups had supratherapeutic levels of 51.04% and 47.72% (p < 0.001), respectively. Renal impairment significantly influenced vancomycin levels.

Conclusions: Vancomycin TDM is crucial for optimizing treatment outcomes, particularly in renal impairment. Implementing pharmacist-guided initial dose adjustments may improve target level attainment, especially in renal impairment patients, reducing toxicity risks and enhancing therapeutic success. This study supports the importance of standardized monitoring protocols for vancomycin therapy.

Keywords: Vancomycin, Therapeutic Drug Monitoring, Pharmacist

Background: Trovafloxacin (trova), which is a quinolone antibiotic agent, was withdrawn from a global market because of serious liver injury. Trova is known to cause idiosyncratic liver injury as severe adverse events. However, the mechanism of pathogenesis is unknown. On the other hand, we have reported that reactive metabolite induces the release of damage-associated molecular patterns（DAMPs）that activate immune cells, which causes the idiosyncratic drug-induced serious adverse effects.
Aims: We tested whether trova or its reactive metabolites can activate inflammasomes in the human hepatocarcinoma functional liver cell-4 (FLC-4) cells and the human macrophage cell line (THP-1 cell).
Methods: FLC4-cells were cultured with 3.0-30 µM trova for 7 days. The supernatant from the FLC-4 cells was added to THP-1 cells, which was incubated for 24 hr. These supernatants were used for measurement of IL-1β production and caspase-1 activity. One-aminobenzotriazole (ABT, 1 mM) and Ac-YVAD-cmk (YVAD, 1 µM) were used to inhibit cytochromes P450 activities and caspase-1 activity, respectively. The protein of DAMPs were measured by the western blotting.
Results: The supernatant from an incubation of FLC-4 cells with trova increased the IL-1β production and caspse-1 activity of THP-1 cells. In addition, this increases were inhibited by adding ABT or YVAD. HSP40 was significantly increased in the supernatants from FLC-4 cells incubated with trova.
Conclusions: These results demonstrated that the reactive metabolite of trova can cause the release of HSP40 and activate inflammasomes, which can cause immune-related adverse events.
Keyword: trovafloxacin, idiosyncratic drug induced liver injury, reactive metabolite, DAMPs, inflammasome

Background: The therapeutic effect and adverse reactions of vancomycin are closely related to the concentration in vivo, and the individual differences are significant. It is easily affected by various factors such as age, weight, liver and kidney function, and severe infections.

Aims: To ensure the safety and effectiveness of vancomycin administration, a liquid chromatography-tandem mass spectrometry (LC-MS/MS) method was developed for the determination of vancomycin plasma concentration and applied to clinical sample detection.

Methods: Gradient elution was performed with 0.1% formic acid in water (A) and acetonitrile (B) as the mobile phase at a flow rate of 0.3 mL·min-1. Retrospective analysis was conducted on the test results of 247 patients undergoing vancomycin treatment.

Results: Vancomycin exhibited a good linear relationship within the concentration range of 1.56 mg·L-1 to 100 mg·L-1 (r = 0.9996), with a lower limit of quantitation of 1.56 mg·L-1. The intra-day and inter-day relative standard deviations were less than 15%, and the extraction recovery rate ranged from 95.26% to 101.54%. The plasma concentration attainment rate was unsatisfactory across all age groups, with only 13.77% of patients aged 14 to 60 years achieving the target concentration standard.

Conclusions: The detection method established in this study is suitable for clinical vancomycin therapeutic drug monitoring. The vancomycin plasma concentration in different patients is significantly affected by creatinine clearance, and actively carrying out vancomycin monitoring is of great significance for improving patient efficacy and safety.

Key Words: Vancomycin, Plasma concentration, LC-MS/MS, Clinical application

Objectives: Sepsis remains a leading cause of mortality in intensive care units (ICUs), with methicillin-resistant Staphylococcus aureus (MRSA) infections presenting significant treatment challenges. The impact of MRSA co-infection on sepsis outcomes necessitates further exploration.
Methods: We conducted a retrospective observational cohort study using the Medical Information Mart for Critical Care IV (MIMIC-IV-2.2) database. This cohort study included sepsis patients, scrutinizing baseline characteristics, MRSA co-infection, antimicrobial susceptibility, and their relations to mortality through Cox regression and Kaplan-Meier analyses.
Results: Among 453 sepsis patients analyzed, significant baseline characteristic differences were observed between survivors (N=324) and non-survivors (N=129). Notably, non-survivors were older (70.52±14.95 vs. 64.42±16.05, P<0.001), had higher lactate levels (2.82±1.76 vs. 2.04±1.56 mmol/L, P<0.001), and higher SOFA scores (8.36±4.18 vs. 6.26±3.65, P<0.001). Cox regression highlighted SOFA score (HR=1.122, P=0.003), body temperature (HR=0.825, P=0.048), and age (HR=1.030, P=0.004) as significant predictors of 28-day mortality. MRSA co-infection was found in 98.7% of cases without a significant effect on 28-day mortality (P=0.9). However, sensitivity to cephalosporins, meropenem, and piperacillin/tazobactam was associated with reduced mortality. The area under the ROC curve for the combined model of age, SOFA, and body temperature was 0.73, indicating a moderate predictive value for 28-day mortality.
Conclusion: While MRSA co-infection's direct impact on 28-day sepsis mortality is minimal, antimicrobial sensitivity, especially to cephalosporins, meropenem, and piperacillin/tazobactam, plays a critical role in improving outcomes, underscoring the importance of antimicrobial stewardship and personalized treatment strategies in sepsis care.
Keywords: MRSA, Antimicrobial Susceptibility, Sepsis, 28-Day Mortality

Background:
This study investigates the associations between demographic variables, coping mechanisms, and quality of life (QoL) among HIV-positive individuals receiving antiretroviral therapy (ART) in Ho Chi Minh City, Vietnam. The research specifically explores the influence of socioeconomic status, age, and HIV progression on various QoL domains.

Methods:
A cross-sectional analysis was conducted with 181 HIV-positive participants undergoing ART. Quality of life was assessed using the WHO-HIV-BREF tool, which evaluates four dimensions: physical health, psychological well-being, social relationships, and environmental factors. Participants' coping strategies were evaluated through self-reported measures, covering problem-focused, emotion-focused, and avoidance-oriented approaches.

Results:
The analysis revealed that lower socioeconomic status significantly correlated with diminished quality of life across all domains. Aging was associated with reduced physical functioning and independence, while advanced stages of HIV infection negatively impacted the environmental domain. Positive coping strategies, such as acceptance and reframing, were linked to improved quality of life, whereas humor and self-blame were associated with poorer outcomes. Gender differences were evident, with men demonstrating a higher tendency to adopt substance-based coping methods.

Conclusion:
The findings underscore the critical role of addressing both social and medical determinants in enhancing the quality of life for individuals living with HIV. The study advocates for customized interventions to promote adaptive coping strategies that foster well-being. Future longitudinal research is essential to develop more effective intervention frameworks.

Keywords: COPE Brief, Coping strategies, HIV patients, Quality of life, WHOQoL-HIV-Bref.

Background: Pneumonia is an acute respiratory infection that attacks the lungs caused by viruses, bacteria, parasites, and fungi, which can be transmitted through coughing and sneezing droplets, direct contact with sufferers, and environmental factors. Community-acquired pneumonia is pneumonia that often occurs and can be serious or even fatal. According to PDPI 2014, pneumonia is a disease that has a high crude fatality rate (CFR), which is around 7.6%, in 2020 pneumonia is ranked fifth with a percentage of 52%. Therefore, pneumonia requires proper attention and treatment because this disease is still a major health problem in Indonesia.

Aims: This study was conducted to determine the Characteristics and accuracy of using antimicrobials in pneumonia patients (March-Agustus 2020).

Methods: The research design is in the form of a description analysis study who had met the parameters of the right indication, the right patient, the right drug, and the right dose according to the Indonesian Association of Pulmonary Doctors assesses using medical record data of outpatient adult Pneumonia patients during the period March 2020 - August 2020

Results: The study concluded that out of 34 samples have the correct indication was 100%, right drug 100%, right patient 100%, and right dose 91,2%.

Conclutions: The study showed that all or up to 34 samples diagnosed accurately and given medication according to guidelines.

Keywords: Antimicrobial, Rationality, Pneumonia, secondary hospital

Background:
The situation of methicillin-resistant Staphylococcus aureus (MRSA) infections is severe, and the current clinical options for antibacterial drugs are extremely limited. Vancomycin is the first-line treatment for MRSA and serves as the last line of defense. However, in recent years, vancomycin-resistant Staphylococcus aureus has begun to emerge. As the resistance process intensifies, the clinical field faces the dilemma of having no effective drugs available. Compared to the time and cost required to develop new antibiotics, reversing MRSA resistance to restore its sensitivity to existing β-lactam antibiotics is of significant importance for the clinical treatment of MRSA.

Aims: Reversing MRSA Drug Resistance

Methods: This project aims to design and screen novel nucleic acid drugs, DNAzymes, to specifically silence the expression of the major MRSA resistance gene MecA, thereby reversing MRSA resistance to β-lactam antibiotics. Next, Construction of a meaA DNAzyme/Oxacillin codelivery nanosystem.

Results: Screen a series of 10-23 DNAzymes capable of downregulating the MRSA resistance gene MecA, and validate their enhancement of the bactericidal effects of β-lactam antibiotics at the in vitro level.Construct a co-delivery nanosystem, Oxa/Dz@ZIF-8, incorporating DNAzyme and oxacillin, and successfully treat a mouse model of MRSA-induced bacteremia, achieving promising preclinical results.

Conclusions:The novel nucleic acid drug, DNAzyme, can reverse the resistance of MRSA bacteria, not only providing new insights and research foundations for treating MRSA infections based on existing antibiotics but also offering a new therapeutic strategy for combating other resistant bacteria using existing antibiotics.

Key Words: Methicillin-resistant Staphylococcus aureus, MRSA, Durg Resistant gene, MecA, DNAzyme, Nanoparticle

Background:
Fentanyl, a synthetic opioid with a narrow therapeutic window, has become a major challenge due to its high potency and the increasing prevalence of illicitly manufactured fentanyl, leading to rising overdose fatalities. Traditional monitoring methods are often inadequate in distinguishing between therapeutic use, misuse, and toxicity. A therapeutic drug monitoring and pharmacogenetics-based approach could provide a precision medicine framework to optimize fentanyl use and improve patient safety.

Aims:
This study evaluates TDM strategies, pharmacogenomic applications, and real-time toxicology innovations for fentanyl monitoring and overdose prevention. Additionally, we analyze global policy gaps in integrating these strategies into clinical practice.

Methods:
A systematic review of fentanyl pharmacokinetics, drug metabolism variability, and TDM methodologies was conducted, incorporating clinical case studies from hospitals, forensic laboratories, and harm reduction programs.

Results:
Four key findings emerged:
1. TDM advancements, such as real-time biosensors and LC-MS/MS assays, improve fentanyl exposure assessment.
2. Pharmacogenetics (CYP3A4, ABCB1 polymorphisms) predicts individual fentanyl metabolism and overdose risk.
3. Forensic toxicology biomarkers differentiate between therapeutic and illicit fentanyl use, guiding clinical interventions.
4. Harm reduction strategies integrating TDM enhance naloxone distribution and overdose reversal outcomes.

Conclusions:
TDM, combined with pharmacogenetics, can revolutionize fentanyl management, ensuring precision dosing and reducing opioid-related harms. Integrating these tools into clinical protocols and global policies will enhance patient safety and regulatory efforts.

Keywords: fentanyl, therapeutic drug monitoring, pharmacogenetics, opioid toxicity, forensic toxicology, overdose prevention

Background: Natural salicylates can cause severe poisoning. We present the case of a 78-year-old man who ingested 15 mL of Wintergreen essential oil in a suicide attempt. Twenty-four hours later, he presented confusion, dyspnea, tachycardia, metabolic acidosis, and acute renal failure. Continuous hemofiltration was initiated for 72 hours to enhance the elimination of salicylate. While features of salicylate poisoning are well-reported, mechanisms underlying metabolic acidosis remain to be fully elucidated.

Aims: i) To describe kinetics of methylsalicylate and salicylates; ii) To estimate pharmacokinetic parameters during hemofiltration; iii) To investigate mechanisms involved in the onset of metabolic acidosis using metabolomics.

Methods: Essential oil, plasma, and urine samples were analyzed using GC-EI-MS to quantify methylsalicylate and salicylate concentrations. Plasma pharmacokinetics parameters were determined using WinNonlin®8.3. Untargeted metabolomics analyses were performed on plasma and urine using LC-HRMS/MS.

Results: The 15-mL ingested equaled about 15 g of methylsalicylate (85% m/v). On admission, methylsalicylate concentrations were <1 mg/L in blood and urine, with a salicylate concentration of 900 mg/L. During hemofiltration, elimination kinetics changed from zero-order (Km = 186.5 mg/L) to first-order (T1/2 = 5.5 h) as salicylate levels fell below Km. Metabolomic analysis identified 13 metabolites of methyl salicylate. Metabolisms of acylcarnitine and dicarboxylic were altered and correlate with the deficit in bicarbonate.

Conclusion: Methylsalicylate is rapidly hydrolyzed to salicylic acid, resulting in acidosis, partly explained by salicylic acid and its metabolites. Impaired mitochondrial β-oxidation, ω-oxidation markers, and disrupted acylcarnitine metabolism are consistent with ketoacidosis.

Key words : Essential oil, Methylsalicylate, Hemofiltration, Pharmacokinetic, Metabolomics

Background
Brigatinib is widely used to treat Anaplastic lymphoma kinase (ALK)-positive non-small cell lung cancer. However, severe adverse effects associated with brigatinib, such as liver dysfunction, may involve immune system activation.
To evaluate whether brigatinib activates the immune system, we investigated inflammasome activation using THP-1 cells. Additionally, we analyzed whether reactive metabolites activate inflammasomes in THP-1 cells.

Methods
Differentiated THP-1 cells were cultured with brigatinib for 24 hours. FLC-4 cells were cultured with brigatinib for 7 days, and then the supernatant was added to differentiated THP-1 cells and incubated for 24 hours. IL-1β concentration in the THP-1 culture medium was measured using an ELISA kit. Caspase-1 activity was also measured using the Caspase-Glo® 1 Inflammasome Assay. Damage-associated molecular patterns (DAMPs) were evaluated by western blotting using the hepatocyte supernatant.

Results
Treatment of THP-1 cells with brigatinib significantly increased IL-1β production and caspase-1 activity. The supernatant from FLC-4 cells treated with brigatinib also increased IL-1β production and caspase-1 activity. Brigatinib significantly increased the release of heat shock proteins (HSP) 90 and S100A6 from FLC-4 cells.

Conclusions
Brigatinib demonstrated inflammasome activation in THP-1 cells, both directly and through its reactive metabolites. The release of HSP90 and S100A6 from hepatocytes was caused by the reactive metabolites of brigatinib, suggesting a potential role in the development of idiosyncratic liver injury. Serum levels of HSP90 and S100A6 may be potential biomarkers for brigatinib-induced liver injury.

Keywords
Brigatinib, inflammasome, damage-associated molecular patterns, immune-related adverse effects

Background and Aims: Organic anion-transporting polypeptides (OATP)1B are drug transporters mainly expressed in the sinusoidal membrane. Many studies have suggested that OATP1B activity is affected by genetic factors, the uremic toxin 3-carboxy-4-methyl-5-propyl-2-furanpropanoic acid (CMPF), and inflammatory cytokines, such as tumor necrosis factor-α (TNF-α) and interleukin-6 (IL-6). This study evaluated the influence of these factors on OATP1B activity in patients with chronic kidney disease (CKD) using coproporphyrin-I (CP-I), an endogenous substrate of OATP1B.

Methods: The study recruited 73 patients with CKD who were not taking OATP1B inhibitors. CP-I and CMPF concentrations were measured by ultra-high-performance liquid chromatography coupled to tandem mass spectrometry, inflammatory cytokines by ELISA, and OATP1B1*15 by real-time PCR.

Results: Plasma CP-I concentration was higher in OATP1B1*15 carriers than in non-carriers (p = 0.003). In all patients, CP-I did not correlate significantly with CMPF, IL-6, TNF-α, or eGFR. However, when the dataset was cut off at CMPF concentrations of 8 μg/mL, 4 μg/mL, 3 μg/mL, or 2 μg/mL, CMPF correlated positively with CP-I, and correlation coefficient tended to be higher as plasma CMPF concentration was lower (rs = 0.264, p = 0.047; rs = 0.344, p = 0.018; rs = 0.342, p = 0.031; rs = 0.409, p = 0.042, respectively).

Conclusions: OATP1B1*15 impacted OATP1B activity in patients with CKD, but IL-6 and TNF-α did not. However, the impact of CMPF on OATP1B activity was limited to low CMPF concentrations, and the effect could be saturated at high concentrations.

Keywords: Organic anion-transporting polypeptides 1B, Coproporphyrin-I, uremic toxin 3-carboxy-4-methyl-5-propyl-2-furanpropanoic acid

Background: A 42-year-old man was found dead lying next to his couch in his living room. According to police investigations the victim was HIV positive and suffered from AIDS. In his home many medications and syringes could be found.The mother of the deceased confirmed that her son was an alcohol and drug addict. According to her he had already injected rim cleaner in the past. In his kitchen a bottle of "Multi Gel Remover®" was found.
METHODS: Cerebrospinal fluid and peripheral blood (vena femoralis) were screened by immunoassay for different drugs and substance classes of forensic relevance. Peripheral blood and cerebrospinal fluid were analyzed for ethanol by GC headspace. General unknown analyses for drugs and central nervous active substances was performed by GC/MS with heart blood and stomach content. GHB, GBL, tramadol and valproic acid were quantified by LC-MS/MS while citalopram, norcitalopram, quetiapin and norquetiapin were quantified using HPLC.
RESULTS: GHB, GBL, valproic acid, tramadol, trazodon, citalopram and desmethylcitalopram could be detected in peripheral blood, heart blood and stomach content. GHB, GBL and valproic acid were also found in cerebrospinal fluid. No illegal drugs were found.
CONCLUSION: Based on the autopsy findings, case history and forensic-toxicology results the cause of death was due to an aspiration of stochmach content into the respiratory system most likely caused by massive overdose of GHB after GBL intake in combination with citalopram.

Abstract
Background: Methotrexate (MTX) is widely used in autoimmune diseases; however, its narrow therapeutic index increases the risk of toxicity, particularly when misadministration occurs. This case report highlights the management of MTX toxicity with drug-induced liver injury (DILI) in a 24-year-old female with relapsing-remitting multiple sclerosis (RRMS).

Case Presentation: A 24-year-old female with RRMS presented with upper respiratory infection symptoms, mucositis, and elevated liver enzymes after inadvertent ingestion of MTX instead of azathioprine for approximately three weeks. Laboratory findings confirmed significant hepatic transaminitis (AST 128 U/L, ALT 293 U/L) and MTX toxicity. Therapeutic drug monitoring (TDM) guided treatment, showing declining MTX levels. Management included intravenous leucovorin rescue therapy, aggressive IV hydration, serial liver function monitoring, and supportive care. The patient exhibited gradual improvement in liver function and mucositis, with MTX levels declining to <0.01 µmol/L.

Conclusion: This case emphasizes the critical role of TDM and prompt intervention in MTX toxicity. Vigilant medication reconciliation and patient education are essential to prevent dosing errors.

Key Words: Methotrexate toxicity,drug induced liver Injury (DILI),relapsing-remitting multiple sclerosis (RRMS),Methotrexate level,TDM guided treatment

Objective:
This study aims to discover predictive biomarkers for acute diquat (DQ) poisoning by analyzing clinical characteristics and lipidomic profiles, ultimately advancing our understanding of toxicological mechanisms and improving patient prognosis

Method:
A retrospective study was conducted on 50 cases of acute DQ poisoning admitted or presenting at the First Affiliated Hospital of Anhui Medical University between February 2022 and October 2024. High-resolution mass spectrometry was used to analyze lipid profiles from serum samples of 32 patients. Cox proportional hazards regression models were employed to assess factors associated with prognosis.

Results:
Multivariate Cox regression analysis, adjusting for potential confounders such as gender and the need for continuous renal replacement therapy, identified serum DQ levels (HR: 1.379, 95% CI: 1.194–1.593), oral dose (HR: 1.003, 95% CI: 1.002–1.092), and age (HR: 1.063, 95% CI: 1.015–1.114) as significant independent predictors of prognosis. Furthermore, in cases where serum DQ concentrations were unavailable, urine DQ levels (HR: 1.002, 95% CI: 1.001–1.003) and HCO3- levels (HR: 0.865, 95% CI: 0.761–0.984) emerged as significant predictors. Additionally, novel lipid biomarkers were identified, including PC (16:0/20:4) (HR: 1.203, 95% CI: 1.030–1.406), PC (16:0e/18:2) (HR: 0.742, 95% CI: 0.604–0.911), and PE (18:0p/20:3) (HR: 1.151, 95% CI: 1.053–1.257).

Conclusion:
Elevated DQ levels and disruptions in kidney function and lipid metabolism significantly impact the prognosis of acute DQ poisoning. The identification of specific lipid biomarkers provides valuable insights for developing personalized treatment strategies to improve patient outcomes.

Keywords:
Diquat poisoning, Biomarkers, Clinical analysis, Lipidomics, Prognosis

Background: In recent years, mental well-being has become a critical component of overall health, driving increased awareness, advocacy, and intervention efforts. The rise in stress-related disorders, anxiety, and depression, coupled with the lasting effects of global health crises, has intensified the demand for accessible and effective mental health treatments.

Aims: In this presentation the growing interest in naturally occurring psychedelics as potential therapeutic agents, with a focus on psilocybin will be provided. The latest advancements in psychedelic research, the potential for psilocybin-based treatments, and the need for controlled, evidence-based approaches to harness its therapeutic potential while mitigating risks will be eluded to.

Results: Psilocybin, a psychoactive compound found in over 200 species of mushrooms, commonly known as "magic mushrooms" or "shrooms". Clinical research has highlighted psilocybin’s ability to alter perception, enhance emotional processing, and promote long-term psychological benefits. These mushrooms additionally contain psilocin, that is nearly twice as potent as psilocybin. While these compounds show promise, their use is not without risks, as adverse effects such as tachycardia, ataxia, hyperkinesis, seizures, and even renal failure have been reported. Despite these challenges, psilocybin’s chemical structure and neurological activity continue to inspire drug discovery efforts aimed at developing safer, more targeted psychotropic therapies.

Conclusion: As the demand for effective neuropsychiatric treatments continues to grow, exploring the balance between efficacy, safety, and accessibility remains a global priority in addressing the burden of psychiatric disorders.

Keywords: Psilocybin, magic mushrooms, psychoactives, psychedelics, toxcicity, drug development

Backgrounds: Voriconazole is a commonly used triazole antifungal drug in clinical practice, which has the advantages of high bioavailability and a broad antibacterial spectrum. Visual and auditory impairments, as common adverse reactions of voriconazole, have increasingly attracted clinical attention.

Aims: To explore the application of therapeutic drug monitoring in the individualized administration of voriconazole and summarize the experience of pharmaceutical care.

Methods: During the drug treatment process of an elderly patient with pulmonary infection caused by Candida krusei, adverse reactions of visual and auditory hallucinations occurred. Through analyzing the patient's condition and the characteristics of the drugs, and combining the results of voriconazole therapeutic drug monitoring and CYP2C19 gene detection, the clinical pharmacist suggested adjusting the administration regimen of voriconazole to provide a safe and effective treatment plan for voriconazole in clinical practice. Additionally, regular follow-ups were carried out for the patient, the education on the patient's medication compliance was strengthened, and the relevant knowledge of safe medication was popularized.

Results: The physician adopted the suggestions of the clinical pharmacist, effectively reducing adverse reactions such as visual and auditory hallucinations caused by voriconazole and ensuring its therapeutic effect.

Conclusions: Clinical pharmacists participate in clinical treatment, give full play to the advantages of their pharmaceutical knowledge, cooperate with medical staff, assist in formulating rational drug treatment plans, improve the level of drug treatment, provide patients with the best drug treatment plans, and ensure the safety of patients' medication.

Keywords: Voriconazole, TDM, Adverse Reactions, CYP2C19